Dissolving Metal Reductions of Alcohol Derivatives

3 t(L

DISSOLVING METAL REDUCTIONS OF ALCOHOL DERIVATIVES

A thesis presented

PANAYIOTIS ALEXANDROU PROI

in partial fulfilment of the requirements

for the degree

DOCTOR OF PHILOSOPHY

HOF! ANN (1976/1978) AND WHIFFEN LABORATORIES (1978/1979) CHEMISTRY DEPARTMENT IMPERIAL COLLEGE LONDON S',!7 2AY , MARCH, 1980, ACKNOWLEDGEMENTS

I wish to record eu sincere aratitnde to Professor Sir Derek Barton, FRS for tile privilege of working with him on this project and alt the encouragement and assistance he /Las given me. 1r25 dynamic enthusiasm and depth of insight have been a constant source of inspiration.

I also thank Dr. /:.G.I.1. Barrett for his cosupervis- ion, friendship and for reading the manuscript; DrS. R. Bielski and D. PapaioannOu for advice, assistance and f1nendship in the early stages of this project; My wife for her patience and understanding; and, finally, my colleagues in the Hofmann Laboratory, who have made my stay at Imperial College a most memorable and pleasant one.

March, 1980. LIST CF CONTENTS

page

Acknowledgements

Abstract 1

CHAPTER 1 2 Some General Methods for the Deoxygenation of Alcohols

CHAPTER 2 23 Carbon-heteroatom Sigma Bond Cleavages

CHAPTER 3 47 Results and Discussion

82 CHAPTER 4 Experimental

157 References

Publications 175 1.

ABSTRACT

Literature methods for the deoxygenation of alcohols and their derivatives are reviewed. The mechanisms describing the dissolving metal reduction of carbon-heteroatom bonds are classified. The majority of reductions were found to occur via a one-electron process.

Reduction of sterically hindered alkyl carboxylic esters using lithium in ettylamine, potassium/18-crown-6/t-butylamine or potassium/ l8-crown-G-/l,2-dimethoxyethane gave predominantly the corresponding alkanes rather than the parent alcohols. The deoxygenation is shown to proceed via alkyl oxygen cleavage of the derived radical anion giving alkane and carboxylate anion provided that the medium is nucleophile-free.

Reduction of dialkyl carbonates gave alkanes, but not as efficiently as esters. Carbamates deoxygenate even less readily, whereas carbohydrate esters not at all. Dithiocarbonates and dialkylthiocarbamates of primary and secondary alcohols have been deoxygenated in high yield, thus, complementing the selective ester reduction. 2.

CHAPTER 1

SOME GENERAL METHODS FOR THE DEOXYGENATION OF ALCOHOLS

1.1 INTRODUCTION

A useful transformation, frequently encountered in organic synthesis,

is the replacement of a hydroxyl function by a hydrogen atom. The selective removal of a hydroxyl function (deoxygenation) in carbohydrates,

and especially aminoglycoside antibiotics is of current interest. The deoxygenated aminoglycosides often have improved activities against resistant bacteria.

In this chapter the various methods for deoxygenating alcohols.that

have appeared in the literature are summarised. In theory, there are

two ways of deoxygenating an alcohol; either directly on the free alcohol

or indirectly via a derivative. In practice, however, there are very

few cases where the first method can be applied. These cases are special

since they are applicable to allylic and benzylic alcohols only. Most

deoxygenations rely on the indirect method. The various derivatives that

are used vary from simple halides to complex esters, and the reducing'

agents vary from alkali metals to complex hydrides.

1.2 DIRECT DEOXYGENATION

This method involves the reduction of allylic or benzylic alcohols

by alkali metals in ammonia or alkylamines. Thus, reduction of 1-tetralol 1 (1) with lithium in ammonia gave tetralin (2) in quantitative yield.

Reduction of ergosta--3,22-diene-35,I113-diol (3) with lithium in ethylamine 2 gave ergosta-8, 22-diene-3;;-ol (4).

Li /NH 3

TIIF NH Cl

(1) (2)

Li/EtNI12

60%

HO (3)

HO 4.

1.3 INDIRECT DEOXYGENATION

1.3.1 Deoxygenation via Aldehydes and Ketones

One of the oldest methods, applicable to primary and secondary alcohols only was their oxidation to the aldehyde or ketone respectively with subsequent Wolff-Kishner or Clemmensen reduction to the hydrocarbon.

Other methods for reduction of derivatives of oxo-compounds have been developed and reviewed elsewhere.3

1.3.2 Deoxygenation via Halides

The reduction of a halide to a hydrocarbon is a facile process, and since the conversion of an alcohol to a halide is a simple transformation,

the deoxygenation of alcohols via halides has been used extensively by organic chemists. A halide can be reduced by dissolving metal reduction,

.hydride reduction, hydrogenolysis or photolysis in a hydrogen atom donor solvent.

In deoxygenations using dissolving metals the metal could be any-

alkali or alkaline earth in ammonia or alkylamine, or a transition metal with a suitable proton source. Examples are listed below: the zinc dust,

acetic acid and hydrogen chloride reduction of n-hexadccyl iodide gave

n-hexadecane in 85; yield. l Hydrogen chloride limited this method to

non-acid sensitive compounds, for example simple alkyl halides. Alkyl

iodides prepared from toluene-4-sulphonates or methanesulphonates can be

reduced with zinc dust in 1,2-dimethoxyethane, dimethylformamide, dirnethyl-

sulphoxide or hexamethylplrosphoramide, all in one-pot without isolating 3 the intermediate iodide. '6 This method is selective for iodides in

presence of olefins, ketones,m-hydroxyketones,cd -unsaturated ketones,

tertiary_ hydroxyl, epoxides and nitriles. It is limited, however, to primary or non-hindered secondary sulphonates where simple SN2 displacement can occur without complications. The reduction of 33-chloro- androst-5-en-17-one (5) with lithium in ammonia gave 175-hy,lroxyandrost- 7 5-ene (6). Titanocene dichloride (7) with excess finely divided magne- 8 sium metal in water is reported to reduce halides to hydrocarbons.

NaI/7n

HMPA/1050 48% A c0

A c 0

Li/NH3 r

(5)

(6)

II 0

?- + nClOH21Cl + Mg anClOH22

(7) 7.

Lithium aluminium hydride for many years has been known to reduce halides 9 to hydrocarbons in excellent yields. Many other functional groups, however, are simultaneously reduced. The powerful lithium triethylboro- hydride10 is known to reduce hindered halides to hydrocarbons in high yields, for example neopentyl bromide to neopentane in 96', yield. Sodium cyanoborohydridei1 and tetrabutylammonium cyanoborohydride12 in hexamethyl- phosphoramide are excellent selective reductants for primary iodides. A useful reagent for the selective reduction of tertiary, benzylic or allylic halides in the presence of primary and secondary alkyl and aryl halides is B-n-butyl-9-borabicyclo [.3.3.J nonane n-butyl-lithium ate complex

(8). Potassium copper (I) hydride can reduce halides as well as other functional groups13 whereas lithium copper hydride is slightly more selective and can reduce halides in the presence of esters. 14

Another powerful non-selective halide reducing agent is triethyl- silane used in the presence of aluminium chloride.lo Reductions of halides in excellent yields can be achieved with tributylstannane. This method has been reviewed.'16

17 Iodides were cleanly reduced to hydrocarbons with hydrogen on nickel or palladium on carbon.18 For example, 3-deoxy-3-iodo-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (9) was reduced to 3-deoxy-1,2:5,6-di-0-iso- prop lidene —Y-D-glucofuranose (10).17 Other functional groups like benzyl ethers can be simultaneously hydrogenolysed.

Carbohydrate iodides have been photolysed giving dcoxysufiars, e.g.

6-deoxy-G-iodo-1,2:3,4-di-O-isopropylidene-u-D-galactopyranose (11) has been photolysed giving G-deoxy-1,2:3,4-di-0-isopropylidene-o.-D-galacto- 19 pyranose (12). Photolytic methods, however, are not attractive for large scale preparations.

Li B u ~B / Bu

(8)

(9) (10)

hy/;,fe01i

NaOii/pyrex 97

(12) 9.

1.3.3 Deoxygenation via Sulphonate Esters

.Sulphonate esters can easily be prepared from alcohols and sulphonyl chlorides or anhydrides, and their deoxygenation has been achieved by

dissolving metal, metal hydride, electrolytic and photolytic methods.

Trifluoromethanesulphonates have recently been reduced with sodium

in ammonia, e.g. methyl 4,6-0-cyclohexylidene-2-deoxy-2-methoxycarbonyl-

amino-3-0-trifluoromethanesulphonyl-a-D-glucopyranoside (13) gave methyl

4,6-0-cyclohexylidene-2,3-dideoxy-2-methoxycarbonylamino-a-D-glucopyrano-

side (14).`0 The synthetic utility of this method is limited to cases

where the a-substituents are not easily eliminated. Alkyl alkanesulphon- 21 ates are known to deoxygenate with sodium-naphthalene in tetrahydrofuran

or with potssium in hexamethylphosphorictriamide.22 Arylsulphonates such 23,24 as toluene-4-sulphonates are less effective than alkyl analogues.

Toluene-4-sulphonate esters of primary and'sometimes secondary alco-

hols are deoxygenated when treated with lithium aluminium hydride. An

example is the reduction of phenyl 6-0-benzoyl-2,3-di-0-benzyl-3-0-(toluene-

4-sulphonyl)-(3-D-glucopyranoside (15) to phenyl 2,3-di-0-benzyl-3-deoxy- 25 (3-D-glucopyranoside (16). Other procedures involve the copper hydride

reagent of Masamune,14 and the powerful lithium triethylborohydride which

is reported to be superior to LiA1Ii 1, LiI311,1, LiAl(OR) 311, Ali;3 or 13113

and deoxygenates even sterically hindered secondary sulphonate esters.

An electrolytic method has recently been reported27 to selectively

deoxygenate methanesulphonates in the presence of olefins, aromatic func-

tions, esters, nitriles, epoxides and hydroxyls in yields ranging from

GO to 90'7,. For example, the epoxymesylate (17) was reduced to the epoxide

(18) in 87; yield.

10.

Trifluoromethanesulphonates have recently been photolysed giving 20 hydrocarbons, for example (13) gave (14) in 78% yield using hexamethyl- phosphorictrimide as solvent.

(13) (14)

N a/THF Il 11 C18H370. S02Bu nC1838 H C10H8 20%

LAH

oPh PhCH20 Ph

(15)

(16)

electrolysis (> DLSF/Et4NTs 0Ms 100

(17) (18) 11.

1.3.4 Deoxygenation•via carboxylic esters

Carboxylic esters can easily be prepared from alcohols and acid

anhydrides or chlorides, and their deoxygenation has been achieved by

photolytic, dissolving metal and metal hydride methods. Esters, when 28-31 photolysed in aqueous hexamethylphosphorictriamide gave hydrocarbons.

For example, 3-0-acetyl-1,2:5,G-di-O-isopropylidene-u-D-glucofuranose

(19) was reduced to 3-deoxy-1,2:5,G-di-O-isopropylidene-a-D-glucofuranose•

(10).

Esters of tertiary alcohols, when treated with sodium in hexamethyl-

phosphorictriamide and t-butanol, gave high yields of hydrocarbon, whereas

those of primary and secondary alcohols gave a mixture of alcohol and

h}drocarbon,32 Thus, 3c-acetoxy-3c-methyl-5a-cholestane (20) gave 3c-

methyl-5a-cholestane (21). Other functional groups including carbonyls

and olefins were competitively reduced. a-Keto and allylic esters when

treated with an alkali metal in ammonia or alkylamines gave deoxycompounds,

for example reduction of 3(3,12(3-diacetoxy-5a:25R-spirostan-11-one (22) 33 with calcium in ammonia gave 11-oxotigogenin (23). Treatment of 35-

acetoxycholest-4-ene (24) with lithium in ethylamine gave cholest-4-ene 2,34 (25). Esters of alcohols capable of producing long lived radicals

when refluxed with sodium in toluene gave alkyl dimers.35

(19) (10)

12.

N a/HMPA v t-BuOH Ac0 95%

(20)

(21)

13.

Ca/NH3

84%

Ac0

(22)

HO (23)

C $ H17

Li/EtNH2

AGO

(24) (25)

Na/toluene PhCO2CH2Ph o PhCO2H + PhCH2CH2Ph

38%

14.

Carboxylic esters have been reduced to hydrocarbons in poor yields with tributylstannane using radical initiators or ultraviolet light.36

The acid part of the ester was found to bind with the tributylstannyl radical. a-Keto esters of tertiary alcohols have been reduced to ketones by tributylstannane, thus 3-C-acetyl-3-0-benzoyl-1,2:5,6-di-0-isopropylidene-a-D-allofuranose (26) gave 3-C-acetyl-3-deoxy-1,2:5,6-di-0-isopropylidene-a-D-allofuranose (27)37 Chloroformate esters were reduced to 0 alkanes when treated with tripropylsilane and t-butylperoxidc at 140 in sealed vessels.38 The drastic conditions required by this method do not make it synthetically attractive. Trichlorosilane was reported to deoxygenate carboxylic. esters of tertiary alcohols to the hydrocarbon derived from the alcohol, whereas primary and non-hindered secondary to an ether.

Further details are not available yet.39

n Bu 0 n 2 2 PhCO2 + Bu3SnH PIiCO2SnBu3 + C 6H12 130° 2 27 h 20%

n u„SnH

80%

(27) (26)

Pr3Si H CI t-Bu 0 2 2 140° 91°l0 15.

1.3.5 Deoxygenation via Thioesters

0-Alkyl thioesters, dithiocarbonates and thiocarbamates have been successfully used in deoxygenations. 0-Alkyl thioesters are easily prepared, under essentially neutral conditions, by reaction with hydrogen sulphide-pyridine on the intermediate salt prepared by the condenstation of an alcohol with an imidoyl chloride methochloride (prepared from phosgene and a tertiary carboxamide) 40 (Scheme 1). Dithiocarbonates are prepared from alkoxides, carbon disulphide and iodoalkanes. Thio- carbamates are prepared from dithiocarbonates and amines.

pyridine ROIs + R1(C1)C:iMe2C1 > ROC(R1):2NMe Cl

H S 2 RO.CS.R1

Scheme 1

Both thioesters and dithiocarbonates were deoxygenated in excel- 40 lent yields by tri-n-butylstannane. For example n-cholestanyl thio- benzoate (28) gave 5a-cholestane (29), whereas the S-methyl-dithiocarbonate (30) gave 3-deoxy-1,2:5,6-di-O-isopropylidene-ct-I)-glucofuranose

(10). Cyclic thiocarbonates on treatment with tributylstannane fragment with regioselective secondary deoxygenation. For example, the cyclic thiocarbonate (31) gave after hydrolysis 5-deoxy-3-0-methyl-1,2-0- 41 42 isopropylidene-a-D--glucofuranose (32). ' Reductions of thioester derivatives of alcohols with triallcylstannanes constitute the best

16.

methods available so far for deoxygenating alcohols, especially carbo-

hydrates. The only functional group that is competitively reduced are

the halides.

When the S-methyl-dithiocarbonate (30) was pyrelysed, it rearranged

to compound (33), which was desulphurised with Raney nickel to give (10). 43

Pyrolytic methods, however, are not all that attractive in organic syn-

thesis.

Carbohydrate thiocarbamates have been photolysed to deoxysugars in

low yields. For example, 6-0-(N,N-dimethylaminothiocarbonyl)-1,2:3,4-di-

0-isopropylidene-a-D-galactopyranose (34) gave 6-deoxy-1,2:3,4-di-0- 4'45 isopropylidene-a-D-galactopyranose (12),

nBu3SnH

PhCS.0 73%

(28) (29)

nBu3Snii o (10) ~WM

(30) 17.

HO 1. nBu3SnH H 2. 0E1-

(31) (32)

(30) (10)

(33)

S N Me2

hv (12) 15%

(34) 18.

1.3.6 Deoxygenation via Phosphate Esters

N,N,N',N'-Tetramethylphosphorodiamidate esters of alcohols have been reduced with lithium in ethylamine to hydrocarbons in excellent yields. 46 Thus, the phosphoramidate ester (35) gave the deoxygenated compound (36).

Application of this method to the carbohydrate series was not successful, since the products react further under the reduction conditions. For example 1,2:5,6-di-O-isopropylidene-3-0-(N,N,N',N'-tetramethylphosphor- odiamidoyl)-a-D-allofuranose (37) gave the aminal (38).47 Diethyl- phosphate esters of tertiary alcohols have been reduced with lithium in 46 ethylamine to hydrocarbons but these esters were not as useful as the phosphoramidate analogues. Diethylphosphate esters of phenols, however, have been reduced with sodium in ammonia to aromatic hydrocarbons. Thus,

13-naphthyldiethylphosphate gave naphthalene.48

Li/EtNH2

THF/t-BuOH 92%

(35) 19.

Li/EtNII2

t-BuOH 0„ P

(CH) N \ 32 N(CH 3) 2

(37)

NHC2H5

(38)

0 C2 H5

\ P /O r2 H 5 Na/NH3 I I

0 9 5 ;; 20.

1.3.7 Miscellaneous Deoxygenation Reactions

Sulphamoyl esters of alcohols have been reduced to hydrocarbons with sodium in ammonia. Other functional groups like benzylidene, esters sulphonates, carbamates and azides were reduced competitively. For example, reduction of methyl 4,6-0-benzylidene-3-0-(N-dimethylamino- sulphaLrnoyl)-2-0-tetrahydropyranyl-cc-D-glucopyranoside (39) gave methyl

3-deoxy-c-D-glucopyranoside (40). 19

Benzylic and allylic ethers, like esters, deoxygenate when treated with sodium in ammonia or lithium in ethylarnine. Thus, the allylic 9 ether (41) gave p-menth-l-ene (42).

0-Alkyl or 0-aryl isoureas'of non-hindered alcohols or phenols can be hydrogenolysed to the respective alkyl or aryl hydrocarbons. Hindered alcohols, however-,gave rearranged products. The isoureas were prepared from the condensation of the appropriate alcohol with a suitable -carbo- diimide. Thus, 4-phenylphenol was condensed with dicyclohexylcarbo- diimide to •give 0-(4-phenyl)phenyl-N,N'-dicyclohexylisourea (43) which 50 was hydrogenolysed over palladium on carbon giving biuhcny1.

A general method for deoxygenating phenols consists of the cataly-

tic hydrogenolysis of their 1-phenyl-tetrazolyl ethers, thus ether (44)

gave anisole.Jl A less general method for deoxygenating phenols that

bear ortho methoxyl or aryl groups consists of the hydrogenolysis of

their 2,4-dinitrophenylcthcrs to their 2,4-diaminophenylethers, and

then sodium in ammonia reduction to give the deoxygenated hydrocarbon. 52

Other methods for the deoxygenation of alcohols involve the

conversion of the alcohol to a sulphide or a selenide followed by reduc-

tion. Selcnides have been reduced with lithium in ethylamine53 or tri-

n-butylstannane5l in comparable yields. Desulphurisation of the benzyl-

21.

sulphide (45) with nickel in ethanol gave (46). 5

Na/NH3/THF HO Me0H 80

(40)

OMe Li/EtNH2

(41) (42)

N=C=N--O

N H2/Pd/C Ph-Ph J FNH 99%

(43)

22.

OMe

H2/Pd/C Me0

85%

OMe

Na/NH3

Ei/EtNH2 n CHScMe14 29 r C1413O 90%

Ni/EtOH M e0

Me0 77%

(45) (46) 23.

CHAPTER 2

CARBON-HETEROATOM SIGMA BOND CLEAVAGES

2.1 INTRODUCTION

Dissolving metal reductions are classic organic transformations.

In some cases synthetically they have been superseded by metal hydride 56,57.,58,59,60 reagents. Several reviews have appeared in the literature,

the treatises by Smith and Kaiser are excellent. Birch in his

earlier, now dated, review56 has attempted to describe the mechanisms

involved in dissolving metal reductions, and later Grovenstein61 in one

of his papers on the reductions of quaternary ammonium salts discussed

briefly the mechanisms of related fragmentation reactions. Recently,

Bunnett62 has published a paper on the mechanisms involved in the cleav-

ages of carbon-heteroatom bonds in aromatic compounds. In this chapter

:relevant information describing the mechanisms of carbon-heteroatom bond

cleavages is classified. In cases where the authors carried out no

mechanistic inveatigation, a mechanism is proposed from studies on their

results and/or by correlation with related substrates. Reductions of

unsaturated systems are not considered, unless these involve a carbon-

heteroatom sigma bond cleavage during the reaction. Reducing agents

herein described include the alkali and alkaline earth metals in ammonia,

alkylamines, hexamethylphosphorictriamide or ethers with or without the

presence of arenes, and by electrolyses.

In the reduction process, electrons donated from the metal in its

conversion to the derived cation or at the cathode in an electrolytic cell

are transferred to the substrate. The mechanism of transfer is not

considered here. A sigma bond cleavage requires the addition of one or

two electrons to the substrate. Addition of one electron to a carbon-

heteroatom sigma bond will produce a radical anion which can fragment

24.

in two ways producing a free carbon radical and an heteroanion, or a free carbanion and a heteroradical. The free radical may be subsequently reduced to an anion by a further one electron transfer. Additon of two electrons to a carbon-heteroatom sigma bond followed by fragmentation produces a carbanion and a heteroanion (scheme 2)

° C • + X type I

C + X type II

1e _ ---o C

C— C X J --° C + X t ype I I I*

Scheme 2

* Type III may include reactions where proton transfer precedes the

second electron transfer; fragmentation does not, however, occur prior

to the second electron transfer. 25.

The three types of cleavage are hereinafter designated types I,

II, and III.

2.2 TYPE I CLEAVAGE REACTIONS

Cleavages of this type include carbon-fluorine, chlorine, bromine, iodine, oxygen, sulphur, selenium and nitrogen bonds.

2.2.1 Carbon-Halide Bonds

Cleavage of carbon-halogen bond by metal ammonia reagents gives inorganic halide quantitatively and this is the basis of a method for the determination of organic halogen. Alkyl halides undergo four types of reaction with metals in ammonia. They can be reductively cleaved to the corresponding hydrocarbon; they can undergo the Wurtz dimerisation; they can eliminate hydrogen halide to give olefins; and the halogen • can be displaced by the amide anions to form alkylamines. The competitive substitution reaction can be avoided by the use of non-nucleophilic solvents or it can be suppressed by the reduction of temperature.63 The use of lithium, sodium or potassium in ammonia gave virtually identical

results. The main products from alkylchlorides (RC1) were the corresponding hydrocarbons (RH). From the bromides and iodides, increasing

amounts of olefin and dimer were produced; bromides gave 70-80% hydro-

carbon whereas iodides 65-75%. Olefin formation increased in the series

n-butyl % isobutyl < sec-butyl < t-butyl, and dimerisation decreased in

the same order. Primary and secondary benzylchlorides gave bibenzyl (50%) 65'66 whereas tertiary benzylchlorides about 25% dimer?d DeVries supported

the type III cleavage mechanism for a series of benzylhalides. This,

however, has been proved wrong by various other workers. Evidence in 2G.

67 68 favour of type I mechanism was as follows: Jacobus ' reduced optically active cyclopropylbromides with sodium and naphthalene in 1,2-dimethoxyethane and obtained a racemic mixture indicating that the reduction produced a cyclopropylradical which racemised; cyclopropylcarbanions are configurationally stable.69 The presence of the cyclopropylradical during sodium naphthalene reductions of optically active cyclopropyl- halides was recently confirmed by Boche and Schneider.70 The rapid rearrangement of the 3a,5a-cyclocholestan-6-yl radical into the more stable cholest-5-en-3-yl radical is well established.71 Reduction of

6B-chloro-3a,5a-cyclocholestane (47) with sodium-biphenyl in 1,2-dimethoxyethane gave 3a,5a-cyclocholestane (48) and cholest-5-ene (49). The product ratio was dependent on the sodium-biphenyl concentration and the temperature. These results were consistent with the intermediacy of the 3a,5a-cyclocholestan-6-yl radical.72 Garst73 investigated the reaction of sodium-naphthalene in 1,2-dimethoxyethane with 5-hexenyl and cyclopentylmethyl bromides and chlorides. The olefinic halides gave mixtures of 1-hexene and methylcyclopentane, in the monomeric fraction, while only methylcyclopentane was observed in the reaction of halomethyl- cyclopentanes. The authors concluded that cleavage proceeded by formation of a free radical which partially cyclised. Sargent74 investigated the competitive reduction of an equimolar mixture of n-propyl and iso-propyl iodides with sodium-naphthalone in 1,2-dimethoxyethane. The product ratio was found to be consistent with the expected statistical ratio of products for free radical combination.

The reaction of sodium-naphthalene and alkyliodides in 1,2-dimetho-

xyethane gave a mixture of the corresponding aliphatic hydrocarbon,

dimeric hydrocarbon, olefins and alkylated naphthalene and dihydronaph-

thalenes. The origin of the alkylation products has been shown indepen-

dently by Sargent?5 and Garst76 to proceede via coupling of the alkyl free 27.

radical with the arene radical anion. Sargent75 showed that the ratio of aliphatic to alkylation products decreased slightly in the series primary to secondary to tertiary alkyliodides. An SN2 process would require a pronounced increase, whereas a coupling process, a slight decrease. Garst76 investigated the effect of halogen atom variation on the yields of the products and observed that the ratio of aliphatic to alkylation products was constant, and hence independent of halide. An

SN2 process would require a strong dependence on halide.

Similar product investigations were carried out for halobenzenes77 62 and they were consistent with the type I cleavage. Bunnett reported

the trapping of the phenyl radical using the acetone enolate. Recently,

esr studies78 using a continuous flow technique showed the presence of free radicals. The continuous flow technique suppresses radical reduction

giving carbanions. Finally, allyl chloride and bromide have been shown

to fragment by type I cleavage using an electrolytic method.79

8H C 17

Ph-Ph DME

(47)

(43) (4!))

2.2.2 Carbon-Oxygen Bonds

Type I cleavage of carbon-oxygen bonds have been observed in 28.

allylic and benzylic alcohols, ethers and esters, a-ketoesters, phosphate, sulphonate, carboxylic and carbamate esters, alkyl-aryl and diaryl ethers.

Metal-ammonia reagents convert alcohols to the corresponding alkoxides. With simple saturated aliphatic alcohols this is the only process; for allylic and benzylic alcohols, alkoxide formation is accompanied by deoxygenation. Examples have been reported in the previous chapter. If deoxygenation is not'required, the alkoxide can purposely be formed before addition of the reducing agent; if deoxygenation is required alkoxide formation is prevented by addition of a proton source. Double bond migration in deoxygenation of allylic alcohols is frequently encountered, for example sabinol (50) gave a-thugene (51)80 The double bond migration was interpreted by the formation of a mesomeric intermediate.

Birch suggested80 that the deoxygenation of allylic and benzylic alcohols

is a two-electron process (cleavage type III) based on the relatively

easier cleavage of benzyl alcohol compared with dimethylphenylcarbinol.

Nuclear substituents affect the ease of cleavage of benzyl alcohols in

the order o-OMe > m-OMe > p-OMe81 Zimmerman82 interpreted these results

with type I cleavage using a theoretical treatment. Molecular orbital

calculations showed that the electron density of the radical anion of

anisole and the dimethoxybenzenes is greater at the ortho rather than

the meta position, whereas the para position has low electron density.

The deoxygenation is thus explained by expulsion of hydroxide anion from

the initially formed aromatic radical anion. Such expulsion would be

most rapid when the ring position bearing the carbinol moiety is most

electron rich. Since ring atoms para to an electron donor are relati-

vely electron poor compared to the meta and ortho positions one would

anticipate hydroxide expulsion para to methoxyl to be difficult compared

to meta and ortho positions (scheme 3).

29.

Na/NH3

E t0H

(50) (51)

Me0 Me0 Me0 0 a C>

Me 0 Me0 fl

.--OH

C> -C>

OMe OM e

Scheme 3

30.

Deoxygenation of allylic and benzylic ethers has been reported in the previous chapter. Benzyl-phenyl ethers are cleaved to phenol and benzyl hydrocarbon. Thus, ether (52) gave phenol (53) 3 Alkyl-aryl ethers are cleaved to phenol and alkane.84 In decreasing order the effect of aromatic substituents on the ease of cleavage was found to be: o-Otite > m-OMe > H > o-Me > m-Me > p-Me > L-014e . The ease of removal of the alkyl group was found to be in the order of -CH2h, -CH2CO2H > iso -CH C3H7. The sequence was interpreted by Birch84 as 3 > -nC3H7, type III cleavage, and by Zimmerman82 as type II, i.e. expulsion of the alkyl group as an anion from the aromatic radical anion (Scheme 4).

M e0 Na/NH3

EtOH

OMe

(52)

M e0

OMe

(53)

31.

Me 0 M e 0 M e0 Me0

0 — OH M e0 M e0 le H`

Scheme 4

Zimmerman's molecular orbital calculations on the position of the negative charge in the anisole radical anion82 have been disputed by 6 Rogers85 and Burnham8 Rogers was unable to differentiate between the ortho and meta positions by esr studies, whereas Burnham considered various methods for molecular orbital calculations and concluded that the presently available methods did not give a reliable charge distri- bution. Screttas87 however, has proved Zimmerman's calculations right by trapping an ortho carbanion in the anisole radical anion. Both

Birch and Zimmerman have assumed that the alkyl group of alkyl-aryl

32.

ethers was expelled as a carbanion during reduction. A closer examina- tion of the sequence for the ease of removal of alkyl groups, however, indicates that the first two groups in the sequence are good radical stabilising groups. A tertiary alkyl group was not examined, and the primary and secondary groups were found to have the same effect, a fact difficult to explain, and no attempts were made on trapping any radicals.

Clearly, further research is required.

The effect of substitution on the direction of cleavage of diary' 88,89,90 ethers with sodium in ammonia has been investigated by Sowa,

Sawa,9 Pirkle and Zabriskie,52 and Strojny92 and their results show that o-OMe, o-phenyl, o- and p-carboxyl substituents cleave giving phenol whereas o- and p-amino and j-0Me cleave in the opposite direction to give substituted phenol:

i , R = o-OMe , o-Ph, o-0O2H , p-0O211

R = o-NH2 , p-NH2 , p-0Me 3

Eargle93 after an esr study on the cleavage of diaryl ethers proposed a type III cleavage, and in a later publication94 type I. Evans, Roberts r and Tabner 5 have shown the presence of the dibenzofuran radical anion by esr and hence type I cleavage,Bunnett reported62 the trapping of the phenyl radical during the reduction of diphenyl ether demonstrating

cleavage type I. Recently, Japanese workers96 have confirmed Bunnett's results by an electrochemical method.

Simple aliphatic ethers, acetals and ketals are not cleaved by metal-

ammonia reagents. Benzylic acetals and ketals, however, are deoxygenated.

For example, 2-methyl-2-phenyl-1,3-dioxolane (54) gave ethylbenzene when

treated with sodium in ammonia,97 and 2,2-diphenyl-1,3-dioxolane (55)

gave diphenylmethane98 Mechanistic investigations have not been performed

but they may be classified as type I by analogy with the benzylic ether

deoxygenation.

Deoxygenation of allylic, benzylic and a-ketoesters have been reported

in the previous chapter. Reduction of these esters can be classified under

type I. One-electron transfer to the ester produces the radical anion

which fragments via 0-alkyl fission to produce a resonance stabilised

free radical and the salt of the carboxylic acid. The free radical can

either dimerise, or be reduced to the carbanion by a further one-electron

transfer, and thus produce a hydrocarbon on protonation (Scheme 5).

(54)

34.

R1CO + R 2

R R-R

7 e H R ~ R - H

Scheme 5

Carboxylic esters of tertiary alcohols have been deoxygenated with sodium

in hexamethylphosphorictriamide as reported earlier, in the previous

Chapter. Esters of tertiary and hindered secondary alcohols have been 99 deoxygenated by lithium in ethylamine. The mechanism for these deo-

xygenations will be discussed in full detail in the following Chapter.

It will suffice to report here that esters fragment by type I to produce 100 hydrocarbons. Vora and Holy have reported that ketones were formed

by the action of sodium and naphthalene in tetrahydrofuran on simple

aliphatic esters. Thus, ethyl hexanoate produced ketone (56). The ketones

could have been formed either by the coupling of the naphthalene radical anion

with ester radical anion or via an SN2 displacement of ethoxide. Definite

conclusion can not be drawn from these results since the authors did not

vary the ratio of sodium-naphthalene to ester. A second report appeared 101, 102 recently on the formation of ketones from esters. Benzoate

esters of benzhydrol on treatment with lithium-naphthalene in tetra-

hydrofuran gave benzhydryl-phenyl ketones, thus the benzoate ester (57)

gave the ketone (58). Benzoate esters of alcohols, however, produced

alcohol, benzil and recovered starting material although there was an

excess of lithium. The results were interpreted as follows: the radical

35.

anion of the ester cleaved by 0-alkyl fission to give the ditolylmethyl radical which on one-electron transfer, gave ditolylmethy1 anion which with unreacted ester gave ketone (58). Alternatively, the radical anion of the ester coupled with the ditolylmethyl radical to give (58) (Scheme

6).

Na/C 10H8 5H11CO2C2H5 n C THF 35%

n 5H11 (56)

0 Li/C108 H

THF 37%

(57)

(58) 36.

0 • /CHAr2 ---fl p h co2 + Ar2CH Ph

1 e 2 Ar2 CH. --p Ar CH-

Ar CH P h co2CHAr2 -2 p h COCHAr2 0- Ar2CH ' P h OCHAr2 P h COCHAr2

Scheme 6

The deoxygenation of phosphodiamidate and diethylphosphate esters

has been reported in the previous Chapter. The ease of reduction of

diethylphosphate esters of phenols and tertiary alcohols is compatible with type I cleavage. Bunnett, also, reported62 the trapping of phenyl

radical during the reduction of phenyldiethylphosphate.

Carbamate esters of alcohols on treatment with sodium in ammonia

do not cleave. Benzylic, allylic and phenolic analogues, however, 103, 104 cleave to give alkylamines The fact that only alcohols capable

of producing resonance stabilised radicals, cleave is here interpreted

as evidence for 0-alkyl fission of the carbamate radical anion. Sub-

sequent loss of carbon dioxide, and protonation gives the alkylamine

(Scheme 7).

RO N H R1 + ---° R O R1N H + ~ 2 C 0 2 ONHR1

Scheme 7

37.

Examples of the deoxygenation of sulphonate esters have been reported in the previous Chapter. Closson has reported21that the slow addition of dilute solutions of sodium-naphthalene in tetrahydrofuran to dilute solutions of alkyl alkanesulphonate esters gave hydrocarbons, whereas addition of sulphonate esters to concentrated solutions of sodium- naphthalene in tetrahydorfuran gave alcohols. These results are consistent with a one-electron transfer to sulphonate esters leading to carbon- oxygen fission (type I), and a two-electron transfer leading to sulphur- oxygen cleavage (type III) (Scheme 8).

e 1 - R 0 -S+ R ' R -+ RS0 3 0 o- 12+ R0-S-R

2 e 0^ I RO -R1 RO OZ 0-

Scheme 8

In an electrochemical study of the reduction of alkyl toluene-4-sulphonates 105 a two-electron mechanism (type III) was reported A closer study of

the results of these authors shows, however, that when the total current

required for the electrolysis was equivalent to two electrons, the only

product was alcohol, whereas when it was equivalent to approximately one

electron there was mass loss. Clearly, hydrocarbons were formed which 38.

escaped undetected as gases. Electrolysis of allyl toluene-4-sulphonate was shown to proceed by type I cleavage. 79

2.2.3 Carbon-Sulphur Bonds

Type I cleavage of carbon-sulphur bonds have been observed in sulphides, thioketals and hemithioketals. Dissolving metal reduction of benzyl-alkyl sulphides giving toluene and alkylthiol has been reported ,106,107 and used for the protection of the thiol group The ease of dialkylsulphide cleavage is in the order tertiary > secondary> primary 108, 109 > methyl consistent with type I cleavage. Alkyl-aryl sulphides 108 are reduced to arylthiol and alkane. Lithium or sodium in ammonia reduction of vinylsulphides gave the corresponding olefin with retention 110 of configuration. Bunnett reported62 the trapping of the phenyl

radical during the reduction of diphenylsulphide by potassium in ammonia.

More recently, Japanese workers96 reported the electrochemical cleavage

of sulphides by type I, confirming Bunnett's result. 1,3-Oxathiolanes 111,112 and 1,3-oxathianes are reduced to alkoxythiols The ease of

cleavage increasing with the degree of substitution, suggesting a type 111 I pathway. The presence of phenylsubstituents activates the product

(benzyloxythiol) to further reduction so that the final product is a

hydrocarbon.97 Finally, 1,3-dithiolanes and 1,3-dithianes are converted

to hydrocarbons on treatment with excess lithium in ethylamine.

2.2.4 Carbon-Selenium Bonds

Benzyl-alkyl selenides, like ethers and sulphides, when treated 114 with sodium in ammonia give toluene and alkyl selenol whereas alkyl-

aryl selenides give alkane and aryl selenol.53 Not many examples of 39.

dialkylselenide cleavages have been reported.53 Bunnett62 described that the cleavage of diphenylselenide occurs at least partially by type I, but types II and III might also be opperating concurrently. By analogy with ethers and sulphides it is here classified a type I.

2.2.5 Carbon-Nitrogen Bonds

Benzylic amines, unlike alcohols, are not cleaved by dissolving

metal reagents. Triphenylmethylamine with excess potassium in ammonia 115 gave triphenylmethane and potassium amide Selective removal of the

N-benzyl group can be achieved for amines capable of stabilising a 116 negative charge for example the protected amine (59) gave (60). No

work has been carried out on the mechanism of the above cleavages. They

are possibly type I.

NHCH2Ph N HCH2Ph

N N\ Na /NH3 c> ~-N\ > ~ > i [ H NH CH2Ph N CH2ph 2Ph (59). (60)

117 Ugi has reported the cleavage of isonitriles giving hydrocarbons

and cyanide anion with metals in ammonia.. The order of reactivity was

found to be tertiary > secondary > primary > phenyl, and hence type I.

The Emde fission of tetraalkylammonium salts giving hydrocarbons

and tertiary amines by sodium amalgam in aqueous alcohol or water has

been known since 1912.118 A modification of this reaction requires the

use of sodium in ammonia, and it has been studied in detail. An

example of the synthetic use of this reaction is the conversion of (61) 119 to (62).

40.

Na/ NH3

(62)

Birch has reported81 the cleavage of phenyltrimethylammonium and benzyl- trimethylammonium iodides to benzene and toluene respectively with sodium in ammonia. Hence benzyl and phenyl groups are cleaved in prefer-

ence to alkyl groups. Bunnett has reported62 the trapping of phenyl radical during the reduction of triphenylmethylammonium •iodide,indicating 61,120 thus atype I cleavage. Grovenstein has reported the following

reactivity series for. cleavages of tetraalkylammonium salts: primary

< secondary < methyl « tertiary, and suggested type I cleavage for

secondary and tertiary groups, and type III for methyl and primary ones. 121 Hazlehurst, Holliday and Pass have reported that traces of ethane were

obtained from reactions of tetraalkylammonium halides containing at least

one N-methyl group and also from tetramethylammonium salts, and have

suggested that the ethane was likely formed by combination of methyl

radicals. Grovenstein61 however, could not repeat their results on the

reduction of tetramethylammonium salts. Combination of two methyl

radicals is unlikely, since the lifetime of the methyl radical is too

short to encounter a second methyl radical. In a subsequent paper, 41.

122 Grovenstein reported that the product ratio (cyclopropane/methane) of

the reduction of cyclopropyltrimethylammonium iodide was dependent on the

concentration of sodium and on the mode of addition. Low concentration

of sodium favoured formation of cyclopropane and high concentration of

sodium methane. These results were consistent with type I cleavage for

cyclopropyl, and type III for methyl groups. Govenstein's reports that

primary alkyl groups cleave by type III have been proved wrong by two

groups of workers working independently, by trapping primary alkyl radicals 123 during the reduction of tetraalkylammonium salts. Remers and Weiss

reported the trapping of the primary radical produced by reduction of the

ammonium salt (63) with lithium in ammonia in the absence of a proton 124 source, giving (64). Angers and Zieger have reported the reduction

of 5-hexenyltrimethylammonium iodide with lithium-naphthalene in tetra-

hydrofuran to methylcyclopentane and hex-l-ene, confirming thus the

mechanism as type I. Electrolytic reduction125 of allylic and benzylic

ammonium salts has shown that the cleavage of allylic and benzylic groups 122 proceeds by type I showing thus that Grovenstein's report about the

cleavage of allyltrimethylammonium chloride was erroneous.

MeO

(63) (64) 42.

2.3 TYPE II CLEAVAGE REACTIONS

No evidence for the existence of type II cleavage reactions is reported in the literature. Here the cleavage of carbon bonded to ger- manium, tin, lead, phosphorus, arsenic, antimony and bismuth are classified type II.

Carbon-silicon bonds are reported62 to be inert to treatment with potassium in ammonia. In this respect tetraphenylsilane was found to 126 resemble tetraphenylmethane, which was also unreactiue, Tetraphenyl- ,127 germane tetramethylstannane128 and tetraphenylstanane129 were reduced with excess sodium in ammonia to phenyl or methyl sodium, and triphenylgermanide, trimethylstannide and triphenylstannide respectively.

These results, however, do not distinguish between type I, II or III cleavage. Reduction of triphenylphosphine, -arsine, and -stibine with two equivalents of lithium in tetrahydrofuran gave phenyllithium which was trapped with triphenylchlorosilane, and diphenylphosphide, diphenyl-

arsenide, and diphenylstibide, which were oxidised to diphenylphosphinic, 130 -arsinic and -stibinic acids or were alkylated, Again, these results

do not identify the cleavage mechanism since the metal was always in

excess. Bunnett reported62 the cleavages of triphenylphosphine, -arsine,

-stibine, and -bismuth. Since no phenyl radicals were detected, the

reduction was probably type II or III. Clearly, further research is

required. Herein, they are classified type II on the basis of the

electronegativity of the heteroatoms being lower than that of carbon.

2.4 TYPE III CLEAVAGE REACTIONS

Type III cleavage reactions include the reduction of carboxylic

acids, esters, and amides, sulphonic esters, epoxides and N-methyl

cleavages of tetraalkylammonium salts.

43.

131 Reduction of aliphatic carboxylic acids gave aldehydes, thus dehydroabietic acid (65) on treatment with lithium in ethylamine gave 132 the aldehyde (66). Aldehydes are formed on hydrolysis of imines which are isolable intermediates. These were thought to be formed via 133 geminal hydroxyamines (Scheme 9).

Li/EtNH2

6 h

CO 2H (66) (65)

L i /MeNH2 CH3(CH2)3C H 4P CH3(CH2)3CHO 66%

R--C le R—C -C:). ~0- 0-

/°C H3NH R—C le dR _C 2 :\c/° H 0 H NHCH3

H30+ RCH=NCH. 3 RCHO

Scheme 9 44.

Carboxylic esters have been reduced since 1903 by the Bouveault- 134 Blanc method to two alcohols. This method involves refluxing the 134 ester with a metal, usually sodium, in anhydrous ethanol or with 135 sodium in ammonia in the presence of ethanol_ Kharasch has shown that addition of esters to a solution of two equivalents of sodium in ammonia without the presence of proton source other than ammonia a dianion was produced which on hydrolysis gave aldehydes, and on alkylation gave alkyl ketones (Scheme 10).

0 1 2e H20 RCO2R RCHO R 0 R2X RCOR2

Scheme 10

The Bouveault-Blanc reduction is therefore considered to be a two-electron reduction of an ester via the aldehyde (Scheme 11). 0 RCO2 R1 e2 0_ R10 H ROR R 0i

0- 0' 1e ~. EtOH RCHO RVH fl 1e R R H H

RCH2O ~H3 R CH 2 0H

Scheme 11 45.

Aliphatic carboxamides undergo reduction by sodium in ethanol and ammonia to afford aldehydes, for example, N-methylacetanilide gave 137 acetaldehyde, Reduction of carboxamides proceed via dianions to 137 a-hydroxyamines, which resist further reduction, and hydrolysis leads to aldehydes (Scheme 12). The amount of aldehyde obtained was found to be a function of the acid strength of the proton donor, more aldehyde being isolated with acetic acid (ammonium acetate) than with ethanol, thus

N,N-diethylhexanamide gave 53% hexanal with sodium-acetic acid in ammonia 138 whereas with sodium-ethanol in ammonia only 23% . 0- RCONR2 2e H+ H 20 R N R' H 2

RCHO + H NR2

Scheme 12

The reduction of sulphonate esters has been discussed under type I cleavage reactions. Type III cleavage reactions to give alcohols and 21 sulphonate anions occur with an excess of dissolving metal.

The reduction of N-methyl tetraalkylammonium salt has been discussed under type I cleavage reactions.

Reduction of epoxides gave the more highly substituted alcohols via

a dianion rather than a radical anion.98 Reduction of propylene oxide with sodium in ammonia gave isopropanol rather than n-propanol.31 Reduc- 139 tion of steroidal epoxides confirm that the more highly substituted 140 alcohol is formed. Henbest with lithium in ethylamine and hindered 141 steroidal epoxides, and Brown with lithium in ethylenediamine and

hindered unstable bicyclic epoxides have demonstrated the synthetic

superiority of these reagents over lithium aluminium hydride. In all the

above cases reduction occurred via the most stable carbanion which on 46.

protonation gave the most highly substituted alcohol.

2.5 CONCLUSION

The majority of reductions occur via a one-electron process; only five types of compounds are reduced via a two-electron process. It is most reasonable that radical anions of carbon-heteroatom bonds cleave by type I if the heteroatom is more electronegative than carbon, and by type II if carbon is more electronegative than the heteroatom. Type

III cleavages occur in compounds like carboxylic acids, esters, amides, and sulphonate esters, where the carbon-heteroatom bond is flanked by electron-sinks; cleavage of the radical anion of these compounds would lead to high energy intermediates, hence protonation and a second electron transfer occur before cleavage. Epoxides and N-methyltetra- alkylammoniun salts also cleave via type III. Cleavages of thio- epoxides and aziridines have not been reported in the literature; at least aziridines are expected to cleave like epoxides. The cleavage of epoxides and methylammonium salts is unusual as far as the two electron transfer to an antibonding sigma orbital is concerned. 47.

CHAPTER 3

RESULTS AND DISCUSSION

The reduction of carboxylic esters by alkali metals is a classic transformation. Excess of metal, usually sodium, in refluxing anhydrous 134 135 ethanol or sodium in ammonia in the presence of ethanol provides two alcohols (Bouveault-Blanc; Chapter 2), whereas two gram atoms of metal 142- per mole of ester in a refluxing hydrocarbon solvent gives the acyloin 115 144 . The treatise by Ruhlmann , reviewing the acyloin condensation conducted in the presence of chlorotrimethylsilane, and more recently the 145 one by Bloomfield are excellent.

There are reports in the literature of reductions in liquid ammonia

146-150 and aromatic hydrocarbon solvents35 where acids, alcohols and other 146 anomalous products were found. Wenkert observed mainly podocarpic acid

(67) on treatment of the hindered ester. (68) with lithium in ammonia, whereas treatment of the ester (69) gave mainly the alcohol (70). The alkyl residue was not investigated. This reaction was claimed as an efficient method for the hydrolysis of hindered esters, but has not found a wider 150, application. Bell however, isolated the alcohol (71) as the major product from the ester (72), and was unable to repeat Wenkert's results.

Stetter35 has reduced a series of benzoates with sodium in refluxing toluene and obtained benzoic acid in high yield and alkyl diners in 30 to 50% yields (Chapter 1). From methyl and ethyl benzoates two unidentified gases were obtained.

Barton's coworkers, at Chelsea College, accidently discovered that

treatment of 33,12a-diacetoxy-13a-oleanane (73) with lithium in ethyl-

amine gave 13a-oleanan-3E3-01(74a) in 35% yield. The complete deoxygenation

of the 12a-acetate was a surprising result as the 12a-alcohol was expected

either via the Bouveault-Blanc reduction or via the acyloin condensation.

48.

Deoxygenation is a synthetic transformation of considerable importance and the readily available acetate esters are admirable substrates. An investigation of the synthetic potential and mechanism of the reaction was undertaken at Imperial College, and partly at Chelsea College in the early stages of this work.

The 12a-acetate of (73) is axial and hindered, whereas the 3R-

acetate is equatorial and non-hindered. This led to the hypothesis that the mechanism involved radical fragmentation of the initially formed radical anion via alkyl oxygen cleavage when the cleavage is attended

by a sufficient release of unfavourable steric interactions (deoxygena-

tion), otherwise via acyl oxygen cleavage to regenerate the alcohol

(scheme 13).

CO 2 M e HO

(68) (67) 77% 23%

LiINH3 + THF

OH (69) 3% (70) 62%

49.

CO Et OH Li/NH3

THF ref. 147

30 0 40%

Na/Li/NH3

t-AmOH H dioxan CO ie ref. 148

THF/t-BuOH 40% ref. 149

•Li/NH 3

ref. 150

CO 2H

(72)

50.

Li/EtNH2

85%

A c0

(73)

(74a) R = HO— (74b) R = AcO-

R 0 0- N R ' CO2

ROH

i R CHZOH

R—H R1COCH(OH)R1 Scheme 13 51.

5a-Cholestane-35,68-diol (75) having an equatorial (35) and an axial (66) hydroxy group was chosen for testing the above hypothesis.

The 65-hydroxy group has three 1,3-diaxial interactions with the protons

4 and 8 and the 19-angular methyl, which make it more sterically hindered than the 35-hydroxy group. The difference in the steric'environment of the two hydroxy groups is well documented in the literature as exemplified by the rates of ester hydrolysis. Hence reduction of diesters of the diol

(75) with lithium in ethylamine according to the above hypothesis should selectively deoxygenate the 6 position.

(75)

The preparation of the diol (75) is summarised in scheme 14. Ben- zoylation of cholesterol (76) with benzoyl chloride in pyridine gave cholesteryl benzoate (77) in 94% yield. Subsequent treatment with N-bromoacetamide in the presence of aqueous perchloric acid gave 35-benzoyloxy-

5a-bromocholestan-65-o1 (78) contaminated with 35-benzoyloxy-5a,Ga-epoxy- cholestane (79) and 35-benzoyloxy-5a,63-dibromocholestane (80). The epoxide was presumably formed via the isomeric bromohydrin (81), whereas the dibromide (80) via the usual electrophilic addition of bromine to olefins. Lithium aluminium hydride reduction of the pure bromohydrin (78) gave the 33,65-diol (75) in 81% yield, and cholestan-30,55-diol (82) in

7% yield which on treatment with acetic anhydride-pyridine gave 35- 52.

0 HO P h 0

(?5) (77)

P h)4\0 HO B;" OH H OH

(78) (75)

i, PhCOC1/pyridine; ii, CH3CONHBr/HC104/H20/dioxan,

iii, LiA1H4/tetrahydrofuran

Scheme 14

0 Ph 0

OH (79) a-epoxide (84) (3-epoxide (82) R = 110- (83) R = Ac0- 53. acetoxy-cholestan-58-ol (83). Reduction of the bromohydrin (78) presumably proceeds via 53,68-epoxide (84) which gives rise to the diols (75) and

(82). Reduction of the crude product obtained from the treatment of cholesteryl benzoate (77) with N-bromoacetamide gave a complex mixture, separa- ble by chromatography, consisting of cholesterol (76) 7%, cholestan-38,58- diol (82) 7%, cholestan-38,5a-diol (85) 9%, and cholestan-38,613-diol (75)

70%.

The following esters were prepared from cholestane-38,613-diol (75) and the corresponding acid anhydrides or chlorides (see experimental) in pyridine:- 38,68-diacetoxy-5a-cholestane (86), 38,613-diformyloxy-5a- cholestane (87), 38,613-dipropanoyloxy-5a-cholestane (88), 313,613-bis-(2- methylpropanoyloxy)-5a-cholestane (89), 38,68-dibenzoyloxy-5a-cholestane

(90), 313,68-bis-(2,2-dimethylpropanoyloxy)-5a-cholestane (91), 38,68-bis-

(l-adamantanecarbonyloxy)-5a-cholestane (92) (prepared using n-butyl-

lithium and adamantane-l-carbonyl chloride (93)). From cholestan-38,5a- diol (85) the esters 38-acetoxy-cholestan-5a-ol (94), 313,5a-diacetoxy-

cholestane (95) and 30-(2-methylpropanoyloxy)-cholestan-5a-ol (96) were

prepared, and reduced with lithium in ethylamine. The results are summari-

sed in Table 1

Clearly the more hindered axial ester (68) was selectively deoxy-

genated to give 5a-cholestan-30-ol (97). Treatment of the diformate (87)

with ethylamine in the absence of lithium spontaneously gave the diol (75).

Ethylamine was too powerful a nucleophile and another reducing system

was therefore sought after. Lithium in refluxing benzylamine or ethyl-

enediamine produced red and blue coloured solutions respectively..

Reductions carried out in these amines were examined in more detail

by the Chelsea College group. Reduction of the diacetate (86) with lithium

in ethylenediamine gave 5a-cholestan-38-ol (97) and the diol (75) in 31 0'

and 53% yields respectively, comparable to lithium in ethylamine. Lithium 54.

Substance number R

(24) Ac0-

(49) H-

(76) HO-

(77) PhCO2-

(100) HCO2- 55.

Substance number R1 R2 R3

(80) PhCO2- Br- Br- (81) PhCO2- HO- Br- (85) HO- HO- H- (86) Ac0- H- Ac0- (87) HCO2- H- HCO2- (88) EtCO2- H- EtCO2-

(89) 1PrCO2- H- 1PrCO2- (90) PhCO2 H- PhCO2- (91) tBuCO2- H- tBuCO2

(92)

(94) Ac0- HO- H- (95) AcO- Ac0- H-

(96) 1PrCO2 HO- H (97) HO- H- H-

(98) H- H- IIO- (99) HO- HO- HO-

(101) IICO2- II0- HCO2-

(102) Ac0- HO- Ac0-

(103) Ac0- Ac0- Ac0- (104) H- HO- H-

(110) Ac0- H- Ii- (111) CH3COCH2CO2- II-

(114) CO2- H- H-

(126) tBuCO2- H- H- 56.

Substance number X

(93) -COC1

(105) -CII2OAc

(106) -C1120H

(107) -CO2Et

(108) -COZH

(109) -COCH(OH)

(112) -CO2 (CH2 )17CH3

(115) CONI1E t

(116) -CHO 57.

TABLE 1

Products Ester (% yield) (97) (75)

1. (86) 32 40

2. (87) 0 75

3. (88) 15 61

4. (89) 16. 55

5. (90) 0 78

In entry No. 5, the crude product was

acetylated prior to separation. 58.

in refluxing tetramethylethylenediamine, potassium in refluxing t-butylamine, potassium/18-crown-6/triethylamine, and calcium/18-crown-6/t- butylamine failed to produce coloured solutions. Lithium/naphthalene/ tetrahydrofuran, lithium/benzophenone/di-isopropylamine/tetrahydrofuran, and aluminium amalgam in tetrahydrofuran failed to reduce the diacetate

(86). Sodium-potassium eutectic in 1,2-dimethoxyethane/tetrahydrofuran reduced the diacetate (86) to the diol (75) Without any deoxygenation. i'~~t:1i: ^ 1~1tt1 arl'i 1'S- rrl'n-ri in t- butylaminc:, 1 ,2-flIrthr,z (:thaiti, f.Pr tC•tra- hydrofuran at room temperature, however, produced dark blue solutions comparable in colour with sodium in liquid ammonia. Although the fact that blue coloured solutions can be obtained by solubilising alkali r metals in ether solvents by crown ethers was reported in the literature 51 in 1970, no reports of any attempted reductions have appeared as yet. The diformate (87) was found to be stable in t-butylamine and therefore, reductions of esters were attempted with potassium/18-crown-6/t-butylamine.

The results are summarised in Table 2.

Clearly hindered secondary alcohols were selectively deoxygenated.

Bulky acyl groups increased the yields of deoxygenation. Furthermore, deoxygenation of the equatorial alcohol was also observed, and the yield increased with the bulkiness of the acyl residue.

The tertiary and axial 5a-position of steroids was next examined. 152 Cholestan-3S,5a,68-triol (99) was prepared by the method of Fieser from cholesterol (76) and formic acid/hydrogen peroxide followed by hydrolysis of the derived diformate (101). Acetylation of the triol (99) with acetic anhydride-pyridine gave the diacetate (102), whereas acetylation of (102) with acetyl chloride in refluxing chloroform in the presence of N,N-dimethylaniline gave the triacetate (103). The reduction results of 5a-esters are summarised in Table 3. The acetate esters of tertiary alcohols were found to deoxygenate as readily as the esters of sterically hindered 59.

TABLE 2

Products (% yield) Ester (29) (98) (97) (75)

1. (86) 11 1 51 23

2. (87) 0 0 0 86

3. (89) 7 4 65 9

4. (90) 5 0 45 36

5. (91) 30 10 37 7

6. (92) 45 6 27 8

All reductions were carried out with

potassium/18-crown-6 in t-butylamine

except entry No. 1 in 1,2-dimethoxyethane. 60.

TABLE 3

Products (% yield) Ester (29) (49) (76) (97) (104) (85)

1. (97) - - - - 27 39

2. (95) 4 - - 57 0 18

3. (95) 0 - - 66 0 8

4. (102) - - - - 29 55

5. (85) - - - - - 79

6. (103) 0 14 34 - 0 0

7. (103) 0 12 24 0 23 -

Runs 3 and 6 were carried out with lithium

in ethylamine. 61.

secondary alcohols. The formation of cholest-5-ene (49) and cholesterol

(76) by the reduction of the triacetate (103) was probably the result of displacement of the acetate group from C-6 by a carbanion at C-5 (or vice versa).

Reduction of the primary esters 1-acetoxyoctadecane and 1-acetoxymethyladamantane (105) with potassium/18-crown-6/t-butylamine gave 1-octadecanol and 1-hydroxymethyladamantane (106) in 78% yields without any deoxygenation.

Reduction of ethoxycarbonyl-l-adamantane (107) gave adamantane-l- carboxylic acid (108) and a trace of 1-hydroxymethyladamantane (106), but no adamantanoin (109). Cholesteryl acetate (24) and 38-acetoxy-5a- cholestane (110) gave 20% and 30% deoxygenation yields respectively, no acetoin was, however, isolated. Reduction of the acetate (110) at -600 gave 5a-cholestane (29) in 6% yield,and 5a-cholestan-30-yl acetoacetate

(111) in 2% yield. Clearly, at low temperature the deoxygenation was suppressed, and competing with the Claisen condensation. Reduction in the presence of t-butanol suppressed the deoxygenation but not as markedly as the effect of temperature. Reduction of 1-(1-adamantanecarbonyloxy)-- octadecane (112) gave unexpectedly 1-octadecane in 40% yield, 1-octadecanol in 53% yield, and .adamantane-l-carboxylic acid in 90% yield.

Having established a potentially useful and selective method for the deoxygenation of tertiary acetates, and esters of sterically hindered secondary alcohols, a study of the mechanism of the reaction was undertaken.

An attempt to trap the radical with thioglycolic acid at C-5 before it was reduced to the C-5 carbanion during the reduction of the triacetate (103) failed. Results similar to those in the absence of thioglycolic acid were obtained. Attempts to trap carbanions with iodomethane, ch1orotrimethylsilane or propyloxyprop-2-ene during the reduction of the diacetate (86) also failed.

Attempts to trap isobutyric acid as its p-bromophenacyl ester (113)

(113)

after the reduction of the di-isobutyrate ester (89) gave a very low yield of 6%. When sodium isobutyrate was subjected to the reduction conditions only 25% was isolated as its p-bromophenacyl ester (113). It was not clear, however, whether the isobutyric acid was reduced to isobutyraldehyde or lost on handling. Reduction of 38,68-bis-(1-adamantanecarbonyloxy)-5a-cholestane

(92) gave adamantane-l-carboxylic acid in 92%, substantially higher than the total yield for deoxygenation. 38-(1-Adamantanecarbonyloxy)-5a-cholestane

(114) was chosen for further study since it permits ready identification of the fragments derived from both acyl and alkyl residues on reduction, and the number of possible products from (114) are fewer than those from the diester (92). The ester (114) was prepared using potassium hydride, 18-crown-6,

and 1-adamantanecarbonyl chloride (93). The results of the reduction of

the ester (114) in potassium/18-crown-6/t-butylamine or lithium in ethylamine

at various temperatures are summarised in table 4. Adamantane-l-carboxylic

acid (108) was recovered in 87% yield when treated with potassium/18-crown-6/

t-butylamine. Under more forcing conditions (excess metal, and longer reac-

tion time) the acid (108) was, however, reduced by lithium in ethylamine to

the aldehyde (116) and alcohol (106) (Chapter 2). In all cases reduction 63.

TABLE 4

temp. metal Products (% yield) (oC) (29) (97) (108) (106) (115)

1. +46 K 43 57 96 2 -

2. +20 K 43 37 84 0 -

3. +20 K 45 44 93 7 -

4. +20 K 30 57 92 0 -

5. -45 K 27 66 77 5 -

6. -53 K 15 81 71 0 -

7. -73 Li 1 93 0 69 0

8. +17 Li 7 85 4 4 92

9. +17 Li 4 94 4 65 0

10. +17 Li 5 92 2 29 51

11. +78 Na 0 58 0 66 -

Reactions were carried out in t-butylamine and THF

(1,5,6), t-butylamine and ether (2), t-butylamine with

potassium added last (3), 1,2-dimethoxyethane and iodomethane

(4), ethylamine and tetrahydrofuran (7,8), ethylamine and

excess lithium (9), or ethylamine tetrahydrofuran, and

t-butyl acetate (10). Reaction 11 was carried out under

standard Bouveault-Blanc conditions. 64.

of the ester (114) gave adamantane-l-carboxylic acid (108) substantially predominating over 5a-cholestane (29). The possibility that this difference resulted from competitive hydrolysis by adventitious water was unlikely since rigorous drying was used and in entry 4, Table 4, iodomethane was added before the ester to scavenge any water. The yield of 5a-cholestane (29) was decreased at lower temperature. Hence the radical anion fragmentation reaction leading to deoxygenation must have a finite activation energy. A rough estimate of the activation energy (Ea) was made using the Arrhenius equation:

E a k = Ae RT and assuming that the ratio of the reaction rates at two different temperatures was proportional to the ratio of the percentage yield of deoxygenation at those temperatures:

k293 % deoxygenation at 293 K % deoxygenation at 220 K k220

k293 __ Ea Ea 293 R + 220 R k220

45 Ea 1 ln _ 15 R 220 293

-1 where R = 8.314 JK mol.

E - 2.303 x 8.314 x log3 E a 1 1 220 293

E = 8 KJ mol-1. a

Deoxygenation was a minor pathway on lithium in ethylamine reduction giving the alcohol (97) and the amide (115) owing to competitive transacylation.

In the presence of excess electrons entry 9, Table 4, or at low temperature entry 7, Table 4, both transacylation and deoxygenation were suppressed and 65.

the two-electron Bouveault-Blanc reduction giving the two alcohols (97) and

(106) predominated. The fact that the acid was always predominant compared with the alkane in the reduction of esters with potassium/18-crown-6/t-butyl-

amine led to the conclusion that a deacylation other than hydrolysis was

taking place. Ester deacylation by alkoxide was shown to compete with reduc-

tion by the isolation of 5a-cholestane (29) during the reduction of 1-ethoxy-

carbonyladamantane (107) in the presence of 5a-cholestan-38-ol (97). 18-Crown-

6 was found to be fragmented on reaction with potassium in t-butylamine. When the blue colour faded, acidification followed by acylation with 1-naphthoyl

chloride gave products including N-t-butyl 1-naphthalenecarboxamide and the

esters (117), (118) and (119). These were characterised by spectral data and

high resolution mass spectroscopy.

CO2(CH2)2O(CH2)2OR

(117) R = -H (118) R = -CH2CH2OEt (119) R = -(CH2)20 (CH2)20Et

(120) HO 66.

Clearly, during ester reduction complete deoxygenation was prevented by competitive deacylation by crown fragments. The so-formed acylated fragments were subsequently deoxygenated giving the carboxylate anion. The amount of crown used in reduction was always in excess of the ester; frequently extra 18-crown-6 had to be added during the reduction to sustain the blue colour. On one occasion a catalytic amount of 18-crown-6 was used during the reduction of the triacetate (103) in t-butylamine and the major product (not isolated under ordinary reduction conditions) was 5a,6a-epoxycholestan-38- of (120). 18-Crown-6 was found to sulubilise rubidium in t-butylamine producing ablue coloured solution which reduced the diacetate (86) as efficiently 153 as potassium. Recently Barrett has shown that reduction of esters with sodium-potassium eutectic in t-butylamine in the presence of hexamethyl- hexa-aza-18-crown-6 gave high yield of alkanes even with the primary acetates that gave no deoxygenation with potassium/18-crown-6/t-butylamine. Hexamethyl- hexa-aza-18-crown-6 would be expected to fragment less readily than 18-crown-6 2 providing thus a nucleophile-free medium for deoxygenation to occur. Pete's3 observations that alkyl carboxylates deoxygenate on treatment with sodium/ hexamethylphosphoric triamide/t-butanol to alkanes are consistent with our observations that in a nucleophile-free medium deoxygenation is the major 154 pathway. Recently Pinnick has reported that the treatment of alkyl esters with sodium in liquid ammonia gave alcohols in high yields, except in the case of allylic alcohols where deoxygenation was observed. The acyl residue was not investigated. In the case of hindered esters, and in particular t-butyl 32 mesitoate, only starting material was observed. Contrary to our, and Pete's 154 observations, hindered esters deoxygenate most readily, hence Pinnick's observations seem to be compatible with amminolysis, rather than Bouveault-

Blanc reduction.

Terminal cyclic carbonates and thiocarbonates on treatment with potassium/l8-crown-6/t-butylamine would be expected to deoxygenate to the primary alcohol via the radical anion or the secondary alcohol via the dianion

67.

(Scheme 15).

X-

o 0 i x-

RCH2 H O RCH(OH)CH3

Scheme 15

The cyclic carbonate (121) was prepared from decane-1,2-diol and phosgene whereas the cyclic thiocarbonate (122) from decane-1,2-diol and N,N'-thiocarbonyl-di-imidazole. Reduction of (121) and (122) with potassium/18-crown-

6-/t-butylamine gave predominantly the primary alcohol, consistent with deoxygenation via the radical anion. The Chelsea College group reduced

3a,5a-cyclocholestan-66-yl acetate (123) with lithium in ethylamine and obtained 3a,5a-cyclocholestane (48) and cholest-5-ene (49) in 7 and 38% yields respectively, consistent with deoxygenation via a radical at C-6.

68.

(121) X = 0

(122) X = S

OAc

(123)

(124)

(125)

(127) 69.

Attempts to find an easily accessible nucleophile-free reductant failed. Treatment of 3S-(1-adamantanecarbonyloxy)-5a-cholestane (114) with lithium in tetramethylethylenediamine and toluene in the presence of biphenyl gave 5a-cholestan-3S-ol (97) in quantitative yield. One equivalent of the biphenyl was consumed to give a mixture of ketones most reasonably (124) and

(125) and their respective alcohols. An attempt to reduce ester (114) with lithium in tetramethylurea failed. 5a-Cholestan-3(3-ol (97) was the only alkyl product; no deoxygenation was detected. Amides were detected (IR and NMR) probably arising by decomposition of tetramethylurea to dimethylamide followed by transacylation. The solvation of alkali metals in t-amides and tetra- 155 alkylureas to give blue coloured solutions was reported by Dewald in 1977.

The solution from tetramethylurea was reported to be unstable, consistent with our observations. Sodium in diethylacetamide, and sodium-potassium eutectic 155, 156 in tetraethylurea are reporeted to give stable blue coloured solutions, but these were not examined.

Reduction of 313-(2,2-dimethylpropanoyloxy)-5a-cholestane (126) with potassium/18-crown-6/t-butylamine gave 5a-cholestane (29) and 5a-cholestan-

3S-ol (97) in 65% and 32% yields respectively. Attempts to utilise the ob- servation that transacylation was competitive to reduction, by transacylating the product under reduction conditions with ethyl pivaloate or 2,3,6- trimethylphenyl pivaloate only slightly increased the yield of alkane (29) to 73% and 67% respectively, due to the fact that both ethyl and 2,3,6- trimethylphenyl pivaloates are reduced. A vinyl ester would be expected to reduce less readily than an alkyl ester. Attempts to prepare 1-(2,2- dimethylpropanoyloxy)-2-methylpropene (127) under both acidic or basic 157 conditions all failed, the aldol condensation being faster than acylation.

Attempts to deoxygenate carbohydrate esters were not successful. Reduc- tion of 3-0-acetyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (19) or

1,2:5,6-di-O-isopropylidene 3-0-(2-methylpropanoyl)-a-D-glucofuranose (128)

70.

OMe

(19) R = Ac0- (130) R = Ac0-

(128) R = 1PrCO2- (131) R = HO- (129) R = HO-

(143) R= M e

OMe Ph

(132) R = 110-

(133) R = Ac0- (141) (140)

(134) X = 0

(132) X = S

(133) X = NH (135) R = HO- (136) R = Ac0- (134) X = N502 71.

gave mainly the alcohol (129). Reduction of the diacetate (130) gave a mixture of the diol (131) and tetra-ol (132) whereas on longer reaction times the only product was the tetra-ol (132). Reduction of the cyclic carbonate (134) gave the diol (135), whereas the cyclic thiocarbonate (137) gave a multitude of products. The iminocarbonate (138) gave the diol (135) and an unidentified product. The cyclic thiocarbonate (140) and the cyclic trithiocarbonate (141) gave complex mixtures.

Reduction of the toluene-4-sulphonate (142) gave the alcohol (97) as the only non-sulphur containing product, whereas the bis-toluene-4-sulphonate

(143) gave a multitude of products.

158 Recently, Berndt reported an e.s.r. study on alkyl radicals obtained by sodium-potassium eutectic reductions of oxalate esters of bulky alcohols.

No method of preparation or yields of the alkyl products were reported. The reduction of oxalates was investigated as a synthetic method for the deoxygenation of alcohols. Di-(5a-cholestan-3(3-yl) oxalate (144) was prepared from

5a-cholestan-33-ol (97) and oxalyl chloride in pyridine in 2% yield, from sodium hydride and oxalyl chloride in tetrahydrofuran in 6% yield; from sodium hydride and diethyl oxalate the mixed ester ethyl 5a-cholestan-3S-y1 oxalate (145) and the cathylate (146) were obtained whereas under acidic conditions and diethyl oxalate compound (147) (the product of aromatic electrophilic substitution of toluene) was isolated as the only product. Reduc- tion of the diester (144) with both potassium/18-crown-6/t-butylamine, and sodium-potassium eutectic in tetrahydrofuran gave only 10% deoxygenation.

Reduction of the thioacetate (148) gave mainly the alcohol (76) and only 8% deoxygenation. The benzimidate (149) gave the alcohol (76) as the only product whereas the Vilsmeier salt (150) gave mainly the alcohol (97);

amines, however, interact with Vilsmeier salts and this reaction should have

been carried out in an ether solvent rather than t-butylamine. Reduction 46 of Ireland's phosphorodiamidate (152) with potassium/18-crown-G/t-butylamine 72.

(142) (146) R = EtO.00.0-

(147) R =

(144)

R1 = C2H50- R 2

(145)

73.

1 Substance number H2

(150) C1 Me2Ii:CHO- H-

(151) HCO2- H-

(152) (Me0N)2P02- H-

(153) C1.00.0- C1.00.0-

(154) EtO.00.0- EtO.00.0-

(156) iPrO.00.0- 1Pr0.00.0-

(158) tBu0.00.0- tBuO.00.0-

(159) 1PrO.00.0- H-

(160) CN.00.0 /N.00.0 \

(162) EtNH.00.0- EtNH.00.0-

(164) Et2N.00.0- H-

(165) MeS.CS.0- MeS.CS.0-

(166) MeS.CS.0- McS.00.0-

(167) MeS.CS.0- HO-

(168) EtNH.CS.0- EtNH.CS.0-

(169) tBuNH.CS.0- tBuNH.CS.0-

(170) tBuNH.CS.0- MeS.CS.0-

(171)

/continued...

74.

.../continued

H1 H2 Substance number

(172) ~N.CS.0- H- (--

(173) McS.CS.0- H-

(174) E t 2N . C S. 0- I I-

(175) Me2N. (CH2) 2N (Me) . CS. 0- H-

(178) 1Pr2N.CS.0- H-

(179) Me2N.N(Me).CS.0- H-

(182) MeO- H-

(183) tBuCO2- HO-

(184) c0CO - HO- 2 75.

Substance number R

(148) hie. CS. O-

(149) Ph.C(NH).0-

(155) EtO.00.0-

(157) 1PrO.00.0-

(161) CN.00.0-

EtNH.00.0- 76.

gave the alakane (29) as the only product.

A series of carbonates and carbamates were prepared and their reduction examined. The 3S,613-bis-carbonates and bis-carbamates were prepared from the dichloroformate (153) which was prepared from the diol (75) and phosgene.

Treatment of the dichloroformate (153) with ethanol gave the dicathylate

(154) in 63% and cholesteryl cathylate (155) in 31% yield; with 2-propanol gave the bis-carbonate (156) in 72% and the cholesteryl carbonate (157) in

25% yield; with potassium t-butoxide in t-butanol at 600 only cholesterol

(76) was isolated and no trace of the bis-carbonate (158) was detected. The carbonate (159) was prepared from 5a-cholestan-3S-ol (97), phosgene and 2- propanol in 87% yield. Attempt to prepare the bis-carbamate (160) from the dichloroformate (153) and piperidine failed and the cholesteryl carbamate

(161) was isolated in 75% yield. Treatment of the dichloroformate (153) with ethylamine gave the bis-carbamate (162) and the cholesteryl. carbamate

(163) in 35 and 21% yield respectively. The carbamate (164) was prepared from

5a-cholestan-3(3-ol (97) and diethylaminocarbonyl chloride (from triethylamine and phosgene) in 80% yield. Reduction of carbonates and carbamates gave mainly the starting alcohols with little deoxygenation. The results are summarised in Table 5.

Dithiocarbonates (xanthates) and thiocarbamates were prepared and treated with potassium/18-crown-6/ t-butylamine to investigate their deoxygenation. Initial transfer of an electron to a xanthate or thiocarbamate gives a radical anion which is expected to collapse to thiocarboxylate anion

(specially stabilised by the sulphur) and carbon radical leading to alkane, like the ordinary ester reduction.

Xanthates were prepared using sodium hydride, carbon disulphide and iodomethane. During the preparation of the bis-xanthate (165), however, from the diol (75), sodium hydride, carbon disulphide and iodomethane in reflux- 77.

TABLE 5

Products Substrate (% yield) (29) (97) (75)

1. (154) 0 20 30

2. (154) 0 0 66

3. (156) 0 41 24

4. (159) 12 83 -

5. (164) 4 80 -

All reductions were carried out with

potassium/18-crown-6/t-butylamine

except entry 2 (lithium in ethylamine).

(C 2H5)2N .0 S.0 (CH. 2)17CH 3

(176) 78.

ing tetrahydrofuran the monoxanthate monothiocarbonate (166) and 38-(methylthio)thiocarbonyloxy-5a-cholestan-68-o1 (167) were obtained. The bis- xanthate (165) was prepared without any complications, however, from the diol (75), n-butyl-lithium, carbon disulphide and iodomethane in tetrahydrofuran at -200. Thiocarbamates were prepared from xanthates by solvol- 159 ysis in amines The 38,68-bis-(N-ethylaminothiocarbonyloxy)-5a-cholestane

(168) was prepared from bis-xanthate (165) and ethylamine in 78; yield.

Attempt to prepare the bulky 38,68-bis-(N-t-butylaminothiocarbonyloxy)-5a- cholestane (169) failed. The reaction stopped at the monothiocarbamate monoxanthate (170) which decomposed under more vigorous conditions. The thiocarbamates (171) and (172) were prepared in 71 and 70% yields respectively. The xanthate (173) was prepared in 91% yield from which the thiocarbamates (174) and (175) were prepared in 92 and 84% yields respectively.

N,N-Diethylaminothiocarbonyloxyoctadecane (176) was prepared in 70% yield, and 1,2:5,6-di-0-isopropylidene-3-0-(N,N-diethylaminothiocarbonyl)-a-

D-glucofuranose (177) was prepared from the xanthate (30) in 56% yield.

The results of the reduction of xanthates and thiocarbamates are summarised in Table 6.

Clearly both primary and secondary alcohols can be deoxygenated in

high yield via their derived dialkylaminothiocarbamates with potassium and

18-crown-6 in t-butylamine or 1,2-dimethoxyethane and this method comple-

ments the selective ester reduction described earlier.

The thiocarbamate (168) is considered to undergo a base promoted

decomposition to ethyl thioisocyanate and alkoxide thus suppressing the

deoxygenation reaction. The difference in deoxygenation of the xanthate

(165) with lithium/ethylamine and potassium/18-crown-6/t-butylamine may

reflect the difference in both the rate of thiocarbamate formation during

the reduction (the ethylaminothiocarbamate being formed faster than t-butyl- 79.

TABLE 6

Substrate Products (% yield)

1. (165) (75) 38

2. (165) (29) 38, (98) 2, (97) 19, (75) 8

3. (168) (75) 68

4. (168) (97) 18, (75) 45

5. (171) (29) 62, (98) 15, (97) 12, (75) 5

6. (172) (29) 74, (97) 14

7. (174) (29) 86, (97) 8

8. (174) (29) 58, (97) 40

9. (175) (29) 83, (97) 12

10. (176) CH3(CH CH3 87, CH3(CH2 0H 12 2)16 )17 11. (177) (10)14, (129) 55

All reductions were carried out at room temperature, except entry 8

(-30°C). Entries 2, 4-11 were carried out with potassium and

18-crown-6 in t-butylamine except entry 6 (in 1,2-dimethoxyethane)

Entries 1 and 3 were carried out with lithium in ethylamine. 80.

amino), and the rate of decomposition to thioisocyanate. At low temperature the deoxygenation was suppressed suggesting that the deoxygenation fragmenta-

tion of the radical anion may require a finite activation energy. The

deoxy-sugar (10) obtained from reduction of the thiocarbamate (177) was

identical to a sample prepared by the Barton40 method from the xanthate

(30) and tri-n-butylstannane.

(177)

The preparation of the sterically hindered thiocarbamates (178) and

(179) proved to be difficult giving mixtures of many products including

elimination products and they were abandoned.

In an attempt to prepare alkenes from 1,2-bis-thiocarbamates the bis-

thiocarbamate (180) was prepared in 51% yield and reduced with potassium/

18-crown-6/t-butylamine to give a mixture of products. The attempt to

prepare the alkene on the bis-thiocarbamate (180) was obviously too ambi-

tious, since isopropylidene can easily be eliminated by an a-carbanion!

Finally, a brief investigation of the reduction behaviour of

epoxides was undertaken. Epoxides are known to give the more highly

substituted alcohol on treatment with alkali- metals in amines. If the

reduction proceeds via an one-electron transfer to the radical anion the

81.

E t 2 N.CS•0-

-0•CS.NEt2

-0

(180) (181)

most stable radical would be expected giving rise to the least substituted alcohols; if via a two-electron transfer to the dianion the most stable anion would be expected to give rise to the most highly substituted alcohol

(Scheme 16). Reduction of 1,2-epoxydecane with potassium/18-crown-6/ t-butylamine followed by acylation of the products with 3,5-dinitrobenzoyl chloride gave decan-2-yl 3,5-dinitrobenzoate in 38% yield and in another reduction which was followed by oxidation and. treatment with 2,4-dinitro-

phenylhydrazine gave the 2,4-dinitrophenylhydrazone of methyl n-octyl ketone in 35% yield. Dimeric products were also obtained but no primary

alcohols was detected. Clearly, the reduction proceeded via the dianion

confirming the literature reports (Chapter 2).

le R \ ~ R CH 2CH2OH 0 R / 0 2e R\/ RC H(OH)CH3

Scheme 16 82.

CHAPTER 4

EXPERIMENTAL

Melting points were determined using a Kofler hot stage. Ultraviolet spectra were recorded on a Unicam SP 800 ultraviolet spectrophotometer.

Nmr spectra were recorded in deuterochloroform or carbon tetrachloride with tetramethylsilane as an internal reference on a Varian T60, EM-360, or

Perkin Elmer R 32 instruments. Infrared spectra were recorded on a Perkin

Elmer 298, 257, or 157 instruments. Optical rotations were recorded in chloroform, unless otherwise stated, on a Perkin Elmer 141 Polarimeter.

Analytical gas liquid chromatograms were recorded on Perkin Elmer Sigma 3 instrument, on a column <1 /8 " o.d., 2 m long) packed with 10ō silicone

OV-17 on chromosorb.

Analytical thin layer chromatography was carried out using silica GF254 plates or Merck precoated silica plates. Preparative layer chroma- GF254 tography (plc) was carried out using GF254 silica plates, developing sol- . vents are noted in parenthesis.

Ultraviolet inactive compounds on tic were visualised with iodine, anisaldehyde: sulphuric acid : methanol = 1 : 1 : 18 and warming (PANS reagent), charing with sulphuric acid or with a hot wire. In general column chromatography was carried out on silica M.F.C. or Merck Kieselgel G0.

Rapid medium pressure chromatography was carried out on Merck Kieselgel II type 60.

The following grades of solvent were employed: light petroleum - redistilled b.p. 40-600 fraction; petroleum - redistilled b.p. 60-S0° fraction; benzene, toluene - redistilled, sodium dried; triethylamine,

pyridine - redistilled from potassium hydroxide and stored over 4A molecu-

lar sieve; ethylamine - redistilled from sodium hydroxide and used 83.

immediately; t-butylamine - redistilled from potassium and used immediately; methanol, ethanol, acetone - AnalaR reagents; dichloromethane, chloroform - redistilled; ethyl acetate - redistilled; diethyl ether, tetrahydrofuran, dioxan, dimethoxyethane - freshly distilled from potassium, lithium aluminium hydride or potassium/benzophenone ketyl; other reagents and solvents were 160 purified according to standard procedures .

Work-up refers to dilution of reaction mixtures with water and extraction of the products into ether. Organic extracts were dried over anhydrous sodium or magnesium sulphate. Solvents were removed under reduced pressure at or below 60o using a rotavaporator. Repeated procedures and physical and spectroscopic data are described in full in the first instance only.

Nitrogen gas was deoxygenated by chromium (II) chloride solution

(three dreschel bottles) and dried with concentrated sulphuric acid, phosphorus pentoxide and sodium hydroxide/soda lime towers.

Microanalysis and mass spectral measurements were carried out by the respective laboratories, Imperial College.

The following abbreviations are used in this chapter:

Ac acetyl (CH3C0) Me methyl br broad Ph phenyl t-Bu t-butyl i-Pr iso-propyl d doublet q quartet dd double doublet s singlet

DME 1,2-dimethoxyethane t triplet

Et ethyl THF tetrahydrofuran

LAH lithium aluminium hydride TMEDA N,N,N',N'-tetramethylethylenediamine m multiplet TAIU N,N,N',N'-tetramethylurea 84.

Cholesteryl Benzoate (77):- To a solution of cholesterol (76 ) (40 g,

104 mmol) in pyridine (250 ml) a solution of benzoyl chloride (14 ml,

120 mmol) in toluene (50 ml) was added and the mixture allowed to stand for 24 h, poured into ice-water and the solid filtered off. Crystallisa- tion from dichloromethane-methanol gave the ester (77 ) (47.8 g, 94%) as square white plates, m.p. 151-2°, IaI23 -16.10(c, 1.433) (lit.161 162 0 m.p. 150-1° ; lit. m.p. 147°, -15°), vmax (nujol) 1715, 1310, 1275, IaID -1 1250, 1110, 1070, 1025, 1000, 715 cm , S (CC14) 0.68 (3H, s, 18-Me),

0.80, 0.92 (side chain Me's), 1.08 (3H, s, 18- Me), 4.6 (1H, br, ;,'1 13 Hz, 2 3a-H), 5.4 (1Hi, m, W1 12 Hz, 6-H), 7.3 and 8.0 (5H, m, aromatic-H). 2

N-Bromoacetamide:- Acetamide (20 g, 339 mmol) was dissolved in bromine

(18 ml, 340 mmol) cooled to -10°, cold aqueous potassium hydroxide (60%) added dropwise with swirling and cooling until the colour became pale yellow. Water was removed under reduced pressure(0.1 mm at 100), salt

(40 g) was added to the residue, the mixture extracted with chloroform

(6 x 50 ml), the organic extracts dried in the dark, filtered and the product precipitated quickly with light petroleum giving N-bromoacetamide 163 as white needles (25.G g, 55%), m.p. 105-6°, (lit m.p. 105-6°).

33-Benzoyloxy-5a-bromo-5a-cholestan-6-ol (78 ):- To a suspension of cholesteryl benzoate (77) (10 g, 20,4 mmol) in purified dioxan (100 ml) under argon in a dark flask, aqueous perchloric acid (0.28 M; 4 ml) was added followed by N-bromoacetamide (99.4%; 7.4 g, 53.3 mmol) with vigorous stirring for 0.5 h. The reaction mixture was cooled to 0° with an ice- salt bath, water (75 ml) was added followed by aqueous sodium sulphite

(10a ro,; until the yellow colour was discharged). The mixture was extracted with diethyl ether, washed with water, dried, filtered and crystallised twice from dichloromethane - light petroleum giving the bromohydrin (78)

(5.1 g, 42%) as white needles, m.p. 166-8°, IaID3 -24.3° (c, 4.516), 85.

164 (lit. m.p. 173-4°, IaI D -22°), (nujol) 3430, 1720, 1280, 710 cm-1 , vmax 6 (CDC13) 0.70 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's), 1.37 (3H, s,

19-Me), 4.2 (1H, m, N, 8Hz, 6a-H), 5.7 (1H, br, W1 18Hz, 3a-H), 7.3-7.6

and 7.9-8.1 (5Ii, m, aromatic-H). Concentration and crystallisation of the

mother liquors from dichloromethane-methanol gave a mixture of two compounds

(1.4 g) which on repeated crystallisation gave 36-benzoyloxy-5a,6a-epoxy-

5a-cholestane (79) (498.2 mg, 5%), m.p. 167-9°, mixed m.p. with authentic 5r sample 167-9°, IaI2D3 -29.5°(c, 3.336), (lit. m.p. 169°, lair) -30°),

(ntijol) 1710, 1275, 1110, 700 cm-1, 6 (CDC13) 0.62 (3H,. s, 18-Me), 0.30, vmax 0.93 (side chain Me's), 1.12 (3H, s, 19-Me), 2.9 (1H, br, d, J = 4Hz,

66-H), 5.23 (IH, br, W1 20Hz, 3a-H), 7.3-7.6 and 7.9-8.2 (5H, m, aromatic-

H). The mother liquors were separated by plc (5% diethylether-petroleum)

and the least-polar material identified as 36-benzoyloxy-5a, 66-dibromo-

5a-cholestane (80) (923.3 mg, 7%), m.p. 134-5° (from chloroform-methanol)

IaID3 -32.4° (c, 0.395) (lit,166 m.p. 135-6°, la'D -33°).

36-Benzoyloxy-5a,6a-epoxy-5a-cholestane (79):- To a solution of choleste-

ryl benzoate (77) (3 g, 6.12 mmol) in dichloromethane (15 ml) a solution

of m-chloroperbenzoic acid (94.2%; 1.3 g, 6.48 mmol) in dichloromethane

(20 ml) was added with stirring over a period of 20 min and stirred for

an extra 80 min. Aqueous sodium sulphite (10%; 20 ml) was added and the

organic layer washed with sodium hydrogen carbonate, water, brine, dried,

evaporated and the residue crystallised from dichloromethane-petroleum to

give the epoxide (79) as white needles (2.4 g, 77%), m.p. 167.5 -160°,

IaI 23 -29.27° (c, 4.119).

Reduction of crude product from preparation of 36•-benzoyloxy-5a-bromo-5a-

cholestan-.6E3-ol (78):- Cholesteryl benzoate (77) (80 g, 163 mmol) in

dioxan (1 1)was treated with aqueous perchloric acid (0.057 M; 50 ml) and

N-bromoacetamide (53.2 g, 385 mmol) and worked up as before. The crude

product (94.6 g) in THF (500 ml) was added to a suspension of LAII (20 g, 86.

526 mmol) in THF (100 ml) and the mixture was stirred and refluxed for 48 h

under nitrogen. A saturated aqueous sodium sulphate solution (40 ml) was

added cautiously, and the white precipitate was filtered and washed with hot THF. The combined organic layers were evaporated to dryness and the

crude product (62 g) chromatographed (silica MFC; 1.3Kg). Overlapping

fractions were rechromatographed and/or acetylated prior to chromatography.

Elution with 25% ethyl acetate-toluene gave cholesterol (49) (4.43 g, 162 7%), m.p. 148-9°, from ethyl acetate, IesI23 - 39.0° (c, 1.671), (lit.

m.p. 149°, 'alp -39 °), 6 (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.93 (side

chain Me's), 1.03 (3H, s, 19-Me), 3.4 (1H, br, W1 20Hz, 3a-H), and 5.3 2 (1H, m, W1 8Hz, 6-H). Elution with 30% ethyl acetate-toluene gave choles-

tane-36,56-diol( 82) (4.68( g , 7%),o) m.p. 147-9°, from ethyl acetate, Ia I23 165,1 7 + 53.0° (c, 1.246), (lit. m.p 149°, lair) + 53°), v (nujol) 3280, max 1050 cm 1, 6 (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.97, 3.6-4.3 (3H, m, 2

exch. D20, 3a-H, 3-OH, 5-OH), m/e 404 (M+), 386 (M-H20), 368 (M-2H20),

353 (M-2H20-Me), 332, which on treatment with acetic anhydride-pyridine 0 165,167 gave 36-acetoxy-cholestan-5(3-ol (83), m.p. 80-1 , from acetone, (lit.

m.p. 80-1°), v max (nujol) 3560, 3300, 1710, 1285 cm 1. Elution of the column with 20% toluene-ethyl acetate gave cholestane-38,5a-diol (85 )

(5.93 g, 9%), m.p. 225-6°, as leaflets from ethyl.acetate, IaI23 + 19.6° 8 (c,c, 0.135)0.135 (lit.165,1mm.p. 225°, Iaj D + 20 1. .Elution with 10% toluene-

ethyl acetate gave 5a-cholestane-36i66-diol (75) (46.19 g, 70%), m.p.

190-2°, as long needles from ethyl acetate, IaID3 + 12.2° (c, 1.143 in 165,168 0 ethanol), (lit. m.p. 192° , IaID + 13°), (nujol) 3390, 1045, vmax cm 1, 6 (pyridine-d5/D20) 0.73 (3H, s, 18-Me), 0.90, 0.98, - 4.0 (2H, m,

3a-H, 6a-H).

5a-Cholestane-36,66-diol (75 ):- A solution of pure freshly prepared

bromohydrin ( 78) (10 g, 17 mmol) in THF (60 ml) was added to a suspension

of LAH (4.08 g, 107 mmol) in TIIF (60 ml) and the mixture was refluxed 87.

under nitrogen for 48 h. Saturated aqueous sodium sulphate (10 ml) was added dropwise with vigorous stirring and cooling. The.precipitate was filtered, washed with hot TIIF and the total solution evaporated to dryness. The residue was recrystallised from ethyl acetate giving long white 0 needles (3.9 g, 57%) m.p. 191-2 of 5a-cholestane-3,6,-diol (75 ) 165 (lit m.p. 192°). The mother liquors were chromatographed (silica H,

15 g) giving cholestane-33,53-diol (82) (479.8 mg, 7%) m.p. 148-9° 165 0 (lit. m.p. 149 ) and more 33,63-diol (75) (1.72 g,; total 5.62 g, 81%).

33,63-Diacetoxy-5a-cholestane (86 ):- To a solution of 5a-cholestane-33,

63-diol (75 ) (10 g, 25 mmol) in pyridine (100 ml) acetic anhydride

(14 ml) was added and the mixture allowed to stand for 17 Ii at 23°.

Work-up and crystallisation gave the diacetate (86 ) (12 g, 99j) as hexa- gonal white plates m.p. 138-9°, from dichloromethane-methanol, IaJ 3 165,168 o 0 23.0° (c, 2.133), (lit. m.p. 139 , I a i D (CHC13) 1725, - 23 ), vmax 1260 cm-1, ō (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's),

1.00 (3H, s, 19-Me), 2.02 and 2.05 each (3H, s, Ac0), 4.7 (1H, br,

W, 20Hz, 3a-H), 4.9 (1H, m,. W1 8Hz, 6a-H). z

General Procedure for Lithium-Ethylamine Reductions:- All glassware was

oven-dried before use. Ethylamine (2-5 ml) was distilled from sodium

hydroxide straight into the reaction vessel equipped with a dry ice-

acetone condenser. Freshly cut lithium metal (100 mg) was added to the

amine and the mixture stirred under dry oxygen-free nitrogen until the

dark blue colour appeared. A solution of the ester (100 mg) in THF

(1 ml) was added dropwise to the blue coloured solution until the blue

colour was discharged. On reappearance of the blue colour more ester

solution was added until the blue colour was discharged again and so on

until all the ester was added. After the addition was complete the

mixture was stirred until the blue colour persisted. The excess lithium 88.

was quenched by the dropwise addition of methanol with cooling (exothermic reaction). When all the lithium had dissolved the solvents were removed under reduced pressure, the residue was diluted with water and extracted with ether. The organic layer was washed with aqueous hydrochloric acid

(1 AS), water, dried, filtered and the solvent removed under reduced pressure. The product was recrystallised or chromatographed. Reductions were carried out in refluxing ethylamine (+ 170), unless otherwise stated.

Althernatively, the ester was dissolved in ethylamine and lithium metal added last. The mixture was stirred until the permanent blue colour appeared and worked up as above.

General Procedure for potassium/18-Crown-6/t-Butylamine Reductions:-

Small freshly cut pieces of potassium metal (20 mgatom) were added to a solution of 18-crown-6 (5 mmol) in dry t-butylamine (20 ml; freshly distilled from potassium) under dry oxygen-free nitrogen and. stirred for

a short time until a dark blue colour developed. A solution of ester

(1 mmol) in THF (5 ml) was immediately added on appearance of the blue colour at such a rate that the blue colour did not disappear for long

times. After addition of all the substrate and reappearance of blue colour, the reduction was complete and the excess potassium destroyed with

absolute ethanol. The solvents were removed under reduced pressure, water was added to the residue, and the products extracted into ether, the

ethereal layer washed with water, dried, filtered, evaporated to dryness

and the products chromatographed. The aqueous layer was acidified with

aqueous hydrochloric acid (GM) to pH 1 extracted with ether, and the

organic layer washed with water, dried, filtered, the solvent removed

under reduced pressure and the residue recrystallised to give the acid. 89.

Reduction of 33,12x-Diacetoxy-l3a-oleanane (73):- To a solution of 38,

12x-diacetoxy-13a-oleanans6(73) (58.9 mg, 0.11 mmol), 6 (CDC13) 0.86,

0.95, 1.07, 1.20, 2.03 (6II, s, 2Ac0), 4.5 (1H, t, J = 7Hz, 3a-H), 5.4

(1H, m, W1 9Hz, 12(3-H) in ethylamine (13 ml) at 0° lithium metal (80 mg, z 11 mgatom) was added and the dark blue solution stirred at 23° for lh, then

cooled to 0° and methanol (10 ml) added. After 1 h,solid ammonium chlo-

ride (0.5 g) was added and the amine removed at 40°. The residue waq

diluted with water, extracted with ether, dried, filtered and evaporated

giving 134-oleanan-3(3-ol (74a) (40.4 mg, 85%), 6 (CDC13) 0.76 (311, s),

0.86 (9H, s), 0.96 and 1.08 each (6Ii, s), and 3.2 (1H, t, 3a-H).

Treatment with acetic anhydride (1 ml) and pyridine (1 ml) gave the acet-

ate (74b) m.p. 239-240°, from chloroform-methanol, IaI12)3 + 20.7° (c, 0.479),

(lit. m.p. 285°, la I +21°, 1it171m.p.239--240° (CHC1~ 1720 cm ,6(CDC13) D ),\max 0.86, 0.88, 0.98, 1.09, 2.04 (3H, s, Ac0), 4.5 (1H, t, J = 7 Hz, 3a-II).

18-Crown-6:- To a warm solution of tetraethyleneglycol (243 g, 1.25 mol)

and potassium hydroxide (416 g, 6.3 mol) in TIIF (1 1) a solution of bis(2-

chloroethyl)ether (447 g, 3.125 mol) in THF (210 ml) was added in a stream

with vigorous stirring. The reaction mixture was heated under reflux

with stirring for 18 h, cooled and the solvent removed under reduced

pressure to give a brown slurry to which dichloromethane (750 ml) was

added. The mixture was filtered and the residue washed with dichloro-

methane (100 ml), the combined filtrate and washings dried, evaporated

under reduced pressure and distilled under nitrogen to give a liquid (220 g)

b.p. 110-210°/0.02 mm. The distillate was dissolved in acetonitrile

(500 ml) and the solution cooled to -45°, the resultant precipitate of

18-crown-6/acetonitrile complex was filtered, and distilled, under nitrogen,

to give pure 18-crown-6 (100 g, 30;,), b.p. 116-8°/0.02 mm, m.p. 38-8.5°, 172 ait. m.p. 38.5°), 6 (CC14) 3.56 (s), m/e 265 (M + 1), 264 (M+), 262,

221, 177, 133, 117, 101, 89. 90.

K/18-Crown-6/Triethylamine:- K (100 mg, 2.5 mgatom), 18-crown-6 (100 mg, 0.38 mmol) in triethylamine (3 ml) under nitrogen for 5.5 h at 23° failed to produce a coloured solution.

Li-Tetramethylethylenediamine:- Li (100 mg, 14 mgatom) and tetramethylethylenediamine (5 ml) under reflux under nitrogen failed to produce a coloured solution

K/t-BuNH2_- K (100 mg, 2.5 mgatom) and t-BuNH2 (3 ml) under reflux under nitrogen failed to produce a coloured solution.

Ca/18-Crown-6/t-BuNH2_- Calcium (washed with ether, followed by soaking in 2% ethanolic hydrogen chloride until silvery, washed with ethanol, and dried)

(100 mg, 2.5 mgatom) in t-BuNH2 (5 ml) and 18-crown-6 (100 mg, 0.38 mmol) under nitrogen at 230 failed to produce a coloured solution.

Li/Benzylamine:- Li (50 mg, 7 mgatom) in dry benzylamine (3 ml) was refluxed until the red colour developed.A solution of 38,65-diacetoxy-5a-cholestane (86)

(10 mg) in THF (0.5 ml) was added dropwise and the mixture refluxed for 1 h, cooled, poured in hydrochloric acid (GM; 10 ml), extracted with ether, the organic layer washed with water and dried. Tic indicated 5a-cholestan-35-ol (97) and 35,65-diol (75) plus another two unidentified less-polar than cholestanol

(97) products.

Li,Ethylenediamine:-•Li (50 mg, 7 mgatom) in dry ethylenediamine (3 ml) was refluxed until the blue colour developed. A solution of 35,65-diacetate (86) in THF (0.5 ml) was added and the mixture refluxed for 1 h. Tlc indicated four compounds as in the Li/benzylamine reaction.

Reduction of 35,65-Diacetoxy-5a-cholestane (86):- The results are summarised in

Table 7. Table 7

run diacetate solvent metal crown/ Products (%) (86) (ml) (mgatom) other (mmol) (mmol) (29) (98) (97) (75)

1 0.10 EtNH2 13 Li 21 - 0 0 32 40 2 0.14 t-BuNH2 3 K 2.5 1.8 0 0 62 29 THF 1 3 0.20 t-BuNH2 3 K 2.5 0.4 0 0 56 27

...continued 91.

TABLE (continued)

run diacetate solvent metal crown/ Products (%) ( 86 ) (ml) (mgatom) other (mmol) (mmol) (29) (98) (97) (75)

4 0.17 t-BuNII2 5 Rb 2.3 2.3 0 0 30 45 THF 0.3

5 1.49 DME 20 K 51 5.3 11 0.7 51 23 THF 3

6 0.24 DME 5 Na/K - 0 0 0 100 TIIF 1 alloy

7 0.26 D?IE 5 K 5 0.38 0 0 35 34 THF 0.5

8 0.36 THF 7 Li 29 naphtha- No reaction lene 29'

9 0.11 i-Pr2NH 3 Li 14 benzo- No reaction phenone THF 0.5 0.5

10 0.18 THF 10 Al/Hg 10 - No reaction

Reduction of 313,613-Diacetoxy-5a-cholestane (86) with K/18-Crown-6/DME and CII.I Quench:- To a partial solution of K(lg, 25 mgatom) and 18-crown-

6 (1.6 g, 6 mmol) in DME (10 ml) a solution of the 38,63-diacetate (86)

(440 mg, 0.90 mmol) in THF (5 ml) was added at 23° under nitrogen. The mixture was cooled to -78o and quenched with iodomethane (7 ml) followed by absolute ethanol (2 ml),-aqueous ethanol and water. The products were extracted into ether, washed with brine, dried and chromatographed (plc;970 ethyl acetate--petroleum) to give 5a-cholestane (2 9 ) (35 mg, 10%), m.p. 79-80°, from acetone, (a(D3 + 23.9° (c, 1.252), (1it162 m.p. 80°, 92.

+ 24° ~aID ), 6'(CC14) 0.67 (311, s, 18-Me), 0.77, 0.82, m/e 372 (M+) 357 (M-Me), 217, 149; 38-methoxy-5a-cholestane (182) (132.5 mg, 37%), m.p. 73 82-3°, from methanol, 'alp + 19.01° (c, 1.721), (lit1 m.p. 83-4°,

IaID + 20°), 6 (CC14) 0.67 (3H, s, 18-Me), 0.82, 0.92, 3.23 (3H, s,

OMe), and 4.4 (1H, br, W, 18 Hz, 3a-H), m/e 402 (M+), 370 (M-iMeOH), 355

(M-McOH-Me), ; 5a-cholestan-38- of( 97 ) (49 mg, 14;M,) m.p. 141-2° from 162 ethyl acetate, IaI 23 + 24.1° (c, 0.236), (lit m.p. 142°, + 24°), IaID 6 (CDC13) 0.67 (3H, s, 18-Me), 0.80, 0.90, 3.5 (1H, br, W1 18Hz, 3a-H),

m/e 38S (M+), 370 (M-H 0) , 355 (M-H 0-Me) plus a few minor products more- 2 2 polar than 5a-cholestane (29 ) which were not identified.

Reduction of 38,68-Diacetoxy-5a-cholestane (86) with K/18-Crown-6/DME

and Trimethylsilylchloride:- To a partial solution of K (1 g, 25 mgatom)

and 18-crown-6 (1.6 g , 6 mmol) in DME (15 ml) a solution of diacetate

(86)(500 mg, 1.02 mmol) in THF (6 ml) and trimethylsilylchloride (2.6 ml,

20 mmol) was added. Twice extra K (0.7 g; total 1.7 g, 43.6 mgatom) and

18-crown-6 (1.3 g and 0.5 g; total 3.4 g, 12.88 mmol) was added. Work up

and plc gave 5a-cholestane (29) (37.9 mg, 10%); a mono trimethylsilyl

ether of 5a-cholestane 38,68-diol (75) (267.1 mg, 55%), 'max (CC14) 3630,

1250, 1090, 1065, 1050, 860 cm-1, 6.(CC14) 0.06 (9H, s,.Me3Si0), 0.70

(311, s, 18-Me), 0.83, 0.93, 3.1-3.8 (3H, m, 3a-H, 6a-H, OH), m/e 476

(M),461 (M-Me), 386 (M-Me3SiOH), 369 (M-Me3SiO-H20), 321, 246, 232,

which on treatment with methanolic hydrogen chloride gave 38,68-diol (75 )

(by tic); and 5a-cholestan-38-o1 (97) (108.6 mg, 28%).

Reduction of 38,68-Diacetoxy-5a-cholestane (86) with K/18-crown-6/DME

in the Presence of a Vinyl ether:- To a partial solution of K (1 g,

25.6 mgatom) and 18-crown-6 (300 mg, 3 mmol) in DME (10 ml) a solution 174 of the diacetate (86 ) (697 mg, 1.43 mmol) in propyloxy-prop-2-ene

(3 ml) [b.p. 86-92° 6 (CDC13) 0.95 (3H, t, J = 7Hz, CH2C13), 1.2-1.8 93.

(2H, m, CH2CH2CH3), 1.80 (3H, s, olefinic Me), 3.60 (2H, t, J = 7 Hz,

0CH2 Et), 3.8 (2H, s, olefinic-H)]was added. Extra 13-crown-6 (800 mg, total 1.6 g, 6 mmol) was added. Work up and chromatography (silica II,

10 g) gave 5a-cholestan-33-ol (97 ) (261.9 mg, 47%) and 3!3,613-diol (75 )

(120.8 mg, 21%).

In another experiment the vinyl ether (5 ml), the diacetate (86 )

(240 mg, 0.49 mmol) K (600 mg, 15 mgatom) and 18-crown-6 (400 mg, 1.51 mmol) were stirred under nitrogen at 23o in the absence of amine. No blue colour was observed, and a complex mixture was obtained (tic).

313,G8-Diformyloxy-5a-cholestane (87 ):- To a solution of 3(3,68-diol

(75 ) (100 mg, 0.25 mmol) in pyridine (2 ml) formic acetic anhydride (2 ml) was added with cooling and shaking. Work up and crystallisation gave the diformate (87) as white needles (98 mg, 86%), m.p. 92.5-94.5°, from ether-methanol, Ial 23 - 28.T (c, 0.290), v (CHC13) 1720, 1170 cm 1, max d (CDC13) 0.67 (3II, s, 18-Me), 0.82, 0.92 (side chain Me's), 1.03 (3H, s,

19-Me), 4.9 (1H, br, ist 20Hz, 3a-H), 5.1 (1H, m, W1 8Hz, 6a-H), 8.03 and

8.10 each (1H, d, H CO2), m/e 460 (Mt), 414 (M-HCO2H), 368 (M-2HCO2H),

260 (Found: C, 75.55; H, 10.52. C29H4804 requires C, 75.61; H, 10.50%).

Reduction of 3(3,65-Diformyloxy-5a-cholestane (87 ):- A solution of the diformate ( 87 ) (76 mg, 0.16 mmol) in THF (1 ml) was added to a partial solution of lithium (100 mg, 14 mgatom) in EtNII2 (3 ml). Work up and

crystallisation gave 313,6j3-diol ( 75)(50 mg, 75%). Treatment of the

diformate (87 ) (5 mg) with EtNH2 (0.2 ml) at 2° spontaneously gave 35,63-

diol( 75 )(by tic). To a partial solution of K (100 mg, 2.56 mgatom)

and 1S-crown-6 (77 mg, 0.29 mmol) in t-BuNH2 (4 ml) solid diformate (87 )

(73 mg, 0.16 mmol) was added at once. Work up and crystallisation gave

36,6f3-diol (75 ) (55 mg, 86%) .

94.

35,63-Dipropanoyloxy-5a-cholestane ( 88):- To a solution of 3(3,6(3-diol

(75) (142.2 'mg, 0.35 mmol) in pyridine (2 ml) propionic anhydride (2 ml)

was added, and the mixture allowed to stand 17 h. Work up and crystal-

lisation gave the dipropionate (88 ) (151.5 mg, 83%) as white needles,

m.p. 125-7.5°, from dichloromethane-methanol, IajD3 -26.4° (c, 0.125),

(nujol) 1742, 1185, cm-1, 6 (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 vmax (side chain Rte's), 1.03 (3H, s, 19-Mie), 1.13, 1.17, 1.25, 1.23 (6H, two

overlapping triplets, CH3CH2CO2), 2.3 (41I, two overlapping q., CH3CH2CO2),

4.7 (1H, br, W, 20Hz, 3a-H), 4.97 (1H, m, Wt 8IIz, 6a-H), m/e 516 (e)

442 (M-CH3CH2CO2H), 3G3 (Ri-2CH3CH2CO2H), 255, 228, 213, 57 (CH3CH2C0)

(Found: C, 76.54; H, 10.97. C33H5604 requires C, 76.69; H, 10.92%).

Reduction of 38,68.-Dipropanoyloxy-5a-cholestane ( 88 ):- To a solution of

313,613.dipropionate (88 ) (68.6 mg, 0.13 mmol) in EtNH2 (4 ml) Li metal G (100 mg, 14 mgatom) was added and the mixture stirred. for 2 h. Work up

and plc gave 5a-chole.stan-38-ol ( 97 ) (8 mg, 15%) and 3(3,6(3-diol ( 75 )

(33 mg, 61%) .

Phthaloyl Chloride:- A mixture of phthalic anhydride (40 g, 270 mmol)

and phosphorus pentachloride (60 g, 288 mmol) was heated to 150 °for 12 h

and then the temperature was gradually raised to 2500 during which time

the phosphorus oxychloride produced distilled over (1050). The pressure

was then reduced and the product distilled over. Vacuum distillation of

the distillate gave phthaloyl chloride (53.5 g, 97%) as a colourless 175 0o 0.4 mm (lit. 131-3°0 /9-10 mm), v (film) 3100, oil, b.p. 84-8 max 3060, 3030, 1850, 1820-1730, 1595, 1575, 1260-1190, 1110, 960, 910-840,

775, 750, 715, 690-650 cm-1.

Isobutyryl Chloride:- Isobutyric acid (6 g, 68 mmol) was added dropwise

to phthaloyl chloride (16 g, 79 mmol) at 140° and the product distilled

over. The distillate was redistilled giving the product (7 g, 97) 95.

as a colourless liquid b.p. 92° (lit.176 b.p. 92°), v (film) 1810, max 1770, 940, 850, 690 cm-1, 6 (CDC13) 0.20 (6H, d, J = 7 Hz, Me2CH ),

1.83 (111, m, Me2CH) .

34,60-Bis-(2-methylpropanoyloxy)-5a--cholestane ( 89 ):- To a solution of

38,68-diol ( 75 ) (801.5 mg, 1.98 mmol) in toluene (25 ml) and pyridine

(10 ml), a solution of freshly distilled isobutyryl chloride (2.3 g,

21 mmol) in toluene (10 ml) was added, and the mixture was stirred overnight. Work up and crystallisation gave the di-isobutyrate (89) as white prisms (830 mg, 77%) m.p. 119.5-120.5°, from dichloromethane- methanol, la1223 - 22.2° (c, 1.325), (CHC13) 1720, 1160 cm-1, 6 vmax (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's), 1.05 (3H, s,

19-Me), 1.14 and 1.17 each (6H, d, J = 7Hz, Me2CII), 2.5 (2H, m, Me2CH),

4.6 (1H, br, W1 18 Hz, 3a-H), 4.9 (111, m, W1 8Hz, 6a-H), m/e 544 (Mt) 456 z z (M-Me2CHCO2H), 368 (M-2 Me2CHCO2H), 353 (M-2Me2CHCO2H-Me), 255, 213, 71

(Me2CHCO) (Found_ C, 77.25; H, 11.18.. requires C, 77.15; C35146004 H, 11.10%).

Reduction of 3(3,64-Bis-(2-methylpropanoyloxy)-5a-cholestane (89 ):-

To a partial solution of K (800 mg, 20 mgatom) and 18-crown-6 (875.8 mg,

3.3 mmol) in t-13uIH2 (10 ml) a solution of 38,6/3-di-isobutyrate ( 8 9 )

(434.1 mg, 0.80 mmol) in THF (10 ml) was added. The reaction was quenched with ethanol, the solvents removed under reduced pressure, the residue diluted with water, extracted with dichloromethane, the organic layer washed with water, dried and chromatographed (silica H, 10 g). Elution with petroleum gave 5a-cholestane ( 29 ) (20 mg, 7%); elution with 15%

ether-petroleum gave 5a-cholestan-68-o1 ( 98) (13 mg, 4%) m.p. 80-1°, from 177 m.p. 81°, IaI + 8°), ethyl acetate, laI2D3 + 7.5° (c, 0.376), (lit. D (CC14) 3635, 1040 cm-1, 6 (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92, vmax 3.78 (11I, m, W1 8Hz, 6a-H) , m/e 388 (M+) , 370 (P.1-H20) , 355 (M-H90-Me) , 230, 96.

216. Further elution with 20% ether-petroleum gave 5a-cholestan-35-o1

(97 ) (201.1 mg, 65%); elution with ether gave 35,613-diol ( 75 )

(30 mg, 9%). The aqueous layer was adjusted to pH 7 with aqueous hydrochloric acid (1 M), treated with a solution of p-bromophenacyl bromide

(500 mg, 1.80 mmol) in ethanol (40 ml) and the mixture refluxed for 2h.

The mixture was concentrated under reduced pressure, the concentrate extracted with ether and chromatographed (silica 60, 15 g; eluant 4% ether- petroleum) and rechromatographed (plc; 10% ether-petroleum) to give the isobutyric acid p-bromophenacyl ester (113) (25.4 mg, 6%; based on ester giving twice as much acid) as white needles, m.p. 76-70, from methanol, 176 0o (lit. m.p. 77 ) identical with an authentic sample prepared from isobutyric acid (1 ml) and p-bromophenacyl bromide (500 mg). In a blank experiment, solid sodium isobutyrāte (80 mg, 0.73 mmol) was added to a partial solution of K (140 mg, 3.6 mgatom) and 18-crown-6 (190 mg,

0.72 mmol) in t-BuNH2 (5 ml). The reaction was quenched with ethanol, the solvents removed under reduced pressure, the residue neutralised with

aqueous hydrochloric acid, treated with p-bromophenacyl bromide (250 mg,

0.90 mmol) in ethanol (30 ml), and refluxed for 3 h, worked up and

chromatographed (plc; 10% ether-petroleum) to give the p-bromophenacyl

ester of isobutyric acid (52 mg, 25%; based on the salt). The remaining

reductions are summarised in Table 8.

TABLE 8

run di-isoburyrate solvent metal crown Products (%) ( 89 ) (ml) (mgatom) (mmol) (mmol) (97) (75)

1 0.20 , EtNH, 3 Li 14 16 55

2 ` 0.19 1 D',E 5 5 0.38 37 30 THF 0.5

...CONTINUED... 97.

Table /continued

run di-isobutyrate solvent metal crown Products (%) ( 89 ) (ml) (mgatom) (mmol) (mmol) (97) (75) i

3 0.20 t-BuNH2 4 K 2.5 0.38 71 19 THF 0.5

4* 0.19 t-BuNH2 14 K 22 1.25 33 53

* In run 4 the ester was added over a period of 19 Ii; no blue colour was present after 3 h.

35,68-Dibenzoyloxy-5a-cholestane (90 ):- To a solution of 35,613-diol (75)

(685.7 mg, 1.70 mmol) in triethylamine (25 ml) and chloroform (25 ml) a solution of benzoyl chloride (4 ml) in benzene (4 ml) was added and the mixture allowed to stand for 2 h. Work up and crystallisation gave the dibenzoate (90) as white needles (915.5 mg, 88%), m.p. 187-9.50, from dichloromethane-methanol, 1a123 -39.0° (c, 0.200), v (nujol) 1715, max 1600, 1490, 1310, 1275, 1175, 1100, 1070, 1025, 710 cm 1, S (CDC13)

0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's), 1.23 (3H, s, 19-Me),

4.9 (1H, br, W, 18 Hz, 3a-H), 5.1 (1H, m, W1 8Hz, 6a-H), 7.3-7.5 and 2 7.8-8.1 (10 H, m, aromatic-H), m/e 612 (M ), 490 (M-C6H5CO2H), 368,

(M-2C6II5 CO H) , 353 (M-2C6H5 CO H-Me) , 255. (Found: C, 80.35; II, 9.46. 2 2 04 requires C, 80.34; H, 9.21%). C41H56

Reduction of 35,63-Dibenzoyloxy-5a-cholestane (90 ):- To a solution of

35,65-dibenzoate ( 90 ) (88.2 mg, 0.14 mmol) in EtNH9 (3 ml) Li (100 mg,

14 mgatom) was added and the mixture stirred for 1.5 h. The reaction was quenched with methanol, the solvents removed under reduced pressure, the residue treated with acetic anhydride (10 ml) and pyridine (3 ml) at 00 and allowed to stand at 230 for 17 h. Work up and crystallisation 98.

gave 35,613-diacetoxy-5a-cholestane (86 ) (55 mg, 780).

To a partial solution of K (1.8 g, 46 mgatom) and 18-crown-6

(2.5 g, 9.4 mmol) in DME (15 ml) a solution of 38,65-dibenzoate (90)

(212 mg, 0.35 mmol) in THF (5 ml) was added. Work up and plc gave

5a-cholestane (29 ) (7 mg, 5%), 5a-cholestan-38-o1 (97) (61.2 mg,

45%) and 5a-cholestane-38,68-diol (75) (51.2 mg, 36%).

38,68-Bis-(2,2-dimethylpropanoyloxy)-5a-cholestane (91 ):- To a suspension of sodium hydride (80% oil dispersion; 1.5 g) in THF (10 ml) a solution of 313,613-diol (75) (1.21 g, 3 mmol) in THF (50 ml) containing imidazole (20 mg) was added slowly under nitrogen and the mixture refluxed for 2 Ii. Pivaloyl chloride (4 ml) was added to the refluxing mixture, and the mixture refluxed for a further 0.5 h. Excess sodium hydride was quenched with acetic acid, the mixture worked up and chromatographed

(silica H, 14 g). Elution with 5% ether-petroleum gave the 38,68-dipivaloate (91) (257.4 mg, 15%), m.p. partly at 123-5° and finally at

150-2°, from chloroform-methanol, Ia1D23 - 25.4° (c, 0.761), vmax

(nujol) 1730, 1275, 1150 cm 1, 8 (CC14) 1.13 and 1.17 each (9H, s,

Me3C), 4.7 (2H, m, 3a- and Ga-H), m/e M (absent), 470 (M-Me3C.0O2H),

455, 385, 368 (M - 2Me3C.0O2H), 353 (M-2Me3C.0O2H -Me), 58, 57 (Me3C)

(Found: C, 77.55; H, 11.40. requires C, 77.57; H, 11.26%). C37H6404 Further elution of the column with 15; ether-petroleum gave 38-(2,2- dimethylpropanoyloxy)-5a-cholestan-68-o1 (184) (291.8 mg, 20%),m.p.

181-3°, from dichloromethane-methanol, IaI123,3 - 5.4° (c, 0.652),

(nujol) 3540, 1705, 1290, 1185, 1155 -1, vmax cm S (CDC13), 1.18 (9H, s, Me3C) , 3.7 (1H, m, W, 8Hz, Ga-H) , 4.7 (1H, br, W, 18Hz, 3a-H) , m/e 488 (M+) , 470 (M-H20) , 386 (M-Me3CCO2H) , 368 (M-Me CCO2I1 - H 0) 3 2 ' 353 (M-Me30002H-H20-Me), 228, 213, 57 (Me3C)(Found: C, 78.41; H,

11.68. C requires C, 78.63; II, 11.55%). Further elution 32H5603 with 99.

ethyl acetate gave unreacted starting material (663.1 mg, 55%).

Reduction of 33,63-Bis-(2,2-dimethylpropanoyloxy)-5a-cholestane (91 ):-

To a partial solution of K (800 mg, 20 mgatom) and 18-crown-6 (2.2 g,

8.3 mmol) in t-BuNIi2 (30 ml) a solution of 313,6t3-dipivaloate ( 91 )

(552.8 mg, 0.97 mmol) in THF (4 ml) was added. Work up and chromatography (silica H, 10 g) gave 5a-cholestane ( 29 ) (108.6 mg,

30%), 5a-cholestan-63-ol (98) (36.6 mg, 10%), 5a-cholestan-33-ol (97 )

(140.5 mg, 37%) and 36,66-diol ( 75 ) (26.8 mg, 7%) .

In an earlier experiment using K (300 mg, 7.7 mgatom), 18-crown-6

(200 mg, 0.76 mmol), t-BuNH9 (4 ml) and 33,63-dipivaloate ( 91 ) (75.2 mg, 0.13 mmol) in THF (0.5 ml) obtained 5a-cholestan-33-ol ( 97 )

(40.5 mg, 79%) and 36,66-diol (75 ) (5.1 mg, 9%) .

36,63-Bis-(1-adamantanecarbonyloxy)-5a-cholestane ( 92 ):- To a solution of 33,63-diol (75 ) (1.46 g, 3.61 mmol) in THF (15 ml) a solution of n-butyllithium (1.49 M; 5 ml) was added at 0° under nitrogen, the solution was allowed to warm up to 23°, and a solution of adamantane-l- 178 carbonyl chloride ( 93 ) (1.76 g, 8.8 mmol) in benzene (3 ml) was added and stirred at 23 for 24 h. The reaction was quenched with acetic acid (2 ml), worked up and chromatographed twice (silica H, 20 g and

12 g). Elution with 2% ether-petroelum gave the diadamantanoate ( 92 )

(460 mg, 17%), m.p. 294-300° (decomp) from dichloromethane-methanol,

IaI12213 - 20.4° (c, 1.419), (nujol) 1728, 1235, 1070 cm-1, S(CDC13) max 0.67 (3H, s, 18-Me), 0.80, 0.90 (side chain Me's), 1.03 (3H, s, 19-Me),

1.7, 1.9, 1.95 (30 H, m, adamantyl-H), 4.6 (1H, br, W1 20Hz, 3a-H),

4.8 (1H, m, W1 8Hz, 6a-H), m/e 729 at 12 eV and 290° (M+), 543 (M-

2H), 368 (M-2C CO H), 353 (r.1-2C CO2H-Me), 135 (CM5) C10H15CO 10H15 2 10H15 (Found: C, 80.50; H, 10.58. C,...11 requires C, 80.72; H, 10.51%). 76 04 Elution with 10% ether-petroleum gave 36-(1-adamantanecarbonyloxy)- 100.

-5a-cholestane-66-ol (184)(198.5 mg, 10%), m.p. 249-50°, needles from ethyl acetate, -0.51°, .1x123 - 1.84°, 1a123 - 1.95°, gal?3 578 546 2.56° (c,0.976), vmax (CHC13) 3500, 1710, 1330, 1270, 1105, Ia1436 - 1075 cm 1, 6 (CDC13) 0.67 (3H, s, 18-Me), 0.80 , 0.90 (side chain

Me's), 1.07 (3H, s, 19-Me), 1.7, 2.2 (15 H, m, 3.7 (1H, m, C10H15), W, 9 Hz, 6a-H), 4.7 (1H, br, W1 18Hz, 3a-H), m/e M+ (absent), 548

(M-H20), 383, 368 (M-H20-C10H15CO2H), 253, 135, (C101115) (Found:

C, 80.66; II, 10.96. H 0 requires C, 80.51; H, 11.02%). Further C38 62 3 elution with ethyl acetate gave starting material (871 mg, 60%).

Reduction of 3(3,65-Bis-(1-adamantanecarbonyloxy)-5a-cholestane (92 ):-

To a partial solution of K (150 mg, 3.8 mgatom) and 18-crown-6 (450 mg,

1.70 mmol) in t-BuNH2 (8 ml) a solution of 35,65-diadamantanoate (92 )

(334.7 mg, 0.46 mmol) in THF (12 ml) was added. The reaction was quenched with ethanol, the solvents removed under reduced pressure and the residue chromatographed (alumina H, 14 g) to give 5a-cholestane

(29 ) (77.4 mg, 45%), 5a-cholestan-66-o1 (98 ) (10.6 mg, 6%), 5a -cholesL an-35-01 (97 ) (47.5 mg, 27%) and 35,65-diol (75) (15.5 mg, 8%). The alumina was acidified with aqueous hydrochloric acid (6 M; 100 ml), allowed to soak for 24 h, ether was added, the mixture stirred for a

further 24 h and filtered off. The alumina was washed with ether and

the combined organic layers washed with brine. The ether layer was

extracted with aqueous sodium hydrogen carbonate, the aqueous layer

acidified with aqueous hydrochloric acid (6M; 10 ml) and extracted with

ether. The organic layer was washed with brine, water, dried and chro-

matographed (silica 60, 10 g; eluant 2% ether-petroleum) and the prod-

uct recrystallised twice from ether to give adamantane-l-carboxylic acid

(108 ) (153 mg, 92; based on ester giving two equivalents of acid), m.p.

175-6° sublimed at 150-5° from plates to needles, (lit. m.p. 181°),

v (CIIC1 ) 3500-2200, 1730-1680, 1280, 1100 cm 1, m/e 180 (M max 3 t), 101,

135 (C10H15).

33-Acetoxycholestan -5a-ol (44):- To a solution of 5a-cholestane-33,5a- diol ( 85 ) (200 mg, 0.5 mmol) in pyridine (2 ml) acetic anhydride (1 ml) was added and the mixture allowed to stand for 16 h. Work up and crystallisation gave 33-acetoxycholestan - 5a-ol ( 94) (212 mg, 96%), as leaflets from dichloromethane-methanol, m.p. 185-6°, IaI23 + 9.6° (c; 1.859), 165,1 (lit m8p. 185°, lai + 12°). D

Reduction of 33-Acetoxycholestan - 5a-ol ( 94 ):- To a partial solution of

K (1.3 g, 33 mgatom) and 18-crown-6 (700 mg, 2.6 mmol) in t-BuNH2 (20 ml) a solution of 33-acetoxycholestan- 5a-ol (94) (290 mg, 0.65 mmol) in THF

(3 ml) was added. Extra 18-crown-6 (700 mg; total 1.4 g, 5.3 mmol) had to be added. Work up and plc (25% ethyl acetate-benzene) gave cholestan-5a-ol

(104) (68.5 mg, 27%) m.p. 106-7°, from acetone, IaI23 + 14.4° (c, 1.268), 180 ° 28 ° 181 0 (lit. m.p. 102-3 , IaID + 13.6 and lit. m.p. 109-110°, IalD + 11.2 ),

(nujol) 3620, 3455, 1170, 965, 955, 935, 920, 885 cm-1, 6 (CDC13) ''max (220 Milz) 0.66, 0.86, 0.88, 0.92, 0.98, m/e 388 (tri+) , 370 (M-H20) , 355

(M-H 0-Me), 215. (Found: C, 83.57; H, 12.64. Calc. for C : C, 83.43; 2 27II48 H, 12.46%); and cholestane-35,5a-diol ( 85 ) (102 mg, 39%).

33,5a-Diacetoxy-5a-cholestane ( 95 ):- To a solution of 33-acetoxy cholestan-5a-ol (94) (200 mg, 0.45 mmol) and N, N-dimethylaniline

(1.68 ml, 13 mmol) in ethanol-free chloroform (40 ml), acetyl chloride

(3 ml) was added and the mixture refluxed under nitrogen for 17 h. Work up and filtration (silica MFC, 6 g) eluant 50% dichloromethane-petroleum and crystallisation gave the diacetate ( 95 ) (116 mg, 53%) as needles

from dichloromethane-methanol, m.p. 139.5-140°, IaI23 + 31.4° (c, 165 0.223), (lit. m.p. 141, IaID + 31.5°), v (CHC13) 1725, 1265cm 1 max , 102.

d (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain ;,Ie's), 1.03 (3H,

s, 19-Me), 2.03 and 2.07 each (311, s, Ac0), 5.7 (1H, br, W, 20 Hz, 2 3cc-H)

Reduction of 33,5ct-Diacetoxy-5n-cholestane ( 95):- To a partial solution

of Ii (620 mg, 16 mgatom) and 18-crown-G (442 mg, 1.7 mmol) in t-DuNH2

(10 ml) a solution of 363,5a-diacetate (95) (150 mg, 0.31 mmol) in THF

(3 ml) was added. Work up and plc gave 5a.-cholestane (29 ) (5 mg, 4%),

5a-cholestan-3G-ol ( 97) (67.9 mg, 57%), and 33,5a-diol ( 85) (22.1 mg,

18;).

To a solution of 38,5x-diacetate (95) (58.5 mg, 0..12 mmol) in

EtNH2 (12 ml) Li (200 mg, 29 mgatom) was added. Work up and plc gave

5a-cholestan-3(3-ol (97) (30.7 mg, 66%), and 313,5a-diol (85 ) (4 mg, 8%). •

3(3 -(2-Methylpropanoyloxy)_cholestan-5a-ol (96 ) :- To a solution of 313,5a-

diol (85) (200 mg, 0.5 mmol) in pyridine (2 ml) a solution of isobutyryl

•chloride (2 ml) in benzene (2 ml) was added and the mixture allowed to

stand at 23o for 16 h. Work up and crystallisation gave the isobutyrate

(96) (227 mg, 97%), m.p. 163-3.5°, from dichloromethane-methanol,

I0(I 23 + 8.0° (c, 0.622), (nujol) 3445, 1730, 1700, 1230, 1165 cm Vmax -1,

S (CDC13) 0.67 (311, s, 12-Me) , 0.82, 0.92 (side chain ;tile's), 0.03 (3K, s,

19-Me), 1.10 (GH, d, J = 7 Hz, Mc2CH), 2.4 (1H, m, LIe2CH), 5.2 (1H, Ur,

V, 18Hz, 3a-U), m/e 474 (IS ) , 456 (M-IIu0) , 386 (M-LIe2CIICO2H) , 363 (M-

H20-Me2CHCO2H) , 353 (i.1-I120-Me2CHC09II-Me) , 213, 147, 71(LIe2CHCO) . (Found:

C, 73.70; 11, 11.53. C 11 0 requires C, 78.42;H, 11.46%). 31 54 3

Cholestane-313,5a,63-triol (99 ):- A solution of cholesterol (76 ) (20 g,

51.8 mmol) in formic acid (90%; 200 ml) was heated to 900 until the 3(i-

formate ester (100) separated out. - The mixture was allowed to cool down 103.

to 230, treated with hydrogen peroxide (30%; 20 ml) and stirred for GO h.

Water (300 ml) was added with stirring and the precipitated 313,GB-diformyloxy-cholestan-5a-ol (101) collected, v (nujol) 3455, 1725, 1210 cm-1, max S (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain F.Ie's), 1.16 (3H, s,

19-Me), 4.81 (1H, m, W, 6Hz, 6a-H), 5.2 (1H, br, W, 22Hz, 3a-H), 7.95 and

) , 458 (M-H 0) , 430 (M-IICO2H) , 384 (M- 8.05 each (1H, s, IiCO2), m/e 476 (M+ 2 2HCO2H), 55; the diformate (101) was taken up in TIIF (125 ml) and .a methano- lie solution of potassium hydroxide (5%; 300 ml) was added and the solution allowed to stand at 23° for 2 h. The solvent was removed under reduced pressure, the residue dissolved in chloroform and the organic layer acidified with dilute hydrochloric acid, washed with water, dried,filtered and the solvent removed under reduced pressure. The residue was crystallised from methanol to give the triol (99 ) (20.8 g, 95%) as white needles, m.p. 238-9°, 152 (lit. m.p. 239°), (nujol) 3400, 1070, 1040 CM vmax

3(3,6(-Diacetoxy-cholestan-5a-ol (102):- A solution of cholestane-31',,5a,6-trio?

(99) (14.6 g, 34.76 mmol) in pyridine (300 ml) was treated with acetic anhydride (20 ml) and the mixture allowed'to stand at 23° for 16 I. Work up and crystallisation gave the diacetate (102) (16.4 g, 94%) as needles, from dichloromethane-light petroleum, m.p. 165-7° (lit.182m.p. 165°), v (nujol) max 3470, 1730, 1715, 1365, 1265, 1240, 1165, 1030 cm-1, S (CDC13) 0,67 (3H, s,

18-Me) , 0.32, 0.92 (side chain Me's) , 1.13 (3H, s, 19-Me), 2.02 and 2.03

each (3H, s, Ac0) , 4.6 (lli, m, ", 7Hz, 6a-H), 5.2 (1H, br, W, 20Hz, 3a-H).

Reduction of 3 ,sfl-Diacetoxy-cholestan-5a-ol ( 102):- To a partial solution of

11 (1.6 g, 41 mgatom) and 18-crown-6 (4 g, 15 mmol) in t-I;uNII2 (25 ml) a

solution of the diacetate (102) (760 mg, 1.51 mmol) in TIIF (10 ml) was added

Work up and chromatogranhy (silica MFC, 13 g; eluant benzene) gave cholestan-

5a-ol (104) (172 mg, 297), and 3(3,5a-diol (85 ) (337 mg, 55%). 104.

Attempt to Reduce 3(,5a-Dihydroxy-5a-cholestane (85):- To a partial solution of K (550 mg, 14 mmol) and 1S-crown-6 (5.7 mmol) in t-BuNH9 (10 ml) a solution of 3?,5a--diol (85 ) (250 mg, 0.62 mmol) in THF (6 ml) was added.

Work up and crystallisation gave only starting material (198 mg, 72;).

313, 5a, GI-Triacetoxycholestane (103):- To a solution of 31i , 6(3--diacetoxy- cholestan-5p-o1 (102) (15 g, 29.8 mmol) in dry ethanol-free chloroform

(250 ml), and freshly distilled N,N-dimethylaniline (GO ml), acetyl chloride

(50 ml) was added and the mixture refluxed under nitrogen for GO h. Work up and filtration (neutral alumina, grade III, 150 g; eluant 505 ether- petroleum) gave the triacetate (103) (12- 6 g, 77f0) as needles from methanol, m.p. 148.5-9°, IaID23 - 30.9°(c, 0.23), (1it 183 m.p. 149°, lit 184 Iad D - 34.6°), (nujol) 1740, 1725, 1240, 1035 , (CDC13) max cm-1 S 0.63 (3H, s, 18-Me), 0.82, 0.90 (side chain Me's), 1.18 (3H, s, 19-Me), 2.00 (3H, s,Ac0),

2.06 (611, s, 2AcO) , 4.7 (1H, br, `,1 20Hz, 3a-H) , 5.8 (lii, m, W, 7Hz, 6a-H) . 2

Reduction of 3,5a,63-triacetoxy-5a-cholestane (103):- The results are summarised in Table 9

TABLE 9 run ester solvent metal crown/ Products (%) (mmol) (ml) (mgatom) other (103) (mmol) (49) (76) (75) (99)

a a 1 0.18 EtNH2 25 Li 43 - 0 81 ' 0 8

b 2 0.19 EtNH2 25 Li 46 IISCII„CO21I `2.2 ' 0 27 0 14

3 0.62 EtNit„ 5 Li 36 ! - 14G 34 17 5

4 0.60 EtN1I,, 8 •Li 3G - 11 33 11 3 TIIF 4

5 1.86 1 t-BuNI19 20 K 51 13 12 24 d e i TIIT 10

6 0.67 i t-BuNli9 10 Ii 6 ; 0.10

7. 0.18 t-t3ui7ll,, 10 ; K 23 11 52 TIIF G cont ituJrcl 105.

Table/continued a The cholesterol obtained was treated with Ac20/pyridine to give 38-cholesteryl acetate (24) (25.8 mg, 33%; based on triacetate QO3)), m.p. 114-5°, 162 (lit. m.p. 110°). b A less polar than cholesterol product was present (tic). c Cholest-5-ene (49), m.p. 90-1°, from acetone, IalD-3 - 58.9° (c, 1.128)

(lit. m.p. 95°, IaID -56°), 6 (CC14) 0.67 (3H, s, 18-Me), 0.82, 0.92, 0.93, 1.22 (3H, s, 19-Me), 5.1 (1H, m, , 8Hz, 6-H). 2

Cholestan-5a-ol (104) was obtained (103.5 mg, 23%). e A mixture of diols and triol contaminated with crown residues was also obtained. r. .1 5a,6a-Epoxycholestan-38-ol (120) mg, 52?~) , m.p. 143-4143-4° ,,IaID3 139'16r - 43.7° (c, 0.126), (1it m p. 142.5°', IaID - 46°), 6 (CDC13) 0.67 (3H, s, 18-Me), 0.32, 0.92 (side chain Me's), 1.06 (3H, s, 19-Me), 2.82 (111, br, d, J = 3Hz, 68-H), 3.8 (1H, br, W1 18Hz, 3a-H), was 2 obtained among _a multitude of products.

Cholestan-5a-ol (104) (8.4 mg, 12%) was obtained.

1-Chlorocarbonyladamantane (93):- Adamantane-l-carboxylic acid (6 g, 33 mmol) was refluxed in thionyl chloride (10 ml) for 0.5-h and the excess thionyl chloride distilled off to give the acid chloride (6.36 g, 97%) as a white p 178 0o solid, m.p. 54-6 (lit. m.p. 54-6 ), v (nujol) 1830, 1790, 1130, 935, max 945, 915, 730, 750, 660 cm-1.

1-Hydroxymethyladamantane (106):- To a suspension of LAH (120 mg, 3.16 mmol)

in TIiF (3 ml) a solution of 1-chlorocarbonyladamantane (G00 mg, 3.02 nunol)

in Tiff (10 ml) was added with stirring under nitrogen. The excess LAH was

quenched with saturated aqueous sodium sulphate, the precipitate filtered

off, washed with hot TIiF (5 ml), the combined organic layer evaporated

to dryness and the residue recrystallised from dichloromethane-petroleum 106.

78 to give the alcohol (106) (480 mg, 96%), m.p. 117-8° (lit1 m.p. 115-6°), vmax (nujol) 3220, 1050 cm-1, 6 (CC1 4) 1.46, 1.66, 1.73, 2.00 (15H, m,

C10H15), 3.06 (211, s, CH OH).

1-Ethoxycarbonyladamantane (107):- To a solution of 1-chlorocarbonyladamantane (1.5 g, 7.56 mmol) in absolute ethanol (10 ml) pyridine (1 ml) was added and the mixture allowed to stand for two days. Evaporation of the-solvents followed by vacuum distillation gave the ester (1.48 g, 94%) as a colour- o 179 0o less liquid with a strong smell, b.p. 99 /0.3 mm, (lit. h.p. 122-3 /9 mm) vmax (film) 1730, 1230, 1075 cm-1, ō (CC14) 1.20 (3H, t, J =7Hz, CH3CIi20), 1.7 1.86, 2.06 (1511, m, C__11_,), 00 (2H, q, J = 7 Hz, CH.CH20). iy IJ 4.

Reduction of 1-Ethoxycarbonyladamantane:- To a partial solution of K (1.4 g,

36 mgatom) and 18-crown-6 (1.55 g, 5.37 mmol) in t-BuNH2 (10 ml) a solution of 1-ethoxycarbonyladamantane (636.1 Mg, 3.06 mmol) in ether (3 ml) was added. A gas was evolved from the surface of K. The amine was removed under reduced pressure and the excess K was quenched with dilute hydrochloric acid (1M; 48 ml) and ether was added. The organic layer was -extracted with sodium hydrogen carbonate, dried and evaporated to give a trace of

1-hydroxymethyladamantane ( 6 3 ppm). The aqueous layer was acidified with hydrochloric acid and extracted into ether to give adamantane-l-carboxvlic acid (522.2 mg, 95%).

Adamantanoin (109):- Small pieces of freshly cut sodium metal (222 mg,

9.7 mgatom) were refluxed in dry xylene (10 ml) under nitrogen with stirring

until the sodium became a sand. A solution of 1-ethoxycarbonyladamantane

(1 g, 4.8 mmol) in xylene (3 ml) was added over a period of 2 h with reflux-

ing and stirring under nitrogen. The reaction was quenched with sulphuric

acid (20%; 2 ml) worked up, chromatographed (silica II, 12 g; eluant 10%

ether-petroleum) separated by plc (40;, ether-petroleum), and the product

107.

recrystallised from ethyl acetate to give the acyloin (109) (235 mg., 9%) , o0 186 0o m.p. 261-3 lit. m.p. 223-4 acetic acid), v (nujol) max -1 3430, 1700, 1005 cm , S (CDC13) 1.5-2.5 (30H, m, adamantyl-H), 4.1 (1H,

br, CHOH) , m/e 328 (M4) , 266, 165 (M-C10H15CO) , 135 (C101i15)

1-Acetoxymethyladamantane (105):_ To a solution of 1-hydroxymethyladaman-

tane (668.6 mg, 4 mmol) in pyridine (5 ml) acetic anhydride (5 ml) was added

and the mixture allowed to stand at 23° for 17 h. The mixture was poured

into water and the product extracted - into ether, `-gashed with sodium hydro-

gen carbonate, dried and the solvent removed under reduced pressure to

give the acetate as a colourless liquid (815 mg, 07%), v (film) 1725, max 1240, 1030, 990 cm 1, S (CDC13) 1.53, 1.53, 1.70, 1.73, 1.96 (15 H, m, 187 C10H15), 2.06 (3H, s, Ac0), 3.66 (2H, s, CII20Ac), (lit. 1.54, 1.71,

1.99, 2.00, 3.63 ppm, b.p. 110-3(3/2.5 mm).

Reduction of 1-Acetoxymethyladamantane:- To a partial solution of K (400

mg, 10 mgatom) and 18-crown-6 (620 mg, 2.35 mmol) in t-h'uNH2 (12 ml) a

solution of the acetate (254.6 mg, 1.22 mmol) in ether (2 ml) was added.

Work up and crystallisation gave. 1-hydroxymethyladamantane (154.6 mg, 78%).

1-Acetoxyoctadecane:- To a solution of 1-octadecanol (5.41 g, 20 mmol)

in pyridine (25 ml) acetic anhydride (5 ml) was added and the mixture

allowed to stand at 23° for 16 h. Work up and crystallisation from ether- o 188188 0 methanol gave the acetate (6.11 g, 98%) as needles m.p. 33-4 32°) -1 (film) 1740, 1235, 1040, 730 cm , S (CDC13) 2.03 (3H, s, Ac0), vmax 4.05 (2H, t, J = 7Hz, CII„OAc) .

Reduction of 1-Acetoxyoctadecane:- To a partial solution of .h (500 mg,

13 mgatom) and 13-crown-6 (1.07 g, 4.06 mmol) in t-I3uNi12 (10 ml) a solution

of the acetate (626.6 mg, 2.00 mmol) in ether (10 ml) was added. Work up 108.

and crystallisation gave 1-octadecanol (420 mg, 73), m.p. 57-9° as leaflets 188 from ethyl acetate (lit. m.p. 59.4-59.8°).

Cholesteryl Acetate (24):- To a solution of cholesterol (76 ) (20 g,

51.8 mmol) in pyridine (100 ml) acetic anhydride (10 ml) was added and the mixture was allowed to stand at 23° for 16 h. The mixture was poured into water, the precipitate collected and recrystallised from dichloromethane-methanol to give the ester (24) (21.5 g, 97%), as white needles, 1 162 I m.p. 115-6°, (a p3 - 47° (c, 0.217), (lit. m.p. 116°, la!D -47°), S

(CC14) 0.67 (311, s, 18-Me), 0.80, 0.92 (side chain Ale's), 1.00 (3II, s,

19-Me) , 1.93 (311, s, Ac0) , 4.4 (1H, br, 1'J, 18IIz, 3a-H) , 5.33 (111, m, ?"1 2 3Hz, 6-11).

Reduction of 33-Cholesteryl Acetate (24):- To a partial solution of K

(1.5 g, 36 mgatom) and 18-crown-6 (3.7 g, 14 mmol) in t-BuNII2 (15 ml) a

solution of the acetate (24) (1.05 g, 2.45 mmol) in THF (12 ml) was

added. Work up and chromatography (silica II, 12 g) gave cholest-5-ene (49)

(181.2 mg, 20%), and cholesterol (76) (722.9 mg, 76%) .

1-Adamantanecarbonyloxy-l-octadecane•(112):- To a suspension of sodium

hydride (50% oil dispersion; 2 g, 41.6 mmol) and imidazole (100 mg) in

THF (10 ml) a solution of 1-octadccanol (6.7 g, 24.8 mmol) in THF (75 ml)

was added and the mixture refluxed under nitrogen for 3 h. A solution of

adamantane-l-carbonyl chloride (5.5 g, 27.7 mmol) in toluene (20 ml) was

added and the mixture refluxed under nitrogen for 20h. Work up and

chromatography •(silica MFC 130 g; eluant 5;, ether-petroleum) gave the

ester (112) (9.55 g, 39,) as white needles from petroleum-ethanol, m.p.

37-8°, vmax (nujol) 1730, 1230, 1075,cmn 1, 6 (CC14) 1.7 and 1.8 (15 H,

m, C10I115) , 3.9 (21I, t, J = 61iz , OCII0C1I9) , m/c 432 (M+) , 297 (H-C l0II15) ,

252 (H-C II CO 11) , 181 (C 1I CO 11 ) , 135 (C II 5) . (Found: C, 80.59; 10 15 2 10 15 2 2 10 15 109.

H, 12.42. C29115202 requires C, 80.43; II, 12.12%).

Reduction of 1-Adamantanecarbonyloxy-l-octadecane (112):- To a partial solution of IC (1.3 g, 33 mgatom) and 18-crown-6 (2.5 g, 9.5 mmol) in t-BuNH2 (10 ml) a solution of ester (112) (711.8 mg, 1.65 mmol) in ether

(5 ml) was added. Work up and chromatography (silica H, 10 g) elution with 188 petroleum gave n-octadecane (169 mg, 40%), m.p. 27-8° (1it m.p. 28.18°), m/e 254 (M±), 225, 211, 197, 133, 169, 155, 141, 127, 113, 85, 71, elution with 10% ether-petroleum gave a mixture of four compounds (11.3 mg), m/e

165 CH20) and 135 (C10I115)' further elution with 20% ether-petrol- (C10H15 eum gave 1-octadecanol (236.2 mg, 53%). Acidification of the aqueous layer and extraction with ether gave adamantane=l-carboxylic acid (266.2 mg,

90%).

5a-Cholestan-313-ol (97):- To a solution of cholesterol (76) (150 g,

339 mmol) in ethanol (4.5 1) Pt02 (2 g) was added and the mixture stirred under hydrogen at 23° and atmospheric pressure until the hydrogen absorp-

tion ceased (approx. 10 1 of hydrogen gas was absorbed). The solvent

was removed under reduced pressure, the residue dissolved in dichloromethane

and filtered .on an alumina column (600 g), eluant dichloromethane. The

solvent was removed, and the residue recrystallised from ethyl acetate to

give the product (97) (135 g, 90%) as white leaflets, m.p. 141-2°, 162 IaI23 + 23.6° (c, 1.569) (lit. m.p. 142°, IaI D + 24°), 6 (CDC13) 0.67 + (3H, s, 18-Me), 0.82, 0.90, 3.5 (1H, br, 1 20Hz, 3a-H), m/e 388 (M ),

370 (n-HZ ) , 355 (M-H20-Me) .

5a-Cholestan-3;-y1 Acetate (110):- To a solution of 5a-cholestan-3(3-ol

( 97) (5 g, 12.83 mmol) in pyridine (50 ml acetic anhydride (5 ml) was

added and the mixture allowed to stand at 23° for 17 h. Work up and crys-

tallisation gave the ester (110) (5.4 g, 97%) as white needles, from 110.

162 dichloromethane-methanol, m.p. 110-i°, 'al" + 12.60 (c, 1.373), (lit. m.p. 111°, IaI D + 13°).

Reduction of 5a-Cholestan-31-y1 Acetate (110):- The results are summarised in Table 10

TABLE 10 run ester solvent I K crown temp. t-BuOH Products (%) (110) (ml) (mgatom) (mmol) (°C) (mmol) (mmol) (29) (97)

1 0.78 t-BuNH2 10 20 4.9 23 - 30 50 TIIF 4

2 0.69 t-BuNH2 8 20 3.3 23 - 23 51 THF 3

3 1.00 t-BuNH2 10 . 3 2.5 23 - 25 70a Et20 2

4 0.80 t-BuNH2 10 20 3.8 23 0.81 16 37 TIIF 4

5 0.79 t-BuNH2 10 20 3.7 23 0.81 16 57 THF 4 6 0.79. t-BuNH2 10 15 2.6 0 - 20 73 Et20 2

7 0.95 t-BuNH2 10 15 3.8 -60 - 6 73b Et20

a The products were treated with 2,4-dinitrophenylhydrazine before chromatography; no acetoin osazone was isolated however. b The blue colour did not discharge at all. Starting material was isolated from the reaction mixture (38.8 mg, 9%) together with 5a-cholestan-38-yl acetoacetate (111) (6.6 nig, 1.5%), m.p. 96-7° 189 (Et20) 1735, and 1720 cm (CHC) (lit. m.p. 970), vmax -1, vmax 1740-1700, 1320-1240, 1180, 1150, 1000 cm 1, S (CDC13), 0.67 (311, s, 13-;.Ie), 0.82, 0.92, 2.22 (3H, s, CH3C0), 3.37 (2H, s, exch. D20, COCH2CO2), and 4.7 (1H, bx, VT 20Hz, 3a-H). Taking into account the recovered starting material the product Table/continued

composition was 5a-cholestane (29 ) (9%), (3-ketoester (111) (2%) and 5a-cholestan-3;3-ol (97 ) (81%).

Acetoin 2,4-Dinitrophenylosazone:- An aqueous solution of acetoin (85%;

1 ml) was added to a solution of 2,4-dinitrophenylhydrazine (3 g) and concentrated sulphuric acid (8 ml) in methanol (100 ml), the mixture refluxed on a steam bath, the precipitate filtered and triturated twice in boiling ethanol to give the osazone as an orange microcrystalline mass (1.14 g,

26%) m.p. > 3300 (lit. m.p. 330-70 (decomp.), lit. m.p. 346-9°), m/e 446 (M+), 429, 264, 183, 142.

38-(1-Adainantanecarbonyloxy)-5a-cholestane (114):- A solution of 5a- cholestan-3(3-ol (97 ) (4.66 g, 12 mmol) and 4-(N,N-dimethylamino)pyridine

(200 mg, 1.6 mmol) in pyridine (300 ml) was treated with a solution of adamantane-l-carbonyl chloride (2.5 g, 12.6 mmol) in benzene (10 ml) and the mixture was allowed to stand at 20o for 60 h, refluxed for 50 h, and allowed to stand at 20°for 3 weeks. No products were detected by tic.

To a suspension of sodium hydride (50% oil dispersion; 1.5 g, 31 mmol) in THF (8 ml) a solution of 5a-cholestan-38-ol (97 ) (4 g, 10.3 mmol) and imidazole (40 mg) in THF (25 ml) was added and the mixture refluxed for

3 h, under nitrogen. A solution of adamantane-l-carbonyl chloride (2.45 g,

12.3 mmol) in THF (10 ml) was added and the mixture refluxed for 24 h, a further portion of acid chloride (0.5 g, 2.5 mmol) was added and the mixture refluxed for a further 24 h. Work up, chromatography (alumina grade III, 50 g; eluant 5% chloroform-petroleum) and crystallisation from dichloromethane gave~, the pproduct (114)) (1 .7 g, 3030%),;'^) , m.p . 213-222213-2..~°

al23 + 14.1° (c, 2.594), vmax (nujol) 1723, 1235, 1030 cm-1, 6 (CC14) 112.

0.67 (3H, s, 18-Me), 0.83, 0.93, 1.7, 1.8 (15I-I, m, C H ), 4.55 (1H, br, 10 15 W, 17Hz, 3a-H), m/e 550 (M ) , 370 (M-C 2H) , 355 (M-C H-Me) , 10H15CO 10H15CO2 193, 181 (C10H15CO2H2), 159, 158, 135 (C1011 ). (Found: C, 82.99; 15 H, 11.43. C38H 02 requires C, 82.85; H, 11.34%). 62

To a suspension of KH (50% oil dispersion; 4.6 g, 57 mmol) in THF

(20 ml) under nitrogen a solution of 5a-cholestan-38-ol (97) (10 g, .

25.8 mmol) and 18-crown-6 (686 mg, 2.6 mmol) in THF (75 ml) was added and

the mixture heated to reflux for 3 h. Adamantane-l-carbonyl chloride

(8 g, 40.3 mmol) in benzene (15 ml) was added to the mixture at 20° and

the mixture stirred at 20° for 24 h. The reaction was quenched with

glacial acetic acid (1 ml) followed by water and the product extracted

into benzene, washed with sodium hydrogen carbonate, water, dried and

chromatographed (silica ISFC 200 g; eluant 5% ether-petroleum) giving the

ester (114) (8.5 g, 60%) as large needles on slow crystallisation from di-

chloromethane.

Reduction of 38-(1-Adamantanecarbonyloxy)-5a-cholestane (114):- The results

are summarised in Table 11

TABLE 11

Ester Solvent metal crown t Products (%) (114) (ml) (mgatom) (mmol) (°C) (mmol) (29) (97) (108) (106) (115)

a 1.04 t-BuNII2 30 K 38 9 + 2 46 43 57 96 2 THF 10 a 0.84 t-BuNH2 25 K 31+13 6 + 4 46 32 68 81 0 TIIF 25 b 1.09 t-BuNH2 8 K 20 2 + 3 20 48 32 63 0 THF 10 c 1.11 t-BuNH2 10 K 20 3 + 2 20 53 43 36 0 TIIF 13 d 1.05 t-BuNH2 25 K 13 2 + 2 20 50 26 86 0 Et„0 50 continued... 113.

Table/continued

Ester Solvent metal t Products (%) crown I (114) (ml) (mgatom) (mmol) (°C) (mmol) (29) (97) (108) (106) (115)

1.03 t-BuNH2 10 K 13 4 20 43 37 84 0 Et20 75

1.03 t-BuNH2 20 K 14 4 20 45 44 93 7 _f

1.20 DME 15 K 2 + 25 7 20 30 57 92 0 9 .Mel 2 DME 40

1.09 t-BuN1I2 30 K 36 6 -45 27 66 77 5 -h THF 20

1.04 t-BuNH2 30 K 36 6 -53 15 81 71 0 -h THF 20

1.15 EtNH2 20 Li 22 - 17 7 35 4 4 922"i THF 20 k 1.17 EtNH2 80 Li 274 - 17 4 94 4 65 0

1.03 EtNH2 40 Li 65 - 17 5 92 2 29 51Z THF 30

1.17 EtNH2 20 Li 29 - -73 1 93 0 69 0.5m THF 10

1.06 TMEDA 10 Li 14 Ph-Ph 20 0 94 1 0 -n I PhMe 5 2

1.06 TMU 20 Li 14 - 20 p

a A mixture of minor compounds was also obtained. Ū A mixture of five compounds (8.4mg), m/e 416, 402, 387, 165 (C10II15CR20), 135 (C101115) was also obtained.

A mixture of five compounds (10 mg) m/e 388, 233, 215, 165 CH20), 135 was also obtained. (C10H15 (C10H15)

d A mixture of five compounds (34.1 mg) m/e 618, 603, 474, 446, 402, 370, 328 (M+ adamantanoin) , 165 (C H CH 10 15 20), 135 (C10H15) was also obtained. 114.

Table/continued

A mixture of five compounds (11.1 mg) m/e 412, 387, 194, 165 135 (C 15) was also obtained. (C10II15CH20), 1Ō

The reduction was carried out by adding K last (in the absence of THF or Et20). A mixture of five compounds (21 mg) was also obtained.

9 Iodomethane was added prior to addition of ester. A precipitate formed immediately on addition of Mel, and the ester was added as a solution in DME. The reduction took 34 h to go to completion; the blue colour disappeared after 6 h. i2 The reaction required 4 h to go to completion. A mixture of six compounds was also obtained, which was separated by plc (17% ether-petroelum) and the major product RF 0.25 isolated (10 mg), m.p. 80-6°, vmax (CHC13) 1090, 980, 960 cm-1, 6 (CG14) 0.92, 0.96, 1.00, 1.20, 1.47, 1.53, 1.63, 1.68, 1.93, 2.80; m/e (180°, 12 eV) 518, 467, 464, 439, 411, 383; m/e (180°, 70 eV) 620, 588, 546, 518, 467, 464, 439, 411, 383, 257, 211, 183, 135; m/e (300, 12 eV) 235, 194, 176, 165, 135; m/e (30°, 70 eV) 341, 235, 194, 165, 135, 93, 79, 58; m/e (120°,70 eV)490, 416, 398, 387, 383, 369, 247, 243, 149, 135; m/e (140°, 12 eV) 494, 387.(Found: C, 80.22; H, 11.64. C 03 requires C, 80.22; H, 11.34% and T,7+ 568). 38H64

N-Ethyl 1-adamantanecarboxamide (115) (218.8 mg, 92%) from dichloromethane as white needles, m.p. 128-133° (sublimes), (lit192 m.p. 138°), (CHC13) 3465, 3400, 1710, 1685-1630, 1380, 1350, 1290, 1260- vmax 1200, 1150, 1125, 1100, 1040, 975, 915 cm-1, 6 (CDC13) 1.12 (3H, t, J = 7Hz, CH3CH2), 1.72, 1.76, 1.85, 1.88, 2.02 (15H, m, C10H15), 3.37 (2H, m, CH3CH2), 5.6 (1H, br, NH), m/e 207 (e) 135 (C10H15)

A solution of the ester114( ) (16 mg) in EtNH2 (8 ml) was stood at 23° for 8 h. No aminolysis occurred during this period (by tic).

k The ester was added last as a solid. A mixture of minor compounds (23 mg) was also obtained.

1 A solution of t-butyl acetate (192 mg, 1.66 mmol) in THF (3 ml) was added prior to the addition of the ester. A mixture of minor products (29.4 mg) was also obtained. 115.

Table/continued

m A mixture of three compounds (23.6 mg) was also obtained.

II Biphenyl (174.3 mmg, 54M,a ) was recovered from the reaction mixture, m.p. 70-1° (lit.193 m.p. 710), 6 (CC14) 7.1-7.5 (m). A mixture of compounds (65 mg) possibly consisting of some 1-adamantyl-[4-(4- phenylcyclohexyl)] (124) and 1-adamantyl42-(4-phenylcyclohexyl)] ketones (125), v (CHC1 ) 1700, 1600, 1500, 900 cm-1, 6 (CDC13) max 3 1.0-1.5 (m, cyclohexyl), 1.7, 1.9, 2.0 (m, C H ), 7.2-7.3 (m, 10 15 aromatic-H), m/e 322 (M+), 163 CO), 135 (C ); another (C10H15 10H15 mixture (132.9 mg), (CHC13) 3400, 1700, 1600, 1500, 910, 840 vmax cm-1, 6 (CDC13) 0.81-1.5 (m, non-steroidal), 1.6-2.0 (m, C10H15), 3.8-4.3 (m, CHOH), 6.1 (br, olefinic), 7.1-7.7 (m, aromatic-H);

t Tic indicated 5a-cholestan-3(3-ol (97) with two more polar compounds 3) 3360, 1650-1600, 1140 cm-1, 6 (CC14), 3 (s). vmax (CHC1

Reduction of Adamantane-l-carboxylic Acid:- To a partial solution of K

(500 mg, 13 mgatom) and 18-crown-6 (460 mg, 1.7 mmol) in t-BuNH2 (8 ml)

solid potassium adamantanoate (331.9 mg, 1.52 mmol) was added. Work up

gave adamantane-1-carboxylic acid (239.9 mg, 87%). To a solution of ada-

mantane-l-carboxylic acid (397 mg, 2.20 mmol) in EtNH2 (20 ml) Li (250 mg,

36.mgatom) was added and the mixture stirred for 6 h at 17°. Extra Li

(100 mg, 14 mgatom) ivas added every 2"h. The reaction was quenched after

6 h with saturated aqueous ammonium chloride (8 ml) at -78°, the mixture

extracted with ether, washed with hydrochloric acid (10%; until acidic),

sodium hydrogen carbonate, water, dried and the solvent removed under redu-

ced pressure, v (CHC1 ) 3500, 1730, 1670 cm-1, and the mixture chroma- max 3 tographed (silica H, 10 g) to give 1-formyladamantane (116) (182.9 mg,

51%), vmax (CHC13) 2700, 1720, 1150, 1110, 990, 910 cm-1, 6 (CC14) 1.67,

1.70, 1.78, 2.0G (15 H, m, 9.18 (1II, s, -CIIO) [which gave a crys- C10H15), talline hydrazone when treated with 2,4-dinitrophenylhydrazine and concentra-

ted sulphuric acid in methanol, m.p. 230-1° from ethyl acetate-methanol 186 (lit. m.p. 225°)] and 1-hydroxymethyladamantane (32.9 mg, 9%). 116.

Acidification and extraction of the aqueous layer gave starting material

(40.7 mg, 10%).

Reduction of 1-Ethoxycarbonyladamantane in the presence of 5a-Cholestan-

33-ol (97):- To a solution of 5a-cholestan-33-ol (97 ) (420 mg, 1.08 mmol)

and 18-crown-6 (1.20 g, 4.53 mmol) in t-BuNH2 (20 ml) IC (800 mg, 20.51 mg-

atom) was added and the mixture stirred until the blue colour appeared.

A solution of 1-ethoxycarbonyladamantane (230 mg, 1.35 mmol) in THF (1 ml)

was added, and the reaction quenched with aqueous hydrochloric acid (1 M;

10 ml). Work up and chromatography (silica H, 10 g) gave 5a-cholestane

( 29) (61.3 mg, 15%), a mixture of two compounds (12.2 mg) cochromatograph-

ing with adamantanoin (109) and 1-hydroxymethyladamantane (106), v max (CHC13) • 3400, 1720 cm-1 m/e 328 (Pd+ C CH.OH.CO•C ), 166 (BI+ CH2OH), 10H15 10I-I15 C10H15 165 (C10H15CH20), 135 and 5a-cholestan-33-ol ( 97) (290.5 mg, 69%). (C10H15); Acidification and extraction of the aqueous layer gave adamantane-l-carboxyl-

is acid (205.8 mg, 85%).

Bouveault-Blanc reduction of 33-(l-adamantanecarbonyloxy)-5a-cholestane

(114):- To a suspension of sodium sand (2.5 g, 1.08 mgatom) in toluene

(3 ml) a suspension of ester (114) (250 mg, 0.45 mmol) in dry absolute,

ethanol (1 ml) wasadded at 600 with stirring. The excess sodium was

quenched with ethanol, the solvents removed under reduced pressure, the

residue diluted with water, extracted with ether, the organic layer washed

with water, dried and separated by plc (30% ether-petroleum) to give

1-hydroxymethyladamantane (49.6 mg, 66%) and 5a-cholestan-33-ol (97 )

(103 mg, 58%).

33-(2,2-Dimethylpropanoyloxy)-5a-cholestane (126):- To a solution of 5a-

cholestan-3(3-ol (97) (10 g, 26 mmol) in pyridine (30 ml) a solution of

pivaloyl chloride (10 ml) in dichloromethane (20 ml) was added and the 117.

mixture was heated to 500 for 17 h. Work up and crystallisation from ether- methanol, followed by chloroform-ethanol gave the ester (126) (11.13 g,

91%) as white needles, m.p. 164-6°, IaI 23 + 14.5° (c, 0.5), v (nujol) max 1720, 1280, 1170, 1140, 1030, 1005 cm-1, 6 (CDC13) 0.70 (3H, s, 18-Me),

0.92, 0.96, 1.23 (9H, s, i,Ie3C) , 4.6 (1H, br, W, 18 Hz, 3a-H) , m/e 472 (M ) 2 406, 370 (ICI-Me3C.0O2H) , 355 (M-Me3C.0O2H-Me) . (Found: C, 81.20; H, 12.01.

02 requires C, 81.28; H, 11.95%). C32H56

Reduction of 313,-(2,2-Dimethylpropanoyloxy)-5a-cholestane (126):- The results are summarised in the Table 12.

TABLE 12

Ester Solvent K Crown Products (%) (126) (ml) (mgatom) (mmol) (mmol) (29) (97) • 1.04 t-BUNH,, 20 3.5 65 32 20 THF 5 a 1.12 t-BuNH2 59 10.6 73 23 25 THF 7 b 1.06 t-BuNH2 56 12 67 17 30 THF 4

a Ethyl pivaloate (1.04 g, 8 mmol) was added after the ether (126). h and crown were added in three portions. Extra ethyl pivaloate (2.2 g,17 mmol) was added. b 2,3,6-Trimethylphenyl pivaloate (3.5 g, 16 mmol) in THF (2 ml) was added all at once to the reaction mixture. Immediately on addition the blue colour disappeared and a precipitate was formed. The reaction mixture was stirred for 16 h. K and crown were added in three portions. The reaction required three days, during which time the blue colour disappeared. 118.

Ethyl Pivaloate:- A solution of absolute ethanol (16 g, 348 mmol) in pyr-

idine (26 g, 329 mmol) was treated with pivaloyl chloride (30 ml, 243 mmol)

and the mixture allowed to stand at 23o for 17 h. The mixture was distilled

and the fraction distilling at 98-1280 was collected, diluted with water,

washed with hydrochloric acid, sodium hydrogen carbonate, aqueous copper

sulphate to remove traces of pyridine, dried and distilled over xylene

collecting the fraction boiling at 106-121°. This fraction was redistil-

led twice collecting the fractions distilling at 116-120° and 118-120°

respectively. A final distillation gave pure ethyl pivaloate (25 g, 79%), 0 194 o -1 b.p. 118 (lit. b.p. 118.5 ), vmax (film) 1725, 1280, 1160, 1035,cm ,

6 (CDC13) 1.23 (9H, s, Me3C), 1.27 (3H, t, J = 7Hz, CH3CII20), 4.10 (2H,

q, J = 7Hz, CH3CH2O).

2,3,6-Trimethylphenyl Pivaloate:- To a suspension of sodium hydride (80%

oil dispersion; 3.8 g, 127 mmol) in THF (15 ml) a solution of 2,3,6-trimethyl-

phenol (13.6 g, 100 mmol) and imidazole (250 mg, 3.7 mmol) in TIIF (30 ml)

was added under nitrogen and the mixture heated to reflux for 1 h. A sol-

ution of pivaloyl chloride (16.5 g, 137 mmol) in THF (5 ml) was.added to the

mixture with gentle refluxing, and the mixture stirred for 17 h at 23°.

Excess sodium hydride was quenched with glacial acetic acid, work up and

chromatography (neutral alumina grade I, 200 g; eluant 8% ether-petroleum)

gave the ester (19.2 g, 37%) as an oil which crystallised on standing at

230 after 10 days, m.p. 26-80, v (film) 3020, 1750, 1280, 1250, 1195, max 1130, 1070, 1030, 900, 820, 805 cm-1, 6 (CC14) 1.36 (9H, s, Me3C), 1.93,

2.02, 2.22 each (3H, s, 3 Me), 6.73 (2H, s, aromatic-H), m/e 220 (e),

136 (C9H110H), 53. (Found: C, 76.50; Ii, 9.39. C14II 02 requires C, 76.33; 20 II, 9.15%) .

Pivalic Anhydride:- To a solution of pivaloyl chloride (61.05 g, 506 mmol)

in TIIF (150 ml) solid sodium hydroxide (10.15 g, 254 mmol) was added in 119.

portions at such a rate to keep the THF refluxing, followed by triethylamine (27 g, 267 mmol) and the mixture was refluxed for 2 h. The solvents were removed under reduced pressure, and the residue washed with benzene,

filtered, the filtrate concentrated and distilled under nitrogen twice

collecting the fractions distilling at 190-•2°, giving the anhydride (30.8 g, 194 0o 650) (lit. b.p. 190 ), (film) 1810, 1745, 1265, 1060-990, 940, 360, max 760 cm 1.

Attempts to Prepare 1-(2,2-Dimethylpropanyloxy)-2-methylpropene (127):-

Pivalic anhydride (3.7 g, 20 mmol) was added to redistilled isobutyraldehyde

(720 mg, 10 mmol), 6 (CC14) 9.4 (1H, d, J = 2Hz, P:Ie2CHCH0), followed by

toluene-4-sulphonic acid (30 mg, 0.1 mmol) and the mixture was refluxed for

20 h, cooled to 23°, poured into aqueous sodium carbonate, extracted into

ether, dried, and the solvents removed under reduced pressure. After 3 h nmr

showed only starting material. After 20 h the starting material (6 9.4 ppm)

disappeared but no singlet at 7.1 (C:CHOCO, enol ester) was observed.

To a mixture of pivalic anhydride (5 g, 27 mmol) and toluene-4-sulphonic

acid (40 mg, 0.2 mmol), a solution of isobutyraldehyde (500 mg, 7 mmol) in

CC14 (3 ml) was slowly added over 1.5 h at 100° and the mixture refluxed •

for 20 h to give a mixture, 6 (CC14) 7.1 (enol ester) and 11.96 (-CHO,

aldol condensation product) in the ratio 1 : 7.

A mixture of isobutyraldehyde (360 mg, 5 mmol), N,N-dimethylaminopyridine

(65 mg, 0.5 mmol), triethylamine (1 g, 10 mmol) and pivalic anhydride

(4.65 g, 25 mmol) was heated at 90° for 18 h. Nmr indicated mainly aldol

condensation product.

Reduction of 18-Crown-6:- A partial solution of Ii (300 mg, 7.7 mgatom) and

13-crown-6 (900 mg, 3.41 mmol) in t-BuNH2 (20 ml) was stirred under nitrogen

at 23° for 13 h. By this time all the K dissolved and the blue colour 120.

disappeared. The solution was acidified with aqueous hydrochloric acid

(1M), the water evaporated under reduced pressure, benzene was added and

distilled off to azeotrope the remaining water. The residue was dissolved

in dichloromethane, dried, and the solvent removed under reduced pressure,

vmax (CH Cl2) 3350, 3100, 1600, 1350, 1240, 1210, 1110-1060, 960, 840 cm 1,

6 (CDC13) 1.40 (s), 3.6 (s), 3.7 (s). The residue was dissolved in analaR

chloroform and triethyalmine (5 ml)was added, followed by 1-naphthoyl

chloride (from 1.5 g acid and thionyl chloride) and the mixture was allowed

to stand at 20° for 18 h. The solvents were removed under reduced pressure,

the residue extracted thoroughly with benzene-petroleum (1 : 1), filtered, • the filtrate evaporated to dryness (1.83 g) and chromatographed (silica H,

12 g) to give ethyl 1-naphthoate (361 mg), v (film 3090, 3050, 1730-1700, max 1595, 1580, 1510, 1280, 1240, 1200, 1130, 1070, 1040, 1020, 780, 655, 6

(CC14) 1.36 (3H, t, J = 7Hz, CH3CIi2), 4.30 (2H, q, J = 7Hz, CH3CH2O),

7.2-8.2 (6H, m, aromatic-H), 8.7-9.0 (1H, m, aromatic-H), naphthoic anhydrid o 195 0o 145-6, (lit. m.p. 145), (CHC13) 1780, 1715, 1595, (120 mg), m.p. vmax 1575, 1500, 1165, 1120, 1080-1020, 980-920 cm 1, 6 (CDC13) 7.2-8.5 (6H, m,

aromatic-H), 8.9-9.2 (1H, m, aromatic-H), a mixture of naphthoic acid and

N-t-butyl 1-naphthalenecarboxamide (259.2 mg), (CHC13) 3520, 3430, 3400- vmax 2300, 1725-1650, 1595, 1575, 1500, 1300-1170, 1145, 1120, 6 (CDC13) 1.60

(s), 7.3-8.5 (m), 8.9-9.2 (m) which was dissolved in dichloromethane and

washed thoroughly with 5% sodium hydrogen carbonate, water, dried, separated

by plc (50% ether-petroleum) and crystallised from chloroform-ether to

151-2°, v (nujol) 3315, 1640, 1620, 1590, 1575, give white needles m.p. max 1525, 1310, 800, 775 cm-1, 6 (CDC13) 1.60 (9H, s, Me3C), 7.3-8.6 (7H, m,

aromatic-H), m/e 227 (M+), 212 (M-Me), 171 (M-C4H8), 155 (C10H7C0), 127,

H, 7.59; N, 6.42. (C10H 7), 57 (C4H9). (Found: C, 79.26; C15H17N0 requires C, 79.26; H, 7.54; N, G.16). Further elution of the column

(ethyl acetate) gave a black tar (412 mg) and a mixture of several uv-

(CHC13) 1710, 1130, 910 cm-1, 6 (CDC13) 0.9-1.6 active compounds, vmax 121.

(m), 3.5-4.0 (m), 4.5-4.8 (m), 7.3-8.3 (m), 8.9-9.2 (m) which was rechromatographed on a column (silica H, 12 g), eluant 15-6070 ethyl acetate-petroleur collecting two major fractions A and B. Fraction A (134.3 mg) was separated by plc (507, ethyl acetate-petroleum) giving two fractions Al (87.6 mg),

6 (CDC13) 1.00 (t, J = 8Hz), 1.4 (t, J = 7Hz), 3.1 (q, J = 7Hz), 3.8

(m), 4.5 (m), 7.2-9.0 (m), and A, (65 mg),vmax (film) 3370, 1715, 1595,

1580, 1510, 1230, 1245, 1200, 1150-1120, 1070, 1045, 785 cm 1, 6 (CDC13)

3.7 (m), 3.9 (t), 4.6 (t), 7.3-8.3 (m), S.8-9.1 (m), m/e 260 (Tri+), 242

(M-H20), 199 (C10H7 CO CH2CH2), 155 (C10H_C0), 127 (C10H7 ). (Found: M+ 2 260.1049. C15H1604 requires 260.1049) identified as the ester (117).

Al was separated by plc (40% ethyl acetate-petroleum) to give two fractions

A11 (12.4 mg) which was still a mixture, 6 (CDC13) 1.00 (t, J = 7IIz), 1.3

(t, J = 7Hz), 3-4 (m), 4.5 7.3-8.2 (m), m/e 255, 227 (M+ amide), 212,

198, 155 (C10H7C0), 127 (C10 H,!), and Al2 (57.3 mg) a mixture of two compounds one being A2 , 6 (CDC13) 1.0 (t, J = 8Hz), 1.3 (t, J = 7Hz), 3.1

(q, J = 7Hz), 3.6 (m), 7.2-3 (m), m/e 332 (M+), 260 (M+ for A2), 242

(MA2-H20), 212 , 199 (C10H7 CO CH2H2C ), 155 (C10H15) , 127 (C (Found: 2 10 M}332.1625. requires 332.1624) identified as the ester (118). C19H2405 Fraction B (158.4 mg) was reseparated by plc (47% ethyl acetate-petroleum)

giving a brown viscous oil (131 mg), vmax (CHC13) 1715, 1595, 1580, 1280,

1260-1190, , 1140-1090, 1070 cm-1, 6 (CDC13) 1.2 (t, J = 7Hz), 3.6 and

3.65 (s), 3.9 (t), 4.6 (t), 7.4-8.3 (m), 8.3-9.0 (m), m/e 376 (M'), 304

(M-C4H0) , 2S6 (M-C 4II1002) , 274 (M-C5H1002) , 260 (M-C6H1202) , 221 (M-

H 2 20), 199 (Ct0R7 CO CH2Ci1„), 172 (C H7CO2H), C10H7C0), 216 (C10 7CO2CH CH 2 10 376.1890. C 11 requires 155 (C10H7C0), 127 (C10H7). (Found: ,'d 21 2806 376.1886), identified as ester (119).

1,2-Dihydroxydecane:- To redistilled dec-1-ene (17.6 g, 126 mmol) in

formic acid (100%; 53 ml) 11202 (28%; 20 ml) was added and the mixture

stirred at 20o for 17 h. The acid was removed under reduced pressure and 122. the residue refluxed with alcoholic potassium hydroxide (7%; 500 ml) for

1 h. Work up and crystallisation first from ethanol and then from acetone 196 gave the diol (9.1 g, 42%), m.p. 47-90 (lit. m.p. 48-90 (nujol) ),1) max 3320, 3220, 1140, 1100, 1070, 875 cm-1, S (CDC13) 0.8-1.5 (17H, m, C3H17)

3.1-3.8 (3H, m), 3.9-4.2 (2H, m).

D,L-4-Octyl-1,3-dioxolan-2-one (121):- To a solution of phosgene (2 g, 20 mmol) in dichloromethane (50 ml) a solution of 1,2-dihydroxydecane (3.5 g,

20.1 mmol) in dichloromethane (20 ml) and pyridine (10 ml) was added with stirring and cooling, and the mixture stirred at 200 for 16 h. Work up and chromatography (silica 60, 45 g) gave on elution with 10% ether-

petroleum a mixture of three unidentified minor products. Elution with

40% ether-petroleum gave the cyclic carbonate (121) (2.9 g, v 72%), max (film) 1820-1780, 1160, 1060, 770, 720 cm-1, S(CC14) 0.8-1.7 (17H, m),

3.7-4.1 (1H, m), 4.2-4.7 (2H, m), m/e 201 (M + 1), 200 (M ), 199 (M-1),

138, 110, 109, 96, 82, 67, 55. (Found: C, 66.00; H, 10.28. C 11H. 03 requires C, 65.97; H, 10.07%).

N-Trimethylsilylimidazole:- Freshly distilled hexamethyldisilazane (45.3

g, 281 mmol), imidazole (24.8 g, 365 mmol) and concentrated sulphuric acid

(0.2 ml) were refluxed for 3 h and the product distilled at 910/10 mm and

redistilled at 870/9 mm to give N-trimethylsilylimidazole.(37.4 g, 95%), 197 nD7 1.4767 (lit. b.p. 910/12 mm, nD0 1.4756), (film) 1255, 1165, max 1070, 1060, 830, 760 cm-1, S (neat) 0.00 (9II, s, LIe3Si) , 6.70 (2I1, m) ,

7.23 (1H, m).

N,N'-Thiocarbonyl-di-imidazole:- To a solution of trimethylsilylimidazole

(12.8 g, 91 mmol) in dry benzene (40 ml), thiophosgene (3.52 ml, 46 mmol)

was added with cooling and stirring for 1.5 h and the solvents removed

under nitrogen under reduced pressure at 200 to give the product as a o0 198 0 yellow solid (8.11 g, 99%), m.p. 90-5 m.p. 105-6°). 123.

D,L-4-Octyl-1,3-dioxolan-2-thione (122):- To a solution of decane-1,2-diol

(3.5 g, 20.1 mmol) in THF (30 ml), a solution of N,N'-thiocarbonyl-di-

imidazole (5.2 g, 29 mmol) in THF (15 ml) was added and the mixture reflux-

ed under nitrogen for 18 h. The solvent was removed under reduced pressure,

the residue dissolved in dichloromethane, washed thoroughly with hydrochlo-

ric acid (1M), brine, dried, and the solvent removed under reduced pressure.

The crude product was chromatographed (silica 60, 32 g) elution with 2%

ether-petroleum gave a minor non-uv-active product. Further elution with

.5% ether-petroleum gave the cyclic thiocarbonate (122) (2.3 g, 64%),

(film) 1320-1270, 1165, 980 -1, 6 (CDC1 ) 0.8-2.00 (17H, m), 4.1- vmax cm 3

4.5 (1H, m), 4.6-5.1 (2H, m), m/e 216 (M+),.183, 138, 109, 83, 54. (Found:

C, 61.17; II, 9.49. C I12002S requires C, 61.09; H, 9.32%) . 11

Reduction of D,L-4-Octyl-1,3-dioxolan-2-one (121):- To a partial solution

of K (1.3 g, 33 mgatom) and 18-crown-6 (2 g, 7.6 mmol) in t-BuNH2 (25 ml)

a solution of the carbonate (121) (749.3 mg, 3.75 mmol) in ether (4 ml) was

added. The reaction was quenched with ethanol and acetylated with acetic

anhydride-pyridine. Work up and chromatography (silica H, 10 g; eluant

2% ether-petroleum) gave a mixture of 1-decyl and 2-decyl acetates (38 mg,

5%), vmax (CHC1 3) 1730, 1260-1190 cm 1, 6 (CC14) 1.93 (s, Ac0), 3.93

(t, AcOCH2CH2), 4.73 (m, CH3CHOAcCH2), m/e 199 (M-1), 185, 97, 83, 69, 60,

43 (CH3C0); elution with 4% ether-petroleum gave 1,2-diacetoxydecane (650.5

mg, 67%), vmax (film) 1760-1735, 1260-1210, 1045 cm-1, 6 (CC14) 1.97

(6H, s, 2Ac0), 4.03 (2H, m, CH2OAc), 4.93 (1H, br, CHOAc), m/e I,I+ (abs'nt)

215 (M-CII3CO) , 198 (M-AcOH) , 135, 156 (M-ACOII-CII3CO) , 138 (M-2AcOH) , 125,

86, 69, 61 (Ac01I2) , 43 (CH3C0) .

Reduction of D,L-4-Octyl-1,3-dioxolan-2-thione (122):- To a partial

solution of K (900 mg, 23 mgatom) and 18-crown-6 (1.8 g, 6.82 mmol) in

t-BuNH2 (25 ml) a solution of the cyclic thiocarbonate (122) (823 mg,

3.81 mmol) in TIIF (5 ml) was added. More Ii (1 g; total 1.9 g, 49 mgatom) 124.

and 18-crown-6 (1.7 g; total 3.5 g, 13.25 mmol) was added to maintain the

blue colour. The reaction was quenched with ethanol and the products acetyl-

ated with acetyl chloride and pyridine in dichloromethane. Work up gave

a red-brown tar which was extracted with ether, the ethereal solution fil-

tered (silica H, 10 g) to give a solid (793 mg) which was chromatographed

(silica H, 12 g; eluant petroleum) to give dec-1-ene (14 mg, 5%) (glc

retention time 1.2 min), a mixture of 1-decyl and 2-decyl acetates (259 mg,

32%) (eluant 20; benzene-petroleum), 2-decyl acetate (8%; glc retention time

7.0 min) and 1-decylacetate (26%; glc retention time 9.6 min), S (CC14)

1.95 (s, Ac0), 3.93 (t, CH2CH9OAc), 4.7 (m, CHOAc), m/e 201 (M + 1), 200

(M+), 199 (M-1), 168, 140 (M-AcOH) 112, 43 (CH3CO); 1,2-diacetoxydecane

(344 mg, 35%) (eluant 50% benzene-petroleum), S (CC14) 1.97 (6H, s, Ac0),

4.03 (2Ii, m, CII20Ac) , 4.93 (1H, br, CHOAc) , m/e 259 (M + 1) , 109 (M-Ac0) ,

185, 156, (M-Ac0H-CH3C0), 138 (M-2AcOH)., 125 (C9H17), 96, 86, 70, 61

(Ac0H2), 43 (CH3CO). Further elution of the column with.10-20% ether-

petroleum gave a mixture of compounds, (62.5 mg) two of which were uv-

active, S (CC14) 2.00 (s), 2.10 (s), 2.26 (s), 2.56 (s), 4.0 (m), 4.9 (br),

5.76 (s), m/e 300, 230, 229, 200, 199, 168, 153, 125, 111, 98, 85, 69, 43.

1-Acetoxydecane:- To a solution of 1-iododecane (4.6 g, 17 mmol) in THF

(20 ml) powdered and freshly fused potassium acetate (10 g, 102 mmol) was

added, followed by 18-crown-6 (900 mg, 3.4 mmol) and the mixture was

refluxed for 20 h, cooled to 230, diluted with water, extracted with ether,

the organic layer washed with water, dried, and evaporated. The residue

was chormatographed (silica 60, 50 g) eluant 20% benzene-petroleum to

give 1-acetoxydecane as an oil (2.71 g, 79%),v (film) 1745, 1235, 1040, max cm-1, 6 (CC14) 1.95 (3H, s, Ac0), 3.93 (2H, t, J = 6Hz, CH2 OAc), m/e 201

(M + 1) , 140 (M-AcOii) , 112, 83, 70, 61 (AcOII9) , 57, 56, 55, 43 (Ac) , 41,

29, 111.199 m/e 70, 57, 56, 55, 43, 41, 29, 27. 125.

1,2-Epoxydecane:- To a solution of dec-l-ene(96ō; 3.45 g, 24 mmol) in dichloromethane (10 ml) a solution of m-chloroperbenzoic acid (95%;5 g,

27 mmol) in dichloromethane (70 ml) was added over a period of 20 min at 23° and the mixture stirred for a further 40 min. The excess peracid was quenched with aqueous sodium sulphite (10%; until negative to iodide- starch paper). The organic layer was washed with aqueous sodium hydrogen carbonate, saturated brine, dried, evaporated and distilled to give a colourless oil (2.88 g, 78%), b.p. 97-9°/20 mm Hg, d (CDC1,) 235-2.55 196 (1H, m, 2-H), 2.6-3.08 (2H, m, 1-H), (lit. b.p. 890/10 mm Hg).

2-Acetoxydecane:- To a suspension of LAH (317 mg, 8 mmol) in THF (10 ml) a solution of 1,2-epoxydecane (447 mg, 2.86 mmol) in THF (5 ml) was added under nitrogen at 20° and the mixture refluxed for a further 0.5 h. The excess LAH was quenched with aqueous saturated sodium sulphate, the mixture was filtered and the precipitate washed with hot THF. The solvent was removed under reduced pressure and the residue acetylated with acetic anhydride-pyridine. The mixture was poured into ice-water and extracted witl ether. The ethereal solution was washed with water, dilute aqueous hydrochloric acid, dilute saturated sodium hydrogen carbonate, brine, dried,

and the solvent removed under reduced pressure to give 2-acetoxydecane

(492mg, 86%) as an oil, v ax (film) 1735, 1240, 1120, 1045, 1018, 950 cm-1,

6 (CC14) 1.93 (3H, s, Ac0), 4.73 (1H, m, CHOAc).

1,2:5,6-Di-0-isopropylidene-a-D-glucofuranose (129):- Concentrated sulphu-

ric acid (d 1.34; 60 ml), was added to acetone (1.5 1 ) at 5° followed by

anhydrous a-D-glucose (62.5 g, 347 mmol) and the mixture was stirred vit,o-

rously for 3 days during which time all glucose dissolved. The reaction

mixture was cooled to 10°, neutralised with gaseous ammonia, filtered, and

concentrated under reduced pressure. Water (100 ml) was added to the con-

centrate and the mixture was evaporated under reduced pressure to remove 126.

acetone condensation products. The residue was shaken with water (250 ml) and chloroform (100 ml). The aqueous layer was extracted with chloroform

(3 x 50 ml), the chloroform solutions washed with water (3 x 50 ml) and evaporated to dryness. The residue was filtered on alumina (500 g) using light petroleum as eluant to remove non-polar material and the product washed off the column with methanol. The product was dissolved in benzene, charcoaled and crystallised from hot benzene-petroleum to give (129) 200 ° (20 g, 23%) as white pplates m.p.p. 110-1° (lit. 110-1 (nujol) ),\)max 3420, 1250, 1220, 1070, 1060, 1030, 1005, 850 cm-1, S (CDC13) 1.35, J 1.40, 1.45, 1.50 (12II, s, Me2C), 2.6 (1H, br, exch. D20, -OH), 4.0-4.5

(5H, m, 3a-, 4a-, 5-, 6-H), 4.6 (1H, d, J = 3 Hz, 213-H), and G.0 (lII, d,

J = 3Hz, 13-H).

3-0-Acetyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (19 ):- A solution of 1,2:5,6-di-0-isopropylidene-a-D-glucofurnnose (129) (9.5 g, 36.5 mmol) in pyridine (100 ml) was treated with acetic anhydride (3.7 ml, 39 mmol) and the mixture allowed to stand at 23° for 2 days. Work up gave an oil

(9.65 g,. 87%) which crystallised after three days standing at 23°, giving large prisms, m.p. 58=G10, and recrystallised from aqueous ethanol, m.p. 201 62°,. (1it m.p. 62°), v (film) 1750, 1220, 1160, 1050, 350 cm max -1, S (CDC13) 1.33, 1.40, 1.53 (12H, 3s, Me2C), 2.10 (3H, s, Ac0), 4.0-4.35

(4H, m, 4a-, 5-, 6-1H), 4,52 (1H, d, J = 4Hz, 21-H), 5.30 (lIi, m, 3a-II),

5.93 (1H, d, J = 4Hz, 1G-H).

Reduction of 3-0-acetyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose

(19):- To a solution of the acetate (19) (103 mg, 0.36 mmol) in LtNH2

(3 ml) Li (120 mg, 18 mgatom) was added and the mixture stirred for 0.5 h after the blue colour appeared. The reaction was quenched with methanol

(2 nil) at -200 followed by acetic acid (0.3 ml). The solvents were removed under reduced pressure, pyridine (3 ml) and acetic anhydride (10 m1)were added 127. and the mixture stirred for 16 h at 230. The mixture was poured into brine at 0o and the products extracted into ethyl acetate. The organic layer was dried, filtered and evaporated to dryness. Plc (30% ethyl acetate- benzene) gave an unidentified non-polar product (9 mg, 5.8 mg) (from cyclohexane), m.p. 166-9° (decomp), v (cyclohexane) 1730, 1120, 1075, max -1, a 710 cm mas (cyclohexane) 206 nm (c 7000), m/e 384, 366, 105, 57, 43. (Found: C, 79.08; H, 9.72. requires C, 79.12; H, 9.78%); and C19H2802 3-0-acetyl-1,2;5,6-di-O-isopropylidene-a-D-glucofuranose (129) (54 mg,

50%). In two other experiments where the reaction mixture was not acetylated before chromatography the only product observed on tic was the alcohol

(129) in 19 and 24% yields respectively. The solvents (EtNH2) and methanol

(used to quench the reaction) were distilled at atmospheric pressure, collec-

ted in a cold trap at -78° and the nmr spectrum of the distillate recorded.

This showed the presence of ethylamine 1.06 (3II, t, J = 7Hz, CH3CH2N), and

2.66 (2H, q, J = 7Hz, CH3CH2N) and methanol, 3.27 (s), 3.23 (2H, br, exch.

D20, NH2).

1,2:5,6-Di-0-isopropylidene-3-0-(2-methylpropanoyl)-a-D-glucofuranose (128):--

To a solution of 1,2:5,6-di-0-isopropylidene-a-D-glucofuranose (129) (5 g,

19 mmol) in pyridine (40 ml), isobutyryl chloride (3 g, 28 mmol) was added

and the mixture allowed to stand for 66 h. Work up gave the product (128)

as an oil (6.1 g, 96%), b.p. 600/10-5 mmHg, 43 1.4431, IaID3 - 300 (c, 8)

(film) 1740, 1250, 1220, 1190, 1150, 1070, 1020, 850 cm 1, S (CDC13) vmax 1.13,1.25 and 1.32 (12H, 3 s, Me2C) , 1.46 (611, d, J = 7Hz, Me2CH) , 2.4

(1H, m, Me2Cii) , 4.0-4.4 (411, m, 4a-, 5-, 6-H), 4.46 (111, d, J = 4Hz, 2(3-11) ,

5.3 (1H, m, 3a-H), 5.88 (11I, d, J = 4Hz, 113-H), m/e P:I (absent) 316, 101, 71

(C4H70). (Found: C, 57.88; H, 7.98. requires C, 58.17; H, 7.93%). C16II2607

Reduction of 1,2:5,G-Di-O-isopropylidene-3-0-(2-mcthylpropanoyl--a-D-gluco-

furanose (128):- To a solution of Li (80 mg, 11 mgatom) in EtNII9) (3 ml) 128.

a solution of the isoburyate ester (128) (188 mg, 0.57 mmol) in THF (0.5 ml) was added at 0° and the mixture stirred at 0 for 1 h. The reaction was quenched with methanol and the solvents removed under reduced pressure,

pyridine (1 ml) and acetic anhydride (10 ml) were added at 0° and the mixture stirred for 16 h at 23°. Work up and crystallisation gave 3-0-acetyl-

1,2:5,6-di-0-isopropvlidene-a-D-glucofuranose (19) (87.5 mg, 51%).

Methyl 4,6-0-Benzylidene-a-D-glucopyranoside(131):- Methyl a-D-glucopyran-

oside (132) (60 g, 309 mmol), powdered'and freshly fused zinc chloride (57 g,

418 mmol) and benzaldehyde (freshly distilled; 150 ml) were vigorously stirred for 48 h. The mixture was poured slowly with stirring into cold water (1.25 1) and the mixture refrigerated for 16 h. Petroleum (75 ml) was added and the mixture stirred for 0.5 h. The solid was filtered, washed

twice with cold water, petroleum, water, dried in vacuum at 70° and recrystallised from chloroform-petroleum giving the product (53 g, 61%) as needles, m.p. 163-4°, Iaj23 + 108° (c, 1.633 in BtOIi) (lit202 m.p. 163-4°, D laI D + 108°), (nujol) 3380, 1085, 1070, 1030, 1000, 750, 700, S (CDC1 vmax 3) 3.4 (3H, s, IMO), 3.5-4.4 (6H, m, 28-, 3a-, 48-, 5a-, 6-H), 4.76 (1H, d,

J = 4Hz, 18-II), 5.5 (1H, s, PhCH), 7.2-7:5 (5H, m, aromatic-II).

Methyl 4,6-0-Benzylidene-2,3-di-0-acetyl-a-D-glucopyranoside (130):- A

solution of methyl 4,6-0-benzylidene-a-D-glucopyranoside (131)'(1.g, 3.55

mmol) in pyridine (10 ml) was treated with acetic anhydride (1 ml) and the

mixture allowed to stand at 23° for 16 h. Work up and crystallisation from

dichloromethane-petroleum gave the diacetate (130) (857 mg, 66%), m.p. 0o 203 ° 108-9 m.p. 109°), ō (CDC13) 2.03 and 2.08 each (3I1, s, Ac0), 3.42

(3H, s, Me0-) , 3.5-4.5 (4II, m, 43-, 5a-, 6-H), 4.95 (311, m, 13-, 28-, 3a-H),

5.5 (1H, s, C6115CH) , 7.3 (511, m, aromatic-H).

Reduction of Methyl 4,G-0-Benzylidene-2,3-di-0-acetyl-a-D-glucopyranoside (130) 129.

To a solution of the diacetate (130) (101.5 mg, 0.28 mmol) in EtNH2 (3 ml) under argon Li (180 mg, 26 mgatom) was added and the mixture stirred at

17o for 3 h. The reaction was quenched with methanol the solvents were removed under reduced pressure, the residue treated with acetic anhydride- pyridine and worked up to give methyl-2,3,4,6-0tetra-0-acetyl-a-D-glucopyranosid

(133) (58 mg, 58%) as an oil identical with an authentic sample. In another experiment Li (170 mg, 24 mgatom) was added to a solution of the diacetate (130)(136 mg, 0.37 mmol) in EtNH2 (3 ml), when the blue colour appeared, the reaction was quenched with methanol, ammonium chloride (1 g) was added, the mixture diluted with water and extracted with ethyl acetate.

The organic layer was washed-with brine, dried and evaporated to give N- ethylacetamide (76 mg, 59%; based ontetra-acetate giving 4 equivalents of acetamide), vmah (CHC13) 3440, 3300,1_680-1620, 1570-1500, 1290-1190 cm-1,

(CDC13) 1.1 (3H, t, J = 6Hz, CH3CH2), 2.00 (3H, s, CII3C0), 3.3 (21i, m,

CH3CH2NH), 6.9 (1H, br, exch. D20, NHCO). To a partial solution of K

(1 g, 26 mgatom) and 13-crown-6 (750 mg, 2.84 mmol) in t-BuNH9 (8 ml) a solution of the diacetate (130) (344 mg,0.94 mmol) in THF (2 ml) was added.

The reaction was quenched with ethanol, •the solvents removed under reduced pressure, and the residue treated with acetic anhydride-pyridine. Work up and plc gave-methyl 2,3-di-0-acetyl-4,6-0-benzylidene-a-D-glucopyranoside

(130) (120 mg, 35%) and the tetra-acetate (133) (108 mg, 32%)..

Methyl 2,3,4,6-Tetra-0-acetyl-a-D-glucopyranoside (133):- To a solution of methyl a-D-glucopyranoside (132) (100 mg, 0.51 mmol) in pyridine (1 ml), acetic anhydride (2 ml) was added and the mixture allowed to stand at 23° for 17 h.

The product was obtained as an oil after work up (170 mg, 92%) which crys- 0 0 203 tallised after two months, m.p. 100-2 , IaID + 131 (c, 0.367) (lit. -1 m.p. 1050, 130.50), (film) 1745, 1220, 1030, 930, 895, 755 cm , IaID '.>max a (CDC13) 1.08, 2.00, 2.03 and 2.07 each (3H, s, Ac0), 3.40 (31I, s, Me0),

4.2 (1H, m, 5a-H), 4.8-5.6 (6H, m, 13-, 23-, 3a-, 4(3-, 6-H). 130.

1,2:5,G-Di-O-Isopropylidene-D-mannitol (135):- D-mannitol (21.8 g, 120 mmol) and anhydrous zinc chloride (120 g, 882 mmol) were stirred in acetone (600 m] for 24 h, poured in aqueous potassium carbonate (100%, w/v; 140 ml), and the mixture shaken vigorously with ether (G00 ml). The acetone-ether solution was filtered and the solid washed with acetone-ether (1:1; 2 x 200 ml).

The combined organic solutions were concentrated under reduced pressure and then heated for 2 h in vacuo at 600. The residue was vigorously refluxed for 20 min with petroleum (5 x 500 ml). The resulting solutions were rapidly filtered, the filtrates were allowed to cool slowly, and then refrigerated.

The fine crystals were recrystallised from hot petroleum and then ethyl acetate-light petroleum to give the diol (135) (15.8 g,.50%), m.p. 121-2° 204 (lit. 122°), S (CDC13) 1.35 and 1.42 (each (GH, s, Me2C), 2.5-2.7 (2H, m, exch. D20, -OH), 3.5-4.3 (8H, m, 1-, 2-, 3-, 4-, 5-, 6-H).

3,4-0-Carbonyl4,2:5,6-Di-0-isopropylidene-D-mannitol (134):- To a solution of 1,2:5,6-di-O-isopropylidene-D-mannitol (135) (1 g, 3.8 mmol) in chloroform (50 ml) and pyridine (1.2 g, 15 mmol) a solution of phosgene (400 mg,

4 mmol) in chloroform (40 ml) was added slowly over a period of 1 h. The reaction mixture was stirred for 18 h, the solvents removed under reduced pressure, and water added to the residue. The product was extracted with chloroform, washed with brine, dried, filtered and evaporated. The product was crystallised from ethyl acetate-light petroleum, and recrystallised from dichloromethane-petroleum to give the carbonate (134) as needles (594 mg, 54' 205 0 m.p. 145-7° , (lit. 146-7°), v (nujol) 1820, 1790, 1255, 1215, 1180, rnax 1130, 1070, 835 cm-1, 6 (CDC13) 1.35 and 1.46 each (6I1, s, Me2C), 3.8-

4.6 (8H, m, 1-, 2-, 3-, 4-, 5-, G-H).

1,2:5,6-Di-O-Isopropylidene-3,4-0-Thiocarbonyl-D-mannitol (137):- To a solution of 1,2:5,6-di-O-isopropylidene-D-mannitol (135) (1.2 g, 4.6 mmol) in TIIF (20 ml) N,N'-thiocarbonyl-di-imidazole (1.65 g, 9.3 mmol) was added 131. and the mixture refluxed for 7 h under nitrogen. The solvent was removed and the residue dissolved in dichloromethane, washed with cold dilute hydrochloric acid, water, dried and the solvent removed under reduced pressure. The residue was recrystallised from ethyl acetate-light petroleum to give the product (137) (1.13 g, 85%) as white needles, m.p. 165- 0 0 6.5 , 1041 23 -15.6 (c, 0.154), v (nujol) 1330, 1300, 1260, 1245, 1205, max 1165, 1145, 1060, 980, 960, 860, 835 cm 1 , A (EtOH) 234 nm (c 15000), max 267 (600), ō (CDC13) 1.35 and 1.45 each (GH, s, I,Ie2C), 3.9-4.4 (6H, m, 1-,

2-, 5-, G-H), 4.5-4.3 (2H, m, 3-, 4-H) , m/e 304 (Mt), 289 (M-Ne), 101.

(Found; C, 51.42; 11, 6.64. requires C, 51.31; H, 6.62%). C13112006S

3,4-Di-0-Acetyl-1,2:5,6-di-0-isopropylidene-D-mannitol (136):- To a solution of 1,2:5,6-di-O-isopropylidene-D-mannitol (135) (524 mg, 2 mmol) in pyridine (3 ml), acetic anhydride (1 ml) was added and the mixture was stirred at 23° for 18 h. Work up and crystallisation from ether gave the diacetate

(136) (567 mg, 82%), m.p. 122-3°,.IaI 23 + 27.1° (c, 1.359) (lit. m.p.

123°, IaID + 26.7), S (CDC13) 1.32 and 1.37 each (6H, s, Ile2C), 2.10

(6H, s, 2Ac0), 3.8-4.3 (6H, m, 1-, 2-, 5-, 6-H), 5.2-5.5 (2H, m, 3-, 4-11).

3,4-0-Iminocarbonyl-1,2:5,6-di-0-isopropylidene-D-mannitol (138):- A solution of n-butyllithium in hexane (1.7 M; 6.5 ml) was added to a solution of 1,2:5,6-di-O-isopropylidene-D-mannitol (135) (2.62 g, 10 mmol) in dry

THF (20 ml) under nitrogen at 23°. After 30 min the reaction mixture was cooled to 0° and a solution of cyanogen bromide (1.28 g, 12.1 mmol) in THF 0 (10 ml) was added dropwise. The mixture was allowed to warm to 23 over a period of 1.5 h and the solvent and excess cyanogen bromide were removed under reduced pressure. The residue was diluted with water and thoroughly extracted with chloroform. The organic layer was washed with brine, dried, and the solvent removed to give the iminocarbonate (138) (2.81 g, 98%), 132. contaminated with 5-10% carbonate (134) (by infrared). Attempts to purify the product by fractional recrystallisation from chloroform-petroleum, ethyl acetate-petroleum, dichloromethane-petroleum or ethyl acetate failed 07 giving always a crystalline mixture, m.p. 133-5°, (lit2 m.p. 133.5-8°), v (nujol) 3355, 1820, 1800, 1705, 1260, 1240, 1210, 1150, 1070, 840 cm-1, mah 6 (CDC13) 1.33, 1.43 each (6H, s, Me2C), 3.82-4.5 (811, m, 1-, 2-, 3-, 4-, 5-,

6-H).

A portion of the above product (572 mg, 2.0 mmol) was treated with toluene-

4-sulphonyl chloride (383 mg, 2 mmol) in pyridine (4 ml) for 4 days at

230. The solvent was removed under reduced pressure and the residue dissolved in chloroform, the organic layer washed with brine, dried, and the solvent evaporated to dryness. The residue was chrematographed (silica

H, 12 g) eluant 30% ethyl acetate-petroleum to give 1,2:5,6-Di-O-Isopropyl- idine-3,4-0-(N-toluene-4-sulphonyliminocarbonyl)-D-mannitol (139) (382.2 mg, 44%), from dichloromethane-petroleum, as heavy prisms m.p. 119-121°, 208 (lit. m.p.. 119.5-1 20°), 6 (CDC13) 1.27, 1.4 each (6H, s, Me2C), 2.40

(3H, s, Me-C6H4-), 3.83-4.26 (6H, m, 1-, 2-, 5-, 6-H), 4.4-4.8 (2H, m, 3-,

4-H), 7.1-7.9 (4H, m, aromatic-H).

Reduction of 3,4-0-Carbonyl-1,2:5,6-di-O-isopropylidene-D-mannitol (134):-

To a partial solution of K (500 mg, 13 mgatom) and 18-crown-6 (860 mg,

3.26 mmol) in t-BuNII2 (20 ml) a solution of the cyclic carbonate. (134)

(509 mg, 1.77 mmol) in THF (5 ml) was added and the reaction quenched

with methanol, the solvents removed under reduced pressure and the residue

acetylated with acetic anhydride-pyridine. Work up (extraction with ethyl

acetate) and chromatography (silica H, 10 g) gave (eluant 35% ether-petrol-

eum) an unknown compound(32.6mg),vmax (CHC13) 3500, 1720, 1280-1200, 1110,

1070, 1020 cm-1, 6 (CDC13) 2.05 (311, s, Ac0), 2.4 (21I, m), 4.0G (211, t,

J = 7IIz), 5.5 (11I, m), m/e 431, 415, 341, 331, 273, 215, 199; and

(eluant 40;, ether-petroleum) 3,4-di-0-acetyl-1,2:5,6-di-O-isopropylidene- 133.

-D-mannitol (136) (423 mg, 69%), recrystallised from ether, m.p. 122-3°, 206 0 (lit. 123°), 6 (CDC13) 1.26, 1.33, 1.36 (12 H, 3 s, 2.Ie2C), 2.06 (6H, s, 2Ac0), 3.3-4.3 (GH, m, 1-, 2-, 5-, 6-H), 5.0-5.36 (2I1, m, 3-, 4-H).

Reduction of 1,2:5,G-Di-O-isopropylidene-3,4-0-thiocarbonyl-D-mannitol

(137):- To a partial solution of K (G00 mg, 15 mgatom) and 18-crown-G

(502 mg, 1.90 mmol) in DME (8 ml) a solution of the cyclic thiocarbonate

(137) (122 mg, 0.40 mmol) in THF (1 ml) was added and the reaction quenched with ethanol, the solvents removed under reduced pressure, and the residue treated with acetic anhydride-pyridine. Tlc indicated a multitude of

products containing sulphur.

Reduction of 3,4-0-Iminocarbonyl-1,2:5,6-di-0-isopropylidene-D-mannitol

(138):- To a partial solution of K (300 mg, 20 mgatom) and 13-crown-G

(800 mg, 3 mmol) in t-BuNH2 (10 ml) a solution of the iminocarbonate (138)

(250 mg, 0.87 mmol) in THF (5 ml) was added and the reaction quenched with

ethanol, the solvents removed under reduced pressure, and the residue

treated with acetic anhydride-pyridine. The mixture was poured into water,

extracted with ether, the ethereal layer washed with water, dilute hydro-

chloric acid, saturated sodium hydrogen carbonate, water, dried and

evaporated to give a mixture of two compounds, (CS2) 1745, 1225, vmax 1070, 760 , 735 cm-1. The mixture was separated by plc (50% ether-

petroleum) to give a product (30 mg), 6 (CDC1,) 1.30 and 1.35 (6H, 2 s,

Me2C), 2.00 and 2.03 (6II, 2 s, 2Ac0), 3.6-4.3 (411, m), 4.55 (2H, d), 5.3

(111, m), 5.8 (1H, m), m/e 331, 273, 257, 155, 101; and 3,4-di-0-acetyl

1,2:5,6-di-0-isopropylidene-D-mannitol (136) (90 mg, 30%).

Reduction of meso-4,5-Diphenyl-1,3-dioxolane-2-thione (140):- To a partial

solution of K (500 mg, 13 mgatom) and 18-crown-G (1 g, 3.79 mmol) in t-BuNI' 209 (8 ml) a solution of meso-4,5-diphenyl-1,3-dioxolane-2-thione (79 mg, 134.

0.31 mmol) in TIIF (0.5 ml) was added and the reaction quenched with ethanol to give a complex mixture.

Reduction of 1,2-Dideoxy-3,4:5,G-di-O-isopropylidene-1,2-thiocarbonyl- dithio-D-glucitol (141):- To a partial solution of K (400 mg, 10 mgatom) and 18-crown-6 (450 mg, 1.70 mmol) in t-BuNII2 (12 ml) a solution of the 21 trithiocarbonate (141) (210.9 mg, 0.63 mmol) in THF (5 ml) was added.

More K (500 mg; total 900 mg, 23 mgatom) and 18-crown-6 (200 mg; total

650 mg, 24.62 mmol) had to be added. The reaction was quenched with ethanol, the solvents removed under reduced pressure, and the residue acetylated with acetic anhydride-pyridine. Tic indicated a multitude of products containing sulphur. Work up and plc twice (10°0 ethyl acetate- benzene) gave a compound (20 mg) as a dark oil, containing sulphur, v max -1 (CS2) 1745, 1700, 1225, 1130, 1070, 950, 845 cm , S (CC14) 1.28, 1.33

(s, Me2C), 2.00 (s, Ac0), 2.28 (s, AcS), 3.9-4.2 (m),.5.3-6.0 (m).

5a-Cholestan-313-yl Toluene-4-sulphonate (142):- To a solution of 5a-cholestan-3(3-ol (97) (3.9 g, 10 mmol) in pyridine (25 ml) toluene-4=sulphonyl chloride (2.35 .g, 12 mmol) was added and the mixture was stood at 23° for

60 h. The mixture was poured into water and the product extracted with

ether, the organic layer washed with water, sodium hydrogen carbonate,

hydrochloric acid, sodium hydrogen carbonate, brine, dried and crystallised

twice from dichloromethane-methanol to give the sulphonate (142) (4.90 g, 211 0 90;;) as needles, m.p. 136-7° , (lit. 135-6°), S (CC14) 0.67 (3H, s,

18-Me), 0.85, 0.95, 2.43 (3H, s, Me-Ph), 4.3 (1H, br, W1 20Hz, 3a-II),

7.1-7.3 and 7.56-7.86 (41I, ABq, aromatic-H).

Reduction of 5a-cholestan-33-y1 Toluene-4-sulphonate (142):- To a

partial solution of K (600 mg, 15 mgatom) and 18-crown-6 (G00 mg, 2.27 mmol;

in t-BuNH2 (15 ml) a solution of the sulphonate (142) (701.4 mg, 1.29 mmol) 135.

in THF (8 ml) was added. The blue colour on addition of the sulphonate turned yellow, then orange, then green and finally blue again. The reaction was quenched with ethanol and worked up in the usual way to give a complex mixture of sulphur containing compounds. The mixture was chromatographed (silica H, 10 g) to give 5a-cholestan-38-ol (97) (365.6 mg,

73%).

Reduction of Methyl 4,6-0-Benzylidene-2,3-di-0-toluene-4-sulphonyl-a.-

D-glucopyranoside (143):- To a partial solution of K (950 mg, 23 mgatom) and 18-crown-6 (1 g, 3.79 mmol) in t-BuNH2 (6 ml) a. solution of the bis- 212 sulphonate (143) (243.3 mg, 0.41 mmol) in THF (3 ml) was added, the reaction quenched with ethanol,the solvents removed under reduced pressure, and the residue treated with acetic anhydride-pyridine to give a multitude of products.

Di-(5a-Cholestan-38-yl) Oxalate (144):- (i) To a solution of 5a-cholestan-3(3-ol ( 97) (5 g, 12.83 mmol) in pyridine (40 ml), oxalyl chloride

(0.5 ml, 5.35 mmol) was added at 0° and the mixture allowed to stand for

16 h at 200. Further addition of oxalyl chloride (0.1 ml, 1.17 mmol) caused no further change (tic). Work up and filtration (silica Ii, 20 g) eluant 15%, ether-petroleum gave a mixture of two compounds and 5a-cholestan- n-ol (97). The mixture was chromatographed (silica H, 10 g), eluant

2% ether-petroleum, giving mainly the least-polar product (tic, Rr 0.72 in 50 benzene-petroleum) which was recrystallised twice from ethyl acetate giving di-(5a-cholestan-33-y1) oxalate (144) as small needles

(350 mg, 2%), m.p. 212-S0, IaI3 + 19.0°(c, 1.329), vmax (nujol) 1745, -1 1180 cm-1, vMax (CHC13) 1760, 1740, 1150, 1000, 910, 905 cm , d (CDC13)

0.70, 0.90, 0.96, 4.5-5.2 (3a-II), m/e 831 (f+), 572, 516, 488, 383, 370,

355, 215. (Found: C, 30.66; H, 11.40. CJ5H9404 requires C, 80.90;

H, 11.40%). Elution with 5 ether-petroleum gave the more-polar product 136.

(RF 0.29 in 50% petroleum-ether) which was recrystallised from chloroform- ethanol to give ethyl 5a-cholestan-36-yl oxalate (145) (210 mg, 3%), m.p.

114-5°, IaID3 +13.5° (c, 2.277), (nujol) 1745, 1190 cm-1, 8 (CDC13) vmax 0.70 (3H, s, 18-Me), 0.90, 0.96, 1.36 (3H, t, J = 7Hz, OCH2CH3), 4.36

(2H, q, J = 7Hz, CH3CH2O), 4.83 (1H, br, Wl 16Hz, 3a-H), m/e 488 (M), 473 z (M-Me), 388, 370, 355, 215. (Found: C, 76.16; H, 10.83. requires C31II5204 C, 76.18; H, 10.72%). Elution with ether gave unreacted 5a-cholestan-36-ol

(4 g, 80%).

(ii)To a suspension of sodium hydride (80% oil dispersion; 500 mg, 16.6 mmol) in THF (5 ml) containing imidazole (20 mg) a solution of 5a-cholestan-

3-ol (97 ) (3.2 g, 8.25 mmol) in THF (30 ml) was added under nitrogen and the mixture refluxed for 2.5 h. Oxalyl chloride (0.35 ml, 4.1 mmol) was added slowly at such a rate as to keep the mixture refluxing with stirring for 17 h at 20°. Excess sodium hydride was quenched with acetic acid, and the mixture worked up and chromatographed (silica 60, 30 g; eluant 2% ether-petroleum) to give after crystallisation from ethyl acetate di-(5a- cholestan-36-y1)oxalate (144) (822.7 mg, 6%). Further elution with 5% ether-petroleum gave ethyl 5a-cholestan-36-y1 oxalate (145) (322.1 mg, 8%) after crystallisation from chloroform-ethanol; and elution with ether gave

5a-cholestan-36-ol (97) (2.24 g, 70%).

(iii)To a suspension of sodium hydride (50% oil' dispersion; 289.1 mg, 6 mmol) and imidazole (20 mg) in THF (3 ml) a solution of 5a-cholestan-36-ol (97 )

(1 g, 2.57 mmol) in THF (10 ml) was added under nitrogen and the mixture refluxed for 3 h. Redistilled diethyl oxalate was added (20 g, 137 mmol) and the mixture refluxed for a further 12 h. (No change was observed after the second addition of diethyl oxalate). The excess diethyl oxalate was removed under reduced pressure (420/0.5 mmHg) and the residue chromatographed on silica 60 (18 g). Elution with 30% benzene-petroleum gave ethyl 36-ethoxycarbonyloxy-5a-cholestane (146) (106.2 mg, 9%), from chloroform-methanol

137.

0 213 0 ° (lit. m.p. 105.5-106 ), (nujol) 1745, as long needles, m.p. 106-7 v max 1265, 1250,1110 cm 1, d (CDC13) 0.76 (3H, s, 18-Me), 0.92, 1.02, 1.38

(3H, t, J = 7Hz, CH3CH2O), 4.23 (2H, q, J = 7Hz, CH3CH2O), 4.56 (1H, br,

W 16 Hz, 3a-H) , m/e 460 (M÷), 445 (M-Me) , 370 (M-C2H5OH-0O2) , 355 (M-

C2H5OH-CO2-Me), 306, 215; elution with benzene gave ethyl 5a-cholestan-38-

yl oxalate (145) (264.1.mg, 21%) from chloroform-ethanol. Further elution

with ether gave starting material (97) (611 mg, 61%).

(iv) To a solution of 5a-cholestan-38-ol (97) (1 g, 2.57 mmol) in diethyl

oxalate (54 g, 370 mmol) and toluene (50 ml), toluene-4-sulphonic acid

monohydrate (300 mg, 1.53 mmol) was added and the mixture refluxed for 70 h.

The water produced was removed by azeotropic distillation with toluene

(total volume of toluene used 600 ml). The diethyl oxalatq was distilled

under reduced pressure and the residue filtered (silica H, 10 g; eluant

petroleum) to give 3c-(methylphenyl)-5a-cholestane (147) (850 mg, 71%)

(film) 2920, 2860, 1460, 1450, 1380, 1360, 670 cm 1, S (CC14) 0.82, vmax 174 0.83, 0.90, 7.16 (4H, s, aromatic-H), m/e 462 (e), 447 (M-Me), authentic

m/e 462, 447, 405, 322.

Reduction of Di-(5a-cholestan-38-yl)0xalate (144):- (i) To a solution of

the oxalate (144) (110.6 mg, 0.13 mmol) in THF (20 ml), Na-K alloy (500 mg;

from 300 mg Na and 800 mg K) was added and the mixture refluxed under

nitrogen for 16 h. The excess alloy was quenched with absolute ethanol,

the solvents removed under reduced pressure, the residue diluted with water,

extracted with ether, washed with dilute hydrochloric acid, saturated

sodium hydrogen carbonate, water, dried and evaporated. The residue was

chromatographed (silica H, 9 g) to give 5a-cholestane (29 ) (9.6 mg, 10%),

and 5a-cholestan-38-ol (97 )(76 mg, 74%).

(ii) To a partial solution of K (500 mg, 13 mgatom) and 18-crown-6 (500 mg,

1.89 mmol) in t-BuNH2 (12 ml) a solution of the oxalate (144) (100.8 mg, 138.

0.12 mmol) in THF (8 ml) was added and the reaction quenched with ethanol.

Work up and chromatography (silica H, 8 g) gave 5a-cholestane (29 ) (7.6 mg,

8%), and 5a-cholcstan-38-ol (97) (82 mg, 88%)

Reduction of 38-Meth-ji-(taiQcurbony1)oxycholest-5-ene(148):- (i) To a partial solution of K (GOO mg, 15 mgatom) and 18-crown-6 (2.3 g, 8.71 mmol) 214 in t-BuNH2 (25 ml) a solution of thioacetate (148) (510 mg, 1.15 mmol) in THF (6 ml) was added and the reaction quenched with ethanol. A thiol, probably ethanethiol, was given off during the reaction. Work up and chromatography (silica H, 10 g) gave cholest-5-ene (49) (27 mg, 6%) and cholesterol (76 ) (384 mg, 87%).

(ii) To a partial solution of K (900 mg, 23 mgatom) and 18-crown-6 (1.7 g,

6.44 mmol) in t-BuNH2 (18 ml) a solution of the thioacetate (148) (753.2 mg, 1.70 mmol) in THF (5 ml) was added and the reaction quenched with ethanol. Work up and chromatography (silica H, 10 g) gave cholest-5-ene (49)

(53.8 mg, 8%) and cholesterol (76) (546.8 mg, 83%).

Reduction of 38-Phenyl-(iminocarbonyl)oxycholest-5-ene (149):- To a solution 215 of benzimidate (149) (166 mg, 0,34 mmol) [ 3) 3330, 1630, 1580, vmax (CHC1 1070, 910 cm 1, S (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain PM's),

1.06 (3H, s, 19-Me), 4.83 (1H, br, W 16Hz, 3a-H), 5.4 (1H, m, W1 8Hz, 6-H), 2 2 6.5 (1H, br, NH), 7.3-7.9 (5H, m, aromatic-H) ] in EtNH2 (4 ml), Li (300 mg,

43 mgatom) was added and the reaction quenched with methanol. Work up and

crystallisation gave cholesterol (76) (98 mg, 75%).

Reduction of 5a-cholestan-38-yloxymethylenedimethylammonium chloride (150):-

To a solution of phosgene (600 mg, 6 mmol) in dichloromethane (10 ml) a

solution of N,N-dimethylformamide (125 mg, 1.71 mmol) in dichloromethane

(1 ml) was added at 0°. After 0.5 h the excess phosgene and the solvent

were removed under reduced pressure, the residue dissolved in dichlorome- 139.

thane (10 ml) and a solution of 5a-cholestan-3a-ol (97 ) (555 mg, 1.43 mmol) in THF (20 ml) was added, the solvent removed under reduced pressure, and the residue dissolved in THF (20 ml). The solution was added via two-tipped

needle to a partial solution of K (2.2 g, 56 mgatom) and 18-crown-6 (2.54 g,

9.62 mmol) in t-BuNH2 (15 ml). The addition require 4 h by which time the

blue colour disappeared without reappearing. The reaction was followed by

the disappearance of 5a-cholestan-33-y1 formate (151) (quenching aliquots

with water) on tic. The reaction was quenched with methanol and worked up

in the usual way. Chromatography (silica MH:C, 20 g) gave a mixture of four

compounds (120 mg), and 5a-cholestan-3S-ol (97) (260.6 mg, 47%).

Reduction of 0-(5a-cholestan-3S-yl) N,N,N',N'-tetramethylphosphorodiamidate

(152):- To a partial•solution of K (200 mg, 5 mgatom) and 18-crown-6

(250 mg, 0.95 mmol) in t-BuNH2 (3 ml) a solution of the phosphorodiamidate174

(152) (15 mg, 0.03 mmol) in t-BuNH2 (1.5 ml) was added, and the mixture

quenched with ethanol. Work up and filtration (silica MFC, 1 g) gave 5a-cho-

lestane ( 29) (7.7 mg, 72%) as the only product.

3a,6a-Bis-chlorocarbonyloxy-5a-cholestane (153):- To a solution of phosgene

(4.9 g, 49 mmol) in ethanol-free chloroform (30 ml) a solution of 5a-cholest-

'ane-3s,6a-diol (75) (1.51 g, 3.74 mmol) in chloroform (60 ml) and pyridine

(700 mg, 8.86 mmol) was added dropwise at 0°, and the mixture was allowed

to stand at 23° for 17 h. When the optical rotation of the solution sta-

bilised [ lal23 - 30.4° (c, 1.557) ] the excess phosgene was removed under

reduced pressure to give the bis-chloroformate (153) (1.98 g, 100%), 6

(CDC13) 0.72 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's), 1.03 (3H, s,

19-Me), 4.66 (1H, br, WI 18 Hz, 3a-H), 4.93 (1Ii, m, W1 8Hz, 6a-H). The 2 product was used in the next step without further purification. 140.

35,65-Bis-ethoxycarbonyloxy-5a-cholestane (154):- To solid 38,65-bis-

chlorocarbonyloxy-5a-cholestane (153) (656.8 mg, 1.24 mmol) absolute ethanol

(20 ml) was added, followed by pyridine (2 ml) and the mixture was allowed

to stand at 23° for 24 h. The solvents were removed under reduced pressure,

the residue diluted with water, extracted with ether, dried, filtered and separated by plc (benzene) to give 35-ethoxycarbonyloxy-cholest-5-ene (155) 216 (179 mg, 31%) as needles from dichloromethane-methanol, m.p. 83-4° (lit. m.p. 83-4°), S (CDC13), 0.67 (3H, s, 18-Me), 0.82, 0.90 (side chain Me's)

1.00 (3H, s, 19-Me), 1.23 (3H, t, J = 7Hz, CH3CH2O), 4.17 (2H, q, J = ?Hz,

CH3CH2O), 4.7 (1H, br, 3a-H), 5.4 (1H, m, W1 8Hz, 6-H); and the dicathylate z (154) (431.2 mg, 63%), which was recrystallised from dichloromethane-methanol as prisms, m.p. 144-5°, IalD23 - 21.1° (c, 0.384), (CIiC13) 1735, 1270- vmax 1190 cm-1, S (CDC13) 0.67 (3H, s, 18-Me), 0.80, 0.90 (side chain Me's),

1.00 (3H, s, 19-Me), 1.27 (6H, t, J = 7Hz, 2CH3CH2O), 4.10 (4H, q, J = 7Hz, A- 2 CH3CH2O), 4.6 (1H, br, 3a-H), and 4.8 (1H, m, W, 7Hz, 6a-H), m/e M

(absent), 458 (M-EtOH-0O2), 368 (M-2Et0H-2CO2) 353, 260, 255, 247, 228, 213,

147, 81. (Found: C, 72.11; H, 10.31. C33H5606 requires C, 72.21; H, 10.29%).

38,65-Bis-(2-propyloxycarbonyloxy)-5a-cho1estane (156):- To solid 35,65- bis-chlorocarbonyloxy-5a-cholestane (153) (656.8 mg, 1.24 mmol), absolute isopropanol (20 ml) was added followed by pyridine (2 ml) and the mixture was allowed to stand for 24 h at 23°. Work up and plc (benzene) gave 33-(2- propyloxycarbonyloxy)-cholest-5-ene (157) (146.3 mg, 25%), crystallised from acetone, m.p. 110-1°, IaI32)3 - 32.1°(c, 1.636), (CC14) 1735, max 1260 cm-1, S (CDC13), 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's),

1.00 (3H, s, 19-Me), 1.30 (6H, d, J = 6HZ, Me2CH0-), 4.4 (1H, br, W1 17Hz,

3a-H), 4.9 (1H, m, Me2CHOCO), 5.4 (1H, m, Pil 8Hz, 6-II), m/e 472 (M+), 368

(M-Pr10H-0O2), 353 (M-Pr10H-CO2-Me), 260, 247, 227, 147, 81. (Found: C, 78.0

H, 11.30. requires C, 78.75; H, 11.09%); and 35,65-bis-(2-prop- C31H5203 yloxycarbonyloxy)-5a-cholestane (156) (517 mg, 72%), recrystallised from

141.

chloroform-methanol, m.p. 122-4°, ial23 - 21.3° 3 (c, 0.954), vmax (CHC1 ) 1730, 1270-1190 cm-1, S (CDC13) 0.68 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's), 1.01 (3H, s, 19-Me), 1.30 (12H, d, J = 6Hz, Me2CHOCO), 4.27-

5.33 (4H, m, 3a-H, 6a-H, 2CHMe2), m/e M (absent), 472 (M-Pr1OH-0O2), 368

(M-2Pr10H-2CO2-), 353 (M-2Pr1OH-2CO2-Me), 318, 255, 247, 228, 213, 81.

(Found: C, 72.88; H, 10.61. C 06 requires 35H60 C, 72.86; H, 10.49%).

Attempt to Prepare 313,6S-Bis(2-methylpropyloxycarbongloxy)-5a-cholestane

(158):- To a solution of the dichloroformate (153) (197 mg, 0.37 mmol) in t-butanol (10 ml) resublimed potassium t-butoxide (188.8 mg, 1.68 mmol) was added and the mixture allowed to stand at 60° for 2 days. The solvent was removed under reduced pressure, the residue diluted with water, extracted with ether, dried and evaporated to give cholesterol (76) (130 mg,

90%).

30-(2-Propyloxycarbonyloxy)-5a-cholestane (159):- To a solution of phosgene

(6.4 g, 64 mmol) in dichloromethane (30 ml) a solution of 5a-cholestan-313- of (97) (3 g, 7.73 mmol) in dichloromethane (50 ml) and pyridine (2 ml) was added at 0° over a 0.25 h period, and the mixture was allowed to stand for 17.h at 20°. The excess phosgene and solvent were. removed under reduced pressure., and the residue was dissolved in iso-propanol (32 ml) and pyri- o dine (2 ml) and allowed to stand for 17 h at 20 . The solvent was removed under reduced pressure, and worked up in the usual way, to give 3/3-carbonate

(159) (3.2 g, 87%) as leaflets from acetone, m.p. 84.5-5°, IajD3 + 14.5°

(c, 1.660), max (nujol) 1740, 1265, 1255 cm-1, S (CDC13) 0.67 (3H, s,

18-Me), 0.82, 0.92, 1.33 (6H, d, J = 7Hz, Me2CH), 4.5 (1H, br, 3a-H),

4.8 (1H, m, Me2CH), m/e 474 (M+), 370 (M-Pr1OH-0O2), 355 (M-Pr1OH-CO2-Me),

320, 230, 215, 81. (Found: C, 78.67; H, 11.74. requires 78.43; C31H5403 C, H, 11.46%). 142.

Attempt to prepare 35,65-Di-(N-piperidinocarbonyloxy)-5a-cholestane (160):-

To solid dichloroformate (153) (657 mg, 1.24 mmol), piperidine (20 ml) was 0 added and the mixture allowed to stand at 23 for 24 h. Work up and plc (30% ethyl acetate-petroleum) gave 35-(N-piperidinocarbonyloxy)-cholest-5-ene

(161) (462 mg, 75%) as needles from chloroform-methanol, m.p. 178-81°, lal23

- 43.20 (c, 0.247), vmax (nujol) 1705 cm-1, S (CDC13) 0.67 (3H, s, 18-Me),

0.80, 0.90 (side chain Me's), 1.00 (3H, s, 19-Me), 3.36 (4H, m, CH2NCH2),

4.43 (1H, br, W1 16Hz, 3a-H), 5.36 (1H, m, W, 8Hz, G-H), m/e 497 (M+), 451

368 (M-C5H11N-0O2), 353, 260, 255, 247, 213, 147, 81. (Found: C, 79.52;

H, 11.18; N, 2.81. C35II55NO2 requires C, 79.61; H, 11.14; N, 2.81%); and a minor uncharacterised product (50 mg) as needles from chloroform-methanol, m.p. 205-8°, Ia1223 -21.33° (c, 1.294), (CHC13) 1670, 1260-1190, 1150, vmax 1080-1020 cm-1, S (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's),

1.02 (3H, s, 19-Me), 3.4 (5H, m, CH2NCH2), 4.5 (1H, br, 3a-H), 4.6 (1H, m,

W1 10 Hz, 6a-H), m/e 603, 577, 551, 386, 368, 353, 301, 275, 255, 247, 231, 2 213, 107, 81. (Found: C, 78.39; H, 11.17, N, 3.28%).

Attempt to prepare 3(3,65-Bis-(N-ethylaminocarbonyloxy)-5a-cholestane (162):-

To a solution of phosgene (8 g, 81 mmol) in dichloromethane (31 ml) a solution of 35,65-diol (75) (330 mg, 0.82 mmol) in dichloromethane (29 ml) and triethylamine (2 ml) was added and allowed to stand until the optical rotation of the solution stabilised at ca -250. The excess phosgene was removed under reduced pressure, the residue was dissolved in ethylamine 0 (25 ml) and allowed to stand at 17° for 2 h and 0 for 18 h. Work up and plc

(ether)gave a glass probably 35-N-ethylaminocarbonyloxycholest-5-ene (163)

(80 mg, 21%), S (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92 (side chain Me's),

1.00 (3H, s, 19-Me), 1.25 (3H, t, J = 7Hz, NCH2CH3), 3.23 (2H, m, HNCH2CH3),

4.56 (2H, br, 3a-H and NH), 5.4 (1H, m, W, 8 Hz, 6-H); and a glass probably 2 35,G5-bis-(N-ethylaminocarbonyloxy)-5a-cholestane ( 162) (156 mg, 35%)

6 (CDC13) 0.67 (3H, s, 18-Me), 0.80, 0.90 (side chain Me's), 0.98 (3H, s, 143.

19-Me) , 1.20 (6H, 2t, J=6Hz, NCH2CH3), 3.17 (4H, m, HNCII2CH3) , 4.60 (1H,

br, 3a-H), 4.8.(1H, m, 6a-H), 4.9 (2H, m, exch. D20, 2NH).

33-(N.N-Diethylaminocarbonyloxy)-5a-cholestane (164):- To a solution of

phosgene (3 g, 30 mmol) in dichloromethane (50 ml) triethylamine (10 ml,

72 mmol) was added at 0° and the mixture allowed to stand for 5 h at

20°. A solution of 5a-cholestan-3S-ol (97) (2 g, 5.15 mmol) in dichloro-

methane (15 ml) was added and the mixture was stirred 20° for 17 h.

The solvents were removed under reduced pressure, the residue diluted with

water extracted with ether, washed with water, dried, crystallised from

ethanol recrystallised from acetone to give the 3f3-carbamate (164) (2 g, 80%)

as needles, m.p. 122-2.5°, (a~ D3 + 17.2°, (c, 1.230), vmax (nujol) 1700, -1 1270, 1170 cm , S (CC14) 0.67 (3H, s, 18-Me), 0.82, 0.92, 1.23 (6H, t,

J = 7Hz, 2CH3CH2N) , 3.27 (4H, q, J = 7Hz, 2CH3CII2N) , 4.6 (1H, br, W, 18

- Hz, 3a-H), m/e 487 (M+), 486, 472 (M-Me), 428, 370 (M-Et2NH-0O2), 355

(M-Et2NH-CO2-Me), 316, 257, 215, 113, 95, 81. (Found: C, 79.07; H, 12.04;

N, 2.89. requires C, 78.79; H, 11.78; N, 2.87%). C32H57NO2

The Reductions of Carbonates and Carbamates are summarised in Table 13

TABLE 13

Substrate solvent metal crown Products (%) (mmol) (ml) (mgatom) (mmol) (29) (98) (97) (75)

(154) t-BuNH2 8 K 13 3.4 0 0 20 30a 0.15 THF 2

(154) EtNH2 3 Li 14 - 0 0 0 66b 0.11

(156) t-BuNH2 5 K 13 3.8 0 0 41 214 0.17 THF 1

/continued... 144.

Table/continued...

Substrate solvent metal I crown Products (%) (mmol) (ml) (mgatom) I (mmol) (29) (98) (97) (75)

(159) t-BuNH2 25 K 15 6 12 - 83 - 1.02 THF 4

(164) t-BuNH2 30 K 23 5.3 4 - 80 - 0.91 THF 6

a 5a-Cholestane (29) 6S-cholestanol (98 ) were detected by tic. v 5a-Cholestane (29 ) and 36-cholestanol (97 ) were detected by tic.

Two other compounds were also detected by tic.

3S,66-Bis-j(methylthio)thiocarbonyloxy1-5a-cholestane (165):- To a solution

of 5a-cholestane-3S,6(3-diol (97 ) (400 mg, 1 mmol) in THF (10 ml), sodium

hydride (80% oil dispersion; 150 mg, 5 mmol) was added and the mixture

refluxed for 24 h under nitrogen. Carbon disulphide (0.15 ml, 2.5 mmol)

was added at 23° followed after 1 h by iodomethane (0.2 ml, 3.2 mmol) the

mixture was stirred at 230, for another 1 h, and the excess sodium hydride

quenched by acetic acid (0.5 ml), followed by water (1 ml). The mixture

was extracted with ether, washed with sodium hydrogen carbonate, dried and

separated by plc (5% ether-petroleum) to give 3S-[(methylthio)thiocarbonyl-

oxyl-6S- r(S-methylthio)carbonyloxy1-5a-cholestane (166) (300 mg, 51%),

m.p. 162-3.5°, from dichloromethane-methanol, IaID3 - 54.1° (c, 0.562), -1 vmax (nujol) 1700, 1225, 1135, 1060 cm (cyclohexane) 1720, 1220, , vmax 1135, 1060-1010, 760 cm-1, Xmax (cyclohexane) 276 nm (e 11 000), 225

(8 000), 207 (9 000), (CHC13) max 230 (11 000), d (CDC13) 0.67 (3H, s, 18-Me), 0.80, 0.90 (side chain Me's), 1.03 (3H, s, 19-Me), 2.28 (3H, s,

McS.00.0), 2.52 (3H, s, MeS.CS.0), 5.05 (1H, m, ;91 311z, 6a-H), 5.50 z (11I, br, W, 16Hz, 3a-H) , m/e 569 (M + 1), 519, 508, 461 (M-MeSH-COS), 402, r 145,

368 (M-2MeSH-COS-0O2), 255, 161, 95, 81. (Found: C, 65.61; H, 8.92.

03S3 requires C, 65.47; H, 9.22%); and 35- [(methylthio)thiocarbonyl- C31H53 oxy'-5a-cholestan-613-01 (167) (120 mg), d (CDC13) 0.68 (3H, s, 18-Me), 0.82,

0.92 (side chain Me's), 1.00 (3H, s, 19-Me), 2.33 (3H, s, CH3S.CS.0), 3.56

(1H, m, 6a-H), 5.0 (1H, br, 3a-H) which was taken up in THF (5 ml) and 0 a solution of n-butyl-lithium (1.6 M; 1 ml) in hexane was added at -20 followed after 3 h by carbon disulphide (1 ml) and iodomethane (3 ml) after

2 h. The reaction was quenched with acetic acid (1 ml) worked up and

chromatographed (plc; 5% ether-petroleum) to give 35,68-bis- r(methylthio)

thiocarbonyloxyl-5a-cholestane (165) (45 mg, 8%), recrystallised from ether-

methanol, m.p. 136-8°, 1a1 23 - 53.9° (0, 0.193), vmax (CHC13) 1170, 1150,

1060-1030, 965 cm 1, A (cyclohexane) 276 nm (c 20 000), 227 (15 000), max 210 (15 000), d (CDC13) 0.67 (3H, s, 18-Me), 0.80, 0.90 (side chain Me's),

1.08 (3H, s, 19-Me), 2.53 and 2.55 each (3H, s, MeS.CS.0), 5.4 (1H, br,

W, 20 Hz, 3a-H), 5.73 (1H, m, W, 7Hz, 6a-H), m/e M+ (absent), 476 (M-MeSH- 2 2 COS), 368 (M-2MeSH-2COS), 353, 255, 95, 81. (Found: C, 63.85; H, 3.68.

024 requires C, 63.68; H, 8.96%). To a solution of 35,65-diol (97 ) C31H52 (400 mg, 1.00 mmol) in THF (10 ml) n-butyl-lithium (1.6 M; 3.12 ml) was

added at -20° with stirring under nitrogen. The mixture was stirred for

2.5 h, carbon disulphide (0.5 ml, 4 mmol) was added and stirred for 1 h

followed by iodomethane (0.5 ml, 8 mmol). The mixture was stirred for 1 h,

acetic acid (1 ml) was added followed by water (1 ml) and the mixture

extracted with ether. The ether layer was washed with water, dried chroma-

tographed (neutral alumina grade I, 8 g; eluant petroleum), and the residue

crystallised from chloroform-methanol to give the product as needles

(310 mg, 53%).

Reduction of 35,65-Bis r(methylthio)thiocarbonyloxyl-5a-cholestane (165):-

(i) A solution of the dixanthate (165) (35 mg, 0.06 mmol) in THF (0.5 ml)

was added to a partial solution of Li (80 mg, 11 mgatom) in BtNH2 (2 ml) 146.

the reaction quenched with methanol and the crude product acetylated with acetic anhydride-pyridine. Plc (benzene) gave 35,68-diacetoxy-5a-cholestane

( 86) (111 mg, 38). Three less-polar compounds were also present (tic).

(ii) to a partial solution of K (1 g, 26 mgatom) and 18-crown-6 (2.5 g,

9.46 mmol) in t-BuNH2 (10 ml) a solution of the dixanthate (165) (190 mg,

0.32 mmol) in THF (3 ml) was added. Work up and plc (20% ethyl acetate- benzene) gave 5a-cholestane (29) (47 mg, 38%), 5a-cholestan-68-ol (98 )

(2.3 mg, 2%), 5a-cholestan-3S-ol (97) (24 mg, 19%), and 38,68-diol (75 )

(11 mg, 8%).

38,65-Bis-(N-ethylaminothiocarbonyloxy)-5a-cholestane (168):- To a solution of 5a-cholestane-38,68-diol (75) (404 mg, 1.00 mmol) in THF (10 ml) a solution of n-butyl-lithium (1.54 M; 3 ml) was added at 23° under nitrogen and with stirring. After 1 h carbon disulphide (2 ml) was added followed after 1 h by iodomethane (2 ml), the reaction was quenched with acetic acid

(1 ml) and worked up. The crude product was treated with ethylamine (20 ml), the amine removed after 1 h, and the product separated by plc (40% ether- petroleum) to give the bis-thiocarbamate (168) (450 mg, 78%), m.p. 169-72°

plates from methanol, -31.3° (c, 0.495), (CHC13) 3430, 3400, Ia123 'max 3240, 1330, 1295, 1120, 1050, 1000, 960, 910 cm-1, A (EtOH) 242.5 nm max (e 26 000), S (CDC13) 0.67 (3H, s, 18-Me), 0.82, 0.92, 3.5 (4H, m, 2CH3CH2N),

5.3 (1H, br, W1 18Hz, 3a-H), 5.6 (1H, m, W1 8Hz, 6a-I1), 6.2 and 7.2 each Z L (1H, br, exch. D20, NH), m/e 578 (M+), 473 (M-EtNI12-COS), 402, 38G, 368

(M-2EtNH2-2COS),353, 255, 247, 213, 81, 60. (Found: C, 68.72; H, 10.29;

N, 4.82. N202S2 requires C, 68.46; H, 10.11; N, 4.84%). C33H58

An Attempt to Prepare 38,65-bis(N-t-butylaminothiocarbonyloxy)-5a-cholestane

(169):- Dixanthate (165) (300 mg, 0.51 mmol) was dissolved in t-BuNH2

(15 ml) and the solution allowed to stand at 23° for 7 days, and refluxed

for 4 days. Work up and plc (8% ether-petroleum) gave an oil probably 147.

3$-(N-t-butylaminothiocarbonyloxy)-65- [(methylthio)thiocarbonyloxy] -5a- cholestane (170), 6 (CDC13) 0.67 (3H, s, 18-Me), 0.80, 0.90 (side chain

Me's), 1.08 (3H, s, 19-Me), 1.32 (9H, s, Me3C), 2.55 (3H, s, MeS), 5.3

(1H, br, W 16Hz, 3a-H), 5.8 (1H, m, N1 7Hz, 6a-H), 6.7 (1H, br, NH), 2 2 which was redissolved in t-BuNH2 and heated in a sealed vessel to give a

mixture of compounds.

3s,68-Bis-(N-pyrrolidinothiocarbonyloxy)-5a-cholestane (171):- Dixanthate

(165) (300 mg, 0.51 mmol) was allowed to stand in pyrrolidine (5 ml) at

23° for 18 h, the solvent removed and the crude product chromatographed on

silica (eluant 20% ether-petroleum) and crystallised from acetone to give

the bis thiocarbamate (171) as white rods (230 mg, 71%), m.p. 236-8°,.

IaID3 - 23.32° (c, 0.952), (nujol) 1260, 1230 cm (EtOH) vmax 1, ~'max 245 nm (e 27 000), 6 (CDC13) 0.67 (3H, s, 18-Me) 0.80, 0.90 (side chain

Me's), 1.05 (3H, s, 19-Me), 3.3-4.0 (8H, m, 2C112NCH2), 5.27 (1H, br,

+1 22 Hz, 3a-H), 5.6 (1H, m, W. 7Hz, 6a-H), m/e 630 (M at 12eV), 499

(M-C4H9N-COS), 466, 368 (M-2C4H9N-2COS), 353 (M-2C4H9N-2COS-Me), 255, 247,

213, 132, 81. (Found: C,. 70.52; H, 9.97; N, 4.44. C37H62N202S2 requires

C, 70.42; H, 9.91; N, 4.44%).

3S-N-Piperidinothiocarbonyloxy-5a-cholestane (172):- To a suspension of

sodium hydride (80% oil dispersion; 150 mg) and imidazole (10 mg) in THF

(3 ml) a solution of 5a-cholestan-313-ol (97 ) (1.17 g, 15 mmol) was added

and the mixture refluxed for 3 h under nitrogen. Carbon disulphide (1 ml)

was added at 23° followed by iodomethane (1 ml) and piperidine (4 ml)

and the mixture stirred for 16 h at 23°. Further piperidine (4 ml) was

added and the mixture refluxed for 2 h, the solvents removed under reduced

pressure, the residue crystallised from ether-methanol and recrystallised

from light petroleum to give the thiocarbamate (172) (1.08 g, 70%), m.p.

190.5-1.5°, 1al-- + 10.00 (c, 0.52), v (CHC1 ) 1490, 1440, 1290 cm-1, max 3 148.

(nujol) 1500, 1460, 1430, 1290, 1260, 1250, 1180 cm-1, S (CDC13) vmax 0.63 (3H, s, 18-Me), 0.80, 0.83 (side chain Me's), 0.91 (3H, s, 19-Me),

3.43-4.26 (4H, m, CII—2 NCH2), 5.28 (1H, br, W1 24Hz, 3a-H). (Found: C,

76.86; II, 11.12; N, 2.71. C33H57NOS requires C, 76.83; H, 11.14; N, 2.71%).

n-1(Methylthio)thiocarbonyloxyl-5a-cholestane (173):- To a suspension of sodium hydride (80% oil dispersion; 1.00 g, 33 mmol) and imidazole

(150 mg) in THF (15 ml) a solution of 5a-cholestan-33-ol (97) (10 g,

25.77 mmol) in THF (80 ml) was added and the mixture refluxed for 3 h under nitrogen. Carbon disulphide (3 ml, 50 mmol) was added and refluxing continued for a further 0.25 h, iodomethane (4 ml) was added at 23° and the mixture stirred for 1 h. The reaction was quenched with acetic acid

and worked up in the usual way. The crude product was filtered in light

petroleum-benzene (1 : 1) down a silica column and recrystallised twice

from ether-methanol to give the xanthate (173) (11.2 g, 91%), m.p. 87-8°, 213 (lit. m.p. 87.5-88°).

3(3-(N,N-Diethylaminothiocarbonyloxy)-5a-cholestane (174):- To a solution

of xanthate (173) (620 mg, 1.30 mmol) in light petroleum (10 ml) diethyl-

amine (10 ml) was added and the solution allowed to stand at 23° for 66 h.

The solvents were removed under reduced pressure and the residue washed

down an alumina column (20 g; eluant 3% ether-light petroleum) and the

product recrystallised from acetone to give the thiocarbamate (174) (600 mg,

92%), m.p. 137-9°, la123 + 7.9° (c, 1.191), vmax (nujol) 1510, 1315,

1285, 1250, 1240, 1180 cm-1, X (EtOH) 248.5 nm (E 12 500), S (CC14) max 0.67 (3H, s, 18-Me) , 0.83, 0.92, 1.20 (6H, 2t, 2CII3CH2N) , 3.16-4.06 (4H, m,

2CH3CH2N) , 5.27 (1H, br, Wi 18Hz, 3a-H) , m/e 503 (M+), 370 (M-Et2NH-COS) ,

355 (M-Et2NH, COS-Me), 316, 215, 135, 100, 95, 81. (Found: C, 76.43;

H, 11.59; N, 2.76. N0S requires C, 76.29; H, 11.40; N, 2.78%). C32H57 149.

N-Diethyl-N-r2-(N,N-dimethylamino)ethyllaminothiocarbonyloxy-5a-cholestane

(175);- To a solution of the xanthate (173) (520 mg, 1.09 mmol) in petroleum (9 ml), N,N,N'-trimethylethylenediamine (3 ml) was added and the mixture allowed to stand at 23° for 3 days. The solvents were removed under reduced pressure and the residue chromatographed (alumina H, 14 g) to give the thiocarbamate (175) (485 mg, 84%), solidifies on standing, m.p.

91-2°, IaI23 + 8.1° (c, 1.186), (CHC13) 2780, 1495, 1400, 1310, 1290, max 1150, 1130, 1095, 1010, 955, 915 cm-1, a (EtOH) 247.5 nm (e 15 000), max 6 (CC14) 0.63 (3H, s, 18-Me), 0.83, 0.92, 2.23 (6H, s, Me2N-), 2.50 (2H, br, t, J = 8Hz, CH2NMe2), 3.05 and 3.27 (3H, 2s, McNCH2), 3.50 and 3.80

(2H, 2t, J = 7Hz, MeNCH,), 5.17 (1H, br, W; 17Hz, 3a-I1) , m/e 532 (M ) , 370 LJ L (M-Me2NCH2CH2NHMe-COS), 355 (M-Me2NCH2CH2NHMe-COS-Me), 316, 85, 71, 58,

57, 55, 43. (Found: C, 74.54; H, 11.54; N, 5.21. C33H60N20S requires

C, 74.39; H, 11.35; N, 5.26%).

N,N-Diethylaminothiocarbonyloxyoctadecane (176):- To a suspension of sodium

hydride (50% oil dispersion; 2 g, 42 mmol) and imidazole (50 mg) in THF

(20 ml) a solution of octadecan-1-ol (5 g, 18.52 mmol) in THF (30 ml) was

added and the mixture was refluxed for 2 h under nitrogen. Carbon disul-

phide (6 ml) was added with stirring at 23°, after 0.5 h iodomethane (6 ml)

was added, and the excess sodium hydride quenched with acetic acid, diethyl-

amine (50 ml) was added and the mixture stirred for 18 h at 23°. The sol-

vents were removed under reduced pressure and the residue worked up and

chromatographed (silica 60, 60 g; eluant 20% benzene-petroleum) to give

the thiocarbamate (176) (5 g, 70%) from acetone-ethanol, as fine needles

m.p. 37.5-38°, 4) 1495, 1320, 1280, 1240, 1180, 1150, 1095, 1075, uriax (CC1 1040, 990 cm-1 (EtOH) 247.5 nm (c 14 500), 6 (CC14) 1.00 (6H, br, t, , Xmax J = 7Hz, 2 CH3CH2N), 3.17-4.00 (4H, m, 2 CH3CII2N), 4.3 (2H, t, J = 7Hz,

CH2CH2O), m/e 385 (DI+), 384, 368, 352, 134. (Found: C, 71.78; H, 12.53;

N, 3.64. C23H47N0S requires C, 71.62; H, 12.29; N, 3.63%). 150.

The Reductions of Thiocarbamates are summarised in Table 14,

TABLE 14

Substrate Solvent Metal crown Products (%) (mmol) (ml) (mgatom) (mmol) (29) (98) (97) (75)

(168) EtNH2 2 Li 14 - 0 0 0 68a 0.06

(168) t-BuNH2 8 K 8 1.4 0 0 18 45b 0.21 THF 2

(171) t-BuNH2 10 K 11 1.6 62 15 12 5 0.20 THF 1

(172) DME 10 K 19 4 74 - 14 - 0.71 THF 5

(174) t-BuNH2 8 K 5 1.6 86 - 8 - 0.64 THF 6

(174) t-BuNH2 40 K 20 5.7 58 - 40 - C 0.73 THF 10

(175) t-BuNH2 20 K 20 7.6 83 - 12 - 0.58 THF 4

n (176) t-BuNH215 K 23 4.2 C18H370H 12 1.42 nC18H38S7 THF 5

a Two less-polar products were present (tic).

Two uv-active products were also present (tic).

C Reduction carried out at -300.

1 ,2:5,6-Di-O-isopropylidene-3-0-(N,N-diethylaminothiocarbony1)-a-D-glucofuranose (177):- To a solution of 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (129) (1.7 g, 6.54 mmol) in dimethyl sulphoxide (2 ml) an aqueous 151. solution of sodium hydroxide (3.75 M; 2 ml) was added followed by carbon disulphide (2 ml), the mixture was stirred for 10 min, iodomethane (2 ml) was added and the mixture stirred for 1 h, The mixture was poured into ice- water (50 ml), the aqueous phase decanted and the process repeated twice.

The oil was dissolved in methanol (5 ml) and added to ice-water (50 ml), the water decanted, the oil dissolved in diethylamine and allowed to stand at 20° for 20 h. Work up and chromatography (silica H, 12 g; eluant 20%, ether-petroleum) gave the thiocarbamate (177) (1.37 g, 56%) crystallised from acetone and recrystallised from ether-petroleum, m.p. 51-3°, IaID3 17 - 55.2° (c, 1.045), (1it2 m.p. 51-3°, IaI 23 -38°), vmax (nujol) 1515,

1320, 1300, 1290, 1245, 1215, 1165, 1145, 1060, 1010, 360, 840 cm-1,

(EtOH) 249.5 nm (6 16 000), S (CDC13) 1.18 and 1.25 each (3H, s, Xmax Me2C), 1.30 (6H, s, Me2C), 1.40 (6H, 2t, J = 7Hz, 2CH3CH2N-), 3.20-4.37

(8H, m, 2CH3CH2N, 4-, 5-, 6-H), 4.73 (1H, d, J = 4IIz, 2-H), 5.70 (1H, m,

3-H), 5.83 (1H, d, J = 4Hz, 1=H), m/e 375 (M ), 360 (M-Me), 342. (Found:

C, 54.40; H, 7.91; N, 3.53. Calc. for C17H29N06S: C, 54.37; H, 7.79;

N, 3.73%).

Reduction of 3-0-(N,N-Diethylaminothiocarbonyl)-1,2:5,6-di-0-isopropylidene-a-

D-glucofuranose (177):- To a partial solution of K (1 g, 26 mgatom) and

18-crown-6 (1.3 g, 4.92 mmol) in t-BuNH2 (20 ml) the thiocarbamate (177)

(918 mg, 2.45 mmol) in THF (4 ml) was added. Work up and chromatography

(silica H, 10 g) gave 3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose

( 10) (85 mg, 14%) as a colourless oil, S (CDC13) 1.33, 1.36, 1.43 and

1.52 (12H, 4s, 2Me2C), 2.23 (2H, dd, J1 = 14Hz, J2 = 4Hz, 3-H), 3.8-4.2 (4H, m, 4-, 5-, 6-Ii), 4.74 (1H, br t, J2 = 4Hz, 2-I1), 5.84 (1H, d, J2 = 4Hz,

1-H) , m/e Ai (absent) , 229 (M-Me) , identical with an authentic sample;

1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (129) (352.1 mg, 55%), and 152. a more-polar minor compound which was not characterised.

3-Deoxy-1,2:5,6-di-0-isopropylidene-a-D-glucofuranose (10):- A solution of 218 the xanthate ( 30) (1.75 g, 5 mmol) in toluene (40 ml) was added over 1 h to tri-n-butylstannane219(3.5 g, 12 mmol) in toluene (30 ml) under reflux under nitrogen. Refluxing was continued overnight and the solvent was removed under reduced pressure. The residue was chromatographed (silica

60, 30 g) to give the deoxy-compound (10 ) (925 mg, 76%) as an oil, IaID3

-7.3° (c, 9.327) (lit.40 IaID° - 7.5°).

3,4-Bis-0-(N,N-diethylaminothiocarbonyl)-1,2:5,6-di-0-isopropvlidene-D-mannitol

(180):- To a suspension of sodium hydride (80% oil dispersion; 3 g, 100 mmol) and imidazole (50 mg) in THF (80 ml) a solution of l,2:5,6-di-O-isopropylidene-D-mannitol (135) (6.6 g, 25 mmol) in THF (30 ml) was added and the mixture refluxed for 5.5 h, carbon disulphide (6 g, 79 mmol) was added at

20° and the mixture stirred for 0.5 h, followed by iodomethane (10 g,

70 mmol) and the mixture was worked up after 0.5 h stirring. The crude product was dissolved in diethylamine (60 ml) and the solution was allowed to stand at 20° for 2 days. `York up and chromatography (silica 60, 70 g;

eluant 30% ether-petroleum) gave the bis-thiocarbamate (180) (6.27 g, 51%)

as needles from acetone, m.p. 104-50, IaI12213 + 69.3° (c, 1.298), vmax

(CHC13) 1500, 1310, 1280, 1260-1190, 1155, 1140, 1060, 980, 860 cm-1,

(EtOH) 248.5 nm (c 29 500), S (CDC13) 1.13-1.53 (18H, m, 2rde2C and Amax 2NCH2Cy3), 3.73-4.17 (8H, m, 2NCH2CH3, 1-,6-H), 4.3 (2H, m, 2-, 5-H),

6.37-6.43 (2H, m, 3-, 4-H), m/e 492 (rd+), 477, 359, 318, 258, 227, 217,

C, 53.84; H, 8.32; N, 5.72. S2 requires 169, 100. (Found: C22H40N2 6 C, 53.63; H, 8.19; N, 5.69%).

Reduction of 3,4-Bis-0-4 ,N-diethylaminothiocarbonyl)-1,2:5,6-di-0-isoPropyl-

idene-D-mannitol (180):- To a partial solution of K (1.1 g, 28 mgatom) 153. and 18-crown-6 (2 g, 7.57 mmol) in t-BuNH2 (20 ml) a solution of the bis- thiocarbamate (180) (690.9 mg, 1.40 mmol) in THF (5 ml) was added. Extra

18-crown-6 (0.5 g; total 2.5 g, 9.47 mmol) was added. The reaction was quenched with methanol and the product acetylated with acetic anhydride- pyridine to give after work up a multitude of products.

Attempts to Prepare 38-(di-isopropylamino)thiocarbonyloxy-5a-cholestane

(178):- (i) A solution of the xanthate (173) (520 mg, 1.09 mmol) in di- isopropylamine (10 ml) was allowed to stand at 23° for 66 h and refluxed for a further 4 days. Tlc indicated only starting material. (ii) A solution of the xanthate (173) (730 mg, 1.53 mmol) in di-iso-propylamine

(4 ml) was heated in a sealed tube at 120° for 2 days to give 3 major and 2 minor products; two of the major products were uv-active and more- polar than the starting material, and the other major product was non- uv-active and had an RF value equal to that of cholest-2-ene (181). The products were not further investigated.

22 t. N,N',N'-Trimethylhydrazine:- A solution of 1,1-dimethyl-2-formyl hydrazine

(21 g, 250 mmol) in ether (200 ml) and THF (50 ml) was added dropwise to a suspension of lithium aluminium hydride (10 g, 263 mmol) in ether (200 ml) under nitrogen and with stirring for 2 h. Ethyl acetate (50 ml) was added followed by wet ether, water (10 ml) and hydrochloric acid (6M; 250 ml).

The organic layer was discarded and the aqueous layer concentrated to 125 ml

The concentrate was added dropwise to a hot mixture of sodium hydroxide

(280 g, 7 mol) in water (75 ml), the liberated trimethylhydrazine being collected as fast as it was formed. The distillate was saturated with solid sodium hydroxide keeping the temperature below 30°, the organic phase was separated, dried over fresh sodium hydroxide and redistilled twice from sodium hydroxide and molecular sieves (4A size), to give the hydrazine as a colourless liquid (5 g,27%), b.p. 62-4°, n23 1.6882 (lit. 221 154.

b.p. 62-40, n21 1.6847), (film) 3400-3200, 1490 cm-1, S (CC14) 2.33 vmax (6H, s, Me2N), 2.43 (3H, s, MeN).

Attempts to Prepare 38-N,N,N'-trimethylhydrazinothiocarbonyloxy-5a-cholestane (179):- (i) A solution of the xanthate (173) (600 mg, 1.25 mmol) in petroleum (5 ml) was treated with trimethylhydrazine (205.8 mg, 2.78 mmol) and the mixture allowed to stand at 23o for 6 weeks, and refluxed for 3 days.

Only starting material was present after this period. (ii) To a solution of 5a-cholestan-38-ol (97) (933 mg, 2.40 mmol) in THF (25 ml) a solution of n-butyl-lithium (1.54M;1.6 ml) in hexane was added at 200 under nitrogen and the solution stirred for 40 min. Carbon disulphide ( 0.5 ml, 8.3 mmol) was added and the mixture stirred for 0.5 h. A solution of chloro- acetic acid (205.5 mg, 2.17 mmol) in THF (8 ml) was added followed by pyridine (2 ml) and trimethylhydrazine (500 mg, 6.76 mmol), the mixture was stirred for 17 h and worked up. Tlc (both silica and alumina) indicated no less-polar product than 5a-cholestan-38-ol (97). Nmr of the crude product indicated no hydrazine peaks. (iii) A solution of xanthate (173)

(20 mg) in trimethylhydrazine (3 ml) was heated at 950 under argon for 17 h

(no trace of product), and 24 h at 1350 to give a minor more-polar uv-active material which was not further investigated.

Reduction of l,2-Epoxydecane:- To a partial solution of K (1.7 g, 43 mgatom) and 18-crown-6 (1.45 g, 5.49 mmol) in t-BuNH2 (10 ml) a solution of

1,2-epoxydecane (691.5 mg, 4.42 mmol) in ether (3 ml) was added under nitrogen. Extra 18-crown-6 (300 mg; total 1.75 g, 6.63 mmol) had to be added. Once the blue colour reappeared after the epoxide was added the reaction was quenched with 507, aqueous acetic acid, the solvents removed under reduced pressure, the residue was neutralised with hydrochloric acid

(1M), the products extracted with ether, washed with brine, dried and chromatographed (silica 60, 10 g; eluant petroleum). The major fraction 155. was treated with freshly prepared 3,5-dinitrobenzoyl chloride (1 g, 4.5 mmol) and pyridine (1 ml) in benzene (3 ml), the mixture refluxed for 2.5 h and chromatographed (silica 60, 10 g; eluant petroleum to 5% ether- petroleum gradient) to give a mixture of compounds (48 mg),v max (CHC13)

3400, 3050, 1725, 1630, 1600, 1550, 1275, 1120, 1080, 1020 cm 1, and decan-

2-y1 3,5-dinitrobenzoate (593 mg, 38%) m.p. 41-2° (li t. m.p. 44°),

v (film) 3080, 1720, 1630, 1600, 1550, 1275, 1175, 1120, 1080, 925, 825, max -1 780, 730 cm , 6 (CDC13) 1.46 (3H, d, J = 7Hz, CH3CH), 5-5.5 (1H, m,

CH3CH), 9.13 (3H, s, aromatic-H), m/e 352 (M+), 195 (C6H3N204C0), 140

(C101110) .

(ii) To a partial solution of K (1.49 g, 38 mgatom) and 18-crown-6 (1.22 g,

4.64 mmol) in t-BuNH2 (10 ml) a solution of 1,2-epoxydecane (934.9 mg)

6.31 mmol) in t-BuNH2 (5 ml) was added under argon. Extra 18-crown-6

was twice added (1 g and 500 mg; total 2.72 g, 10.31 mmol). The solvents

were removed under reduced pressure and the reaction quenched with aqueous

sulphuric acid (5%;.until neutral). Work up and chromatography (alumina

grade III, 16 g) and (silica H, 10 g) gave three fractions A, B, and C.

Fraction A was a hydrocarbon mixture (22 mg) m/e 140 (C10H20). Fraction

B was a mixture of alcohols (277 mg), v (film) 3400, 1100 cm 1, 6 max (CDC13) 3.2-3.6 (br), and fraction C a mixture of two alcohols (553.3 mg),

v (film) 3300, 1120 cm 1, 6 (CDC13) 3.2-4.0 (br). Fraction B in max aqueous acetic acid (50%; 1 ml) was treated with sodium dichromate (387.8 mg,

1.30 mmol) and sulphuric acid (16%; 3 ml) to give a mixture of compounds,

6 (CDC13) 3-3.3 (m); the mixture was treated with 2,4-dinitrophenyl-

hydrazine (250 mg) in methanol (4 ml) and concentrated sulphuric acid (1 ml)

• to give a mixture of at least three compounds. Plc (10% ether-petroleum)

gave a minor unidentified product as a yellow viscous oil (99 mg, 3%),

v (film) 3240, 3110, 1620, 1595, 1520, 1510, 1330, 1140, 920, 830, max -1 745 cm , 6 (CDC13) 1.1-1.4 (m), 1.4 (3H, s), 2.1-2.4 (m), 3.3-3.7 (1H,

m), 4.3 and 4.33 each (1H, s), 7.9 (1H, d, J1 = 10Hz, 6-H), 8.2 (1H, 156.

dd, Jl = 10Hz , J2 = 3Hz, 5-Ii), and 9.1 (1H, d, J2 = 3Hz, 3-H), m/e 492

(M+), 297 (M-C6H3N404) ' 157 (C 0), 141 139 10H21 (C10H21), (C10H19). Fraction C, was treated with sodium dichromate (940 mg, 3.15 mmol) and sulphuric acid (20%; 3 ml)in acetic acid (2 ml) to give after chromato-

H, 10 graphy (silica g) methyl n-octyl ketone (346.4 mg, 35%), vmax (film) -1 1715, 1160, 920, 740 cm , d (CDC13) 1.0-1.4 (15H, m), 2.11 (3H, s, CH3C0),

2..42 (2H, t, J = 7Hz, CH2CH2C0) which was treated with 2,4-dinitrophenylhydrazine to give the hydrazone, m.p. 73.5-40, needles from ethyl acetate,

(nujol) 3330, 3090, 1640, 1620, 1595, 1510, 1260, 1140, 1100, 835 vmax and 740 cm 1, S (CDC13) 2.05 (3H, s, CH3C:N), 2.43 (2H, t, J = 7Hz,

CH2CH2), 7 .76 (1H, d, J1 = 10Hz, 6-H), 8.16 (111, dd, J1 = 10Hz, J2 = 3Hz,

5-H), 9.0 (1H, d, J2 = 3Hz, 3-H), m/e 336 (M+), 238, 178. (Found: C, 57.23;

H, 7.21; N, 16.59. C 04 57.13; H, 7.19; N, 16H24N4 requires C, 16.66%); and another more-polar product, v (film) 3380, 1715 cm-1, m/e max 312, 171 (C8H17CHOHCH2CH2), 157 (C8H17CHOHCH2), and 141 (CyH17CO). 157.

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By ROSIN B. BOAR,* LAURETTE JOUKHADAR, JAMES F. McGHIE, and SATISH C. MISRA (Department of Chemistry, Chelsea College, London SW3 6LX) and ANTHONY G. M. BARRETT, DEREK H. R. BARTON,* and PANAYIOTIS A. PROKOPIOU (Department of Chemistry, Imperial College, London SW7 2AY)

Reprinted from

Journal of The Chemical Society Chemical Communications 1978

The Chemical Society, Burlington House, LondonWIV OBN

68 J.C.S. CHEM. COMM., 1978

Metal—Amine Reduction of Sterically Hindered Esters to Alkanes, A New Method for the Deoxygenation of Hindered Alcohols

By ROBIN B. BOAR,* LAURETTE JOUKHADAR, JAMES F. MCGHIE, and SATISH C. MISRA (Department of Chemistry, Chelsea College, London SW3 6I.X)

and ANTHONY G. M. BARRETT, DEREK H. R. BARTON,* and PANAYIOTIS A. PROKOPIOU (Department of Chemistry, Imperial College, London SW7 2AY)

Summary Acetates of sterically hindered secondary a b alcohols and of tertiary alcohols are reduced by lithium in 0 0 ethylamine to afford predominantly the corresponding O C R 0 C-R alkanes, rather than the parent alcohols. )

THE selective replacement of a hydroxy group by hydrogen (al (I) (deoxygenation) is a synthetic transformation of consider- 0- I bl able importance.' We report that sterically hindered ~• + 0=C—R alcohols are conveniently and efficiently converted into the corresponding alkanes by metal-amine reduction of the ~0 derived esters with carboxylic acids. The only side- --+R-CO reaction is the regeneration of the starting alcohol. Typical examples are summarised in the Table. The readily available acetate esters are admirable substrates. So far, we have mainly used lithium in ethylamine as the reducing 1 system, but other metals (Na, K) and other amines are also effective. The rapid rearrangement of the 3a,5-cyclo-5a-cholestan- 6-yl radical into the more stable cholest-5-en-3-yl radical is well established." Lithium-ethylamine reduction of 3a,5- cyclo-5a-cholestan-6s-y1 acetate gave a hydrocarbon fraction (45%) which comprised cholest-5-ene (85%) and SCHEME TABLE. Metal-amine reduction of esters.a Starting material Product(s) (%)b (1) 3p,6p-Diacetoxy-5x-cholestane 5a-Cholestan-3s-ol (46):5x-Cholestane-3f3,6P-diol (35) (2) SE-Cholestan-3s-ol (60); 5a-Cholestane-36,61-diol (29) (3) 313,6 ji-Dibenzoyloxy-5x-cholestane 5z-Cholestane-36,613-diol (80) (4) 3 s, 6 s-D i f ormyl oxy-5x-ch ol es ta n e 5x-Cholestane-36,68-diol (86) (5) 3 f3,613-Di-isobutyryloxy-5x-cholestanes Sx-Cholestan-3s-ol (16); 5a-Cholestane-3s,6s-diol (55) (6) 3s, 6s-Di f ormyloxy-5x-cholestane 5x-Cholestan-3s-ol (71); 5x-Cholestane-38,66-diol (19) (7) 3 g,613-Dipropanoyloxy-5x-choles tane 5x-Cholestan-3s-o1 (15); SŒ-Cholestane-3s,6s-diol (61) (8) 3s, 6S-Dipival oyloxy-5x-choles tane 5x-Cholestan-3s-ol (79) ; 5x-Cholestane-3j3,613-diol (9) (9) 3 f3,52-Diacetoxycholestane 5a-Cholestan-3s-ol (66); Cholestane-3s,5x-diol (8) (10) 3s,5z,6 s-Triacetoxycholestane Cholesterol (81): cholestane-3/3,52,6t3-triol (8) (11) 3/3,12a-Diacetoxy-13E-oleananec 13E-Oleanan-313-ol (85) (12) 3/1 25-Diacetoxy-5E-lanost-8-ene 5a-Lanost-8-en-3p-o1 (75); 5E-Lanost-8-ene-36,25-diol (10) (13) Caryolan-1-ol acetate, - Caryolane (90) a Reductions were carried out with Li—EtNH„ except for entries (2), (4), (6), and (8) where K—ButNH=-18-crown-6 was used. Typi- cally, the ester (100 mg) in dry amine was added to a partial solution of lithium (60 mg) in dry amine (10 ml) at 0 °C. The mixture was allowed to reflux for 1 h, then Bu,OH (5 ml) was added. Normal work-up procedures gave the products indicated. b Yields refer to pure, isolated material. c Satisfactory analytical and spectroscopic data were obtained for all new compounds reported herein. e R. B. Boar, L. Joukhadar, M. de Luque, J. F. McGhie, D. H. R. Barton, D. Arigoni, H. G. Brunner, and R. Giger, J.C.S. Perkin I, 1977, 2104. a D. H. R. Barton and A. Nickon, J. Chem. Soc., 1954, 4665, and references cited therein. J.C.S. CHEM. COMM., 1978 69

3x,5-cyclo-5x-cholestane (15%). This result, together with tion of cholesterol by the reduction of 31$,5z,6s-triacetoxy- the particular efficiency with which esters of tertiary cholestane is probably the result of displacement of the alcohols are reduced, leads us to favour a mechanism acetate group from C-6 by a carbanion at C-5. involving radical fragmentation of the initially formed The fact that reduction only occurs with esters of steric- radical anion (I) (Scheme). Mode (a), and thence deoxy- ally hindered alcohols confers upon this method a selectivity genation, evidently becomes the favoured process when not often possible with alternative deoxygenation processes.' cleavage of this C—O bond is attended by a sufficient Attention is drawn (see Table) to the use of 18-crown-6 release of unfavourable steric interactions. Otherwise, as a solubilising agent for reductions with potassium in mode (b) is preferred, and the alcohol is regenerated. t-butylamine. Under the reaction conditions, reduction of radicals to the corresponding carbanions must be rapid. Thus, the forma- (Received, 12th October 1977; Com. 1065.)

2 R. E. Ireland, D. C. Muchmore. and U. Hengartner, J. Amer. Chem. Soc., 1972, 94, 5098; D. H. R. Barton and S. W. McCombie, J.C.S. Perkin I, 1975, I574; D. H. R. Barton and R. Subramanian, J.C.S. Chem. Comm., 1976, 867; J.C.S. Perkin I, 1977, 1718; H. Deshaves, J. P. Pete, and C. Portella, Tetrahedron Letters, 1976, 2019; J. A. Marshall and M. E. Lewellyn, J. Org. Chem., 1977, 42, 1311; H. Redlich, H.-J. Neumann, and H. Paulsen, Chem. Ber., 1977, 110, 2911; J. P. Pete, C. Portella, C. Monneret, J. C. Florent, and Q. Khuong-Huu, Synthesis, in the press. ' A. L. J. Beckwith and G. Phillipou, J.G.S. Chem. Comm., 1971, 658, and references therein. Dissolving Metal Reduction of Carboxylic Esters. A Re-evaluation of the Mechanism

By ANTHONY G. M. BARRETT,* and PANAYIOTIS A. PROKOPIOU (Department of Chemistry, Imperial College, London SW7 2AY) DEREK H. R. BARYON (Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur-Yvette, France) and ROBIN B. BOAR and JAMES F. MCGHIE (Department of Chemistry, Chelsea College, London SW3 6LX)

Reprinted from Journal of The Chemical Society Chemical Communications 1979

The Chemical Society, Burlington House, London W1V OBN 1173 J.C.S. CHEM. CozM., 1979

Dissolving Metal Reduction of Carboxylic Esters. A Re-evaluation of the Mechanism

By ANTHONY G. M. BARRETT,* and PANAYIOTIS A. PROKOPIOU (Department of Chemistry, Imperial College, London SW7 2AY) DEREK H. R. BARTON (Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur-Yvette. France) and ROBIN B. BOAR and JAMES F. McGHIE (Department of Chemistry, Chelsea College, London SW3 6LX)

Summary The deoxygenation of carboxylic esters by [(R'CO,R)-• -a R'CO9 + R. --r R- R-H] was the pre- reduction using potassium solubilised by 18-crown-6 in dominant pathway [hereinafter, pathway (a)]. Otherwise t-butylamine or lithium in ethylamine . is shown to the alcohol was regenerated C(R'CO,R)-• R'CO. RO-] proceed via alkyl oxygen cleavage of the derived radial [hereinafter, pathway (b)]. Typically diesters (la and ib) anion; in non-nucleophilic media deoxygenation giving gave 5a-cholestan-314-ol (1c) (60 and 79% yield, respectively) alkane and carboxylate anion is the major pathway. where the more hindered axial (6s) ester was selectively deoxygenated. THE reduction of carboxylic esters by alkali metals is a Our recent results are consistent with the hypothesis that classic organic transformation. Excess of sodium in aliphatic or alicyclic esters normally react by path (a) ethanol provides two alcohols (Bouveault-Blanc) whereas provided that the medium is nucleophile-free. molten sodium in refluxing toluene gives. the acyloin. TABLE 1. Reduction of esters and carboxylic acids.a Substrate Products (% yield) 1 (Id) (le) (45), (ic) (27), (Ig) (8), (If) (6). (2b) (92) 2 (2b) No reaction; 87% (2b) recovered 3 (2b) (2e) (51) [via (2f)]. (2b) (10). (2c) (9) 4 (2g) + (lc) (lc) (69), (le) (15), (2b) (85) (2h) ble[CH,']170H (53), Me[CHi]16Me (41), 5 (2b) (30) 6 (3a) n-CeH17CH(X)C110Y X=Y=OAc (67); X= H, Y=OAc+X=OAc, Y=H (5) 7 (3b) n-C6H17CH(X)CH3Y X=Y=OAc (35) ; (1) X=H, Y=OAc (26); X=OAc, Y=H (8); n-C,H17CH=CH2 (5) a; R1 = R= = AcO e; R1 = R2 = H b; R1 = R= = Bu1C0i f; RI = H, R2 = OH a Reactions 1, 2, and 4-7 were carried out using potassium c; R1 = OH. R= = H g; 122 = R2 = OH and 18-crown-6 in t-butylamine at room temperature and reaction d; R1 = R2 = 113CO3 [see (2)] h; R1 = R3CO2. R2 = H (3) with lithium and ethylamine at 17 °C. The crude products from reactions 6 and 7 were acetylated prior to separation. Recently the selective deoxygenation (Li, EtNH2;I K, 18-crown-6, ButNH,;I or Na, hexamethylphosphoric tri- Adamantane-l-carboxvlic esters of sterols were chosen amide, ButOH 9 of hindered alkyl carboxylates giving for study since these permit ready identification of the alkanes was reported. We suggested that deoxygenation fragments derived from both acyl and alkyl residues on

J.C.S. CHEM. COMM., 1979 1174

reduction. Adamantanecarboxylate esterst [prepared not increased. The yields of acid (2b) and alkane (le) using KH, 18-crown-6, and (2a)] and cyclic carbonates (3a were decreased at lower temperature. Deoxygenation was and b) were reduced by their addition in tetrahydrofuran a minor pathway (owing to competitive deacylation) on (THF) to potassium and 18-crown-6 in t-butylamine. The lithium-ethylamine reduction giving (ic) and (2d). In the reduction was complete when the blue colour was restored; presence of excess electrons or at low temperature both quenching and chromatography gave the products shown in transacylation [giving (2d)] and radical anion fragmentation Tables 1 and 2. In all cases reduction of the ester (1h) [giving (le)] were suppressed and the two-electron Bou- gave 5x-cholestane (le) and acid (2b) with the latter veault-Blanc products (lc) and (2c) formed. Entry 4, Table 1 shows that ester deacylation by an alkoxide com- peted with reduction. In entry 7, Table 1, predominance of the primary acetate was consistent with deoxygenation via the radical anion, not the dianion.

n -CeH17--r0 (2) (=R3X) 0 X a; X = COC1 e; X = CHO _ _ b; X = CO,H f; X = CH(-O)O or C 1(-O)NEt (3) c; X = CH,OH g; X = CO,Et d; X = CONHEt h; X = CO,[CH,]17Me a; X=0 b; X =S

substantially predominating. The possibility that this 18-Crown-6 was found to be fragmented on reaction with difference resulted from competitive hydrolysis by adven- potassium in t-butylamine. When the blue colour faded titious water was unlikely since rigorous drying was used acidification followed by acylation with 1-naphthoyl and in entry 5, Table 2, iodomethane was added before the chloride gave a complex mixture. Chromatography gave ester to scavenge any water. The ratio of (le) ; (2b) was products including N-t-butyl-1-naphthamide and the oily esters (4a, b, and e) characterised by spectral data and high TABLE 2. Reduction of the ester (1h)a • Amount/mmol of Yield of products CO2LCH21Z 0-[CH2]2OR Ester (lh), metal°, 18-crown-6 (le) (lc) (2b ) (2c) (2d) 1 1.04, 38, 11 43 57 96 2 2 0.84, (31 )- 181, 32 68 81 0 (6 t- 4) 3 1.03, 13, 4 43 37 84 0 (4) 4 1.03, 14, 4.5 45 44 93 7 5 1.20, 28, 7 30 57 92 0 a; R=H 6 1.09, 36, 6 27 66 77 5 b; R = CH,CH,OEt 7 1.04, 36, 6 15 81 71 0 c; R = (CH,CH10),Et 8 1.17, 29,0 1 93 0 69 0 9 1.15, 22, 0 7 85 4 4 92 resolution mass spectroscopy. Clearly, during ester reduc- 10 1.17, 272, 0 4 94 4 65 0 11 1.03, 65, 0 5 92 2 29 61 tion complete deoxygenation was prevented by competitive 12 0.45, 100, 0 0 58 0 66 0 deacylation by crown fragments. The so-formed acylated fragments were subsequently reduced [pathway (a)] giving a Reactions were carried out at 46 (1,2), 20-(3-5), 17 the carboxylate anion. Thus, in the absence of nucleo- (9-11), -45 (6), -53 (7), or -73 °C (8), in t-butylamine and '1•lIF (1- -3, 6, 7), t-butylaminti with potassium philes [pathway (a)] predominated. The selective deoxy- added List (4), 1.2-dimethuxyuthane and iodomcthane (5), genation of hindered esters followed from suppression of ethylamine and TIIF (x, 9), ethylamine (10), or ethylamine competitive deacylation.5 THP, and t-butyl acetate (11). In reaction 2 extra crown and putassium were adJed after the ester. Reac- tion 12 w.ts Larricd out under standard I3ouveault- Blanc conditions. b Reactions 1-7, metal = K; 8-11, Li, and 12, Na. (Received, 2nd October 1979; Com. 1065.)

t All new compounds were fully characterised by microanalysis and spectral data.

1 R. B. Boar, L. Joukhadar, J. F. McGhie, S. C. Misra, A. G. M. Barrett, D. H. R. Barton, and P. A. Prokopiou, J.C.S. Chem. Comm., 1978, 68. ' H. Deshayes and J.-P. Pete, J.C.S. Chem. Comm., 1978, 667. Cf. H. W. Pinnick and E. Fernandez, J. Org. Chem., 1979, 44, 2810. Novel Method for the Deoxygenation of Alcohols

By ANTHONY G. M. BARRETT• and PANAYIOTIS A. PROKOPIOU (Department of Chemistry, Imperial College, London SW7 2AY)

and DEREK H. R. BARTON (Institut de Chimie des Substances Naturelles, C.N.R.S., Gif -sur-Yvette, France)

Reprinted from Journal of The Chemical Society Chemical Communications 1979

The Chemical Society, Burlington House, London W1V OBN J.C.S. CHEM. COMM., 1979 I175

Novel Method for the Deoxygenation of Alcohols

By ANTHONY G. M. BARRETT• and PANAYIOTIS A. PROKOPIOU (Department of Chemistry, Imperial College, London SW7 2AY) and DEREK H. R. BARTON (Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur-Yvette, France)

Summary Primary and secondary alcohols have been deoxygenated in high yield by the reduction of derived thiocarbamates in t-butylamine with potassium solubilised by 18-crown-6.

RECENTLY we reported the selective deoxygenation of hindered alcohols by the lithium and ethylamine reduction of the derived carboxylic esters.' For example 3)4,6p- diacetoxy-5x-cholestane (la) gave 5a-cholestan-3s-ol (1 b) (1) (60%) and 57.-cholestane-313,6s-diol (ic) (29%). Since car- a; R'=R'=Ac0 g; R'=H. R2 =HO boxylic esters are readily available from alcohols the deoxy- b; R'= HO, 122 =H h; R'=R'=H genation provides a useful synthetic method. Herein we report that non-hindered secondary and primary alcohols c; RI= R2=HO 1; 13.1=CH,-[CH,],-N•CS•O, can be readily converted into alkanes by the reduction of d; R' = R2 =McS•CS•O R2 =H e; R1=R1= EtNH•CS•O j; R'=Et,pi•CS•O, R2 =H their dialkylaminothiocarbonyl derivatives with potassium t ~ and 18-crown-6. This complements the selective ester f; R1 =R 1 = CH,-[CH,],-N k; R'=Me,NCH,CH,N(Me) reduction. •CS•O •CS•O, R'=H

TABLE. Potassium 18-crown-6 reduction of dithiocarbonates available from the alcohol via the methylthiothiocarbonyl and thiocarbamates& derivative and dialkylamine.2 Starting material Product(s) (% yield) The deoxygenation herein described is more convenient than many existing methods. Carbohydrate thiocarba- 1 (Id) (lh) (38), (lb) (19), (lc) (8), mates have been converted into alkanes via photolytic (1g) (2) 2 (le) (lc) (46), (lb) (18) homolysis.2,4 3 (1f) (1h) (62), (Ig) (15), (lb) (12), (1c) (5) 4 (11) (1h) (74), (lb) (14) (1h) (86), (lb) (8) Xō 6 (Ii) (lh) (58), (Ib) (40) 7 (1k) (lh) (83), (lb) (12) 8 Me[CH2]170•CS•NEt, Me[CH3]1,Me (87), Me[CH],]17 OH (12) HH 9 (2a) (2b) (55), (2c) (14) O~ " All reductions were carried out in t-butylamine (entries 1-3, 6-9) or 1,2-dimethoxyethane (entry 4) at room temperature (2) except entry 7 (-30 °C). New compounds were characterised a; R=Et2N•CS•O by spectral data and microanalyses. All yields refer to pure b; R=HO isolated materials. c; R=H Reductions of the dithiocarbonate (1d) and thiocarba- We consider that the mechanism of reduction of these mates (1e, f, i-k and 2a) by potassium in t-butylamine thiocarbonyl derivatives is comparable to that presented solubilised by 18-crown-6 are in the Table. Typically the in the preceding communication for ordinary esters.' That thiocarbonyl derivative (1 mmol) in tetrahydrofuran (THF) is, that a transfer of an electron to give a radical anion is was added dropwise at room temperature to potassium followed by the collapse of the latter to thiocarboxylate (12 mg atom) and 18-crown-6 (3 mmol) in t-hutylamine or anion (specially stabilised) and carbon radical. It was 1,2-dimethoxyethane (20 nil). The reduction was complete consideration of this mechanism that led us to the method when the blue colour of the solution was restored. Clearly presented above. both primary and secondary alcohols can be thus conveniently deoxygenated. The thiocarbamates are readily (Received, 2nd October 1979; Corn. 1054.)

1 R. B. Boar, L. Joukhadar, J. F. McGhie, S. C. Misra, A. G. M. Barrett, D. H. R. Barton, and P. A. Prokopiou, J.C.S. Chem. Comm., 1978, 68; see also H. Deshayes and J.-P. Pete, ibid., p. 567. D. H. R. Barton, R. V. Stick, and R. Subramanian, J.C.S. Perkin I, 1976, 2112. ' R. H. Bell. D. Horton, and D. M. Williams, Chem. Comm., 1968, 323; R. H. Bell, D. Horton, D. M. Williams, E. Winter-Mihaly, Carbohydrate Res., 1977, 58, 109. ' See also T. Tsuchiya, I. Watanabe, M. Yoshida, F. Nakamura, T. Usui, M. Kitamura, and S. Umezawa, Tetrahedron Letters, 1978, 3365; T. Tsuchiya, F. Nakamura, and S. Umezawa, ibid., 1979, 2805; W. Tochtermann and R. G. H. Kirrstetter, Chem. Ber., 1978, 111, 1228; R. G. H. Kirrstetter, ibid.. 1979, 112, 2804. ' A. G. M. Barrett, P. A. Prokopiou, D. H. R. Barton, R. B. Boar, and J. F. McGhie, J.C.S. Chem. Comm., preceding communication.