Diastereoselectivity, with

Versatile [3 + 2]-cydoaddition pathways to five-membered carbocydes involve the trimethylenemethane (= 2-methylene-propanediyl) synthon (B.M. Trost, 1986). Palladium(0)-induced 1,3-elimination at suitable reagents generates a reactive n -2-methylene-l,3-propa-nediyl complex which reacts highly diastereoselectively with electron-deficient olefins. The resulting methylenecyclopentanes are easily modified, e. g., by ozonolysis, hydroboration etc., and thus a large variety of interesting cyclopcntane derivatives is accessible. 

Boland applied this methodology to Garner s aldehyde, and found the addition to be substrate-controlled rather than reagent-controlled (Scheme 9.13b) [68]. Viny-lepoxide 15 could thus also be obtained with high diastereoselectivity with achiral 9-MeO-9-BBN. 

As with oxathianes 3 (R1 = CH, R2 = H), which bear a close structural resemblance to 17, the addition of organometallic reagents is highly diastereoselective with a predominant chelation-controlled attack of the nucleophile from the Rc-sidc35 -40. In the case of vinylmagnesium bromide a considerable enhancement of the diastereo selectivity could be attained by adding... 

Addilion of benzophenone to the lithium derivative 2 (M = Li) proceeds in a stereorandom fashion, which is attributed to the participation of radicals, detected by ESR and produced by single-electron transfer (SET)12. The magnesium derivative reacts with 90% diastereoselectivity with no SET being recorded. Benzaldehyde as the carbonyl compound affords the [1/, 1(1S)]-and [15,1(1/ )]-diastereomers in a 70 30 mixture, with 40% de12. Enhanced selectivities are achieved with camphor-derived 2-(2-oxazolyl)isoquinolines12a. 

The lithium cnolate generated by deprotonation of 2-/m-butyl-6-methyl-l,3-dioxan-4-onc, readily available from polyhydroxybutyric acid (PHB), predominantly affords the diastereo-mers 7 when reacted with aldehydes. The diastereomeric ratios of aldol adducts 7/8, produced by reactions with aliphatic aldehydes, range from 87.5 12.5 to >99 1. Pure diastereoiners7are obtained by recrystallization in 25-74% yield116-118. Only marginal diastereoselectivities with respect to the carbinol center are obtained with aromatic aldehydes111-119. Benzoylation of the dioxanones 7, followed by reduction with lithium aluminum hydride, affords enan-tiomerically and diastereomerically pure triols 9 in >85% yield 11. ... 

As an alternative to lithium enolates. silyl enolates or ketene acetals may be used in a complementary route to pentanedioates. The reaction requires Lewis acid catalysis, for example aluminum trifluoromethanesulfonate (modest diastereoselectivity with unsaturated esters)72 74 antimony(V) chloride/tin(II) trifluoromethanesulfonate (predominant formation of anti-adducts with the more reactive a,/5-unsaturated thioesters)75 montmorillonite clay (modest to good yields but poor diastereoselectivity with unsaturated esters)76 or high pressure77. 

The enantiomerically pure, doubly activated a, /j-olefinic sulfoxides 46-5095 98 undergo highly diastereoselective Diels-Alder cycloadditions with cyclopentadiene, and pyridyl vinylic sulfoxide 5199 reacts diastereoselectively with furan. It is noteworthy that olefins singly-activated by only a sulfinyl group are not effective partners in Diels-Alder cycloadditions, as we have found after many attempts and as has been reported recently98. 

The diastereoselectivity observed in simple systems led to investigation of enantiomerically pure aldehydes. It was found that the E- and Z-2-butenylboronates both exhibit high syn-anti diastereoselectivity with chiral a-substituted aldehydes. However, only the Z-isomer also exhibited high selectivity toward the diastereotopic faces of the aldehyde.38... 

Detailed studies have been carried out on the stereoselectivity of a- and -substituted aldehydes toward the tartrate boronates.47 a-Benzyloxy and (3-benzyl oxy-a-methylpropionaldehyde gave approximately 4 1 diastereoselectivity with both the R, R- and S, S- enantiomers. The stereoselectivity is reagent (tartrate) controlled. The acetonide of glyceraldehydes showed higher stereoselectivity. 

Indium chloride in polar solvents such as acetone or acetonitrile leads to good diastereoselectivity with cyclohexanecarboxaldehyde and other representative aldehydes.176... 

A better diastereoselectivity with Cu-catalyzed cyclopropanation was discovered. 

A polymeric version of Jacobsen s Cr-salen catalyst has also been reported <06TA1638>. This polymeric catalyst worked well with a variety of amines, showed excellent enantio- and diastereoselectivity with an enantiomeric excess of 90-98%. Most importantly the catalyst was reusable with no loss in stereoselectivity of the products. 

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

In an analogous approach, the chiral stabilized azomethine ylide 165, generated in situ via Lewis acid-catalyzed condensation of (53 )-5-phenylmorpholin-2-one 164 with 2,2-dimethoxypropane, was trapped diastereoselectively with singly and doubly activated dipolarophiles such as the acrylate (Scheme 24). The cycloadduct 84 was then employed to furnish enantiomerically pure 5,5-dimethylproline derivatives (see Section 11.11.6.3), <2001SL1836>. 

However, similar cyclization of the related diamide 6 results in the -/-lactone 7, formed with moderate diastereoselectivity with the pro-R carbonyl group. The unexpected asymmetric bias is ascribed to the highly strained diamide ring of 6. 

Tolman and co-workers (67) investigated a series of pyrazolyl-derived ligands for this reaction. Initial investigations centered on the use of tris(pyrazolyl) phosphine oxide (95) as a ligand with chirality derived from camphor. Diastereoselectivities with ethyl diazoacetate are poor, slightly favoring the cis isomer, and enantioselectivities are modest, Eq. 50. The BHT esters greatly increase the diastereoselectivity of this process (96 4) at the expense of enantioselectivity (10% ee for trans isomer). 

With the proper choice of reaction conditions, diastereoselective synthesis of a-allenic alcohols 69 and 70 from propargylic epoxide 68 was achieved [80, 81], With RMgBr and 5 mol% of CuBr/2PnBu3, anti allenic alcohols 69 are obtained with up to 100% diastereoselectivity. On the other hand, syn allenic alcohols 70 can be prepared with 88-96% diastereoselectivity with RMgCl, Me3SiCl and 5mol% CuBr (Scheme 3.36). 

The silyl effect is also seen for chiral a-methyl-/f-silyloxypropanals (Eq. 9.148), although the improvement from >95 5 (Eq. 9.145) to 99 1 is not dramatic. Additions to chiral -oxygenated aldehydes are also more diastereoselective with the TMS-sub-stituted reagent (Eq. 9.149). The origin of this effect remains to be discovered. 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

The catalyst can also have a significant influence on the stereoselectivity of cyclopropanation reactions [1023], For instance, cyclopropanation of styrene with ethyl diazoacetate and copper or rhodium catalysts normally proceeds with low diastereoselectivity. With ruthenium porphyrines as catalysts, however, up to 92% de can be achieved [1041,1042]. 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

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