Enol silanes enantioselectivities

J0rgensen and co-workers (230) reported the aldol reaction between enolsilanes and ketomalonate esters. Catalyst 269c proved to be nearly nonselective in these reactions. Optimal conditions involve the use of < /-269d in Et20 at -78°C. The reactions are quite sluggish under these conditions. Benzosubarone-derived enol-silane affords the aldol adduct in 93% ee, Eq. 200, while propiophenone enolsilane provides the aldol product in 90% ee under identical conditions, Eq. 201. Other nucleophiles are less selective. No model was advanced to account for the observed enantioselectivities. 

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

Ferraris D, Young B, Cox C, Drury HI WJ, Dudding T, Lectka T (1998b) Diastereo- and enantioselective alkylation of alpha-imino esters with enol silanes catalyzed by (R)-Tol-BINAP-CuC10(4).(MeCN)(2). J Org Chem 63 6090-6091... 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

In contrast, enol silanes add to aldehydes with moderate to good enantioselectivity using Cu(OTf)2 and bisoxazoline 141 as a ligand (Sch. 34) [69]. The syn/anti selectivity was low and generally (Z) enolates gave higher yields. 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

Oxazaborolidenes. Corey has reported the use of a novel oxazaborolidene complex 41 prepared from borane and A-tosyl (5)-tryptophan. This complex functions in a catalytic fashion in enantioselective, Mukaiyama aldol addition reactions (Scheme 8-3) [17]. The addition of ketone-derived enol silanes 42-43 gives adducts in 56-100% yields and up to 93% ee. The use of 1-trimethylsilyloxycyclo-pentene 43 in the addition reactions to benzaldehyde affords adducts 46 as a 94 6 mixture of diastereomers favoring the syn diastereomer in 92% ee. Addition reactions with dienol silanes 44 furnishes products 47 in up to 82% ee. Corey also demonstrated the use of these adducts as important building blocks for the synthesis of corresponding dihydropyrones treatment of 47 with trifluoroacetic acid affords the cyclic product in good yields. 

The catalytic, enantioselective additions of thioacetate-derived enol silanes has also been studied by Keck (Eq. (8.15)) [29]. In these studies, the active catalyst (62) is readily generated upon mixing binol, TiCl2(0/Pr)2, and 4 A molecular sieves in Et20 at -20 °C followed by an aging period. The addition reactions are best conducted with 10 mol% catalyst in ether at -20 °C the f rt-butyl thioacetate adducts are isolated in up to 98% ee and 90% yield. 

Lectka and co-workers have simultaneously developed similar phosphine-transition metal catalysts for the same transformation [54a, 54b, 54c, 54d]. These researchers were interested in testing the reactivity of a-imino esters toward enol silane nucleophiles upon chelation with a late transition metal (Ag(I), Cu(I), Ni(II), and Pd(II)) as a means of substrate activation. This ultimately led to the development of a catalytic, enantioselective alkylation of a-imino esters with enol silanes in up to 98% ee and in high chemical yields (Scheme 28). 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

An enantioselective process which provides a powerful illustration of this phenomena has been documented by Evans (Scheme 11) [24]. In this work, the addition of enol silanes 79 to a-benzyloxyacetaldehyde is catalyzed by the optically active Cu(ll) bis(oxazoline) complex 80, furnishing adducts 82 in excellent... 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

A related Mukaiyama aldol catalyst system reported by Keck prescribes the use of a complex that is prepared in toluene from (R)- or (S)-BINOL and Ti(0 Pr)4 in the presence of 4 A molecular sieves. In work preceding the aldol addition reaction, Keck had studied this remarkable catalyst system and subsequently developed it into a practical method for enantioselective aldehyde allylation [95a, 95b, 95c, 96]. Because the performance of the Ti(IV) complex as an aldol catalyst was quite distinct from its performance as a catalyst for aldehyde allylation, a careful examination of the reaction conditions was conducted. This meticulous study describing the use of (BINOL)Ti(OiPr)2 as a catalyst for aldol additions is noteworthy since an extensive investigation of reaction parameters, such as temperature, solvent, and catalyst loading and their effect on the enantiomeric excess of the product was documented. For example, when the reaction of benzal-dehyde and tert-butyl thioacetate-derived enol silane was conducted in dichlo-romethane (10 mol % catalyst, -10 °C) the product was isolated in 45% yield and 62% ee by contrast, the use of toluene as solvent under otherwise identical conditions furnished product of higher optical purity (89% ee), albeit in 54% yield. For the reaction in toluene, increasing the amount of catalyst from 10 to 20 mol %... 

The catalytic process has found successful application in several natural product total syntheses. In 1996, Simon reported a synthesis of the antitumor dep-sipeptide FR-9001,228 in which the aldol addition reaction of 168 and the ethyl acetate-derived enol silane furnished a key synthetic intermediate (Eq. 23). The enantioselective aldol addition reaction of 168 was conducted with 165 and its enantiomer ent-165 to separately provide both enantiomers of the aldol adducts 169 and 170 (Scheme 14). These were then utilized in the preparation of diastereomeric seco acids 171 and 172 [101]. Macrocyhzation of 172 through a Mitsonobu reaction yielded the desired natural product 173. 

The addition of ketone-derived enol silanes and aldehydes in the presence of 184 at -78 °C in propionitrile afforded the aldol adducts in excellent yields as well as diastereo- and enantioselectivity (Eq.29) [106]. The versatility of this catalyst is evidenced by the fact that enol silanes derived from aliphatic methyl and ethyl ketones as well as acetophenone are substrates for the aldol addition reaction. 

The use of these boryl complexes in catalytic, enantioselective additions to aldehydes by silyl ketene acetals has also been the subject of intense investigation by Yamamoto (Eq. 30) [108]. Although ethyl and benzyl acetate-derived enol silanes furnished racemic products, the phenyl acetate-derived trimethylsilyl ketene acetals proved optimal, giving adducts in up to 84% ee. Additionally, Yamamoto has documented the use of 184 in aldol addition reactions of propionate- and isobutyrate-derived enol silanes (Eqs. 31 and 32). Thus, the addition of the phenyl acetate derived (E)-enol silane afforded adducts as diastereomeric mixtures with the syn stereoisomer displaying up to 97% ee (Eq. 32). 

For an enantioselective addition of enol silanes to acetals mediated by a boryl complex incorporating a chiral indolyl group, see Kinugasa M, Harada T, Oku A (1996) J Org Chem 61 6772... 

Titanium-based Lewis acids are widely used in the Mukaiyama reaction, i. e. the condensation of an enol silane and an aldehyde, giving 3-hydroxycarbonyl derivatives. In this context, BINOL-derived chiral titanium complexes were used in the condensation of thioester-derived ketene silyl acetals with a large range of aldehydes, in high yields and enantioselectivities (Scheme 7.39). ... 

Stoltz reported the extension of their methodology to silyl enol ether substrates (Scheme 4.18) [36]. In many cases these enolate precursors are easier to prepare compared to their enol carbonate counterpart. The addition of diallyl carbonate was necessitated to generate the enol carbonate in situ. Tetrabutylammonium difluoro-triphenylsiUcate (TBAT) was also required to activate the cleavage of the enol silane in situ at a temperature for asymmetric induction to occur. Nearly identical levels of enantioselectivity were obtained with this system. 

Kobayashi and coworkers reported addition of enol silanes (72) to aldehydes (71) catalyzed by Cu(OTf)2/(52) (Scheme 17.14) [19]. Moderate to good enantioselectivities could be obtained with low syn/antiselectivity. The reduced enantioselectivity relative to bidentate acceptors employed may be attributed to single-point coordination to the Lewis acid. This point is noteworthy, as acceptors restricted to single-point coordination continue to be challenging substrates in copper-catalyzed aldol reactions. 

Beck EM, Hyde AM, Jacobsen EN. Chiral sulfinamide/ achiral sulfonic acid cocatalyzed enantioselective protonation of enol silanes. Org. Lett. 2011 13 4260-4263. 

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