Chiral IPC

Since selectivity is a prerequisite for resolution, a temperature increase strongly impacts both selectivity and resolution. The variability of the van t Hoff lines explains the seemingly erratic result of the influence of tanperature on the figures of merit of the method. For example, at lower temperatures, the resolution of model peptides with +1 and +3 net charges improved and worsened, respectively [27]. In chiral IPC, T < 0°C was successfully used to improve enantioresolution [28]. Similarly, lower temperatures provided better resolution in the analysis of a new aminoglycoside antibiotic [29] and for characterization of maize products [30]. Conversely, an increased resolution at 70°C was observed when the ion-pair mechanism was exploited under IPC-capillary zone electrophoresis of cationic proteomic peptide standards [31]. 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

P-Allyl-to-(isopinocampheyl)borane exhibits high stereoselectivity in reactions with chiral a-substituted aldehydes.40 The stereoselectivity is reagent controlled, in that there is no change in stereoselectivity between the two enantiomeric boranes in reaction with a chiral aldehyde. Rather, the configuration of the product is determined by the borane. Both enantiomers of (Ipc)2BH are available, so either enantiomer can be prepared from a given aldehyde. 

Chiral boranes, such as isocamphenyl derivatives (Ipc BH, IpcBH2, and... 

Scheme 2.34. Preparation of chiral alkylcopper reagents (Ipc = isopinocampheyl).

Figure 5. Chiral allylic boranes used as chiral auxiliary reagents in enantioselective additions to carbonyl compounds. (Only one isomer is shown for simplicity. For reagents 12 and 64-66, (—)-Ipc is shown.).

ClBH2SMe2 BCI3, (PhCH2NEt3)Cl (Ipc)2BCl (chiral) A1C13... 

Dialkylalkoxyborane 29 is treated with ethanolamine to liberate homoallylic alcohol 7 - this work-up allows the recycling of the chiral auxiliary.13 After precipitation of the (IPC)2B-ethanolamine adduct 30 it can be transformed into the allylating agent 27 via compound 31. 

For the purpose of asymmetric allylborations, chiral diols have been used as excellent directing groups. Chiral i -allyldiisopinocampheylboranes (allylB(Ipc)2) were found to be excellent alternatives. There are useful reviews of... 

In the case of 6.62, the hydride transfer takes place one atom away from the chiral centre. This factor is responsible for low optical purities observed in the reduction of ketones using (IPC)2BH, 6.62 or (IPO2BD (Scheme 6.22). 

Boron reagents such as ( + )- or (-)-(Ipc)2BOTf are chiral promoters in aldol condensations. " Enolization of an achiral ketone with (Ipc)2BOTf forms a chiral enolate and thus imparts diastereofacial selectivity (DS) for condensation with a chiral aldehyde. If the ketone is chiral, the DS of the reagent may be matched or mismatched with the... 

Enolization and protonation. 4-Substituted cyclohexanones undergo enolsilylation on treatment with chiral lithium amides 3, 4, and the dilithio derivatives of a urea. Enantioselective enolborination is accomplished with a combination of (-)-Ipc BCl and sparteine. ... 

Several other chiral boron reagents are available for asymmetric aldol reactions however, each of these compounds must be synthesized in the laboratory. In certain situations, some will give higher stereocontrol than the Ipc ligands, and hence for a given reaction their application could be pursued. Chiral reagents 53 and 54 have been used in the synthesis of bryostatin 7 [36] and the Taxol side-chain [37], respectively, while bis-sulfonamide 55 has been used in the synthesis of a C24-C35 segment of FK-506 (Scheme 9-18) [38]. 

Using chiral ketone 11 instead of a chiral aldehyde, the same principle of enhancing substrate control can be applied. In this case, the induction from ketone 11 was moderate (82%ds), while using matched Ipc ligands on boron, the reaction proceeded with 98% ds to afford adduct 12 which was then transformed into aldehyde 97 [6 b]. 

As previously mentioned, certain methyl ketone aldol reactions enable the stereocontrolled introduction of hydroxyl groups in a, 5-anti relationship (Scheme 9-7) [9], and this was now utilized twice in the synthesis. Hence, methyl ketones 48 and 98 were converted to their respective Ipc boron enolates and reacted with aldehydes 97 and 99 to give almost exclusively the, 5-anti aldol adducts 100 and 101, respectively (Scheme 9-34). In the case of methyl ketone 48, the j -silyl ether leads to reduced stereoinduction however, this could be boosted to >97%ds with the use of chiral ligands. In both examples, the y9-stereocenter of the aldehyde had a moderate reinforcing effect (1,3-syn), thus leading to triply matched aldol reactions. Adducts 100 and 101 were then elaborated to the spiro-acetal containing aldehyde 102 and ketone 103, respectively. 

Our synthesis of the C1-C7 fragment 227 of oleandolide started with a substrate-controlled tin-mediated aldol reaction of a-chiral ketone (5)-18 which afforded syn adduct 52 with 93% ds. This same transformation could also be achieved using reagent control with (Ipc)2BOTf, albeit with lower selectivity (90% ds). In a key step, treatment of the aldol adduct 52 with (-i-)-(Ipc)2BH led to controlled reduction of the C3 carbonyl together with stereoselective hydrobora-tion of the C -Cv olefin, affording the desired triol 228 with 90% ds. 

When we discussed how -enolates of ethyl ketones such as 207 gave 1,3-control in the aldol reaction, we noted that there was 1,4-control too. Paterson did the same reaction on the corresponding methyl ketones and found that the lithium enolate (M = Li in 234) was unselective. The boron enolate with an achiral group 9 (M = dicyclohexyl-B) was selective giving 88 12 syn anti-235 in 84% yield but with a chiral group [M = (-)-(Ipc)2B] the stereoselectivity was significantly better35 (92 8). 

Thus, from optically impure a-pinene (94% e.e.), the TMED 2 BH2IPC bis adduct is obtained " in optical purity approaching 100%. Other chiral monoalkylboranes and boronic acids important in asymmetric synthesis " , are available via IpcBHj and (Ipc)2BH. 

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... 

---