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Highly Enantioselective Synthesis of Γ-, Δ-, and E-Chiral 1-Alkanols Via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)–Cu- Or Pd-Catalyzed Cross-Coupling

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Highly Enantioselective Synthesis of Γ-, Δ-, and E-Chiral 1-Alkanols Via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)–Cu- Or Pd-Catalyzed Cross-Coupling Highly enantioselective synthesis of γ-, δ-, and e-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling Shiqing Xu, Akimichi Oda, Hirofumi Kamada, and Ei-ichi Negishi1 Department of Chemistry, Purdue University, West Lafayette, IN 47907 Edited by Chi-Huey Wong, Academia Sinica, Taipei, Taiwan, and approved May 2, 2014 (received for review January 21, 2014) Despite recent advances of asymmetric synthesis, the preparation shown in Schemes 1 and 2 illustrate the versatility of ZACA of enantiomerically pure (≥99% ee) compounds remains a chal- represented by the organoaluminum functionality of the ini- lenge in modern organic chemistry. We report here a strategy tially formed ZACA products. Introduction of the OH group for a highly enantioselective (≥99% ee) and catalytic synthesis by oxidation of initially formed alkylalane intermediates in of various γ- and more-remotely chiral alcohols from terminal Scheme 2 is based on two considerations: (i) the proximity of the alkenes via Zr-catalyzed asymmetric carboalumination of alkenes OH group to a stereogenic carbon center is highly desirable for (ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situ lipase-catalyzed acetylation to provide ultrapure (≥99% ee) di- oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols functional intermediates, and (ii) the versatile OH group can R S α ω produced both ( )- and ( )- , -dioxyfunctional intermediates (3) be further transformed to a wide range of carbon groups by – ee ≥ ee in 80 88% , which were readily purified to the 99% level tosylation or iodination followed by Cu- or Pd-catalyzed cross- by lipase-catalyzed acetylation through exploitation of their high α ω coupling. The TBS-protected OH group (OTBS) serves not only selectivity factors. These , -dioxyfunctional intermediates serve as a source of OH group in the final desired alkanols, but also as versatile synthons for the construction of various chiral com- as a proximal heterofunctional group leading to higher enan- pounds. Their subsequent Cu-catalyzed cross-coupling with vari- tioselectivity in lipase-catalyzed acetylation (11, 12). As long as ous alkyl (primary, secondary, tertiary, cyclic) Grignard reagents the α,ω-dioxyfunctional chiral intermediates (R)-3 and (S)-4 and Pd-catalyzed cross-coupling with aryl and alkenyl halides pro- ≥ ee ceeded smoothly with essentially complete retention of stereo- can be readily prepared as enantiomerically pure ( 99% ) chemical configuration to produce a wide variety of γ-, δ-, and substances, their subsequent Cu- or Pd-catalyzed cross-coupling e-chiral 1-alkanols of ≥99% ee. The MαNP ester analysis has been would proceed with retention of all carbon skeletal features to γ applied to the determination of the enantiomeric purities of δ- and produce a wide range of - and more-remotely chiral alcohols in ≥ ee e-chiral primary alkanols, which sheds light on the relatively un- high enantiomeric purity ( 99% ). developed area of determination of enantiomeric purity and/or Results and Discussion absolute configuration of remotely chiral primary alcohols. Some key features of the ZACA reaction include (i) catalytic asymmetric C–C bond formation, (ii) use of alkene substances of symmetric synthesis remains as a significant challenge to one-point-binding without requiring any other functional groups, synthetic organic chemists as the demand for enantiomeri- A and (iii) many potential transformations of the initially formed cally pure compounds continues to increase. Chirality plays a vi- – tal role in chemical, biological, pharmaceutical, and material alkylalane intermediates (6 10). The ZACA reaction shows sciences. The US Food and Drug Administration requires that a broad substrate scope and a high synthetic potential. With all chiral bioactive molecules have to be as pure as possible, containing a single pure enantiomer, because chirality signifi- Significance cantly influences drugs’ biological and pharmacological proper- ties. As a consequence, development of new methods for Chirality plays a vital role in chemical, biological, pharmaceu- asymmetric synthesis of enantiomerically pure compounds tical, and material sciences. The preparation of enantiomeri- (≥99% ee) continues to be increasingly important (1–5). We cally pure compounds is a very important and challenging area. ≥ recently reported a highly selective and efficient method (6) for In this paper, we developed a highly enantioselective ( 99% ee the preparation of 2-chirally substituted 1-alkanols via a se- ) and widely applicable method for the synthesis of various γ quence consisting of (i) Zr-catalyzed asymmetric carboalumi- - and more-remotely chiral alcohols, many of which cannot be – – satisfactorily prepared by other existing methods, via the nation of alkenes (ZACA reaction hereafter) (7 10) in situ – – iodinolysis of allyl alcohol, (ii) enantiomeric purification by ZACA/oxidation lipase-catalyzed acetylation Cu- or Pd-cata- lyzed cross-coupling from terminal alkenes. We also demon- lipase-catalyzed acetylation (11, 12) of both (S)- and (R)-ICH CH 2 strated MαNP ester analysis is a convenient and powerful (R)CH OH (1), the latter obtained as acetate, i.e., (R)-2, and 2 method for determining the enantiomeric purities of δ- and (iii) Cu- or Pd-catalyzed cross-coupling (13, 14) (Scheme 1). e-chiral primary alkanols. This finding is anticipated to shed As satisfactory as the procedure shown in Scheme 1 is, how- light on the relatively undeveloped field of determination of ever, its synthetic scope is limited to the preparation of 2-chirally enantiomeric purity and/or absolute configuration of remotely substituted 1-alkanols. In search for an alternative and more chiral primary alcohols. generally applicable procedure, we came up with a strategy shown in Scheme 2, which, in principle, should be applicable to Author contributions: S.X. and E.N. designed research; S.X., A.O., and H.K. performed the synthesis of γ- and more-remotely chiral alcohols of high research; S.X., A.O., H.K., and E.N. analyzed data; and S.X. and E.N. wrote the paper. enantiomeric purity. In contrast to Scheme 1, the alkylalane The authors declare no conflict of interest. intermediates prepared by the ZACA reaction of tert-butyldi- This article is a PNAS Direct Submission. methylsilyl (TBS)-protected ω-alkene-1-ols are to be subjected to 1To whom correspondence should be addressed. E-mail: [email protected]. α ω in situ oxidation with O2 to introduce OH group of , -dioxy- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. functional chiral intermediates (3) (Scheme 2). The strategies 1073/pnas.1401187111/-/DCSupplemental. 8368–8373 | PNAS | June 10, 2014 | vol. 111 | no. 23 www.pnas.org/cgi/doi/10.1073/pnas.1401187111 Downloaded by guest on September 26, 2021 Scheme 1. Strategy for the synthesis of enantiomerically pure 2-alkyl-1- alkanols. Scheme 2. Strategy for the synthesis of γ- and more-remotely chiral 1-alkanols. these in mind, we applied this catalytic asymmetric protocol to- ward the preparation of α,ω-dioxyfunctional key intermediates To further demonstrate the high efficiency of ZACA–lipase- 3 by ZACA reaction of a few representative TBS-protected catalyzed acetylation tandem process for preparation of both ω-alkene-1-ols (Table 1). Thus, commercially available 3-buten-1-ol, (R)- and (S)-α,ω-dioxyfunctional alcohols, one control experi- 4-penten-1-ol, and 5-hexen-1-ol were protected with TBSCl ment of lipase-catalyzed acetylation of racemic 3b, prepared in and imidazole and subjected to the ZACA reaction using Et3Al n 45% yield by rac-(EBI)ZrCl2-catalyzed carboalumination, was or Pr3Al (two equivalents), isobutylaluminoxane (IBAO, one R 3b ≥ ee equivalent) (15, 16), and a catalytic amount of (–)- or (+)-bis- performed. Under the optimal conditions, ( )- of 99% (neomenthylindenyl)zirconium dichloride [(–)- or (+)-(NMI) ZrCl ] was formed in only 30% recovery by Amano lipase PS-catalyzed 2 2 rac 3b S 3b (17, 18), and then oxidized in situ with O . The crude alcohols 3 acetylation of - . Furthermore, ( )- was obtained in a 2 ee were obtained in 67–78% yields, and their enantiomeric purities disappointingly low recovery of 10% with only 87.8% (Table 2, ranged from 80% to 88% ee (Table 1). entry 11). Thus, it is practically impossible to provide highly pure S 3b rac 3b Enantiomeric purification of α,ω-dioxyfunctional inter- ( )- by lipase-catalyzed acetylation of - . These results – mediates 3 of 80–88% ee obtained by the ZACA reaction was clearly indicate that the ZACA lipase-catalyzed acetylation carried out by lipase-catalyzed acetylation (11, 12), and the tandem protocol provides a more efficient, satisfactory, and results are summarized in Table 2. Amano lipase PS from general route to both (R)- and (S)-α,ω-dioxyfunctional alcohols Pseudomonas cepacia (Aldrich) was generally superior to Amano in high enantiomeric purity, which should serve as versatile di- lipase AK from Pseudomonas fluorescens (Aldrich) in the puri- functional chiral synthons. fication of (R)-3a and 3b (Table 2, entries 1–2 and 5–6). Also, Having established the feasibility of efficiently synthesizing 1,2-dichloroethane proved to be a superior solvent than THF for α,ω-dioxyfunctional chiral alcohols 3 in a highly enantioselective the purification of (R)-3a and 3b (Table 2, entries 2–3 and 6–7). and efficient manner, we then turned our attention to the syn- Thus, (R)-3a, 3b, and 3c were readily purified to the level of thesis of γ- and more-remotely and barely chiral (19–21) alcohols ≥99% ee by Amano lipase PS-catalyzed acetylation with vinyl of high enantiomeric purity, which have not previously been acetate in 1,2-dichloroethane in 60–73% recovery yields. Simi- readily accessible, via key intermediates 3 by Cu- or Pd-catalyzed larly, Amano lipase PS-catalyzed acetylation of (S)-3b of 85% ee cross-coupling reactions. (R)-3a of ≥99% ee was converted to provided acetate (S)-4b, which was hydrolyzed with KOH to tosylate (R)-5.(R)-6 and (S)-7 of ≥99% ee were then synthesized CHEMISTRY form (S)-3b of 97.6% ee in 82% recovery.
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