37<? / / 9 /

Mo.ntxj

I. ON THE MECHANISM OF ACID PROMOTED REARRANGEMENT OF PCU-

DERIVED PINACOLSII. SYNTHESIS OF A TRIMETHYLTRISHOMOCUBYL

HELICAL TUBULAND DIOL

THESIS

Presented to the Graduate Council of the

University of North Texas in Partial

Fulfillment of the Requirements

For the Degree of

MASTER OF SCIENCE

By

Zenghui Liu, B.S., M.S.

Denton, Texas

May, 1995

37<? / / 9 /

Mo.ntxj

I. ON THE MECHANISM OF ACID PROMOTED REARRANGEMENT OF PCU-

DERIVED PINACOLSII. SYNTHESIS OF A TRIMETHYLTRISHOMOCUBYL

HELICAL TUBULAND DIOL

THESIS

Presented to the Graduate Council of the

University of North Texas in Partial

Fulfillment of the Requirements

For the Degree of

MASTER OF SCIENCE

By

Zenghui Liu, B.S., M.S.

Denton, Texas

May, 1995

Liu, Zenghui, I. On the Mechanism of Acid Promoted Rearrangement of PCU-derived

Pinacols. II. Synthesis of a Trimethvltrishomocubvl Helical Tubuland Diol. Master of

Science (Organic Chemistry), May, 1995, 87 PP., 7 tables, 21 illustrations, bibliography,

67 titles.

I. Reductive dimerization of pentacyclo[5.4.0.0.2A()3,10.0^'9]undecane-8-one-

(PCU-8-one, 53) affords a mixture of meso and d,l pinacols (55a and 55b respectively).

Acid promoted rearrangement of 55a and 55b conceivably can proceed with migration of

C(7)-C(8) and/or C(8)-C(9) to form the corresponding pinacolone(s). In our hands, acid

promoted rearrangement of 55a and 55b each proceeds with exclusive migration of C(7)-

C(8) bond, thereby affording 58a and 59a respectively. Mechanistic features of this

rearrangement are discussed.

II. 4,7,1 l-trimethylpentacyclo[6.3.O.O.2A()3,lO.o5,9]unciecane-ejc0-4,ex0-7-diol

(23a) was successfully synthesized. This diol crystallizes in a helical tubuland lattice

although its molecular structure does not possess C2 rotational symmetry.

ACKNOWLEDGMENTS

The following people are gratefully acknowledged:

1. Professor Alan P. Marchand for both of his academic guidance and kindly

supporting me as a research assistant;

2. Professor Simon G. Bott for performing all the X-ray crystallographic studies

presented in chapter 1 and X-ray crystallographic studies on compound 19 presented in

chapter 2;

3. Professor Roger Bishop, Drs. Donald C. Craig and Ian G. Dance for their X-ray

crystallographic studies presented in chapter 2;

4. Dr. Andrew Burritt for his performing the calculations presented in chapter 1;

5. Dr. Vijay. R. Gadgil for having fully characterized compound 55 and also for

having developed the method to isolate compound 53b presented in chapter 1.

in

TABLE OF CONTENTS

Page

LIST OF TABLES v

LIST OF ILLUSTRATIONS vi

Chapter

I. ON THE MECHANISM OF ACID PORMOTED

REARRANGEMENT OF PCU-DERIVED PINACOLS 1

Introduction 1

Results and Discussion 31

Experimental Section 46

Conclusions 53

References 54

H. SYNTHESIS OF A TRIMETHYLTRISHOMOCUBYL

HELICAL TUBULAND DIOL 58

Introdcution 58

Results and Discussion 69

Experimental Section 79

Conclusions 84

References 85

IV

LIST OF TABLES

Chapter I

Table Page

I. Product Distribution of l-Phenyl-4-butyl-cyclohexane-diol 8

n. Kinetic Results of Pinacolic Conversion of Dimethylcyclopentane-diol 12

in. Pinacolic Rearrangement of Alicyclic Glycols 25

IV. Pinacolic Rearrangement of Bicycloalkane-l,l'-diols 26

V. Product Distribution of Pinacolic Rearrangement 28

VI. Results of the MMX Conformational Search of Protonated 53a 43

VII. Results of the MMX Conformational Search of Protonated 53b 44

LIST OF ILLUSTRATIONS

Chapter I

Figure Page

I. X-ray Structure Drawing of 53a 33

DL X-ray Structure Drawing of 54a 35

IE. X-ray Structure Drawing of 56a 39

IV. X-ray Structure Drawing of 57a 39

V. X-ray Structure Drawing of 58a 40

VI. Lowest Energy Rotational Conformation of Protonated 53a 43

VII. Lowest Energy Rotational Conformation of Protonated 53b 44

Chapter n

Figure Page

I. Three Type of Unimolecular Complexes 59

II. Schematic Representation of a and P-Cyclodextrin 59

in . Crystal Structure of a Complex Formed by Hydrogen Sulfide (s)

Trapped inside a Cage of b-Hydroquinones 60

VI

Figure Page

IV. A Stereodiagram of the Stacking of Two Complexes along c Axis

to Form Closed Cavities in the Crystal 61

V. The Orientation of the n-Heptyl Alcohol Molecule

within the Cage Defined by Dianin's Compound 61

VI. Projection View in ab Plane of One Canal of

the Helical Tubuland Lattice Adopted by Diols 4-9 62

VII. Projection View of the Diol Host Network in 4 63

VIE. Diagrammatic Representation of the Sequence of Hydrogen-bonded Diol Molecules Comprising One Spiral Turn around the Tube 64

IX. Exaggerated Perspective View of the Helices Formed

by Hydrogen-bonded Diol Molecules in One Tube of 4 65

X. X-ray Structure Drawing of 19 72

XI. X-ray Structure Packing Diagram of 23a 74

XII. Model of the Crystal Lattice Adopted by Diol 23a 75

XIII. X-ray Structure Drawing of 23b 77

XIV. Crystal Lattice Formed by 23b 78

vn

CHAPTER I

ON THE MECHANISM OF ACID PROMOTED REARRANGEMENT OF

PCU-DERIVED PINACOLS

Introduction

The conversion of substituted 1,2-diols, R2C(OH)-C(OH)R2, into RC(0)-CR3,

with concomitant shift of a substituent from the carbon atom which is forming the carbonyl

group to the carbon atom which is losing its hydroxyl group is known as pinacol-

pinacolone (or pinacolic) rearrangement. 1 The corresponding rearrangement of epoxides,

deaminations of 2-amino alcohols, halohydrin rearrangements, and the corresponding

rearrangement of acyloins also belong to the same class of chemical transformations. This

review will focus upon studies of acid promoted rearrangements of 1,2-diols.

I. Mechanism

A. Carbocation Mechanism

A carbocationic mechanism (Scheme 1) has been suggested for the acid-promoted

pinacol rearrangement of 1,2-diols:^

Scheme 1

R2<f-fR2 OH OH

fast

R 'V*

RC~ CR2

R2<f- CR2

OHOH2

rate determing

OH R,-COR

R2<j> CR2

OH +

1

The intermediate carbocation 1 can rearrange to form product or instead may simply return

to the diol. The relative rates of return vs. rearrangement of the intermediate carbocation

depend upon the properties of the medium and of the diol. The intermediate carbocation

may be a bridged, nonclassical ion or a mixture of equilibrating classical ions. Kinetic

evidence^ which supports this mechanism includes (i) evidence of return, i.e., exchange of

oxygen of diol with ^O-labeled water, (ii) near unit slope for log k vs. (-H0) plot and (iii)

positive value of AS*.

Stiles and Mayer^ proposed an alternative mechanism which involves a hydrated

carbocationic intermediate (Scheme 2) in an effort to interpret the data obtained via their

studies of relative migratory aptitudes of alkyl groups in pinacol rearrangements:

Scheme 2

R R I I

R - C C —R • + '

OH OH2

R I

R - C -I OH

1 , * R

R

OH2

Exchange of water

kr Product

Collins and co-workers^ have carried out isotopic labeling studies on the pinacol

rearrangement of triarylethlene glycols. It was noted that (i) the primary kinetic isotopic

effect, kn/kD, is ca. 3 when the rearrangement is performed under various acidic

conditions. This value is in the high range of the expected kH/kD for an intramolecular

hydride shift;^ (ii) the ratio of phenyl vs. hydride migration varies from 7.33 to 0.041 in

different acid media; and (iii) the threo and erythro forms of diol 2 rearrange at the same

rates and interconvert early in the reaction to afford the same 50:50 mixture of diols.

n u nu, Uh

Ph

Ph Ph Ph

Threo-2

Ph

Erythro-2

The following kinetic pathway has been proposed to explain the experimental

observations.^

OH OH I I

Ph2C—CHPh

H20 OH I I

Ph2C—CHPh

OH + I

Ph2C— CHPh

'Ph Ph3CCHO

'H "Ph2CHCOPh

The variation of the ratio (kph/kH) in different acids has been interpreted in terms of the

relative populations of intermediate conformations, a and b (Scheme 3), as determined by

the properties of the solvent media employed, in each case.^

Scheme 3

OH HO,

stable conformation 3

H- 41

Ph2CHCOPh

rotation

II

kph p h

v Ph3CCHO

In a weakly ionizing solvent, conformation a obtained from the lowest energy

conformation of the reactant, 3, is relatively short-lived. Therefore, hydride shift occurs

soon after the formation of a. However, in a strongly ionizing solvent, e.g., concentrated

sulfuric acid, a is sufficiently long-lived to enable equilibrium between a and b to be

established, in which the equilibrium favors b. Consequently, under such conditions,

phenyl shift dominates in the rearrangement.

More recently, elaborate studies on the kinetics and mechanism of dehydration of 4

have been carried out by Pocker and Ronald.^ The reactions are characterized by the

simultaneous formation and accumulation of an intermediate epoxide that eventually is

converted into product pinacolone.

Ri

OH OH I I

- r C - R

^2

4 a. Rj — R2 — Ph b. Ri = Ph, R2 = p-CH3C6H4

1 c. Ri = R2 = p-CH3C6H4 d. Rj =R2 = p-CH3OCH3C6H4

e. R] = P-CH3OQH4, R2=Ph

Two possible kinetic schemes are consistent with the observed data. One of these

(Scheme 4) involves the partition of glycol (G) into epoxide (E) and ketone (K). The

conversion of G to K explains the relatively large amount of ketone that is formed in the

early stage of the reaction. This scheme implies that a concerted process is involved in each

of the conversions.

Scheme 4

G

The other kinetic scheme (Scheme 5) involves the partition of a carbocationic

intermediate (R) into epoxide (E) and ketone (K).

Scheme 5

G

K

The kinetic pathway shown in Scheme 4 assumes a concerted ring opening and

migration (see below) needed for the rearrangement of epoxide to ketone. The anticipated

high level of steric strain concomitant with simultaneous ring opening and migration argues

against the formation of 5.

Ar-

il

/ ? \ c — c:

' * \

\ / > A *

Herlihy^ has found that propanal is formed as the major product of the rearrangement

of propane- 1,2-diol in aqueous acid. Kinetic evidence shows this reaction is a typical

carbocation mechanism as shown in Scheme 1 in which unimolecular loss of H2O occurs

from the protonated pinacol, thereby affording a carbocation. The rate of loss of optical

activity (ka) is greater than the loss of diol (kre) over the range of the acid conditions

investigated. The ratio of the oxygen exchange to the racemization is about 0.5. The

following reaction pathway has been suggested to account for these observations:

H+ + HOCHMeCH2OH

k2 (rate determing)

^ + .

MeCHCH.OH

H2OCHMeCH2OH

- • MeCH2CHO

The epoxide mechanism is not operative here, because the experimental results show that

acid-catalyzed hydrolysis of the epoxide affords only propanediol.

Pinacol rearrangement of either cis- or trans-1,2-dimethylcyclohexane-1,2-diol

affords 1-acetyl-1-methylcyclopentane along with a small amount of 2,2-

dimethylcyclohexanone.^ The r a t e variation with acidity, the solvent deuterium isotopic

effect, and the Arrhenius parameters are consistent with the carbocation mechanism. The

pinacol rearrangement is accompanied by (i) rearrangement of one diol to the other, and (ii)

exchange of oxygen-18 with the solvent. These observations suggest that the following

pathway for this transformation is operative:

CH3 CEL *3

cis

CH CH,

H3C COCH3

major

CH3 OH

trans

HOC

minor

Both the cis and trans-diols rearrange thorough the same intermediate, due to the

conformational flexibility of cyclohexanediols. The conformation may be either a or b as

shown below:

Me. . Me

Ion a may be formed via loss of an axial hydroxyl from the m-diol or via loss of an

equatorial OH group from the trans-diol, whereas ion b may be formed by loss of an

equatorial hydroxyl group from the cw-diol or by loss of an axial OH group from the trans-

diol. Once again, the epoxide mechanism is not operative here, since acid-catalyzed

rearrangement of the corresponding epoxide produced only trans-diol.

It is well known that when a /-butyl group is introduced into a cyclohexyl ring, it has

a strong preference to occupy the equatorial position. Therefore this system is always a

useful "conformationally biased system''.^ The products of BF3-promoted rearrangement

of l-phenyl-4-r-butyl-cyclohexanediols, 5-8, are shown in Table 1.1®

Table 1. Product Distribution of l-Phenyl-4-butyl-cyclohexane-diol

Starting Compound

Product (%) Starting Compound a b c

5 93 7 6 90 10 7 67 33 8 61 39

OH t-Bu, Ph t-Bu, OH OH

5

OH Ph

OH OH

6

OH t-Bu t-Bu,

OH OH

8

Ph

- B \ , B u > C V P h h ' XCHO

a

These data are best explained in term of a mechanism which involves a carbocationic

intermediate (Scheme 6).

10

Scheme 6

t-Bu, OH

v / X r ^ p h - n ^ O H

t-Bu Ph

OH OH

I t-Bu

Ph <"^OH

H

Ph t-Bu OH

OH

t-Bu OH

Ph H

OH

t-Bu Ph

H" OH

t-Bu

H /•

I-OH

'Ph

This kinetic scheme is consistent with what has been proposed to account for the course of

pinacol rearrangement of l,2-dimethylcyclohexane-l,2-diol and of 1-phenylcyclohexane-

1,2-diol.10

Pinacol rearrangements of l-phenylcyclohexane-l,2-diols are believed to occur via

the following mechanistic pathway: H

11

OH OH OH

OH

Ph Ph

Ph OH

1-A BF3

V - v y ^ h Ph

OH

CHO cx CH=OH" H Ph

Ph 30 % (cis-diol )a

16 % (trans-diol) Ph Ph

OH

70 % (cis-diol f 84 % (trans-diol)'

OH Ph Ph

OH Ph OH OH

OH

a. Product composition from cis-diol. b. product composition from mms-diol.

The stereochemistries of the methyl and hydroxyl groups in the 1,2-

dimethylcyclopentanediols are known with certainty. Isotopic tracer studies performed in

connection with pinacol rearrangements of this system have been reported by Bunton and

Carr 12

MeyC Tar

OH OH Me OH Me

CIS major trans major

12

Table 2. Kinetic Result of Pinacolic Conversion of Dimethylcyclopentane-diol

Entry log k 0

a vs. [Ho] AS*Ve.u. E/kcal-moH k(D20)/k(H20)b

Qs diol linear,

slope=1.05 9.3 30 2.1

Trans-diol linear,

Slope=1.02 9.6 31 2.1

a. in 96% D2O; b. 59.7 °C in HC104 solution.

The observations suggest that this reaction proceed via a typical carbocation

mechanism. The cw-diol does not exchange its oxygen with water but instead rearranges to

trans-diol, ketone, and tar. It has been suggested that the methyl group migrates soon after

the carbocationic intermediate has been formed. However, the interactions between the

migrating CH3 group and the migration terminus are not strong enough to completely

suppress the formation of 9, which leads to the production of trans-diol (Scheme 7).

Scheme 7

e y / M e ^

OH OH

M e > +OI^ OH

o H 9

H2O*

HO*

Me OH

OH

- j£J£> Me i H

Me" +

OH

Me

/ ¥ j > - o

Me

13

The frans-diol exchanges oxygen with ^O-labeled water five times faster than it

decomposes, but it does not rearrange to ds-diol. This evidence suggests that the following

kinetic scheme is operative:

vQE> Me%

OH Me 0 H Me

k - 2

Me k_2/k3 = 5

\ ' o H

no | | k3

Tar Mi

OH OH

Kleinfelter and c o - w o r k e r s 13 have carried out the rearrangement of endo-2-ip-

anisyl)-exo-2,ejco-3-dihydroxynorborane. Based on their results, they proposed the

following mechanistic pathway for this reaction:

14

H Q H

+H+ fast

fast

HQ. H

slow fast

At = Ph, p-Anisyl

However, the results of isotopic labeling and stereochemical studies support a non-classical

carbocationic mechanism (Scheme 8): 14

Scheme 8

ti

Ar=Ph, p-Anisyl

15

On the other hand, studies of the pinacolic rearrangement of e*o-l,exo-2-dihydroxy-1,7,7-

trimethyl-3-phenylnorborane15 support a mechanism (Scheme 9) that is not consistent with

the non-classical carbocationic intermediates:

Scheme 9

10

H+

H+

11

Na/Butanol

Isomerization

Ph

Ph Ph

Cr037Py

It seems quite clear that the transformation of 10 to 11 proceeds via endo,endo-2,3-

hydride shift (Scheme 10).

Scheme 10

16

10 OH OH

Ph -- D

Ph

11

B. Concerted Mechanism

A mechanism that involves carbocationic intermediates appears to operate for pinacol

rearrangements in solution. However, gas-phase pinacol rearrangements appear to proceed

in a different way.

In the gas-phase, pinacol rearrangement can be promoted by gaseous Br<|>nsted acids

such as D3+, CH5+/C2H5+ and t-C4H9"1". Mass spectrometric and radiolytic methods

have been employed to monitor the behavior of gas-phase pinacol transformations. 16,17

Gas-phase pinacolic rearrangements of cis- and trans-1, 2-dimethylcyclopentane-l,

2-diol have been studied. 16 it was concluded that the pinacolic rearrangements proceed via

a concerted mechanism (Scheme 11):

Scheme 11

17

OH OH

+ H+

+OH2 OH

rate-determing

OH+

- H+

The results of intermolecular competition experiments indicate that the cw-diol

rearranges more rapidly than does the trans-diol. Simultaneous migration of the methyl

group and the leaving of a molecule of water is indicated. For rearrangement of both cis-

and trans-1,2-dimethylcyclohexane-l,2-diols, the experimental results can be accouted for

via the following kinetic scheme:^

18

+ H Me Me)

OH OH

CHq

*- < Me Me>

OH OH2+

I

>^OH

Me Me> \+ '

8

^ C - C

Me

\ / COMe

In agreement with the corresponding behavior of the l,2-dimethylcyclopentane-l,2-

diols, cis- and trans-1,2-dimethylcyclohexane-1,2-diols rearrange in the gas-phase via a

mechanism which differs from that in solution. Thus, (i) there is no evidence of carbonium

ion formation in the gas-phase reaction, and (ii) no epimerization occurs in the presence of

water. Therefore, it was concluded that the dehydration and the migration steps must be

concerted. The difference between the rearrangement rates can be accounted for in terms of

stereochemical factors and relative neighboring group migratory aptitudes.

Ab initio SCF-MO calculations have been performed for the gas-phase reaction

pathway, and the question of migratory aptitude has been a d d r e s s e d . 18 The model for

these calculations is shown below:

19

13a,b,c,d

c°«e*

Path ***

12a,b,c,d

a: R = Me

d: R =

e: R = H

w 0 '

.H-i

H H

t H+

14a,b,c,d

O 1

H, A, . • > " H - O r \ V * H

R

17a,b,c,d

W O t

Z.H R^X+Z^H

H

18a,b,c,d

t

H A\H h ' O-H

19a,b,c,d

t

H * N

H H

15a,b,c,d

15a,b,c,d H

O

H*"

H V _ - 0

h h r

16a,b,c,d

15a,b,c,d

The theoretical results show that the activation energy of the pinacolic rearrangement

via the concerted mechanism is always lower than that which proceeds via a carbonium

intermediate mechanism. These computational results support the gas-phase experimental

observations. 17

Stereospecific Lewis acid-promoted pinacol-type rearrangement in aprotic solvents

have been reported (Scheme 12). 19

20

Scheme 12

H3C ? R' HsC\ o \ ^ Et3Al/CH2Cl2> \ h

Hvwvy \ -78 °c Rvxxy \ / OH / R

MsO H

R2 a. R - / = = <

Ri R3

b. R = R' = Et, 11-C4H9, n-C8H17, ^ ^

When R (the migrating group, Scheme 12) is an alkenyl group, its stereochemical

configuration (Z- or £-) remains unchanged before and after its migration. When R=R'=Et,

n-C4H9, «-C8Hi7, and cyclohexyl, the configuration of the migration terminus is inverted

(> 95% e.e.). These results can be rationalized in terms of a "push-pull" concerted

mechanism for the transformation (Scheme 13):

Scheme 13

X — " R

H3C f f p-

O ) " Push " U > o / y

XlF.tr. , .AlEt2

o*\Xoy M e " Pull"

21

II. Steric Course

There are two fundamental questions that relate to the steric course of the pinacolic

rearrangement^: (i) What is the stereochemical fate of the migrating group? (ii) What is the

stereochemical fate of the migration terminus? With respect to the first question, it might be

anticipated that the configuration of the migration group is retained.^0,21 This expectaion

has been confirmed by the experiment conducted by Beggs and Meyers^, as shown

below:

HO £ H 3 s £ H 3 H r H O v ^ s - B u p, tL i H3C ?^S-Bu s 3Cv O

H,C s-Bu 3

Path 2 HO. yCH3

~ H,C (unlikely) / ' — \ - B u s

h 3 c

s-Bus = (S)-sec-Butyl

The results of studies conducted by Stiles and Mayer suggest that Path 1 is the more likely

of these two mechanistic alternatives.^

With respect to the second question, it has been established that the configuration at

the migrating terminus proceeds with predominant (but not exclusive) inversion of

configuration.20,21 jf the pinacolic transformations occur via a carbonium intermediate,

electronic considerations require that the migrating group must be properly aligned, as

shown below;23

22

R

' O ^ , k\ NR4

0 5

R-

R3nN

v o r > R -

o V""R4

R<

For example, the pinacolic deamination of substrate 20 as shown below gives 88% of 21a

(which results via migration of the labeled Ph group) and 12% of the other isomer, 21b.21

The product distribution depends upon the ratio of the intermediate conformations a and b,

which in turn is determined by the nature of the acid medium.

Me

C

Ph*

OH

20 stable conformation

H v 0 r ~ " s y P h * cv"»Ph

U OH

NPh* h*.9+ w '

M e " 0 v _ > h

*Ph \

H ^ C

Me^

/ Ph

O

21a Labelled Ph* migrates, configuration of migration terminus inverted (88 %)

\f Ph O

Ph*

21b Unlabelled Ph migrates, configuration of migration terminus retained (12 %)

23

Numerous examples show that the migrating group always prefers to be

antiperiplanar with respect to the leaving group. For example, pinacol 22 gives two

products a and b under acid conditions (Scheme 14).24

Scheme 14

0 H TsOH/AcOH • R reflux, 30 min

22

R = Me, Et, i-Pr, t-Bu, 4-MeOQH4, Ph

However, the stereochemical course of the pinacolic rearrangement is frequently

complicated by other factors such as reactant isomerization, product isomerization, and the

nature of the acidic medium e m p l o y e d . 2 5

III. Effect of Ring Size

Pinacolic rearrangements of alicyclic glycols have been investigated extensively. In

most of the reactions studied, ring size is one of the major structural features that influences

the extent of ring expansion. It has been reported that the order of the ring strain is: C6 <

C7 < C5 < C8.26 Therefore, relief of ring strain provides an important driving force for

ring expansion of five-membered rings, while six-membered and seven-membered rings

display a reduced tendency toward ring expansion.

M e e r w e i n 2 7 carried out the rearrangement of a series of glycols which possess the

general formula 23. Cyclopentyl glycols (23c and 23d) give more ring expanded products

24

than are formed via pinacol rearrangment of the corresponding cyclohexyl glycols (23a and

23b, respectively).

OH OH v V 1

(CH2)n 4 V — c — R

1 — 7 ;

23a, n=6; R=Me 23b, n=6: R=Et

23c, n=5; R=Me 23d, n=5; R=Et

The results^ obtained via deamination of some amines and amino alcohols with the

general formula 24 indicate once again that cyclopentyl analogs (n=5) proceed to afford

more ring expanded products than do the corresponding cyclohexyl compounds (n=6).

I V H NHo I \ l I 1

(CHA-! > - C - R

I / i

24.X=H, OH: R=H, Me, Ph: n=5, 6.

The acid promoted conversion of several alicyclic glycols to a mixture of spiro-ketone

and a diene has been reported (Table 3).28 These results indicate that ring size is one of

factors that influences the extent of the ring expansion reaction.

Table 3 Pinacolic Rearrangement of Alicyclic Glycols

25

Entry Glycol % Spiro ketonea % Diene 1 Bicyclobutyl-1,1 "-diol o o r

H

2 Bicyclopentyl-1,1 "-diol 86e 10® 3 Cyclopentylcyclohexane-1,1 "-diol 19.8d 80.2 4 Bicyclohexyl-1,1 '-diol 12.7C 88h

5 Bicycloheptyl-1,1 -diol 1.25*' 98.75 6 Bicyclooctyl-1.1 '-diol 1.83* 98.17

a. All yields represent product ratio; percent chemical yields are less. b. Diene not reported, c. Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 2753. d. Consists of two ketones. See Sands, R. D.; B otter on, D. G. J. Org. Chem., 1963,28, 2690. e, Isolated as the semicarbazone. See Q-i-Khuda, J. Indian Chem. Soc., 1939,16, 525. f, Greidingern, D. S.; Ginsberg, D. J.Org. Chem., 1957,22, 1406. g, Isolated as the maleic anhydride adduct. See f. h, Barnette, E. de B.; Lawrence, C. A. J. Chem. Soc . 1935, 1104.

The major products of entries 1 and 2 (Table 3) are spiroketones, while the other

alicyclic glycols (entries 3-6) mainly form diene products. It is reasonable to expect that

spiroketone formation can relieve the ring strain that is inherent in four and five-membered

rings, while diene formation is the preferred way to relieve ring strain in the other examples.

In the case of l-(l'-hydroxycyclopentyl)-l-hydroxycyclohexane, carbonium ion b (below)

is more strained than the parent glycol a, because formation of the ion results in formation

of an eclipsed conformation in the six-membered ring. With two highly strained rings, b

appear to rapidly lose a proton and water before it has enough time to rearrange to form the

spiroketone.

. O H OH ^ OH

OHO OX) a

26

A mixture of 25, 26, 27 has been prepared, and pinacol rearrangement of this

mixture with 25% sulfuric acid for 2.5 hours has been carried out.28

OH OH OH OH

o OH OH

25 26

The product distribution thereby obtained is listed in Table 4.

Table 4 Pinacolic Rearrangement of Bicycloalkane-1,1 '-diols

27

Product Percentage vield from

25 26 27 28 14.9 29 85.1 30 14.5 31 85.5 32 0.0 33 100 34 0

C K ) 28 29 30

(p Q-O (p 31 32 33 34

27

The reason why 25 and 26 prefer to rearrange while 27 prefers diene formation is that 25

and 26 can relieve ring strain by ring expansion, while ring expansion will result in an

increase in the ring strain in 27.

The synthesis and pinacolic rearrangement of 35-38 have been carried out by

Botteron and Wood.27

OH OH

\ I I -Ph (CHjVI / C - C \

I / 1

35. n=6; R=H

37. n=6; R=Me

R \ i

( p u C

O II C—Ph

36. n=5; R=H

38. n=5; R=Me

O

\ f V r ~ \ ( W „ - l C - C - R ( j ^ V i \ . c — c /

Ph

\

a

The product distribution thereby obtained is shown in Table 5.

Table 5 Product Distribution of Pinacolic Rearrangement

28

Compound Product Distribution

Compound a b c 35 25 10 65 36 7 0 93 37 0 28 72 38 0 20 80 35a 68 23 9 36b 0 0 100

Inspection of Table 5 shows that the percentage of product obtained via the expansion of

the five-membered ring is greater than that from the six-membered ring (i.e. 36c > 35c and

38c > 37c), in agreement with the "ring strain release theory".

Mundy and co-workers compared the effects of various reaction conditions on the

course of pinacolic rearrangements. They suggested that concentrated sulfuric acid at 0 °C

would be the reaction condition of choice for the examination of subtle effects such as the

ring size effect. Under these conditions, no secondary rearrangement takes place, and the

rearrangement proceeds in high yield.29 The following rearrangements of 39, 43, 47

were carried out under these conditions:

OH OH Qv P

CK3-O-O C^)-Oo 39 40 41 (62.0±8.7) 42 (38.0±8.7)

cPb-- ® o • do• c5o 43 44 45 (3.5±2.5) 46 (96.5±2.5)

29

- P

cR}-CK>tiO*CO 47 48 (23.0±11.9) 49 50 (77.0±1.9)

The following ring expansion trends are noted: C6 to C] > C5 to C6 > C7 to C8.

The result can be interpreted by a combination of "ring strain release" and "ease of

carbonium ion formation".30 Jt w a s reported that the order of the increasing ring strain is:

C6 < C7 <C5 < C8,26 and the order of "ease of carbonium ion formation" is C7 > C5 >

C6.31

In the case of pinacol rearrangement of 39, although the five-membered ring has a

greater tendency toward undergoing ring expansion than does the six-menbered ring, it is

easier to form a carbonium ion in the five-membered ring than in the six-member ring.31

The latter effect dominates in this case. Thus, the yield of 41 is greater than that of 42.

For 43, both "ring strain release" and "ease of carbonium ion formation" favor the

formation of 46. In the case of 47, both factors favor the formation of 50.

As the above discussion indicates, the mechanism of the pinacol rearrangement has

been extensively investigated, and some of its mechanistic aspects have been elucidated.

However, some intriguing questions remain (e.g., concerted vs. stepwise mechanism).

Furthermore, other factors which might influence migratory aptitude in addition to the

inherent properties of the migrating group are not fully understood. In an effort to gain

additional insight into the detailed mechanism of the acid promoted pinacol rearrangement,

two pinacols (53 a and b) were synthesized via reductive coupling of

pentacyclo[5.4.0.02A()3,10.05,9]unclecane-8-one (51, i.e., "PCU-8-one"). The distinct

advantages of this system include the following: (i) All these pinacols possess twofold

30

symmetry, and the two endo hydroxyl groups of each PCU-derived pinacol are chemically

equivalent. Thus, it is possible to compare the migratory aptitude between the C(7)-C(8)

and C(9)-C(8) a-bonds by obtaining the relative yields of two possible products which

might result via migration of these two different C-C a-bonds. (ii) the cage moieties in the

PCU-derived pinacols are highly rigid; the only "flexibility" which these pinacols possess

involves rotation of the two cage moieties about the C(8)-C(8') a-bond. This greatly

simplifies the task of molecular calculations on this system, which would be highly

complex if performed for conformationally mobile system.

Results and Discussion

1. Reductive Dimerization of PCU-8-one (51) and Cyclopropanated PCU-8-one (52)

The syntheses of PCU-8-one 51 and cyclopropanated PCU-8-one 52 are shown in

Scheme 15.32

Scheme 15

Diels-Alder ^

Ethylene Glycol

TsOH, Reflux

Wolff-Kishner HC1/THF

25 °C

51. X=CH

52. X =<|

Sodium promoted reductive dimerization of 51 affords a mixture of several isomeric

PCU-derived pinacols. Analysis of the NMR spectrum of the product mixture suggests

that 53a and 53b are the major product (Scheme 16). Structures of other possible PCU-

derived pinacol isomers (53c-f) are shown in Scheme 17. Flash chromatographic

separation of the mixture thereby obtained afforded a single, pure isomer 53a, mp 226.0-

227.0 °C. Pure 53b, mp 223.0-224.0 °C, was isolated indirectly through its derivative

55. Similarly, sodium promoted reductive dimerization of 52 affords a mixture of several

31

32

249.5-250.0 °C, was obtained via flash chromatographic separation and fractional

recrystallization of this mixture. Other possible structures for 56b-f are shown in Scheme

16 and 17.

Scheme 16

Na, dry THF

argon, sonicate

51 X=CH2

5 2 X = C ^

53 X=CH2

54 X=C^

HO OH HO OH

53a X=CH2

54bX=cC]

53b X=CH2

54a X=C^j

Scheme 17

53c X=CH2 53d X=CH2

54c X= 54dX=C^]

3QS><J(QS> HO OH

53e X=CHo

54eX = c d

HO OH

53f X=CH2

54f X =<]

The proton noise-decoupled NMR spectrum of 53a contains 11 peaks. A

singlet at 8 87.67 in the corresponding APT (Attached Proton Test)33 13c NMR spectrum

of 53a corresponds to C(8) and C(8'). Two triplets at 8 30.56 and 35.14 correspond to

C(4), C(4'), C(ll) , and C(ll ') . The remaining eight signals, which were identified as

33

methine carbons by the APT spectrum, represent 16 tertiary carbons. The following

conclusions about the molecule can be drawn:

1. The presence of a singlet at 8 87.67 in the APT spectrum of 53a suggets that this

product resulted via reductive dimerization of 51. The carbon, hydrogen elemental

microanalytical results also agreed with the assigned structure for 53a.

2. The presence of 11 carbon peaks in the NMR spectrum of 53a indicates the

existence of a twofold symmetry element in the structure of 53a {e.g., mirror plane or C2

axis).

3. An absorption at 3437 cm"^ in the ER. spectrum of 53a indicates the presence of O-

H.

The structure of this isomer was shown unequivocally to be 53a via single crystal

X-ray structural a n a l y s i s . ^ 4 An x-ray structure drawing of 53a is shown in Figure 1.

CI 04

Figure 1. X-ray Structure Drawing of 53a

34

In order to facilitate separation and characterization of 53b, the mixture of isomeric

pinacols was converted into a mixture of the corresponding cyclic sulfite esters. The

conversion was achieved by reacting the mixture of isomeric pinacols with SOCI2 in

pyridine at ca. 0 °C (58% y i e l d ) . 3 5 Fractional recrystallization of the mixture of cyclic

sulfite esters thereby obtained afforded pure 55, mp 178.5-179.5 °C.

The proton-decoupled NMR spectrum of 55 contains 22 peaks. The presence

of a lone pair of electrons on the sulfur removes the C2 axial symmetry that otherwise is

characteristic of 53b. The C(8) and C(8') singlets absorb at 8 96.76 and 101.19,

respectively. An IR spectrum of 55 contains no O-H absorption in the region 3100-3500

cm"l. Elemental microanalytical results were consistent with the assigned structure for 55.

The structure of 55 was established unequivocally via application of X-ray crystallographic

methods.34

55

Hydrolysis of 55 afforded a single, isomerically pure pinacol 53b in 89% yield.

The NMR and IR spectra of 53b are similar to those of 53a. The 13c NMR signal which

corresponds to C(8) is located at d 85.60. Its structure follows directly from the structure

of its precursor, 55. A C2 symmetry element can be found in the structure of 53b. The

structures of both 53a and 53b having thus been established, it now is possible to

35

distinguish between 53a and 53b on the basis of the appearance of their respective

NMR spectra.

The IR and NMR spectra of 54a are similar to those of 53b. However, in the

proton noise-decoupled NMR spectrum of 54a there two methylene carbon signals

located at 8 4.88 and 5.07, which correspond to the four methylene carbons in the

cyclopropane rings of 54a. Elemental microanalytical results are consistent with the

assigned structure for 54a. The structure of 54a was established unequivocally via

application of X-ray crystallographic methods .34 A structure drawing of 54a is shown in

Figure 2.

Club ClOa

Figure 2. X-ray Structure Drawing of 54a

36

2. Acid-promoted Pinacol Rearrangements of 53a, 53b and 54a

2. Acid-promoted Pinacol Rearrangements of 53a, 53b, and 54a

Compounds 53a, 53b and 53a conceivably could undergo acid-promoted pinacol

rearrangement by either (or both) of two mechanistic pathways, i.e. with migration of the

C(7)-C(8) and/or C(8)-C(9) bonds to afford the corresponding pinacolones (i.e, 56a and

56b respectively, Scheme 18; 57a and 57b respectively, Scheme 19; 58a and 58b

respectively, Scheme 19).

Scheme 18

migrate C(7)-C(8)

HO

m&so-pinacol (53a)

migrate C(8)-C(9)

37

Scheme 19

migrate C(7)-C(8)

57a X=CH

0H2+ HO

d,/-pinacol: 53b X=CH2

54aX=C^j

migrate C(7)-C(8)

57b X=CH2

58b X= [ = < ]

Acid promoted rearrangements of each of 53a and 53b were carried out by using

CF3SO3H as catalyst. The experimental results showed that in each case rearrangement of

53a and of 53b proceeds with exclusive migration of C(7)-C(8) a-bonds, thereby

affording only 56a, mp 195.0-196.0 °C, and 57a, mp 151.0-152.0 °C, respectively, each

in ca. 90% yield.

Analysis of the NMR spectrum indicates the absence of C-OH absorption in

56a; however, a carbonyl carbon resonance is observed at 8 219.19. The presence of 22

peaks in the NMR spectrum of 56a indicates the loss of twofold symmetry that had

been present in the starting material 53a. The singlet at 8 58.60 can be assigned to the only

quaternary carbon, four triplets to four methylene carbons, and sixteen doublets to the

38

remaining methine carbons. The absorption at 1683 crrfl in the IR spectrum of 56a can be

assigned to the C=0 stretching vibration. It seems quite unusual for this polycyclic ketone

to display its C=0 stretching absorption < 1700 cm'l, since cyclic ketones generally

display this absorption at ca. 1715 cm"*. However, this observation is consistent with

those for the other reported spiroketones shown in Scheme 20. Elemental microanalytical

results are consistent with the assigned structure for 56a.

Scheme 20

IR (KBr) 1680 cm"1 (s)36

O.

IR (KBr) 1650 cm"1 (s)37

IR (KBr) 1694 cm"1 (s)38 IR 1692 cm'1 (s)38

The forgoing spectral data are not sufficient to assign the structure of 56a. Instead, this

was accomplished unequivocally via single crystal X-ray structural analysis.3^ An X-ray

structure drawing of 56a is shown in Figure 3. Inspection of this structure drawing

indicates that 56a resulted via acid-promoted pinacol rearrangement of 53a with

concomitant migration of C(7)-C(8) bond.

39

Figure 3. X-ray Strructure Drawing of 56a

Similarly, acid promoted rearrangement of 53b resulted in exclusive formation of 56a with

concomitant migration of the C(7)-C(8) bond. An X-ray structure drawing of 57a is

shown in Figure 4.34

Figure 4. X-ray Structure Drawing of 57a

40

Pinacol rearrangement of 54a was carried out by heating a solution of 54a in acetic

acid for 1 h in the presence of a catalytic amount of TsOH. In our hands, acid-promoted

pinacol rearrangement of 54a proceeded with the exclusive migration of the C(7)-C(8) 0-

bond, thereby affording 58a, mp 190.0-190.5 °C, as the only product (82% yield). The

IR and ^3C NMR spectra of 58a are similar to those of 56a and 57a. However, in the

proton noise-decoupled 1 3C NMR spectrum of 58a, there are four methylene carbon

signals located at 8 4.24, 4.78, 4.96 and 5.14 respectively, which correspond to four

methylene carbons in two cyclopropane rings of 58a. The structure of 58a was

established unequivocally via single crystal X-ray structure studies.34

C71b

ClOa Cllb

C72b

C8b

Clb

C9a

C7la

Figure 5. X-ray Structure Drawing of 58a

41

The mechanism of the acid-promoted pinacol rearrangement has been investigated

extensively. Although a stepwise mechanism which involves formation of a discrete

carbocation intermediate has been s u g g e s t e d ^ , recent results of theoretical calculations

suggest that a concerted mechanism instead may be f a v o r e d . ^ Gas phase experimental

r e s u l t s 16' 17 a i s o indicate that a carbocationic intermediate is not involved in the

rearrangement process. In addition, some experimental r e s u l t s ^ obtained for pinacol-type

rearrangements in solution have been rationalized in terms of a concerted mechanism.

Migratory aptitudes in the pinacol rearrangement have also been studied extensively.

Various experimental techniques have been employed for this purpose. For example, the

results of isotopic labeling studies, as shown in Scheme 6, suggest the following migratory

tendences of alkyl groups in pinacol rearrangements: >4000:17:1 for f-butyl, ethyl and

methyl migrations, respectively^.

Scheme 21

CH, CH, „ + 0 CH I * 3 I 3 H + „ „ »* 1

3

t-Bu- c — c - c h 3 • H £ ~ c 9 — t _ B u

I I ' OH OH CH3

98.6%

CH, O O I* II IU I

t-Bu— C — C-CH3 t-Bu- C C-CH 3 I I 3 I

C H 3 c h 3 c h 3

0% 1.4%

42

Scheme 21 (Continues)

C H O C H , O C H -3 3 I 3 H + I L I

C 2 H 5 - ( ? — C - C H 3 H 3 C - C — C - C 2 H 5

I I I O H O H

C H 3

57%

C H 3 O O C H 3

C 2 H 5 — C F — C - C H 3 C 2 H 5 - H - — C — C H 3

C H 3 C H 3 C H 3

26% 17%

However, migratory aptitude is determined by other factors in addition to "inherent"

migrating ability. Migratory aptitude also may depend upon the structure and/or

conformation of the substrate molecule. For example, the migratory aptitude of hydride

(H-C bond) vis-d-vis alkyl groups (C-C bond) can be reversed simply by changing the

configuration of the reaction terminus at C(l) and C(2) of the stereoisomeric 5-f-butyl-2-

chloro-2-phenyl-cyclohexanols (Scheme 22)10.

Scheme 22

t-Bu Ph ^ t-Bu

a Ag+ Ph

O

t - B u v / s a A g + ^ t-Bu. / \ .Ph • t - B u . /

In both cases, the group which migrates preferentially is that which is oriented

antiperiplanar to the leaving CI group (C-Cl bond). Similarly, rearrangement of 22

43

(Scheme 14) proceeds with migration of the C-C bond which is situated more nearly

antiperiplanar with respect to the protonated OH group. 4

Molecular mechanics calculations performed by using the MMX force field were

employed to analyze the acid-promoted pinacol rearrangement of PCU-derived pinacol

systems.^ A conformational search of the protonated PCU-derived piancols 53a and

53b was performed, and the torsion angles C(7)-C(8)-C(8')-OH2+ and C(9)-C(8)-C(8')-

OH2+, were determined for the conformations whose total energies lie within 3 kcal-mol" *

of that of the lowest energy structure (see Figures 6 and 7, respectively). The results of

these calculations are summerized in Tables 6 and 7, respectively.

Table 6. Results of the MMX Conformational Search of Protonated 53a

Steric

Energy Boltzmann

C<?nf flccal mol"1^ (25°C) C(9YC(S)-Cm-GHo+ Cf7KWVC(W>»>+ HO-CY 8VCC 8'VOHo+

1 138.64 90.37% -62.21 170.58 52.52 2 140.35 5.16 0.35 -117.27 118.43 3 140.43 4.48 -173.76 59.73 -52.93

Figure 6. Lowest Energy Rotational Conformation of Protonated 53a

44

Table 7. Results of the MMX Conformational Search of protonated 53b

Steric

Energy Boltzmann

Conf (kcal mol"h (25!Q a9umcmoH<>+ C(7)-C(S)-C(8>QH?+ HO-CY 8VCC 8'VOHo+

1 137.41 95.41% -75.92 165.67 43 .41

2 139.19 4 .86 -178.81 64 .93 -52.81

Figure 7. Lowest Energy Rotational Conformation of Protonated 53b

The computational results (Table 6 and Table 7) indicate that for both protonated diols 53a

and 53b the molecular structures with the lowest energy (populated to the extent of greater

than 90% according to a Boltzmann distribution) are as shown in Figure 6 and 7. The

C(7)-C(8) bonds lie in a more nearly antiperiplanar relationship to the protonated OH group

than do the C(9)-C(8) bonds. Thus, it seems that the C(7)-C(8) a-bonds have the higher

tendency to migrate than do the C(9)-C(8) a-bonds, as is observed experimentally.

However, according to Curtin-Hammett principle, "the ratio of products formed from

conformational isomers is not determined by the conformation population ratio."41

45

Therefore, additional calculations need to be carried out to more fully characterize the

potential energy surface of this reaction in order to locate possible transition state for the

various bond migration process and to determine whether the lowest energy transition state

is formed from the most thermodynamically stable conformation. The possibility of the

formation of an intermediate prior to the carbocation migration step also should be

considered.

Experimental Section

Melting points are uncorrected. NMR spectra were recorded on Varian Gemini 200

spectrometer which was operated at 200 MHz for and at 50 MHz for nuclei

(Me4Si internal standard). IR spectra were obtained on a Nicolet model 20-SXB Fourier

transform infrared spectrophotometer. Reactions which required sonication were

performed in an AmericanBrand® ultrasonic cleaning apparatus (input power 85 W).

Elemental microanalyses were performed by M-H-W Laboratories, Phoenix, AZ.

Sodium Promoted Reductive Dimerization of 51. To a solution of PCU-8-

one 51 (10 g, 63 mmol) in freshly distilled THF (50 mL) under argon was added sodium

metal (2.2 g, 95 mmol), and the resulting mixture was sonicated at room temperature for 1

h. The progress of the reaction was monitored via thin layer chromatographic (tic) analysis.

Upon completion of the reaction, the organic phase was concentrated in vacuo. Water (50

ml) was added to the residue, and the resulting aqueous suspension was extracted with

EtOAc (3 x 50 mL). The combined organic layers were washed sequentially with water (20

mL) and brine (20 mL), dried (Na2S04) and filtered, and the filtrate was concentrated in

vacuo. The residue, a yellowish solid, was purified via column chromatography on silica

gel by eluting with 5% EtOAc-hexane. A mixture of isomeric pinacols including 53a and

53b (5.0 g, 48%) was thereby obtained as a colorless microcrystalline solid: mp 220-225

°C.

This material was recrystallized from 25% EtOAc-hexane to afford a colorless

microcrystalline solid (3g). This solid was further purified via repeated column

chromatography on silica gel (400 mesh) by eluting with 5% EtOAc-hexane. Pure 53a

(200 mg) was thereby obtained as a colorless microcrystalline solid: mp 226.0-227.0 °C;

IR (KBr) 3437 (br, m), 2950 (s), 2852 (m), 1288 (m), 1267 (m), 1027 cm"1 (m); l H

46

47

NMR (CDCI3) 8 0.94 (dt, J =11.6, 3.6 Hz, 2 H), 1.14 (AB, Jab=10.4 Hz, 2 H), 1.61

(AB, Jab =10.4 Hz, 2 H), 2.13 - 2.62 (m, 18 H), 2.76 (m, 2 H); l^C NMR (CDCI3) 8

30.56 (t), 35.14 (t), 37.46 (d), 39.94 (d), 41.46 (d), 42.62 (d), 42.92 (d), 44.78 (d),

46.72 (d), 47.96 (d), 87.67 (s); Anal. Calcd for C22H26O2: C, 81.95; H, 8.13. Found:

C, 81.85; H, 8.05. The structure of 53a was established unequivocally via single crystal

X-ray structural analysis.34

In order to isolate isomerically pure 53b, it was necessary to separate this material as

the corresponding cyclic sulfite ester, 55, from the mixture of 53a and 53b produced via

sodium promoted reductive dimerization of 51. Thus, a mixture of isomeric pinacols 53a

and 53b (1.88 g, 5.8 mmol) in anhydrous pyridine (30 mL) was cooled to 0 °C via

application of an external ice-water bath. To this cold solution was added with stirring

SOCI2 (0.65 mL, 8.7 mmol). The resulting mixture was stirred at 0 °C for 1 h after the

addition of SOCI2 had been completed. Water (50 mL) was added to the reaction mixture,

and the resulting aqueous suspension was extracted with EtOAc (2 x 50 mL). The

combined organic layers were washed sequentially with water (20 mL), saturated aqueous

Q1SO4 (2 x 20 mL), water (2 x 20 mL), and brine (lOmL). The organic layer was dried

(Na2SC>4) and filtered, and the filtrate was concentrated in vacuo . The pale red residue

was purified via column chromatography on silica gel (200-425 mesh) by eluting with 5%

EtOAc-hexane. A mixture of isomeric cyclic sulfite esters (1.24 g, 59%) was thereby

obtained as a colorless microcrystalline solid: mp 134.0-138.0 °C. Repeated

recrystallization of this material from CH2Cl2-hexane afforded pure isomerically 55 (200

mg) as a colorless microcrystalline solid: mp 178.5-179.5 °C; IR (KBr) 3000 (w), 2955

(s), 2945 (s), 2859 (s), 1450 (w), 1302 (w), 1267 (w), 1211 (s), 1205 (s), 964 (m), 929

(m), 817 cm-1 (m); lH NMR (CDCI3) 8 0.99 (m, 2H), 1.12-1.24 (m, 2H), 1.60-1.74 (m,

2H), 2.12-3.02 (m, 18 H); 13c NMR (CDCI3) 8 29.68 (t), 29.81 (t), 35.03 (t), 35.36 (t),

48

37.66 (d), 37.75 (d), 38.57 (d), 39.55 (d), 40.93 (d), 41.06 (d), 41.38 (d), 44.29 (d),

44.50 (d), 44.90 (d), 45.30 (d), 46.17 (d), 46.92 (d), 47.35 (d), 47.40 (d), 47.47 (d),

96.76 (s), 101.19 (s); Anal. Calcd for C22H24O3S: C, 71.71; H, 6.56. Found: C, 71.84;

H, 6.51. The structure of 55 was established unequivocally via single crystal X-ray

structural analysis.34

Pure 53b was obtained via hydrolysis of 55. Thus, to a solution of 55 (200 mg,

0.54 mmol) in EtOH (20 mL) was added powdered KOH pellets (4 g, excess), and the

resulting mixture was refluxed for 2.5 h. The reaction mixture then was allowed to cool to

room temperature. Water (100 mL) was added and the aqueous suspension was extracted

with Et20 (3 x 50 mL). The combined extracts were washed sequentially with water (2 x

20 mL) and brine (20 mL), dried (Na2S04), and filtered. The filtrate was concentrated in

vacuo , and the solid residue was purified via column chromatography on silica gel by

eluting with 10% EtOAc-hexane. Pure 53b (155 mg, 0.48 mmol, 89%) was thereby

obtained as a colorless microcrystalline solid: mp 223.0-224.0 °C; IR (KBr) 3530 (s),

2973 (s), 2841 (s), 2653 (m), 1445 cm"l (m); lH NMR (CDCI3) 8 0.95 (dt, J = 12.4, 3.6

Hz, 2 H), 1.20 (d, J = 9.2 Hz, 2 H), 1.64 (d, J = 10.6 Hz, 2 H), 2.15-2.60 (m, 18 H),

2.79 (m, 2 H); 13c NMR (CDCI3) 8 29.91 (t), 34.84 (t), 37.14 (d), 41.14 (d), 41.50 (d),

43.64 (d), 43.84 (d), 46.91 (d), 85.60 (s). Anal. Calcd for C22H26O2: C, 81.95; H,

8.13; Found: C, 82.02; H, 7.98.

Sodium promoted reductive dimerization of 52. To a solution of

cyclopropanated PCU-8-one 52 (1.8 g, 9.7 mmol) in dry THF (30 mL), was added Na

(0.33 g, 14.3 mmol) under argon atmosphere. The resulting mixture was sonicated at

room temperature for ca. 40 min. The reaction was monitored via thin layer

chromatography (tic) analysis. The organic phase was transferred to another flask and

concentrated in vacuo. Water was added to this residue and the resulting mixture was

49

extracted with EtOAc (2 x 15 mL). The combined organic phases were washed

sequentially with water (10 mL), brine (10 mL), dried (Na2SC>4), and filtered. The filtrate

was concentrated in vacuo, thereby affording a mixture of isomeric pinacols as a yellow oil

(1.9 g). The mixture was further purified via column chromatography on silica gel (mesh

250-400) by eluting with 5% EtOAc-hexane. A colorless oil was thereby obtained which

solidified upon trituration with hexane. The resulting solid was found to be a mixture of

two isomeric pinacols (100 mg): 13c NMR 8 87.51 (s), 85.39(s), 52.97 (d), 52.63 (d),

51.22 (d), 49.67 9d), 48.52 (d), 46.94 (d), 45.26(d), 44.28 9d), 44.00 (d), 421.95 (d),

41.82 (d), 41.67 9d), 41.51 (d), 41.03 (d), 37.67 (d), 37.35 (d), 31.55 (t), 31.32 (t),

30.58 (t), 29.99 (t), 5.06 (t), 4.97 (t), 4.86 (t). This mixture was further purified via

column chromatography on silica gel (250-400 mesh) by eluting with 2% EtOAc-hexane.

Fractional recrystallization of the sample thereby obtained from hexane afforded a colorless

microcrystalline solid as isomerically pure 54a (ca. 20 mg): mp 249.0-250.0 °C; IR (KBr)

3600 (m, sharp), 3441 (m), 2968 (s), 2942 (s), 1265 (m), 1039 cm"1 (m); ! h NMR

(CDCI3) 8 0.20-0.42 (m, 4H), 0.43-0.63 (m, 4H), 0.80-1.03 (dt, 7=11.7, 3.4 Hz, 2H),

1.11-1.30 (s, 2H), 1.42-1.62 (m, 2H), 1.671.83 (m, 2H), 2.30-2.93 (m, 14H);

NMR (CDCI3) 8 85.40 (s), 53.00 (d), 51.27 (d), 46.92 (d), 44.30(d), 44.03 (d), 41.70

(d), 41.54 (d), 37.38 (d), 31.35 (t), 30.02 (t), 5.08 (t), 4.88 (t); Anal. Cald. for

C26H30O2: 83.38; H, 8.54. Found: C, 83.31; H, 8.33. The structure of 54a was

established unequivocally via application of X-ray crystallographic methods.^4

Acid Promoted Rearrangement of 53a. A mixture of 53a (280 mg, 0.86

mmol) and CH2CI2 (30 mL) was cooled to -78 °C via application of an external dry ice-

acetone bath. To this cold mixture was added with stirring TfOH (a few drops, catalytic

amount), and the resulting mixture was stirred at -78 °C for 0.5 h. The cold bath was

removed, and the reaction mixture was allowed to warm gradually to room temperature. At

50

ca. -10 °C, the colorless reaction mixture was observed to have darkened to a deep brown

color. The reaction mixture was stirred overnight at room temperature. Dilute (10%)

aqueous NaHCC>3 (15 mL) was added to the reaction mixture, and the resulting mixture

was extracted with CH2CI2 (3 x 15 mL). The combined organic extracts were washed

sequentially with water (10 mL) and brine (10 mL) and filtered, and the filtrate was

concentrated in vacuo . The residue, a brownish solid, was purified via column

chromatography on Florisil (200 mesh) by eluting with EtOAc. Crude 56a (250 mg,

96%) was thereby obtained as a pale yellow microcrystalline solid: mp 176-181 °C. The

crude product was further purified via repeated column chromatography on silica gel (400

mesh) by eluting with 10% EtOAc-hexane. Pure 56a was thereby obtained as a colorless

microcrystalline solid: mp 195.0-196.0 °C; IR (KBr) 2942 (s), 2854 (m), 1683 (m), 1451

cm-1 (w). ! h NMR (CDCI3) 8 0.80-0.95 (m, 1H), 1.12-1.66 (m, 8 H), 2.11-2.91 (m,

15 H). !3c NMR (CDCI3) 8 28.80 (t), 29.96 (t), 32.96 (t), 34.93 (d), 36.78 (d), 36.99

(d), 37.56 (d), 37.59 (t), 39.77 (d), 40.63 (d), 41.04 (d), 41.32 (d), 42.83 (d), 43.22 (d),

44.56 (d), 46.27 (d), 46.50 (d), 46.78 (d), 47.84 (d), 55.16 (d), 58.60 (s), 219.19(s).

Anal. Calcd for C22H24O: C, 86.80; H, 7.95. Found: C, 86.55; H, 8.01. The structure

of 56a was established unequivocally via single crystal X-ray structural analysis.^

Acid Promoted Rearrangement of 53b. A mixture of 53b (180 mg, 0.56

mmol) and CH2CI2 (30 mL) was cooled to -78 °C via application of an external dry ice-

acetone bath. To this cold mixture was added with stirring TfOH (few drops, catalytic

amount), and the resulting mixture was stirred at -78 °C for 0.5 h and kept stirring at room

temperature overnight. Workup was performed in the manner described above for the

corresponding acid promoted rearrangement of 53a. The crude product (160 mg, 94%)

was purified via column chromatography by eluting with 10% EtOAc-hexane. Pure 57a

(150 mg, 0.49 mmol, 88%) was thereby obtained as a colorless microcrystalline solid: mp

51

151.0-152.0 °C. IR (KBr) 2935 (s), 2864 (s), 1683 (m), 1452 (w), 1203 cm"1 (w); *H

NMR (CDCI3) 8 0.87 (m, 1 H), 1.08-1.70 (m, 6 H), 1.92-2.85 (m, 17 H); NMR

(CDCI3) 8 29.19 (t), 30.67 (t), 33.10 (t), 35.64 (d), 36.11 (d), 37.40 (q), 37.65 (d),

37.68 (t), 38.76 (d), 42.42 (d), 42.81 (d), 42.88 (d), 42.96 (d), 43.78 (d), 44.05 (d),

44.63 (d), 46.52 (d), 46.56 (d), 46.93 (d), 5.35 (d), 59.73 (s), 219.34 (s). Anal. Calcd

for C22H24O: C, 86.80; H, 7.95. Found: C, 86.90; H, 7.95. The structure of 57a was

established unequivocally via single crystal X-ray structural a n a l y s i s . 3 4

Acid promoted rearrangement of 54a. To a solution of pinacol 54a (14 mg,

0.037 mmol) in HOAc (10 mL) was added TsOH (3 mg, catalytic ammount). The

resulting mixture was refluxed for 1 h and then allowed to cool to room temperature.

Water (20 mL) was added to quench the reaction. The resulting mixture was then extracted

with CH2CI2 (3 x 10 mL). The combined organic phases were washed with water, filtered

through a pad of silica gel, and eluted with EtOAc. The filtrate was concentrated in vacuo

to afford a brownish solid residue as the crude product. This material was dissolved in

CDCI3 (0.5 mL), and the resulting solution was used for NMR studies. The NMR

spectrum of this solution indicated that only one compound had been produced by the

reaction. The solution was concentrated in vacuo, and the solid residue was further

purified via column chromatography on silica gel (200 mesh) by eluting with EtOAc:hexane

(1:10), thereby affording a colorless microcrystalline solid 58a (11 mg, 82.5%): mp

190.0-190.5 °C; IR (KBr) 2946 (s), 2857 (m), 1681 (m) cm"1; *H NMR (CDCI3) 8

0.27-0.66 (m, 8 H), 0.89 (dt, /=12.4 Hz, 7=3.4 Hz, 1H), 1.20-1.43 (m, 2 H), 1.51-1.81

(m, 5 H), 2.14 (d, 7=12.4 Hz, 1 H), 2.33-2.47 (m, 1 H), 2.50-3.06 (m, 10 H);

NMR (CDCI3) 8 4.24 (t), 4.78 (t), 4.96 (t), 5.14 (t), 29.61 (t), 29.92 (s), 30.73(t), 34.44

(s), 36.47 (d), 37.81 (d), 37.92 (d), 38.92, 41.81 (d), 42.82 (d), 42.88 (d), 43.10 (d),

43.61 (d), 44.43 (d), 45.38 (d), 47.56 (d), 50.56 (d), 52.57 (d), 52.69 (d), 55.32 (d),

52

59.86 (s), 219.20 (s); Anal. Cald for C26H28O: C, 87.60; H, 7.92. Found: C, 87.43; H,

7.88. The structure of 58a was establised unequivocally via single crystal X-ray structure

studies.34

Conclusions

Three isomerically pure PCU-derived pinacols 53a, 53b and 54a were successfully

synthesized and characterized. Acid-promoted rearrangement of each of the three pinacols

proceeds smoothly with the exclusive migration of C(7)-C(8) o-bond, thereby affording

only 56a, 57a and 58a, respectively. Computational results show that in the lowest

energy conformations of both protonated 53a and 53b, C(7)-C(8) bonds lie in a nearly

antiperiplanar relationship to the C(7')-0(H2+) bonds. However, further calculations are

required in order to elucidate the reaction mechanism.

53

References

1. Ingold, C. K. Structure and Mechanism in Organic Chemistry, Cornell University

Press: Ithaca, NY, 1969, p. 724.

2. See: de Mayo, P., Ed. Molecular Rearrangement, Wiley-Interscience: New York, 1963,

Vol. 1, pp. 15-19.

3. Collins, C. J. Quart. Rev. (London) 1960,14, 357 .

4. Herlihy, K. P. Aust. J. Chem. 1981,34, 107 and references cited therein.

5. Stiles, M.; Mayer, R. P. J. Am. Chem. Soc. 1959, 81, 1497.

6. (a) Collins, C. J. / . Am. Chem. Soc., 1955, 77, 5517. (b) Collins, C. J.; Rainey, W.

T.; Smith, W. B.; Kaye, I. A. ibid. 1959, 81, 460. (c) Collins, C. J.; Bowman, N. S.

ibid. 1959, 81, 3614.

7. (a) Pocker, Y.; Ronald, B. P. J. Am. Chem. Soc. 1970, 92, 3385. (b) Pocker, Y.;

Ronald, B. P. J. Org. Chem. 1970,35, 3362.

8. Bunton, C. A.; Carr, M. D. J. Chem. Soc. 1963, 5854.

9. Carey, F. A.; Sunderg, R. J. Advancd Organc Chemistry Part A: Structure Mechanism,

Plenum Press: New York, NY, Third Edition, 1990, P. 137.

10. Barili, P. L.; Berti, G.; Macchia, B.; Monti, L. J. Chem. Soc. (C) 1970, 1168.

11. Berti, G.; Macchia, B.; Monti, L. J. Chem. Soc. (C) 1971, 3771.

12. Bunton, C. A.; Carr, M. D. J. Chem. Soc. 1963, 5861.

54

55

13. (a) Kleinfelter, D. C.; Schleyer, P. von. R. / . Am. Chem. Soc. 1961, 83, 2329. (b)

Kleinfelter, D. C.; Dye, T. E. J. Am. Chem. Soc. 1966,88, 3174-6.

14. (a) Collins, C. J.; Benjamin, B. M. J. Am. Chem. Soc. 1964, 86, 4913. (b)

Benjamin, B. M.; Collins, C. J. ibid. 1966, 88, 1556.

15. Bushell, A. W.; Wilder, P. J. Am. Chem. Soc. 1967,89, 5721.

16. Petris, G. D.; Giacomello, P.; Picottic, T.; Pizzabiocca, A.; Renzi, G.; Speranza, M.

/ . Am. Chem. Soc. 1986,108, 7491.

17. Petris, G. D.; Giacomello, P.; Picottic, T.; Pizzabiocca, A.; Renzi, G.; Speranza, M.

J. Am. Chem. Soc. 1988,110, 1098.

18. (a) Nakamura, K.; Osamura,Y. Tetrahedron Lett. 1990,31, 252. (b) Nakamura, K.;

Osamura,Y. J. Phys. Org. Chem. 1990,3, 737. (c) Nakamura , K.; Osamura, Y. J. Am.

Chem. Soc. 1993,115, 9112.

19. (a) Suzuki, K.; Katayama, E.; Tsuchihashi, G. Tetrahedron Lett. 1983,24, 4997. (b)

Suzuki, K.; Katayama, E.; Tsuchihashi, G. ibid. 1984, 25, 1817. (c) Tsuchihashi, G.;

Tomooka, K.; Suzuki, K. ibid. 1984, 25, 4253. (d) Suzuki, K.; Tomooka, K.;

Shimazaki, M.; Tsuchihashi, G. ibid. 1985,26, 4781.

20. de Mayo, P. reference 2, pp. 24-25.

21. Ingold, C. K. reference 1, pp. 500-503.

22. Beggs, J. J.; Meyers, M. B. J. Chem. Soc.(B) /970, 930.

23. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry, Pergamon Press:

Oxford, 1983, pp. 190-191.

56

24. Takeuchi, K.; Yoshida, M.; Nishida, M.; Kohama, A.; Kitagawa, T. Synthesis

1991, 37.

25. Mundy, B. P.; Otzenberger, R. D. J. Chem. Edu.1971,48, 431.

26. Streitwieser, A., Jr. Solvolytic Displacement Reactions, McGraw-Hill: New York,

1962, p. 95.

27. Botteron, D. G.; Wood, G. J. Org. Chem. 1965,33, 3871. See also references 4 and

5 cited therein.

28. Sands, R. D. Tetrahedron 1965,21, 887. See also references 1-4 cited therein.

29. Mundy, B. P.; Srinivasa, R. Tetrahedron Lett. 1979,28, 2671.

30. Mundy, B. P.; Srinivasa, R.; Otzenberger, R. D.; DeBernardis, A. R. ibid. 1979,29,

2673.

31. Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 221.

32. (a) Marchand, A. P.; Allen, R.W. J. Org. Chem.. 1974, 39 , 1596. (b) Singh, V.

K.; Raju, B. N. S.; Deota, P. T. Synth. Comm. 1986,16, 1731. (c) Eaton, P. E.;

Cassar, L.; Hudson, R. A. and Hwang, D. R. J. Org. Chem. 1976, 41, 1445.

33. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identification of

Organic Compounds, John Wiley & Sons: New York, Fifth Edition, 1991, pp 276-278.

34. Bott, S. G. unpublished results. All single crystal X-ray structure determinations

presented in this chapter were performed by Dr. Simon G. Bott. The author gratefully

acknowledges Dr. Bott for his x-ray crystallographic studies presented in this chapter.

57

35. Gadgil, V. R. unpublished results. The author gratefully thanks Dr. Gadgil for his

having fully characterized cyclosulphite ester of d,/-pinacol and having developed the

method to isolate d,l -pinacol.

36. Wynberg, H.; Boelema, E.; Wieriga, J. H.; Strating, J. Tetrahedron Lett. 1970,

3613.

37. Marchand, A. P.; Vidyasagar V.; Watson, W. H.; Nagl, A.; Kashyap, R. P. J. Org.

Chem. 1991,56, 282.

38. Marchand, A. P.; Reddy, G. M.; Deshpande, M. N.; Watson, W. H.; Nagl, A.; Lee,

O. S.; Osawa, E. J. Am. Chem. Soc. 1990,112, 3521.

39. Stiles, M.; Mayer, R. D. J. Am. Chem. Soc. 1959, 81, 1497.

40. Burritt, A. unpublished results. The author gratefully thanks Dr. Burritt for his

calculations presented in this chapter.

41. Carey, F. A.; Sunderg, R. J. reference 9, P.215-216.

CHAPTER II

SYNTHESIS OF A TRIMETHYLTRISHOMOCUBYL HELICAL TUBULAND DIOL

Introduction

The study of inclusion phenomena, or "host-guest chemistry", has received increasing

attention recently due to its theoretical and practical significance.^ Inclusion complexes

refer to systems in which guest species are complexed by host species through non-

covalent interactions. 1 Two kinds of inclusion complexes have received considerable

attention: In the first, a guest species is accommodated by a unimolecular host (in solution

or in the solid state), e.g., the "crown ether type" compounds (Figure 1) and cyclodextrins

(Figure 2). In the other, guest molecules are bound by crystalline multimolecular inclusion

hosts. The former class is commonly subclassified to include "perching complexes",

"nesting complexes" and "capsular complexes", according to their visualized shapes

(Figure 1). The latter class is further subclassified into true clathrate or "cage-type",

"channel- or canal-type" and "layer-type" according to the structural features of the host's

crystal lattice. For example, (3-hydroquinone^>3,4 an(} Dianin's compound^ are clathrate-

type hosts which trap their guest molecules in discrete closed cavities or cages. Urea and

t h i o u r e a ^ belong to the canal-type in which guest species occupy continuous canals

running throughout the crystal. Graphite is an example of the layer-type hosts which

accommodate guest molecules within the interlayer spaced

58

59

CH.

a r t .

r\.n^

Figure 1. Three types of unimolecular complexes: 1 is a perching complex, 2 is a nesting complex, and

3 is a capsular complex. Left: CPK models1' right: crystal structures. (Reproduced from Cram, D. J.

Angew. Chem. Int. Ed. Engl. 1988,27, 1010.)

OH

Figure 2. Schematic representation of a and 0-cyclodextrin (a and 0-CD) formed by six and seven of a-

1,4-linked D-glucopyranose units. Inclusion phenomena are found both in crystal and in solution.

(Reproduced fromMacNicol, D. D.; McKendrick, J. J.; Wilson, D. R. Chem. Soc. Rev. 1978,7, 65.)

A structure drawing of an inclusion complex of the cage-type formed between

hydroquinone (host) and hydrogen sulfide (guest, denoted S) is shown in Figure 3.7 The

60

"roof' and the "floor" of each cage are comprised of hexagons of hydrogen-bonded

hydroxyl groups. The "wall" consists of six C6H4 groups, three of which originated from

the top and three from the bottom. The guest molecule, H2S (S), is trapped between these

hexagonal (OH)6 circles.

HO KD-0'1 p-hydroquinone

Figure 3. Crystal structure of a complex formed by hydrogen sulfide guest (S) trapped inside a cage of P-

hydroquinones. All hydrogen atoms have been omitted for clarity. (Reproduced from Mak, T. C. W.; Tse,

J. S.; Tse, C.; Lee, K.; Chong, Y. J. Chem. Soc. Perkin Trans. 2 1976, 1169.)

The structure of Dianin's compound, 4-p-hydroxyphenyl-2,2,4-trimethylchroman, is

shown below.

Figure 4 shows a stereo view of cages built up by Dianin's compound**. These cages

possess the capability to accommodate various guest molecules. A stereo view of a

Dianin's complex (guest: w-heptyl alcohol) is shown in Figure 5.8

61

Figure 4. A stereodiagram of the slacking of two complexes along the c axis to form the closed cavities

in the crystal. (Reproduced from Flippen, J. L.; Karle, J. / . Phys. Chem. 1971,75, 3567.)

Figure 5. The orientation of the n-heptyl alcohol molecule within the cage comprised by Dianin's

compound. (Reproduced from Flippen, J. L.; Karle, J. J. Phys. Chem. 1971, 75, 3567.)

Bishop and coworkers found that compounds 4-9 belong to the novel canal-type host

f a m i l y . 9 These new canal-type inclusion complexes are distinct from unimolecular

complexes and other crystalline multimolecular complexes such as those hosted by |3-

62

hydroquinone and Dianin's compound. The host lattices adopted by this new family are

built up by the diol units and linked by the spines of intermolecular hydrogen bonds in a

spiral pattern (Figure 6). These new host compounds are therefore named "helical

tabuland" hosts.

W HjC V V CHj

HO, OH

CH,

HO

HjC

.OH

CH,

s<-j

Figure 6. Projection view in the ab plane of one canal of the helical tubuland lattice adopted by diols 4-

9. Key hydrogen atoms defining the van der Waals boundary of the host canals are shown as solid black

spheres. The hydrogen bonded spines are circled in these diagrams and the hydrogen bonds represented as

dashed lines. (Reproduced from Bishop, R.; Craig, D. C.; Dance, I. G.; Scudder, M. L.; Marchand, A. P.;

Wang, Y. / . Chem. Soc. Perkin Trans. 2 1993, 937.)

63

A projection view of the diol network in crystal (4)3-EtOAc is shown in Figure 7. M This

structure is constructed by hydrogen-bonded spines of the type -O-H-O-H-O-H- O-H-.

The diol molecules radiate from and interconnect these spines. Six spines surrounding

each canal form a hexagonal ring.

Figure 7. Projection view of the diol host network in (4): the filled circles and dotted lines represent OH

hydrogen atoms and hydrogen bonds, respectively; other hydrogen atoms are omitted for clarity. ITie

hydrogen-bonded spines are circled, and die tubes are outlined as triangles. (Reproduced from Dance, I. G.;

Bishop, R.; Hawkins, S. C.; Lipari, T.; Scudder, M. L.; Craig, D. C. J. Chem. Soc. Perkin Trans. 2

1986, 1300.)

64

Figure 8. Diagrammatic representation of the sequence of hydrogen-bonded diol molecules (denoted

HOC-COH) comprising one spiral turn around the tube. (Reproduced firom Dance, I. G.; Bishop, R.;

Scudder, M. L. J. Chem. Soc. Perkin Trans. 2 1986, 1310.)

Figure 8 reflects the key elements of the structure.11 Diol molecules are hydrogen-

bonded around a tube in the spiral sequence. In this sequence, each diol donates two

hydrogens and accepts another pair of hydrogens to form hydrogen-bonds. One complete

turn of each spiral chain consists of six diol molecules. Figure 9 is an exaggerated view of

part of a double helix formed by hydrogen-bonded diol molecules which constitute one

such canal. 11 The boundary of the canal is formed by hydrogen atoms of saturated

hydrocarbons. The cross section of each channel, which is defined by the van der Waals'

radii of these hydrogen atoms, is approximately triangular. Each diol interconnects two

hydrogen-bonded spines and provides two C-OH bonds which determine the first

orientation of the spiral chain. The host molecule consists of two different faces, which are

syn and anti, respectively, to the C-0 bonds. When the diol molecules bridge the spines,

they present syn and anti faces alternately towards the center of the canal, as shown in

65

Figure 8. There is only one type of canal in crystal lattice. The size and shape of the canal

are determined by both the syn and anti portions of the host.

pr

Figure 9. Exaggerated perspective view of the helices formed by hydrogen-bonded diol molecules in one

tube of (4): all except one diol molecule are represented diagrammatically as the connector of the two OH

groups. (Reproduced from Dance, I. G.; Bishop, R.; Scudder, M. L J. Chem. Soc. Perkin Trans. 2 1986,

1310.)

Studies of the above diols and related compounds have been employed: (i) to design

and to synthesize new members of the helical tubuland host diol family, (ii) to investigate

their inclusion properties, and (iii) to develop an understanding of the molecular factors

which result in this unusual behavior. According to earlier studies, the following tentative

molecular determinants have been proposed as the "membership rules" of the helical

tabuland family: 12,13

(1) The diol molecules must have a average C2 rotational symmetry in solution.

Thus, diol 10 does not form helical tubuland structure. ^

66

10 11

(2) The molecular structure must contain certain degree of flexibility which allows

the skeleton to adopts the conformation required by the crystal lattice. Diol 11 lacks this

kind of flexibility in its structure and therefore crystallizes in a different type of crystal

lattice.

(3) Substituent groups around the periphery prevent the diol forming a helical lattice.

Heteroatoms may interfere with the hydrogen bonding in the host. For example, diol 12

adopts pillared hydrogen-bonded structures. 15 Substituents located nearby the tertiary C-

OH carbons also should be avoided. For example, diol 13 does not crystallize in a helical

tubuland lattice.^

HO.

H3C

O

OH

CH3

12 13

(4) The two hydroxyl groups must be separated by a molecular bridge, which plays

an important role in buttressing the canal walls against collapse to a more dense structure.

Thus, e.g., diol 14 adopts a totally different crystal structure which involves hydrogen

bonded layers^.

67

14

(5) Whether or not the diol has a bridge on the side opposite to the hydroxyl groups

is optional. In fact the size of the bridge may even be modified to control the canal

dimensions.

(6) It was reported that diols 15 and 16 do not adopt the helical tubuland latt ice . 16

It is therefore suggested that the substituent on the tertiary alcohol carbon must be a methyl

group, which appears to be the right size, shape, and rigidity to support the canal wall

structure.

HOL ^ . „OH

R

15. R=H; 16. R=C2H5 17

Alicyclic compound 17 has been designed and synthesized to examine the above

molecular determinants, especially the effect of determinant (2) on the formation of helical

tubuland lattice. 13 This compound meets all the requirements listed as determinants except

(2). X-ray structural studies indicated that compound 17 indeed crystallizes with the

helical tubuland lattice. Its inclusion behavior was also evidenced by proton NMR, IR and

elemental microanalysis. It was noted that the cross-ring O-C—C-O torsion angle (163.1°)

68

in this diol is significantly different from those in diol 4 (73.8°) and diol 7 (97.4°) while the

cross-ring (Me)(OH)C—C(OH)(Me) distance in 17 (3.65 A ) is close to the corresponding

measurements in diol 4 and diol 7 (3.71 and 3.82 A respectively). Therefore, the cross-

ring O-C—C-O torsion angle is not important in the prediction of helical tubuland structure

and it was concluded that molecular determinant (2) can also be satisfied if the necessary

degree of twist is incorporated as part of the alicyclic skeleton. Thus, a wide range of

carbocyclic skeletons will have the capability to function as molecular spacer groups that

support the formation of helical tubuland structure, if the molecular determinants are met

To discover more new members of the helical tubuland diol family and to determine

the importance of the molecular determinant (1), 4,7,11-

trimethylpentacyclo[6.3.0.02»6.05,9]un(jecane.ejCo.4)ej|[:o.7_(jioi (23a), a methyl-

substituted analogue of 17, was synthesized and its crystal structure was determined.

Me

-OH

23a

Results and Discussion

Target molecules 4,7,1 l-trimethylpentacyclo[6.3.0.()2A()3> 10.o5>9]Undecane-4,7-

diols 23a-d were synthesized as shown in Scheme 1 by using cage diester 1 8 ^ as the

starting material.

A Scheme 1

a, b

O

o-/^-OEn ...0(0)CEt E t C ( 0 ) 0 ^ * - ' — " Bn,

18 1 9

ch 2 h Me

20 21

H Me

H Me

Me Me Me

OH HO OH

23a

H Me

Me \ g

23b H Me

23c 23d

(a) lJvTa/MeOH; 2. (CH2COOH)2; 3. NaHC03 (100%);17 (b) KOH/H2O (1:1), BnCl, TABA18 (76%); (c)

CH3PPh3Br, BuLi, THF (63%); (d) H2 (40 psi), Pd/C , EtOH (95%); (e) Jones Reagent,19 Acetone

(74%); (f) 1. CH3MgBr, Et20; 2. NH4CI, H2O (87%).

69

70

Preparation of the starting material 18 was carried out as described in Scheme 2^>

20-23 starting with hexachlorocyclopentadiene and benzoquinone.

Scheme 2

CL XI MeOv OMe MeOv ,OMe

CI. J J ^ C l

MeO OMe

L - OH - O H

OH

MeOv .OMe

-OH

OH EtCOO'

OOCEt

18

(a) KOH/MeOH (76-77%); (b) Benzoquinone, C6H5CH3, reflux, overnight (82%); (c) NaBH4,

Cecl3.7H20, MeOH (60%); (d) hv, Acetone (90%); (e) Li/NH3, t-BuOH, THF, -33 °C (92%); (f)

EtCOOH, H2SO4 (conc.), reflux, 72 h (51%).

71

It is necessary to convert cage-diester 18 to cage-diether 19, since subsequent

reaction of 18 with methylenetriphenylphosphine was found to afford the corresponding

Wittig product only in very low yield (<10%). In addition, cage diol 24 displays very poor

solubility in most common organic solvents.

24

Conversion of 18 to 19 was performed in two steps: (1) hydrolysis of 18 to give cage-diol

2 4 ( 2 ) reaction of diol 24 (without further purification) with benzyl chloride and 50%

aqueous KOH solution. The latter reaction was performed in presence of

tetrabutylammonium bisulphate (TBAB), a phase transfer catalyst . 18 Application of this

two-step procedure afforded 19 (76% yield) as a colorless microcrystalline solid: mp 111-

112 °C. The 1H NMR spectrum of 19 contains an AB pattern [8A 4.42 (2 H), 8B 4.50 (2

H) JAB=12.0 Hz], which can be assigned to the methylene group situated between the

phenyl group and the oxygen. The multiplet signal at 8 7.31 (10 H) can be assigned to the

phenyl protons. The proton noise-decoupled NMR spectrum of 19 contains a total of

11 peaks, a result which indicates that the molecule contains a twofold symmetry element.

A triplet at 8 71.18 and four doublets at 8 127.54,127.69, 128.39 and 138.13 respectively

in the NMR (APT spectrum) suggest the presence of a benzyl group in 19. The IR

spectrum of 19 contains absorptions at 1753 (C=0), 1068 (C-O-C), 732 and 692 cm~ 1

(monosubstituted phenyl group). Elemental microanalytical results are consistent with the

assigned molecular formula for 19. Unequivocal verification of the structure of 19 was

72

secured via single crystal X-ray structural analysis.^ An X-ray structure drawing of 19 is

shown in Figure 10.

0 4

ar ftttuis

C 1 1 6

C 1 1 7

0 1 1 1

C114

C115

Figure 10. X-ray Structure Drawing of 19

Wittig reaction of 19 with methylenetriphenylphosphine gave product 20 (63%

yield) as a colorless solid: mp 71-72 °C. The *H NMR spectrum of 20 contains a singlet at

8 4.75, which can be assigned to the methylene group at C (11). The NMR spectrum

of 20 indicates the absence of a carbonyl carbon signal in the region ca. 8 200 and the

presence of C=C double bond signals at 8 98.82 and 156.15. The IR spectrum of 20

contains absorptions at 1683 (C=C), 1093 (C-O-C), 745 and 698 cm"* (monosubstitued

phenyl group). Elemental microanalytical results are consistent with the assigned molecular

formula for 20.

Catalytic hydrogenation of 20 performed in the presence of a catalytic amount of

10% Pd on activated charcoal gave 21 (95% yield) as a colorless microcrystalline solid: mp

207-208 °C. This reaction resulted in addition of hydrogen to the C=C double bond in 20

with concomitant removal of the benzyl group. The *H NMR spectrum of 21 contains a

73

doublet at 8 0.87 (7=6.7 Hz, 3 H) which can be assigned to the methyl group at C (11). In

addition, two broad singlets appear at 8 3.82 and 3.88 which can be assigned to the two

hydroxyl groups. No proton signal which might correspond to a phenyl group (i.e. in the

region 8 7-9) is present in the *H NMR spectrum of 21. The proton noise-decoupled

NMR spectrum of 21 contains a total of 12 peaks, none of which correspond to aromatic

carbon signals. Two C-OH groups, C(4) and C(7) can be observed at 8 74.81 and 75.28,

respectively. The foregoing NMR data are consistent with the expectation that the

presence of a methyl group at C(11) removes the C2 symmetry which originally existed in

the molecule of its precursor 20. The IR spectrum of 22 contains strong O-H absorption at

3239 cm~l. Elemental microanalytical results are consistent with the assigned molecular

formula for 21.

Cage diol 21 was oxidized by Jones r e a g e n t ^ to cage dione 22 in 74% yield;

Compound 23 was thereby obtained as a colorless solid: mp 52-53 °C. The proton noise-

decoupled l ^c NMR spectrum of dione 22 contains 12 carbon resonances. Absorptions at

8 210.97 and 211.42 account for two carbonyl carbons C(4) and C(7), and the remaining

ten carbon signals fall in the aliphatic region (8 10-50). The IR spectrum of 22 contains a

strong C=0 absorption at 1750 cm~l. Elemental microanalytical results are consistent with

the assigned molecular formular for 22.

Grignard reaction of 22 with methylmagnesium bromide in anhydrous Et20

afforded a mixture of isomeric trimethyltrishomocubane diols 23a-d as a colorless

microcrystalline solid: mp 155-163 °C. Flash column chromatographic purification of this

product mixture afforded a single pure isomer 23a as a colorless microcrystalline solid: mp

211-212 °C. The proton noise-decoupled 13c NMR spectrum of 23a contains 14 peaks.

The signal at 8 14.80 can be assigned to the methyl group at C(ll). The other two signals

74

at 8 23.09 and 23.45 can be assigned to the remaining methyl groups at C(4) and C(7).

Two singlets at 8 82.01 and 82.35 correspond to C(4) and C(7). The remaining nine

methine carbon signals fall in the aliphatic region (8 10-50). The IR spectrum of 23a

contains strong O-H absorption at 3313 cmr 1. Elemental microanalytical results are

consistent with the assigned molecular formula for 23a.

The foregoing spectral data were not sufficient to determine the structure of 23a. Its

structure was unequivocally established via application of X-ray crystallographic

m e t h o d s . 2 5 An X-ray structure packing diagram of 23a is shown in Figure 11.

Figure 11. X-ray structure packing diagram of 23a

75

The results of x-ray crystallographic studies indicate that 23a does indeed cystallized

in a helical tubuland lattice (Figure 11).26 The methyl groups at C(ll) protrude into the

central canal. The central canal is too small to accommodate any guest molecule due to the

Figure 12 Model of the crystal lattice adopted by diol 23a

76

presence of methyl groups (Figure 13). This is the first helical tubuland structure where the

diol does not have actual C2 rotational symmetry in so lut ion .25 it is therefore resonable to

suggest that the existence of C2 symmetry in the isolated molecule is not a structure

requirement which must be met in order for a tertiary diol to crystallize in a helical tubuland

lattice. Therefore, a wider range of tertiary diols are expected to adopt a helical tubuland

lattice.

Isomer 23b, mp 206-207 °C, was obtained via fractional recrystallization of the

mixure of 23b, c and d. The proton noise-decoupled NMR spectrum of 23b contains

14 peaks. The signal at 8 14.64 can be assigned to the methyl group at C(11). Two signals

at 8 23.14 and 23.47 can be assigned to the remaining methyl groups at C(4) and C(7).

Two singlets at 8 82.02 and 82.25 correspond to C(4) and C(7). The remaining nine

methine carbon signals fall in the aliphatic region (8 10-50). Elemental microanalytical

results are consistent with the assigned molecular formula for 23b. The structure of this

isomer was showed unequivocally to be 23b via the results of single crystal X-ray

structure s tud ies .24 An X-ray structure drawing of 23b is shown in Figure 13.

Since the diol 23b does not possess a carbocyclic skeleton with average C2 rotational

symmetry. It is expected that this diol would not form the helical tubuland lattice. This

prediction is comfirmed experimentally (Figure 14).

77

Figure 13. X-ray Structure Drawing of 23 b

78

Figure 14. Crystal Lattice formed by 23b

Experimental Section

Melting points are uncorrected. (200 Hz) and l^C (50 MHz) NMR spectra were

recorded using a Varian Gemini-200 FT-NMR spectrometer and are reported as chemical

shift (8) relative to SiMe4. IR spectra were obtained by using a Nicolet 20 SXB FTIR

spectrometer.

ejco-7,ejco-ll-Bis(benzyloxy)pentacyclo[6.3.O.o2>6.o3,lO>05,9]unje.

cane-4-one (19). To a solution of 1 8 ^ (4.8 g, 14.8 mmol) in MeOH (50 mL) was

added Na (30 mg, 1.3 mmol), and the resulting mixture was stirred for 1 h. Oxalic acid

(0.5 g, excess) was then added to neutralize the solution. The resulting mixture was filtered

through a pad of NaHC03. The filtrate was concentrated in vacuo to afford a gummy

residue. To this residue was added 50% aqueous KOH (5 mL, excess) and

tetrabutylammonium bisulfate (TBAB, 250 mg, catalytic amount), followed by benzyl

chloride (4 mL, excess). The resulting mixture was stirred overnight at ca. 50 °C. The

reaction was quenched via addition of water (50 mL). The reaction mixture was then

extracted with Et20 (3 x 50 mL). The organic layer was washed sequentially with water

(50 mL) and brine (30 mL), dried (Na2S04) and filtered. The filtrate was concentrated in

vacuo , thereby affording an oily residue. The residue was purified via column

chromatography on silica gel by eluting with EtOAc-hexane (1:10). Compound 2 (4.2 g,

76%) was thereby obtained as a colorless microcrystalline solid: mp 108.0-110.0 °C. An

analytical sample, mp 111.0-112.0 °C, was obtained by repeated recrystallization of this

sample from EtOAc-hexane; IR (KBr) 3671 (m), 3391 (w), 3281 (w), 2993 (s), 2966 (s),

2863 (s), 2822 (m), 2774 (w), 1754 (s), 1486 (m), 1452 (m), 1349 (s), 1178 (s), 1103

(s), 1069 (s), 1020 (s), 918 (m), 732 (s), 692 (s) cm"l; lH NMR (CDCI3) 8 2.29 (m, 4

H), 2.63 (s, 4 H), 4.08 (s, 2 H), 4.42 (AB, JAB = 12.0 Hz, 2 H), 4.50 (AB, JAB = 12.0

79

80

Hz, 2 H), 7.31 (m, 10 H); NMR (CDCI3) 5 38.70 (d), 42,28 (d), 46.23 (d), 46.81

(d), 71.18 (t), 84.42 (d), 127.54 (d), 127.69 (d), 128.39 (d), 138.03 (s), 215.73 (s);

Anal. Calcd for C25H24O3: C, 80.62; H, 6.49. Found: C, 80.47; H, 6.61. The structure

of 2 was established unequivocally via single crystal X-ray structural analysis.

exo-4,ejt0-7-Bis(benzyloxy)-ll-methyleiiepeiitacyclo[6.3.0.0^»^.

0340. 05>9]-undecane (20). A suspension of methyltriphenylphosphonium bromide

(4.3 g, 12 mmol) in dry THF (150 ml) was cooled to -78 °C via application of an external

dry ice-acetone bath. To the resulting suspension was added n-BuLi (2.5 M solution in

hexane, 4.8 mL, 12 mmol), and the resulting mixture was stirred at this temperature under

argon for 1 h . A solution of 2 (3.0 g, 8.0 mmol) in dry THF (100 mL) was added to the

above mixture. The external cold bath then was removed, and the reaction mixture was

allowed to warm gradually to room temperature with stirring overnight. The reaction

mixture was refluxed for 1 h and allowed to cool to room temperature. Water (100 ml) was

added, and the resulting mixture was extracted with hexane (3 x 100 mL). The organic

layer was washed sequentially with water (50 mL) and saturated aqueous NH4CI solution

(50 mL), dried (Na2SC>4), and filtered. The filtrate was concentrated in vacuo, thereby

affording an oily yellow residue. This residue was purified via column chromatography on

silica gel (200 mesh) by eluting with EtOAc-hexane. A colorless oil was thereby obtained

which solidified upon trituration with EtOH at 0 °C. The resulting solid (crude 20, 1.8 g, 5

mmol, 63%) displayed mp 70.0-72.0°C. Recrystallization of this sample from EtOAc-

hexane afforded pure 20: mp 70.0-71.0 °C; IR (KBr) 3056 (m), 3021 (m), 2987 (s), 2973

(s), 2882 (s), 2831 (m), 2352 (w), 2331 (w), 1683 (m), 1492 (m), 1442 (m), 1394 (w),

1350 (s), 1309 (m), 1281 (m), 1210 (m), 1182 (m), 1093 (s), 1080 (s), 985 (m), 884 (s),

844 (m), 752 (s), 698 (s) cm'l; lH NMR (CDCI3) 5 2.22 (s, 2 H), 2.33 (s, 4 H), 2.82

(m, 2 H), 3.94 (s, 2 H), 4.46 (AB, JAB = 11.8 Hz, 2 H), 4.55 (AB, Jab = 11.8 Hz, 2

81

H), 4.75 (s, 2 H) 7.31 (m, 10 H); 13c NMR (CDCI3) 8 40.77 (d), 45.63 (d), 47.92 (d),

48.03 (d), 71.05 (t), 84.02 (d), 98.82 (t), 127.48 (d), 127.52 (d), 128.32 (d), 138.65 (s),

156.15 (s); Anal. Calcd for C26H26O22: C, 84.29; H, 7.07. Found: C, 84.10; H, 7.16.

ex0-4,ex0-7-Dihydroxy-ll-methylpentacyclo[6.3.0.0.2,6.o3,10.

05>9].Undecane (21). To a solution of 20 (1.65 g, 4.2 mmol) in EtOH (100 mL), was

added 10% Pd/C (300 mg, catalytic amount). The resulting mixture was shaken under H2

atmosphere (40 psig) overnight on a Parr hydrogenation apparatus. The mixture was

filtered through Celite, and the filtrate was concentrated in vacuo. Crude 21 (0.77 g, 4.0

mmol, 95%) was thereby obtained as a colorless microcrystalline solid. Fractional

recrystallization of this material from EtOAc afforded pure 21 as a colorless microcrystalline

solid: mp 207.0-208.0 °C; IR (KBr) 3239 (s), 2959 (s), 2890 (s), 2342 (w), 1452 (m),

1335 (s), 1280 (m), 1185 (m), 1055 (s), 801 (m) cm"l; lH NMR (DMSO-d6) 8 0.87 (d,/

= 6.7 Hz, 3 H), 1.79 - 2.39 (m, 9 H), 3.82 (br s, 1H), 3.88 (br s, 1H), 4.46 (m, 2 H);

13c NMR (DMSO-d6) 8 15.05 (q), 38.48 (d), 38.66 (d), 40.94 (d), 47.80 (d), 48.01 (d),

48.10 (d), 48.90 (d), 49.77 (d), 51.44 (d), 74.81 (d), 75.28 (d); Anal. Calcd for

C12H1602: C, 74.97; H, 8.39. Found: C, 74.70; H, 8.25.

ll-Methylpentacyclo[6.3.0.02>6.o3,10.o5,9]undecane-4,7-dione (22).

Preparation of Jones' Reagent: 19 To a solution of CrC>3 (2.7 g, 27 mmol) in water (8 mL)

was added carefully concentrated H2SO4 (2.3 mL). The resulting solution was then used

as obtained in the procedure which follows. A solution of cage-diol 21 (600 mg, 3.1

mmol) in acetone was titrated by dropwise addition of Jones' Reagent while stirring at room

temperature. A green precipitate of chromium (III) salt was formed during the reaction.

Titration was continued until the acetone layer became brownish. The mixture was filtered

through a pad of NaHCC>3, and the filtrate was concentrated in vacuo. The residue was

dissolved in Et20, and the resulting ethereal solution was washed with water (2 X 50 mL),

82

dried (MgS04), and filtered. The filtrate was concentrated in vacuo to afford an oily

residue. This residue was purified via column chromatography on silica gel by eluting with

EtOAc:hexane (1:5). A colorless oil (570 mg) was thereby obtained which solidified upon

trituration with Et20 at ca. 0 °C. Recrystallization of the solid thereby obtained afforded

pure 23 (423 mg, 2.3 mmol, 74%) as a colorless microcrystalline solid: mp 52.0-53.0 °C;

IR (KBr) 3281 (m), 2960 (s), 2918 (m), 2870 (m), 1750 (s), 1444 (w), 1151 (m), 1068

(m) cm"1; ! h NMR (CDCI3) 8 0.83 (d, J = 6.7 Hz, 3 H), 1.95-2.26 (m, 5 H), 2.31-2.50

(m, 2 H), 2.58-2.78 (m, 2 H); NMR (CDCI3) 8 211.42 (s), 210.97 (s), 48.20 (d),

47.42 (d), 46.91 (d), 45.54 (d), 44.01 (d), 41.83 (d), 41.80 (d), 37.59 (d), 36.09 (d),

13.67 (q); Anal. Calcd for C12H12O2: C, 76.57; H, 6.43; Found: C, 76.83; H, 6.60.

4,7,ll-Trimethylpentacyclo[6.3.0.02>6.03»l®.0^'^]undecane-4,7-

diols (mixture of isomers 23a-d). A stirred solution of 22 (433 mg, 2.3 mmol) in

anhydrous Et20 (taken from a freshly opened can) under argon was cooled externally to ca.

-5°C via application of an external ice-salt bath. To this solution was added a solution of

methylmagnesium bromide in Et20 (3 M, 25 mL, 75 mmol) dropwise with stirring, and the

resulting mixture was stirred at -5 °C for 3 h. The external cold bath was removed, and the

reaction mixture was allowed to warm gradually to room temperature and then stirred

overnight. The reaction mixture was cooled externally in an ice-water bath. Saturated

aqueous NH4CI (50 mL) was added slowly to quench the reaction, whereup two layers

separated. The aqueous layer was extracted with Et20 (3 x 100 mL), and the combined

organic layers were dried (MgSC>4) and filtered. The filtrate was concentrated in vacuo,

thereby affording a gross mixture of isomeric diols 23a-d (445 mg, 87%) as a colorless

microcrystalline solid: mp 155-163 °C. The mixture of isomeric diols was purified via

column chromatography on silica gel (250-400 mesh) by eluting with EtOAc. The first

fraction thereby obtained afforded 23a (102 mg, 20%) as a colorless microcrystalline solid:

83

mp 211.0-212.0 °C; IR (KBr) 3314 (s), 3256 (s), 2969 (s), 2928 (s), 2921 (s), 1738 (w),

1453 (m), 1366 (m), 1278 (m), 1109 (s) cm"l; lH NMR (CDCI3) 8 0.90 (d, /=7.0 Hz, 3

H), 1.30 (s, 3 H), 1.35 (s, 3 H), 1.55 (s, 2 H), 1.79-1.98 (m, 4 H), 2.08-2.19 (m, 1 H),

2.28-2.56 (m, 4 H); 13c NMR (CDCI3) 8 82.35 (s), 82.01 (s), 56.19 (d), 53.88 (d),

53.56 (d), 53.05 (d), 50.94 (d), 50.23 (d), 44.37 (d), 41.96 (d), 39.94 (d), 23.45 (q),

23.09 (q), 14.80 (q); Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.23;

H, 8.96. The structure of 23a was established via single crystal X-ray structure analysis.

The second isomer 23b was isolated via fractional recrystallization of the mixture of

23b, c and d from ethyl acetate. Pure 23b was thereby obtained as a colorless

microcrystalline solid (ca. 20 mg), mp 206.0-207.0 °C; IR (KBr) 3320 (s), 2957 (s), 2892

(m), 1440 (w), 1376 (m), 1298 (m), 1161 (w) cm"1; *H NMR (CDCI3) 8 0.82 (d, 7=6.6

Hz, 3H), 1.30 (s, 3H), 1.33 (s, 3H), 1.37-1.48 (m, 2H), 1.76-1.98 (m, 3H), 1.98-2.28

(m, 4H). 2.41-2.62 (m, 2H); 13c NMR (CDCI3) 8 14.64 (q), 23.14 (q), 23.47 (q), 40.28

(d), 40.99 (d), 45.44 (d), 49.94 (d), 50.04 (d), 53.21 (d), 53.36 (d), 54.73 (d), 56.73 (d),

82.02 (s), 82.25 (s); Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.19;

H, 8.96. The structure of 23b was established via single crystal X-ray structural studies.

Conclusions

4,7,1 l-ttimethylpentacyclo[6.3.0.02Ao5'9]undecane-e*0-4,£JC0-7-diol (23a) was

synthesized and fully characterized. X-ray crystallographic studies show that this diol

formed the helical tubuland lattice although its molecular structure does not possess actual

C2 rotational symmetry. It is therefore reasonable to expect that a wider range of tertiary

diols will recrystallize in a helical tubuland lattice.

84

References

1. Cram, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1009.

2. MacNicol, D. D.; McKendrick, J. J.; Wilson, D. R. Chem. Soc. Rev. 1978, 7, 65.

3. Hagan, M. Clathrate Inclusion Compounds, Reinhold: New York, 1962.

4. Powell, H. M. In Non-Stoichiometric Compounds, Mandelcorn, L., Ed., Academic

Press: New York, 1964, p. 438.

5. Fetterky, L. C. in Non-Stoichiometric Compounds, Mandelcorn, L. Ed., Academic

Press: New York, 1964, p. 491.

6. Gamble F. R. and Geballe, T. H. in Treatise on Solid State Chemistry, Hannay, N. B.

Ed., Plenum Press: New York, 1976, Vol. 3, p. 89.

7. Mak, T. C. W.; Tse, J. S.; Tse, C.; Lee, K.; Chong, Y. J. Chem. Soc. Perkin Trans. 2

1976, 1169.

8. Flippen, J. L.; Karle, J. / . Phys. Chem. 1971, 75, 3567.

9. (a) Dance, I. G.; Bishop, R.; Hawkins, S. C.; Lipari, T.; Scudder, M. L.; Craig, D. C.

J. Chem. Soc., Perkin Trans. 2 1986, 1299; (b) Bishop, R.; Craig, D. C.; Scudder, M.

L. Supramol. Chem. 1993,2, 123-131.

10. Dance, I. G.; Bishop, R.; Hawkins, S. C.; Lipari, T.; Scudder, M. L.; Craig, D. C. J.

Chem. Soc. Perkin Trans. 2 1986, 1300.

11. Dance, I. G.; Bishop, R.; Scudder, M. L. J. Chem. Soc., Perkin Trans. 2 1986,

1310.

85

86

12. Bishop, R.; Dance, I. G.; Hawkins, S. C.; Scudder, M. L. J Incl. Phenom. 1987,5,

229.

13. Bishop, R.; Craig, D. C.; Dance, I. G.; Scudder, M. L.; Marchand, A. P.; Wang, Y.

J. Chem. Soc. Perkin Trans. 2 1993, 937.

14. Hawkins, S. C.; Bishop, R.; Craig, D. C.; Dance, I. G.; Rae, A. D.; Scudder, M. L.

J. Chem. Soc. Perkin Trans. 2 1993, 1737.

15. Bishop, R.; Craig, D. C; Dance, I. G.; Kim, S.; Mallick, M. A. I.; Pich, K. C.;

Scudder, M. L. Supramol.Chem. 1993,1, 171-178.

16. Bishop, R.; Choudhury, S.; Dance, I. J. Chem. Soc. Perkin Trans. 2 1982, 1159.

17. Marchand, A. P.; Sharma, G. V. M.; Annapurna, G. S.; Pednekar, P. R. J. Org.

Chem. 1987,52, 4784.

18. Freedman, H. H.; Dubois, R. A. Tetrahedron Lett. 1975, 3251.

19. (a) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem. Soc. 1953,

2548. (b) Fieser, L. F.; Fieser, M. Reagents for Org. Syn. Vol 5,1967, John Wiley and

Sons: New York, pp. 142.

20. Gassman, P. G.; Marshall, J. L. in Organic Synthesis; Baumgarten, H. E., Ed. John

Willey and Sons: New York, 1973, Vol. 5, pp. 424-428.

21. McBee, E. T.; Diveley, W. R.; Burch, J. E. J. Am. Chem. Soc. 1955, 77, 385.

22. Marchand, A. P.; Chou, T-C. J. Chem. Soc., Perkin Trans. I, 1973, 1948.

87

23. Marchand, A. P.; LaRoe, W. D.; Sharma G. V. M.; Suri, S. C.; Reddy, D. S. J. Org.

Chem. 1986,51, 1622.

24. Bott, S. G., unpublished result. The author thanks Professor Bott for his x-ray

crystallographic studies on compound 19 presented in this chapter.

25.Bishop, R.; Craig, C. D.; Scudder, M. L. unpublished results. The author gratefully

acknowledge Professor Bishop, Drs. Craig and Scudder for their x-ray crystallographic

studies on compounds 23a and b presented in this chapter.

26. Bishop, R. Personal communication.