Sakurai reaction stereoselectivity

The intramolecular Sakurai reaction allows for the synthesis of functionalized bicyclic systems. By proper choice of the reaction conditions, especially of the Lewis acid or fluoride reagent used, high stereoselectivity can be achieved, which is an important aspect for its applicability in natural products synthesis. 

Propargylsilanes can also be employed in the Sakurai reaction. For example the enone 6, containing a propargylsilane side chain, undergoes an intramolecular Sakurai reaction, catalyzed by an acidic ion-exchange resin—e.g. Amberlyst-15—to give stereoselectively the bicyclic product 7 in good yield ... 

Allyl- and vinylsilane chemistry was one of the first areas of reagent synthesis impacted by CM methodology. Allylsilanes are commonly employed in nucleophilic additions to carbonyl compounds, epoxides, and Michael acceptors (the Sakurai reaction) vinylsilanes are useful reagents for palladium-coupling reactions. As the ubiquitous application of CM to this substrate class has recently been described in several excellent reviews, this topic will not be discussed in detail, with the exception of the use of silane moieties to direct CM stereoselectivity (previously discussed in Section 11.06.3.2). 

This Sakurai reaction has been used for a stereoselective synthesis of nootkatone (2),4 an eremophilane sesquiterpene. Thus the trienone 1 cyclizes to 2 at 0° in the presence of C2H5A1C12 in 50% yield. TiCl4 and BF3 0(C2H5)2 are less effective catalysts (28% and 23% yields of 2). 

Intramolecular Sakurai reaction (7, 371). The intramolecular conjugate addition of an allylsilanc group to an a,f3-enone can be effected with high stereoselectivity. Thus... 

Sakurai reaction (7, 371).4 Blumenkopf and Heathcock5 have examined the stereochemistry of the Sakurai reaction and of the di-n-alkyl cuprate addition as applied to 4- and 5-methylcyclohexenones. The stereoselectivity of the former reaction can be higher than that of the latter reaction, and can even be in a different sense. 

Another type of convertible nucleoside phosphoramidite, a derivative of (5 S)-5 -C-(5-bromo-2-penten-l-yl)-2 -deoxyribosylfuranosyl thymidine (49), has been reported. The synthesis of this phosphoramidite was stereoselective and involved a Sakurai reaction between 5 -C-thymidine aldehyde and allyltrimethylsilane. Seela has reported the synthesis of the ribosyl-phosphoramidite derivatives of 7-bromo- and 7-iodo-8-aza-7-deazapurine-2,6-diamine (50a,b) from advanced synthetic precursors and of the bromo- and iodo-derivatives at the 5-position of uracyl phosphoramidite (51a,b). He further described the effect on base-pair stability due to their incorporation into oligonucleotide duplexes. ... 

In 1976 we reported that aldehydes and ketones are efficiently allylated with allyl-trimethylsilane in the presence of a substoichiometric amount of I iLf, [332]. Subsequently, BU4NF, a fluoride ion source, was found to be an effective catalyst of this allylation reaction [333]. After these initial reports of the Hosomi-Sakurai reaction, several allylsilanes, including highly functionalized compounds, were used for regio- and stereoselective allylation of a variety of carbon electrophiles [6, 13, 14, 334]. In the nineteen-eighties, some Lewis acids (TMSOTf [335], TMSI [336]... 

Previous work on intramolecular Sakurai reactions using allylsilanes has now been extended to include propargyl silanes. Using this method a number of bicyclic allene products were prepared in stereoselective fashion (Scheme 49). 

The 5-lactols and their acetylated derivatives (2, 8) are activated by acid to form oxonium cation intermediates (3, 9), which are attacked by nucleophiles to provide the substituted tetrahydropyrans with good stereoselectivity (Scheme 3) [13]. As the nucleophiles, allylsilane 4 (Hosomi-Sakurai reaction), silyl enol ethers 5 (Mukaiyama aldol) and EtaSiH (reduction) have frequently been used. Since the axial attack of the nucleophiles determines the product s... 

The aldehyde 218 possessing 2,6-frans-tetrahydropyran, was synthesized as shown in Scheme 48. /3-Keto ester 220 was reduced by Noyori hydrogenation [97] to give 6-hydroxy ester 221 in 94% ee, which was converted into iodide 222. Asymmetric alkylation using Myers chiral auxiliary [98] with 222, followed by acid treatment, furnished 5-lactone 223 with high stereoselectivity. Reductive acetylation, axial allylation by the Hosomi-Sakurai reaction, and ozonolysis completed the synthesis of 218. 

Further broadening the methodology, the conversion of a (Z)-2,4-dienyl ether into its ( )-isomer has been exemplified in the presence of Pd(II) (Scheme 17) [35]. Alternatively, the Sakurai reaction was employed by the same authors to convert stereoselectively 2,4-dienyl(trimethyl)silane and aldehyde into 2,4-dienol adducts in the presence of Lewis acid. 

Scheme 8,17 Stereoselective construction of cyclic ethers using the TST-RCM in conjunction with the Sakurai reaction.

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

The nature of the Lewis acid catalyst has been found to play a pivotal role in the chemo- and stereoselectivities of the Sakurai-Hosomi reaction. For example, the reaction of 33, which contains both allylsilane and allylstannane moieties, with benzaldehyde leads to the silyl-substituted homoallylic alcohol 34 in moderate yield when a mild Lewis acid such as Et3Al is used. On the other hand, when BF3 OEt2 or fluoride ion is employed,... 

A stereoselective tandem Sakurai-carbonyl-ene reaction for the synthesis of steroid derivatives has been reported [48]. When LtAlCl2 and la were employed in this cyclization, stereochemical control was different. The cyclization product obtained with la is only 19 (Sch. 17), even though the starting material contained all four geometrical isomers use of LtAlCl2 resulted in a mixture of two different stereoisomers in lower yield. 

Stable pentacoordinated allylsiliconates have been employed in aldehyde addition reactions. These reagents require no activation by Lewis acids or Lewis bases, but have found only limited applications in synthesis to date. The use of these agents in addition to aldehydes was first described in 1987 by Corriu [59] and Hosomi [60] and by Kira and Sakurai [61] in 1988. In these reactions, the addition of a catechol or 2,2 -biphenol-derived allylsiliconate to an achiral aldehyde led to the highly regio- and stereoselective formation of homoallylic alcohols. For example, the addition of the catechol-derived 2-butenylsiliconate 81 (90/10 E Z) provided a diastereomeric mixture of homoallylic alcohols 74 and 75 in a 90/10 ratio (Scheme 10-33) [60c]. 

TiCl4 is used extensively as a Lewis acid in numerous organic transformations, forming adducts that mediate reactivity. Such reactions include Diels Alder, 54,355 hetero Diels Alder,356 cyclization of olefinic aldehydes,357 Flosomi Sakurai allylic coupling reactions,358 cyclopropanations,359 chal-cogen-Baylis Flillman,360 Mukaiyama Aldol reactions,36 363 reductions of ketones to alcohols 364 and stereoselective nucleophilic additions to aldehydes.365... 

In Fig. 10, reaction of 1 with chlorosilane 6 yielded the N-silyl derivative 7 that was not isolated but directly transformed into alkene 8 (the precursor of epoxide 3 of Fig. 9) under Sakurai s conditions. Both the yield (50%) and the stereoselectivity (80 20 for the indicated isomer) were not very high, but the road was paved toward a better process. 

Substituted 4-methylenetetrahydropyrans are formed stereoselectively by a Bi(III)-promoted intramolecular Sakurai cyclisation (Scheme 7) <01TL8685> and Sn(ll) catalyses the reaction of acetals with the allylsilane 9 which also yields the 4-methylene compounds (Scheme 8) <01Ba569>. 

A mimetic reaction has been developed extensively and is known to proceed with the aid of a metal ion such as Zn(II). As has been achieved in the stereoselective reductions by NAD(P)H-models in which one of enantiofaces is frozen, freezing of a face of the pyridine ring in pyridoxal or its model compound will result in the stereoselective mimetic transamination. Kuzuhara and his co-workers have synthesized pyridoxamine analogues that have planar chirality and have succeeded in observing asymmetric transamination (Iwata et al. 1976, Kuzuhara et al. 1977, 1978, Sakurai et al. 1979, Ando et al. 1982, Tachibana et al. 1982a,b, Breslow et al. 1980). The reaction is shown in Scheme 31 and the results are summarized in Table 30. 

J. Org. Chem. 2(X)4, 69,4(X)5—4(X)6. Iodine as a very powerful catalyst for three-component synthesis of protected homoal-lylic amines, (c) J.-R. Ella-Menye, W. Dobbs, M. BUlet, P. Klotz, A. Mann, Tetrahedron Lett. 2005, 46, 1897-19(X). Unexpected 1,2 syn diastereoselectivity in the three-component aza Sakurai-Hosomi reaction, (d) M. Sugiura, K. Hirano, S. Kobayashi, J. Am. Chem. Soc. 2004, 126, 7182-7183. a-Aminoallylation of aldehydes with ammonia stereoselective synthesis of homoallylic primary amines, (e) M. BiUet, P Klotz, A. Mann, Tetrahedron Lett. 2(X)1,42, 631-634. Syn diastereoselectivity in the synthesis of homoallylamine using crotylsilane in the three-component reaction, (f) L. Niimi,... 

Other Lewis acid mediated C-C bond forming reactions of silylated C-nucleophiles include the Mukaiyama aldol and Michael additions of enolsilanes ), the related reaction of allylsilanes described by Sakurai ) as well as similar reactions of Me3SiCN ). Other "inert C-nucleophiles such as dialkylzinc compounds also react with carbonyl compounds in the presence of Lewis acids ). We ourselves have utilized many of these processes in performing stereoselective reactions, particularly in achieving diastereofacial selectivity in the reactions... 

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