A-chiral allylboronates

The poor diastereoselectivity of the reactions of chiral aldehydes and achiral allylboronates appeared to be a problem that could be solved by recourse to the strategy of double asymmetric synthesis.f Our studies thus moved into this new arena of asymmetric synthesis, our objective being the development of a chiral allylboron reagent capable of controlling the stereochemical outcome of reactions with chiral aldehydes independent of any diastereofacial preference on the part of the carbonyl reaction partner. 

Our development of the tartrate ester modified allylboronates c.h suggested to us that many of these problems could be avoided by using the reaction of a chiral aldehyde and a chiral allylboronate as a means of establishing the stereochemistry of the sugar backbone. This strategy has been used in our synthesis of the AB disaccharide unit of olivomycin A (Figures 16, 17).3 ... 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of natural products. However, enantioselective methods for homoallylamine are quite undeveloped. In 1995, Itsuno and co-workers reported the first example of enantioselective allylation of an imine (Scheme 7) [13]. The reaction of N-trimethylsilylbenzaldimine 19 with a chiral allylboron reagent 20 in ether at -78 °C afforded the corresponding homoallylamine 22 in 73% ee. 

Copper(II)-catalyzed Boryl Addition to Allylic Carbonates. The conversion of allylic carbonates to chiral a-substituted allylboronates was also investigated by Hoveyda, who was able to accon ilish this transformation with a Cu(II)-NHC complex. This reaction proceeds in a vinylogous fashion to Sawamura s, but under these conditions, (E)- and (Z)-allylic carbonates undergo substitution to produce opposite enantiomers of product with similar yields and selectivity. This methodology is also tolerant of substitution at the a- or -position and is effective for di-or trisubstituted alkyl (linear or branched) or aryl alkenes delivering a quaternary a-chiral allylboronate product with up to 98% enantioselectivity (eq 49). 

Hoffmann RW. a-Chiral allylboronates reagents for asymmetric synthesis. Pwre A/)/)/. Chem. 1988 60 123-130. 

The enantioselectivities of the reactions of representative achiral aldehydes and chiral allylboron reagents arc compared in Table 4. A comparison of the enantioselectivities of the (Z )-2-butenyl reagents appears in Table 5, while Table 6 provides a similar summary of the reactions of the (Z)-2-butenyl and 3-methoxy-2-propcnyl reagents. A 3-diphenylamino-2-propenyl reagent was recently reported102. 

One additional chiral allylboron reagent has been described that is worthy of mention. This is a chiral y-alkoxyallylboronate75. 

An extremely attractive feature of the route outlined at the beginning of this section for the transformation of boronates 3 or 4 to a-substituted allylboron compounds 5 is that reagents with very high enantiomeric purity (> 90% ee) may be prepared when precursors such as 3 and 4, and therefore also ate complex 1, contain a suitable diol chiral auxiliary17. The following syntheses of (S)-68, lib9, and 1310 illustrate this feature. 

Single Asymmetric Induction Reactions of Chiral a-Substituted Allylboron... 

Chiral, nonracemic allylboron reagents 1-7 with stereocenters at Cl of the allyl or 2-butenyl unit have been described. Although these optically active a-substituted allylboron reagents are generally less convenient to synthesize than those with conventional auxiliaries (Section 1.3.3.3.3.1.4.), this disadvantage is compensated for by the fact that their reactions with aldehydes often occur with almost 100% asymmetric induction. Thus, the enantiomeric purity as well as the ease of preparation of these chiral a-substituted allylboron reagents are important variables that determine their utility in enantioselective allylboration reactions with achiral aldehydes, and in double asymmetric reactions with chiral aldehydes (Section 1.3.3.3.3.2.4.). 

Double asymmetric reactions of chiral a-substituted allylboron reagents 1-5 and chiral aldehydes are summarized in this section. 

The addition of allylboronates 1 to the chiral oxime 2 results in the formation of a hydroxyl-amine. This is a general method for the subsequent reductive generation of primary homoallyl-amines, but with poor diastereoselectivity in the case of 3 and 4. A diastereomeric ratio of 90 10 is achieved in the addition reaction, using the chiral allylboronate 59 (double stcrcodifferenti-ation). 

Scheme 8. Stereoinduction model for the additions of chiral a-chloro allylboronate 23.

A copper-catalyzed reaction using a chiral diphosphine hgand, DuPHOS, with an added lanthanide salt, provides good levels of enantioselectivity (67-91% ee) in additions of the simple allylboronate 31 to both aromatic and aliphatic ketones that present a large difference of steric bulk on the two sides of the carbonyl group. One such example is shown in Eq. 81. On the basis of B NMR experiments and on the lack of diastereoselectivity in crotylation reactions, the... 

With the analogous reagent 125, however, the corresponding allylboronate intermediate 126 is thought to favor a transition structure 127 where the a-substituent is positioned in a pseudo-axial orientation in order to escape nonbonding interactions with the bulky tetraphenyl dioxaborolane (Eq. 99). This way, a Z-configured allylic alcohol unit of opposite configuration is obtained in diol product 128. This type of steric control with chiral a-substituted allylboronates... 

The reaction of 2-(l-alkyl-2-alkenyl)-l,3,2-dioxaborolancs with a suitably chosen aldehyde resulting in further C—C bond formation with chirality transfer is described in Section D.1.3.3.3.3. A number of analogous reactions of chiral allylboronic esters with aldehydes are described there as well. 

The enantioselective addition of ally organometallics to carbonyls has become one of the workhorses of organic synthesis. Dennis Hall of the University of Alberta reports (J. Am. Chem. Soc. 125 10160, 2003) the scandium triflate catalysis chiral allylboronic acids become more effective tools. The best of these, the Hoffmann camphor derivative 2, adds to aldehydes under Sc(OTf), catalysis with excellent enantiomeric excess. The reaction works equally well for methallyl, and for the E and Z crotyl boronic acids. The crotyl derivatives react with the expected high diastereocontrol. A limitation to the boronate additions is that branched chain aldehydes give low yields. 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

Chiral a-carbamoyloxy-2-alkenylboronates react with Grignard reagents with complete a- and diastereoselectivity through rearrangement of an intermediate ate -complex, yielding chiral allylboronates, which were oxidized to... 

A chiral allylic alcohol (3-carbanion equivalent has also been developed which utilizes a DIPT-modified E)-y-(dimethylphenylsilyl)allylboronate reagent. This method involves treating the product homoallylic alcohol with Dimethyl-dioxirane and subjecting the derived epoxide to an acid-catalyzed Peterson elimination. This sequence has been applied in the synthesis of the trioxadecalin ring system of the mycalamides (eq 10). ... 

Roush, W. R., Grover, P. T. Diisopropyl tartrate (E)-Y-(dimethylphenylsilyl)allylboronate, a chiral allylic alcohol 3-carbanion equivalent for the enantioselective synthesis of 2-butene-1,4-diols from aldehydes. Tetrahedron Lett. 1990, 31,7567-7570. 

---