Selective Asymmetric Boron Aldol Reactions

Conventional asymmetric aldol reactions have been performed by using chiral enolates and achiral carbonyl compounds. A chiral boron enolate generated from a chiral oxazolidone derivative (26 and 28), dialkylboron tri-fiate, and diisopropylethylamine reacts stereoselectively with aldehydes to afford the corresponding syn aldol adducts (27 and 29) in good yields with excellent diastereoselectivity (Eqs. (8) and (9)) [12]. The opposite sense of asymmetric induction is achieved by changing the chiral auxiliary. Several other chiral auxiliaries have also been developed for highly diastereoselec-tive synthesis of syn aldol adducts (Eqs. (10)-(13)) [13]. 

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Typical Procedure for syn-Selective Asymmetric Boron Aldol Reaction (Eq. (17)) [13]... 

SCHEME 2.109 Evans auxiliary performing highly iyn-selective asymmetric boron aldol reaction. 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

The boron-aldol reaction of the p-methoxyben-zyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stereodifferential aldol reaction with chiral boron ligands [7]. The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. 

Altogether, four asymmetric, a r/-selective, boron aldol reactions were employed in this highly convergent synthesis (26 steps longest linear sequence, 5.3% overall yield), which ensured a high level of stereocontrol throughout. 

Scheme 5.58 Selection of chiral boron catalysts used for the asymmetric Mukaiyama aldol reaction.

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

ANTI-SELECTIVE BORON-MEDIATED ASYMMETRIC ALDOL REACTION OF CARBOXYLIC ESTERS SYNTHESIS OF (2S, 3R)-2,4-DIMETHYL-1,3-PENTANEDIOL... 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

ANTI-SELECTIVE BORON-MEDIATED ASYMMETRIC ALDOL REACTION OF 116... 

Anti-selective Boron-mediated Asymmetric Aldol Reaction of Carboxylic Esters. 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

Asymmetric Aldol Reactions. Reaction of (1) with Boron Tribromide in CH2CI2 affords, after removal of solvent and HBr, a complex (5) useful for the preparation of chiral enolates (eq 5). Complex (5) is moisture sensitive and is generally prepared immediately before use. For propionate derivatives, either syn or, less selectively, anti aldol adducts may be obtained by selection of the appropriate ester derivative and conditions. Thus reaction of f-butyl propionate with (5) and triethylamine produces the corresponding E 0) enolate, leading to formation of anti aldol adducts upon addition to an aldehyde (eq 6). Selectivities may be enhanced by substitution of the t-butyl ester with the (+)-menthyl ester. Conversely, reaction of 5-phenyl thiopropionate with (5) and Diisopropylethylamine affords the corresponding Z(0) enolates and syn aldol products (eq 7). ... 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

Treatment of aldehyde ent-91c with R,R)-2 9 resulted in the stereoselective (selectivity = 9 1) formation of adduct enf-105c, via the mismatched double asymmetric reaction discussed previously (Eq. (11.17)). Aldehyde 251, derived in two steps from olefin e r-105c, underwent an asymmetric aldol reaction [206] with the boron enolate of 252, generating adduct 253 stereoselectively. Adduct 253 was converted in five steps to aldehyde 254, which underwent a matched double asymmetric reaction with (S,S)-219, affording stereoheptad 255 in 90% yield (selectivity =>98 2). Adduct 255 was then elaborated to aldehyde 256, which was directly submitted to the matched double asymmetric reaction with R,R)-2 9, affording the advanced adduct 257 (selectivity=>98 2), which was converted in seven steps to the C(l)-C(13) fragment 250 of (-t-)-damavaracin D. 

Their 3,3 -substituents are utilized not only for their steric bulk, but also for the coordination to metals. Yamamoto and coworkers employed a boron complex of 3,3 -bis(2-hydroxyphenyl) BINOL in the asymmetric Diels-Alder reaction of cyclopentadiene and acrylaldehyde (equation 70) . The ligand possesses two additional hydroxy groups and forms a helical structure on coordination. The catalyst is considered to function as a chiral Brpnsted acid and a Lewis acid. The complex was also used in the Diels-Alder reactions and aldol reactions of imines. Although addition of diethylzinc to aldehydes gives low ee using BINOL itself or its 3,3 -diphenyl derivative, the selectivity can be increased when coordinating groups are introduced at the 3,3 -positions. Katsuki and... 

Other oxazolidinones have been used as chiral auxiliaries in asymmetric aldol reactions. Bomane derivatives 1.121 (X = O or S) and 1.122 are readily transformed into V-acyl derivatives. The reactions of their boron or titanium enolates with aldehydes give the same selectivities as Evans s reagents [426, 428, 429, 431, 436], iV-Acylimidazolidinones 1.131 and 1.132 [449, 1270] lead to similar results, but the selectivities observed are somewhat lower. 

Chiral amides (222) and (223) and imides (224) and (225) have also been studied as reagents for asymmetric aldol reactions. These reagents show excellent diastereofacial preferences as their boron and zirconium enolates, but generally show poor selectivity as their lithium enolates. The reader is referred to other chapters in this volume for a discussion of these and related reagents. 

Independent work on asymmetric aldol reactions by Evans et al. led to the development of alternative chiral boron enolates that exhibit >100 1 facial selectivity. A pair of chiral N-acyl-2-oxazolidones (35)... 

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