Preparation of steroid-like compounds via acid promotedolefinic cyclizationsCitation for published version (APA):Corvers, A. (1977). Preparation of steroid-like compounds via acid promoted olefinic cyclizations. Eindhoven:Technische Hogeschool Eindhoven. https://doi.org/10.6100/IR121700

DOI:10.6100/IR121700

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PREPARATION OF STEROID-LIKE COMPOUNDS

VIA ACID PROMOlED OLEFINIC CYCLIZATIONS

A. GORVERS

PREPARATION OF STEROID-LIKE COMPOUNDS

VIA ACID PROMOTED OLEFINIC CYCLIZATIONS

PROEFSCHAl FT

TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL EINDHOVEN, OP GEZAG VAN DE RECTOR MAGNIFICUS, PROF.DR. P. VAN DER LEEDEN, VOOR EEN COMMISSIE AANGEWEZEN DOOR HET COLLEGE VAN DEKANEN IN HET OPENBAAR TE VERDEDIGEN OP

VRIJDAG 4 MAART 1977 TE 16.00 UUR.

DOOR

ANTONIUS GORVERS

GEBOREN TE EINDHOVEN

DRUK: WIBRO HELMONO

Dit proefschrift is goedgekeurd door de promotors

prof. dr. H.M. Buck en

prof. dr. H.D. Huisman

Aan mijn ouders Aan Elly

Man bas been up against Nature; from now on he will be up against bis own nature.

Dennis Gabor

Chapter

Chapter

Chapter

I

Contents

General introduetion

1.1 The biosynthesis of stePaids

1.2 Heteroeyelie stePaids

RefePenaes and Notes

11 Model reactions for A-B ring closure reactions of thiophene containing

compounds

11.1 IntPoduetion

11.2 Synthesis and eyalization of

A-B Ping elosure model systems

11.3 Experimental

Heferenoes and Notes

111 Synthesis of thiophene containing

steroid-like molecules via olefinic cyclization reactions

III.1 Introduetion

111.2 Thiophene ineoPporation in (E)­

and (Z)-alkenes: precursors for

steroid-like eompounds

111.3 Aeid,promoted cyclization ex­

pePiments of the (E}- and (Z)­

olefinio systems

III.4 Discussion of the expePimental

ratio (E/Z) of isomers obtained

from the Wittig reaetion

9

16

23

Chap'ter

Chap'ter

Chap'ter

III.S The Stork-Eschenmaser hypo­

thesis 111.6 Vivo versus vitro cycZizations

III.7 ExperimentaZ

Beferences and Notes

1\/ Alternative syntheses for precursors of tetracyclic compounds

IV.1 Introduetion

IV.2 Syrithesis of (E)-aZkene pre­

cursors via the Wadsworth-Emmons

reaction

IV.3 Synthesis of (E)-aZkene pre­

cursors via the CZaisen re­

arrangement IV.4 ExperimentaZ

Referenaes and Notes

" Synthesis of thiophene analogues of estrone: 13c-NMR measurements of these compounds and their precursors

V.1 Synthesis of thiophene analogues

of estrone V.2 Evidenae for the trans~anti~trans

geometry in the tetracycZia products

V.3 EzperimentaZ

Referenaes and Notes

44

57

"I Quanturn mechanica! calculations on 71

cyclization reactions; a MIND0/3 study VI.1 Introduetion

VI.2 Calculations on the cyclization

of the 2-but-3-enyZ ayaZopentenyZ cation

SuJDJDary

SaJDenvattÎng

Levensloop

Dank-vvoord

VI.3 Cyelizations of the (E)- and

(Z)-2-pent-3-enyl eyelopentenyl

eation

Refe~enees and Notes

82

84

86

87

CHAPTER I

General introduetion

1.1 The biosynthesis of steraids

Research in the field of olefinic cyclization reactions, occurring in vivo as well as in vitro, was particularly stimulated by the discovery of enzymatic processes in which squalene is synthesized from activated acetic acid, present

in biosystems as acetyl coenzyme A (acetyl-CoA) 1 - 3 • The in vivo

synthesis of squalene starts with a number of steps by which acetyl-CoA is converted into mevalonic acid. The latter com­

pound is subsequently converted into an equilibrium mixture of dimethallyl and isopentenyl pyrophosphate. Coupling of "activa­ted" isoprene (2-methylbuta-1,3-diene) 12:, withits isomer 1È_

yields geranyl pyrophosphate (~) which on its turn is coupled with another molecule isopentenyl pyrophosphate (.:!2:,) to give farnesyl pyrophosphate Cl)· In a final step squalene (~) is

formed by the tail to tail linkage of two farnesyl units 4• The

energy for these enzymatically catalyzed reactions is supplied

by the energy-rich molecules ATP (~denosine IriEhosphate) and NADPH 2 (reduced ~icotin-amide-~denosine-ginucleotide-Ehosphate); ATP is used for the synthesis of isopentenyl pyrophosphate, while NADPH 2 plays a crucial role in the coupling of the two farnesyl pyrophosphate units (fig. 1.1). Squalene acts as the

general precursor for steroid-synthesis in animal and ve­getable life. Depending on the particular organism squalene

or 2,3-epoxysqualene is enzymatically converted into one of the several classes of steroids, consisting of tetra-

and pentacyclic compounds. The conversion of squalene into

lanosterol is well documented (see Chapter III.6). Another

9

...

1 tT

3

4

OH I

__ .,..,.. HOOC-CH-C- CH -CH OH 2 I 2 2

...

19.

CH3

CH 2

' C-CH-CH-OPP / 2 2

CH3

2

Fig. 1.1 Biosynthesis of squalene starting from activated

acetic acid

reaction path leads to cycloartenol ~ which replaces lanos­

terol as the principal triterpene in higher plants. Still

10

another example forms the conversion of squalene into 6-

amyrin §_.

H

HO HO

5

Intriguing is the stereospecificity of these enzymatically

formed steroids. In some structures the trans,anti,trans

geometry has been established (dammaradienol l), while in

other systems a syn substitution pattern is found. This phe­nomenon has been explained in terms of folding on the enzyme.

If 2,3-epoxysqualene is folded in a chair-chair-chair confor-

mation, dammaradienol l is formed while

(precursor for i) is generated from the conformation (see also Chapter III.6).

~ H -~ -"' . .

HO

7

protolanosterol ~

chair-boat-chair

8

From the examples given, it goes without saying that the

enzyme plays an essential role in these cyclization reactions

as is outlined in Chapter III.S.

11

1.2 Heteroeyclic steroida

Since the discovery of hormones and their function in the human body, organic chemists became interestad in the synthesis of modified steroid systems, mainly for the pur­pose to get more insight into the structure-activity relation­ship, but also to study the biologica! activity of modified steraids as such. A special group of modified steraids are those containing hetero-atoms 5 • In most cases it concerns compounds in which one or two carbon atoms from the steroidal skeleton (positions 1-17) are replaced by nitrogen, oxygen and/or sulphur atoms. The synthesis of a great number of these compounds occurs analogous to the Torgov synthesis for carbocyclic steraids (fig. 1.2).

0 HO

~ ~MgB, ~ eH O)lXJ__Y) Áxv Áv y)

3 c~o

0

'fJ base

0 0

Fig. 1.2 Synthesis of heterocyclic steroid systems according to the Torgov synthesis (X and Y are hetero-atoms)

Using 2-methylcyclohexane-1,3-dione insteadof 2-methylcyclo­pentane-1,3-dione the corresponding D-homo steraids are syn­thesized. The 13-aza-analogs become available when succinimide is used insteadof the 1,3-dione. Cyclodehydratation is brought about by phosphorusoxychloride and subsequently hydragenation of the formed iminium salt affords the 13-aza­steroids. Other entries in the field of heterocyclic steraids

12

were developed by the application of the Diels-Alder reaction and condensation reactions between hydrogenated pyridazines and (di)enamines. However, no st.erochemical difficulties are encountered in the preparatien of the majority of hetero­cyclic steroids, for these compounds possess double honds between the positions C(8)-C(9) and C(14)-C(15). Conversion of these systems into the saturated structures with the spa­cial geometry most commonly found in nature (e.g. tPans~anti~

tPans on C(9), C(8) and C(14)) is achieved in only poor yield (S-101) by a five-step reduction-oxidation sequence.

5 steps

Fig. 1.3 Preparatien of 6-aza-, 6-oxa- and 6-thiaestrone methyl ether

From this point of view the synthesis of heterocyclic analogs of steraids is not attractive.

This thesis deals with the synthesis of the two possible estrogens, having thiophene as A ring. In Chapter II the reactivity of thiophene towards electrophiles is discussed, foliowed by the synthesis and cyclization of two thiophene derivatives under mild reaction conditions.

Chapter III describes the synthesis of thiophene con­taining steroid-like molecules. The required precursors were prepared via a modified Wittig reaction, with special atten­tion on the dependenee of the E/Z ratio on the base used. The most favourable conditions were applied for the prepara­tion of (E)- and (Z)-alkene precursors. It was found experi­

mentally that only the (E)-alkene derivatives could be converted into tetracyclic compounds.

13

In Chapter IV two alternative routes are discussed, which both yield pure (E)-alkene precursors, in contrast to the methad given in Chapter III (via the Wittig-Schlosser reac­tion), which yields products contaminated with 5-10% of the other isomer.

Special attention is paid to the stereogeometry of the epoxide ring during the desired 0 ,2] methyl shift from C(17) to C(13): "estrone" formation takes place in case of the a­epoxide, while a mixture of dienes was isolated under the same reaction conditions starting from the ~-epoxide. The t~ans~anti>t~ans contiguration on the junction atoms, most commonly for natura! steroids, was confirmed by the 13c-NMR measurements.

In order to obtain more quantitative data, quanturn roe­ehanical calculations were performed on model systems for D-C ring closure. The results confirm the Stork-Eschenmoser hypothesis: cyclization takes place via the chair conforma­tion and ring closure of (E)-alkenes is energetically favoured with respect to (Z)-alkenes.

14

Referenaes and Notes

1. R.B. Clayton, Quart. Rev •• lQ_, 168 (1965) and references therein

2. J.W. Cornforth and G. Popják, Biochem. J., lQl, 553 (1966); J.W. Cornforth, Quart. Rev., ~. 125 (1969)

3. I.D. Frantz and G.J. Schroepfer Jr., Ann. Rev. Biochem., 36, 691 (1967); C.J. Sih and H.W. Whitlock, Ann. Rev. Biochem., 37, 661 (1968)

4. L.J. Mulheirn and P.J. Ramm, Chem. Soc. Rev., .!_, 259

(1972) 5. H.O. Huisman, Bull. Soc. Chim. Fr., (1968) 13; Angew.

Chem. , g, 511 ( 19 71)

15

CHAPTER 11

Model react:ions :tor A-B ring ciosure react:ions

o:f t:hiophene. cont;aining coiD.pounds

II.1 Introduetion

Soon after the discovery of thiophene 1 its reactivity in electrophilic reactions was established. Thiophene reacts very rapidly with a number of electrophilic reagents (chlorine, bromine, pyrosulphonic acid, sulphuric acid and nitric acid) to yield mono- and polysubstituted thiophenes 1 depending on the reaction conditions. No catalyst is required for these reac­

tions. On the other hand, acyl- and alkylthiophenes are formed

only under Friedel-Crafts conditions. Lewis acids, such as aluminum chloride, stannic chloride and boron trifluoride com­plexes, and Br~nsted acids as 85% orthophosphoric acid, hydro­fluoric acid or sulphuric acid bring about these reactions 1

•

The sequence of addition of the reactants is very important. Aluminum chloride, for example, rapidly polymerizes thiophene. During the aluminum chloride catalyzed acylation of thiophene, special conditions must be maintained to avoid resinification. The acyl group is selectively introduced on the 2-position in contrast to alkylation in which a 1:1 mixture of 2- and 3-alkylthiophenes is formed. Intramolecular ring closures starting from acid chlorides were carried out by Fieaep et al. 2

Fig. 2.1 Ring ciosure of thienylalkaloylchlorides

16

and Cagniant et aZ. 3• They found that thienylbutanoyl and

thienylpentanoyl chloride are converted into the fused six­and sevenmembered ring compounds (fig. 2.1) under Friedel­

Crafts conditions. Recently, Loozen,. found that benzo [Q.] thiophenes are

easily accessible from suitable functionalized thiophenes.

("o n R O~MgBr "-sy THF . 0

~ 's~

R=H,alkyt

Fig. 2. 2 Synthes is of ben zo [Q.] thiophenes, s tarting from alkanoylthiophenes

R

Treatment of alkanoylthiophenes with the Grignard derivative of 1-(1,3-dioxolan-2-yl)-2-bromoethane ( . 2.2) yielded the expected alcohols which were subrnitted to the action of 10% refluxing sulphuric acid tobring about hydrolysis, cyclization

and aromatization to the benzo [Q.] thiophenes. In 1970 Gourier and Canonne 5 reported the ring closure

of substituted 5-(2-thienyl)pent-1-enes under rather drastic conditions (acetic acid with 5 vol. % sulphuric acid at reflux)

R=H,olkyl

Fig. 2. 3 Synthesis of tetrahydrobenzo [Q.] thiophenes

to gi ve the corresponding 4, 5, 6, 7 -tetrahydrobenzo [Q.] thiophenes via the secondary carbocation interrnediates (fig. 2.3). This once more emphasizes the reactivity of thiophene in electro­

philic reactions.

17

II.2 Synthesis and ayaLization of A-B Ping aLosuPe modeL

systems

In order to establish the reactivity of thiophene towards

relatively mild electrophiles, ring ciosure of the easily accessible compounds 3a and 3b was studied. Their preparation and cyclization is outlined in fig. 2.4 and fig. 2.5.

0 1. BuLi

S ~J1 THF 2.Br o

4a

n oJ H,O+

1 a

H 0

(0 2a

3a

Fig. 2.4 Synthesis of 4,4-dimethyl-4,5,6,7-tetrahydrobenzo[~J­thiophene

Thiophene was lithiated in tetrahydrofuran at -20° to afford 2-thienyllithium which on treatment with 1-(1,3-dioxolan-2-yl)-2-bromoethane yielded acetal ~· Hydralysis of the acetal moiety of~ produced 3-(2-thienyl)propan-1-al (Za) which was converted into alkene 3a after reaction with isopropylidene triphenylphosphorane. Compound 3a failed to cyclizise in cold formic acid, but was rapidly converted into the bicyclic pro­duct~ in formic acid with 10 vol. % trifluoroacetic acid or in methylene chloride with 25-50 vol. l trifluoroacetic acid. In a similar reaction sequence alkene 3b was prepared starting

from 3-bromothiophene 6 as precursor for 3-thienyllithium7

(fig. 2. 5).

18

0 l Buli oJ Ha+ ((Jo !. 3 A

Br ~J,THF 2. Br o

1 b 2 b

(rPPh,

oO CF3 COOH ö) CH2Ciz

4 b 3 b

Fig. 2.5 Synthesis of 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[~J­thiophene

Again in methylene chloride with 25 vol. % trifluoroacetic acid a rapid ring closure led to 4b. These results are in good agreement with the observations of Gourier 5 (vide supra).

!1.3 Experimental

General remarks

1H-NHR data were obtained on a Varian A60 using TMS (8=0.0) as internal standard. 13c-NMR data were recorded on a Varian HA 100 equipped with a Digilab FTS-NMR-3. IR spectra were measured on a Perkin-Elmer 237. Microanalyses were carried out in our laboratories by Messrs. P. van den Bosch and H. Eding.

• 1-(1 ,3-Dioxolan-2-yl)-2-(2 thienyl)ethane (la) To a salution of 17 g (0.2 mol) of thiophene in 60 ml of tetra­

hydrofuran, 100 ml of n-butyllithium (20% in hexane) was added dropwise at -20° under a nitrogen atmosphere. The mixture was stirred for 2 hr, whereupon 36 g (0.2 mol) of 1-(1,3-dioxolan-2-yl)-2-bromoethane8 was added. After 1 hr the reaction mixture

19

was allowed to warm up to room temperature and left overnight. The reaction was quenched with water and the product isolated by ether extraction. Drying, remaval of the solvent and dis­tillation gave 24.1 g (75%) of product, bp 65-68° (0.005 mm).

NMR (CC1 4): 6 1.80-2.20 (m,2,C~2CH2Th); 2.82-3.15 (m,2,C~2Th); 3.70-4.10 (m,4,dioxolane protons); 4.88 (t,1,C~); 6.75-7.15

(m,3,Th-~).

• 1-(1,3-Dioxolan-2-yl)-2-(3-thienyl)ethane (~) Under a nitrogen atmosphere a salution of 66.0 g (0.4 mol) of 3-bromothiophene in 100 ml of tetrahydrofuran was added drop­wise to ZOOmlof n-butyllithium (20% in hexane) at -70°. After 1 hr 72.5 g (0.4 mol) of 1-(1,3-dioxolan-2-yl)-2-bromo­ethane8 was added. The reaction mixture was stirred for 4 hr at -70° and for 1} hr at 25°. Water was carefully added to destray organolithium compounds. Aqueous work-up yielded 33.2 g (45%) of product, bp 75-80° (0.005 mm).

~ 3-(2-Thienyl)propan-1-al (Za) A mixture of 18.4 g (0.1 mol) of~. 60 ml of tetrahydrofuran and 140 ml of N hydrochloric acid was stirred vigorously under reflux. After 1! hr the reaction mixture was poured into water and extracted with ether. Drying and evaporating of the ether yielded crude aldehyde which was distilled to give 11.2 g

0 -1 (80%) of product, bp 60 (0.7 mm). IR (nujol): 1720 cm (C=O). NMR (CC1 4): 6 2.60-2.92 (m,2,C~2CHO); 2.95-3.35 (m,2,C~2Th); 6.73-7.22 (m,3,Th-~); 9.79 (t,1,C~O).

~ 3-(3-Thienyl)propan-1-al (2b) This compound was prepared analogous to 2a, bp 65° (0.5 mm).

~ 2-Methyl-5-(2-thienyl)pent-2-ene (3a) To a suspension of 21.6 g (0. OS mol) isopropyltriphenylphos­phonium bromide 9 in 40 ml of tetrahydrofuran was added 34 ml of n-butyllithium (15% in hexane) at 15° (nitrogen atmosphere). To the clear deep-red salution 6.6 g (0.05 mol) of Za in 10 ml of tetrahydrofuran was added. Aqueous work-up afforded 5.5 g (70%) of 3a, bp 69-72° (4.5 mm). NMR (CC14): 6 1.60, 1.69

20

(d,6,2x C~3 ); 2.13-2.62 (m,2,C~2CH2Th); 2.73-3.17 (m,2,ThC~2 ); 5.10-5.45 (m,1,C~); 6.72-7.25 (m,3,Th-~).

• 2-Methyl-5-(3-thienyl)pent-2-ene (3b) Preparedas for 3a, bp 72-74° (3 mm).

• 4, 4-Dimethyl-4 ,5 ,6, 7-tetrahydrobenzo [2J thiophene ( 4a) A salution of 2.0 g (0.012 mol) of 3a in 5 ml of methylene chloride was added to a mixture of 15 ml methylene chloride and 5 ml of trifluoroacetic acid at room temperature. After ! hr the reaction mixture was poured into water and the pro-~ duet extracted into petroleum ether 40-65. Drying and stripping off the solvent yielded 2.0 g of crude product. Filtration over a silica column (petroleum ether 40-65 as eluens) gave 1.8 g (90%) of pure 4a, bp 88-90° (10 mm). NHR (CC1 4): ó 1.34 (s,6,2x C~3 ); 1.48-2.06 (m,4,2x C~2 ); 2.35-2.75 (m,2,ThC~2 ); 6.83 (AB pattern,2,Th-~).

• 7, 7-Dimethyl-4, 5 ,6, 7-tetrahydrobenzo [!?.] thiophene ( 4b) Preparedas for 4a, bp 90-92° (10 mm).

21

RefePenaes and Notes

1. A. Weissberger, "The Chemistry of Heterocyclic Compounds", Volume III, H.D. Hartough, Thiophene and lts Derivatives, Interscience Publishers Inc., New York, N.Y., 1952, Chapters 6, 7 and 8 and references cited therein.

2. L.F. Fieser and R.G. Kennelly, J. Amer. Chem. Soc.,~. 1611 (1935).

3. P. Cagniant and J. Deluzarche, Compt. Rend., 222, 1301 (1946); P. Cagniant and D. Cagniant, Bull. Soc. Chim. France, 1152 (1956); ibid. 62 (1953); ibid. 680 (1955).

4. H.J.J. Loozen and E.F. Godefroi, J. Org. Chem., ~. 1056

5.

6.

7.

8.

9.

22

(1973). J. s. P. G. G.

Gourier and P. Canonne, Can. J. Chem., ~. 2587 (1970).

Gronowitz, Acta Chem. Scan.,~. 1045 (1959). Hoses and S. Gronowitz, Arkiv. Kemi., ~. 119 (1962). Buchi and H. Wuest, J. Org. Chem., 34, 1121 (1969). Wittig and D. Wittenberg, Ann. Chem., 606, 1 (1957).

CHAPTER 111

Synthesis of thiophene containing steroid-like

Inolecules via olefinic cyclization reactions

III.1 Introduation

In the last two decades much progress has been made in the field of steroid synthesis. The elucidation of the mecha­nism of the biosynthesis of lanosterol from 2,3-epoxysqualene strongly accelerated the development of model compounds. On the whole acid promoted cyclization reactions (one of the basic concepts of the in vivo synthesis) afford a general approach for the synthetic preparatien of estrogens. The strategy for this type of cyclization is outlined in Chapter I. Recently, progesterone 1 and estrone 2 have been synthesized in this way. In a multi-step sequence P.A. Barttett and w.s. Johnson prepared 1 and converted this compound in one step

to the basical structure ~. a precursor for estrone (fig. 3.1).

RO RO

2

Fig. 3.1 Olefinic cyclization reaction as key-step in the synthesis of estrone

Based on the outlined synthetic approach, modified compounds of type 1 (fig. 3.1) were prepared with thiophene as A-ring,

as will be described in Section III.Z.

23

III.2 Thiophene incoPpoPation in (E)- and (Z)-alkenes:

pPeaursors for steroid-like aompounds

Thiophene was taken as A-ring for several reasons: (i) The ring is iso-electronic with benzene. (ii) The presence of sulphur creates an active site which may be of importance for model studies under vivo conditions. Since the cyclization can be generated via a 2- and 3-sub­stituted thiophene, the presence of sulphur can manifest

itself in quite different ways. (iii) The high reactivity för electrophilic substitution reaction which is well documented.

As a start the preparatien of compounds 1 was undertaken following the method of P.A. Bartlettand w.s. Johnson 2 •

1\

-Yo r)o o

. + Th ~

Ph/ 0 0

1g, Th=2-thienyl ~Q. Th=3-thienyl

Th

7a- d

\_/

H OH

1\ 0 0

Rli THF

Th

(R=o-Bu,Ph)

lÖ Th~

1

-

6a-d

Fig. 3.2 Preparation of thiophene containing precursors

for olefinic cyclization reactions

24

Surprisingly, the Wittig reaction of 3a and 3b with ylid _! 3

under Schlosser conditions (see Section 111.4) with n-butyl­lithium as base (fig. 3.2, R=n-butyl) afforded in excess the (Z)-disubstituted olefins Sc and Sd, respectively (E/Z=O.l). The (Z)-configuration was firmly established with 13c-NMR spectroscopy by the method of de Haan and van de Ven 4

•5

•

However, the (E)-alkenes are necessary to obtain complete cyclization as will be shown in Section 11!.3. It has been claimed2 that the Wittig Schlosser reaction, performed with

3-phenylpropan-1-al and ylid _!, yields the (E)-alkene con­taminated with only 2% (Z)-isomer. Our finding prompted us to reinvestigate this reaction; the results are gathered in

Table III.l.

Table III.l E/Z ratio of the product from the reaction of 3-phenylpropan-1-al with ylid ±in dependenee of the base (reaction carried out in THF at specified temperature)

base (solvent) temperature time a) ratio E:Zb)

n-BuLi (hexane} 20° 70 h 50:50 n-BuLi (hexane) -50° 24 h 10:90

n-BuLi (hexane) -30° 3 h 50:50 n-BuLi (hexane) -30° ~ h 50:50

n-BuLi (hexane) -30° 1 5 min 60:40 2 n-BuLi (hexane) -30° 5 min 40:60 2 tert-BuLi (hexane) -30° 5 min 75:25 2 tert-BuLi (hexane)c) -30° 1 h 90:10

PhLi (benzene/ether) -78° 5 min 95: 5

a)time between the extra addition of base and quenching of. the betaine anion (25, fig. 3.9) with methanol; b)as deter­mined with 13c-NMR;-c)2.5 equivalents lithium perchlorate

are added before the addition of the extra base

25

The results clearly demonstrate a considerable influence of

the base used. Also a salt effect is established. Sehtosser

and ao-workers 6 •7 paid no attention to the influence of the

base in the oxaphosphetane (~, fig. 3.9) isomerization pro­

cess. Corey 8, on the other hand, obtained the best results

using n-BuLi or sea-BuLi in the Wittig-Schlosser reaction. Andereon et at. 9 observed no isomerization of the interme­

diate oxaphosphetane in the synthesis of gossyplure by em­ploying sodium diisopropylamide as base, whereas Zeeten 10

obtained good results by using phenyllithium. From Table III.1 it may be concluded that the Wittig-Schlosser reaction,

performed at -78° with phenyllithium as base, gives a rather high yield of the (E)-alkenes. This condition for the re-

action of the aldehyde and 3b with ylid i yielded 90% of the (E)-isomers Sa and Sb and 10% of (Z)-isomers Sc and

Sd (determined by 11"ë-NMR:-:ee fig. 3.2). Hydrolysis-;;-f diketals ~ foliowed by cyclodehydratation gave cyclopen-tenones 6a-~. Lithium aluminum hydride reduction at -30° afforded the cyclopentenals 7a-~ in almest quantitative yield which, due to their susceptibility to dehydratation, were used without further purification.

III.3 Aeid promoted eyatization experiments of the (E)­

and (Z)-otefinia systems

The (E)-olefinic compounds 7a and 7b could be converted into the tetracyclic products and (see fig. 3.3). Tin tetrachloride promoted cyclization (in methylene chloride) proved to be the most effective procedure. The use of excess tin tetrachloride lowered the yield as could be confirmed by performing the reaction at higher temperatures.

Lower yields were also found in the formolysis of compounds 7a and 7b (at 0°, or at room temperature) and in cyclization experiments with nitromethane.

26

70 7b

!Sn Ct 4 CH 2 ct 2

CH3

8a 8 b

Fig. 3.3 SnC1 4 promoted ring ciosure of (E)-alkene precursors

The moderate yield of tetracyclic products Cabout 50%) may be

due to polymerization of the thiophene nucleus, caused by

the action of Lewis acids on thiophene. Furthermore, it was

observed, that (E)-isomers 7a and 7b, containing about 10%

of (Z)-isomer ~ and 7d, gave relatively low yields of tetra­

cyclic compounds as was the case with the products, free of

(Z)-isomer.

The behaviour of alkene precursors 7c and 7d in cycli­

zation experiments was quite different from that of the eer­

responding (E)-isomers. The farmer substances failed to give

tetracyclic compounds when treated with formic acid at 0°

or with tin tetrachloride in methylene chloride at various

temperatures. Low temperature NMR studies revealed that

neither cyclopentenol 7c nor cyclopentenene 6c could be

converted into tetracyclic compounds, even in the presence

of the very streng fluoro sulphonic acid. In the case

of 6c the carbonyl group was protonated. Excess acid only

brought about protonation and polymerization of the thio­

phene with the (Z)-double bond unaffected. The conversion

of cyclopentenol 7c into the corresponding chloride was 0 achieved with thionyl chloride at -20 (S02ClF or cn2c1

2 as solvent). Addition of aluminum chloride caused resini-

27

fication of the product. No tetracyclic compound was observed.

In the literature, little attention is paid to the cycliza­tion of (Z)-polyenes. Only small ring cyclizations of (Z)­alkenes are reported 11 • Formalysis of (Z)-sulphonate ester ~1 2 , 1 3 gives the cis-monocyclic alcohol~ and the epimeric

mixture of the cis-2-decalols ll (fig. 3.4 eq (1)).

H .

ct) +

: H

H

QY--w \_) 0 H

+

12 13

15

Fig. 3.4 Cyclizations of (Z)-alk'enes

!;I I ctrOH(1) . . H

11

H w (2)

0 H

14

(3)

Another example of (Z)-alkene cyclization is given by w.s. Johnson 14 and D.J. Goldsmith 15 (fig. 3.4 eq. (2)), who per­formed the cyclization of the (Z)-dienic acetal ~ which -after a degradation and oxidation sequence- yields a mixture of cis-decalones and • An unexpected result was obtained by Eschenmoser 16 (fig. 3.4 eq. (3)) by ring closure of 15

into the substituted trans-decalin system.

28

Stork 17, however, proved that the boron trifluoride cata­

lyzed cyclization of the closely related farnesic acid pro­ceeds by a two step mechanism. After cyclization and depro­tonation a monocyclic product was isolated which was fully identical with the product acquired from the ring ciosure of the (E)-isomer cyclization. Reprotonation and ring closure yielded the trans bicyclic product ~· It is evident, that the last mentioned reaction mechanism must be quite different from the other two reactions mentioned in fig. 3.4. Cycli­zation of the all (E)-isomers of the alkenes of fig. 3.4 (eq. (1) and (2)) yields products with the opposite stereo­geometry. The high stereoselectivity o~ the discussed re­actions are in full agreement with the predictions of the Stork-Eschenmoser hypothesis (Section III.S).

III.4 Diseussion of the experimentaZ ratio (E/ZJ of isomers

obtained from the Wittig reaation

Undoubtedly, the Wittig reaction 18 is one of the most im­portant methods for the synthesis of olefinic systems. This reaction has been used for the preparation of di-, tri- and tetrasubstituted olefins. The sequence of the reaction con­sists of three steps. Addition of a phosphorane lL to an aldehyde (or ketone) gives the intermediate betaines 18a and 18b (fig. 3.5). After the formation of the phosphorus­oxygen bond a fast eliminatien of trialkylphosphine oxide from the oxaphosphetanes 19a and 19b occurs by syn-elimi­nation leading to the (E)- and (Z)-olefins. Certain features of the reaction are well established. Non-stabilized phos­phoranes (e.g. ~) give an excess of (Z)-olefins, contrary to stabilized phosphoranes and phosphonoacetates (e.g. ~

and ~. fig. 3.6) which yield (E)-alkenes predominantly. Kinetic studies have shown a slow and reversible formation of the betaines 23a and 23b from resonance stabilized phos­

phoranes. Preferential formation of the threo betaine 23a is observed in the reaction of stabilized phosphoranes with

29

l

Fig. 3.5 Reaction mechanism for the Wittig reaction

+­Ph3 P-CHMe ------ Ph3 P=CHMe

20

•0 + -/I Ph

3P-èH-C-0Et _,. _____ .,. .... Ph

3 P= CH-COOEt

n o •o

( )

11 __ -,' l

RO P-CH-C -OEt 2

ll Fig. 3.6 Non-stabilized and stabilized phosphoranes

30

/ R

3-cHO +

1 2 R3-P= CHR

23o

' H R3 R2 H

Fig. 3.7 Wittig reaction with stabilized phosphoranes

aldehydes. Due to the relatively slow eliminatien of tri­phenylphosphine oxide, the intermediate betaines 23a and

23b have a better chance to equilibrate leading .to the for­mation of the most stable isomer (e.g. 2 ~23b). This thermodynamically controlled reaction course is in contrast

with the kinetically controlled reaction products generated from non-stabilized phosphoranes. Phosphonoacetates (~)

behave in a similar manner as the phosphoranes ll· In the presence of lithium salts, the betaines are

strongly solvated with lithium ions, so that the rate of the forward reaction is lowered to such an extend that it becomes determining for the over-all rate of formation. Betaine re­

versibility becomes important; interconversion to the most stabie betaine (the threo form) is favoured which leads to the (E)-olefin. A considerable dependenee on salt cation concentratien is found for the Wittig reaction in non-polar

solvents, thus increases the amount of (E)-isomer. Exclusion of metal salts in non-polar solutions of ylids during the

31

Wittig reaction affords (Z)-olefins. This is in good agree­

ment with the observations of Vedejs and Snoble 19• They

suggest that in the absence of salts the Wittig reaction can be described as a TIZ + TI 2 cycloaddition according to the

s a rules of Woodward and Hoffmann. Orthogonal approach of

the TI-honds of the ylid and the aldehyde would lead directly to the most hindered oxaphosphetane (e.g. the

erythro form) which results in the formation of the (Z)­

alkene:

a{<"----. R

CH 3 H

H H

H CH3 R

Fig. 3.8 TI; + TI! cycloaddition of an ylid and aldehyde in the Wittig reaction

Reaction of pivalaldehyde (fig. 3.8 R= tert-butyl) with ethylidenephosphorane resulted in the formation of the eer­responding alkene with an E:Z ratio of 1:99. Salteffects

I

are explained by the formation of betaine-lithium halide adduct as a competing reaction. Bahlosser and ao-workers 1

showed that the betaine-lithium halide adducts which are formed during the Wittig reaction, rapidly equilibrate when treated with another equivalent of phenyllithium or n-butyl­lithium. The following adoption was made for explanation

of the stereochemical course of the reaction: the initially

formed erythro betaine-lithium halide adduct 24a is con­verted into anion 25a after treatment with an extra equiva­lent base (fig. 3.9). A rapid equilibrium between the two possible forms of~ is reached, in which 25b predominates. Protonation and eliminatien of triphenylphosphine oxide

gives the (E)-olefin. The above described mechanism for

the modified Wittig reaction was further elaborated by

32

P~PK+ Oli

' ' ' , ', 1 2

H R H R

erythro

Rli rapid ------ ---

ROH

threo

Fig. 3.9 Schlosser modification of the Wittig reaction

Bahlosser and aollaborators 7 in 1970. They concluded that only (E)-alkenes çould be obtained via the modified Wittig reaction in the presence of soluble lithium salts. Only in that case the betaines exist in the threo form.

III.S The Stork-Esahenmoser hypothesis

It is striking that many of the natural occurring steroirlal compounds derived from the (in general most stable (E)-poly­enes) consist of trans,anti.trans structures. Basedon the stereochemistry of some polyene cyclizations Stork 17 and

Esahenmoser 20 developed a stereoelectronic theory explaining

and predicting the course and stereoselectivity of polyene

cyclizations. They postulated that the concerted formation of

33

a cyclohexane ring in cationic cyclization reactions of open

chain polyenes must proceed via an anti-parallel mechanism. In fig. 3.10 this is illustrated for the ring A/B cyclization

of a squalene fragment.

OH

Fig. 3.10 Ring A/B cyclization of

squalene according to the

Stork-Eschenmoser hypothesis

Electrophilic attack of the generated C(2) cation on the C(6)­

C(7) double bond and a simultaneous nucleophilic attack of the

C(10)-C(11) double bond occurs in such a way, that the first mentioned addition takes place in a tPans manner with regard to the other one. Extension of this postulate would always

result in a polycyclic product having the tPans,anti~tPans, anti,tPans geometry. This postulate, however, cannot account

for the in vivo cationic cyclization of 2,3-epoxysqualene into lanosterol, because in the intermediate protolanosterol the methyl group on C(lO) is expected to be situated syn towards the hydrogen atom on C(9), as can be concluded from the confi­guration of lanosterol. This suggests that the vivo cycliza­

tion brings the 2,3-epoxysqualene in a coiled conformation from which the configuration of lanosterol can be generated21 • 22 •

An other hypothetical model for this vivo cyclization is out­lined in Section III.6.

III.6 Vivo vePsus vitPo eyelizations

In the previous Sectien it was outlined that the Stork­

Eschenmoser hypothesis is probably valid only for non-enzymatic cyclization reactions. The suggestion was made that under vivo

conditions the enzyme folds the substrate thus generating a

34

conformation which can only be obtained under these specific conditions 23 • First of all the accepted substrate folding will be more specified. Finally, another approach is offered which is developed by W. de Loos of our department 2 ~. Model­studies are in prögress to support this hypothesis.

Two fundamental routes can be distinguished for the squa­lene conversion: an oxidative and a non-oxidative route. BZoah

and Tahen 25 verified that the oxidative cyclization of squa­lene in the presence of 2H20 or H2

18o did not result in the formation of labeled lanosterol, whereas the enzymatically ca­talyzed cyclization in the presence of 18o2 yielded lanosterol

labeled with 180 in the hydroxyl group. Corey and van TameZen 23

showed that 2,3-epoxysqualene is an intermediate which can be converted anaerobically to lanosterol. The enzymes squalene­epoxidase and epoxysqualene-cyclase are believed to catalyze these reactions. Another intriguing feature concerns the ste­reochemistry of this reaction. Squalene which possesses no asym­metrical carbon atoms is converted into a molecule with seven asymmetrical centers. However, one stereoisomer is formed only. This is explained by assuming that the 2,3-epoxysqualene chain is folded and held in such a manner that its conformation in the substrate-cyclase complex favours the formation of protolanosterol by proper w-orbital interactions. This orienta­tion on the enzyme is believed to occur in a chair-boat-chair conformation, visualized in fig. 3.11.

R

Fig. 3.11 Orientation of 2,3-epoxy­squalene on the enzyme

35

A concerted cyclization will yield protolanosterol as inter­mediate which rearranges to lanosterol by two consecutive 1 ,2-

hydride and two 1,2-methide shifts foliowed by proton elimina­

tion on C(9) (steroidal numbering):

HO HO \ ~ CH3 èH3

Fig. 3.12 Enzymatically controlled rearrangement of proto­lanosterol to lanosterol

Note, that during the cyclization the cationic center moves via C(6) and C(10) which are tertiary cent~rs to C(14) which is a secondary center (squalene numbering). This must be due

tosome unknown interaction of the enzyme and C(14), most probably a favourable orientation on the enzyme. The favour­able orientation of the C(15)-n-lobe, which is directed to­wards the C(10)-n-lobe may be of importance for the forma­tion of a C-C bond between the atoms C(15) and C(10). It is at this stage that the non-enzymatic process differs from the enzymatic one. The vitro reaction stops at the formation of a tricyclic compound having a five-membered C ring 23

•

R

1.§.

It must be clear that there is a pronounced influence of th~

enzyme on the cyclization process. Thermodynamically a five­

membered ring is the most favoured one. In spite of this fact

the reaction proceeds via a less stable secondary cation to

36

a tertiary one in the final D ring closure. In order to ex­

plain this feature, W. de Loos 2 ~ proposes a two-step mechanism.

The cyclization process is interrupted after the chair-boat

cyclization of the A/B ring system by trapping the cation at the a side with an active site of the cyclase enzyme (for in­

stance the nitrogen atoms in histidine). This site creates

a leaving group or back-shielding via the enzyme which forces

the incoming (entering) double bond in a chair-cyclohexenyl

conformation, generating a six-membered C ring with the right configuration.

Fig. 3.13 Two-step mechanism for the cyclization of 2,3-

epoxysqualene to protolanosterol

On the other hand, w.s. Johnson and aollaborators 11 took profit from the possibility that relatively stable tertiary carbenium

ions generated during the reaction, can be used for weli-con­trolled cyclization reactions under non-enzymatic conditions

leading to steroids as is outlined in the Introduetion (III.l).

III.7 Experimental

• 2,5-Bis(1,3-dioxolan-2-yl)-12-(2-thienyl)(E)dodec-9-ene (Sa) To'a solution of i, prepared from 6.3 g (0.01 mol) of the corresponding iodide and 5 ml phenyllithium (2 N in benzene/

ether mixture, 70/30) in 30 ml tetrahydrofuran at 0°, 1.4 g (0.01 mol) of aldehyde 3a in 5 ml tetrahydrofuran was added

dropwise at -78° (nitrogen atmosphere). After ~ha ser.ond

equivalent of phenyllithium was added, followed by excess of methanol (after 5 min). Aqueous work-up foliowed by chromato-

37

graphy over silica (chloroform as eluens), gave 2.S9 g (70\) of pure Sa. NMR (CC14): 6 1.24 (s,3,C!:!3); 1.33-2.60 (m,8,

4x C!:!2); 1.61 (s,4,o2cc!:!2-c!:!2co2); 2.7S-3.10 (m,2,Th-C!:!2); 3.90 (s,8,dioxolane protons); S.40-S.60 (m,2,C!:!=C!:!); 6.6S-7.16

( m, 3 , Th-!:!) •

• 2,S-Bis(1,3-dioxolan-2-yl)-12-(3-thienyl)(E)-dodec-9-ene

(Sb) Prepared as for Sa.

• 2,S-Bis(1,3-dioxolan-2-yl)-12-(2-thienyl)(Z)dodec-9-ene

(Sc) To a salution of!, prepared from 6.3 g (0.01 mol) of the corresponding iodide and 6 ml of n-butyllithium (20\) in hexane) in 30 ml of tetrahydrofuran at 15°, 1.4 g (0.01 mol) of aldehyde 3a in 5 ml of tetrahydrofuran was added dropwise at -78° (nitrogen atmosphere). After! h the temperature was raised to -30°; then a secend equivalent of n-butyllithium was added foliowed by excess of methanol. Aqueous work-up as for Sa yielded 2.64 g (72\) of product. lts speetral data were fully identical with these of • c20 H30o4s (366.52): Calcd C 65.54, H 8.25; found C 65.71, H 8.37.

• 2,5-Bis(1,3-dioxolan-2-yl)-12-(3-thienyl)(Z)dodec-9-ene (Sd) Preparedas for Sc. c20H30o4s (366.52): Calcd C 6S.S4, H 8.25; found C 65.71, H 8.37.

• 12-(2-Thienyl)(E)dodec-9-ene-2,5-dione A salution of 1.65 g (0.045 mol) of in a mixture of 30 ml of methanol and 60 ml of 0.5 N hydrochloric acid was stirred for l h at 50-60° under nitrogen. The reaction mixture was diluted with water and the product extracted into ether. Drying and remaval of the solvent left 1.15 g (92%) of crude oily product which was used without purification.

• 12-(3-Thienyl)(E)dodec-9-ene-2,5-dione

• 12-(2-Thienyl)(Z)dodec-9-ene-2,5-dione ... 12-(3-Thienyl)(Z)dodec-9-ene-2,5-dione

38

were prepared as described in the previous experimental .

... 2- [6-(2-Thienyl) (E)hex-3-eny~ -3-methylcyclopent-2-enone

(6a) A mixture of 7.5 g (0.027 mol) of dione (see preceding syn­

thesis), 60 ml of ethanol and 20 ml of 0.1 N aqueous sodium hydroxide was refluxed for! h (nitrogen atmosphere). The salution was poured into water and the product isolated by ether extraction. Drying and stripping off the solvent gave crude product. Column chromatography (Si02 ,CHC1 3) gave 6.1 g

(87%) of pure product. NMR (CC1 4): o 1.97 (s,3,C!:!3); 2.00-

2.60 (m, 10,5x C!:!2); 2.62-2.98 (m,2,ThC!:!2); 5.23-5.52 (m,2,

C!:!=C!:!); 6.60-7.08 (m,3,Th-!:!) .

... 2- [6-(3-Thienyl) (E)hex-3-eny:j] -3-methylcyclopent-2-enone (6b)

Prepared as for 6a .

... 2- [§- (2-Thienyl) (Z)hex-3-eny~ -3-methylcyclopent-2-enone

(6c) Preparedas for 6a. c16H20os (260.40): Calcd C 73.80, H 7.74; found C 73.91, H 7.92 .

... 2-~-(3-Thienyl)(Z)hex-3-eny~ -3-methylcyclopent-2-enone (6d)

Preparedas for 6a. c16H20os (260.40): Calcd C 73.80, H 7.74;

found C 73.87, H 7.84 .

... 2- [6- (2-Thienyl) (E)hex-3-enyi) -3-methylcyclopent-2-en-1-ol

(7a) To a salution of 520 mg (2 mmol) of 6a in 10 ml of ether

78 mg (2 mmol) lithium aluminum hydride was added portions­wise at -30°. After ! h 1 N aq~eous sodium hydroxide salution

was added. Drying and evaparatien of the ether layer gave 480 mg (92%) of product. No saturated alcohol could be de­tected by 1H-NMR spectroscopy. This product was used without

purification for cyclization experiments. NMR (CC1 4): o 1.63

(s,3,C!:!3); 1.70-3.22 (m,13,6x C!:!2+CHO!:!); 4.42-4.73 (m,1,C!:!OH);

39

5.27-5.63 (m,2,C~=C~); 6.67-7.12 (m,3,Th-~).

• 2- ~-(3-Thienyl)(E)hex-3-enyD -3-methylcyclopent-2-en-1-ol

(7b) • 2- @-(2-Thienyl)(Z)hex-3-eny~ -3-methylcyclopent-2-en-1-ol

(7c) • Z~~-(3-Thienyl)(Z)hex-3-eny~ -3-methylcyclopent-2-en-1-ol

(7d) were prepared as for ?a.

• 5-Methyl-12, 13-lli} thienotricyclo [7. 4. 0. 0 4

' 8] tridec-4-ene (Sa)

Toa salution of 480 mg (1.8 mmol) of 7a in 10 ml of methylene

chloride was added dropwise 460 mg (1.8 mmol) of $tannic

chloride at -95° (nitrogen atmosphere). After 1 h the mixture was poured into a saturated ammonium chloride solution. The water layer was extracted twice with methylene chloride and

.the çombined organic layers were dried and concentrated. Column chromatography (Si02 , pet. ether 40-65) yfelded 215 mg (0.9 mmol} of product (49%), mp 73.5-75.5°~ c16H20s (244.40): Calcd C 78.63, H 8.25; found C 78.70, H 8.37. NMR (CC1 4):

ö 1.65 (s,3,C~3 ); 0.83-3.10 (m,1S,aliphatic protons}; ~.02

(AB pattern,2,Th-~).

• 5-Methyl-13, 12- [Q] thienotricyclo [7. 4. 0. o4 ' 8) tridec-4-ene (Sb)-

Preparedas for Sa, mp 59.5-61.5°. c16H20s (244.40): Calcd C 78.63, H 8.25; found C 78.45, H 8.50. NMR (CC1 4): o 1.65 (s,3,C~3 ); 0.90-3.00 (m,15,aliphatic protons); 6.78 (AB pattern, 2,Th-~).

40

BefePences and Notes

1. W.S. Johnson, H.B. Gravestock and B.E. HcCarry, J. Amer. Chem. Soc., 21., 4330 (1971).

2. P.A. Bartlettand W.S. Johnson, J. Amer. Chem. Soc., 95, 7501 (1973).

3. ~.S. Johnson, M.B. Gravestock and B.E. McCarry, J. Amer. Chem. Soc., 93, 4332 (1971).

4. J.W. de Haan and L.J.M. van de Ven, Org. Magn. Resonance, ~. 147 (1973).

5. The assignment of the (E) and (Z) structure of alkenes is based on the difference in chemical shift of the allylic carbon atoms. Comparison of the spectra of Sc and Sd with those of 4-(2-thienyl)but-1-ene and 2,5-bis(1,3-dioxolan-2-yl)nonane revealed the (Z) conformation as can be seen from the subjoined Table.

1 3 5. 0 / c , / c ~ _rl'"c

Th/ C ~t,-2 4

compound values for the allylic carbon atoms (in ppm downfield from TMS)

c2(E) C2(Z) Me c5(E) c5(Z) Me

Scb 35.71 30.54 5. 17 33.80 28.50 5.30

5d? 35.29 30.08 5.17 33.66 28.27 5.39 -d

35.55 32.86 6a - - -6bd 34.36 - - 32.86 - --

aTh=thiophene ring (2- or 3-substituted); bData of the (Z)­and (E)-isomers were measured in the mixtures (E/Z=O.l); cAó=C(E)-C(Z); dCompounds 6a and 6b from Chapter IV

The Aó values are in good agreement with those measured in

disubstituted olefins by de Haan and van de Ven. By computer

41

simuiatien the coupling constants of the olefinic protons in the cliones derived from and were determined. The values found are characteristic for (Z)-alkenes, 10.85 and

11.06 Hz respectively. 6. H. Schlosser and K.F. Christmann, Angew. Chem., Intern. Ed.

Eng!.,.§_, 126 (1966); Ann. Chem., 708, 1 (1967).

7. M. Schlosser, K.F. Christmann and A. Piskala, Chem. Ber., 1 3 2814 (1970).

8. E.J. Corey and H. Yamamoto, J. Amer. Chem. Soc.,~. 226

(1970) j ibid. 92, 6637 (19-70); ibid. ~. 6638 (1970).

9. R.J. Andersen and C.A. Henrick, J. Amer. Chem. Soc., 97,

147 (1975).

10. P.J. Zeelen, private communication. 11. W.S. Johnson, Acc. Chem. Res., _!_, 1 (1968).

12. W.S. Johnson, D.H. Bailey, R. Owyang, R.A. Bel!, B. Jacques and J.K. Crandell, J. Amer. Chem. Soc., 86, 1959 (1965).

13. W.S. Johnson and J.K. Crandell, J. Org. Chem., lQ, 1785

( 196 5 ).

14. W.S. Johnson, A. van der Gen and J.J. Swoboda, J. Amer. Chem. Soc.,~. 170 (1967).

15. D.J. Goldsmith, B.C. Clark, Jr. and R.J. Joines, Tetra­hedron Letters, 1211 (1967).

16. P.A. Stadler, A. Nechvatal, A.J. Frey and A. Eschenmoser, Helv. Chem. Acta, iQ, 1373 (1957).

17. G. Sterk and A.W. Burgstahler, J. Amer. Chem. Soc., 21. 5068 (1955).

18. Por a review see: J. Reucroft and P.G. Sammes, Quart. Rev., ll• 135 (1971).

19. E. Vedejs and K.A.J. Snoble, J. Amer. Chem. Soc., 95,

5778 (1973).

20. A. Eschenmoser, L. Ruzicka, 0. Jeger and D. Arigoni, Helv. Chem. Acta, 38, 1268 (1955); ibid. 38, 1890 (1955).

21. P. van Pelt, Thesis, Eindhoven (1975).

22. See for two reviews: L.J. Mulheirn and P.J. Ramm, Chem.

42

Soc. Reviews,_!_, 259 (1972); L. Zechmeister, Fortschritte

der Chemie organischer Naturstoffe, Teil XXIX, R. Goldsmith,

Biogenetic Synthesis of Terpenoid Systems, p. 364,

Springer Verlag, Wien (1971) and references cited therein. 23. E.E. van Tamelen, J. Willet, M. Schwartz and R. Nadeau,

J. Amer. Chem. Soc., 88, 5937 (1966),

24. W. de Loos, forthcoming Thesis, Eindhoven. 25. T.T. Tchen and K. Bloch, J. Amer. Chem. Soc.,~' 1516

(1956); J. Biol. Chem., 226, 931 (1957).

43

CHA,PTER IV

Alternative syntheses :for precursors

of tetracyclic compounds

IV.1 Introduetion

In the previous Chapter the synthesis was described of

compounds of type l which served as precursors for tetracy­cles. These materials prepared via the Schlosser modifica­tion of the Wittig reaction still contained 5-10% of (Z)­isomer. In order to obtain pure (E)-compounds alternative

routes towards this type of compounds were developed.

IV.Z Synthesis of (E)-aZkene precursors via the Wadsworth­

Emmons reaetion

In Section 1I1.4 the E/Z ratio of isomers obtained from the Wittig reaction and its modifications is discussed. üne

of these modifications concerns the reaction of resonance­stabilized phosphoranes or phosphonoacetate anions with al­

dehydes and ketones known as the Wadsworth-Emmons reaction, which leads to (E)-alkenes selectively. Application of this method by reacting the aldehydes 1 and !Q (for their pre­paration see Sectien 11.3) with the triethylphosphonoacetate

anion afforded the thienyl substituted (E)-ethylpentenoates Za and Zb (fig. 4.1). The 1H-NMR spectra of the afore men­

tioned compounds revealed a JCH=CH=16 Hz, which is charac­teristic for (E)-alkenes. Reduction of Za and 2b proved to be

the most successful approach with diisobutylaluminum hydride 1

yielding the allylic alcohols 3a and 3b. Applying other

reducing reagents, such as lithium aluminum hydride 2 only

saturated products could be isolated, due to 1,4-addition of

44

H 0 O Na+

Th J+ (Eto)2 ~ ~OEt 0

1 a Th=2-thienyl

1 b Th=3-thienyl

1. Buli 2.oxirane

0\'0Et -r0

n..

Dibai-H

(OH r0

3a,~

JO 0 A0~MgCI

5

Cu Cl

n 0 1\

HO OH

p- TSA

Th

Fig. 4.1 Synthesis of (E)-precursors for cyclization reactions

the hydride. Treatment of the allylic alcohols 3a and 3b with sodium hydride and excess methyl iodide afforded the methyl ethers 4a and 4b in quantitative yield. The copper promoted coupling 3 of the farmer products with Grignard derivative ~ (vide infPa) gave compounds 6a and 6b, respectively, in ex­

cellent yield. Inspeetion of-;he 13c-NMR spectra proved that

the coupling had occurred with complete retentien of the

45

geometry of the double bond. No (Z)-isomer could be detected (see also Chapter III, note 4 and 5). Performing coupling experiments with ~ and the chlorides derived from the aleo­hals 3, in the absence of copper salts, the SN2 products (e.g. !l and the SN2' products (!) were formed in a 1:1 ratio.

Cl

Thj + ff1 -----Th ÄO~MgBr

+ 6

The Grignard derivative was prepared starting from 2-methyl­furan. Lithiation with n-butyllithium in tetrahydrofuran and subsequent alkylation with oxirane produced 2-(5-methyl-2-furyl)ethanol. Conversion into the corresponding chloride under neutral conditions was accomplished by the action of triphenylphosphine in CC14 at refluxq. Grignard derivative ~ was formed by the action of magnesium on the chloride in ether (not in tetrahydrofuran). Acid catalyzed ring opening of the furan ring by the method of Johnson 5 led to the di­ketals 7a and 7b. These compounds were fully identical with the (E)-alkenes, obtained from the Wittig-Schlosser reaction, in the presence of phenyllithium as base (see Section III.2).

IV.3 Synthesis of (E)-alkene preaursors via the Claisen

re arrangement

The synthetic route, given in Section IV.2, for molecules of type l cannot be applied to prepare compounds which are prone to attach by acids, as acidic conditions are necessary for the conversion of!+ l (e.g. a furan nucleus as A ring), Therefore, a different reaction sequence was developed whereby the A ring compound was introduced in one of the last steps, which permits a rather quick transposition of hetero­cycles as A ring compounds. For this purpose 11 was synthe­sized as general precursor for compoundsof type l (fig. 4.2).

46

D 1.n,-Bu U

2.Br~Br 0

HO

1. EtO+OEt

0 OEt

~ I

OH 2. OH-11

!1. HrOH, p-TSA

2.0W

1\ 0 0

12

I Pb(OAcl liCI

1\ 0 0

Cl

13

~Br 0 9

l1.M~ 0 2.~H

~ 0 10

1\ 0 0

0

Fig. 4.2 Reaction sequence for the preparation of J1.

Treatment of 5-methylfuryllithium with 1,3-dibromopropane 5

at -30° afforded bromide 2_ from which a Grignard derivative could be prepared with magnesium in ether. Reaction with freshly distilled acroleine afforded allyl alcohol ~· The

47

crude ~was converted after treatment with excess ethyl ortho­acetate and a catalytic amount of propionic acid into the ethyl ester of (E)-alkene compound !1, exclusively. This Claisen rearrangement proceeds via a (u! + u; + a;) electro­cyclic process which always results in the formation of (E)­alkenes. This was confirmed by IR (streng absarptien at 970 cm- 1 ((E)-alkene) and no absarptien at 730 cm- 1 ((Z)-alkene)) and 13c-N"MR spectroscopy. The crude ester was saponified to the acid under standard conditions. Acid-base extraction yielded the pure acid ll· Acid catalyzed furan ring opening 5

produced the diketal ~ after saponification. Halodecarboxy­lation of the acid with iodine and lead tetraacetate 6 result­ed in the formation of iodolactone When this reaction was performed on a model system (formed from 1-bromo-2-(1,3-dioxo­lan-2-yl)ethane via the sequence given in fig. 4.2) the desired iodide could he isolated in high yield. A modified halodecar­hoxylation with lithium chloride and lead tetraacetate 7 did result in the formation of 13 in an over-all yield of 22% starting from 2-methylfuran. It is known that compounds such as are very susceptible for basic reaction conditions 8 •

Reaction of 11 with thienyllithium and furyllithium in tetra­hydrofuran at low temperatures (< -30°) yielded only the ex­pected dehydrohalogenated derivative. Therefore, non-basic coupling experiments of arylcopper compounds and alkyl halides were performed on model systems. These arylcopper reagents, which are known to react with, for example, aryl halides 9 - 1 ~

and alkyne derivatives 15 failed to give suhstitution products when exposed to alkyl halides (4-bromohut-1-ene, 1-phenyl-2-bromoethane). Another methad to produce these types of com­pounds is substitution of an aryl iodide with an alkylcopper­tri-n-butylphosphine complex ar a lithium dialkylcuprate. However, it appeared that this reaction can only he used in case of methyl substitution reactions, due to the high stabili­ty of methylcapper with respect to alkylcopper compounds. This was illustrated hy the capper catalyzed coupling of hut-1-enyl-4-magnesium-hromide with 2-iodothiophene from which no coupled

48

product (e.g. 2-(4-but-1-enyl)thiophene) could be isolated. The oxidative coupling, however, which proceeds via mixed cuprate complexes, afforded coupled products. This reaction is based on the formation of complexes of the type R1R2CuX in which X stands for Li or MgBr. Yields up to 75% are obtained

when R1=sea-butyl or tert-butyl and R2=phenyl 16• To apply this

method on chloride ll, this compound was converted into the corresponding iodide from which a Grignard derivative could be prepared in ether.

1\ 0 0

Naf 11..----

I

15

1.Mg

z.~Cu J. o2

n

7o

On the addition of this Grignard derivative to a suspension of 2-thienylcopper (from 2-thienyllithium and cuprous iodide) at -78° the mixed cuprate was formed, whereupon oxygen (dry air) was passed through the mixture resulting in the formation of 7a in yields of 10-35%. Optimization of this reaction may lead to an effective method for the synthesis of compounds of type z from the easily accessible heterocyclic lithium derivatives and 13.

IV.4 Experimental

~s-(2-Thienyl)(E)pent-2-enoic acid, ethyl ester (Za) To a sodium hydride suspension (80 wt. % in paraffin) in 100 ml of dimethoxyethane (1.8 g, 0.06 mol) was added dropwise 14 g (0.06 mol) triethyl phosphonoacetate (T < 20°, nitrogen atmosphere), foliowed by a solution of 8.55 g (0.06 mol) of~ in 50 ml of tetrahydrofuran at 0° with vigorous stirring.

After 3 hr the reaction mixture was refluxed for 1 hr. Aqueous work-up gave after distillation 8.2 g (65%) of product, bp

49

85-90° (0.005 mm). NMR (CC1 4): ö 1.22 (t,3,Cg3); 2.27-2.71 (m,2,ThCH2cg2); 2.77-3.12 (m,2,Thcg2); 4.12 (q,z,ocg2cH3); 5.67, 5.96 (m,1,cg= CHCOOEt); 6.70-7.23 (m,4,Th-g+cgcoOEt).

• 5-(3-Thienyl)(E)pent-2-enoic acid, ethyl ester (2b) Preparedas for 2a, bp 85-90° (0.001 mm).

• 5- (2-Thienyl) (E)pent-2-enol (3a) A salution of 3.57 g (0.025 mol) of diisobutylaluminum hydride in 10 ml of benzene was added dropwise toa mixture of 2.1 g (0.01 mol) of Za in 50 ml of benzene at 5° (nitrogen atmo­sphere). After 1 hr of stirring at 5-10° a saturated ammonium chloride salution was added. Filtration, separation of the organic layer gave after drying and stripping off the solvent

1.45 g (86%) of product. NMR (CC1 4): ö 3.60 (s,1,0g); 3.90-4.10 (m,z,cg20H); 5.50-5.75 (m,2,cg=cg).

• 5- (3-Thienyl) (E)pent-2-enol (3b) Prepared analogous tp the 2-thienyl substituted derivative 3a.

• 1-Chloro-5.- (2-thienyl) (E).pent-2-ene A salution of 0.45 g (0.03 mol) 3a and 1.5 g (0.003 mol) triphenylphosphine in 20 ml tetra was refluxed for 7 hr. The salution was cooled, filtrated and concentrated, whereupon the residue was stirred for i hr at 0° after the addition of petroleum ether 40-65. Filtratien and evaparatien of the solvent left crude product. Chromatography (Si02 , petroleum ether 40-65) afforded 0.44 g (86%) pure material. NMR (CC1 4): o 3.96 (m,2,cg2Cl).

• 1-Chloro-5-(3-thienyl)(E)pent-2-ene

Prepared as the 2-thienyl substituted analogue.

50

... 1-Methoxy-5- (2 -thienyl) (E)pent-2-ene ( 4a)

A salution of 8.5 g (0•05 mol) of alcohol (3a) in 20 ml of dimethylformamide was added toa suspension of 1.8 g (0.06 mol) of sodium hydride (80 wt. % in paraffin) in 40 ml of dimethylformamide at 50-60°. After 3 hr 14.2 g (0.10 mol) of methyl iodide was added at room temperature. After 16 hr the reaction mixture was worked up as usual to yield 9.0 g (98%) of product (bp 70-73° (0.01 mm)). NMR (CC1 4): ö 3.30 (s,3,0C~3 ) .

... 1-Methoxy-5-(3-thienyl)(E)pent-2-ene (4b) Preparedas for 4a, bp 64-68° (0.005 mm) .

... 2-(5-Methyl-2-furyl)ethanol Toa salution of 8.2 g (0.10 mol) 2-methylfuran in 45 ml of tetrahydrofuran 50 ml of n-butyllithium (20% in hexane) was added dropwise at -30° (nitrogen atmosphere). After 3 hr of stirring at -10°, a salution of 6.6 g (0.15 mol) of oxirane in 10 ml of tetrahydrofuran was added. The reaction mixture was allowed to stand overnight at room temperature and poured into water from which the alcohol was isolated by ether extraction. Stripping off the solvent and distillation at 72-75° (4.5 mm) gave 8.2 g (65%) of product. NMR (CC1 4): o 2.20 (s,3,C~3 ); 2.58-2.88 (m,2,C~2 0H); 3.57-3.89 (m,2,C~2cH20H); 3.95 (s,l,Oli); 5.70-5.95 (m,2,furan protons).

• 1-Chloro-2-(5-methyl-2-furyl)ethane A salution of 12.6 g (0.1 mol) of alcohol and 39.3 g (0.15 mol) of triphenylphosphine in 250 ml of tetra was stirred under reflux overnight. The mixture was cooled, filtered and concentrated. The residue was taken up in petroleum ether 40-65 and stirred for 1 hr at 0°. Filtration, evaparatien of the solventand distillation gave 11.8 g (82%) of product, bp 48-50° (4.5 mm).

51

~Grignard derivative (~)

To 4.8 g (0.2 mol) of magnesium in ether, a salution of 14.5 g (O.l mol) of chloride in 75 ml of ether was added under a nitrogen atmosphere. Thé reaction was initiated by addition of a cristal iodine and a few drops of methyl iodide. Stirring was prolonged. for another hour. This salution was. used in coupling experiments .

... 1- (2-Thienyl) -7- (5-methylfuryl) (E)hept-3-ene (6a) To a mixture of 910 mg (5 mmol) of 4a, 30 mg (0.3 mmol) of cuprous chloride and 70 mg (0.6 mmo!') of triethylphosphite in 10 ml of tetrahydrofuran was added 1. 2. equi valents of Grignard derivative ~ (ethereal solution) at -30° under a nitrogen atmosphere. After ! hr the temperature was raised to 20° and the mixture was allowed to stand overnight. The reaction mixture was poured into a saturated ammonium chloride solution, whereupon the product was extracted into ether. Drying and evaporating of the solvent gave crude material which after column chromatography on silica (chloroform as eluens) gave 1.21 g (931) of product. NMR (CC1 4): 6 1.15-2.90 (m,10,Sx C!!2); 2.20 (s,3,C!!3); 5.35-5.60 (m,Z,C!!=C!!); 5.85 (s,2,furan protons); 6.85-7.25 (m,3, Th-!!) .

... 1-(3-Thienyl)-7-(5-methyl-2-furyl)(E)hept-3-ene (6b) Prepared as for 6a •

... 2, 5-Bis (1, 3-dioxolan-2-yl) -12·{2-thienyl) (E)dodec-9-ene (7a) A mixture of 8.0 g (0.03 mol) of 6a, 0.18 g (0.0012 mol) of p-toluenesulphonic acid, 6.2 g (0.10 mol) of ethylene glycol and a trace of hydroquinone in 50 ml of benzene was refluxed for 136 hr with continuous azeotropic remaval of water. The reaction mixture was poured into water which was rendered alcaline. The benzene layer was wasbed twice with water, dried

and concentrated to furnish after chromatography 9.8 g (871) of pure 7a and 0.4 g (SI) of starting material.

52

• 2,5~Bis(1,3-dioxolan-2-yl)-12-(3-thienyl)(E)-dodec-9-ene (7b)

Prepared as for 7a.

• 6-(5-Methyl-2-furyl)hex-1-en-3-ol 10 A salution of 10.15 g (0.05 mol) 1-bromo-3-(5-methyl-2-furyl)­propane5 (~) in 40 ml ether was added to a stirred suspension of 2.4 g (0.1 mol) magnesium and 20 ml ether, whereupon the mixture was refluxed for 1 hr. To the formed Grignard deriva­tive a salution of 2.8 g (0.05 mol) acroleine in 50 ml ether was added dropwise. After 2 hr the reaction mixture was

poured into a saturated ammonium chloride solution. Ether extraction, drying and evaporation of the solvent afforded crude product. Chromatography (Siü2 , CHC1 3 with 1 vol. % MeOH)

yielded 8.1 g (80%) pure lQ· NMR (CHC1 3): o 1.33-1.82 (m,4,C~2c~2CH(OH)); 2.20 (s,3,C~3 ); 2.31-2.70 (m,2,furan-c~2 ); 3.11 (s,1,0~); 3.89-4.13 (m,1,C~OH); 4.82-5.28 (m,2,CH=C~2 ); 5.80 (s,2,-furan-~); 5.53-6.08 (m,1,

C~=CH2 ).

•8-(5-Methyl-2-furyl)(E)oct-4-enoic acid, ethyl ester A stirred mixture of 15.0 g (0.08 mol) !Q, 61.2 g (0.38 mol) triethyl orthoacetate and 0.24 g (0.003 mol) propionic acid was slowly heated to 130° with continuous remaval of ethanol.

Evaporation of the orthoacetate under reduced pressure yielded crude ester in essentially quantitative yield. NMR (CC1 4): ó 1.20 (t,3,0CH2c~3 ); 1.20-1.73 (m,6,C~2 c~2CH= CHC~2 ); 2.21 (s,3,C~3 ); 2.34-2.61 (m,4,furan-c~2 and c~2COOH); 3.98 (q,2,0C~2 cH3 ); 5.38 (m,2,C~=C~); 5.80 (s,2,furan-~).

• 8-(5-Methyl-2-furyl)(E)oct-4-enoic acid 11 Crude ester (21.8 g, 0.1 mol)(see previous synthesis) was refluxed for 1 hr in 140 ml 4N sodium hydroxide salution in a .water-ethanol mixture (1:1 v/v) to yield after an acid-base

extraction 15.7 g acid (83%). NMR (CC1 4): ó 8.73 (s,1,COO~).

53

• 9,12-Bis(dioxolan-2-yl)(E)tridec-4-enoic acid (~) A mixture of 19.0 g (0.1 mol) ll• 24.8 g (0.4 mol) ethylene glycol, 0.17 g (0.001 mol) p-toluenesulphonic acid and a trace of hydroquinone was refluxed for 72 hr with continuous removal of water. Aqueous work-up gave the crude glycol ester of ~. which was saponified as given for ll· Chromatography (Si02 , CHC1 3 with 10 vol. % MeOH) yielded 24.5 g acid~

(75%). NMR (CC1 4}: o 1.28 (s,3,C!!3); 1.59 (s,4,02CC!!2C!!2C02); 1.43-2.40 (m,8,C!!2C!!2C!!2CH=CHC!!2}; 2.45 (m,2,C!!2COOH); 3.88, 3.92 (2x s,8,dioxolane protons); 5.48 (m,2,C!!=C!!); 11.0 (s,1,COO!!)·

• 2,5-Bis(1,3-dioxolan-2-yl)-12-chloro(E)dodec-9-ene (ll) A mixture of 5.0 g (0.015 mol) ~. 50 ml benzene and 7.5 g (0.015 mol) lead tetraacetate (with 10-20 wt. % adhesive acetic acid) is stirred for 1! hr (nitrogen atmosphere). To the homogeneaus salution 6 ml dry ether was added, whereupon the temperature was raised to 65-75°. Every 20 min 0.2 g (0.005 mol) anhydrous lithium chloride was added (five portions). After the addition of wet ether the mixture was filtrated, extracted with 0.1 N sodium hydroxide (for the recovery of starting material), dried and concentrated to give 3.65 g (75%) of 13.

-1-IR (nujol): 970 cm (E)-alkene. NMR (CC1 4): o 3.41 (m,2,C!!2Cl). 13c-NMR absorptions for C(l)-C(12) are 24.48, 110.54, 37.38, 34.27, 112.18, 32.33, 24.92, 33.70, 134.54, 127.04, 36.97, 45.04 and for the dioxolane carbons attached to C(2) and C(5) 65.73 and 65.42, respectively.

• 2, 5-Bis ( 1 , 3-dioxolan-2 -yl) -12 -iodo (E) dodec-9-ene (_!i)

A salution of 0.32 g (0.001 mol) ll• 0.45 g (0.003 mol) sodium iodide, a trace magnesium oxide and 10 ml butan-2-one was stirred at reflux overnight (nitrogen atmosphere). Werk­

up as usual yielded quantitatively iodide _!i (0.41 g). NMR (CC1 4): o 2.97 (m,2,C!!zi).

54

~Preparation of 2,5-bis(1,3-dioxolan-2-yl)-12-(2-thienyl) (E)dodec-9-ene (7a) via the oxidative coupling of unsymme­trical cuprate complexes

Toa suspension of 2-thienylcopper (prepared from 0.76 g (0.009 mol) thiophene, 4.5 ml 2N methyllithium (in ether) and 0.92 g (0.005 mol) cuprous iodide in 20 ml tetrahydrofuran) was added a salution of the Grignard derivative of ~ (prepared from 0.41 g (0.001 mol) ~ and 0.075 g (0.003 mol) magnesium in 10 ml ether) at -78° (nitrogen atmosphere). After 10 min dry air was passed through the reaction mixture until no more black precipitate was formed. Ether and water was added, the mixture filtrated and extracted twice with ether. The ethereal salution was dried and concentrated to left crude oil from which compound 7a was isolated after chromatography (Si02 , CHCI 3) in 10-35% yteld.

55

Referenaee and Notee

1. L.J. Zakharkin and I.M. Khorlina, Tetrahedron Letters, 619 (1962); J.A. Marshall, N.H. Andersen and J.W. Schlicher, J. Org. Chem., 35, 858 (1970).

2. R.F. Nystrom and W.G. Brown, J. Amer. Chem. Soc., I_Q, 3738 (1948); F.A. Hochstein and W.G. Brown, J. Amer. Chem. Soc., ZQ, 3484 (1948).

3. A. Commerçon, M. Bourgain, M. Delaumeny, J.F. Normant and J. Villieras, Tetrahedron Letters, 3837 (1975).

4. J. Hooz and S.S.H. Gilani, Can. J. Chem., 46, 86 (1968). 5. W.S. Johnson, T-t Li, C.A. Harbert, W.R. Bartlett, T.R.

Herrin, B. Staskin and D.H. Rich, J. Amer. Chem. Soc., 92, 4461 (1970).

6. R.A. Sheldon and J.K. Kochi, Org. Reactions, ~~ 359 (1972).

7. A.J.H. Klunder, private communication. 8. M.E. Jung, Tetrahedron, 3 (1976). 9. M. Nilsson and C. Ullenius, Acta Chem. Scand., 24, 2379

(1970).

10. C. Ullenius, Acta Chem. Scand., ~. 3383 (1972). 11. M. Nilsson, C. Ullenius and 0. Wennerström, Tetrahedron

Letters, 2731 (1971). 12. J.F. Normant, Synthesis, 63 (1972). 13. N. Gj~s and S. Gronowitz, Acta Chem. Scand., ~. 2598

(1971). 14. D.A. Shirley, B.H. Gross and P.A. Roussel, J. Org. Chem.,

lQ_, 225 (1955). 15. R. Oliver and D.R.M. Walton, Tetrahedron Letters, 5209

(1972). 16. G.M. Whitesides, W.F. Fischer Jr., J.S. Filippo Jr.,

R.W. Bashe and H.O. House, J. Amer. Chem. Soc.,~. 4871 (1969).

56

CHAPTER V

Synthesis of thiophene anologues of estrone:

13c NMR ID.easureiD.ents of these coiD.pounds

and their precursors

V.1 Synthesis of thiophene anaZogues of estrone

In Chapter III the preparatien of tetracyclic compounds 1

3a and 3b has been discussed. These structures proved to be excellent precursors for the conversion into estrogen-like compounds. The following reaction sequence seemed to be the · most attractive for the preparatien of the estrogens:

Epoxidation of the alkene moiety, foliowed by a boron tri­fluoride etherate promoted ring opening of the epoxide gene­rates an intermediate carbenium ion. The stereogeometry of this ion is crucial for the further course of the reaction, because the [1, 2] methyl shift must praeeed auprafaaial"ly,

as is imposed by the rules of Woodward and Hoffmann 2 • In Fig. 5.1 the two possibilities are shown, starting from the a- or B-epoxide. The orientation of the angular C(14) hydragen atom in ion !! is sterically unfavourable to undergo a [1, 2] shift. The methyl group, on the other hand, has the correct orientation to shift to the angular position. Ion Za is formed

after the [1,2] methyl shift and from this oxygen-stabilized species the corresponding carbonyl derivative is obtained.

57

a- epoxide f3- epoxide

sr/3 Sj:SCH3 Sl j BF3"Et,O j ••r,.,o

FS):5"3 s~CH3 ) :1a s i 1b

I j OBF3 FS)?CH3 s;b

S :2o s + 2b

Fig. s. 1 BF 3.Et2o promoted a- and a-epoxide ring opening

In ion 1b the methyl group and the hydrogen atom compete for the Q, ~ shift. Since the hydrogen shift is faster 3

• '* ' 5,

ion 2b is generated. Product formation depends on a further backbone rearrangement in the steroid frame, which also occurs in the rearrangement of protolanosterol to lanosterol (see Section 1.1 and III.6). These shifts, however, are enzymati­cally controlled 6 , since lossof the C(9) hydragen as a proton (in protolanosterol) terminates this process with formation of lanosterol.

The epoxides 4a and 4b were prepared via the correspond­ing chlorohydrins. Reaction of 3a with N-chlorosuccinimide (NCS) in a tert-butanol-water mixture at 10° gave a 1:1 mix­

ture of the chlorohydrins Sa and Sb. At this temperature no radical chlorinated structures were observed. Both Sa and Sb

58

NCS + 3a Sa Sb

Sa K2co3 BF3. Et20

Sb

4a 6a

CH 3 CH30

1. NCS BF3.Et

2o

2. K2co

3

3b ~ §_Q_

Fig. 5.2 Preparation of the thiophene analogues of estrone

afforded the ~-epoxide 4a by the action of an excess potas-

sium carbonate in methanol. This epoxide was converted into estrone analogue 6a upon treatment with boron trifluoride etherate in benzene. In a similar reaction sequence tetra­cycle 3b could be converted into 6b in high yield (fig. 5.2). Straightforward epoxidation of 3a and 3b with m-chloroper­

benzoic acid at -40° afforded the corresponding S-epoxides 4c and 4d in essentially quantitative yield (steric approach of the peracid from the less hindered side). The low tem­perature was chosen to avoid oxidation of the thiophene sul­phur. The 13c-NMR spectrum of 4c revealed that this compound

was contaminated with only 5% of the ~-isomer 4a. Trestment

of epoxides 4c and 4d with freshly distilled boron trifluoride

59

l m-Ct-C6

H4

COOOH l m-Ct~6H4COOOH PH3 ;~H3 . 0 '

4c 4d

Fig. 5.3 Preparation of the S-epoxides from the alkene derivatives by means of peracid oxidation

etherate in benzene yielded a mixture of labile products in which apolar structures predominated. The RF values of these compounds were almost equal to the RF value of and 3b. However, no absorption in the alkene region ( 1H-NMR) was observed, which indicated double bonds between the junction

·carbon atoms. This type of rearrangement was also found by BePti et aZ. 3 in A-nor steroids and also by BascouZ et al.~

in the hopene series. Although no detailed study was made of the products formed, strong evidence is offered for the following reaction products:

+ 7 8

The combined apolar structures, generated from several con­secutive hydride shifts, were separated first from the other products (all minor constituents and polymerie material). Column chromatography (Sio2 , petroleum ether 40-65) yielded

two fractions (Rp=0.42 and 0.36). The first fraction consisted of compounds of type ! which may be generated from l by a

60

Q,~hydrogen shift. The two methyl groups absorp at 6=0.93

and 0.97 as doublets with JCH -H=7 Hz. The second fraction contained a component having ~ strong methyl absorption (singulet) at 8=1.70, which must be due to structure 7 (in

structure 3a and 3b öCH =1.65). 3

V.2 Evidenee for the trans~anti~trans geometry in the

tetraeyelie produets

In Sectien III.5 the Stork-Eschenmoser hypothesis is discussed. This hypothesis states that concerted cyclization

reactions lead to a trans~anti~trans geometry on the junction carbon atoms. Insome cases, however, a stepwise ring ciosure

(via deprotonation and reprotonation) was observed which led

to eis-substituted products. The 13c-NMR data presented in Table V.1 can be used to sustain the assignment of the former configuration to the tetracyclic products described in this

thesis. This can be accomplished in the first place by com­

parison of the 13c-NMR chemical shifts of the derivatives studied bere with those of steraids of known trans~anti~trans

arrangement. A very useful example of this kind is provided by the spectra of the compounds 6a, 6b and estrone acetate 7

(see Table V.1). The assignments of the signals belonging to positions C(1) through C(6) were made by reference to the

compounds 4a and 4b described in Chapter II. In the latter models, unambiguous assignments were possible by a combina­tion of signals areas and multiplicities, known substitution rules· of cyclohexanes 8 and selective decoupling experiments. Similar decoupling experiments were carried out for 6a and 6b in order to locate the signal of C(5) (allylic protons

at relatively low field). The remaining signals of 6a and 6b correspond quite nicely with those of the C and D ring of

estrone acetate. As a rule, the deviation does not exceed ea

1.5 ppm with the exception of the carbonyl frequencies in 6a and 6b and C(10) in 6b. Carbonyl shifts are known to be more susceptible towards changes in solvent and/or concen-

61

Table V .1 13C-NMR data of cyclic compoundsa

17 17

compounds at om

4ab 4bb number 3a 21 .1.!?. 4c 1.2. §.! ft ll - -1 125.94 - 126.03 - - 126.50 - 126.06 - 126.4 2 122.46 122.19 122.72 122.63 123.34 123.07 122.08 123.22 123,16 119.2 3 - 127.88 - 128.14 129.38 - 128.76 - 128.92 149.5 4 134.81 134.54 136.04 135.25 136. 17 136.66 136.04 136.26 135.72 1Z1. 9

5 26.33 26.91 26.29 26.78 26.95 26.40 26.78 26.15 26.63 137.8 6 21.70 21 . 17 29.29 28.89 27.79 28.41 28.28 28.03 27.66 29.7 7 39.44 40.27 42.48 42.52 42.30 42.90 42.92 39.74 4C.S9 26.8

8 33.97 34.67 49.76 50.42 44.64 44.13 44.86 44.65 44.83 38.6

9 144.69 147.25 1 39.61 141.16 141.11 139.64 140.94 139.84 140.93 44.7

10 31.67 33.48 32.55 34.32 32.29 30.22 31.98 27.60 29.24 138.2

11 - - 28.94 28.89 29.38 29.18 28.76 32.70 32.64 26.1

12 - - 136.70 136.48 72.48 72.28 72.30 49.32 49.57 32.2

13 - - 52.71 52.71 47.24 46.98 47.02 50.72 50.72 47.9

14 - - 26.78 26.68 23.03 24.72 24.53 22.81 22.81 50.8

1 5 - - 38.29 38.20 33.17 33.84 33.70 36.83 36.83 21.8

16 - - 129.56 129.73 68.77 69.43 69.48 221.38 221.38 35.6

17 - - 14.69 14.60 16.45 16.1 s 16.32 15.17 15.23 218.7

18 - - - - - - - - - 13.7

aAtom numbering as given in the heading of the Table; bcompound numbering of Chapter II

trations than aliphatic or olefinic carbon signals. For the deviation of C(10) in 6b vide infra.

In order to substantiate the 13c-NMR shift arguments used in the previous paragraph, it would be of interest to "test" their sensitivity towards changes in the geometries at the ring junctions. Some time ago, Datling and Grant

publisbed the 13c-NMR chemica! shifts of a number of perhydro­anthracenes and perhydrophenantrenes, including examples with various combinations of ais and syn ring junctions 8

• In Table V.2 the 13c-NMR shifts of the junction atoms of four isomerie perhydrophenantrenes are listed tagether with the differential shifts with respect to the trans~anti,trans isomer.

Table V.2 Values of the junction carbon atoms (in ppm downfield of TMS)

compound C(11) Ma C(12) Ma c ( 13) Ma C(14) Ma

TAT 10b .

43.61 - 48.21 - 48.21 - 43.61 -TAC lOb 44.20 0.59 38.47 -9.74 42.27 .:..5,94 37.96 -5.65 TSC lOb 36.47 -7. 14 47.70 -0.51 42.35 -5.86 38.38 -5.23 csc 1öb 38.08 -5.51 41.68 - -6.53 41.68 -6 .S3 38.06 -6.53

adifferential shifts with respect to the TAT-isomer;bT=trans,

A=anti, C=cis, S=syn

In these compounds differences of aa 6-10 ppm are found for at least two of the four backbene carbon signals whenever ais and/or syn configurations occur. A priori, it seems rea­sonable to expect that similar differences would also occur between the signals of estrone acetate and those of the 6a,6b pair if these would include ais and/or syn junctions. This is certàinly not the case, which can be used to strengthen the arguments put forward in the previous paragraph. Corres­ponding structural evidence cannot be obtained for compounds

3a and 3b in a direct manner. This problem can be approached

as follows: androstane with a known trans,anti,trans arrange­ment serves as a starting point, the shifts are known 7 •

63

On the other hand, compound ~ resembles 3a and 3b more close­ly, the differences being the benzene moiety as opposed to the thiophene rings in 3a and 3b. It should be emphasized at this point, that although the shifts of compound ~ can be constructed simply by the application of additive substi­tuent effects, the accuracy of such an approach is limited. This is caused primarily by the f~ct that the additivity of the substituant effects suffers considerably in crowded mole­cular part which are encountered in the compounds under con­sideration. The details for three of the ring junction carbon atoms will be given below.

1 10

androstone

1. C(14): the original value in androstane 7 amounts to 54.7 ppm; a e-correction of -2.5 ppm for the removal of the methyl group at C(13) (structure ~) yields 52.2 ppm.

2. C(8): the value of 36.0 ppm, found in androstane, must be corrected twice (yc=3 ppm) for the removal of two y-methyl groups at C(10) and C(13). This brings the v'alue for C(S) in structure ~on 42.0 ppm.

3. C(9): the shift in androstane is 55.1 ppm; application of a S-correction of -2.5 ppm for a methyl group removal yields a value of 52.6 ppm. If the A ring in structure 9 is an aromatic nucleus an extra downfield shift of +

2 ppm gives a C(9) absorption of aa 54.5 ppm. Some minor effects are neglected (internal y-gauche inter­actions), because these will cancel partially. No correction is applied for the ó 13 • 17 bond by lack of suitable correction

factors. In Table V.3 the data of the junction atoms of compounds 3a, 3b and ~are gathered (steroidal numbering).

64

Table V.3

compound values of the junction carbon

atoms (in ppm downfield of TMS)

c (9) C(8) C(14) 3a 52.71 42.48 49.76 -3b 52.71 42.52 50.42 -9 54.4 42.0 52.2 -

It can be concluded that, within the restrictions of the approach used (vide supra), the shifts of compound i can be predicted and deviate from those of 3a and by no more than aa 2.0 ppm. This calculation can thus be constructed as supporting the trana,anti,trans contiguration in compounds 3a and 3b.

As mentioned above, the C(10) chemical shift of compound 6b deviates markedly from the comparable signal of estrone acetate in contrast with that of C(lO) in compound 6a. This implies a difference between 6a and 6b regarding the chemical shift of C(10). Similar effects arealso present in the other cyclic compounds described in this thesis; within the series ~-§_ C(10) in the "b-compound" absorbs at 1.74 .::_ 0.10 ppm lower field than in the appropriate "a-compounds" (see Table V.l). Attention was called to this phenomenon by de Haan and

ao-hlorkers 9• They ascribe these differential shifts to down­

field y-gauche effects exerted by the sulphur atom on the carbon atom at C(10). Usually, y-gauche effects lead to upfield chemical shifts, also when hetero atoms are in­volved10>11.12. A similar, albeit smaller, effect is observed

in the mobile, acyclic precursors of the cyclic products (Table V.4). The aliphatic carbonsin ~-position with respect to the ring in the 2-substituted thiophenes resonate at aa

1.1 ppm lower field than those in the 3-substituted thiophenes. Finally, it was shown that this differential shielding between

2- and 3-alkylsubstituted thiophenes is probably of a rather general nature, because it is also present in the two n-butyl-

65

Table V.4 13c-NMR measurements on 2- and 3-substituted thiophenes and related çompounqs8

compo"unds atom

(Z)-R 1 R3 (E) -R1R3 (Z)-R2R3 (E) -R2R3 (E)-R1R4 (E)-R2R4 1R5 (E)-R2R5 number

1 - - 121.16 121.04 - 120.73 - 120.97

2 123.99 123.87 - - 123.60 - 123.88 -3 127.58 127.57 126.12 126.07 127.31 125.72 127.58 126.01

4 125.24 125.15 129. 18 12!L 16 124.88 128.76 125.16 129.10

5 145.50 145.48 143.22 143.19 145.26 142.99 145.36 143.06

6 30~88 "30 .97 31.29 31.32 30.92 31.Z3 30 .ss 31.12

7 30.48 35.64 29.31 34.49 35.55 34.36 35.55 34.34 8 129.50 130.08 130. 12 130.71 130. 26 130.79 130.26 130.86

9 131.81 132.29 131 .15 131.83 131 .67 131.14 131. 26 131.10

10 28.39 33.70 28.37 33.75 32.86 32.86 32.15 32.15

11 24.44 24.79 24.83 24.83 28.21 28.23 24.08 24.09

12 32.52 32.41 32.41 32.47 28.80 28.81 140.21 140.20

13 112. 19 112.22 112.23 112.22 154.79 154.75 208.09 208.15 14 34.24 34 •. 41 34.35 34.49 106.79 106.75 32.15 32.15 15 37.76 37.67 37.67 37.72 106.35 106.31 34.94 34.94

16 110.57 110.55 110.59 110.54 150.42 150.38 169.93 170.05 17 24.44 24.79 24.83 24.83 14.11 14.12 17.78 17.78 18 65.76 65.68 65.71 65.73 - - - -19 65.44 65.37 65.45 65.42 - - - -20 - - - - - - - -

66

Table V.4 (continued) 13C-NMR measurements on 2- and 3-substituted thiophenes and related compoundsa

2

at om number 12a 12b R1H R2H

1 129.29 129.29 - 120.82 2 129.07 129.03 123.71 -3 126.60 126.65 127.40 125.81

4 129.07 129.03 124.99 128.72 5 129.29 129.29 144.99 142.57 6 142.79 142.75 30.48 30.44 7 36.92 36.83 36.81 35.38 8 35.29 28.28 138.08 138.60 9 130.57 130.13 116.61 115.71

10 131.67 131.19 - -11 33.66 30.08 - -12 24.70 24.70 - -13 32.47 32.38 - -14 112.18 112.09 - -15 34.32 34.32 - -16 37.63 37.63 - -17 110.50 110.46 - -18 24.70 24.70 - -19 65.59 65.59 - -20 65.33 65.29 - -

11.Jl: E-isom~r ll..2: Z-ir.om~r

compounds llb 14c

- 120.65 123.56 -127.17 125.59 124.75 128.81 145.47 143.06

31,06 31.23 31.27 30.00

124.40 124.84 132.86 132.20

26 .6of 26.33f 18.61g 18.26g

- ---

- -- -- -- -- -- -

15d 16e

- 120.47 123.20 -127.09 125.63 124.48 128.76 145.83 143.41

30.35 30.79 34.72 33.61 22.98 23.25 14.47 14.69

- -- -- -- -- -- -- -- -- -- -- -

~Deviation of the conventional numbering as given in the heading of the Table was preferred in order to obtain comparable data; b13•2-methyl-S-(2-thienyl)pent-2-ene

- d (see Chapter II); cli•2-methyl-5-(3-thienyl)pent-2-ene (see Chapter II); ~·2-butyl-thiophene; el&•3-butylthiophene; f(E)-methyl signal; g(Z)-methyl signal

67

thiophenes (Table V.4).

V.3 ErepePimental

.... 4, Sa-Epoxy- SS-methyl-12, 13- [.b.] thienotricyclo [7. 4. 0. 04 ' 8]-tridecane (4a)

To a salution of 244 mg (1 mmol) 3a in 13,S ml tePt-butanol­water mixture (2:1) was added 130 mg (1 mmol) N-chlorosuccini­mide at 12°. The reaction tnixture was stirred at room tempe­rature until it became homogeneaus (1-1i h). After evaporation of the tept-butanol the residue was taken up in an ether-water mixture. Drying and concentrating the ether phase afforded the crude mixture of the chlorohydrins Sa and Sb, which were identified by their characteristic methyl absorp­tion (1.42 and 1.26 ppm, respectively). The crude chlorohydrins were stirred overnight in a suspension of SOO mg (4 mmol) potassium carbonate in 3 ml methanol to yield after aqueous work-up 170 mg (0.6S mmol) 4a (6S% over-all), mp 129.0-134.S 0

(after trituration with acetone). IR (KBr): 1260 cm- 1 , epoxide. NMR (CDC1 3): ö1.3S (s,3,C~3 ); 0.80-3.00 (m,1S,aliphatic protons); 6.93 (AB pattern,2,Th-~) •

.... 4, Sa-Epoxy- 5 S-methyl-13, 12-[.b.] thienotricyclo [7, 4. 0. o4 • 8]-tridecane (4b)

Preparedas for 4a, mp 147.S-149.S0•

NMR (CDC1 3): ö 1.37 (s,3,C~3 ); 0.80-Z.9S (m,1S,aliphatic pro­tons); 6.78 (AB pattern,2,Th-~) •

.... 4, SS-Epoxy-Sa-methyl-12, 13- [..b.] thienotricyclo [7. 4. 0. o4 • 8]-tridecane 13 (4c)

To a salution of 244 mg (1 mmol) in 10 ml methylene chloride was added dropwise a salution of 223 mg (1.1 mmol) m-chloro­perbenzoic acid (8S% pure) in 1 ml methylene chloride at -40°. Stirring was prolonged for 1 h at -40°, whereupon the mixture was warmed up to room temperature and washed with a saturated

sodium bicarbonate solution. Drying and evaporating of the

solvent yielded 240 mg (92%) 4c, mp 120.0-124.5° (after tri-

68

turation with acetone). -1

IR (KBr): 1260 cm , epoxide.

• 4, 513-Epoxy-5a-methyl-13, 1 Z- [12.] thienotricyclo [7. 4. 0. 04 ' 8]­tridecane 13 (4d)

Preparedas for 4c, mp 124.0-126.5°.

• 413-Methyl-12,13-[~]thienotricyclor.4.o.o 4 • 8 ]tridecan-5-one (6a)

To a salution of 260 mg (2 mmol) epoxide 4a in 5 ml benzene was added 113 mg (1 mmol) boron trifluoride etherate at 5°. After 1 min the reaction was quenched by the addition of ether and water. The organic layer was dried and concentrated to yield after chromatography 210 mg (80%) of pure 6a, mp 174.5-177.50.

IR (KBr): 1735 cm- 1, C=O. NMR (CDC1 3): ó 0.90 (s,3,C~3 ); 1.00-3.10 (m,15,aliphatic protons); 6.93 (AB pattern,2,Th-~).

• 413-Methyl-13, 12- ~] thienotricyclo [7. 4. 0. 04 ' 8] tridecan-5-one (6b)

- 0 Preparedas for 6a, mp 137.5-140.0. NMR (CDC1 3): ó 0.90 (s,3,C~3 ); 1.05-3.05 (m,15,aliphatic protons); 6.80 (AB pattern,2,Th-~).

69

Referenaes and Notes

1. All tetracyclic compounds consist of a racemie mixture (a pair of enantiomers).

2. R.B. Woodward and R. Hoffmann, The conservation of Orbital Symmetry, Academie Press lnc., New York (1970).

3. G. Berti, F. Bottari, A. Marsili, I. Morelli and G. Mandelbaum, Tetrahedron Letters, 529 (1968).

4. J. Bascoul and A. Crastes de Paulet, Bull. Soc. Chem. Fr., 189 (1969).

5. J.R. de Dobbelaere, Thesis Eindhoven (1976); P. van Pelt, Thesis Eindhoven (1975).

6. J.W. Cornforth, Angew. Chem., ~. 903 (1968). 7. J.B. Stothers, Carbon-13 NMR Spectroscopy, Academie Press,

New York (1972). 8. D.K. Dalling and D.M. Grant, J. Amer. Chem. Soc.,~.

1827 (1974). 9. J.W. de Haan, M.E. van Dommelen and L.J.M. van de Ven,

submitted for publication. 10. E.L. Eliel, W.F. Bailey, L.D. Kopp, R.L. Willer, D.M.

Grant, R. Bertrans, K.A. Christensen, D.K. Dalling, M.W. Duch, E. Wenkert, F.M. Schell and D.W. Cochran, J. Amer. Chem. Soc.,~. 322 (1975); W. Kitching, M. Marriott, W. Adcock and D. Doddrell, J. Org. Chem., !:!_, 1671 (1976); J.B. Lambert, D.A. Netzel, H. Sun and K.K. Lilianstrom, J. Amer. Chem. Soc., 2!, 3778 (1976).

11. E.L. Eliel, V.S. Rao, F.W. Vierhapper and G. Zuniga Juaristi, Tetrahedron Letters, 4339 (1976); E.L. Eliel, V.S. Rao and F.G. Riddell, J. Amer. Chem. Soc., 98, 3583 (1976).

12. G. Barbarella, P. Dembach, A. Garbesi and A. Fava, Org. Magn. Res., !, 108 (1976).

13. The 1H-NMR spectrum is identical with the spectrum of the corresponding a-isomer.

70

CHAPTER VI

Quantuin. Inechanical. .calculations on

cyclization reactions: a MIND0/3 study

VI.l Introduetion

In the last decade·s much progress has been made in the development of several Molecular Orbital calculation methods. These methods proved to be very suitable to obtain a more quantitative picture of, for example, structure-reactivity relationships or activatien energies of a reaction. A major drawback, however, lies in the relatively long computing times, necessary for geometry optimization calculations on relatively small and medium-sized molecules. Recently, the MIND0/3 (~odified Intermediate ~eglect of Qifferential Qverlap) pro­gram became available 1 which included an efficient optimiza­tion procedure. This advantage offers the possibility to op­timize large molecules in a reasonable time. The use of the MIND0/3 program for the calculation of the D-C ring ciosure of steroirlal structures (via several routes) afforded a more quantitative picture of the cyclization reactions as outlined in the Sections VI.Z and VI.3.

VI.Z CaZaulations on the cyclization of the 2-but-3-enyl

ayaZopentenyZ cation

In Chapter III the synthesis and ring ciosure of olefinic precursors is discussed, in which the cyclopentenyl cation was generated as an initia tor of the cyclization process. A striking difference was observed between the behaviour of

the (E)- and (Z)-precursors. In order to obtain more informa­tion about the cyclization process, calculations were carried

71

out on the 2-but-3-enylcyclopentenyl cation 2 which can be

derived from 2-but-3-enylcyclopent-2-enol 1 upon treatment

with a proton acidoraLewis acid 2•

H OH

~ 2 3

This compound was chosen as a model system for the D-C ring

closures given in Sectien III.3, since the attack of the cyclopentenyl cation on the double bond may be regarded as

the initia! step in the cyclization process. Although the course of the reaction can be described by several parameters (e.g. bond lengtbs and bond angles), the interatomie distance C(4)-C(9) (for numbering see fig. 6.1) was thought to be the most representative to describe the course of the reaction.

In fig. 6.1 D1 is a dummy atom on the bisactrice of the angle

H(20)-C(9)-H(21) and D2 is a dummy atom in the plane bisecting

the angle C(1)-C(4)-C(5).

14 15 16 19

Fig. 6.1 Atom numbering in cation 2

In view of the calculation technique used, the cyclization

was described as the ring opening of cation ~· First, the heat of formation of ions 2 and 3 was calculated. Optimiza­

tion of the five-membered ring was achieved by varying four parameters (thtr,distances C(1)-C(4), C(4)-C(5) and the angles (1,4,5) and (3,5,4)) with the assumption that the atoms C(1)­C(6) are situated in on~ plane. The atoms C(6)-C(9) are si­tuated in another plane perpendicular to the plane of the

five-membered ring. Changing the dihedral angle gave a slight raise in energy of the system under discussion. The position

of the hydragen atoms is as shown in fig. 6.2.

72

Fig. 6.2 Optimized structures for the open and cyclized c9H13 cation ~

The calculation of ion ~ proceeded in a similar fashion. The cyclohexane nucleus was assumed to have the chair configura­tion. The atoms C(7), C(8) and C(9) were placed in a plane parallel to the plane defined by C(4), C(S) and C(6), in which also the cyclopentene ring was situated (see also fig. 6.2). The five- and six-membered rings have been optimized independently. Data obtained in this way were used to con­struct the geometry of ion l·

In order to keep the number of running parameters as low as possiblè all other calculations were carried out with an "average" five-membered ring (the average of the cyclo­pentene ring in~ and ~). In Table VI.1 the interatomie dis­tances are gathered. Por most other distances and angles standard values have been used (e.g. C(sp3)-C(sp3)=1.54 ~; C(sp 3)-C(sp2)=1.50 R; C(sp2)-C(sp 2)=1.34 ft; C-H=1.08 ~; angle C(sp 3)=109.5°; angle C(sp2)=120°).

Table VI. 1

Interatomie distances in the "average" cyclopentene ring

C(1) C(2) C(3) C(4) C(Z) 1. 54 - - -C(3) 2.40 1.50 - -C(4) 1. 52 2.43 2.30 -C(5) 2.44 2.41 1.39 1.46

As stated, the distance C(4)-C(9) was used to describe the

course of the reaction. By varying this distance the ring opening was simulated. The following parameters were optimized:

73

the distance C(7)-C(8); the angles (6,7,8), (5,6,7), (5,4,9), (22,4,D2) and (8,9,D 1); the rotations around the axis C(S)­C(6), C(6)-C(7), rotation of n1 around the C(8)-C(9) bond and rotatien of C(9) around the C(4)-C(S) bond. In fig. 6.3 the heat of formation (f!H~) is plotted versus the C(4)-C(9) distance for the ring opening of the chair conformation (~)

and for the boat conformation (X) of l· For the boat ring opening (X) the parameters given above were optimized, which resulted in an activation energy of 21.8 kcal/mol; in the case of the chair ring opening the same parameters were optimized except for the angle (5,6,7) and the rotation around the C(S)­C(6) axis. When this rotation was also taken into account the activation energy dropped from 20.6 to 19.2 kcal/mol C•J. The transition state (TS) for the chair cyclization is reached at

a C(4)-C(9) distance of 2.3 R; for the boat cyclization at 2.25 R. During the cyclization some main characteristics of

230

220

210 ~~----------L---------~------~~-------L---------~---1.6 1.6 2.0 2.2 2.4 2.6

---interatomic distance c(4).c(g)(~)

Fig. 6.3 The energy profiles for chair (A) and boat (X) ring opening of l

74

charge density 0.4

1 0.3

0.2

0.1

0.0

1.6 1.8 2.0 2.2 2.4 2.6

--- interatomie distonce c(4)-c(g)(i)

Fig. 6.4 Change of the positive charge on C(3) (A), C(4) (X) and C(8) (•) during ring opening of ~ (boat)

charge density n4

1 0.3

n2

0.1

no

1.6 Hl 2.0 2.2 2.4 2.6

--- interatomie distance c(4)-c(9)(.&)

Fig. 6.5 Change of the positive charge on C(3) (A), C(4) (X) and C(8) (•) during ring opening of~ (chair}

75

intera tomic ( $. ) tSO distance

1 1.45

1.40

1.35

X --

x-x-x x--x x--/ .,.......-x

x-x x •• ".

...............

". ""· ~.

~

\. - interatomie distance c(4)-c(9) --·-·

1.6 1.8 2.0 2.2 2.4 2.6

Fig. 6.6 The course of the distances C(8)-C(9) (Ä) and C(7)­C(8) (X) as a function of the C(4)-C(9) distance during chair ring opening of 1

interatomie ( $_) 1.SO di stance

1 1.45

1.40

1.35

x __ x ____

x-x-x-x ._-x __ x __ x_ ~x

___,...interotomic distance

1.6 1.8 2.0 2.2 2/. 2.6

Fig. 6.7 The course of the distances C(8)-C(9) (Ä) and C(7)­

C(8) (X) as a function of the C(4)-C(9) distance during boat ring opening of l

76

the system underwent a considerable change. In fig. 6.4 and 6.5 the flow of positive charge in the system is clearly demon­strated for the chair and boat ring opening of l· The charge density on the allylic positions C(3) and C(4) drops, while at the same time the charge on C(8) builds up when the reac­tion proceeds. Another characteristic phenomenon is the change in the C(8)-C(9) distance, which goes from a C(sp 2)­C(sp2) bond (1.33 X) toa C(sp2)-C(sp3)bond (1.48 X). A similar change in bond length is demonstrated for the C(7)­C(8) bond (a C(sp3)-C(sp 2) bond). During the cyclization a carbenium ion is generated on C(8). The course of these two distauces is plotted in fig. 6.6 (chair ring closure) and fig. 6.7 (boat ring closure). In Table VI.2 the most essential results for ~ and ~ are gathered as we11 as for the transition states.

Table VI. 2

compound t.H0 f charge density on

(kcal/mol) C(3) C(4) C(5) C(8)

2 217.5 0.235 0.283 -0.072 -0.032 -3 218.6 0.053 0.096 -o. 1 o 7 0.437 -

TS ~. chair 236.7 0.185 0.273 -0.089 0.079

TS ~' boat 239.3 0.165 0.265 -0.095 0.115

In the approach given above the reaction is described using one single parameter (the C(4)-C(9) distance) as the reaction coordinate, while all other ten variabie parameters have been optimized at each step. Another approach has also been tried out, viz. to describe the potential energy surface for the reaction using two rotations around the C(6)-C(7) and C(7)­C(8) honds as main parameters, while all other parameters were optimized in each point. However, the presence of local minima on the surface turned out to be so cumbersome, that

only a crude outline of the energy profile could he establish­ed. Therefore, this approach was abandoned.

77

VI.3 Cyalizations of the (E)-and (Z)-2-pent-3-enylayalo­

pentenyl aation

In the previous Section a baat and chair cyclization of a molecule C.V is discussed, in which no stereochemical problems are encountered. In Section III. 3 a remarkàble difference is observed between (E)-and (Z)-precursors under cyclization conditions. In the literature 3 cyclization of (Z)~olefins is described, although the (Z)-olefins under discussion failed to gi ve tetracyclic structures (Sec ti on II I. 3) under various reaction conditions. In order to obtain more insight in the

cyclization of (E)-and (Z)-alkenes the various cyclization possibilities of the c10 H15 cation 4 were studied (fig. 6.8).

Fig. 6. 8 Cyclization of the different c1 0H1 5 ca ti ons

In Table VI.3 the energies and main charge densities are gathered of the various species. In compound~ one hydragen was replaced by a methyl group to give 4a and 4b, respectively. The energy of these systems was obtained by performing one SCF (§.elf f.onsistent field) calculation; no further optimiza­tions were carried out. The assumption was made that the

transition state for the cyclization of ! + ~was reached at the same C(4)-C(9) distance as for the conversion ~ + l· The transition state of the structures 4a and 4b and the molecules

Sa and Sb were calculated by optimizing the afore mentioned parameters. Note that the cyclization of an (E) compound via

a chair conforination leads to the anti configuration and via

the boat conformation to the syn configuration. A similar

78

Table VI. 3

charge density on

compound t.Ho f (kcal/mol) c (3) C(4) c (8)

4a 208.2 0.234 0.282 -0.063 -4b 211 . 7 0.23S 0.282 -O.OS9 -Sa, chair 216.4 0.062 0. 114 0.419

Sb, chair 217.7 0.064 0. 112 0.414 Sa, boat 2 21.9 O.OS7 0.119 0.413 Sb, boat 217.4 O.OS3 0.094 0.435 4a, TS, chair 228.3 0.183 0.284 0.032

4b' TS, chair 234.7 0.149 0.242 0.084 4a, TS, boat 233.4 0.1 S6 0.2S9 0.083

4b' TS, boat 238.6 0.129 0.252 0.094

argumentation for (Z) alkenes leads to syn products from a chair cyclization and an anti product from the boat conforma­

tion. In Table VI.4 the activation energies are given for the several ring closures.

Table VI. 4

Activation energies for cyclizations (kcal/mol)

compound chair conformation boat conformation

4a 20.1 2S.2 -4b 23.0 26.9 -

The activation energies for the different cyclization pro­cesses (Table VI.4) put the Stork-Eschenmoser hypothesis in

a quite new perspective. The hypothesis states that concerted cyclizations of (E) alkenes yield trans-substituted products,

while (Z) alkenes afford ais-substituted compounds. This

implies, as is confirmed by the calculations and shown in Table VI.4, that vitro product formation will always take

place via the chair conformation (the thermodynamically favoured route) of the generated cyclohexyl cation.

79

In the second postulate of their hypothesis, Stork and Eschenmoser pointed at the role of the enzyme during vivo cyclizations. It is assumed (Section 111.6), that before cycli­

zation of 2,3-epoxysqualene takes place, the molecule is folded by the enzyme in a chair-boat-chair conformation, which pro­motes the formation of protolanosterol. Thus, the B-ring formation proceeds in an energetically unfavoured way (if the enzyme-substrate interaction is nottaken into account), for an (E)-alkene (e.g. 2,3-epoxysqualene) is cyclized in a boat conformation. These calculations substantiate once more the essential role of the enzyme-substrate interaction. It should be borne in mind, however, that all calculations were performed with total neglect of solvation energy. Consequent­ly, these calculations can only serve as a quanturn chemica! model.

80

Referencee and Notes

1. R.C. Bingham, M.J.S. Dewar and D.H. Lo, J. Amer. Chem. Soc., 21, 1285 (1975).

2. A closely related system has been cyclized by W.S. Johnson, see reference 3.

3. W.S. Johnson, Acc. Chem. Res., l, 1 (1968).

81

Suininary

This thesis deals with the syn.thesis of some thiophene

analogues of the hormone estrone. An important aspect of the reaction is the concerted cyclization of the appropriate polyene leading to the tetracyclic skeleton. Such a process

is observed in the enzymatically controlled synthesis of steroids from which the conversion of squalene into lanosterol

is the best known. The preparation of alkenes occurs via the Wittig-Schlosser

reaction. A reinvestigation of this reaction revealed that

the product distribution depends on the base used and the presence of salts. When phenyllithium is used as base, (E)­alkenes are formed predominantly, whereas the use of n-butyl­lithium mainly results in the formation of (Z)-alkenes. The

(E)-alkenes cyclized to tetracyclic structures in contrast to the (Z)-alkenes which, even under the most widely divergent reaction conditions, failed to cyclize.

The (E)-alkenes, formed in the Wittig-Schlosser reaction, are contaminated with 5-10~ of the (Z)-isomer. This could be overcome by the development of another synthetic route. The key step in this sequence is the Wadsworth-Emmons reaction which is based on the reaction of stabilized phosphonoacetate anions with aldehydes or ketones with formation of (E)-alkenes exclusively. The synthesis of the desired (E)-olefins can also be achieved via a Claisen rearrangement. This approach offers a general route to steroids with a heterocyclic A­ring.

The conversion of the tetracyclic alkenes to the estrogen­

like compounds proceeds via the epoxides. This reaction ap-

82

pears to be fully dependent on the geometry of the molecule: treatment of the ~-epoxide with BF3 resulted in a ~'~ methyl shift from C(17) to C(13) (steroidal numbering) with forma­tion of the estrone derivative, whereas from the B-epoxide a mixture of dienes is isolated under the same reaction condi­tions, resulting from a [1 , 2) hydrogen shift from C ( 14} to C(13}. These [1 ,2] shifts proceed suproafaaial'Ly. Therefore, the selectivity of these reactions can be explained by the fact that in the a-epoxide the hydrogenatom is sterically hindered by the BF3-complexated oxygen atom. Due to the absence of steric hindrance, the methyl shift can easily occur. In the a-epoxide the U • z] hydrogen and the 6 , 7J me­thyl shift are competitive. In this case the hydrogen shift predominates.

The transsanti,trans geometry at the junction carbon atoms is proved by comparison of the 13c-NMR data of the tetracyclic compounds with those of estrone acetate and with model compounds.

finally, quanturn mechanica! calculations (MIND0/3) are performed on model systems for the D-C ring closure, as takes place in the above described cyclization process. It is shown that for cyclizations in the chair configuration a lower activation energy is necessitated than for ring closures in the boat configuration. An analogous picture is found by the comparison of (E)- and (Z)-alkenes. Cyclization of the (E)-alkene in the chair or boat configuration is energeti­cally favoured over the ring closure of (Z)-alkenes. These results are in agreement with the Stork-Eschenmoser hypo­thesis.

83

SaiDenvatting

In dit proefschrift wordt de totaalsynthese beschreven

van thiofeen-analoga van het hormoon oestron. Een belangrijk aspect van deze bereiding is de reactiestap, waarbij het tetracyclisch basisskelet van deze structuren in een stap

wordt gevormd (de olefinische cyclisatie). Op deze wijze wordt in de natuur op enzymatische wijze een aantal steroïden bereid. De bekendste omzetting van dit type is die van

squaleen naar lanosterol. De bereiding van ~lkenen verloopt via de Wittig-Schlosser

reactie. Bij nader onderzoek van deze reactie bleek de geo­metrie van het gevormde product afhankelijk te zijn van de gebruikte base en van de aanwezigheid van zouten. Bij het ge­bruik van fenyllithium als base vindt overwegend (E)-alkeen­vorming plaats, terwijl bij n-butyllithium als base voorname­lijk (Z)-alkenen worden geïsoleerd. De (E)-olefinen cycliseren tot de tetracyclische structuren in tegenstelling tot de (Z)­

alkenen, welke zelfs onder de meest uiteenlopende reactie­omstandigheden niet ringsluiten.

De {E)-alkenen, die gevormd worden tijdens de Wittig­Schlosser reactie, zijn echter steeds verontreinigd met 5-101 (Z)-isomeer. Dit probleem werd ondervangen door het ontwikke­len van een nieuwe syntheseroute. De sleutelstap hierbij is een Wadsworth-Emmons reactie, welke verloopt via gestabili­

seerde fosfonoacetaat anionen. Uitsluitend (E)-alkenen worden

onder deze reactieomstandigheden gevormd. De synthese van de benodigde (E)-olefinen bleek ook mogelijk via een Claisen omlegging. Hiermee is de mogelijkheid geboden voor een alge­

mene syntheseroute van steroïden met een heterocyclische A-

84

ring. De omzetting van de tetracyclische alkenen naar de

oestrogene verbindingen vindt plaats via de overeenkomstige epoxiden. Deze reactie blijkt geheel afhankelijk te zijn van de geometrie van het molecule: in het a-epoxide treedt onder invloed van BF3 een ~~~methylverhuizing op van C{17) naar C(13) (steroïde nummering) onder vorming van de oestron­derivaten, terwijl het a-epoxide onder analoge omstandigheden een mengsel van diënen geeft ten gevolge van een G ~~water­stofverhuizing (van C(14) naar C(13)). Deze G,~verhuizingen vinden suprafaciaal plaats. De selectiviteit kan daarom ook worden verklaard door het feit, dat in het a-epoxide het waterstofatoom sterisch gehinderd wordt door het met BF3 gecomplexeerde zuurstofatoom. De optredende methylverhuizing kan dan ongehinderd plaatsvinden. In het a-epoxide zijn de waterstof- en de methylverhuizing concurrerende reacties. De waterstofverhuizing heeft hier dan de voorkeur.

De t~ans,anti,trans geometrie in de hierboven besproken tetracyclische verbindingen kon worden vastgesteld met behulp van 13c-NMR spectroscopie door het onderling vergelijken met het oestron acetaat enerzijds en met een modelverbinding anderzijds.

Tenslotte zijn quanturnmechanische berekeningen (MIND0/3) uitgevoerd aan modelsystemen voor D-C ringsluiting, zoals deze plaatsvindt bij het hierboven vermelde cyclisatieproces. Hierbij is aangetoond, dat voor de cyclisaties in de stoel­vorm een lagere activeringsenergie nodig is dan voor ring­sluitingen via de bootvorm. Een analoog beeld is verkregen bij het vergelijken van (E)- en (Z)-alkenen. Voor de ring­sluiting van een (E)-alkeen in de stoel- of bootvorm is even­eens een lagere activeringsenergie nodig in vergelijking met het (Z)-alkeen. Deze resultaten zijn in overeenstemming met de hypothese van Stork en Eschenmoser.

85

Levensloop

De schrijver van dit proefschrift werd geboren op 20 januari 1950 te Eindhoven. Na het behalen van het diploma HBS-B aan het St. Joriscollege te Eindhoven werd in het­zelfde jaar begonnen met de ingenieursstudie op de afdeling der Scheikundige Technologie aan de Technische Hogeschool Eindhoven. Het kandidaatsexamen werd in september 1970 afge­legd. In september 1972 behaalde hij met lof het ingenieurs­diploma met als afstudeerrichting Organische Chemie.

Vanaf 15 september 1972 tot 1 februari 1977 was hij als wetenschappelijk medewerker verbonden aan het laboratorium voor Organische Chemie. Het in dit proefschrift beschreven onderzoek werd gestart in maart 1974 onder leiding van prof. dr. H.M. Buck.

86

Dankwoord

Bij het onderzoek, dat geleid heeft tot dit proefschrift, hebben velen een bijdrage geleverd door middel van hulp bij de synthese van verbindingen, het interpreteren van spectra en het uitvoeren van quanturnmechanische berekeningen ener­zijds, en door middel van het geven van suggesties anderzijds. Voor al deze hulp ben ik hen zeer erkentelijk.

Verder zou ik mijn dank willen uitspreken tegenover diegenen, die een bijdrage hebben geleverd tot de uiteinde­lijke vormgeving van dit proefschrift.

87

88

Stellingen

1. De NMR gegevens van het complex van bicyclo ~.2.Dnona-2,4,7-trien-9-on met SnC1 4 zijn ontoereikend voor een structuurtoekenning.

A. Diaz, J. Fulcher, R. Cetina, M. Rubio en R. Reynoso, J. Org. Chem., 40, 2459 (1975)

2. De reactiviteit van 3-(1' ,3' ,3'-trimethyl-2'-ketocyclo­hexyl)-propionzuur is uitstekend verklaarbaar indien een evenwicht met het overeenkomstige intramoleculaire lactol wordt verondersteld.

W.L. Meyer, G.B. Clemans en R.A. Manning, J. Org. Chem., 40, 3686 (1975)

3. Het feit, dat het fenyl- en het 1-bicyclo ~.2.~ hexa-2,5-dienylkation niet zijn aangetoond bij de omlegging van het (3-cyclo-prop-1-enyl)cyclopropenylkation, kan met behulp van orbital isomerie worden verklaard.

R. Weiss en S. Andrae, Angew. Chem., 86, 276 (1974)

4. Bestudering van industriële ontzwavelingskatalysatoren, zoals het met zwavel verrijkte Co0-Mo03-y-Al 20 3 systeem, dient in situ plaats te vinden.

P.C.H. Mitchell en F. Trifiro, J. Catal., 33, 350 (1974)

s. Bij de vivo cyclisatie van (S}-2,3-epoxysqualeen tot

lanosterol kan de 3a-positie van de hydroxylgroep door geometrische factoren worden bepaald.

6. De door Gotthardt en Hammond verkregen hoofdcomponenten bij de bestraling van cyclodeca-1,5-dieen zijn beter thermisch dan fotochemisch te verklaren.

H. Gatthardt en G.S. Hammond, Chem. Eer., 109, 3767 (1976)

7. De verhoogde solvolysesnelheid van het anti-9-tricyclo-~.2.1.02•5] nona-3,7-dienyltosylaat ten opzichte van

anti-7-norbornenyltosylaat moet eerder worden gezocht in de a-bijdrage van de C(1)-C(2) binding dan in een homo­conjugatie met het u-systeem van het norbarneen gedeelte.

L.A. Paquette en I.A. Dunkin, J. Amer. Chem. Soc., QI, 2243 (1975)

8. De door Lautenschlaeger veronderstelde intermediairen bij de additie van SC1 2 op norbornadieen geven geen verklaring voor de selectiviteit van de reactie.

F. Lautenschlaeger, J. Org. Chem., ~. 1679 (19~6)

9. Het gebruik van CH2=14cH-CH3 bij de met Bi 2o3-Mo0 3 gekata­

lyseerde oxidatie van propeen tot acroleine geeft geen extra inzicht in het mechanisme van dit proces.

rd W.M.H. Sachtler en N.H. de Boer, Proc. 3 Int. Congres on Catalysis Amsterdam, North Holland Publ. Cy., 1975, Amsterdam

10. De door Soják en anderen op grond van gaschromatografisch gedrag voorgestelde voorkeursstructuren van 1-penteen derivaten zijn strijdig met resultaten van spectra­metrische technieken en van krachtveldberekeningen.

L. Soják, J. Hrivnák, P. Majer en J. Janák, Anal. Chem., !i• 293 (1973)

11. De opleving van het Nederlands in Frans-Vlaanderen, de oudste haard van de Nederlandse taal en cultuur, dient door de Nederlandse en Belgische overheid gesteund en begeleid te worden.

12. De benaming "Limburg 11 voor het noordelijke deel van deze Nederlandse provincie is onjuist en dient bij een even­tuele provinciale herindeling van Nederland te worden gewijzigd in een historisch meer verantwoorde benaming.

13. Het opnemen van vreemde woorden in het Nederlands moet eerder als een verarming dan als een verrijking van deze taal worden beschouwd.

A. Corvers Eindhoven, 4 maart 1977