Alcohols optically active, synthesis

The 7, i5-unsaturated alcohol 99 is cyclized to 2-vinyl-5-phenyltetrahydro-furan (100) by exo cyclization in aqueous alcohol[124]. On the other hand, the dihydropyran 101 is formed by endo cyclization from a 7, (5-unsaturated alcohol substituted by two methyl groups at the i5-position. The direction of elimination of /3-hydrogen to give either enol ethers or allylic ethers can be controlled by using DMSO as a solvent and utilized in the synthesis of the tetronomycin precursor 102[125], The oxidation of the optically active 3-alkene-l,2-diol 103 affords the 2,5-dihydrofuran 104 in high ee. It should be noted that /3-OH is eliminated rather than /3-H at the end of the reac-tion[126]. 

Other uses of Snp2 are in the synthesis of fluorophosphate glasses having low melting temperatures (13—15), in formation of transparent film (16), and in the preparation of optically active alcohols (17). 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Hydroboration - regloseiective and stereoselective (syn) addition of BH3 (RBH2, R2BH) to olefins. Synthesis of alcohol including optically active alcohols from olefins. Also useful In synthesis of ketones by stitching ot olefins and CO... 

An asymmetric synthesis has used the reduction of imonium salts to optically active tertiary amines with lithium aluminum alkoxy hydrides derived from optically active alcohols (538,539). 

A chiral protective group was developed for use in the synthesis of optically active alcohols. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

The optically active iodide 153 (Scheme 43) can be conveniently prepared from commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate (154) (see Scheme 41). At this stage of the synthesis, our plan called for the conversion of 153 to a nucleophilic organometallic species, with the hope that the latter would combine with epoxide 152. As matters transpired, we found that the mixed higher order cuprate reagent derived from 153 reacts in the desired and expected way with epoxide 152, affording alcohol 180 in 88% yield this regioselective union creates the C12-C13 bond of rapamycin. 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

An efficient synthesis of optically active pentanedioates is possible using ester enolates based on chiral alcohols. This is illustrated by the addition of the lithium (fl-cnolate of (1 R,2S,5R)-5-methyl-2-(1-methyl-l-phenylethyl)cyclohexyl propanedioate to methyl ( )-2-butenoate at — 100 °C which shows simple and induced diastereoselectivity. 

Chiral alcohols have also been used in an asymmetric synthesis of sulphoxides based on halogenation of sulphides. Johnson and coworkers have found319 that the reaction of benzyl p-tolyl sulphide with JV-chlorobenzotriazole (NCBT) followed by addition of (—) menthol and silver tetrafluoroborate afforded diastereoisomeric menthoxysulphonium salts 267 which, upon recrystallization and hydrolysis, gave benzyl p-tolyl sulphoxide with 87% optical purity (equation 145). More recently, Oae and coworkers reported320 that optically active diaryl sulphoxides (e.e. up to 20%) were formed either by hydrolysis or thermolysis of the corresponding diaryl menthoxysulphonium salts prepared in situ from diaryl sulphides using ( —) menthol and t-butyl hypochlorite. 

Durst and coworkers were the first to report the condensation of chiral a-sulphinyl carbanions with carbonyl compounds477. They found that metallation of ( + )-(S)-benzyl methyl sulphoxide 397 followed by quenching with acetone gives a mixture of dia-stereoisomeric /i-hydroxy sulphoxides 398 in a 15 1 ratio (equation 233). The synthesis of optically active oxiranes was based on this reaction (equation 234). In this context, it is interesting to point out that condensation of benzyl phenyl sulphoxide with benzaldehyde gave a mixture of four / -sulphinyl alcohols (40% overall yield), the ratio of which after immediate work-up was 41 19 8 32478. 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Example Optically active acid (16) was needed (p T 107 ) for the synthesis of an ant alarm pheromone. The branch point ( in 16) is also the chiral centre so it is better to avoid disconnections there. The 1,2 C-C disconnection (16a) is ideal as it gives synthon (17), for which we use a malonate ester, and halide (18), available from optically active alcohol (19), a major by-product from fermentation. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Synthesis of optically pure compounds via transition metal mediated chiral catalysis is very useful from an industrial point of view. We can produce large amounts of chiral compounds with the use of very small quantities of a chiral source. The advantage of transition metal catalysed asymmetric transformation is that there is a possibility of improving the catalyst by modification of the ligands. Recently, olefinic compounds have been transformed into the corresponding optically active alcohols (ee 94-97%) by a catalytic hydroxylation-oxidation procedure. 

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