Diastereomeric mixture, intermediate alcohols

Exposure of the diastereomeric mixture of alcohols 497 to TFA leads to the construction two nonaromatic rings via a cation-alkene cyclization process. The chroman 498 is isolated as a 1 1 mixture of epimeric alcohols and is a key intermediate during cannabinoid synthesis (Equation 203) <2000JOC6576>. 

In another approach, the alcohol moiety, formed by an enzymatic hydrolysis of an ester, can act as a nucleophile. In their synthesis of pityol (8-37a), a pheromone of the elm bark beetle, Faber and coworkers [17] used an enzyme-triggered reaction of the diastereomeric mixture of ( )-epoxy ester 8-35 employing an immobilized enzyme preparation (Novo SP 409) or whole lyophilized cells of Rhodococcus erythro-polis NCIMB 11540 (Scheme 8.9). As an intermediate, the enantiopure alcohol 8-36 is formed via kinetic resolution as a mixture ofdiastereomers, which leads to the diastereomeric THF derivatives pityol (8-37a) and 8-37b as a separable mixture with a... 

Like Still s reagent, tributyl[(methoxymethoxy)methyl)etannane incorporates an alcohol protective group that can be conveniently unmasked under mild acidic conditions. However, an advantageous feature of this MOM ether derivative is that, in contrast to Still s reagent, it is achiral. In many applications the introduction of an additional chiral center into synthetic intermediates is undesirable because of the complications associated with the manipulation, analysis, and purification of diastereomeric mixtures. 

On the other hand, when the allylic benzimidate 13 was treated with phenylselenenyl bromide, cyclization occurred to form the intermediate diastereomeric iminium salts 14 which were directly converted in good yield into the corresponding synjanti mixtures of amino alcohol derivatives 15. The stereoselectivity of the cyclization was determined by hydrodeselenation of the purified diastereomeric mixtures, hydrolysis of the benzoate esters and comparison of the resulting amino alcohols with authentic samples245. 

Attempts to extend this methodology to a-sulfinyl derivatives of other esters have been only moderately successful. As shown in Scheme 14, ester (215) may be deprotonated by r-butylmagnesium bromide and added to aldehydes, although not to ketones. The intermediate P-hydroxy-a-sulfinyl esters, in each case a mixture of diastereomers, are reduced to obtain diastereomeric mixtures of -hydroxy esters. The diastereomeric ratio of these materials does not reveal the degree of asymmetric induction in the original aldol reactions, because of the unknown stereochemistry of the desulf urization step. Aldols (216) were converted by a three-step process into secondary alcohols (217), which were found to have isomeric purities of 33.5% enantiomeric excess for R = Ph and 80% enantiomeric excess for R = n-heptyl. 

By examining Scheme 1 it is possible to verify the key role of the base as catalyst for the overall process and to justify the lack of stereoselectivity which, in general, has been observed in nitroaldol additions. In fact, the reversibility of the nitroaldol process, as well as the difficulty of a stereoselective protonation of the stereogenic center of the nitronate intermediates, leads to a mixture of diastereomeric 2-nitro alcohols. 

Nakai and coworkers have reported that a mixture of diastereomeric tin precursors 28 can be used to provide highly enantio enriched products, as shown for the conversion of 28 to 29 (Scheme 8). Furthermore, reduction of 29 is diastere-oselective to afford (following chiral auxiliary removal) enantio enriched (3-amino alcohols, 30 [22]. In another report, Nakai has described the conversion of the diastereomeric organolithium intermediates from tin-lithium exchange of 28 to copper species which can be used for 1,4 additions to a, 3-unsaturated aldehydes... 

The Boekelheide reaction was applied by the Nicolaou groups in the synthesis of a model system of the thiopeptide antibiotic thiostrepton (302). The tetrahydroquinoline 303 was converted into the A -oxide by /w-CPBA oxidation followed by treatment with TFAA and then hydrolysis to afford key intermediate alcohol 304 as a diastereomeric mixture. 

Vinyl sulfoxide isomerization followed by Mislow-Evans rearrangement was also central to a S5mthetic route toward the hydroazulene moiety of the antibiotic fungal metabolite guanacastepene A fScheme 18.611. In this case, a diastereomeric mixture of vinyl sulfoxides 241 resulted upon oxidation of the starting vinyl sulfide 240. Subsequent treatment with DBU led to the sequential isomerization/[2,31-rearrangement process. Under these conditions, the intermediate sulfenate was converted to the allylic alcohol 242, produced as a 4 1 mixture of epimers. Here, the modest selectivity in formation of the allylic stereocenter was of no synthetic consequence, as the alcohol was subsequendy oxidized to the corresponding enone. Notably, the overall conversion from 240 to 242 represents a 1,3-vinyl-to-allyl heteroatom transposition. 

For the construction of the crucial eight-membered ring of pacUtaxel via Heck cyclization, the vinyl iodide 434 has been used as an intermediate (Scheme 3.83) [135]. To obtain the secondary alcohol in a stereochemically pure form the addition of lithiated aryl bromide 435 to aldehyde 434 was investigated. It turned out that the presence or absence of a TMS-protecting group at the tertiary alcohol was crucial. Thus, TMS-derivative 434 gave a diastereomeric mixture of 436 and 437 after desilylation, whereas the reaction of the free alcohol 438 led to diastereomericaUy pure 440, presumably via a chelate 439 in which the quaternary carbon directs the nucleophilic attack to the opposite face. 

The mechanism proposed for the transformations is illustrated in Scheme 1.77. The P-keto ester 176 approaches the planar iminium ion from the Re-f cQ due to steric hindrance of the bulky substituents at the chiral substituent in the pyrrolidine ring of catalyst 128. Hydrolysis of the enamine intermediate leads to the formation of Michael adducts 178 in a 1 1 diastereomeric mixture. The role of AcONa is therefore to promote the aldol reaction and the consequent consumption of the optically active product 179. Finally, the stronger base (K COj) deprotonates the alcohol and enables the intramolecular Sj 2 reaction, which leads to one-pot formation of the highly functionalized products 177. 

Next, a three-step sequence was employed to convert diastereomeric spirocycles 415 to epoxy ketone 416. This intermediate was subjected to a Wharton rearrangement using 5.0 equiv hydrazine and 0.5 equiv HO Ac to yield the desired transposed allyl alcohol 417-trans in 66% yield as an inseparable diastereomeric mixture. While we observed this tra/w-allyl alcohol in most trials, we found the c/r-allyl alcohol 417-c/r in 42% yield when using 10 equiv HOAc. 

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. 

A tandem hydroformylation/carbonyl ene reaction can be observed in cases, in which substrates with at least two isolated oleftnic bonds are hydro-formylated at only one double bond selectively. Thus hydroformylation of limonene with PtCkCPPlH /SnCk/PPlH or PtCl2(diphosphine)/SnCl2/PPh3 gives a mixture of two diastereomeric alcohols upon carbonyl ene reaction of the intermediate aldehyde, (Scheme 36). Best results are achieved with a PtC Cdppb) complex. The mechanism of the final intramolecular cycli-zation step resembles an acid catalyzed carbonyl ene reaction [89]. 

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