De novo synthesis of 2-substituted syn-1,3-diols via an iterative asymmetric hydration strategy.

As part of our continuing program focused on the de novo asymmetric synthesis of polyketide based natural products,1 we developed a sequential hydration approach (enantioselective hydration 1 to 2 and a diastereoselective hydration 2 to 3) that converts achiral conjugated dienoates into enantiomerically enriched benzylidine protected syn-3,5-dihydroxyesters.2 The transformation relies upon a Sharpless asymmetric dihydroxylation followed by a Pd-π-allyl catalyzed allylic reduction to control both the regio-and enantioselectivity of the first hydration, and an Evans hemiacetal addition to achieve diastereoselectivity in the second hydration.3 With the successful application of this approach to various 1,3-polyol natural products, we targeted the structurally more complex polyene-polyol macrolides (e.g., mycoticin A4, Figure 1). Thus we required a strategy that would address two structural motifs of mycoticin A. That is to say, we required access to both 2-methyl-1,3-diol (C-11 to C-17),3,4 and δ-hydroxy-γ-methyl enoate (C-27 to C-31) subunits. Other approaches to δ-hydroxy-γ-methyl enoate synthons usually involve crotylation/metathesis, aldol/Wittig, or vinylogous aldol sequences; a few other more diverse strategies have been employed in recent years, as well.5 Unfortunately, our initial studies on a new catalytic asymmetric approach using various carbon nucleophiles to install an alkyl group at C-4 was met with little success (i.e., replacing the palladium hydride with a palladium alkyl in the Pd-π-allyl intermediate 5). Scheme 1 Asymmetric iterative hydration of C4-methyl dienoates Alternatively, we envisioned that these two structural features could be prepared from C-4 substituted achiral dienoates by an iterative hydration approach (Scheme 1). This, of course, required that the initial asymmetric hydration reaction be stereospecific, which was demonstrated by substituting DCO2H for HCO2H (Scheme 1, R3 = H; see supporting information). Then, we embarked on an effort to expand the asymmetric hydration methodology to include substituted dienoates (1) for the preparation of the 4-methyl-5-hydroxyenoates (2) and the benzylidine protected 4-methyl-3,5-dihydroxy esters (3) via the substitution of cyclic carbonates 4 and Pd-π-allyl intermediates 5.6 Herein, we describe the successful development of a de novo asymmetric synthesis of these two structural motifs (2 and 3) from simple achiral dienoates (1). While we were initially concerned about the problems associated with enantio- and regioselectivity in both the osmium and palladium steps, the initial dienoates (6a/b) we chose to study proved to be very promising (Scheme 2).7 Thus, exposure of dienoates 6a and 6b to Sharpless dihydroxylation conditions proceeded uneventfully (Table 1), providing diols 7a and 7b in good yields and excellent enantioselectivity. Similarly, the resulting diols were diastereoselectively converted to homo-allylic alcohols 8a and 8b by conversion to a cyclic carbonate and reduction with Et3N•HCO2H (Table 2).8 Finally, both homo allylic alcohols 8a and 8b were readily converted into the benzylidine protected syn-3,5-dihydroxyester 9a and 9b by exposure to the Evans conditions (PhCHO, cat. KOt-Bu, Table 3). Scheme 2 Asymmetric double hydration of (E,E)-dienoate Table 1 Asymmetric dihydroxylation of (E,E)-dienoates Table 2 Diastereoselective carbonate reduction Table 3 Diastereoselective hydration of δ-hydroxyenoates Unfortunately, when we investigated the scope of this reaction sequence we uncovered complications with the dihydroxylation step (Table 1). The simplest dienoate substrate (Table 1, entry d, R = Me)9 underwent dihydroxylation using (DHQ)2PHAL and (DHQD)2PHAL with excellent enantio- and regioselectivity; however, the regioselectivities were diminished for branched-alkyl and aryl substituents (Table 1, entries a-c).10 For instance, when dienoate 10c (R = Ph) was dihydroxylated with the PHAL-linked dimeric ligands the α,β-olefin 12c was preferentially formed (2.5:1). To our delight, switching to a “first-generation” dihydroxylation ligand, DHQ-4-Me-2-Quinolyl ether (DHQ-MEQ), eliminated this problem and gave the desired diol with excellent selectivity in all three cases (entries a-c, Table 1) with greatly improved regio- (> 16:1) and enantioselectivity (73−90 %ee) for the diols 11a-c. The palladium catalyzed reduction proved to be very tolerant to a variety of functionalities, giving excellent yields and selectivities in all cases. As with the diols 7a/b, the diastereomerically pure diols 11a-e were converted into the corresponding cyclic carbonates 13a-e (Table 2) in excellent yields using triphosgene and pyridine in CH2Cl2. We next examined the Pd-catalyzed reduction of the (E,E)-allylic carbonates 13a-e. After some experimentation it was found that the optimal conditions were 1% Pd2(dba)3•CHCl3/PPh3 in THF with 5 equiv. of Et3N•HCO2H.11 In all case the carbonates were cleanly converted into homoallylic alcohols in excellent yields (> 95%). It is worth noting that we have been able to use this procedure for the preparation of multigram quantities of 14b (i.e., several 10 g batches). To demonstrate both the synthetic utility of this oxidation/reduction sequence as well as to assign the stereochemistry of the asymmetric hydration reaction the homoallylic alcohols 14a-d were converted into the 1,3-syn diols 15a-d. Thus exposure of alcohols 14a-d to the Evans 1,3-syn diol protocol provided the benzylidine protected syn-3,5-dihydroxyesters 15a-d. With the exception of the phenyl substituted substrate 14c the benzylidine acetals were formed in good yields (57 to 75%, Table 3).12 We next set out to test the stereospecificity of the overall transformation (6/10 to 9/15). To do so we chose the (Z,E)-methyl substituted dienoate 16 (c.f., Table 4 and Scheme 3). Once again the initial dihydroxylation proved to be problematic. While no regioisomers were detected, the enantioselectivities were unsatisfactory using the PHAL-linked dimeric ligands (Table 4 entries 1−2). Scheme 3 Shi epoxidation of (E,Z)-dienoates Table 4 Asymmetric dihydroxylation of (E,Z)-dienoates We again turned to the DHQ-MEQ ligand but this time we were met with lower ee (entry 3, Table 4). A screening of commercially-available AD ligands was conducted in which the optimum ligand was determined to be (DHQD)2PYR (entry 4, Table 4).13 In an effort to further increase the enantioselectivity, a Shi epoxidation14 was attempted on 16 (Scheme 3). Indeed, epoxide 19 was formed in greater enantioexcess and was subjected to identical Pd-reduction conditions as the carbonate 18. Both 18 and 19 behaved similarly in the reaction giving excellent dr with the epoxide opening having higher yield (98% vs 86%). Finally, the conversion of 20 to the anti-methyl diastereomer 21 occurred in 80% yield and diastereoselectivity (> 95:5) via the Evans protocol.15 In summary we have demonstrated the utility of our asymmetric bis-hydration methodology for the stereospecific conversion of both (E,E)- and (E,Z)-dienoates into either C-4 diastereomer of benzylidine protected syn-3,5-dihydroxy esters (9, 15 and 21).9 Key to this development was the control of regioselectivity in both the osmium-catalyzed asymmetric dihydroxylation and palladium-catalyzed reduction reactions. Further development to improve the enantioselectivity of the oxidation of the (E,Z)-dienoates and its application toward natural product synthesis is ongoing.