Aldol reaction homoallylic alcohol synthesis

Metallic tin, Sn(0), is even more effectively employed. For example, in the presence of Sn(0), allyl bromide and a-halocarbonyl compounds afford nucleophilic organometallic species, which add to aldehydes in good yields to give homoallylic alcohols (12) and g-hydroxycarbonyl compounds (13,14) respectively. a-Diketones could be reduced by activated Sn(0), to give tin(II) enediolates which in turn undergo aldol reaction to form a,g-dihydroxyketones (15,16). This reaction was successfully applied to a stereoselective synthesis of methyl D-glucosaminate (17). 

Stevastelins are depsipeptides exhibiting immunosuppressant activity. The first total synthesis of stevastelin B was described by Y. Yamamoto and co-workers. To construct four consecutive stereocenters, the Evans aldol reaction and the Roush asymmetric allylation were utilized. In the allylation step, the authors used (S,S)-diisopropyltartrate-derived ( )-crotyl boronate. The anti homoallylic alcohol product formed as the only diastereomer. 

The synthesis of methyl ketone 281 began with the reaction between the tetra-substituted allylborane 279 and 2,3-0-isopropylidene-D-glyceraldehyde 48. The resulting homoallylic alcohol 280, obtained in 73% yield and excellent selectivity (exact ratio not defined) [231], was converted in two steps to the methyl ketone 281. Aldol condensation between the lithium enolate of 281 and aldehyde 278 (structure shown in Scheme 11-12) gave, after protection of the initial adduct, the Felkin diastereomer 282 as the only reported product in 54% yield. This adduct... 

Asymmetric allylation of aldehyde 66, available in two steps from 3-hydroxypropionitrile, with allyl borane 67 gave the expected homoallylic alcohol 68 in good yield and with acceptable enantioselectivity. This material was converted uneventfully to a doubly protected dihydroxy aldehyde 69 and thence to 70 along lines similar to our synthesis of 56 from 34 (see Scheme 8). The aldol reaction employed within this five step sequence provided the means to remove vestiges of the minor enantiomer of 69 introduced from the allylation of 66. In an... 

With this preliminary phase of synthetic work accomplished, the more intriguing elements of the anticipated epothilone A synthesis could now begin in earnest. As shown in Scheme 21, the initial merger of fragments 61, 63, and 64 into advanced intermediate 60 proceeded quite smoothly. Treatment of 63 with 2,3 equivalents of LDA in THF at —78°C with warming to —40°C over one hour (to effect both deprotonation of the free acid and formation of the enolate) was followed by the addition of 1.6 equivalents of aldehyde 64, leading to a facile aldol reaction which provided 62 and its C6—C7 syn diastereomer in a 3 2 ratio that favored the desired drawn product. This mixture was carried forward and the acid was esterified directly with the homoallylic thiazole alcohol 61 in the presence of DCC and 4-DM AP to afford, after chromatographic separation, pure 60 (in 52 % yield firom 63) and its alternative syn disposed C6—C7 isomer (in 31 % yield from 63). 

The aldol methodology was applied to the synthesis of FK-5067 Treatment of aldehyde 20 with cyclic borane 21 afforded homoallylic alcohol 22 in 17 1 diastereoselectivity (eq 8). Borane 21 was prepared from the reaction of (5, -1 with 2-acetoxyallyltri-7 butylstannane in CH2CI2 for 5 min at -78 °C, and then at 23 °C for 1.5 h. Reaction of the CH2CI2 solution in situ with aldehyde 20 at -78 °C for 1 h produced homoaUylic alcohol 22 as the major product. The bis(tosyl)amide from which reagent 21 was derived was efficiently recovered for reuse. 

Studies on the stereochemical outcome of the reaction of 2-alkenyl organometallic reagents with aldehydes have increased recently, largely because stereoselectively produced homoallylic alcohols are synthetically equivalent, by cleavage at the carbon-carbon double bond, to the type of aldol adduct stereoisomers required for macrolide antibiotic total synthesis. A new stereoselective synthesis of (Z)-2-alkenyltins (46a) or the corresponding silanes (46b) from allyl or vinyl 9-BBN derivatives has appeared (Scheme 20). The... 

Carreira has demonstrated that the hydroxy-directed nitrile oxide cycloaddition reaction is a general synthetic approach to polyketide fragments, with the intermediate isoxazolines functioning as latent, masked aldol adducts [65], The 1,3-dipolar cycloadditions have been shown to tolerate a large variety of alcohol substrates, including aliphatic allylic, homoallylic, and cyclic allylic alcohols [65-67], A demonstration of the versatility of the approach was reported in the synthesis of erythronolide A (58, Scheme 18.12) [67], This synthetic effort took advantage of two sequential hydroxy-directed nitrile oxide cycloadditions to provide fragments 55 and 57, both of which were obtained with excellent yields and diastereoselectivity (dr2 98 2). 

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