Chiral acylation

Although many carbonyl derivatives act as acyl cation equivalents, R(C=0)" in synthetic chemistry, the inherent polarity of the carbonyl group makes it much more difficult to find compounds that will act as equivalents of acyl anions, R(C=0) . Since the 1960s, major progress has been made in this area, and there are now a wide variety of compound types that can react in this way. As in so many areas of organic chemistry, heterocyclic compounds take pride of place and form the basis of many of the most useful methods. In recent years there has been particular interest in developing chiral acyl anion equivalents that will show high... 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

More recently, the synthesis of relatively stable chiral acyl nitronates by the reactions of acetic anhydride and pyridine with secondary nitro sugar derivatives has been documented (221). 

Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary. 

If, on the other hand, it is assumed that the initial electrophilic attack is reversible and that addition can occur above or below the plane defined by the alkenes, two diastereomeric cations woidd be formed, perhaps in approximately equal concentration. Due to the proximity of the chiral acyl group, the probability of achieving the transition states (approximately represented by 146 and 147) would be unequal and a function of the difference in sizes of groups R and R (146 and 147). 

It can be seen in Figure 11.13 that, although the menthol portions of the esters are mirror images, addition of the chiral acylating reagent generates esters which are not mirror images but are diastereoisomers and thus have different physical properties. 

Figure 5.28 Addition of organometallics on chiral acyl- and sulfinylimines of ethyl trifluoropyr-uvate."" " "...

Robin, J.-P. Dhal, R. Dujardin, G. Girodier, L. Mevellec, L. Poutot, S. (2000) The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety. Tetrahedron Lett., 40,2931-4. 

The l,3-dithiane-l,3-dioxides can also be prepared by sodium periodate oxidation of the 1,3-dithiane, and the irons isomer was thus obtained in a 58% recrystallized yield [81]. Chiral molecules of this type (C2 symmetry ) are particularly suitable for use as chiral acyl anion equivalents [11,82]. 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

For examples of kinetic resolution of alcohols using chiral acylating agents, see Evans DA, Anderson JC, Taylor MK (1993) Tetrahedron Lett 34 5563-5566 Vedejs E, Chen X (1997) J Am Chem Soc 119 2584-2585... 

The diastereoselectivity in 5-exo cyclization of a range of chiral acyl radical equivalents derived from 1,3-dioxolanes and dioxanes has been investigated. Results indicate that selectivity was poor for radicals which cyclised via a twist-boat conformation but high when l,3-dioan-2-yl radicals containing an imposed chair-like conformation were used.173 The 5-exo cyclizations of a-phenylsulfenyl radicals,... 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

The improvement of the enantioselectivity E in kinetic resolution of a primary alcohol (10) through lipase-catalyzed transesterification was studied using a chiral acyl donor 11. The combination of the lipase, solvent and acyl donor was effective for the enantioselectivity.62... 

Figure 11 Representative kinetic resolution of primary alcohol ( )-10 using chiral acyl donor ( )-ll.

The ring opening of 4,4-disubstituted l-tosyl-3-methyleneazetidine-2-carboxylates 53 proceeded smoothly under acidic condition to yield the chiral acyl silane 54 (Equation 12) in quantitative yields and with an enantiomeric excess up to 97% <20030L3691>. 

This means that the chiral catalyst participates in nucleophilic attack on an achiral acyl donor to afford a reactive chiral acyl salt. Nucleophilic attack on this salt by an appropriate nucleophile (an alcohol, amine or 7r-nucleophile) then provides the acylated product and regenerates the catalyst. This latter step determines the stereochemistry, but knowledge of the precise mechanism by which stereochemical information is transferred in most of these processes is still rather limited. 

Although a number of methods for the asymmetric acylation of a-chiral amines using stoichiometric amounts of chiral acylating agents have been developed... 

Isatine derivatives gave the corresponding cycloadducts with high stereoselectivity when irradiated in the presence of furan and benzofuran [72]. The reaction of furan with acyl cyanides yields the corresponding oxetanes, but both diastereoisomeric endo- and exo-oxetanes are formed (Scheme 3.36). When chiral acyl cyanides are used, low asymmetric induction is observed [73]. Furan also reacts with chiral ketones. In this case, an ot-cleavage reaction before the 2+2 cycloaddition modifies the expected products (Scheme 3.37). When (—)-menthone was used as a substrate, a chiral product was obtained as a 2 1 diastereoisomeric mixture the most abundant product has the (1/ , 3R) configuration [74]. When the reaction was performed on carbohydrate 36, a complex reaction mixture was obtained (Scheme 3.38) [74, 75]. 

Better results (80 % ee) have been reported by Mikami, Nakai and co-workers [3c] for the addition of crotyl silane also catalyzed by complex 1. Yamamoto and co-workers [3b] used chiral acyl-oxy boranes to catalyze the Sakurai-Hosomi-reac-tion. While an excellent 96 % ee was obtained for the addition of 2,3 -disubstituted allyl groups, the conversion with parent allyl silane was low (46 %) and the asymmetric induction mediocre (55 % ee). Gauthier and Carreira [5] then made a big leap forward by using the difluorotita-nium-binaphthol complex 3. The catalyst 3 is prepared in situ via the TiF4-binaphthol adduct 4 and formal HF elimination mediated by allyl silane 5. The addition of 5 to aldehydes 6 ( 7) catalyzed by 10 % of 3 proceeds with 61 - 94 % < e and good yields (69-93 %), the best results being observed for aldehydes with tertiary alkyl residues (Scheme 1). 

Chiral secondary a-hydroxy aldehydes, Rf HOHCHO. The chiral acyl derivatives 3, obtained from 1 by lithiation and reaction with an aldehyde followed by Swem oxidation, can be reduced stereoselectively before cleavage to the secondary a-hydroxy aldehydes. 

In a different context, chiral reagents have been implemented in this chemistry. For instance, Liebscher and Itho developed the use of chiral acylating agents such as amino acid-fluorides 158 and -chlorides 156, respectively, (Scheme 21). The outcome of the reaction of isoquinoline (6), TMS-CN (14) and A -protected a-amino acid fluorides is dictated by the nature of the protecting group whereas Cbz- and... 

Di-n-butylboryl Trifluoromethanesulfomte with a tertiary amine also provides the (Z)-enolates of chiral acyl oxazolidinones in >100 1 selectivity for use in subsequent aldol additions With Triethylamine, Diisopropylethylamine (Hunig s base), or 2,6-Lutidine the order of addition is of no consequence to enolization." Triethylamine has traditionally seen the greatest utilization in these reactions based upon cost considerations however, with certain sensitive aldehyde substrates, lutidine provides milder reaction conditions." ... 

Brief reports of cycloadditions with chiral acyl nitroso dienophiles have recently appeared. - In one study, acyl nitroso compound (101) derived from the corresponding hydroxamic acid was added to cy-clohexadiene to afford a 3.5 1 mixture of diastereomeric adducts (102) and (103). It was proposed that dienophile (101) reacts in the cyclic chelated form shown, since the related methyl ether which cannot internally hydrogen bond shows much lower diastereoselectivity. ... 

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