Highly enantioselective synthesis of γ-, δ-, and e-chiral1-alkanols via Zr-catalyzed asymmetric carboaluminationof alkenes (ZACA)–Cu- or Pd-catalyzed cross-couplingShiqing 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 preparationof enantiomerically pure (≥99% ee) compounds remains a chal-lenge in modern organic chemistry. We report here a strategyfor a highly enantioselective (≥99% ee) and catalytic synthesisof various γ- and more-remotely chiral alcohols from terminalalkenes via Zr-catalyzed asymmetric carboalumination of alkenes(ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situoxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-olsproduced both (R)- and (S)-α,ω-dioxyfunctional intermediates (3)in 80–88% ee, which were readily purified to the ≥99% ee levelby lipase-catalyzed acetylation through exploitation of their highselectivity factors. These α,ω-dioxyfunctional intermediates serveas versatile synthons for the construction of various chiral com-pounds. Their subsequent Cu-catalyzed cross-coupling with vari-ous alkyl (primary, secondary, tertiary, cyclic) Grignard reagentsand Pd-catalyzed cross-coupling with aryl and alkenyl halides pro-ceeded smoothly with essentially complete retention of stereo-chemical configuration to produce a wide variety of γ-, δ-, ande-chiral 1-alkanols of ≥99% ee. The MαNP ester analysis has beenapplied to the determination of the enantiomeric purities of δ- ande-chiral primary alkanols, which sheds light on the relatively un-developed area of determination of enantiomeric purity and/orabsolute configuration of remotely chiral primary alcohols.

Asymmetric synthesis remains as a significant challenge tosynthetic organic chemists as the demand for enantiomeri-

cally pure compounds continues to increase. Chirality plays a vi-tal role in chemical, biological, pharmaceutical, and materialsciences. The US Food and Drug Administration requires thatall chiral bioactive molecules have to be as pure as possible,containing a single pure enantiomer, because chirality signifi-cantly influences drugs’ biological and pharmacological proper-ties. As a consequence, development of new methods forasymmetric synthesis of enantiomerically pure compounds(≥99% ee) continues to be increasingly important (1–5). Werecently reported a highly selective and efficient method (6) forthe preparation of 2-chirally substituted 1-alkanols via a se-quence consisting of (i) Zr-catalyzed asymmetric carboalumi-nation of alkenes (ZACA reaction hereafter) (7–10)–in situiodinolysis of allyl alcohol, (ii) enantiomeric purification bylipase-catalyzed acetylation (11, 12) of both (S)- and (R)-ICH2CH(R)CH2OH (1), the latter obtained as acetate, i.e., (R)-2, and(iii) Cu- or Pd-catalyzed cross-coupling (13, 14) (Scheme 1).As satisfactory as the procedure shown in Scheme 1 is, how-

ever, its synthetic scope is limited to the preparation of 2-chirallysubstituted 1-alkanols. In search for an alternative and moregenerally applicable procedure, we came up with a strategyshown in Scheme 2, which, in principle, should be applicable tothe synthesis of γ- and more-remotely chiral alcohols of highenantiomeric purity. In contrast to Scheme 1, the alkylalaneintermediates prepared by the ZACA reaction of tert-butyldi-methylsilyl (TBS)-protected ω-alkene-1-ols are to be subjected toin situ oxidation with O2 to introduce OH group of α,ω-dioxy-functional chiral intermediates (3) (Scheme 2). The strategies

shown in Schemes 1 and 2 illustrate the versatility of ZACArepresented by the organoaluminum functionality of the ini-tially formed ZACA products. Introduction of the OH groupby oxidation of initially formed alkylalane intermediates inScheme 2 is based on two considerations: (i) the proximity of theOH group to a stereogenic carbon center is highly desirable forlipase-catalyzed acetylation to provide ultrapure (≥99% ee) di-functional intermediates, and (ii) the versatile OH group canbe further transformed to a wide range of carbon groups bytosylation or iodination followed by Cu- or Pd-catalyzed cross-coupling. The TBS-protected OH group (OTBS) serves not onlyas a source of OH group in the final desired alkanols, but alsoas a proximal heterofunctional group leading to higher enan-tioselectivity in lipase-catalyzed acetylation (11, 12). As long asthe α,ω-dioxyfunctional chiral intermediates (R)-3 and (S)-4can be readily prepared as enantiomerically pure (≥99% ee)substances, their subsequent Cu- or Pd-catalyzed cross-couplingwould proceed with retention of all carbon skeletal features toproduce a wide range of γ- and more-remotely chiral alcohols inhigh enantiomeric purity (≥99% ee).

Results and DiscussionSome key features of the ZACA reaction include (i) catalyticasymmetric C–C bond formation, (ii) use of alkene substances ofone-point-binding without requiring any other functional groups,and (iii) many potential transformations of the initially formedalkylalane intermediates (6–10). The ZACA reaction showsa broad substrate scope and a high synthetic potential. With

Significance

Chirality plays a vital role in chemical, biological, pharmaceu-tical, and material sciences. The preparation of enantiomeri-cally pure compounds is a very important and challenging area.In this paper, we developed a highly enantioselective (≥99%ee) and widely applicable method for the synthesis of variousγ- and more-remotely chiral alcohols, many of which cannot besatisfactorily prepared by other existing methods, via theZACA/oxidation–lipase-catalyzed acetylation–Cu- or Pd-cata-lyzed cross-coupling from terminal alkenes. We also demon-strated MαNP ester analysis is a convenient and powerfulmethod for determining the enantiomeric purities of δ- ande-chiral primary alkanols. This finding is anticipated to shedlight on the relatively undeveloped field of determination ofenantiomeric purity and/or absolute configuration of remotelychiral primary alcohols.

Author contributions: S.X. and E.N. designed research; S.X., A.O., and H.K. performedresearch; S.X., A.O., H.K., and E.N. analyzed data; and S.X. and E.N. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.1To whom correspondence should be addressed. E-mail: negishi@purdue.edu.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1401187111/-/DCSupplemental.

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these in mind, we applied this catalytic asymmetric protocol to-ward the preparation of α,ω-dioxyfunctional key intermediates3 by ZACA reaction of a few representative TBS-protectedω-alkene-1-ols (Table 1). Thus, commercially available 3-buten-1-ol,4-penten-1-ol, and 5-hexen-1-ol were protected with TBSCland imidazole and subjected to the ZACA reaction using Et3Alor nPr3Al (two equivalents), isobutylaluminoxane (IBAO, oneequivalent) (15, 16), and a catalytic amount of (–)- or (+)-bis-(neomenthylindenyl)zirconium dichloride [(–)- or (+)-(NMI)2ZrCl2](17, 18), and then oxidized in situ with O2. The crude alcohols 3were obtained in 67–78% yields, and their enantiomeric puritiesranged from 80% to 88% ee (Table 1).Enantiomeric purification of α,ω-dioxyfunctional inter-

mediates 3 of 80–88% ee obtained by the ZACA reaction wascarried out by lipase-catalyzed acetylation (11, 12), and theresults are summarized in Table 2. Amano lipase PS fromPseudomonas cepacia (Aldrich) was generally superior to Amanolipase AK from Pseudomonas fluorescens (Aldrich) in the puri-fication of (R)-3a and 3b (Table 2, entries 1–2 and 5–6). Also,1,2-dichloroethane proved to be a superior solvent than THF forthe purification of (R)-3a and 3b (Table 2, entries 2–3 and 6–7).Thus, (R)-3a, 3b, and 3c were readily purified to the level of≥99% ee by Amano lipase PS-catalyzed acetylation with vinylacetate in 1,2-dichloroethane in 60–73% recovery yields. Simi-larly, Amano lipase PS-catalyzed acetylation of (S)-3b of 85% eeprovided acetate (S)-4b, which was hydrolyzed with KOH toform (S)-3b of 97.6% ee in 82% recovery. (S)-3b of 97.6% ee wasfurther subjected to a second round of lipase-catalyzed acetyla-tion/hydrolysis to give (S)-3b of ≥99% ee in 85% recovery (Table2, entry 10).

To further demonstrate the high efficiency of ZACA–lipase-catalyzed acetylation tandem process for preparation of both(R)- and (S)-α,ω-dioxyfunctional alcohols, one control experi-ment of lipase-catalyzed acetylation of racemic 3b, prepared in45% yield by rac-(EBI)ZrCl2-catalyzed carboalumination, wasperformed. Under the optimal conditions, (R)-3b of ≥99% eewas formed in only 30% recovery by Amano lipase PS-catalyzedacetylation of rac-3b. Furthermore, (S)-3b was obtained in adisappointingly low recovery of 10% with only 87.8% ee (Table 2,entry 11). Thus, it is practically impossible to provide highly pure(S)-3b by lipase-catalyzed acetylation of rac-3b. These resultsclearly indicate that the ZACA–lipase-catalyzed acetylationtandem protocol provides a more efficient, satisfactory, andgeneral route to both (R)- and (S)-α,ω-dioxyfunctional alcoholsin high enantiomeric purity, which should serve as versatile di-functional chiral synthons.Having established the feasibility of efficiently synthesizing

α,ω-dioxyfunctional chiral alcohols 3 in a highly enantioselectiveand efficient manner, we then turned our attention to the syn-thesis of γ- and more-remotely and barely chiral (19–21) alcoholsof high enantiomeric purity, which have not previously beenreadily accessible, via key intermediates 3 by Cu- or Pd-catalyzedcross-coupling reactions. (R)-3a of ≥99% ee was converted totosylate (R)-5. (R)-6 and (S)-7 of ≥99% ee were then synthesizedby further transformation of (R)-5 via reduction with LiAlH4

(1.5 equivalents) or CuCl2-catalyzed cross-coupling with ethyl-magnesium chloride (2 equivalents) and 15 mol% of 1-phenyl-propyne (14), followed by removal of the TBS group with

Scheme 1. Strategy for the synthesis of enantiomerically pure 2-alkyl-1-alkanols.

Scheme 2. Strategy for the synthesis of γ- and more-remotely chiral1-alkanols.

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

Entry n (NMI)2ZrCl2 R Product 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

4 4 (–)¶nPr (R)-3c 68 80

3, R or S

OTBSn

i) (−)-(NMI)2ZrCl2 or(+)-(NMI)2ZrCl2 (1%)IBAO (1 equiv) ,†

R3Al (2 equiv) OTBSn

RR2Al

*ii) O2

OTBSn

RHO

*CH2Cl2

†IBAO (isobutylaluminoxane): prepared by mixing equimolar quantities of iBu3Al and H2O.‡Enantiomeric excess determined by chiral GC or 1H NMR analysis of Mosher esters.{The amount of (–)-(NMI)2ZrCl2 used was 3 mol%.

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tetrabutylammonium fluoride (TBAF), in 75% and 80% yieldsover three steps, respectively (Scheme 3).For the synthesis of chiral 4-alkyl-1-alkanols of ≥99% ee,

(R)-3b was first transformed to the corresponding tosylate (R)-8aor iodide (R)-8b. The preparation of (R)-9 was performed by thereduction of tosylate (R)-8a with LiAlH4 followed by TBAFdesilylation in 80% yield over three steps. Tosylate (R)-8a wasalso subjected to the Cu-catalyzed cross-coupling reactions withdifferent alkylmagnesium chloride reagents to provide (R)-10,(S)-11, and (R)-12 in 77–84% yields. Pd-catalyzed Negishi cou-pling of aryl and alkenyl halides was used to introduce aryl andalkenyl groups. The preparation of (R)-13 and (R)-14 of ≥99% eewas carried out by zincation of iodide (R)-8b, Pd-catalyzedNegishi coupling (22, 23) with 4-iodotoluene or (E)-ethyl3-bromoacrylate, and TBAF desilylation in 60% and 58% yieldsover 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,

CuCl2/1-phenylpropyne-catalyzed cross-coupling with alkylmag-nesium chloride reagents (14), and TBAF desilylation in 70–73%yields over three steps, respectively. For the preparation of(R)-16, our initial attempts on the cross-coupling reaction oftosylate (S)-8a with [2-(1,3-dioxan-2-yl)ethyl]magnesium bro-mide under similar conditions proved unsuccessful. The reactionwas not completed, and the product yield was low. When thesubstrate was changed from tosylate (S)-8a to iodide (S)-8b, andan additive N-methylpyrrolidone (NMP, four equivalents) wasadded, the CuCl2/1-phenylpropyne-catalyzed cross-coupling re-action of iodide (S)-8b with [2-(1,3-dioxan-2-yl)ethyl]magnesiumbromide proceeded smoothly. Thus, (R)-16 was synthesized as an

Table 2. Enantiomeric purification of (3) by lipase-catalyzed acetylation

+

cat. Lipase

OAc

ClCH2CH2Cl+

(S)-4(R)-3

OTBSn

RHO

(R)-3

OTBSn

RHO OTBS

n

RAcO

(S)-3

OTBSn

RHO

disfavored favored (S)-3KOH

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.

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

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enantiomerically pure (≥99% ee) compound in 64% yield overthree 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-duction of tosylate (R)-17a with LiAlH4 followed by TBAFdesilylation provided (R)-18 in 75% yield. Cu-catalyzed cross-coupling reactions of tosylate (R)-17a or iodide (R)-17b withvarious alkyl (primary, secondary, tertiary, cyclic) Grignardreagents proceeded smoothly to form a wide range of enantio-merically pure (≥99% ee) chiral 5-alkyl-1-alknols 19–24 afterdeprotection of TBS group (Scheme 6).Having developed a widely applicable route to various γ- and

more-remotely chiral alcohols using the ZACA/oxidation–lipase-catalyzed acetylation–Cu- or Pd-catalyzed cross-coupling pro-tocol, our attention was necessarily and increasingly drawn intothe methods of determination of the enantiomeric purities offinal desired alcohols, which proved to be quite challenging. Formost of the alkanols where the stereogenic center generated wasin the γ or δ position relative to the OH group, such as com-pounds 7, 9, 10, 12, and 13, the enantiomeric purities of ≥99% eewere successfully determined by chiral gas chromatography.

However, initial attempts to determine the enantiomeric excessin more demanding cases, such as 5-alkyl-1-alcohols 19, 20, 21,23, and 24 and 4-alkyl-1-alcohols 11 and 16, using chiral GC andHPLC were unsatisfactory.NMR spectroscopy has become a popular and convenient tool

for the determination of enantiomeric purity and absolute con-figuration of chiral compounds, which is based on transformationof the chiral substrate with a suitable chiral derivatizing agent(CDA) to two different diastereoisomers or conformers that canbe differentiated by NMR spectroscopy. Many CDAs includingα-methoxy-α-(trifluoromethyl) phenylacetic acid (MTPA orMosher acid) (24) have been developed for determining theabsolute configurations and/or enantiomeric excess of secondaryalcohols (24–27). However, few papers reported examples ofprimary alcohols, which mainly focused on the cases of β-chiralprimary alcohols (28–32). Challenges in dealing with primaryalcohols stem from the facts that the distance between groupsR1/R2 of primary alcohols and the aryl ring of CDA is greaterthan that in secondary alcohols, leading to lower shielding effectsand also reducing the conformational preference by increasingthe degree of rotational freedom (Fig. 1). In our previous work,we also used MTPA (24) to determine enantiomeric purities ofβ-chiral primary alcohols (6). However, in cases where the twoalkyl branches of β-chiral primary alcohols at the stereogeniccenter are closely similar to each other, such as C4H9(C3H7)CHCH2OH, the chemical shifts of the diastereomeric MTPAesters were not sufficiently separated to allow quantitativedetermination of the enantiomeric purity by 1H NMR or19F 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 absoluteconfiguration of chiral secondary alcohols (33, 34). The naphthylring of MαNP esters exerts greater anisotropic shielding effectson substituents than phenyl group. As a result, MαNP acid showsgreater 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-pletely separate 1H NMR signals, whereas the diastereomeric

Scheme 5. Synthesis of chiral 4-alkyl-1-alcohols from (S)-3b.

Scheme 6. Synthesis of chiral 5-alkyl-1-alcohols from (R)-3c.

Fig. 1. MTPA and MαNP esters of secondary alcohols as NMR-distinguish-able chiral derivatives.

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MTPA ester 25 had no separation (Fig. 2). The MαNP esteranalysis was also successfully applied to chiral discrimination ofother δ- and e-chiral primary alcohols 11, 14, 16, 20, 21, 23, and24, which demonstrated surprising long-range anisotropic dif-ferential shielding effects. It should be noted that the diaster-eotopic chemical shift differences of MαNP esters were affectedby NMR solvent and resonance frequency (MHz) of NMR.d-Acetonitrile, d-acetone, d-methanol and/or CDCl3 have beenshown to be suitable solvents. The higher the resonance fre-quency, the better discrimination of chemical shifts obtained.

ConclusionsIn summary, we developed a widely applicable method for highlyenantioselective (≥99% ee) synthesis of various γ- and more-remotely chiral alcohols by the ZACA/oxidation–lipase-catalyzedacetylation–Cu- or Pd-catalyzed cross-coupling strategy hereinreported. Once the α,ω-dioxyfunctional chiral intermediates 3were prepared as enantiomerically pure (≥99% ee) compoundsby ZACA/in situ oxidation–lipase-catalyzed acetylation, theirsubsequent Cu-catalyzed cross-coupling with various alkyl (pri-mary, secondary, tertiary, cyclic) Grignard reagents and Pd-cat-alyzed cross-coupling with alkenyl and aryl halides proceededsmoothly with essentially full retention of all carbon skeletal

features to provide various γ-, δ-, and e-chiral 1-alkanols of≥99% ee, many of which cannot be satisfactorily prepared byother existing methods. In view of the easy availability of a widevariety of α-olefins and cross-coupling reagents, we anticipatethat ZACA combined with Cu- or Pd-catalyzed cross-couplingwould provide a general and efficient route to a broad range ofchiral compounds in high enantiomeric purity. We have alsodemonstrated that the MαNP ester analysis is a convenient andwidely applicable method for determining the enantiomericpurities of δ- and e-chiral primary alkanols, which sheds light onthe relatively undeveloped area of determination of enantio-meric purity and/or absolute configuration of remotely chiralprimary alcohols.

Materials and MethodsAll reactions were run under a dry argon atmosphere. THF and ether wasdried by distillation under argon from sodium/benzophenone. CH2Cl2 wasdried by distillation under argon from CaH2. Full experimental details andcompound characterization data are included in the SI Appendix.

ACKNOWLEDGMENTS. We thank the National Institutes of Health (GrantGM 36792) and Purdue University for support of this research. We also thankSigma-Aldrich, Albemarle, Boulder Scientific, and Teijin for support.

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