Syn-Homoallylic alcohols

HOFFMAN - YAMAMOTO Stereoselective adylations Synthesis of syn or anti homoallylic alcohols from Z or E crotylboronate and aldehydes (Hoffman) or of syn homoallylic alcohols from crotylstannanes, BF3 and aldehydes (Yamamoto)... 

Diastereoselective reaction with fl-alkoxy-a-methylpropionaldehydes.1 The reaction of (R,R)-1 with the chiral aldehyde 2a provides the syn-homoallylic alcohol... 

More interestingly, it was found that in the condensation of allylstannane 191 with a-alkoxyaldehyde 193, the stereochemistry of the final adduct could be controlled by the amount of Lewis acid employed. Remarkably, if one equivalent of SnCl4 is used, the anti-homoallylic alcohol 194 is produced exclusively (Scheme 13.68) [87]. In stark contrast, if two equivalents of SnCl4 are employed, the reaction produces only the syn-homoallylic alcohol 195. 

Another synthetic application of Roush s crotylboration methodology using a (Z)-crotylboronate can be found in the formal synthesis of (+)-discodermolide (75)29 (Scheme 3.1z). The aldehyde (S)-67, which was prepared from the Roche ester, reacted with (Z)-crotylboronate (S,S)-43Z to give the syn-homoallylic alcohol 76. Silylation of alcohol and oxidative cleavage of the alkene 77 provided the aldehyde 78, from which the final product (75) can be synthesized according to a known procedure.30... 

The transfer of the allylic moieties from boron to the electrophilic carbonyl carbon proceeds via rearrangement to form intermediate boronic esters C and D (see below). The reaction is highly diastereoselective. The ( )-crotylboronate reacts to give the anfr-homoallylic alcohol and the (Z)-crotylboronate reacts to afford the syn-homoallylic alcohol.This behavior has been interpreted in terms of the Zimmerman-Traxler chair-type transition state model.Because of the double bond geometry, coordination of the (Ei-crotylboronic ester places the Me preferentially equatorial, whereas coordination of the (Z)-crotylboronic ester places the Me axial, as illustrated in the cyclohexane chair-form transition state conformations A and B, respectively. In both cases, the R moiety of the aldehyde must occupy a pseudo-equatorial position to avoid steric repulsion by one of the OR substituents on boron. 

IJ-Sigmatropic Rearrangements Table 6 Synthesis of Syn Homoallylic Alcohols - ... 

Panek and co-workers demonstrated that the reaction of (5)-2-benzyloxypropa-nal (17) with the allylic silane (5)-18 under the influence of Bp3-OEt2 gave the syn homoallylic alcohol 19 with excellent level of Felkin induction [35]. Interestingly, the high level of syn selectivity was also observed in the condensation of 17 and (/ )-18. On the other hand, the reaction of 17 with (5)-18 in the presence of TiCLj produced anti homoallylic alcohol 20 almost exclusively, whereas the reaction with (R)-18 promoted by TiCL afforded syn homoallylic alcohol 21. Presumably, the reactions proceeded through a Cram chelate transition state model... 

The stereochemical complexity of the reaction can be further increased when an ( )- or (Z)-2-butenylsilane reacts with a chiral aldehyde. Herein both diastereo-selection processes are operative, relative (between the reacting faces) and internal with respect to the original stereogenic center in the aldehyde. Thus, the reaction of jff-benzyloxy aldehyde 32 and silane ( )-31 with bivalent Lewis acids (SnCU, TiCU) was examined in the presence of an additive, e.g. MgBr2, ZrCp2Cl2, TiCp2Cl2 (Scheme 10-12) [32]. The reactions all afford mixtures of the four possible diastereomeric products, favoring the syn homoallylic alcohol. When the com-... 

The reaction of //-methyl-2-butenylsilanes 36 and stannanes with chiral a-al-koxyaldehydes has also been reported [33]. Surprisingly, the anti homoallylic alcohols were predominantly observed (94/6, ant i/syn) when a bivalent Lewis acid such as SnCl4 was used (Scheme 10-13). A synclinal transition structure is proposed to account for the observed selectivity. In the chelation-controlled reactions the synclinal transition structure is favored over the corresponding antiperiplanar transition structure because there exists an open space wherein the complexed Lewis acid can reside. The monovalent Lewis acid BF3-OEt2 provides the expected syn homoallylic alcohol, presumably through the antiperiplanar transition structure shown (66% of the product was the syn alcohol 37). 

The Lewis acid-promoted reaction of the allylsilane (R)-43 with either of the (5)-a-alkoxy aldehydes provides some surprising insights (Scheme I0-19) [34]. The BF3-OEt2-promoted reaction of the silane (R)-43 and either (S)-26 or (S)-46 afforded predominantly the syn homoallylic alcohols 50 and 51, even though this is presumed to be a mismatched combination of reagents. The TiCL-promoted reaction of ( )-43 with (5)-26 or (S )-46 also produces the syn homoallylic alcohols, presumably through a Cram chelate transition structure model (albeit with lesser selectivity for 46). These experiments indicate that the chirality of the R-silane re-... 

Another enantiosdective variant of this reaction has been developed with a bi-nol-titanium complex 66 [46]. This catalyst affords homoallylic alcohols in moderate diastereo- and enantioselectivity with 2-butenylsilane ( )-16 and methyl glyoxylate (Scheme 10-25). Reaction of (Z)-16 was much less selective, providing homoallylic alcohols with low enantioselectivity. An antiperiplanar transition structure accounts for the formation of the syn homoallylic alcohol 67. A more reactive complex formed from BINOL and TiF4 has also found utility [46cj. 

The reaction of ( )- and (Z)-71 with aldehydes has been demonstrated to proceed smoothly with high regio- and diastereoselectivity [50]. Reaction of the ( )-71 provides almost exclusively the syn homoallylic alcohols, while (Z)-71 provides the corresponding anti alcohols. The stereochemical course of the reaction has been attributed to the intermediacy of a chairlike, six-membered transition structure assembly which incorporates all three elements and places the C(3) substituent in pseudoequa-torial or pseudoaxial orientations according to olefin geometry (Scheme 10-29). 

The reaction of highly strained allylsilacyclobutanes with aldehydes has recently been developed to produce homoallylic alcohols with a high degree of re-gio- and stereoselectivity (Scheme 10-36) [63]. These species are structurally akin to the allyltrialkylsilanes, but are more mechanistically aligned with the allyltri-halosilanes. The -2-butenylsilacyclobutane upon reaction with an aldehyde at elevated temperature will produce almost exclusively the anti homoallylic alcohol. When the Z-2-butenylsilacyclobutane is used instead, the syn homoallylic alcohol is obtained. The mechanism proposed for the reaction involves the association of aldehyde and allylsilacyclobutane to form an activated pentacoordinate silicon complex. A closed, chair-like transition structure is proposed to account for the observed stereoselectivity in the reaction (Scheme 10-36k A theoretical examina-... 

The stereochemical course of the thermally promoted addition of allylic trialkyl-stannanes to aldehydes is dependent upon the geometry of the 2-butenyl unit [67, 69], The reaction is believed to proceed via a cyclic, six-membered, chair-like transition structure. Reaction of an -2-butenylstannane provides the anti homoallylic alcohol, while an Z-2-butenylstannane affords the corresponding syn homoallylic alcohol (Scheme 10-37). The allylation of aldehydes with allylic stannanes has also been performed under high pressure and neutral conditions [70]. The stereochemical outcome of the reaction of E- and Z-2-butenylstannanes with aldehydes under high pressure was almost identical to the results obtained thermally. 

The Lewis acid-promoted addition of allylic trialkylstannanes to achiral aldehydes has been demonstrated to provide syn homoallylic alcohols in high yield [71 a,b]. The relative stereochemical outcome of the reaction of simple aldehydes with 2-butenylstannanes is discussed earlier in this Chapter. Studies on the addition of al-... 

The reaction afforded the syn homoallylic alcohol highly selectively, although both the E- and Z-olefins were produced in the reaction (Scheme 10-63). 

The BF3-OEt2-promoted reaction of the enantiomerically enriched MOM-pro-tected alkoxystannane (S)-150 with the aldehyde (5)-26 (mismatched series) affords a mixture of syn and anti homoallylic alcohols 152 and 153 (Scheme 10-65) [103]. The matched series gives much higher selectivity for the syn homoallylic alcohol. Reaction of the TBS-protected alkoxystannane (Sl-lSl with the aldehyde (S)-26 provided the syn homoallylic alcohol 154 and a cyclopropane derivative (not shown). When the bivalent Lewis acid MgBr2 was employed, the stereochemical outcome of the reaction was significantly altered. The anti homoallylic alcohol 156 was favored with the MOM-protected alkoxystannane, while the syn homoallylic alcohol 159 was the only product observed with the TBS-protected alkoxystannane. Antiperiplanar transition structures are proposed to account for the observed selectivity in these reactions. 

The diastereoselective production of homoallylic indium alkoxides can be accomplished by a kinetic resolution process [194]. The indium-mediated reaction of benzaldehyde with 2-butenyl bromide has always been observed to be unselec-tive. The use of alkoxide or halide modifiers in the reactions of allylindium reagents has previously been shown to provide synthetically useful reagents [195], Upon addition of 2-butenylindium sesquibromide to benzaldehyde it was determined that newly formed syn and anti homoallylic alcohols undergo decomposition at a similar rate, but as the concentration of the anti homoallylic alcohol reaches zero, the rate of decomposition of the syn alcohol slows dramatically. Thus, the syn homoallylic alcohol can be obtained in high diastereoselectivity, albeit low yield. 

A highly stereoselective synthesis of trifluoromethylated homoallylic alcohols is possible using the transmetallation [Sn(II) to In(IIl)] pathway [205], The indium trichloride/tin-promoted reaction of trifluorobromobutene with various aldehydes afforded the homoallylic alcohols in extremely high yield and diastereos-electivity (Scheme 10-105). The strong preference for the anti products with the simple aldehydes is expected on the basis of previous observations with 2-buteny-lindium reagents explained by the cyclic transition structure xxxiv shown. The syn homoallylic alcohol was obtained upon reaction of glyoxylic acid and 2-pyri-dinyl carboxaldehyde. The syn products were proposed to arise by reaction via the 5-membered chelate transition structures xxxv and xxxvi. 

The (5, 5,5 )-a-methylcrotylboronate 211 reacts in a highly selective manner with a variety of aldehydes to form preferentially the (E)-syn homoallylic alcohols 301 (Table 11-16) [250]. In this reaction, homoallylic alcohols 301 are produced preferentially via transition state 303 since the competing transition state 304 is destabilized by unfavorable 1,3-interactions between the a-methyl and the y-methyl groups of the crotylboronate 211. 

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