Chiral a-methyl

Z)-l-Methyl-2-butenylboronate 7 undergoes an exceptionally enantioselective reaction with benzaldehyde (99% ee), propanal (79%. 98% ee), 2-methyl-2-propenal (85%, 99% ee), and ( )-2-methyl-2-pentenal (81 %, 99% ee)10 38. Excellent enantioselectivity is also realized in reactions of the analogous chiral a-methyl-) y-disubstituted allylboronate27 40. Whether the l,2-dicyclohexyl-l,2-ethanediol auxiliary plays a beneficial role in this reaction, as suggested above for the asymmetric allylboration reactions of 6, has not yet been determined. 

I 7 Versatile Oligo(N-Substituted) Clycines The Many Roles of Peptoids in Drug Discovery Tab. 1.2 Examples of chiral a-methyl N-substituted glycine side chains... 

The oxazoline methodology can be applied in the total synthesis of natural products. For example, in the course of the total synthesis of European pine-saw fly pheromone 47, the key intermediate, chiral a-methyl carboxylic acid 46, was prepared via the reaction of a-lithioethyloxazoline with n-octyl iodide. The product 2-methyl decanoic acid 46 was obtained, after hydrolysis, in 72% ee (Scheme 2-26).51... 

Not surprisingly, these additions favor the anti products in ratios that reflect the steric requirement of the aldehyde substituent (Table 9.54). Additions to chiral a-methyl-/ -oxygenated propanals show remarkable reagent control (Eq. 9.145). The anti adducts are formed to the exclusion of the syn diastereomers when enantiomeric mesylates are employed with the (R)-aldehyde. 

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. 

Racemization of chiral a-methyl benzyl cation/methanol adducts. The rate of exchange between water and the chiral labeled alcohols as a function of racemization has been extensively used as a criterion for discriminating the Sn2 from the SnI solvolytic mechanisms in solution. The expected ratio of exchange vs. racemization rate is 0.5 for the Sn2 mechanism and 1.0 for a pure SnI process. With chiral 0-enriched 1-phenylethanol in aqueous acids, this ratio is found to be equal to 0.84 0.05. This value has been interpreted in terms of the kinetic pattern of Scheme 22 involving the reversible dissociation of the oxonium ion (5 )-40 (XOH = H2 0) to the chiral intimate ion-dipole pair (5 )-41 k-i > In (5 )-41, the leaving H2 0 molecule does not equilibrate immediately with the solvent (i.e., H2 0), but remains closely associated with the ion. This means that A inv is of the same order of magnitude of In contrast, the rate constant ratio of... 

Fig. 8. Preparation and reaction of C-containing chiral a-methyl-a-phenylmalonic acid...

Scheme 9. Stereoinduction model for the additions of chiral a-methyl crotylboronate 21.

The present method is practical and efficient as it employs readily available enantioenriched propargylic alcohols4 as precursors to the allenylindium reagents. With achiral aldehydes the diastereoselectivity is high for branched aldehydes, moderate for unbranched aldehydes, and low for benzaldehyde (Table I).5 With chiral a-methyl aldehydes6 the additions proceed under effective reagent control to afford anti adducts of high ee and with excellent diastereoselectivity (eq. 1 and 2). Comparable results were Obtained with 3 1 dimethyl sulfoxide-tetrahydrofuran (DMSO-THF) as the solvent. 

Chiral a-methyl-a-amino acids The reaction of phenylacetone with (S)-(-)-l in the presence of NaCN in HOAc affords one (R,S)-diastereomer (2), which is converted to the amide 3 on hydrolysis. Hydrogenation of 3 provides (R)-( + )-2-methy 1-3-phenylalanine (4) in >98% ee. 

Chiral a-methyl aldehydes. Reaction of optically active 2,3-epoxy alcohols with AI(CH,)i results in a mixture of two diols that arc not separable by conventional chromatography. However, the 1,2-diol is oxidized by NaI04 to a chiral a-methyl aldehyde, which is easily separated from the 1,3-diol. 

Treatment of N-acyloxazolidinones with di-n-butylboron triflate in the presence of Et3N furnishes the (Z)-(O) boron enolates. These on treatment with aldehydes give the corresponding 2,3-syn aldol products (the ratio of syn- to anti- isomers is typically 99 1 ). On hydrolysis they produce chiral a-methyl-(3-hydroxy carboxylic acids, as exemplified below. The facial selectivity of the chiral boron enolate is attributed to the favored rotomeric orientation of the oxazolidinone carbonyl group, where its dipole is opposed to the enolate oxygen dipole. At the Zimmerman-Traxler transition state, the aldehyde approaches the oxazolidinone appendage from the face of the hydrogen rather than from the benzyl substituent. 

Gennari, C., Vieth, S., Comotti, A., Vulpetti, A., Goodman, J. M., Paterson, I. Diastereofacial selectivity in the aldol reactions of chiral a-methyl aldehydes a computer modelling approach. Tetrahedron 1992, 48,4439-4458. 

Results of reactions of chiral a-methyl aldehydes and several chiral crotyl- and allyl-boron reagents are summarized in Tables 8 and 9. It is apparent from these data that the Brown (Ipc)2B(crotyl) and (Ipc)2B(allyl) reagents (51), (52) and (219) consistently give excellent results for the synthesis of each product diastereomer (Table 8, entries 3-6, 11, 16, 20, and 24 Table 9, entries 1,2, 10 and 18). This is true also for their reactions with chiral a- and 3-alkoxy aldehydes (Scheme 49).i. i4S-i50 Thg tartrate crotylboronates (18) and (19) also display excellent selectivity in the synthesis of crotyl diastereomers (136), (137) and (139) (Table 8, entries 7,10,13,17,25 and 28), but are much less selective for the syndesis of crotyl diastereomer (138), especially from -alkoxy-substituted aldehydes such as (253). Tartrate allylboronate (224) is also less effective than (Ipc)2Ballyl (219) for the synthesis of (257) and (258) in Table 9, and of (266) and (267) in Scheme 49.Substantial improvements in selectivity have been realized by using the taitramide-based allylboronate (228), and the results with this reagent (Table 9, entries 4, 7, 9, 12, 14, 17, 20 and 22) compare very favorably with those obtained with (219). The data... 

Chiral a-methyl aldehydes (43) show exceptional diastereofacial preferences in their Lewis acid mediated reactions with enol silanes (equation i6) 2i 25c-26-64 selected data are reported in Table 8. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the stereocenter when the carbonyl group is bound to the Lewis acid. Additions to chiral a-alkoxy aldehyde (48) were studied with both nonstereogenic (equation 17 Table 9) and stereogenic enol silanes (equation 18 Table 10). (Stereogenic and nonstereogenic are defined according to Mislow and Siegel.) ... 

Table 8 Ratio of Diastereoisomers in the BF3 0Et2-mediated Reactions of Enol Silanes with Chiral a-Methyl...

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