A-Methyl aldehyde

Table 9. Anti-Cram Alkylation of a-Methyl Aldehydes I R2M - 78 °C...

Mukaiyama reactions of a-methyl aldehydes proceed through an open TS and show a preference for the 3,4-syn stereoisomer, which is consistent with a Felkin TS.80... 

Advantage of this chelation has been taken in the construction of compounds with several contiguous chiral centers. Z-2-Butenyl trifluorosilanes give sy -l,3-diols on reaction with a fz -(3-hydroxy-a-methyl aldehydes.111 The stereoselectivity is consistent with a chelated bicyclic TS. 

The corresponding syn-P-hydroxy-a-methyl aldehydes do not react through a chelated TS,112 which appears to be due to steric factors that raise the bicyclic TS by several kcal relative to the anti isomers. The monocyclic six-membered TS does not incorporate these factors and the syn isomer reacts through a monocyclic TS. Figure 9.3 depicts the competing TSs and their relative energies as determined by MNDO calculations. 

Addition to chiral aldehydes. Brown et al.2 have examined the reaction of the chiral aldehyde 2 with the (E)- and (Z)-isomers of (+)- and (- )-l. The stereochemistry at the newly formed bond between C4 and C5 is controlled by the chirality of 1. The reaction affords two of the possible diastereomeric products in 64% de. Similar results have been reported by Roush et al. for reaction of a (3-alkoxy-a-methyl aldehyde. 

The present method is practical and efficient as it employs readily available enantioenriched propargylic alcohols 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). With cHral a-methyl aldehydes 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 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. 

Additions of the presumed /3-oxygenated allylic trichlorostannane to a-methyl, a-benzyloxy and /3-benzyloxy aldehydes are characterized by high reagent-controlled diastereoselectivity (Eq. 48) [70]. In the several examples examined aldehyde facial attack is little influenced by the resident chirality of the aldehyde. The result is particularly striking with the a-methyl aldehyde where the syn, syn adduct is the product of Felkin-Ahn addition and the anti, syn adduct is the anh-Felkin-Ahn or chelation-controlled adduct. 

Trimethylsiloxycyclopropanes, readily available from silyl enol ethers and carbene or carbenoid species, constitute, now, very useful synthetic intermediates . Thus, they undergo acid-, base-inducedor thermal ring-opening into a-methylated aldehydes and ketones in very good yields. The reaction is highly regiospecific in the case of an unsymmetrical ketone, monomethylation can be oriented either to the a- or a -position (equation 58) °°. This sequence has been applied to ethylenic ketones and in the steroid field . ... 

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.) ... 

In the Held of chiral electrophiles, diastereoselective additions of enolsilanes to chiral a-fluoro-a-methyl-P-alkoxy aldehydes, a-methyl aldehydes, a-alkoxy aldehydes, a,p-dialkoxy aldehydes and a-methyl-P-alkoxy aldehydes were reported to proceed with good stereocontrol following Felkin-Anh or chelation models (c/. Section 2.4.4.1). Very good selectivities were reported in the addition of enolsilanes to chiral imines, particularly those derived from carbohydrates (Scheme 17 and 18).i. 6... 

Stereoselective aldol reactions of a-methyl aldehydesThe lithium enolatc of this ethyl ketone (1) reacts with various a-methyl aldehydes to form aldols, which after protection as silyl ethers and thermolysis (500 ) were isolated as the a, / -unsaturated ketones 2 and 3. The diastcrcoselectivity is highly dependent on the R group. Thus... 

Isatins 72 reacted with a-methyl aldehydes (77a) catalyzed efficiently by tetrazole 90a (15 mol%) in the presence of 1 equiv. of water and using phosphoric acid (15 mol%) as co-catalyst at 0°C in isopropanol, to afford the corresponding aldol... 

---