CHAPTER IV SYNTHESIS OF (4S1 5S)-4-(2...
Transcript of CHAPTER IV SYNTHESIS OF (4S1 5S)-4-(2...
CHAPTER IV
SYNTHESIS OF (4S1 5S)-4-(2-HYDROXY-2,2-DlARYL ETHYL)-2,2-DIMETHYL-aIaIawIa'-TETRLL ARYL-1,3-
DIOXOLANE-4,5-DIMETHANOLS AND THEIR CATALYTIC STllDlES
IV.l Introduction
One of the most important breakthroughs in chemical technology in the last
few decades is the enantioselective synthesis of chiral organic compounds via
asymmetric catalytic reaction. Many recent synthetic applications of asymmetric
synthesis are linked to asymmetric catalysis.z In the field of asymmetric catalysis
spectacular progress has been made by using homogeneous catalysts based on
transition metal complexes modified by chiral ligands. Homogeneous
organometallic catalysts can function with ligands like phosphines, alcohols,
amines, arnides, sulphoxides and cyclopentadienyl groups. Examples of reactions
that are successfully investigated in the recent past are hydrogenation, double-
bond migration, hydrosilylation, hydroformylation, olefin codimerisation,
hydrocyanation, coupling between a Grignard reagent and vinylic halide, allylic
alkylation, Diels-Alder reaction, epoxidation and cyclopropanation.
Although acid and base catalysts are widely used to accelerate organic
reactions, the development of chiral base and acid catalysts was a relatively
unexplored area in organic synthesis. However in the last few years, remarkable
progress has been observed in this area. Typial examples are the Sharpless
asymmetric epoxidation,'41 the ketene addition reaction,'42 phase transfer
catalysis143 and proline-catalysed intramolecular aldol c~ndensa t ion . '~~ The
development of chiral Lewis acids and bases is now the subject of intense
research.
IV.1.1 Chiral Hydroxy Compounds used as Iigands or chiral precursors in Asymmetric Synthesis
It is evident from the review (Chapter 1) that, a number of monodentate,
bidentate and polydentate alkoxide ligands have been developed in recent years.5
The most successful strategy for preparing metal alkoxides for use as asymmetric
catalyst has been to employ diols or polyols, so that the metal centre is stabilised
vla chelation. Some of the frequently used alkoxide ligands are listed below
(FigIV. 1).
Fig IV.l
Chiral hydroxy acids such as Tartaric acid, Malic acid, Lacticacid etc
present an attractive source from the chiral pool for the preparation of chiral
synthons (Scheme IV. 1). loo, 145.148
0 HOOC COOH R,o'p; ::- tartaric acid
R2O J \ Ts 0 --OTs
0
Scheme IV.l
A variety of chiral agents derived from hydroxy acids have been widely
used in asymmetric reactions such as Diels-Alder reaction, 2+2 cycloaddition
reactions, Sharpless asymmetric epoxidation, Addition of EtzZn to aldehydes etc.
In many cases only the backbone is left unchanged while the OH andlor the
COOH groups are protected or transformed to give efficient ligands. Some
homogeneous chiral catalysts derived from tartaric acid are listed below
(Fig 1v.21.~
Diels-Alder reaction Epoxidation of ally lic alcohols Oxidation of sulphides
Hy drosily lation of ketones Hy drobomtion of olefms
Use of chiral amino diols as ligands in various asymmetric catalytic
reactions have been reported recently (Fig IV.3). 149-151
M e ... I MC / Ti p h y N ~ f" \,,.ph /sm
OH OH 01 OH
Asymmetric epoxidation of Asymmetric MPV reduction substitutd ally1 alcohol of q l methyl ketones
Stereovelective reduction of prochiral ketones
Fig IV.3
Recently this laboratory has established chiral triesters prepared from
Garcinia acid 156 and Hibiscus acid 157 as efficient chiral diol ligands in
asymmetric Sharpless epoxidation reaction (Scheme 1 v . 2 ) ' ~ ~
Garcinia acid triester ,,:::o -
(CH,),COOH, T(OiPr), (S,S)-Epoxygeraniol
CH2C12, - 2 0 ' ~
:ti: Hibiscus acid tries ter J ..'.,,,/OH
Scheme IV.2
Chiral acetals and ketals act as efficient chiral auxiliaries in asymmetric
synthesis by influencing the face selectivity of a proximal prochiral centre. In the
pharmaceutical, phytopharmaceutical, fragrance and lacquer industries, acetals are
used both as intermediates and as end products.'52
A large array of chemical transformations have been investigated with the
acetal auxiliary in various relative positions to the prochiral centre, either on the
nucleophile or on the electrophile. Perhaps, the most simple conceptual approach
to reaction where the chiral acetal is on the electrophile is the attack of a carbonyl
group next to a chiral acetal (Scheme I V . ~ ) . " ~
R=MeorPh L W 83
LiAM4~gSr2 9
R = -CH20Me L I A h Y 9
Scheme IV.3
The diastereoselective reaction of a chiral nucleophile having an acetal
appendage are very scarce. Thus ketene acetals have been used in asymmetric
synthesis, with diphenyl 1,2-ethane dial seeming to be the best auxiliary in
cycloaddition reactions, as well as in conjugate addition-enolate trapping reactions
(Scheme IV.4).
Ph 1) EtLi -
Ph
1 10
Scheme IV.4
N. 1.2 Asymmetric Diels-Alder Reactions
Efficient synthesis of enantiomerically pure and structurally complex
molecules by inducing asymmetry in carbon-carbon bond forming reactions has
been a great challenge for organic chemists. Among the several methods available
for asymmetric induction during such carbon-carbon bond forming reactions, the
Diels -Alder reaction deserve special mention. After its discovery in 1928, the
Diels-Alder transformation was often said to be the most powerful tool in the
carbon-carbon bond forming reactions in organic synthesis. This transformation
formally belongs to the general class of pericyclic reactions and is a [ 4 ~ + 2 ~ ]
cycloaddition of an electron-rich diene to an electron-poor dienophile. The
importance and usefulness of Diels-Alder reaction arises from the high regio and
stereoselectivity, as well as from the possible use of numerous dienes and
dienophiles bearing a large number of functional groups.
A useful development became possible when it was found that Lewis acids
catalyse the Diels-Alder reaction, allowing to run it in very mild conditions, even
below o'c. '~~ The activation process occurs by coordination of the carbonyl group
of dienophile to the Lewis acid. Chiral auxiliaries of various kinds have been
subsequently developed for thermal or catalytic Diels-Alder reactions, and some
of them are now commercially available. The development of asymmetric Diels-
Alder reaction using metal alkoxide as a catalyst has attracted attention in the
recent literature. The enantioselection of the products depends on the absolute
configuration of the chiral auxiliary residing either in the substrate or in the ligand
on the catalyst. In the substrate control method, the chiral auxiliary is a part of the
diene or dienophile and this method needs separate steps for incorporation and
subsequent removal of chiral auxiliary. These factors can be overcome by
employing chiral catalysts. In metal catalysed asymmetric Diels-Alder reaction,
the source of chirality is manifested by the ligand. This approach not only
eliminates the need for incorporation and removal of the chiral auxiliary, requires
only catalytic amount of the chiral source.
Lewis acids
Frontier Molecular Orbital theory, in addition to predicting endoiexo
selectivity can also explain the role of Lewis acid as a catalyst in Diels-Alder
r e a ~ t i 0 n . l ~ ~ Interaction of chiral lewis acid with a dienophile lowers the energy of
both LUMO and HOMO of the reactant resulting in lower activation energy for
the reaction. In majority of Diels-Alder reactions, the addition of Lewis-acid also
results in maximum selectivity which can be explained as follows. Increase in
reation rate that allows the reaction to be run at lower temperatures and this in turn
allows for differentiation in the diastereomeric transition states. The increase in the
selectivity also depends on the type of complex formed between the Lewis acid
and the dienophile prior to cycloaddition. Often times, bare Lewis acids like TiCI,
or A1C13 can induce polymerisation, react with functional groups andlor accelerate
substrate decomposition. To avoid such undesirable side reactions, sometimes the
metal chlorides have been replaced by the corresponding alkoxides.
In 1979, Koga first reported the use of optically active Lewis acids in
organic reaction^.^ Since then this exciting field of reagent controlled asymmetric
process has shown impressive development and several comprehensive reviews
have been published recently. 153,155
Though it is possible to develop effective chiral Lewis acid catalysts for the
Diels-Alder reaction, simple application of the chiral Lewis acids itself only
achieved moderate asymmetric i n d ~ c t i o n . ' ~ ~ Hence it is necessary to design chiral
auxiliaries that will interact with the Lewis acid to realize high asymmetric
induction.
Chiral Titanium Reagents
Chiral alkoxy titanium complexes prepared from chiral diols have been
used as chiral Lewis acids for the Diels-Alder reaction. Stochiometric amounts of
titanium complexes were first utilised, enantiomeric excesses in the range of
90-95% have been achieved in the condensation of cyclopentadiene and some
specific acrylamides and crotonamides.
Seebach et at and Narasaka et a1 24 found that a class of crotonam~des
(3-acyl-l,3-oxazolidin-2-ones) reacts wtth cyclopentadiene to give cycloadducts in
presence of some titanium complexes (Scheme IV.5). The titanium complexes
(2 mol equiv) were prepared from equimolar amounts of a chiral 1,4-diol
(TADDOL) derived from diethyl tartrate and TiC12(0i-Pr)2 The 3-acyl-1,3-
oxazolidin-2-one have been chosen because they should form a bidentate complex
with chiral titanium complex, resulting in increased stereoselectivity during the
Diels-Alder reaction. Indeed the major product (endo isomer) was obtained with
92% ee. . -'
Scheme IV.5
Narasaka et a1 made the interesting observation that 4 ~ " molecular sieves
allow the use of catalytic amounts of a dialkoxy dichloro titanate, keeping the
enantioselectivity at the level of 90% (close to the ee of the stoichiometric
reaction) (Scheme IV.6). 157, 158
Scheme IV.6
The beneficial effect of molecular sieves was ascribed in part to the
removal of water from the reaction mixture. The same authors found that alkyl
benzenes are excellent solvents for enhancing stereoselectivity of cycloadducts.
Mechanistic Aspects
It is well known that enone dienophiles can be activated by Lewis acids in
catalytic asymmetric Diels-Alder reactions, with improved regio and
stereoselectivity, when compared to that of uncatalysed reactions. The reason for
achieving high enantioselectivity in chiral Lewis acid catalysed Diels-Alder
reaction are not well studied. So, in order to understand the mechanism of
asymmetric induction, the conformational relationship between the chiral auxiliary
and the reaction site as well as the solution structure of Lewis acid-carbonyl
complexes must be elucidated.
Narasaka el al. studied the structure of the titanium complex involved in
scheme 1 v . 6 . ' ~ ~ The 'H NMR investigation gave some structural information on
the single species formed by mixing of the chiral diol and TiClz(Oi-Pr)2. However
it could not be decided if the complex is monomeric or dimeric. The chiral
titanium complex is in equilibrium with the chiral diol, TiC12(Oi-Pr)2 and
2-propanol. It could be seen that addition of molecular sieves (MS 4A) shifts the
equilibrium to the side of the chiral titanium complex. The simultaneous increase
in enantioselectivity comes from a decreased concentration of TiC12(Oi-Pr)2 which
can by itself catalyse the Diels-Alder reaction. It was also found that the
dienophile (3-acyl-l,3-oxazolidin-2-one) and the chiral titanium complex has been
isolated and seems to be the key intermediate in the cycloaddition. Corey et al.
investigated modified titanium catalysts for elucidating the origin of the high
enant iose le~t iv i t~ .~~ A strong influence of groups in meta position of aromatic
rings led the authors to propose the transition state represented in fig. IV.4.
Attractive a-a interactions between a donor aromatic group and the double bond
of the dienophile protects one face and provides high ee.
Fig. IV.4
With this background, preparation of optically pure (4S,5S)-4-(2-hydroxy-
2,2-diary1 ethyl)-2,2-dimethyl-a,aCLa',a'-tetraaryl-l,3-dioxolane-4,5-dimethanols,
which resemble very much with TADDOL have been carried out starting from
trimethyl ester of Garcinia acid. 1,2-Diol moiety of trimethyl ester is protected and
the resulting ketal on Grignard reaction with appropriate reagents furnished the
corresponding -4-(2-hydroxy-2,2-diary1 ethyl)
compounds have been used as efficient chiral iigands i
Diels-Alder reaction of 3-crotonyl oxazolidinone and cyclopentadiene.
IV.2 Results and discussion
N.2.1 Preparation of Trimethyl Ester and Ketal from Garcinia acid
Having two chiral centres and a vicinal diol moiety triesters of Garcinia
acid are expected to find extensive application in asymmetric reactions. The
procedure developed by Ibnusaud and co-workers has been followed for the
preparation of triester.I6O
Treatment of 156 with aqueous sodium hydroxide under refluxing
conditions, followed by the addition of alcohol furnished the highly hygroscopic
trisodium salt 166 (Scheme IV.7).
NaOH 156 - NaO2C
MeOH HO OH
166
Scheme IV.7
A suspension of 166 in appropriate alcohol on refluxing with thionyl
chloride, readily furnished the corresponding triester in good yield and purity
(Scheme IV.8).
SOClz 166 - Mc0,C
MeOH HO OH
167
Scheme IV.8
Protection of vicinal diol moiety of the triester is necessary for further
transformations like Grignard reaction, alkylation etc. Attempts to prepare ketal of
triester following conventional procedures161 were futile as the molecule
underwent lactonisation. This could be due to the fact that conditions for ketal
formation are ideally suited for lactonisation also. The difficulty for the
preparation of acetonide was overcome by following a reported modified
procedure.'62 A solution of triester in acetone is refluxed in the presence of
anhydrous copper sulphate and catalytic quantity of concentrated sulphuric acid.
Workup of the reaction after about four hours, furnished the acetonide 168
(Scheme IV.9).
M a 2 c p e pa..... Anhyd CuS 0,
M a 2 C - Me0,C + HO OH Acetone, H
168
Scheme IV.9
In the case of 168 the yield obtained was very poor (22%) and to improve
the yield, the acetonide formation was tried with 2,2-dimethoxy propane and
catalytic amount of p-toluene sulphonic acid in dry benzene. Even then the
hydrolysis of the triester followed by regular lactonisation was observed.
Protection of vicinal hydroxyl groups of triester using acetophenone dimethyl
acetal also was attempted. However, the ketal formed was found to be
decomposing during isolation.
N.2.2 Preparation of (4S,5S)-4-(2-hydroxy-2,2-diaryl ethyl)- 2,2-dimethyl-a,a,a9,a'-tetraaryl-1 ,3-diawo lane-4,5- dimethanols
Starting from optically active dialkyl tartrates, Seebach and co-workers
have prepared a,a,a',a'-tetra aryl-1,3-dioxolane-4,5-dimethanols (TADDOLs,
169) and used them as efficient chiral ligands in various asymmetric reactiom5
The ketd of diethyl tartrate on Grignard reaction with appropriate aryl magnesium
halide furnished the corresponding TADDOL (Fig. IV.5, Scheme IV. 10).
Scheme IV.10
With the objective of obtaining (4S,SS)-4-(2-hydroxy-2,2-diaryl ethyl)-2,2-
dimethyl-a,a,a',a'-tetraaryl-1,3-dioxolane-4,5-dimethanols, 170a-c, Grignard
reactions on 168 have been carried out following the general method developed by
Seebach et a1 for the preparation of TADDOL using diethyl tartrate. By refluxing
a solution of ketal (168) with appropriate aryl Grignard reagent in dry
tetrahydrofuran furnished 170a-c as oily mass (Scheme IV. 1 1). The formation of
these compounds are thoroughly confirmed by IR, 'H NMR, I3c NMR and Mass
spectra (Fig IV.6, IV.7 & IV.8).
170a : AF pheny I 170b : Ar=4-methy 1 pheny 1
Scheme IV.l l 17Uc : AFI-naphthy 1
The IR,'H NMR and I3c NMR data clearly reveal the absence of carbonyl
group. "C NMR spectra show the expected signal characteristic of the C-2 carbon
of the 1,3-dioxolane ring at -1 15 ppm. Peaks at 6 1.25-1.55 ppm in the 'H NMR
and at -23 ppm in the I3c NMR indicate the methyl groups attached to the
dioxolane ring. The AB pattern in the 'H NMR at 6 3.3 ppm and 3.1 ppm confirms
the presence of methylene group. Peaks around 77-80 ppm indicates the tertiary
carbon atoms as well as C-4 and C-5 of the dioxolane ring. Aromatic protons give
peaks at 7.6-7.23 and aromatic carbon atoms are confirmed by peaks 127-146 in 13 C NMR. These molecules show corresponding molecular ion peaks in the fast
atom bombardment mass spectra at mlz, 662,746 and 962 respectively.
4;s 1:s i j r &it ;b" '4ao' 450 "' rbo 350 E i - % h o o
Fig. IV.6a
Fig. IV.6b
Fig. IV.6c
Fig. IV.6d
- -- -.--.-. ~ ,--- r ---
* / -
-7 cc ,~~ 2 c I
I
L . - L , . L -c u 170b I>
d O O 0 2 0 0 0 1 6 0 0 1 2 0 0 8 0 0 100
W A V E NUMBER I C ~ - I I 1 Fig. IV.7a
, .? -- , -- Fig. IV.7c
.ear--- ib5 -n . . 1 1
d l * , - !
cr___? ..--- 488 U 5 l 582 SUil 6ZB 78P 756 I,L
, Fig. lV.7d
N.2.3 Asymmetric Diels-Alder reaction employing (45, 5s)-4- (2-hydrawy-2,2-diaryI ethyl)-2,2-dimethyZ-aya,ay,a'- tetraawl-1,3-diarolane-4,5-dimethanols as chiral Zigands
Although large number of asymmetric Diels-Alder reactions are known,
greater degree of asymmetric induction can occur with chiral Lewis acids having
Cz-symmetric diols as chiral ligands. To explore the efficiency of (4S,5S)-4-(2-
hydroxy-2,2-diarylethyl) - 2, 2 - dimethyl - a, a, a', a' - tetraaryl -1,3-dioxolane-
4,5-dimethanols as chiral ligands, asymmetric Diels-Alder reactions using these
ligands which lacks Cz- symmetry have been considered.
An examination of the structure of these triols show that the molecular
topology matches with TADDOL derived from dialkyl tartrate except the fact that
C-4 hydrogen is replaced by CHZ-C(Ar)Z-OH. Therefore these triols are nothing
but -4-(2-hydroxy-2,2-diarylethyl) TADDOLs. Hence it is a curiosity to study the
employment of 170a-c as chiral ligands in asymmetric organic reactions.
Therefore a preliminary study was undertaken to assess the influence of
chiral ligands 170a-c derived from 156 on chiral induction in asymmetric Diels-
Alder reaction of 3-crotonyl oxazolidinone and cyclopentadiene. 170a-c are used
as chiral ligands for the preparation of titanium complexes which were used as
catalysts in place of TADDOL-titanium complex. Chiral titanium reagents are
prepared insitu by mixing chiral triols 170a, 170b or 170c and
dichlorodiisopropoxy titanium in toluene at room temperature. Diels-Alder
reaction was carried out using catalytic amount of the titanium reagent. The best
solvents for the Ti-TADDOLate-mediated Diels-Alder reactions are those with
poor donor ability, such as toluene, petroleum ethers, methylene chloride or
mixtures thereof, For the addition of 3-crotonyl oxazolidinone to cyclopentadiene
toluene is the solvent of choice. Hence the reaction is carried out in toluene in
presence of 4 ~ ' molecular sieves.
Scheme IV.12
Fig. IV.9
The reaction proceeded smoothly leading to the formation of endo and exo
cyclo adducts, 171 (Scheme IV.12). The major endo adduct was purified by silica
gel chromatography. The adduct has shown optical activity in each case ( [aID = -
22.96, -16.05 and -13 respectively). This indicates a feasibility of using (4S,5S)-4-
(2-hydroxy-2,2-diary1ethyl)-2,2-dimethyl-a,a,ct',a'-tetraaryl-1,3-dioxolane-4,5-
dimethanols 170a-c as chiral ligands in place of TADDOL. The possible transition
state complex involving 170 is shown in Fig.IV.9. A control Diels-Alder reaction
using TADDOL 169 as chiral ligand was also carried out under identical
laboratory conditions.
Enantiomeric excesses of the endo products were calculated from the
maximum specific rotation values available in the 1 i te ra t~re . l~~
The recorded [a] 0 values and the calculated enantiomeric excesses (ee) of
the endo adducts are given in Table IV.1. The adducts were identified using 'H
and "C NMR spectra (Fig IV. 10, IV. 1 1 &IV. 12).
Table IV.1
Enantiomeric excess (%)
170b
1 7 0 ~
~ e ~ o r t e d ' ~ ~ [ a ] ~ value of 171 when TADDOL (169)
was used as ligand: -191'
-16.058 ~-rL‘%7 -13.000 6.80
171
Ligand used 170a
Fig. IV.l Oa -. . . , . .-.
>"
, . . . . - , , - .~ - .- . -. r- . , --.-- 2 ° C 18,; 16. 140 12. 10. 8 : 3 4. ,3 A ppi ~ Fig. IV.lOb
-.---. --,.-.T.--.-- -. , . .- --.- I 0 6 I I 0 pvm Fig. IV. l la
In conclusion novel triols 170a, 170b and 170c derived from (2S,3S)-
tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid, 156, (Garcinia acid) have
been used as chiral ligands in asymmetric Diels-Alder reactions. The enantiomeric
excesses observed are significant as these chiral ligands are devoid of Cz-
symmetry. However a detailed investigation on the feasibility of using these
ligands in various catalytic systems is required.
IV.3 Experimental
Trisodium (1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate (166)
To an aqueous solution of 156 (1.0 g, 5.25 mmol, in 5 ml water), 2N of
sodium hydroxide solution was added at about 80" C, till reaction mixture is
alkaline (- pH = 9.0). The residue obtained after evaporation under reduced
pressure, was triturated with dry methanol (5 x 25 ml). The solid obtained was
finally dried under vacuum.
Yield : 1.1 g(76.5%)
'H NMR (DzO) : 6 4.08 (s, lH), 3.36 (s, lH), 2.82(d, J = 15.9 Hz, lH), 2.71 (d, J = 15.9Hz, 1H)ppm.
Trimethyl (1S,2S)-1,2-dihydroxy-l,2,3-propanetricarboxylate (167)
To a suspension of 166 (1.0 g, 3.65 mmol) in dry methanol (I0 ml), thionyl
chloride (1.5 ml, 20 mmol) was added at O'C. After refluxing for two hours, the
reaction mixture was cooled and neutralised with saturated aqueous solution of
sodium bicarbonate. The residue obtained upon concentration under reduced
pressure was extracted with chloroform (3 x 20 ml). The combined extract was
dried and concentrated to furnish 167 as yellow oil
Yield : 0.5 g (50 %).
lalo : +22.14 O (c 0.52, CHCl3)
IR (film) : 3494,3009,2969, 1748, 1452, 1128, 1081, 1013 cm-'
'H NMR (CDCI3) : 6 4.98 (s, lH), 3.84 (s, 6H), 3.68 (s, 3H); 3.2 (d, J = 18.0 Hz, lH), 2.80 (d, J = 18.0 Hz, 1H) ppm.
Mass spectrum : ndz 251 (M+l) (loo), 219 (23), 191 (32), 159 (SO), 143 (3), 13 1 (4.5), 99 (lO.S), 90 (IS), 59 (6), 43 (15).
dicarboxylate (168)
To a solution of 167 (1.0 g, 4 mmol) in dry acetone (25 ml), anhydrous
copper sulphate (0.5 g) and a few drops of conc. Sulphuric acid were added. After
refluxing for four hours, the reaction mixture was concentrated followed by
extraction with hexane (3 x 25 ml). The combined extract was dried and
evaporated to yield 168 as a yellow liquid
Yield : 0.25 g (22 %).
lalo : +29.5 O (c 0.95 %, CHC13)
Ill (film) : 2950, 1740, 1440, 1370, 1200, 1080, 1000 cm-'
'H NMR(CDC13) : 6 4.9 3 (s, lH), 3.86 (s, 3H) 3.81 (s, 3H), 3.68 (s, 3H), 2.98 (d, J = 16.04 Hz, lH), 2.85 (d, J = 16.04 Hz, lH), 1.58 (s, 3H), 1.48 (s, 3H) ppm.
13CNMR(CDC13) :6170.6,169.3,167.8,112.8,82.5,78.8,52.9,52.3,51.7,38.9, 27.4,25.5 ppm.
Mass spectrum : ndz 290 (M') (1.0), 274 (19.8), 230 (36.4), 214 (64.4), 198
(19.4), 180 (1 1.2), 172 (loo), 156 (16.4), 144 (29.2), 113
(51.5), 105 (14.2), 73 (41.0), 59(43.3), 43 (92.5).
Prepared by following the reported procedure of Seebach et ~ 1 . ~ Phenyl
magnesium bromide is prepared by adding bromobenzene (3.6 ml, 5.4 g,
34.34 mmol) dissolved in 10 ml dry THF to stirred magnesium turnings (1 g,
41.1 1 mmol). The resulting mixture is heated to reflux for 30 minutes. It is cooled
to O'C and ketal of diethyltartrate (1 .O g, 2.14 mmol) dissolved in 10 ml dry THF
is added dropwise. The reaction mixture is stirred at room temperature overnight
and then heated to reflux for 2 hours. To the chilled reaction mixture saturated
ammonium chloride solution (15ml) was added carefully and the organic phase
was separated. The aqueous phase was further extracted with ether. Combined
organic phase is dried over magnesium sulphate and concentrated under vacuum.
The product is separated by column chromatography using 100% hexane as eluent.
It is obtained as a white solid.
Yield : 0.84 g (85 %).
Melting point : 1 9 2 ' ~ Reported: 1 9 2 ' ~
ID : -73 (c 1.1 %, CHC13) Reported: -68.5'
'H NMR (CDC13) : 6 7.59-7.24 (m, 20H), 4.61 (s, lH), 4.4 (s, lH), 1.1 (s, 6H) PPm.
13cNMR(CDC13) :6145.87,142.56,128.61,128.03,127.60,127.47,127.19,
109.45, 80.86, 78.11, 27.06 ppm
Phenyl magnesium bromide is prepared in the usual manner by adding
Bromobenzene (5.4 ml, 8.11 g, 51.67 mmol) dissolved in 20 ml of dry THF
dropwise to stirred magnesium turnings (1.2g, 49.34 mmol). The resulting mixture
is heated to reflux for 30 minutes. The mixture is cooled to O'C and the ketal 168
(1 .O g, 3.44 mmol) dissolved in 10 ml of dry THF is added dropwise. The reaction
mixture is stirred at room temperature overnight and then heated to reflux for 2
hours. To the chilled reaction mixture saturated aqueous ammonium chloride
solution (20 ml) was added dropwise. The organic phase was collected and the
aqueous layer was further extracted with ether (5x10 ml). The combined organic
phase was dried over MgS04. The solvent was removed under reduced pressure
and the residue is purified by column chromatography over silicagel using hexane
and hexane, chloroform (8:2) as eluents. The pure product is obtained as an yellow
oil.
Yield : 1.0 g (44 %).
ID : -32.56 IJ (c 2.5, CHCI,)
IR (film) : 3400,3056,2912, 1952,1881, 1590, 1488, 1446, 755, 700cm-'
' H N M R ( C D C ~ ~ ) :67.6-7.23(m,30H),5.86(s,lH)3.3(d,J=17.3Hz,lH),3.1 (d, J = 17.3 Hz, lH), 1.25-1.55 (m, 6H) ppm.
' 3 ~ N M ~ ( ~ ~ ~ b ) : 6 146.92, 143.65, 133.58, 132.37, 129.99, 129.49, 129.21,
128.60, 128.39, 128.13, 127.83, 127.24, 127.15, 115.22. 80.53, 78.24, 77.24, 37.12, 31.80,31.56, 29.59,22.58 ppm
Mass spectrum : m/z 662 (M+) (2.2), 658 (2.6), 634 (2.7), 478 (3.0), 415 (5.4),
Following previous procedure 1.0 g of 168 (3.44 mmol) in 10 ml THF is
added to 21 mmol 4-methyl phenyl magnesium bromide (prepared from 4 ml p-
bromo toluene and 1.2 g magnesium turnings) in 10 ml THF. After work-up 170b
was isolated as yellow liquid. It is purified by column chromarography using
hexane chloroform (8:2) as eluent
Yield : 1.2 g (46.7 %).
[al~ : -7.1581J(c 1.2, CHCI,)
IR (film) : 3360, 2928, 1692, 1606, 1510, 1443, 1356, 857, 819,758 cm"
'H NMR (CDC13) : 6 7.75-6.75 (m, 24H), 5.15 (s, 1H) 3.3 (d, J = 17.3 Hz, lH), 3.1 (d, J = 17.3 Hz, 1H),2.48-2.28(m, 18H) 1.3 (s, 6H)ppm.
129.69, 128.94, 127.85, 127.47, 126.73, 126.51, 115.88, 80.09, 79.12, 78.09, 32.65, 30.76, 30.42, 30.07, 23.40, 22.33, 21.73, 21.15, 20.47 ppm.
Mass spectrum : m/z 746 (M') (2), 661 (4), 553 (6), 447 (20), 386 (26), 309 (30), 243 (loo), 183 (48), 167 (70), 136 (34), 105 (loo), 91 (34), 77 (38), 57 (28), 43 (14).
The procedure adopted for 170a was followed using 168 (1.0 g, 3.44
mmol) in 10 ml THF and 21 mmol I-naphthyl magnesium bromide (prepared
from 3.2 ml 1-naphthyl bromide and 0.58 g magnesium turnings) in 10 ml THF.
The crude product was purified by column chromatography using hexane,
chloroform (8:2) as eluent
Yield : 1.5 g (45.8 %).
[a ln : -27.03 (c 2.2, CHC13)
IR (film) : 3392, 2960, 1689, 1603, 1510, 1363, 1164, 1014, 860, 819, 758 cm"
'H NMR (CDC13) : 6 8.2-6.8 1 (m, 42H), 5.57 (s, IH), 2.2 (s, 2H) 1.7 (s, 6H) ppm.
I 3 c NMR(CDCI~) : 6 152.12, 135.47, 128.37, 127.13, 126.54, 125.94, 125.08, 122.25, 121.35, 109.31, 81.09, 80.05, 78.04, 39.55, 25.51 ppm.
Mass spectrum : m/z 962 (M') (2), 911 (2), 781 (2.1), 716 (4.4), 638 (13.3), 570 (6.6), 391 (11.1), 287 (66.6), 232 (44.4), 222 (loo), 157 (loo), 127 (100).
Preparation of diisopropoxy titanium (IV) dichloride
To a solution of titanium (IV) isopropoxide (2.98 ml, 10 mmol) in
dichloromethane (10 ml) was added titanium tetrachloride (1.10 ml, 10 mmol)
slowly at room temperature. On addition of titanium (IV) chloride heat was
evolved. After stirring for 10 minutes, the solution was allowed to stand for 6 hrs
at room temperature and the precipitate was then collected. The precipitate was
washed with hexane (2x5 ml), dried under reduced pressure and then dissolved in
toluene to get 2.5M solution.
Preparation of 3- ((E)-2-butenoyl)-l,3-oxazolidin-2-one
3-((E)-2-butenoyl)-1,3-oxazolidin-2-one was prepared according to the
procedure of ~ v a n s . ' ~ ~
To a solution of 1,3-oxazolidinone (5g, 57.47 mmol) in anhydrous THF
(150 rnl) at - 7 8 ' ~ was added n-butyl lithium (5.4 ml, 1 eqiv). After 15 minutes
freshly distilled 3-(E)-2butenoyl chloride (6.5 ml) was added. The mixture was
stirred at - 7 8 ' ~ for 30 min. and at O'C for 15 min. The reaction was quenched
with excess saturated aqueous ammonium chloride, and the resultant slurry is
concentrated in vacuo. The residue was extracted with ether. Ether layer was
washed successively with saturated aqueous sodium bicarbonate and then with
saturated aqueous sodium chloride. It is dried over magnesium sulphate, filtered
and concentrated in vacuum to yield the product.
3-(((I'S, 2's' 3'R, 4'R)-3'-methyl bicyclo [2.2.1] hept-Sen-2'-y1)-carbony1)-
1,3-oxazolidin-2-one (171): (Employing 170a as chiral ligand)
To a toluene suspension of powdered molecular sieves (4A,lg) added
toluene solution of diisopropoxy titanium (IV) dichloride (1 rnl, 2.5 M), cooled to
- 7 8 ' ~ and added toluene solution of polyol(170a) (200 mg) slowly for a period of
30 min. Slowly warmed to room temperature and stirred for 2 hours. The reaction
mixture was then cooled to -78'~, 3((E)-2-butenoyl)-l,3-oxazolidin-2-one
(388 mg, 2.5 mmol, 1 equiv.w.r.t polyol) in toluene (10 ml) was added, stirred for
15 min. followed by the addition of freshly distilled cyclopentadiene (4.4 ml,
55 mmol) and further stirred for 2-4 hours at - 7 8 ' ~ . The complex was decomposed
by adding a saturated solution of sodium hydrogen carbonate, filtered through
sintered crucible over ceiite bed and extracted with dichloromethane. The organic
layer was washed twice with saturated sodium chloride solution and dried over
anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave a
crude resin, which on silica gel chromatography gave the pure endo adduct 171.
Yield : 250 mg (45.2 %)
'H NMR (CDCb) : 6 1.50 (d, 3H, J=7.05 Hz), 1.82-2.08 (m, 3H), 2.46 (br, lH), 3.65 (br, lH), 3.91 (dd, lH), 4.27-4.46 (m, 2H), 4.75-4.89 (m, 2H), 6.15 (dd, lH, P 2 . 4 Hz, 5.4 Hz,), 6.53 (dd, lH, J=2.3Hz, 5.4 Hz) ppm.
13cNMR(CDC13) :6174.77,153.37,140.04,131.28,62.20,51.64,49.87,47.81, 47.46, 43.35, 36.82, 20.73 ppm.
1,3-oxazolidin-2-one (171): (Employing 170b as chiral ligand)
The procedure adopted for 170a was followed using powdered, activated
molecular sieves (1 g), diisopropoxy titanium (IV) dichloride in dry toluene (1 ml,
2.5 M), 170b (200 mg), 3((E)-2-butenoyl)-l,3-oxazolidin-2-one (388 mg) and
cyclopentadiene (4.4 ml). Work up of the reaction followed by silica gel
chromatography furnished pure endo adduct 171
Yield : 230 mg (41.62 %).
[ a l D : -16.05 ' (c 1.5, CHCI,)
'H NMR (CDCb) : 6 1.50 (d, 3H, J=7.05 Hz), 1.82-2.09 (m, 3H), 2.47 (br, lH), 3.69 (br, lH), 3.84 (dd, lH), 4.28-4.43 (m, 2H), 4.71-4.82 (m, 2H), 6.16 (dd, lH, J=2.6 Hz, 5.4 Hz,), 6.74 (dd, lH, J=2.3Hz, 5.5 Hz) ppm.
l 3 ~ N M ~ ( ~ ~ ~ 1 3 ) :6174.78,153.37,140.04,131.28,62.20,51.64,49.87,47.81, 47.47,43.35, 36.83, 20.73 ppm.
3-(((17S, 2'S, 3'R, 4'R)-3'-methyl bicyclo [2.2.1] hept-5'en-2'-yl)-carbony1)-
1,3-oxazolidin-2-one (171): (Employing 170c as chiral ligand)
The reaction was performed as described in the case of 170a using
powdered, activated molecular sieves (1 g), diisopropoxy titanium (1V) dichloride
in dry toluene (1 ml, 2.5 M), 170c (200 mg), 3((E)-2-butenoy1)-l,3-oxazolidin-2-
one (388 mg) and cyclopentadiene (4.4 ml). Work up of the reaction followed by
silica gel chromatography furnished the pure endo adduct 171
Yield : 200 mg (36.19 %).
[alo : -13.00 O (c 1.5, CHCI,)
'H NMR (CDCb) : 6 1.50 (d, 3H, J=7.0 Hz), 1.8-2.1 (m, 3H), 2.46 (br, IH), 3.65 (br, lH), 3.84 (dd, lH), 4.29-4.48 (m, 2H), 4.75-4.83 (m, 2H), 6.15 (dd, lH, J=2.8 Hz, 5.3 Hz,), 6.75 (dd, lH, J=3.2Hz, 4.9 Hz) ppm.
"C NMR (CDC13) : 6 174.77, 153.84, 140.03, 131.29, 62.24, 51.65, 49.88, 47.82,
47.47, 43.35, 36.83, 20.73 ppnl.