One‐Pot Three‐Component Catalytic Enantioselective Synthesis of Homoallylboronates (2011)

No longer a simple bor(ation): The title reaction between bis(pinacolato)diboron, enals, and 2-(triphenylphosphoranylidene)acetates employing bench-stable copper salts and a simple chiral amine co-catalyst is presented (see scheme). The reaction proceeds through a catalytic asymmetric conjugate borane addition/Wittig sequence wherein the β-boration step is 1,4-selective and gives the corresponding homoallylboronate products with high enantiomeric ratios. The key to success for the one-pot synthesis of the homoallylboranes 4 is the ability to control and develop the challenging catalytic enantioselective β-boration step of the enal component 2 to give the corresponding enantioenriched β-boryl aldehyde intermediate 5 prior to the Wittig step (Scheme 1). However, this type of transformation can be plagued by 1,2-addition to give the product 5’ as well.8 In this context, our previous research has shown that it is possible to achieve highly selective conjugate additions of silyl10a and carbon nucleophiles (organozinc reagents)10b to enals 2 by combining transition-metal and aminocatalysts.10–13 Thus, retrocatalytic analysis suggests that the ability of a chiral amine to lower the LUMO of the enal component 2 by iminium activation14 in combination with copper-catalyzed conjugate addition15 of the Bpin to this intermediate may favor enantioselective 1,4-addition over 1,2-addition to predominantly give the intermediate 5 (Scheme 1). Its subsequent Wittig reaction with 3 would give the enantioenriched homoallylicboronate product 4. Proposed reaction sequence. L=ligand. Herein we disclose the unprecedented one-pot three-component enantioselective catalytic reaction between 1, α,β-unsaturated aldehydes, and (triphenylphosphoranylidene)acetate esters, thereby giving the corresponding homoallylborane products in good yields and up to 97.5:2.5 e.r. This method employs readily available transition metals and chiral amines as co-catalysts. We began our investigation by studying the catalytic one-pot three-component reaction between 1, cinnamic aldehyde (2 a), and the phosphorane 3 a using different copper salts, chiral amines (6), and phosphine ligands (7). Key results are shown in Table 1. We found that performing the one-pot reaction without the use of a chiral amine catalyst (6) gave low 1,4-selectivity in the initial β boration of the enal 2 a, which gave both racemic aldehyde 5 a and 5 a′ in a 67:33 ratio as determined by 1H NMR analysis of the crude reaction mixture prior to the addition of the Wittig reagent 7 a (entry 1). The reaction without the copper(II) triflate (Cu(OTf)2) catalyst but in the presence of the chiral amine 6 a gave a small amount (<2 % conv.) of 5 a (entry 2). To our delight, the homoallylicboronate 4 a was assembled in an asymmetric fashion when commercially available chiral amines 6 a–6 d were used as catalysts in combination with Cu(OTf)2 (5 mol %) as the transition-metal co-catalyst and Ar3P (7) as the ligand in diethyl ether at 22 °C. MeOH (3 equiv) was added to maintain the copper-catalyzed activation of the borane reagent 1. It is noteworthy that we were able to isolate the aldehyde 5 a intermediate (the e.r. could only be determined after conversion of 5 a into 4 a). However, it was hard to purify since it decomposes (e.g., elimination) during silica gel column chromatography to give the starting enal 2 a, which has the same Rf value. The addition of an organic acid additive leads to significant improvement of both the 1,4- and enantioselectivity of the asymmetric β-boration step (entries 7 and 9). In fact, only β boration occurred when 2-fluorobenzoic acid was used as the additive. Thus, the protic acid additive accelerated the catalytic cycle of the iminium formation and as a consequence the chemoselectivity was directed towards 1,4-addition. Of the investigated chiral amines 6, the highest reactivity and enantioselectivity of the BC bond-forming step was achieved when the chiral amine 6 a16 was employed as the catalyst and the corresponding homoallylicboronate product 4 a was isolated in 65 % yield with 97.5:2.5 e.r. (entry 7). Entry[a] Amine 7 Cu salt t [h] Conv. [%][b] e.r.[c] 1[d] – 7 a Cu(OTf)2 1 60 50:50 2 6 a 7 a – 7 <2 n.d. 3 6 a 7 a CuCl 4 <2 n.d. 4 6 a 7 a CuBr 4 <2 n.d. 5 6 a 7 a CuI 4 <2 n.d. 6 6 a 7 a CuOAc 4 <2 n.d. 7 6 a 7 a Cu(OTf)2 1 98 97.5:2.5 8 6 a 7 a CuOCl2 4 <2 n.d. 9[e] 6 a 7 a Cu(OTf)2 1 98 69:31 10 6 a 7 b Cu(OTf)2 4 70 90:10 11 6 a 7 c Cu(OTf)2 4 24 63:37 12 6 a 7 d Cu(OTf)2 4 70 85:15 13 6 a 7 e Cu(OTf)2 4 30 80:20 14 6 b 7 a Cu(OTf)2 1 80 55:45 15 6 c 7 a Cu(OTf)2 2 95 72:28 16 6 d 7 a Cu(OTf)2 1 85 53:47 17 6 e 7 b Cu(OTf)2 7 20 n.d. With these results in hand, we decided to probe the scope of the catalytic one-pot three-component enantioselective reaction using Cu(OTf)2 as the metal catalyst, 6 a as the chiral amine, and 7 a as the phosphine additive in diethyl ether at 22 °C (Scheme 2). The three-component reactions were efficient and proceeded with excellent 1,4-selectivity in the β-boration step and the corresponding homoallylboronates 4 a–4 j were assembled in an asymmetric fashion in good yields and high enantiomeric ratios through the conjugate boron addition/Wittig sequence. The reaction tolerated enals with both aryl and aliphatic substituents at their β position. Moreover, cinnamic enals 2 with an electron-withdrawing group at the para, ortho, or meta position exhibit higher reactivity in the β-boration step (Scheme 1). For example, the β boration of enals 2 d–2 g and 2 j was completed within 35 minutes as determined by 1H NMR analysis. The subsequent addition of the Wittig reagents 3 gave the corresponding homoallylboranes 4 d–4 g and 4 j with 96.5:3.5–97:5:2.5 e.r. after 2 hours. The yields were in the range of 60–67 % because the intermediates decomposed through elimination during the Wittig step to give the enals 2. Thus, a small amount of the corresponding diene A was also formed. We also investigated the reactions with enals 2 wherein either R was heterocyclic or 2 was β substituted. However, the reactions were slower and the corresponding products 4 were formed with lower e.r. values (60:40–65:35). To establish the absolute configuration of the homoallylicboronates 4 and show the synthetic utility of our asymmetric multicomponent reaction, we investigated a one-pot transformation for the assembly of the valuable homoallylic alcohol 8 a (Scheme 3).17, 18 The one-pot reaction was successful and we were able to isolate the corresponding homoallylic alcohol 8 a in 60 % yield. Comparison with the literature revealed that the stereochemistry at C5 was S (−15.30 deg cm3 g−1 dm−1 (c=1.0 g cm−3, EtOH); Lit. (R)-8: +10.40 deg cm3 g−1 dm−1 (c=1.1 g cm−3, EtOH).17 Thus, the absolute configuration of the homoallylboronates 4 is S (R=aryl). We also broadened the scope of the strategy by synthesizing homoallylic amine 8 b in 65 % yield.19 [a] 35 min. [b] 2 h (3 equiv), 60 min. [c] 4 °C, 45 min. One-pot catalytic enantioselective synthesis of homoallylic alcohol 8 a and homoallylic amine 8 b. Based on the absolute configuration of the products 4, the above experimental results, and our previous DFT calculations,10 we propose the reaction mechanism depicted in Scheme 4. The in situ generated LCuIIBpin C species approaches the less sterically hindered Si face (R=aryl) of the β-carbon atom of the imiunium intermediate D. Subsequent CB formation at the Re face of the iminium intermediade E gives F. Hydrolysis and addition of MeOH regenerates the chiral amine catalyst 6, thus leading to formation of a reactive MeOCuIIL species and the β-borylaldehyde intermediate 5. Next, the in situ Wittig reaction with 3 gives the final homoallylboronate product 4. Proposed reaction mechanism. In summary, we have developed an efficient, novel one-pot three-component enantioseelctive reaction between a diboron reagent, α,β-unsaturated aldehydes, and 2-(triphenylphosphoranylidene)acetate esters. The asymmetric multicomponent reaction proceeds through a β boration/Wittig sequence to give the corresponding homoallylboronates with high enantiomeric ratios using simple bench-stable chiral amines and copper catalysts. In addition, the study shows that it is possible to merge the catalytic cycles of transition-metal-catalyzed nucleophilic activation of diboron reagents with amine-catalyzed iminium activation of enals to achieve a highly 1,4- and enantioselective β boration of enals. The one-pot expansion of the co-catalytic three-component reaction to the asymmetric synthesis of homoallylic alcohols was also disclosed. Further development of this type of one-pot multicomponent co-catalytic asymmetric reaction and its application in total synthesis is ongoing in our laboratories. 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