Crotylsilanes chiral

SYNTHESIS OF CHIRAL (E)-CROTYLSILANES [3R- AND 3S-]-(4E)-NIETHYL 3-(DIMETHYLPHENYLSILYL)-4-HEXENOATE (4-Hexenoic acid, 3-(dimethylphenylsilyl)-, methyl ester,... 

Non-racemic a-substituted allylic silanes, in particular crotylsilanes, are very attractive reagents despite their rather tedious preparation. They were found to provide very high transfer of chirality in their additions to achiral aldehydes under Lewis acid catalysis (Eq. 114). These reagents have been tested several times in the context of natural product synthesis. Their diastereoselectivity (syn/anti) depends on several factors, including the natme of the aldehyde substrate, the reagent, and the natme of the Lewis acid employed. For example, the syn product can be obtained predominantly in the reaction of Eq. 114 by switching to the use of a monodentate Lewis acid such as BF3. 

Optically active crotylsilane 22 functions as a chiral carbon nucleophile in TMSOTf-catalyzed reactions with acetals giving homoallylic ethers 23 in high diastereo- and enantioselectivities (equation 14)58,59. 

Treatment of chiral (E)-crotylsilanes 47 with 43a in the presence of BF3-OEt2 gives tetrahydrofuran derivatives in good yield with 96% de. Interestingly, 1,2-silyl group migration competes favorably with elimination of the silyl group after condensation with 43a (equation 30)81. 

Lewis acid-catalyzed stereoselective addition of crotylsilanes to chiral 74 has been studied in detail111,112. The presence of the chiral auxiliary at C2 (e.g. p-tolylsulfinyl or menthoxy carbonyl group) induces the diastereofacially selective addition of cyclopentenones with crotylsilanes. Thus, ( )-crotylsilane favors the erythro product, whilst (Z)-isomer favors the threo product. High enantioselectivity is observed in both reactions (equation 48). In a similar manner, conjugated addition of allylsilane to 75 proceeds with high efficiency (equation 49)113. Interestingly, the yield and enantiomeric excess of the product is dependent on the amount of TiCL used and the best selectivity... 

The Simmons-Smith reaction of chiral ( )-crotylsilane 192 produces 193, which subsequently undergoes a ring-opening reaction followed by cyclization under acidic conditions to give 194 (equation 161)283. 

The total synthesis of (+)-Macbecin I 78 [39] began with aldehyde 73, prepared via the addition of optically pure crotylsilane onto a benzylic acetal, which underwent an SMS reaction to give ester 75 in a 12 1 syn/anti ratio. Oxidative cleavage of the double bond, Wittig olefination of the resulting aldehyde and a reduction-oxidation sequence yielded a,/ -unsaturated aldehyde 76. A second SMS reaction was then performed leading to polyether 77 (dr > 20 1) that contains all the chiral centers of (+)-Macbecin I 78, Scheme 13.31. 

Panek applied the same strategy and used the same optically pure crotylsilane 74 to prepare Epothilone A 81 [40, 41]. The SMS condensation between 74 and 79 afforded ester 80 in 83% yield and with a syn/anti ratio of 15 1. This fragment contains the two chiral centers present at C6 and C7 of Epothilone A 81 (Scheme 13.32). 

Chiral (E)-crotylsilanes have been utilized with Phi = NTs for Cu(I) - catalyzed syntheses of olefinic dipeptide isosteres, examples of which are shown in Scheme 70 [191]. In this case, tosylamidation occurs with allylic inversion,probably via asymmetric tosylaziridination of the C,C-double bond. The diastereos-electivity of product formation is high (>30 1) and appears to be strongly influenced by the hydroxyl group in the starting compounds. 

Leighton et al. used chiral allylsilane and crotylsilane reagents to synthesize two key intermediates, 48 and 50, in the total synthesis of dolabelide D (45), a 24-membered macrolide with cytotoxicity against HeLa-S3 cells26 (Scheme 3.2w). Asymmetric allylation of the aldehyde 46 with the chiral reagent (S,S)-27... 

Synthesis of Chiral (E)-Crotylsilanes [3R and 3S] (4E)-Methyl 3-(Dimethylphenyl)silyl-4-hexenoate. 

The synthesis of optically pure ( )-alkcnyl silanes from C-1 acyloxy ( >crotylsilanes via the suprafacial interchange of a variety of a-substituted esters (Y = H, OCH3, N3, Cl) proceeded with high chirality preservation under mild reaction conditions (entries 7 and 8)8. 

The final approach was elegantly presented by Panek [44]. Several optically active ( )-crotylsilanes are available via stereoselective Ireland-Claisen rearrangement of enantiomerically pure vinylsilanes. Addition of the chiral crotylsilanes to acetals or to mixtures of aldehyde and trimethylsilyl methyl ether is effected by la to afford homoallylic ethers in exceedingly high diastereo- and enantioselectivity (Sch. 13). Occasionally a stoichiometric amount of la is required for allylation of aliphatic acetals, preserving the excellent level of asymmetric induction. The synthesis of (-F)-macbecin I involving triple use of the strategy imderscores the utility of the la-catalyzed asymmetric allylation [44c]. 

Solid-supported synthesis has rapidly emerged as an important strategy in synthetic organic chemistry. Solid-phase methodology is aimed at the direct synthesis of libraries of molecularly diverse compounds for biological evaluation in lead discovery. The asymmetric addition of polymer-supported chiral crotylsilanes to acetals and allylation of polymer-bound acetals linked through an ester with the chiral crotylsilanes has been investigated [44d] la can be employed in these crotylation reactions and results in the formation of polymer-supported homoallylic esters with diastereoselec-tivity similar to that of solution-phase reactions. 

Behrens, K., Kneisel, B. O., Noltemeyer, M., Brueckner, R. Preparation of a-chiral crotylsilanes by retro-[1,4]-Brook rearrangements. A stereochemical study. Liebigs Ann. Chem. 1995, 385-400. 

Several research groups have developed chiral allyl- and crotylsilane reagents and studied the enantioselectivity of their reactions with aldehydes [12, 15]. Of these, the chiral crotylsilane reagents developed by Panek and co-workers (Fig. 11-32) have been most extensively applied to the synthesis of natural products. 

Panek has reported the reactions of chiral crotylsilanes, e.g. (S)-217c, with a variety of achiral acetals, resulting in the formation of homoallylic ethers 348 with high enantio- (>95% ee) and variable diastereoselectivities (Table 11-20) [149, 261]. The acetals can be formed in situ from the corresponding aldehydes via treatment with TMSOBn or TMSOMe in the presence of catalytic TMSOTf. 

As shown in Table 11-20, unbranched aldehydes (e.g. CH3CHO) react much less selectively with chiral crotylsilanes, where the anti adduct 349 is the minor product. This observation can be explained by an increase in product formation through the antiperiplanar transition state 352, which places the ) -methyl group of the crotylsilane in a position gauche to the aldehyde R group. Thus, as the size of the aldehyde R group decreases, transition state 352 becomes more viable. 

Panek and Cirillo demonstrated that the -methyl chiral crotylsilane (5)-217b favors formation of the 5,6-anti diastereomer in the chelate-controlled reaction with the achiral a-benzyloxy aldehyde 353 (Eq. (11.26)) [57, 58]. Here, the synclinal transition state 355 best explains the stereochemistry of the major adduct. 

Reaction of the same aldehyde 97c with enantiomeric crotylsilanes (5)-217 (R=Me, Et) results in preferential formation of the syn,nnft-dipropionates 359. These adducts can arise either through the Felkin synclinal transition state 360 or the Felkin antiperiplanar transition state 361 (Eq. (11.28)). In the reactions of aldehyde 97c with both the (R)- and (S)-crotylsilane reagent 217, the major products result from crotylsilane addition to the aldehyde via the normally favored Felkin orientation in the transition state. The chirality of the crotylsilane and the stereo-electronic preference for anti S e addition then dictate the facial selectivity of the crotylsilane reagent, which is translated into the stereochemistry of the C(5) methyl substituent of the product. 

Reaction of the /y-benzyloxy-o-methyl chiral aldehyde 97a with (/ )-crolylsi-lanes 217 (R = H, Et) under catalysis by TiC affords the ann,antt-dipropionate adduct 362 (Eq. (11.29)). The diastereoselectivity in this reaction is best explained by anti S e addition of the chiral crotylsilane to the least hindered face of the fi-alkoxy aldehyde chelate, as shown in the synclinal transition state 363. Finally, the anri.syn-dipropionate 364 may be obtained as the major adduct when aldehyde 97a is treated under the same conditions with the enantiomeric crotylsilane reagents (5)-217 (Eq. (11.30), R=Me, Et). This adduct should arise from the antiperiplanar transition state 365, where the anti S e facial selectivity of the crotylsilane reagent and the facial bias of the chiral aldehyde are maintained. In these cases, the factors that dictate the utilization of the synclinal vs the antiperiplanar transition states are (1) the requirement that a small substituent (H) occupy the position over the chelate ring, (2) that C-C bond formation occurs anti to the sterically demanding a-methyl group of the aldehyde and (3) the requirement for an anti Se mechanism, which dictates the stereochemistry of C(5) of the adducts 362 and 364. 

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