Highly enantioselective synthesis of γ-, δ-, and e-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of (ZACA)–Cu- or Pd-catalyzed cross-coupling

Shiqing Xu, Akimichi Oda, Hirofumi Kamada, and Ei-ichi Negishi1

Department of , 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 . 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 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--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 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 as the demand for enantiomeri- A and (iii) many potential transformations of the initially formed cally pure compounds continues to increase. 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 scope and a high synthetic potential. With all chiral bioactive have to be as pure as possible, containing a single pure , 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 , (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% 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 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. (S)-3b of 97.6% ee was by further transformation of (R)-5 via reduction with LiAlH4 further subjected to a second round of lipase-catalyzed acetyla- (1.5 equivalents) or CuCl2-catalyzed cross-coupling with ethyl- tion/hydrolysis to give (S)-3b of ≥99% ee in 85% recovery (Table magnesium chloride (2 equivalents) and 15 mol% of 1-phenyl- 2, entry 10). (14), followed by removal of the TBS group with

Table 1. ZACA reaction of TBS-protected ω-alkene-1-ols

i) (−)-(NMI)2ZrCl2 or (+)-(NMI)2ZrCl2 (1%) † IBAO (1 equiv) , R R ii) O2 R3Al (2 equiv) OTBS R2Al OTBS HO OTBS n n * CH2Cl2 * n 3, R or S

‡ Entry n (NMI)2ZrCl2 R Yield, % Purity of 3 ee, % 1 2 (–) Et (R)-3a 78 88 2 3 (–) nPr (R)-3b 72 82 3 3 (+) nPr (S)-3b 67 85

¶ n 44(–) Pr (R)-3c 68 80

† i IBAO (isobutylaluminoxane): prepared by mixing equimolar quantities of Bu3Al and H2O. ‡ determined by chiral GC or 1H NMR analysis of Mosher esters. { The amount of (–)-(NMI)2ZrCl2 used was 3 mol%.

Xu et al. PNAS | June 10, 2014 | vol. 111 | no. 23 | 8369 Downloaded by guest on September 26, 2021 Table 2. Enantiomeric purification of (3) by lipase-catalyzed acetylation cat. Lipase R R R R OAc HO OTBS + HO OTBS HO OTBS + AcO OTBS n n n ClCH CH Cl n 2 2 3 4 (R)-3 (S)-3 (R)- (S)- disfavored favored KOH (S)-3

Entry Substrate Initial purity of 3 ee, % Lipase* Conversion, % Recovery of 3, % Purity of 3 ee, %†

1 (R)-3a‡ 88 Amano AK 30 67 95

2 (R)-3a‡ 88 Amano PS 22 77 98 3(R)-3a 88 Amano PS 18 80 98 4(R)-3a 88 Amano PS 25 73 ≥99 5 (R)-3b‡ 82 Amano AK 36 62 93 6 (R)-3b‡ 82 Amano PS 33 65 ≥99 7(R)-3b 82 Amano PS 28 69 ≥99 8(R)-3c 80 Amano PS 39 60 ≥99 9 (S)-3b§ 85 Amano PS 85 82 97.6 10 (S)-3b§ 97.6 Amano PS 88 85 ≥99 11 rac-3b§ 0 Amano PS 12 10 87.8 Enantiomeric purification of 3 to the ≥99% ee level was highlighted in bold. *Lipase-catalyzed acetylation is S-selective. The acetylation rate of (S)-3 is faster than that of (R)-3. † Enantiomeric excess determined by chiral GC or 1H NMR analysis of Mosher esters. ‡ THF was used instead of 1,2-dichloroethane. §Lipase-catalyzed acetylation was followed by hydrolysis of (S)-4b to give (S)-3b.

tetrabutylammonium fluoride (TBAF), in 75% and 80% yields CuCl2/1-phenylpropyne-catalyzed cross-coupling with alkylmag- over three steps, respectively (Scheme 3). nesium chloride reagents (14), and TBAF desilylation in 70–73% For the synthesis of chiral 4-alkyl-1-alkanols of ≥99% ee, yields over three steps, respectively. For the preparation of (R)-3b was first transformed to the corresponding tosylate (R)-8a (R)-16, our initial attempts on the cross-coupling reaction of or iodide (R)-8b. The preparation of (R)-9 was performed by the tosylate (S)-8a with [2-(1,3-dioxan-2-yl)ethyl]magnesium bro- reduction of tosylate (R)-8a with LiAlH4 followed by TBAF mide under similar conditions proved unsuccessful. The reaction desilylation in 80% yield over three steps. Tosylate (R)-8a was was not completed, and the product yield was low. When the also subjected to the Cu-catalyzed cross-coupling reactions with substrate was changed from tosylate (S)-8a to iodide (S)-8b, and different alkylmagnesium chloride reagents to provide (R)-10, an additive N-methylpyrrolidone (NMP, four equivalents) was (S)-11, and (R)-12 in 77–84% yields. Pd-catalyzed Negishi cou- added, the CuCl2/1-phenylpropyne-catalyzed cross-coupling re- pling of aryl and alkenyl halides was used to introduce aryl and action of iodide (S)-8b with [2-(1,3-dioxan-2-yl)ethyl]magnesium alkenyl groups. The preparation of (R)-13 and (R)-14 of ≥99% ee bromide proceeded smoothly. Thus, (R)-16 was synthesized as an was carried out by zincation of iodide (R)-8b, Pd-catalyzed (22, 23) with 4-iodotoluene or (E)-ethyl 3-bromoacrylate, and TBAF desilylation in 60% and 58% yields over three steps, respectively (Scheme 4). (S)-3b was also used as a key intermediate in the synthesis of chiral 4-alkyl-1-alcohols (S)-10,(S)-12, and (S)-15 via tosylation,

Scheme 3. Synthesis of chiral 3-alkyl-1-alcohols from (R)-3a. Scheme 4. Synthesis of chiral 4-alkyl-1-alcohols from (R)-3b.

8370 | www.pnas.org/cgi/doi/10.1073/pnas.1401187111 Xu et al. Downloaded by guest on September 26, 2021 Scheme 5. Synthesis of chiral 4-alkyl-1-alcohols from (S)-3b.

enantiomerically pure (≥99% ee) compound in 64% yield over three steps from iodide (S)-8b (Scheme 5). A similar synthetic strategy was used in the synthesis of chiral 5-alkyl-1-alknols of ≥99% ee from the intermediate (R)-3c. Re- Fig. 1. MTPA and MαNP esters of secondary alcohols as NMR-distinguish- duction of tosylate (R)-17a with LiAlH4 followed by TBAF able chiral derivatives. desilylation provided (R)-18 in 75% yield. Cu-catalyzed cross- coupling reactions of tosylate (R)-17a or iodide (R)-17b with various alkyl (primary, secondary, tertiary, cyclic) Grignard However, initial attempts to determine the enantiomeric excess in more demanding cases, such as 5-alkyl-1-alcohols 19, 20, 21, reagents proceeded smoothly to form a wide range of enantio- 23, and 24 and 4-alkyl-1-alcohols 11 and 16, using chiral GC and merically pure (≥99% ee) chiral 5-alkyl-1-alknols 19–24 after HPLC were unsatisfactory. deprotection of TBS group (Scheme 6). NMR has become a popular and convenient tool Having developed a widely applicable route to various γ- and for the determination of enantiomeric purity and absolute con- more-remotely chiral alcohols using the ZACA/oxidation–lipase- – figuration of chiral compounds, which is based on transformation catalyzed acetylation Cu- or Pd-catalyzed cross-coupling pro- of the chiral substrate with a suitable chiral derivatizing agent tocol, our attention was necessarily and increasingly drawn into (CDA) to two different diastereoisomers or conformers that can the methods of determination of the enantiomeric purities of be differentiated by NMR spectroscopy. Many CDAs including final desired alcohols, which proved to be quite challenging. For α-methoxy-α-(trifluoromethyl) phenylacetic acid (MTPA or most of the alkanols where the stereogenic center generated was Mosher acid) (24) have been developed for determining the γ δ in the or position relative to the OH group, such as com- absolute configurations and/or enantiomeric excess of secondary 7 9 10 12 13 ≥ ee pounds , , , , and , the enantiomeric purities of 99% alcohols (24–27). However, few papers reported examples of were successfully determined by chiral gas . primary alcohols, which mainly focused on the cases of β-chiral CHEMISTRY primary alcohols (28–32). Challenges in dealing with primary alcohols stem from the facts that the distance between groups R1/R2 of primary alcohols and the aryl ring of CDA is greater than that in secondary alcohols, leading to lower shielding effects and also reducing the conformational preference by increasing the degree of rotational freedom (Fig. 1). In our previous work, we also used MTPA (24) to determine enantiomeric purities of β-chiral primary alcohols (6). However, in cases where the two alkyl branches of β-chiral primary alcohols at the stereogenic center are closely similar to each other, such as C4H9(C3H7) CHCH2OH, the chemical shifts of the diastereomeric MTPA esters were not sufficiently separated to allow quantitative determination of the enantiomeric purity by 1HNMRor 19F NMR analysis. A solution to the difficulty mentioned above was found through the use of 2-methoxy-2-(1-naphthyl)propionic acid (MαNP), which had been used in determining the absolute configuration of chiral secondary alcohols (33, 34). The naphthyl ring of MαNP esters exerts greater anisotropic shielding effects on than . As a result, MαNP acid shows greater discrimination than MTPA (24). Indeed, the two termi- nal methyl groups of the diastereomeric MαNP ester (R,R)- and (R,S)-26, derived from e-chiral alcohol (R)-19, showed com- 1 Scheme 6. Synthesis of chiral 5-alkyl-1-alcohols from (R)-3c. pletely separate H NMR signals, whereas the diastereomeric

Xu et al. PNAS | June 10, 2014 | vol. 111 | no. 23 | 8371 Downloaded by guest on September 26, 2021 1 Fig. 2. Methyl resonances in the H NMR spectra (CDCl3, 600 MHz) of MTPA ester and MαNP ester derived from (R)-19.

MTPA ester 25 had no separation (Fig. 2). The MαNP ester features to provide various γ-, δ-, and e-chiral 1-alkanols of analysis was also successfully applied to chiral discrimination of ≥99% ee, many of which cannot be satisfactorily prepared by other δ- and e-chiral primary alcohols 11, 14, 16, 20, 21, 23, and other existing methods. In view of the easy availability of a wide 24, which demonstrated surprising long-range anisotropic dif- variety of α-olefins and cross-coupling reagents, we anticipate ferential shielding effects. It should be noted that the diaster- that ZACA combined with Cu- or Pd-catalyzed cross-coupling α eotopic chemical shift differences of M NP esters were affected would provide a general and efficient route to a broad range of by NMR solvent and frequency (MHz) of NMR. chiral compounds in high enantiomeric purity. We have also d-, d-, d-methanol and/or CDCl3 have been demonstrated that the MαNP ester analysis is a convenient and shown to be suitable . The higher the resonance fre- widely applicable method for determining the enantiomeric quency, the better discrimination of chemical shifts obtained. purities of δ- and e-chiral primary alkanols, which sheds light on Conclusions the relatively undeveloped area of determination of enantio- In summary, we developed a widely applicable method for highly meric purity and/or absolute configuration of remotely chiral enantioselective (≥99% ee)synthesisofvariousγ- and more- primary alcohols. remotely chiral alcohols by the ZACA/oxidation–lipase-catalyzed Materials and Methods acetylation–Cu- or Pd-catalyzed cross-coupling strategy herein reported. Once the α,ω-dioxyfunctional chiral intermediates 3 All reactions were run under a dry argon atmosphere. THF and was were prepared as enantiomerically pure (≥99% ee) compounds dried by under argon from sodium/benzophenone. CH2Cl2 was by ZACA/in situ oxidation–lipase-catalyzed acetylation, their dried by distillation under argon from CaH2. Full experimental details and compound characterization data are included in the SI Appendix. subsequent Cu-catalyzed cross-coupling with various alkyl (pri- mary, secondary, tertiary, cyclic) Grignard reagents and Pd-cat- ACKNOWLEDGMENTS. We thank the National Institutes of Health (Grant alyzed cross-coupling with alkenyl and aryl halides proceeded GM 36792) and Purdue University for support of this research. We also thank smoothly with essentially full retention of all carbon skeletal Sigma-Aldrich, Albemarle, Boulder Scientific, and Teijin for support.

1. Ojima I, et al. (2010) Catalytic Asymmetric Synthesis, ed Ojima I (Wiley, New York), pp 10. Xu S, Negishi E (2014) Synthesis of chiral heterocyclic compounds via zirconium- 1–998. catalyzed asymmetric carboalumination of alkenes (ZACA reaction). Heterocycles 2. Noyori R (2002) Asymmetric : Science and opportunities (Nobel lecture). An- 88(2):845–877. gew Chem Int Ed Engl 41(12):2008–2022. 11. Chen CS, Fujimoto Y, Girdaukas G, Sih CJ (1982) Quantitative analyses of biochemical 3. Helmchen G, Pfaltz A (2000) Phosphinooxazolines—a new class of versatile, modular kinetic resolutions of . J Am Chem Soc 104(25):7294–7299. – P,N- for asymmetric catalysis. Acc Chem Res 33(6):336–345. 12. Koeller KM, Wong CH (2001) for . Nature 409(6817):232 240. 4. Sharpless KB (2002) Searching for new reactivity (Nobel lecture). Angew Chem Int Ed 13. Negishi E (2011) Magical power of transition metals: Past, present, and future (Nobel Lecture). Angew Chem Int Ed Engl 50(30):6738–6764. Engl 41(12):2024–2032. 14. Terao J, Todo H, Begum SA, Kuniyasu H, Kambe N (2007) -catalyzed cross- 5. Trost BM, Crawley ML (2003) Asymmetric transition-metal-catalyzed allylic alkylations: coupling reaction of grignard reagents with primary-alkyl halides: Remarkable effect Applications in . Chem Rev 103(8):2921–2944. of 1-phenylpropyne. Angew Chem Int Ed Engl 46(12):2086–2089. 6. Xu S, Lee C-T, Wang G, Negishi E (2013) Widely applicable synthesis of enantiomerically pure 15. Huo S, Shi JC, Negishi E (2002) A new protocol for the enantioselective synthesis of tertiary alkyl-containing 1-alkanols by zirconium-catalyzed asymmetric carboalumination of methyl-substituted alkanols and their derivatives through a hydroalumination/ zir- – alkenes and palladium- or copper-catalyzed cross-coupling. Chem Asian J 8(8):1829 1835. conium-catalyzed alkylalumination tandem process. Angew Chem Int Ed Engl 41(12): 7. Kondakov D, Negishi E (1995) Zirconium-catalyzed enantioselective methylalumina- 2141–2143. tion of monosubstituted alkenes. J Am Chem Soc 117(43):10771–10772. 16. Liang B, Negishi E (2008) Highly efficient asymmetric synthesis of fluvirucinine A1 via 8. Kondakov D, Negishi E (1996) Zirconium-catalyzed enantioselective alkylalumination Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)-lipase-catalyzed acety- of monosubstituted alkenes proceeding via noncyclic mechanism. J Am Chem Soc lation tandem process. Org Lett 10(2):193–195. 118(6):1577–1578. 17. Erker G, et al. (1993) The role of torsional isomers of planarly chiral nonbridged bis 9. Negishi E (2011) Discovery of ZACA reaction: Zr-catalyzed asymmetric carboalumi- (indenyl)metal type complexes in stereoselective propene polymerization. J Am Chem nation of alkenes. Arkivoc 2011(viii):34–53. Soc 115(11):4590–4601.

8372 | www.pnas.org/cgi/doi/10.1073/pnas.1401187111 Xu et al. Downloaded by guest on September 26, 2021 18. Negishi E, Huo S (2003) (–)-Dichlorobis[(1,2,3,3a,7a-η)-1-[(1S,2S,5R)-5-methyl-2-(1- 27. Seco JM, Quiñoá E, Riguera R (2012) Assignment of the absolute configuration of methylethyl)]cyclohexyl-1H-inden-1-yl]zirconium and its (+)-(1R,2R,5S)-isomer. e-EROS polyfunctional compounds by NMR using chiral derivatizing agents. Chem Rev 112(8): Encyclopedia of Reagents for , 10.1002/047084289X.rn00180. 4603–4641. 19. Mislow K, Bickart P (1976/77) An epistemological note on chirality. Isr J Chem 15(1-2): 28. Finamore E, Minale L, Riccio R, Rinaldo G, Zollo F (1991) Novel marine polyhydroxylated – 1 6. from the starfish Myxoderma platyacanthum. J Org Chem 56(3):1146–1153. 20. Mislow K (1997) Fuzzy Logic in Chemistry, ed Rouvray DH (Academic Press, New York), 29. Alexakis A, Mutti S, Mangeney P (1992) A new for the determination of the – pp 65 90. optical purity of primary, secondary, and tertiary chiral alcohols and of thiols. JOrg 21. Mislow K (2003) Absolute asymmetric synthesis: A commentary. Collect Czech Chem Chem 57(4):1224–1237. – Commun 68(5):849 864. 30. Ferreiro MJ, Latypov ShK, Quiñoá E, Riguera R (1996) Determination of the absolute 22. Fu GC (2008) The development of versatile methods for palladium-catalyzed coupling configuration and enantiomeric purity of chiral primary alcohols by 1H NMR of reactions of aryl electrophiles through the use of P(t-Bu) and PCy as ligands. Acc 3 3 9-anthrylmethoxyacetates. Tetrahedron Asymmetry 7(8):2195–2198. Chem Res 41(11):1555–1564. 31. Ciminiello P, Dell’Aversano C, Fattorrusso E, Forino M, Magno S (2001) Assignment of 23. Organ MG, et al. (2006) A user-friendly, all-purpose Pd-NHC (NHC=N-heterocyclic the absolute of oxazinin-1: Application of the 9-AMA shift-correla- carbene) precatalyst for the negishi reaction: A step towards a universal cross- β – coupling catalyst. Chemistry 12(18):4749–4755. tion method for -chiral primary alcohols. Tetrahedron 57(38):8189 8192. 24. Dale JA, Mosher HS (1973) Nuclear magnetic resonance enantiomer regents. 32. Fukui H, Fukushi Y, Tahara S (2005) NMR determination of the absolute configuration β – Configurational correlations via nuclear magnetic resonance chemical shifts of di- of -chiral primary alcohols. Tetrahedron Lett 46(30):5089 5093. astereomeric mandelate, O-methylmandelate, and alpha-methoxy-alpha-tri- 33. Harada N, et al. (2000) 2-Methoxy-2-(1-naphthyl)propionic acid, a powerful fluoromethylphenylacetate (MTPA) esters. J Am Chem Soc 95:512–519. for enantioresolution of alcohols and determination of their absolute configurations by the 1 25. Parker D (1991) NMR determination of enantiomeric purity. Chem Rev 91(7): H NMR anisotropy method. Tetrahedron Asymmetry 11(6):1249–1253. 1441–1457. 34. Kasai Y, et al. (2007) Conformational analysis of MαNP esters, powerful chiral reso- 26. Seco JM, Quiñoá E, Riguera R (2004) The assignment of absolute configuration by lution and 1H NMR anisotropy tools—Aromatic geometry and solvent effects on Δδ NMR. Chem Rev 104:17–117. values. Eur J Org Chem 2007(11):1811–1826. CHEMISTRY

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