Crotylboronates chiral

The corresponding crotylboronates, (R,R)- and (S,S)-5 also undergo highly diastereoselective reactions with the same chiral aldehydes, and again the diaster-... 

Solutions to problems (i) and (ii) were already available as a result of studies by Hoffmann and Wuts on the reactions of 7-alkoxyaIlyl-boronates with achiral aldehydes (Figure 6). 3 Relatively little information was available, however, regarding the stereochemistry of such reactions with chiral aldehydes. Hoffman had published several examples of reactions of (E)- and (Z)-crotylboronates (methyl replacing OMe in Figure 6) with chiral aldehydes such as 2-methylbutanal, but the best diastereofacial selectivity that had been reported was only 83 17.14 Thus, it was by no means certain that the chemistry summarized in Figure 7 would be successful.3a... 

Scheme 9. Stereoinduction model for the additions of chiral a-methyl crotylboronate 21.

In earher work, the Hall group found that catalytic amounts of triflic acid promoted the addition of aUylboronates to aldehydes [132], While aUylboration reactions catalyzed by chiral Lewis acids in general led to only low levels of enan-tioselection [133], Hall found that chiral LBA 1 catalyzes the asymmetric addition of allyl- and crotylboronates to various aldehydes to provide products in excellent yields and moderate to high ee s (Scheme 5.71) [134]. Further, double diastereose-lective crotylboration could also be achieved with high selectivities using the... 

Z)-Crotylboration of Boc-prolinal with Chiral (Z)-Crotylboronate 47 Synthesis of fcrf-Butyl 2-(l-Hydroxy-2-methylbut-3-enyl)pyrroKdine-l-carboxylate (48) 81 ... 

Diisopropyl crotylboronates, 1. These chiral crotylboranates are prepared in 98-99% ee from diisopropyl tartrate. 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

The preference for the (Z)-crotylboronate reagent 4 to generate the anti-Felkin homoallylic alcohols 31 and 38 in reaction with a-methyl chiral aldehydes 25 and 32 (Table 11-1) is rationalized by transition state 43, where the R substituent of the aldehyde occupies the least sterically demanding a-carbon position, anti to the forming C-C bond, while the hydrogen occupies the most sterically demanding... 

Figure 11-7. Transition states of (Z)-crotylboronate with a-methyl chiral aldehydes.

Tartrate-derived Chiral Allyl- and Crotylboronate Reagents... 

The tartrate-derived crotylboronate reagents are most useful in the context of double asymmetric reactions with chiral aldehydes [118, 203]. Equations (11.16)-(11.19) demonstrate the utility of ( )-219 and (Z)-213 in the synthesis of dipropionate adducts 105-108. 

In reactions of a-methyl chiral aldehydes with achiral (Z)-crotylboronates, the anti-Felkin adduct (cf. 107b) is favored (for further discussion see Section 11.2) [3, 65]. In the double asymmetric reaction of 97b and (S,S)-213, the anti,syn-di-propionate 107b is obtained with high selectivity (selectivity=95 5). The stereochemistry of 107b is consistent with product formation via the matched anti-Felkin transition state 247. Finally, the, vyn,5y -dipropionate 106c is obtained as the major product from the mismatched reaction of the TBDPS-protected aldehyde 97c with (f ,R)-(Z)-213 this reaction, however, is not sufficiently stereoselective to be synthetically useful (selectivity = 64 36). The mismatched transition state... 

In general, as the aldehyde a-substituents become more sterically demanding, it becomes more difficult to obtain useful levels of diastereoselection for the product expected from reagent control in mismatched double asymmetric reactions between chiral aldehydes and chiral allyl- and crotylboronates [203]. For this reason, in natural product synthesis, mismatched double asymmetric reactions should be designed to occur early rather than late in a synthetic sequence. 

Chiral crotylboronate technology was used three times in the synthesis of the fully functionalized trioxadecalin portion 258 of mycalamide A by Roush and Matron (Fig. 11-25) [207, 208]. 

In Scheme 46, case I is discussed with respect to the crotylboration of (R)-iso-propylidene glyceraldehyde. Altogether 4 diastereomers I to IV may be formed under the influence of the chiral information contained both in the aldehyde and in the crotylboron reagents 46-1 to 46-6 [106,107,108,109]. The simple diaster-eoselectivity, i.e., the relative configuration with respect to C-3/4 is given by the Zimmerman-Traxler closed transition state and is anti for the (E)- and syn for the fZj-crotyl isomers of 46-1 to 46-6. It can be seen from Scheme 46 (sixth col-... 

The stereochemical outcome of this reaction is surprising because it is opposite to the diastereofacial selectivity observed in reactions of (Z)-crotylboronates and a-methyl chiral aldehydes. Rather, the preferential production of (33) parallels the results observed in the type II Lewis acid catalyzed additions of tributylcrotylstannanes and a-methyl chiral aldehydes. 

The stereochemistry of the reactions of chiral carbonyl compounds with nucleophiles has been a topic of considerable theoretical and synthetic interest since the pioneering study by Cram appeared in 1952. The available predictive models focus entirely on the conformational and stereoelectronic demands of the chiral carbonyl substrate, the implicit assumption being that the relative stabilities of the competing transition states are determined only by stereoelectronics and the minimization of nonbonded interactions between the substituents on the chiral center and the nucleophile. These models totally ignore the possibility, however, that the geometric requirements of the nucleophile may also have an effect on reaction diastereoselectivity. Considerable evidence is now available, particularly in the reactions of Type I (Z)-crotylboronates and Z(0)-metal enolates, that the stereochemistry of the nucleophile is indeed an important issue that must be considered when assessing reaction diastereoselectivity. 

Chiral crotylboronates (216) and (217) were among the first chiral allyl metal reagents to be used in double asymmetric reactions. The example in Scheme 47, however, shows that (217) induces only modest changes in the stereoselectivity of the reactions of (249), thus underscoring the need for highly enantioselective chiral reagents. 

Excellent double diastereoselection has also been realized in the reactions of (151) and chiral crotyl-boron reagents (Table 7). Interestingly, the best selectivity for diastereomers (153) and (156) is obtained by using the tartrate crotylboronates (S,S)-(18) and () , )-(19), respectively (entries 2 and 3), while Masamune s 2,5-dimethylborolane reagents (HJl)-(221) and (5,5)-(222) provide the greatest selectivity for diastereomers (152) and (157 entries 7 and 10). Comparative data for the diastereoselectivity ol tained with the achiral crotylteronates (1) and (2) appear in the last two entries of Table 7. 

Results of reactions of chiral a-methyl aldehydes and several chiral crotyl- and allyl-boron reagents are summarized in Tables 8 and 9. It is apparent from these data that the Brown (Ipc)2B(crotyl) and (Ipc)2B(allyl) reagents (51), (52) and (219) consistently give excellent results for the synthesis of each product diastereomer (Table 8, entries 3-6, 11, 16, 20, and 24 Table 9, entries 1,2, 10 and 18). This is true also for their reactions with chiral a- and 3-alkoxy aldehydes (Scheme 49).i. i4S-i50 Thg tartrate crotylboronates (18) and (19) also display excellent selectivity in the synthesis of crotyl diastereomers (136), (137) and (139) (Table 8, entries 7,10,13,17,25 and 28), but are much less selective for the syndesis of crotyl diastereomer (138), especially from -alkoxy-substituted aldehydes such as (253). Tartrate allylboronate (224) is also less effective than (Ipc)2Ballyl (219) for the synthesis of (257) and (258) in Table 9, and of (266) and (267) in Scheme 49.Substantial improvements in selectivity have been realized by using the taitramide-based allylboronate (228), and the results with this reagent (Table 9, entries 4, 7, 9, 12, 14, 17, 20 and 22) compare very favorably with those obtained with (219). The data... 

Table 8 Reactions of a-Methyl Chiral Aldehydes and Chiral Crotylboron Reagents...

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