Crotylsilane Reagents

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 and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

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. 

The observed selectivity for the 5,6-syn adduct 348 can be explained by either the anti Sg synclinal transition state 350 or the anti Se antiperiplanar transition state 351 (Fig. 11-33). It is generally accepted that the silicon substituent adopts a position anti to the incoming electrophile anti Sy so as to minimize steric interactions and to maximize the stereoelectronic effects (3d 2p donation by the silicon substituent) [9, 52]. When explaining the selectivity for products 348, Panek 

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. 

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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... 

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. 

The extensive use of chiral ( )-crotylsilane reagents in the synthesis of oligomycin clearly illustrates the utility of these reagents in solving a wide range of... 

Arefolov A, Panek JS. Crotylsilane reagents in the synthesis of complex polyketide natural products total synthesis of (+)-discodermolide. J. Am. Chem. Soc. 2005 127 5596-5603. 

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. 

The BINOL/BINAP Lewis acid complexes and the CAB catalyst are complementary in the following respects in general, the BINOL/BINAP-Lewis acid complexes provide excellent enantiocontrol in the reactions of aldehydes with allyltri-n-butylstannane, but poor diastereocontrol (syn anti) in the reactions of aldehydes with crotyltri- -butylstannane. In contrast, when the CAB catalyst is used to promote the reaction of aldehydes and crotylsilane or crotylstannane reagents, excellent levels of diastereo- and enantioselectivity are achieved, while in the corresponding reactions with allyltri-n-butylstannane poor levels of enantioselectivity are realized. 

The first example of chiral Lewis base-catalyzed allylation of carbonyl compounds was shown by Denmark et al. [35]. They surveyed a variety of achiral and chiral Lewis bases as stoichiometric reagents to promote the addition of al-lyltrichlorosilane to benzaldehyde and found that the chiral phosphoramide 14 was a superior chiral promoter. When crotyltrichlorosilane was employed, the diastereoselectivity anti/syn) of the product was dependent on the geometry of the crotylsilane. Based on the stereochemical outcome, the reaction was proposed to proceed via closed transition structures involving hexacoordinate siH-conates. The potential for catalysis was proved using a 25 mol % of 14 at -78 °C and a moderate enantiomeric excess was obtained (Scheme 13). 

Interestingly, (E)- and (Z)-crotyltrifluorosilane(19)/CsF systems showed high threo- and erythro-selectivity, respectively, in the addition to aldehydes. As shown in Table VI, the ratio of diastereomers was found to be actually the same as the starting E/Z ratio of crotylsilanes. A simUar selectivity was found for the crotylation of 2-ethylbutanal. The aUyltrifluorosilane/CsF systems are highly promising as synthetic reagents for diastereospecific aUylation of aldehydes. 

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