Process for chiral synthesis of 1-.beta.-methylcarbapenem intermediates

A process is described for selectively obtaining 1-.beta.-methylcarbapenem intermediates. The desired chirality is obtained through the hydrogenation of certain bicyclic .beta.-lactam ring structures containing an exocyclic methylene double bond alpha to the .beta.-lactam ring, in the presence of a Group VIII metal hydrogenation catalyst. The hydrogenation results in a mixture of .alpha.- and .beta.-methyl epimers having a high .beta./.alpha. epimeric ratio. New 1-.beta.-methylcarbapenem intermediates made by the process are also described.

BACKGROUND OF THE INVENTION 
This invention relates to a chiral process for selectively obtaining high 
yields of 1-.beta.-methyl-carbapenem intermediates for the subsequent 
synthesis of 1-.beta.-methylcarbapenem antibiotics. The process involves 
introducing an exocyclic .alpha.-methylene double bond into a bicyclic 
.beta.-lactam ring structure and then subjecting the compound to 
hydrogenation conditions with a Group VIII transition metal hydrogenation 
catalyst which preferentially results in the formation of the 
1-.beta.-methylcarbapenem intermediates. 
1-.beta.-Methylcarbapenems, as described in the reference Heterocycles, 
1984, Vol. 21, pp. 29-40 by D. H. Shih, F. Baker, L. Cama and B. G. 
Christensen, are extremely useful and effective broad spectrum 
antibiotics, useful against a wide variety of bacteria including 
Gram-positive bacteria including S. aureus, Strep. sp., B. subtilis, and 
Gram-negative bacteria such as E. coli, Shigella sp., Enterobacter sp., 
Klebsiella sp., Proteus, Serratia and Pseudomonas sp. 
A method of synthesizing 1-.beta.-methylcarba-penems is described in the 
above-cited reference in which the beta-methyl chirality is introduced 
into the molecule by base-catalyzed alkylation producing a mixture of 
.alpha. and .beta. epimers which are separated by chromatographic 
procedures. 
However, because of the relatively low .beta./.alpha. epimeric ratio 
obtained by this alkylation route, newer methods for obtaining the desired 
.beta.-methyl epimer intermediate on a larger scale are constantly being 
sought. 
SUMMARY OF THE INVENTION 
It has been found that by introducing an exocyclic .alpha.-methylene double 
bond into the secondary ring of a bicyclic .beta.-lactam ring system, and 
then subjecting said compound to hydrogenation conditions utilizing a 
Group VIII transition metal hydrogenation catalyst, the stereochemistry of 
the molecule enables the hydrogenation to proceed stereoselectively to 
produce the .beta.-methyl isomer in a .beta./.alpha. epimer ratio greater 
than 1 and as high as 9:1. 
In accordance with this invention there is provided a process for 
stereoselectively reducing an exocyclic methylene double bond in a 
bicyclic compound of the structural formula (I): 
##STR1## 
where R.sup.2 is independently H, linear or branched C.sub.1 -C.sub.3 
alkyl, which can be substituted with fluoro or hydroxy, and Y is a 
divalent bridging-protecting group, derived from a ketone, aldehyde or 
organosilicon compound, said group being stable to catalytic hydrogenation 
and removable by acid or base hydrolysis, said process comprising the step 
of contacting said compound with a hydrogen atmosphere in the presence of 
a supported or unsupported Group VIII transition metal hydrogenation 
catalyst and in the presence of a solvent for said bicyclic compound, at a 
temperature below the boiling point of the solvent, for a sufficient time 
to yield a mixture of .alpha.- and .beta.-methyl epimers having a 
.beta./.alpha. molar ratio of greater than 1. 
The process is illustrated by the following flow diagram: 
##STR2## 
Further provided is a composition of the following structural formula, 
being an intermediate useful in producing compositions of above-described 
structure (I): 
##STR3## 
wherein R.sup.2 is independently selected from hydrogen, linear or 
branched C.sub.1 -C.sub.3 alkyl, which can be substituted with fluoro, 
hydroxy, or protected hydroxy, R.sup.3 is hydrogen or a protecting group, 
X is sulfur or selenium, Q is hydroxymethyl, carboxy or C.sub.1 -C.sub.4 
alkoxycarbonyl, and R.sup.1 is C.sub.1 -C.sub.4 alkyl, C.sub.6 -C.sub.10 
aryl, heteroaryl, which can contain substituents inert under the reaction 
conditions of forming structures I or IV, and include C.sub.1 -C.sub.4 
alkyl, alkoxy, nitro and the like. 
Furthermore, there is provided a composition of the following structural 
formula, an intermediate formed from the oxidation of structure IV and, 
useful in producing composition (I): 
##STR4## 
wherein R.sup.2 is independently selected from hydrogen, linear or 
branched C.sub.1 -C.sub.3 alkyl, which can be substituted with fluoro, 
hydroxy, or protected hydroxy, R.sup.3 is hydrogen or a protecting group, 
R.sup.6 is hydrogen, a protecting group, or a covalent bond, and where 
R.sup.6 is a covalent bond, R.sup.3 and R.sup.6 are joined to form Y, a 
divalent bridging-protecting group derived from a ketone, aldehyde or 
organosilicon compound, said group being stable to catalytic hydrogenation 
and removable by acid or base hydrolysis. As described above, where 
R.sup.3 and R.sup.6 join to form Y, structure I results. 
DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS 
The basic invention process is best illustrated by reference to the above 
diagram depicting the hydrogenation of structure I. 
As is seen, the .alpha.-exocyclic methylene double bond of I is 
hydrogenated to produce the .beta.-methyl epimer II and the .alpha.-methyl 
epimer III. The hydrogenation conditions employed are conventional in the 
art, and it was found surprisingly that the hydrogenation of structure I, 
particularly where R.sup.2 is 
##STR5## 
gave rise selectively to the .beta.-methyl epimer in the resulting product 
mixture which contained a .beta./.alpha. epimer molar ratio of greater 
than 1. 
The catalyst employed in the hydrogenation is a conventional Group VIII 
transition metal hydrogenation catalyst typically used for olefins which 
can be soluble or insoluble in the reaction medium, but wherein said 
catalyst is generally not effective for causing hydrogenation of the 
bicyclic beta-lactam ring structure under the hydrogenation conditions. 
Preferred metals in the catalyst are nickel, palladium, platinum, rhodium, 
and the metal in the catalyst can be in the form of free metal, salts or 
compounds thereof. The catalysts can be used in the bulk and unsupported 
form, e.g. palladium hydroxide, or in the supported form on a suitable 
substrate, e.g. activated carbon, inorganic sulfate or carbonate, said 
substrate not intervening in the hydrogenation process. Representative 
examples of Group VIII transition metal hydrogenation catalysts which can 
be used include palladium hydroxide, platinum oxide, platinum black, 
platinumon-carbon, palladium-on-carbon, colloidal palladium or platinum, 
platinum or palladium on barium sulfate or barium carbonate, Raney nickel, 
i.e. W-2, W-4, W-6, or other grades as prepared by conventional 
procedures, soluble rhodium catalysts including tris (triphenylphosphine) 
chlororhodium, and the like. The catalyst can be soluble in the solvent 
used, such as the triphenylphosphine rhodium compound, or insoluble, such 
as the heterogeneous catalysts, e.g. Raney Nickel. A preferred catalyst 
for use in the process is Raney Nickel as produced by the conventional 
process described in the reference L. F. Feiser, "Reagents for Organic 
Synthesis", Vol. 1, p. 723 (John Wiley & Sons, New York), incorporated by 
reference herein for that purpose. Catalysts operable in the process are 
produced by conventional procedures. 
Solvents for Structure I which can be used for the hydrogenation of I in 
the process should be inert under the reaction conditions and have a 
boiling point in the temperature range of about 50.degree.-100.degree. C. 
for adequate temperature to be achieved during the process. Representative 
examples of solvents which can be used in the process include protic and 
aprotic liquids such as C.sub.1 -C.sub.3 alcohols, C.sub.3 -C.sub.6 alkyl 
carboxylic esters, C.sub.4 cyclic mono- and diethers, and derivatives 
thereof, which can contain substituents such as lower alkyl and alkoxy, 
inert under the hydrogenation conditions. Representative examples include 
EtOH, MeOH, MeOAc, EtOAc, dioxane, tetrahydrofuran and the like. A 
preferred solvent in the process is EtOH. 
Concentrations of I in the solvent can range from 0.001 to 1 molar and 
preferably 0.1 to 1 molar. 
Temperature employed in the hydrogenation process can range from 
-78.degree. C. up to the boiling point of the solvent. The preferred 
temperature range for conducting the process is about 0.degree. to 
25.degree. C. 
Pressure employed in the process can be anywhere from one atmosphere to 
several atmospheres suitable for standard olefin reduction conditions. 
Preferred is a pressure of about 0-40 psig and particularly about 40 psig, 
containing a substantially hydrogen atmosphere. The hydrogen atmosphere 
can of course contain other gases which are either reducing or inert under 
the reaction conditions such as small amounts of carbon monoxide or carbon 
dioxide and the like. Preferably the atmosphere used in the hydrogenation 
is substantially a hydrogen atmosphere. 
The time involved in the hydrogenation is that sufficient under the 
reaction conditions to obtain substantial catalytic hydrogenation of 
structural formula I to obtain a resulting .beta./.alpha. epimer molar 
ratio of greater than 1. .beta./.alpha. epimer molar ratios of 
substantially greater than 1 are achieved, being generally 1.5 and above 
and can approach a ratio of 9:1 via the hydrogenation step. 
The compounds encompassed by structural Formula I include those compounds 
wherein R.sup.2 is independently selected from H, linear or branched 
C.sub.1 -C.sub.3 alkyl, which can be substituted with fluoro, hydroxy or 
protected hydroxy. The hydroxy protecting groups included herein are known 
in the antibiotic art, are removable by acid or base hydrolysis, and 
include, inter alia, trialkylsilicon groups such as t-butyldiphenylsilyl, 
triphenylsilyl, isopropyldimethylsilyl or dimethyl-t-butylsilyl. 
A preferred hydroxy protecting silyl group, e.g. t-butyldimethylsilyloxy 
can be formed by reacting the hydroxy group, e.g. 1-hydroxyethyl, with 
t-butyldimethylsilyl chloride in a dry solvent such as methylene chloride, 
DMF, or other inert solvents, in the presence of an acid acceptor, e.g. 
triethylamine or imidazole, at -20.degree. to 25.degree. C. for a period 
of 1-2 hours and then isolating and purifying the desired protected 
hydroxy compound by conventional methods. 
When desired to remove the protecting group, such as prior to 
hydrogenation, the protected silyloxy can be treated with fluoride, e.g. 
with tetrabutylammonium fluoride in tetrahydrofuran in dimethylformamide 
solvent at room temperature for 1-2 hours. Isolation and purification of 
the resulting hydroxy compound can be accomplished by conventional 
procedures. Generally, in the hydrogenation step of the methylene double 
bond, it is preferred to deblock the hydroxy group when present in R.sup.2 
prior to the hydrogenation. 
Representative examples of R.sup.2 include H, CH.sub.3 --, CH.sub.3 
CH.sub.2 --,(CH.sub.3).sub.2 CH--, HOCH.sub.2 --, CH.sub.3 CHOH--, 
CH.sub.3 CH[OSi[C(CH.sub.3).sub.3 ](CH.sub.3).sub.2 ]--, (CH.sub.3).sub.2 
COH--, FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, CH.sub.3 CHF--, CH.sub.3 
CF.sub.2 --,(CH.sub.3).sub.2 CF--, CH.sub.3 CH.sub.2 CHOH--and FCH.sub.2 
CHOH--. Preferred is where R.sup.2 is CH.sub.3 CHOH--. 
Y is a bridging-protecting group derived from an aldehyde, ketone or 
organosilicon compound, or equivalent thereof, including acetals, ketals, 
and the like and includes 
##STR6## 
and substituted derivatives thereof, wherein said substituents are inert 
during the subject process described herein and include, inter alia, 
C.sub.1 -C.sub.4 lower alkyl and alkoxy. 
Representative examples of aldehydes, ketones and organosilicon compounds 
which are precursors for Y include those which are known in the antibiotic 
art, e.g., acetone, 2,2-dimethoxypropane, cyclohexanone, 
1,1-dimethoxycyclohexane, methylethylketone, 2,2-diethoxy-n-butane, 
acetaldehyde, acetaldehyde dimethylacetal, acetophenone, 
p-methoxyacetophenone, dichlorodimethylsilane, dichlorodiphenylsilane, 
dichloroethylphenylsilane, dichlorodi-t-butylsilane and the like. A 
preferred reagent for forming the Y moiety is 2,2-dimethoxypropane wherein 
the Y moiety is formed by reacting the deblocked amino alcohol of 
structure V for example with 2,2-dimethoxypropane in the presence of a 
catalyst such as boron trifluoride etherate, toluenesulfonic acid, or the 
like in a solvent such as methylene chloride, ether, chloroform, dioxane 
or the like at a temperature of from -10.degree. C. to 35.degree. C. for 
from a few minutes to 1 hour. 
The bridging-protecting group Y, not readily removable by hydrogenation, is 
removable by acid or base hydrolysis as described in the reference U.S. 
Pat. No. 4,234,596, hereby incorporated by reference for that purpose. 
Structure I is derived as described above from the reaction of ketone, 
aldehyde or organosilicon compound with the deblocked amino-alcohol V, 
where R.sup.3 and R.sup.6 are H: 
##STR7## 
Representative examples of structure I include: 
##STR8## 
Further examples of Structure I for illustration purposes are given below 
in the Table indicating specific values chosen for R.sup.2 and 
bridging-protecting group Y. 
TABLE 
______________________________________ 
Compound R.sup.2 Y 
______________________________________ 
1 H (t-Bu).sub.2 Si 
2 H Ph.sub.2 Si 
3 H 
##STR9## 
4 H (CH.sub.3).sub.2 C 
5 CH.sub.3 (CH.sub.3).sub.2 C 
6 CH.sub.3 
##STR10## 
7 CH.sub.3 (CH).sub.3 Si 
8 CH.sub.3 Ph(CH.sub.3 CH.sub.2)Si 
9 CH.sub.3 CH.sub.2 CH.sub.2 
Ph(CH.sub.3 CH.sub.2)Si 
10 CH.sub.3 CH.sub.2 CH.sub.2 
Ph.sub.2 Si 
11 CH.sub.3 CH.sub.2 CH.sub.2 
##STR11## 
12 CH.sub.3 CH.sub.2 CH.sub.2 
##STR12## 
13 (CH.sub.3).sub.2 CH 
(CH.sub.3).sub.2 C 
14 (CH.sub.3).sub.2 CH 
##STR13## 
15 (CH.sub.3).sub.2 CH 
(t-Bu).sub.2 Si 
16 (CH.sub.3).sub.2 CH 
Ph.sub.2 Si 
17 HOCH.sub.2 Ph.sub.2 Si 
18 HOCH.sub.2 (CH.sub.3)(CH.sub.3 CH.sub.2)Si 
19 HOCH.sub.2 
##STR14## 
20 HOCH.sub.2 (CH.sub.3).sub.2 C 
21 (CH.sub.3).sub.2 COH 
(CH.sub.3).sub.2 C 
22 (CH.sub.3).sub.2 COH 
##STR15## 
23 (CH.sub.3).sub.2 COH 
(CH.sub.3).sub.2 Si 
24 (CH.sub.3).sub.2 COH 
Ph.sub.2 Si 
25 FCH.sub.2 Ph.sub.2 Si 
26 FCH.sub.2 (t-Bu).sub.2 Si 
27 FCH.sub.2 
##STR16## 
28 FCH.sub.2 
##STR17## 
29 F.sub.2 CH 
##STR18## 
30 F.sub.2 CH (CH.sub.3).sub.2 C 
31 F.sub.2 CH Ph.sub.2 Si 
32 F.sub.2 CH (t-Bu).sub.2 Si 
33 F.sub.3 C (t-Bu).sub.2 Si 
34 F.sub.3 C (CH.sub.3).sub.2 Si 
35 F.sub.3 C 
##STR19## 
36 F.sub.3 C 
##STR20## 
37 (CH.sub.3).sub.2 CF 
##STR21## 
38 (CH.sub.3).sub.2 CF 
(CH.sub.3).sub.2 C 
39 (CH.sub.3).sub.2 CF 
Ph.sub.2 Si 
40 (CH.sub.3).sub.2 CF 
(CH.sub.3).sub.2 Si 
______________________________________ 
The structures and formulae representative of Structure I given in the 
above Table are not meant to be limiting and other combinations of R.sup.2 
and Y and their resulting species of Structure I which will be obvious to 
one skilled in the art from this disclosure are also deemed to be included 
within the scope of the invention. 
A preferred compound of structure I for use in the process is: 
##STR22## 
A synthesis of a species of general structure I is given below in the Flow 
Sheet for converting the monocyclic .beta.-lactam ring system into the 
bicyclic system, 8-oxo-3-oxa-1-azabicyclo [4.2.0] octane with the 
exocyclic methylene group alpha to the beta lactam ring and a 
1-hydroxyethyl radical adjacent to the beta lactam carbonyl. 
By the same general procedure, the compounds encompassed by Structure I, 
where R.sup.2 and Y have other values disclosed herein, within the claimed 
definition, are also obtained. 
##STR23## 
In words relative to the above Flow Sheet, starting compound A with the 
indicated stereochemistry where R.sup.4 is H or t-butyldimethylsilyl, is 
known and can be synthesized by the method described in the above-cited 
Heterocycles reference, hereby incorporated by reference for this 
particular purpose. 
The selenation or sulfenylation of A to B is conducted under dry and 
O.sub.2 -free conditions, preferably under nitrogen, by treating A with a 
proton-abstracting agent such as LDA (lithium diisopropylamide) in an 
anhydrous solvent such as THF (tetrahydrofuran), and in the presence of 
HMPA (hexamethylphosphoramide) to increase rate of reaction, followed by 
treating with a selenation or sulfenylation agent. Other proton 
abstracting agents which can be used are lithium hexamethyldisilazide, 
NaH, lithium cyclohexylisopropylamide, and the like. Preferred is LDA. 
Other solvents which can be used in this particular step are glyme, 
diethylether, dimethylformamide, and the like. The solvent should be dry 
and inert under the reaction conditions and preferred is tetrahydrofuran. 
The selenating agent used is a diselenide (or a disulfide if sulfenylating 
such as diphenyldi sulfide), preferably diphenyldiselenide, and the 
reaction is carried out at -78.degree. C. to 0.degree. C. under nitrogen 
atmosphere for a period of time of about 1 to 8 hours to achieve a desired 
yield of the selenated compound B. The same procedure for sulfenylating 
can be generally used with the corresponding disulfide. A mixture of alpha 
and beta selenides is produced, but it is not absolutely necessary to 
perform a separation step since either diastereomer or a mixture can be 
used in the later oxidation step to produce the methylene compound. 
The resulting selenated ester B is hydrolyzed to the acid C by conventional 
alkaline hydrolysis in e.g., aqueous methanol at a temperature of about 
25.degree. to 60.degree. C., for about 2 to 24 hours, under a nitrogen 
atmosphere, to obtain desirable yields of compound C. Other solvent 
combinations can also be used, e.g. aqueous ethanol. 
The resulting acid C is reduced to the primary alcohol D by a suitable 
reducing agent, including BH.sub.3. Me.sub.2 S in solvent THF, at a 
temperature of 0.degree. to 65.degree. C., for about 2 to 24 hours under a 
nitrogen atmosphere to achieve the alcohol. Other reducing agents such as 
lithium aluminum hydride and borane can also be used which are not 
detrimental to the beta-lactam ring. 
The alcohol selenide D is then treated with an oxidizing agent such as 
hydrogen peroxide in acetic acid/THF solvent to form E having the 
exocyclic double bond at the .beta.-position to the B-lactam ring. 
Generally this step is conducted at about 0.degree. to 100.degree. C., for 
a period of time of about 1 to 24 hours. Other oxidizing agents which can 
be used include m-chloroperbenzoic acid, ozone, and NaIO.sub.4 in solvents 
including methylene chloride, toluene, and EtOH. Preferred oxidizing 
system is hydrogen perioxide in acetic acid/THF solvent. 
Following the above oxidation-elimination procedure, the ring nitrogen is 
deblocked, if a conventional blocking group is present, by the procedure 
of acid or base catalyzed hydrolysis, but not hydrogenation, and the amino 
alcohol is joined together by reaction with a divalent bridging-protecting 
group as described herein such as 2,2-dimethoxypropane, or the like, in a 
suitable solvent and presence of a Lewis acid such as BF.sub.3.Et.sub.2 O, 
p-toluenesulfonic acid, chlorosulfonic acid to form F. Other 
bridging-protecting agents which can also be used are cyclohexanone, 
p-methoxyacetophenone or its dimethylketal, or a diorganodichlorosilane 
such as di-t-butyldichlorosilane. Preferred is 2,2-dimethoxypropane, 
reacted in methylene chloride solvent. Following cyclization the 
1'-hydroxy group is deblocked by treating with tetrabutylammonium fluoride 
in DMF to form G. The deblocking of the 1'-hydroxy group has been found to 
be highly favorable in obtaining a high ratio of .beta./.alpha. epimers in 
the subsequent reduction step. 
Following the deblocking step to yield G, the reduction is carried out as 
described hereinabove with Raney Nickel, to yield a mixture of the 
.beta.-methyl and .alpha.-methyl epimers H, being H-.beta. and H-.alpha., 
respectively, with the .beta.-methyl epimer predominating. The resulting 
.beta.- and .alpha.-isomers can be separated by high pressure liquid 
chromatography (HPLC), as for example, on a Pre PAK 500/silica column as 
in conventional practice or by fractional crystallization or the like to 
obtain the .beta.-epimer in high purity. 
The .beta.-epimer once obtained in high purity, can be converted to I and 
then J by using the methods described in U.S. Pat. No. 4,234,596 hereby 
incorporated by reference for that purpose. 
The reaction H-.beta..fwdarw.I establishes the blocking group R.sup.4 and 
is typically accomplished by treating H-.beta. with a base such as an 
alkali metal hydroxide, lithium diisopropyl amide, 
4-dimethylaminopyridine, or n-butyllithium in a solvent such as methylene 
chloride, ether, THF, dioxane, DMF, DMSO or the like, followed by 
treatment with an acyl halide of choice such as an alkanoyl, aralkanoyl or 
nuclear substituted aralkanoyl, or alkyl, aryl or aralkyl, substituted 
aralkyl or substituted aryl haloformate such as allylchloroformate or 
p-nitrobenzylchloro formate or the like at a temperature of from 
-78.degree. C. to 25.degree. C. for from 1-24 hours. 
Alternatively, the protecting group R.sup.4 may be a triorganosilyl group, 
such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, 
isopropyldimethylsilyl, for example, or may be 3,4-dimethoxybenzyl, for 
example. Typically R .sup.4 is established by treating H-.beta. in a 
solvent such as CH.sub.2 Cl.sub.2, dimethylformamide, acetonitrile, 
hexamethylphosphoramide, tetrahydrofuran and the like with a silylating 
agent such as t-butyldimethylchlorosilane, t-butyldiphenylchlorosilane, 
triphenylchlorosilane, and the like at a temperature of from -20.degree. 
to 25.degree. C. for from 0.5 to 24 hours in the presence of a base such 
as triethylamine, diisopropylethylamine, or imidazole or 
4-dimethylaminopyridine. 
The de-blocking reaction I.fwdarw.J is typically conducted by acid 
hydrolysis such as aqueous acetic acid at a temperature of from 25.degree. 
C. to 75.degree. C. for from 5 minutes to 3 hours. 
The oxidation of J to K is accomplished by treating J in a solvent such as 
acetone or the like with Jones reagent at from -78.degree. to 25.degree. 
C. for from one minute to 2 hours. Alternatively, the conversions I to J 
to K may be done in one step by treatment of I as above with Jones reagent 
to give K directly. 
The carboxylic acid K can then be be treated for example, by the method 
described in the above-cited Heterocycles reference and U.S. Pat. No. 
4,383,946 and 4,309,346, all hereby incorporated by reference for this 
purpose, to arrive at subsequent active 1-.beta.-methylcarbapenem 
antibiotics, including 
(-)-(1R,5S,6S)-2-(2-N,N-dimethylamino-2-iminoethylthio)-6-[(1R)-1-hydroxye 
thyl]-1-methylcarbapen-2-em-3-carboxylic acid, useful as described 
hereinabove. 
Preferred process for selectively reducing an exocyclic .alpha.-methylene 
ring double bond of the invention comprises the step of contacting the 
compound: 
##STR24## 
in an organic solvent therefor as described hereinabove, with a hydrogen 
atmosphere at about 40 psig reaction pressure with Raney nickel catalyst 
for a time sufficient to obtain a mixture of .alpha.-methyl and 
.beta.-methyl epimers in a .beta. to .alpha. epimeric molar ratio of 
greater than 1. 
Methods of synthesis are given below in the Diagram, Schemes, and 
discussion, for other starting compounds A, where radical R.sub.2 on the 
beta lactam ring is chosen from other groups within the claimed definition 
therefor. The methods, are taken from U.S. Pat. Nos. 4,309,346 and 
4,383,946, which are incorporated by reference specifically for this 
purpose. 
##STR25## 
In words relative to the above diagram, L-aspartic acid 1 is esterified 
according to well known procedures. R.degree. is a protecting group such 
as benzyl, methyl, ethyl, isopropyl or the like. Typically 1 in a solvent 
such as benzene, toluene, chloroform or the like is treated with an 
esterifying agent such as benzyl alcohol, methanol, ethanol, isopropanol, 
or the like in the presence of p-toluene sulfonic acid, HCl, HBr, or the 
like at a temperature of from 0 to 100.degree. C. for from 1 to 24 hours 
to achieve the desired establishment and hence protection of the carboxyl 
functions. The resulting species 2 in a solvent such as ether, THF, DME or 
the like is treated with trimethylchlorosilane, or the like followed by 
treatment with EtMgBr, MeMgI, .phi.MgBr, t-BuMgCl, or the like at a 
temperature of from -40.degree. to 50.degree. C. for from 1 to 72 hours to 
provide azetidinone 3. Reduction of species 3 with a reducing agent such 
as NaBH.sub.4, or the like in a solvent such as methanol, ethanol, 
isopropanol or the like at a temperature of from -10.degree. to 40.degree. 
C. for from 1 to 6 hours provides 4. (For purposes here, the symbols: Et, 
Me, .phi., iPr, and t-Bu stand for: ethyl, methyl, phenyl, isopropyl, and 
tert-butyl, respectively.) 
Treatment of 4 in a solvent such as methylene chloride, CHCl.sub.3 or the 
like with methane sulfonyl chloride, methane sulfonic anhydride or the 
like in the presence of a base such as Et.sub.3 N, iPr.sub.2 NEt, or the 
like followed by treatment with a stoichiometric to 5-fold excess of 
sodium iodide in acetone yields 5 via 4a. 
The transformation 5.fwdarw.6 establishes the protecting group R.sup.3 
which may be a triorganosilyl group, such as t-butyldimethylsilyl, 
t-butyldiphenylsilyl, triphenylsilyl, isopropyldimethylsilyl, for example, 
or may be 3,4-dimethoxybenzyl, for example. Silyl protection is preferred, 
and typically R.sup.3 is established by treating 5 in a solvent such as 
dimethylformamide, acetonitrile, hexamethylphosphoramide, tetrahydrofuran 
and the like with a silylating agent such as t-butyldimethylchlorosilane, 
t-butyldiphenylchlorosilane, triphenylchlorosilane, and the like at a 
temperature of from -20.degree. to 25.degree. C. for from 0.5 to 24 hours 
in the presence of a base such as triethylamine, diisopropylethylamine, or 
imidazole. 
The transformation 6.fwdarw.7 is accomplished by treating 6 in a solvent 
such as tetrahydrofuran, dimethoxyethane, diethylether or the like with a 
carbanion generically represented by the following structure: 
##STR26## 
wherein M is a metal cation such as lithium, potassium, copper or 
magnesium, for example, and R.sup.a, R.sup.b and R.sup.c are selected from 
alkyl, aryl or aralkyl such as methyl, ethyl, benzyl, methoxybenzyl, 
trityl and phenyl, for example, at a temperature of from -100.degree. to 
0.degree. C. and from 0.5 to 4 hours. 
Typically, the carbanion reagent is prepared prior to addition of substrate 
6 on treatment of the triorganothiomethane with a strong base such as 
n-butyllithium, t-butyllithium, phenyllithium, lithium diisopropylamide 
(LDA) or the like. 
Resulting intermediate 7 can be mono-, or dialkylated at ring position 3. 
Alkylation of 7 provides 8. Typically, 7 is treated with a strong base 
such as lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, 
potassium hydride, lithium hexamethyldisilazide, phenyllithium or the like 
in a solvent such as tetrahydrofuran (THF), hexamethylphosphoramide, 
ether, dimethoxyethane, and the like at a temperature of from -80.degree. 
C. to 0.degree. C. whereupon the alkylating agent of choice, R.sup.2 
X.degree. is added (X.degree. is chloro, iodo or bromo); alternatively the 
alkylating agent may be R.sup.2 -tosylate, R.sup.2 -mesylate or an 
aldehyde or ketone such as acetaldehyde to provide monoalkylated species 
8. 
The eventual 6-substituents (nomenclature relative to final, bicyclic 
structure) can also be established by direct acylation using an acylating 
agent such as N-acyl imidazole or the like. Such N-acyl imidazole 
acylating reagents are listed below. Also given below is a detailed 
description of this second approach for establishing R.sup.2. 
The following list is representative of useful alkylating agents for 
establishing R.sup.2, according to the above scheme: 7.fwdarw.8 (this will 
be referred to as Scheme I, to be distinguished from Scheme II, below, 
which involves acylation): 
ALKYLATING AGENTS 
EQU CH.sub.3 CHO 
EQU CH.sub.2 O 
EQU CH.sub.3 I 
EQU CH.sub.3 COCH.sub.3 
EQU CH.sub.3 CH.sub.2 Br 
EQU (CH.sub.3).sub.2 CHBr 
EQU CH.sub.3 CH.sub.2 CHO 
EQU CF.sub.3 CHO 
EQU CHF.sub.2 CHO 
EQU CH.sub.2 FCHO 
EQU F.sub.2 CHI 
EQU F.sub.3 CI 
EQU CH.sub.3 CF.sub.2 I 
The fluoro compounds CH.sub.3 CHF--, and F--CH.sub.2 --, can be prepared 
from the corresponding hydroxy compounds by treating the hydroxy compound 
with DAST.TM., diethylaminosulfur trifluoride, in an inert solvent such as 
THF, at a temperature of -78.degree. to 25.degree. C. under an inert 
atmosphere for a period of about 1 to 2 hours. As mentioned above, the 
6-substituents may also be established by acylation. Utilization of such 
acylating agents may be demonstrated in the following manner with regard 
to a preferred starting, or intermediate, material 8. 
##STR27## 
The alkylation 7.fwdarw.8, is accomplished as previously described, by 
treating 7 in a solvent such as tetrahydrofuran, dimethoxyethane, 
diethylether, hexamethylphosphoramide, at a temperature of from 
-100.degree. to -20.degree. C. with a strong base such as lithium 
diisopropylamide, lithium hexamethyldisilazide, lithium 
2,2,6,6-tetramethylpiperidide, potassium hydride or the like followed by 
the addition of an equivalent to 10 fold excess of an aldehyde. This 
reaction gives a mixture of isomers from which the desired trans-R form 8 
can be conveniently separated by known methods of chromatography or 
crystallization. Intermediate 7 may proceed directly to 8 as indicated 
above, Scheme I, or it may take the circuitous path via 8'. The direct 
acylation, to 8' is accomplished by treating 7 with two or more 
equivalents of a base such as lithium diisopropylamide, lithium 
hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidide, in a solvent 
such as tetrahydrofuran, diethylether, or dimethoxyethane, for example, at 
a temperature of from -100.degree. to -20.degree. C. with an acylating 
agent such as N-acyl imidazole or the like. Addition of the 7 plus base 
mixture to the acylating agent is preferred. 
Representative acylating agents for this scheme 7.fwdarw.8'.fwdarw.8 are 
listed below. 
##STR28## 
Further with respect to Scheme II, the reduction 8'.fwdarw.8 is 
accomplished by contacting the ketone with a reducing agent such as 
potassium tri(sec-butyl)borohydride, lithium tri(sec-butyl) borohydride, 
sodium borohydride, sodium tris (methoxyethoxy)aluminum hydride, lithium 
aluminum hydride or the like in a solvent such as diethylether, 
tetrahydrofuran, toluene or the like at a temperature of from -78.degree. 
to 25.degree. C. The reaction can conveniently be conducted in the 
presence of an added complexing salt such as potassium iodide, magnesium 
bromide or the like. 
In a similar manner, unresolved 8 (cis and trans) may be oxidized to 8' for 
reduction to 8 as indicated above: 
##STR29## 
The oxidation is accomplished with an oxidizing agent such as dipyridine 
chromium (VI) oxide, trifluoroacetic 
anhydride-dimethylsulfoxidetriethylamine, pyridinium dichromate, acetic 
anhydride-dimethylsulfoxide in a solvent such as methylene chloride, 
acetonitrile, or the like at a temperature of from -78.degree. to 
25.degree. C. for from 5 minutes to 5 hours. 
Now return to the main scheme of synthesis, Diagram I, and the 
transformation 8.fwdarw.9, which is accomplished by treating 8 in a 
solvent such as methanol, ethanol, isopropanol, water or the like at a 
temperature of from 0.degree. to 80.degree. C. with a Lewis acid such as 
mercuric chloride, silver tetrafluoroborate, thallium trinitrate or the 
like. The value of R.sup.5 is determined by the identity of the alcohol 
taken in reaction. 
The triorganylsilyl protecting group R.sup.3 may then be removed from 9 to 
give 10 by treatment with fluoride, e.g. tetrabutylammonium fluoride in 
tetrahydrofuran, in a solvent such as tetrahydrofuran, dimethylformamide, 
ether or the like at a temperature of from -78.degree. to 25.degree. C. 
for from 1 minute to 2 hours. 
The mono-alkylated products 8 through 10, in which R.sup.2 does not contain 
a chiral center, will exist as a mixture of cis and trans structures: 
##STR30## 
the configurational isomerism referring to the 3- and 4-hydrogen atoms on 
the ring. The desired isomer, trans-8 through 10, can be obtained by known 
methods in the art including crystallization and chromatography. The 
resulting trans-10 form can be used directly in producing the desired 
1-betamethyl intermediates, by following the procedure in Heterocycles, 
supra, wherein trans-10 is treated with two equivalents of lithium 
diisopropylamide (LDA) in THF containing one equivalent of HMPA 
(hexamethylphorphoramide) at -78.degree. C. followed by excess methyl 
iodide yields a mixture of the alpha and beta methyl isomers which is then 
selenated and carried through the remaining steps as indicated in the Flow 
Sheet. 
An alternate route for producing the intermediate: 
##STR31## 
where R.sup.2 =CH.sub.3 CHOH--, is given in U.S. Pat. No. 4,206,219, 
hereby incorporated by reference for this particular purpose. 
Also a subject of the instant invention are the compositions produced in 
the above-described process of forming the exocyclic double bond leading 
to the desired 1-.beta.-methylcarbapenem intermediates being compositions 
of the Formula: 
##STR32## 
wherein R.sup.2 is independently selected from hydrogen, linear or 
branched C.sub.1 -C.sub.3 alkyl, which can be substituted with fluoro, 
hydroxy or protected hydroxy, R.sup.3 is hydrogen or a protecting group, 
R.sup.6 is hydrogen, a protecting group, or a covalent bond, and where 
R.sup.6 is a covalent bond, R.sup.3 and R.sup.6 are joined to form Y, a 
divalent bridging-protecting group, derived from a ketone, aldehyde or 
organosilicon compound, said group being stable to catalytic hydrogenation 
and removable by acid or base hydrolysis. The protecting groups R.sup.3 
and R.sup.6 are also removable by acid or base hydrolysis and include the 
triorganosilyl groups known in the art as also represented by R.sup.4 in 
Structure A. 
The compositions include these wherein said R.sup.2 is independently 
selected from H, CH.sub.3 --, CH.sub.3 CH.sub.2 --, (CH.sub.3).sub.2 CH--, 
HOCH.sub.2 --, CH.sub.3 CHOH--, (CH.sub.3).sub.2 COH--, FCH.sub.2 --, 
F.sub.2 CH--, F.sub.3 C--, CH.sub.3 CHF--, CH.sub.3 CF.sub.2, 
(CH.sub.3).sub.2 CF--, CH.sub.3 CH.sub.2 CHOH--,FCH.sub.2 CHOH--, and 
wherein said Y includes 
##STR33## 
Representative Examples of Structure V which include Y through the coupling 
of R.sup.3 and R.sup.6 resulting in Structure I are adequately illustrated 
hereinabove and need not be reiterated but are incorporated by reference 
herein as supplementing disclosure. 
Representative Examples of Structure V where R.sup.3 and R.sup.6 have other 
values than Y are presented in the following Table: 
TABLE 
______________________________________ 
##STR34## V 
Compound R.sup.2 R.sup.3 R.sup.6 
______________________________________ 
1 H H H 
2 CH.sub.3 H H 
3 CH.sub.3 CH.sub.2 
H H 
4 CH.sub.3 CH.sub.2 CH.sub.2 
H H 
5 (CH.sub.3).sub.2 CH 
H H 
6 HOCH.sub.2 H H 
7 CH.sub.3 CHOH H H 
8 (CH.sub.3).sub.2 COH 
H H 
9 DMTBSOCH.sub.2 H H 
10 DPTBSOCH.sub.2 H H 
11 TPSOCH.sub.2 H H 
12 IPDMSOCH.sub.2 H H 
13 CH.sub.3 CH(ODMTBS) 
H H 
14 CH.sub.3 CH(ODPTBS) 
H H 
15 CH.sub.3 CH(OTPS) 
H H 
16 CH.sub.3 CH(OIPDMS) 
H H 
17 (CH.sub.3).sub.2 C(ODMTBS) 
H H 
18 (CH.sub.3 ).sub.2 C(ODPTBS) 
H H 
19 (CH.sub.3).sub.2 C(OTPS) 
H H 
20 (CH.sub.3).sub.2 C(OIPDMS) 
H H 
21 FCH.sub.2 H H 
22 F.sub.2 CH H H 
23 F.sub.3 C H H 
24 CH.sub.3 CHF H H 
25 CH.sub.3 CF.sub.2 
H H 
26 (CH.sub.3).sub.2 CF 
H H 
27 H IPDMS H 
28 CH.sub.3 IPDMS H 
29 CH.sub.3 CH.sub.2 
IPDMS H 
30 CH.sub.3 CH.sub.2 CH.sub.2 
IPDMS H 
31 (CH.sub.3).sub.2 CH 
DMTBS H 
32 HOCH.sub.2 DMTBS H 
33 CH.sub.3 CHOH DMTBS H 
34 (CH.sub.3).sub.2 COH 
DMTBS H 
35 DMTBSOCH.sub.2 DPTBS DPTBS 
36 DPTBSOCH.sub.2 DPTBS DPTBS 
37 TPSOCH.sub.2 DPTBS DPTBS 
38 IPDMSOCH.sub.2 DPTBS DPTBS 
39 CH.sub.3 CH(ODMTBS) 
TPS H 
40 CH.sub.3 CH(ODPTBS) 
TPS IPDMS 
41 CH.sub.3 CH(OTPS) 
TPS DMTBS 
42 CH.sub.3 CH(OIPDMS) 
TPS DPTBS 
43 (CH.sub.3).sub.2 C(ODMTBS) 
H IPDMS 
44 (CH.sub.3).sub.2 C(ODPTBS) 
H DMTBS 
45 (CH.sub.3).sub.2 C(OTPS) 
H DPTBS 
46 (CH.sub.3).sub.2 C(OIPDMS) 
H TPS 
47 FCH.sub.2 IPDMS H 
48 F.sub.2 CH IPDMS H 
49 F.sub.3 C IPDMS H 
50 CH.sub.3 CHF DMTBS H 
51 CH.sub.3 CF.sub.2 
DMTBS H 
52 (CH.sub.3).sub.2 CF 
DMTBS H 
______________________________________ 
The abbreviations used: 
IPDMS = isopropyldimethylsilyl 
DMTBS = dimethylt-butylsilyl 
DPTBS = diphenylt-butylsilyl 
TPS = triphenylsilyl 
The structures and formulas representative of Structure V given in the 
above Table are not meant to be limiting, and other combinations of 
R.sup.2, R.sup.3 and R.sup.6 and their resulting species of Structure V, 
which will be obvious to one skilled in the art in light of this 
disclosure are also deemed to be included within the scope of this 
invention. 
Preferred compositions of Structure V are: 
##STR35## 
Also a subject of the invention are the intermediate compositions to I of 
the Structural formula: 
##STR36## 
wherein R.sup.2 is described hereinabove, R.sup.3 is hydrogen or a 
blocking group, X is sulfur or selenium, Q is hydroxymethyl, carboxy or 
C.sub.1 -C.sub.4 alkoxycarbonyl, and R.sup.1 is C.sub.1 -C.sub.4 alkyl, 
C.sub.6 -C.sub.10 aryl heteroaryl, said aryl and heteroaryl can contain 
substituents including C.sub.1 -C.sub.4 alkyl and alkoxy, nitro and the 
like, which are inert under the reaction conditions. By the term 
"substituted phenyl" is meant substituents inert under the reaction 
conditions leading to the synthesis of structure I and include C.sub.1 
-C.sub.4 alkyl, alkoxy, nitro and the like. 
Representative Examples of Structure IV are given in the following Table. 
__________________________________________________________________________ 
##STR37## IV 
Compound 
R.sup.1 
R.sup.2 R.sup.3 
Q X 
__________________________________________________________________________ 
1 Ph H H HOCH.sub.2 Se 
2 Ph CH.sub.3 H HOCH.sub.2 Se 
3 Ph CH.sub.3 CH.sub.2 
H HOCH.sub.2 Se 
4 Ph CH.sub.3 CH.sub.2 CH.sub.2 
H HOCH.sub.2 Se 
5 Ph (CH.sub.3).sub.2 CH 
H HOCH.sub.2 Se 
6 Ph HOCH.sub.2 H HOCH.sub.2 Se 
7 Ph CH.sub.3 CHOH 
H HOCH.sub.2 Se 
8 Ph (CH.sub.3).sub.2 COH 
H HOCH.sub.2 Se 
9 Ph FCH.sub.2 H HOCH.sub.2 Se 
10 Ph F.sub.2 CH H HOCH.sub.2 Se 
11 Ph F.sub.3 C H HOCH.sub.2 Se 
12 Ph CH.sub.3 CHF 
H HOCH.sub.2 Se 
13 Ph CH.sub.3 CF.sub.2 
H HOCH.sub.2 Se 
14 Ph (CH.sub.3).sub.2 CF 
H HOCH.sub.2 Se 
15 Ph DMTBSOCH.sub.2 
H HOCH.sub.2 Se 
16 Ph DPTBSOCH.sub.2 
H HOCH.sub.2 Se 
17 Ph TPSOCH.sub.2 
H HOCH.sub.2 Se 
18 Ph IPDMSOCH.sub.2 
H HOCH.sub.2 Se 
19 Ph CH.sub.3 CH(ODMTBS) 
H HOCH.sub.2 Se 
20 Ph CH.sub.3 CH(ODPTBS) 
H HOCH.sub.2 Se 
21 CH.sub.3 
CH.sub.3 CH(OTPS) 
H HOCH.sub.2 Se 
22 CH.sub.3 
CH.sub.3 CH(OIPDMS) 
H HOCH.sub.2 Se 
23 CH.sub.3 
(CH.sub.3).sub.2 C(ODMTBS) 
H HOCH.sub.2 Se 
24 CH.sub.3 
(CH.sub.3).sub.2 C(ODPTBS) 
H HOCH.sub.2 Se 
25 CH.sub.3 
(CH.sub.3).sub.2 C(OTPS) 
H HOCH.sub.2 Se 
26 CH.sub.3 
(CH.sub.3).sub.2 C(OIPDMS) 
H HOCH.sub.2 Se 
27 CH.sub.3 
H H COOCH.sub.3 Se 
28 CH.sub.3 
CH.sub.3 H COOCH.sub.3 Se 
29 CH.sub.3 
CH.sub.3 CH.sub.2 
H COOCH.sub.3 Se 
30 CH.sub.3 
CH.sub.3 CH.sub.2 CH.sub.2 
H COOCH.sub.3 Se 
31 CH.sub.3 
(CH.sub.3)CH 
H COOCH.sub.3 Se 
32 CH.sub.3 
HOCH.sub.2 H COOCH.sub.3 Se 
33 CH.sub.3 
CH.sub.3 CHOH 
H COOCH.sub.3 Se 
34 CH.sub.3 
(CH.sub.3).sub.2 COH 
H COOCH.sub.3 Se 
35 CH.sub.3 
FCH.sub.2 H COOCH.sub.3 Se 
36 CH.sub.3 
F.sub.2 CH H COOCH.sub.3 Se 
37 CH.sub.3 
F.sub.3 C H COOCH.sub.3 Se 
38 CH.sub.3 
CH.sub.3 CHF 
H COOCH.sub.3 Se 
39 CH.sub.3 
CH.sub.3 CF.sub.2 
H COOCH.sub.3 Se 
40 CH.sub.3 
(CH.sub.3).sub.2 CF 
H COOCH.sub.3 Se 
41 4-Pyr DMTBSOCH.sub.2 
H COOCH.sub.3 Se 
42 4-Pyr DPTBSOCH.sub.2 
H COOCH.sub.3 Se 
43 4-Pyr TPSOCH.sub.2 
H COOCH.sub.3 Se 
44 4-Pyr IPDMSOCH.sub.2 
H COOCH.sub.3 Se 
45 4-Pyr CH.sub.3 CH(ODMTBS) 
H COOCH.sub.3 Se 
46 4-Pyr CH.sub.3 CH(ODPTBS) 
H COOCH.sub.3 Se 
47 4-Pyr CH.sub.3 CH(OTPS) 
H COOCH.sub.3 Se 
48 4-Pyr CH.sub.3 CH(OIPDMS) 
H COOCH.sub.3 Se 
49 4-Pyr (CH.sub.3).sub.2 C(ODMTBS) 
H COOCH.sub.3 Se 
50 4-Pyr (CH.sub.3).sub.2 C(OTPS) 
H COOCH.sub.3 Se 
51 4-Pyr (CH.sub.3).sub.2 C(OIPDMS) 
H COOCH.sub.3 Se 
52 4-Pyr H DMTBS 
COOH Se 
53 4-Pyr CH.sub.3 DMTBS 
COOH Se 
54 p-Tol CH.sub.3 CH.sub.2 
DMTBS 
COOH Se 
55 p-Tol CH.sub.3 CH.sub.2 CH.sub.2 
DPTBS 
COOCH.sub.2 CH.sub.3 
Se 
56 p-Tol (CH.sub.3).sub.2 CH 
DPTBS 
COOCH.sub.2 CH.sub.3 
Se 
57 p-Tol HOCH.sub.2 DPTBS 
COOCH.sub.2 CH.sub.3 
Se 
58 p-Tol CH.sub.3 CHOH 
TPS COOCH.sub.2 CH.sub.2 CH.sub.3 
S 
59 p-Tol (CH.sub.3).sub.2 COH 
TPS COOCH.sub.2 CH.sub.2 CH.sub.3 
S 
60 p-Tol FCH.sub.2 TPS COOCH.sub.2 CH.sub.2 CH.sub.3 
S 
61 p-Tol F.sub.2 CH IPDMS 
COOCH(CH.sub.3).sub.2 
S 
62 p-Tol F.sub.3 C IPDMS 
COOCH(CH.sub.3).sub.2 
S 
63 p-Tol CH.sub.3 CHF 
IPDMS 
COOCH(CH.sub.3).sub.2 
S 
64 p-Tol CH.sub.3 CF.sub.2 
H COO(CH.sub.2).sub.3 CH.sub.3 
S 
65 p-Tol (CH.sub.3).sub.2 CF 
H COO(CH.sub.2).sub.3 CH.sub.3 
S 
66 p-MeOPh 
DMTBSOCH.sub.2 
H COO(CH.sub.2).sub.3 CH.sub.3 
S 
67 p-MeOPh 
DPTBSOCH.sub.2 
H COOCH.sub.2 CH(CH.sub.3).sub.2 
S 
68 p-MeOPh 
TPSOCH.sub.2 
H COOCH.sub.2 CH(CH.sub.3).sub.2 
S 
69 p-MeOPh 
IPDMSOCH.sub.2 
H COOCH.sub.2 CH(CH.sub.3).sub.2 
S 
70 p-MeOPh 
CH.sub.3 CH(ODMTBS) 
H COOCH(CH.sub.3)CH.sub.2 CH.sub.3 
S 
71 p-MeOPh 
CH.sub.3 CH(ODPTBS) 
H COOCH(CH.sub.3)CH.sub.2 CH.sub.3 
S 
72 p-MeOPh 
CH.sub.3 CH(OTPS) 
H COOCH(CH.sub.3)CH.sub.2 CH.sub.3 
S 
73 p-MeOPh 
CH.sub.3 CH(OIPDMS) 
H COOC(CH.sub.3).sub.3 
S 
74 p-MeOPh 
(CH.sub.3).sub.2 C(ODMTBS) 
H COOC(CH.sub.3).sub.3 
S 
75 p-MeOPh 
(CH.sub.3).sub.2 C(ODPTBS) 
H COOC(CH.sub.3).sub.3 
S 
76 p-MeOPh 
(CH.sub.3).sub.2 C(OTPS) 
H COOC(CH.sub.3).sub.3 
S 
77 p-MeOPh 
(CH.sub.3).sub.2 C(OIPDMS) 
H COOC(CH.sub.3).sub.3 
S 
__________________________________________________________________________ 
The abbreviations for the silyl protecting groups DMTBS et al. are 
described hereinabove and for R.sup.1 include Ph=phenyl, 4-Pyr=4-Pyridyl 
p-Tol=P-tolyl and p-MeOPh=p-methoxyphenyl. 
The structures and formulas representative of Structure IV given in the 
above TabIe are not intended to be limiting, and other combinations of 
R.sup.1, R.sup.2, R.sup.3, Q and X and their resultinq species of 
Structure IV, which will be obvious to one skilled in the art in light of 
this disclosure are also deemed to be included within the scope of this 
invention. 
A Preferred class of the compositions is of the structural formula: 
##STR38## 
wherein R.sup.3 and R.sup.4 are independently hydrogen or a blocking 
group. 
Particularly preferred are the compositions of the structural formula: 
##STR39## 
wherein R.sup.5 is H or C.sub.1 -C.sub.4 alkyl, preferably methyl. 
A further preferred compound is