Catalytic enantioselective synthesis of chiral organic compounds of ultra-high purity of >99% ee

Abstract

Shortly after the discovery of Zr-catalyzed carboalumination of alkynes in 1978, we sought expansion of the scope of this reaction so as to develop its alkene version for catalytic asymmetric C–C bond formation, namely the ZACA (Zr-catalyzed asymmetric carboalumination of alkenes). However, this seemingly easy task proved to be quite challenging. The ZACA reaction was finally discovered in 1995 by suppressing three competitive side reactions, i.e., (i) cyclic carbometalation, (ii) β-H transfer hydrometalation, and (iii) alkene polymerization. The ZACA reaction has been used to significantly modernize and improve syntheses of various natural products including deoxypolypropionates and isoprenoids. This review focuses on our recent progress on the development of ZACA–lipase-catalyzed acetylation–transition metal-catalyzed cross-coupling processes for highly efficient and enantioselective syntheses of a wide range of chiral organic compounds with ultra-high enantiomeric purities.

Despite major advances in organic synthesis predominantly over the past hundred years or so, asymmetric synthesis of chiral organic compounds including the great majority of bioactive compounds, such as amino acids and their oligomers and polymers, i.e., peptides, has remained as one of the “last bastions” to be conquered.

As alarmed by the unfortunate incident of a tranquilizer, Thalidomide,¹⁾ any bioactive organic compounds of biological and medicinal concerns must be prepared in the “YESES” manners, satisfying all of the following requirements including (i) high Yields, (ii) high Efficiency to be reflected most significantly in the number of synthetic steps, (iii) high Selectivity leading to high purity as high as required, (iv) Economy mandating highly catalytic processes, and (v) last but not least, unfailing Safety, which is often closely linked with Selectivity.

As is well known, discovery of the existence of enantiomeric isomers of organic compounds as well as their isolation as enantiomerically pure isomers with the use of tweezers under microscope were performed for the preparation of enantiomerically pure D-(−)- and L-(+)-tartaric acids as early as the mid-nineteenth century by L. Pasteur.^2),3)

Approximately half a century later, the first Nobel Prize in Chemistry was awarded to J. H. van’t Hoff in 1901.⁴⁾ Among his various contributions pertaining to the relationships between configurations of C atoms and various physical and chemical properties including chirality, optical activity, and so on, he predicted that α,ω-di-, tri-, or tetrasubstituted cumulenes, i.e., , can be chiral and optically active in cases where the number of cumulating C=C, i.e. n, is odd and 3 or higher.^5),6)

The second Nobel Prize in Chemistry in 1902 recognized E. Fischer’s astounding achievements in the syntheses of various complex organic compounds including a number of mono- and oligosaccharides.^7),8) As monumental as his diastereoselective syntheses were, additionally and more critically needed were enantioselective syntheses of a wide range of chiral organic compounds, as complementary, supplementary, and hopefully superior routes to the desired chiral organic compounds. This, however, proved to be a highly challenging goal.

Historically, yet another fundamentally significant advance in the asymmetric synthesis of chiral organic compounds was made about half a century later, when K. Ziegler^9),10) of Germany and G. Natta¹¹⁾ of Italy developed their isotactic polymerization of ethylene, propylene, and other alkenes, which led to their Nobel Prizes won in 1963. As both scientifically and industrially significant as these developments have been, these alkene polymerization reactions dealt only with “tacticity”, i.e., relative stereochemistry rather than absolute stereochemistry.

Major revolutionary discoveries and developments along the latter line have been made mostly since the 1970s. Concurrently, a group of industrial researchers at Monsanto, led by W. S. Knowles,^12),13) and R. Noyori in Japan^14),15) reported highly catalytic and selective hydrogenation of alkenes, especially allyllically heterofunctional alkenes. Some promisingly leads reported by H. Kagan in France¹⁶⁾ are also noteworthy. K. B. Sharpless^17),18) with one of his associates T. Katsuki reported asymmetric epoxidation of allylic alcohols in 1980.¹⁷⁾ It should be clearly noted, however, that none of these enantioselective reactions directly involves C–C bond formation.

Discovery and application of Zr-catalyzed methylalumination of alkynes (ZMA)

In 1978, we discovered Zr-catalyzed methylalumination of alkynes (ZMA)^19)–21) and tentatively proposed its mechanism as shown in Scheme 1. The synthetic scope and utility of the ZMA reaction may be most vividly appreciated by noting numerous examples of its application to natural product syntheses. About 150 natural product syntheses were listed in our previous review.²²⁾ Since then, its use in more than 60 natural product syntheses has been reported. Some representative examples are listed in Table 1 and Scheme 2.

Scheme 1.

Zr-catalyzed carboalumination of alkynes (ZMA).

Table 1. Some representative examples of natural products synthesized by using Zr-catalyzed carboalumination of alkynes

Scheme 2.

Syntheses of vitamin A and β- and γ-carotenes by Zr-catalyzed carboalumination of alkynes (ZMA).^23),24)

Discovery of Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)

Encouraged by the discovery and development of the alkyne carboalumination reaction catalyzed by Cp₂ZrCl₂ (ZMA),^19)–21) our search for a more highly coveted alkene-version of the reaction was resumed in the early 1980s. If only the alkyne carboalumination could be modified for discovering the corresponding alkene carboalumination reaction with suitable chiral zirconocene derivatives, we would most likely discover a catalytic and enantioselective C–C bond-forming reaction, namely the ZACA (Zr-catalyzed asymmetric carboalumination of alkenes). We believed that our notion of promoting carbometalation of alkenes with “super-acidic” bimetallic reagents consisting of alkylalanes and 16-electron zirconocene derivatives^21),72) should provide us with desirable alkene carbometalation reactions. This, however, proved to be more challenging and time-consuming endeavor than anticipated. In the end, however, our basic assumptions proved to be reasonable, and what may be termed a “one-step Ziegler-Natta alkene polymerization reaction” was almost single-handedly discovered in 1995 by Dr. D. Y. Kondakov (Scheme 3).^73)–75)

Scheme 3.

Zr-catalyzed asymmetric carboalumination of alkenes (ZACA).

All of the available data and observations are consistent with our notions and belief that the reaction involves Al-promoted carbozirconation of alkenes in accord with widely accepted mechanistic insights in the area of the Ziegler-Natta alkene polymerization. The observed high enantioselectivity seems to strongly favor Al-promoted carbozirconation mechanism as opposed to Zr-promoted carboalumination mechanism. Why did the discovery of the alkene ZACA reaction take such a long time, i.e., 17 years, after the discovery of the Zr-catalyzed carboalumination of alkynes? Arguably, carbometalation is fundamentally less facile than hydrometalation for various reasons which are not discussed here except to point out more stringent steric requirements stemming from shear bulk and more highly directional properties of C relative to H, just to mention a few.

We painfully learned that the reaction of 1-alkenes with alkylalanes in the presence of zirconocene derivatives could undergo a few other competitive side reactions in addition to the desired single-stage carbometalation shown in the green frame of Scheme 4, of which (i) H-transfer hydrometalation,⁷⁶⁾ (ii) the Kaminsky version of Ziegler-Natta polymerization,⁷⁷⁾ (iii) bimetallic cyclic carbometalation,⁷⁴⁾ and (iv) monometallic cyclic carbometalation⁷⁸⁾ are representative. For favorable results, all of the side reactions shown in the red frame of Scheme 4 must be effectively suppressed.

Scheme 4.

Zr-catalyzed asymmetric carboalumination of alkenes (ZACA).

Having learned about these major pitfalls, the remaining major task was to find some satisfactory chiral zirconocene catalysts with sufficiently, but not excessively, bulky ligands to suppress unwanted side reactions, while promoting the desired alkene carbometalation. In this respect, no systematic catalyst optimization involving catalyst design has as yet been made. Instead, a dozen to fifteen known chiral zirconocene complexes were initially screened. Widely used (EBI)ZrCl₂⁷⁹⁾ and its partially hydrogenated derivatives⁸⁰⁾ were less effective. The most effective among those tested is Erker’s (NMI)₂ZrCl₂.⁸¹⁾ Although methylalumination is singularly important from the viewpoint of the synthesis of natural products, it is ironically the uniquely unfavorable case where the ee figures are around 75%, as compared with ethylalumination and higher alkylalumination which proceeds in 90–95% ee. An attractive alternative has been developed by taking advantage of high enantioselectivity observed in ethylalumination and higher alkylalumination.^82),83) There are currently three Zr-catalyzed asymmetric carboalumination protocols that can be used for the synthesis of methyl-branched 1-alkanols (Scheme 5).^82),83)

Scheme 5.

Three protocols for enantioselective synthesis of methyl-substituted 1-alkanols.

Development and application of ZACA reaction

Despite some room for improvement, especially (i) improvement of the enantioselectivity of carboalumination and (ii) realization of higher turnover numbers through elevation of the current level of 20–10³ to ≥10³–10⁴ or higher, the ZACA reaction promises to provide a widely applicable, efficient, and selective asymmetric method for the synthesis of a variety of chiral organic compounds. In view of the abundant presence of deoxypropionate-containing natural products with diverse fascinating biological activities, intense efforts for the development of efficient and stereoselective methods for their synthesis have been made.^84),85) Since deoxypropionates are devoid of heterofunctional groups that could assist asymmetric C–C or C–H bond formation, most of the currently known and widely used methods for their constructions have to install temporary functional or chiral directing groups that are to be removed later. These methods construct deoxypropionate units in a linear-iterative fashion, and one iteration cycle typically requires 3–6 steps to introduce one methyl-branched chiral center.

Through several conceptual and methodological breakthroughs, some highly efficient, selective, and practical processes for the synthesis of deoxypropionates and related compounds containing two or more asymmetric carbon atoms have been developed in the authors’ group through exploitation of the statistical enantiomeric amplification principle (Table 2). These breakthroughs include (i) realization that Me-branched chiral compounds can be synthesized by ZACA reaction via a few alternate and mutually complementary routes (Scheme 5), (ii) unexpected finding that 2,4-dimethyl-1-hydroxybutyl moieties can be readily purified by ordinary chromatography (Scheme 6),⁸³⁾ and (iii) subsequent Pd- or Cu-catalyzed cross-coupling proceeds with essentially full (>99%) retention of newly formed chiral centers (Scheme 7).⁸⁶⁾

Table 2. Statistical enantiomeric amplification in iterative enantioselective process

ee in step or species I (%)	ee in step or species II (%)	Overall ee (%)
70	70	94.0
80	80	97.6
90	80	98.8
90	90	99.4
99	99	99.995

Scheme 6.

Synthesis of all four possible stereoisomers of 2,4-dimethyl-1-hexanols (1).

Scheme 7.

“One-pot” ZACA–Pd-catalyzed vinylation tandem process.

One-Pot ZACA–Pd-Catalyzed Vinylation Tandem Process for One-Step Iterative Homologation by a Propylene Unit. Initially, the authors’ group used a three-step iterative homologation cycle for incorporation of one propylene unit,⁸³⁾ which consisted of (i) ZACA-oxidation, (ii) iodination, and (iii) metalation–Pd-catalyzed vinylation. Since the initial ZACA reaction product is an alkylalane, its direct use in the Pd-catalyzed vinylation was explored by skipping oxidation and iodination, which led to a highly efficient one-pot ZACA–Pd-catalyzed vinylation tandem process for one-step iterative homologation by a propylene unit.⁸⁶⁾ The isoalkyldimethylalanes, generated by ZACA reaction, was directly used for Pd-catalyzed vinylation with (i) Zn(OTf)₂ as an additive, (ii) Pd(DPEphos)Cl₂ and ⁱBu₂AlH (DIBAL-H) in a 1:2 molar ratio as a catalyst system, and (iii) DMF as a solvent. The ZACA reaction of 1-octene proceeded in 75% ee (Mosher ester analysis of 2-methyl-1-octanol after oxidation). After Pd-catalyzed vinylation at elevated temperature (even at 120 °C), the product 7 was formed in 75% ee. Thus, no detectable racemization took place under the conditions of the Pd-catalyzed vinylation.

The one-pot ZACA–Pd-catalyzed vinylation tandem process developed above has been used to the synthesis of α,ω-diheterofunctional deoxypolypropionates and related compounds containing two or more asymmetric carbon atoms,^86),87) e.g., all-(R)-2,4,6,8-tetramethyldecanoic acid, a preen gland wax of graylag goose, Anser anser (Scheme 8).⁸⁷⁾

Scheme 8.

Allyl alcohol-based route to α,ω-diheterofunctional deoxypolypropionates.

Recently, we developed a highly concise, convergent, and enantioselective access to polydeoxypropionates.⁸⁸⁾ ZACA–Pd-catalyzed vinylation was used to prepare smaller deoxypropionate fragments, and then two key sequential Cu-catalyzed stereocontrolled sp³–sp³ cross-coupling reactions⁸⁹⁾ allowed convergent assembly of smaller building blocks to build-up long polydeoxypropionate chains with excellent stereoselectivity. We employed this strategy for the synthesis of phthioceranic acid, a key constituent of the cell-wall lipid of Mycobacterium tuberculosis, in just 8 longest linear steps with essentially full (>99%) stereocontrol (Scheme 9).

Scheme 9.

Highly efficient, convergent, and enantioselective synthesis of phthioceranic acid.

ZACA–lipase-catalyzed acetylation–Pd- or Cu-catalyzed cross-coupling processes

Having developed unprecedentedly efficient methods for the synthesis of deoxypolypropionates with two or more stereogenic carbon centers as discussed above, it was acutely realized that, only if ZACA products containing just one stereogenic carbon center can be readily and predictably purified, the ZACA-based asymmetric synthetic method would become much more widely applicable. The senior author recently became fully aware of the following strengths and weaknesses of the previously known lipase-catalyzed (S)-selective acetylation: (i) Enantiomerically pure (R)-2-methyl-1-alkanols can be reliably obtained from their racemic mixtures, although the maximally attainable yield (or recovery) of (R)-alcohols of ≥98% ee is limited to 50% or, more specifically ≤25% if E = 10, ≤35% if E = 20, and ≤45% if E = 100, where E (enantiomeric ratio or selectivity factor) = ln[(1 − C)(1 − ee)]/ln[(1 − C)(1 + ee)] and C and ee are the extent of conversion and the enantiomeric excess of the unreacted alcohol, respectively.^90),91) As such, it is not an attractive method, especially if the starting 2-methyl-1-alkanols are very expensive; (ii) Much more striking and important is that the lipase-catalyzed acetylation method is practically incapable of providing the ≥99% pure acetates of (S)-2-methyl-1-alkanols from their racemic mixtures in one cycle, since it can be predicted that the maximally attainable yields of ≥99% pure acetates would be ≤1–2% (E ≤ 100).^90),91) Consequently, iterative purification processes, in which the purity of desired compound must be gradually elevated, will be required. This theoretical prediction also points to a significant advantage in being able to start with enantiomerically enriched (S)-2-methyl-1-alkanols as shown in Table 3. Some maximally attainable yields of ≥99% pure acetates of (S)-2-methyl-1-alkanols can be predicted as follows: ≤80% if the initial ee_o is 70% and E is 50; ≤85% if ee_o is 80% and E is 30; ≤95% if ee_o is 90% and E is 20.^90),91) It is clear that neither the ZACA reaction alone nor the lipase-catalyzed acetylation alone is capable of providing a satisfactory method for the synthesis of either R or S isomer of 2-methyl-1-alkanols of ≥99% isomeric purity but that a combination of the two would be, provided that (i) the ZACA reaction is sufficiently enantioselective, preferably 80–90% ee but minimally ≥70% ee and (ii) the E values are sufficiently high, preferably ≥20–30. The ZACA–lipase-catalyzed acetylation sequential process has indeed been successfully applied to the purification of either R or S isomers of 2-methyl-1-alkanols, as represented in Table 4.⁹²⁾ Thus, 2-alkyl-1-alkanols, even in some cases of lacking any proximal π-bonds or heterofunctional groups, have been efficiently synthesized in ≥98% ee by ZACA–lipase-catalyzed acetylation sequential protocol.⁹²⁾

Table 3. Significance of high initial enantiomeric excess (ee_o) and selectivity factor(E) on the maximally attainable yields of (S)-2-alkyl-1-alkanols of >98% ee^90),91)

Table 4. ZACA–lipase-catalyzed acetylation processes for the synthesis of 2-methyl-1-alkanols

As discussed above, the efficiency of the lipase-catalyzed acetylation critically depends on the selectivity factor(E).^90),91) In more demanding (feebly chiral) cases, especially when two alkyl groups are very similar, it is difficult to purify to >98% ee even from enantiomerically enriched mixtures by lipase-catalyzed acetylation. To overcome this difficulty, the ZACA–lipase-catalyzed acetylation–Pd- or Cu-catalyzed cross-coupling sequential process was considered and developed for the synthesis of various feebly chiral 2-alkyl-1-alkanols of >99% ee as outlined in Scheme 10.⁹³⁾ By virtue of the high selectivity factor(E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1-alkanols (3), prepared by ZACA reaction of allyl alcohol, can be readily purified to the level of ≥99% ee by lipase-catalyzed acetylation. A variety of chiral tertiary alkyl-containing alcohols, including those that have been otherwise difficult to prepare, can now be synthesized in high enantiomeric purity by Pd- or Cu-catalyzed cross-coupling of (S)-3 or (R)-4 for introduction of various primary, secondary and tertiary carbon groups with retention of all carbon skeletal features.⁹³⁾

Scheme 10.

Synthesis of feebly chiral 2-substituted 1-alkanols of ≥99% ee.

The ZACA–lipase-catalyzed acetylation–Pd- or Cu-catalyzed cross-coupling process has been applied to highly efficient and enantioselective synthesis of various chiral compounds. (R)-Arundic acid is currently undergoing Phase II development for the treatment of acute ischemic stroke, as well as clinical development in other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease.^94),95) (R)- and (S)-5 of ≥99% ee, prepared via ZACA–lipase-catalyzed purification–Cu-catalyzed cross-coupling (Scheme 11), were transformed into the corresponding (R)- and (S)-arundic acids in 98% yield by oxidation with NaClO₂ in the presence of catalytic amounts of NaClO and 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO). Thus, a highly enantioselective (≥99% ee) and efficient synthesis of (R)- and (S)-arundic acids was achieved in 25% and 28% over five steps, respectively, from allyl alcohol.⁹³⁾

Scheme 11.

ZACA–lipase-catalyzed acetylation–Cu-catalyzed cross-coupling process for the synthesis of (R)- and (S)-arundic acids.

(S)-2-Methyl-3-iodo-1-propanol 6 of ≥99% ee, obtained by ZACA-iodolysis–lipase-catalyzed acetylation from allyl alcohol, was converted to 1,1-dibromo-alkene 7 in 74% yield over four steps.⁸⁷⁾ Compound 7 was further transformed to 8, a potential intermediate for the synthesis of callystatin A, by PdCl₂(DPEphos)-catalyzed Negishi coupling reactions where the second Negishi coupling proceeding with a clean stereoinversion (Scheme 12).⁸⁷⁾

Scheme 12.

ZACA–lipase-catalyzed acetylation–Pd-catalyzed cross-coupling process for the synthesis of (−)-callystatin A.

As satisfactory as the procedure shown in Scheme 10 is, its synthetic scope is limited to the preparation of 2-chirally-substituted 1-alkanols. In search for an alternative and more generally applicable procedure, we developed a new protocol for the synthesis of γ- and more-remotely chiral alcohols of high enantiomeric purity through simple paradigm shift, as summarized in Scheme 13.⁹⁶⁾

Scheme 13.

Synthesis of γ- and more-remotely chiral 1-alkanols of ≥99% ee.

Having developed a widely applicable route to various γ- and more-remotely chiral alcohols by ZACA/oxidation–lipase-catalyzed acetylation–Cu- or Pd-catalyzed cross-coupling protocol, our attention was necessarily and increasingly drawn into the methods of determination of enantiomeric purities of the final desired alcohols, which proved to be quite challenging. For most of alkanols where the stereogenic center generated was in the γ or δ position relative to the OH group, the enantiomeric purities of ≥99% ee were successfully determined by chiral gas chromatography or NMR analysis of Mosher esters.⁹⁷⁾ However, initial attempts to determine the enantiomeric excess in more demanding cases, such as 4-alkyl-1-alcohols and 5-alkyl-1-alcohols, using chiral GC, HPLC and Mosher ester analysis were unsatisfactory.

A solution to the above-mentioned difficulty 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.^98),99) Presumably the naphthyl ring of MαNP esters would exert greater anisotropic shielding effects than α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) phenyl group. Indeed, the two terminal methyl groups of the diastereomeric MαNP ester (R,R)- and (R,S)-13, derived from ε-chiral alcohol (R)-11, showed completely separate ¹H NMR signals, while the diastereomeric MTPA ester 12 showed no separation (Scheme 14). The MαNP ester analysis was also successfully applied to chiral discrimination of other δ- and ε-chiral primary alcohols, which demonstrated surprising long-range anisotropic differential shielding effects. It should be noted that the diastereotopic chemical shift differences of MαNP esters were affected by NMR solvent and resonance frequency (MHz) of NMR. d-Acetonitrile, d-acetone, d-methanol and/or CDCl₃ have been shown to be suitable solvents. The higher the resonance frequency, the better discrimination of chemical shifts obtained.

Scheme 14.

Methyl resonances in the ¹H NMR spectra (CDCl₃, 600 MHz) of MTPA ester and MαNP ester derived from ε-chiral alcohol (R)-11.

ZACA–lipase-catalyzed acetylation–Cu-catalyzed cross-coupling synergy has been applied to a highly enantioselective (>99% ee) and diastereoselective (>98% de) synthesis of chiral C₁₅ vitamin E side-chain 19 (Scheme 15).¹⁰⁰⁾ The key α,ω-dioxyfunctional C₅ synthon 15 (≥99% ee) was readily prepared by ZACA–lipase-catalyzed acetylation, which can be further functionalized at both ends. Two sequential Cu-catalyzed alkyl–alkyl cross-coupling reactions of the enantiomerically pure C₅ iodide 16 were employed as the key steps for preparing the C₁₅ vitamin E side-chain 19, which was shown to be >99% ee by ¹H NMR analysis of its MαNP ester (Scheme 16).¹⁰⁰⁾

Scheme 15.

The synthesis of C₁₅ vitamin E side-chain 19.

Scheme 16.

¹H NMR spectra of diastereomeric MαNP esters of γ-chiral alcohol 19 (CDCl₃, 600 MHz).

Chiral compounds arising from the replacement of hydrogen (H) with deuterium (D) are very important in the fields of organic chemistry and biochemistry. Some of these chiral compounds whose specific rotation values are practically non-measurable, due to very small differences between the isotopomeric groups, exhibit “cryptochirality”^101)–103) representing a class of compounds which have been very difficult to synthesize and distinguish. Our ZACA–lipase-catalyzed acetylation–Cu-catalyzed cross-coupling processes provide a general and efficient method for the highly enantioselective (≥99% ee) and catalytic synthesis of various 1-alkanols of isotopomeric “cryptochirality” (Scheme 17).¹⁰⁴⁾

Scheme 17.

Synthesis of various chiral isotopomers of 1-alkanols.

Three deuterium-substituted δ-chiral isotopomers (R)-22, 23, and 24 were prepared by ZACA/oxidation–lipase-catalyzed acetylation–Cu-catalyzed cross-coupling. ZACA reaction of TBS-protected 4-penten-1-ol followed by in situ oxidation with O₂ provided intermediate (S)-25 of 85% ee in 67% yield. This crude (S)-25 was readily purified to the level of ≥99% ee by Amano PS lipase-catalyzed acetylation in 70% recovery.⁹⁶⁾ After conversion of (S)-25 into iodide, Cu-catalyzed cross-coupling with three different deuterium-substituted Grignard reagents was then used for the synthesis of isotopomers (R)-22, 23, and 24 (Scheme 18).¹⁰⁴⁾ To further demonstrate the high efficiency of ZACA–lipase-catalyzed acetylation tandem process for preparation of α,ω-dioxyfunctional alcohols in high enantiomeric purity, one control experiment of lipase-catalyzed acetylation of rac-25 was performed. Under the optimal conditions, lipase-catalyzed acetylation of rac-25 still only produced (S)-25 of 87.8% ee in a disappointingly low recovery of 10%. Thus, it is practically impossible to synthesize (S)-25 of ≥99% ee through lipase-catalyzed acetylation of a racemic mixture of 25.

Scheme 18.

Synthesis of δ-chiral isotopomers.

As might be expected, none of these isotopomers synthesized above exhibited measurable optical rotation due to very small differences between the isotopomeric groups, such as CH₃ vs. CDH₂, CH₃CH₂ vs. CD₃CH₂, and CH₃CH₂CH₂ vs. CH₃CD₂CH₂. Enantiomeric purities (≥99% ee) of β- and γ-chiral isotopomers, e.g., (S)-21, were successfully determined by ¹H NMR analysis of their Mosher esters.⁹⁷⁾ As shown in Scheme 19, the terminal methyl groups of the diastereomeric Mosher esters (S,R)- and (S,S)-26, derived from γ-chiral alkanol (S)-21, showed completely separate ¹H NMR signals. The enantiomeric purities of more remotely chiral, e.g., δ- and ε-chiral, isotopomers have been determined by the MαNP ester analysis.

Scheme 19.

Methyl resonances in the ¹H NMR spectra (CD₃CN, 600 MHz) of Mosher ester derived from γ-chiral alkanol (S)-21.

Conclusions

The ZACA reaction is a catalytic asymmetric C–C bond forming reaction of terminal alkenes of one-point-binding without requiring any other functional groups, even though various functional groups may be present. Through conversion of terminal alkenes to chiral alkylalanes which allow for a wide range of in situ transformations, ZACA reaction provides a widely applicable, efficient and selective method for catalytic asymmetric C–C bond formation, which has already been used for the syntheses of various chiral natural products as summarized in Table 5. It should be noted that ZACA–lipase-catalyzed acetylation–transition metal-catalyzed cross-coupling processes provide a general and ultimately satisfactory access towards a variety of chiral organic compounds with ultra-high (>99%) purity levels, which have been otherwise very difficult to synthesize. One of the paradigms we rely heavily on is (i) to purify functionally rich and thus readily purifiable intermediates prepared by ZACA reaction to the level of >99% ee by lipase-catalyzed acetylation, and (ii) to further modify through the use of Pd- or Cu-catalyzed cross-coupling proceeding with essentially full (>99%) retention of all carbon skeletal features of intermediates.

Table 5. Natural products and related compounds of biological and medicinal interest synthesized via ZACA reaction

Profile

Ei-ichi Negishi, H. C. Brown Distinguished Professor of Chemistry, Purdue University, grew up in Japan and received his Bachelor’s degree from the University of Tokyo in 1958. From 1958–1966, while working as a Research Chemist at Teijin, Ltd., Japan, Negishi spent 3 years (1960–1963) as a Fulbright-Smith-Mund Scholar at the University of Pennsylvania and obtained his Ph.D. in Chemistry. In 1966, he joined Prof. H. C. Brown’s Laboratories at Purdue as a Postdoctoral Associate and was appointed Assistant to Professor Brown in 1968. Negishi went to Syracuse University as Assistant Professor in 1972 and began his life-long investigations of transition metal-catalyzed organometallic reactions for organic synthesis. Negishi was promoted to Associate Professor at Syracuse University in 1976 and invited back to Purdue University as Full Professor in 1979. In 1999 he was appointed the inaugural H. C. Brown Distinguished Professor of Chemistry. He has received various awards, with the most representative being 1987 J.S. Guggenheim Fellowship, 1996 Chemical Society of Japan Award, 1998 ACS Award in Organometallic Chemistry, 1998–2001 Alexander von Humboldt Senior Researcher Award, Germany, 2000 Sir Edward Frankland Prize, Royal Society of Chemistry, UK, 2007 Yamada-Koga Prize, Japan, 2010 ACS Award for Creative Work in Synthetic Organic Chemistry, 2010 Japanese Order of Culture, 2010 Nobel Prize in Chemistry, 2010 UK Royal Society of Chemistry Honorary Fellowship Award, 2011 Fellow of the American Academy of Arts and Sciences, and 2014 elected into the National Academy of Sciences as a Foreign Associate.

Profile

Shiqing Xu graduated from School of Pharmacy at Fudan University (China) and obtained a B.S. degree in 2004. He received his Ph.D. degree in medicinal chemistry from Fudan University in 2009. From April 2010 to April 2013, he worked as a postdoctoral research associate under the guidance of Prof. Ei-ichi Negishi at Purdue University. He is currently an Assistant Research Scientist in Prof. Ei-ichi Negishi’s group. His research interests include the development of new synthetic methods based on transition metal-catalyzed cross-coupling reactions and transition metal-catalyzed asymmetric carbon–carbon bond forming reactions and natural product synthesis.

Acknowledgements

Our investigation of the Zr-catalyzed carbometalation started, when Dr. D. E. Van Horn discovered the alkyne version of Zr-catalyzed carboalumination in 1978. Our subsequent attempts for discovering its alkene version, i.e., the alkene ZACA reaction, proved to be highly challenging and elusive, but investigations with this goal first led to the development of some interesting and useful chemistry of “ZrCp₂”, most extensively studied by Dr. T. Takahashi. Long-pending discovery of the highly coveted alkene version of ZACA reaction was almost single-handedly discovered by Dr. D. Y. Kondakov in 1995. Its intensive further development was spearheaded by a series of able workers represented by Dr. S. Huo, a tightly collaborating trio of Dr. Z. Tan, Dr. B. Liang, and Dr. T. Novak as well as by others including Dr. Z. Huang, Ms. M. Magnin-Lachaux, Dr. N. Yin, Dr. G. Zhu, Dr. Z. Xu and Dr. G. Wang. Our most recent and current activities are spearheaded by Dr. S. Xu and others, notably those from Teijin, Ltd., Japan, including Mr. A. Oda, Mr. H. Kamada, Mr. Y. Matsueda, and Mr. M. Komiyama, as well as Dr. H. Li and Dr. T. Bobinski, who have been rapidly expanding and elevating the scope and value of the ZACA-based asymmetric syntheses. Last but not least, we thank generous financial supports provided over many years predominately by NSF and NIH, Purdue University, in particular, H. C. Brown Distinguished Professorship Fund, Teijin, Ltd., Japan, and Japan Science and Technology Agency.

References

• 1)   Miller,  M.T. (1991) Thalidomide embryopathy: A model for the study of congenital incomitant horizontal strabismus. Trans. Am. Ophthalmol. Soc. 81, 623–674.
• 2)   Pasteur,  L. (1848) Mémoire sur la relation qui peut exister entre la forme cristalline et la composition chimique, et sur la cause de la polarisation rotatoire (Memoir on the relationship which can exist between crystalline form and chemical composition, and on the cause of rotary polarization). C. R. Acad. Sci. (Paris) 26, 535–538.
• 3)   Pasteur,  L. (1848) Sur les relations qui peuvent exister entre la forme cristalline, la composition chimique et le sens de la polarisation rotatoire (On the relations that can exist between crystalline form, and chemical composition, and the sense of rotary polarization). Ann. Chim. Phys. 24, 442–459.
• 4)   Van’t Hoff,  J.H. (1874) Sur les formules de structure dans l’espace. Arch. Neerl. Sci. 9, 445–454.
• 5)  Van’t Hoff, J.H. (1877) Die Lagerung der Atome im Raume. Friedrich Vieweg und Sohn, Braunschweig.
• 6)   Yosida,  T.,  Williams,  R.M. and  Negishi,  E. (1974) A stereoselective synthesis of trans-1,4-dialkyl-1,2,3-butatrienes via hydroboration. J. Am. Chem. Soc. 96, 3688–3690.
• 7)   Fischer,  E. (1891) Ueber die configuration des traubenzuckers und seiner isomeren. Ber. Dtsch. Chem. Ges. 24, 2683–2687.
• 8)   Fischer,  E. and  Thierfelder,  H. (1894) Verhalten der verschiedenen zucker gegen reine hefen. Ber. Dtsch. Chem. Ges. 27, 2031–2037.
• 9)   Ziegler,  K.,  Holzkamp,  E.,  Breil,  H. and  Martin,  H. (1955) Polymerisation von äthylen und anderen olefinen. Angew. Chem. 67, 426.
• 10)   Ziegler,  K.,  Holzkamp,  E.,  Breil,  H. and  Martin,  H. (1955) Das Mülheimer normaldruck-polyäthylen-verfahren. Angew. Chem. 67, 541–547.
• 11)   Natta,  G. (1956) Stereospezifische katalysen und isotaktische polymere. Angew. Chem. 68, 393–403.
• 12)   Vineyard,  B.D.,  Knowles,  W.S.,  Sabacky,  M.J.,  Bachman,  G.L. and  Weinkauff,  D.J. (1977) Asymmetric hydrogenation. Rhodium chiral bisphosphine catalyst. J. Am. Chem. Soc. 99, 5946–5952.
• 13)   Knowles,  W.S. (2002) Asymmetric hydrogenations (Nobel Lecture). Angew. Chem. Int. Ed. 41, 1998–2007.
• 14)   Miyashita,  A.,  Yasuda,  A.,  Takaya,  H.,  Toriumi,  K.,  Ito,  T.,  Souchi,  T. and  Noyori,  R. (1980) Synthesis of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), an atropisomeric chiral bis(triaryl)phosphine, and its use in the rhodium(I)-catalyzed asymmetric hydrogenation of α-(acylamino)acrylic acids. J. Am. Chem. Soc. 102, 7932–7934.
• 15)   Noyori,  R. (2002) Asymmetric catalysis: science and opportunities (Nobel Lecture). Angew. Chem. Int. Ed. 41, 2008–2022.
• 16)   Dang,  T.P. and  Kagan,  H.B. (1971) The asymmetric synthesis of hydratropic acid and amino-acids by homogeneous catalytic hydrogenation. J. Chem. Soc. D 10, 481.
• 17)   Katsuki,  T. and  Sharpless,  K.B. (1980) The first practical method for asymmetric epoxidation. J. Am. Chem. Soc. 102, 5974–5976.
• 18)   Sharpless,  K.B. (2002) Searching for new reactivity (Nobel Lecture). Angew. Chem. Int. Ed. 41, 2024–2032.
• 19)   Van Horn,  D.E. and  Negishi,  E. (1978) Controlled carbometalation. The reaction of acetylenes with organoalane-zirconocene dichloride complexes as a route to stereo- and regio-defined trisubstituted olefins. J. Am. Chem. Soc. 100, 2252–2254.
• 20)   Negishi,  E.,  Okukado,  N.,  King,  A.O.,  Van Horn,  D.E. and  Spiegel,  B.I. (1978) Double and multiple catalysis in the cross-coupling reaction and its application to the stereo- and regioselective synthesis of trisubstituted olefins. J. Am. Chem. Soc. 100, 2254–2256.
• 21)   Negishi,  E.,  Van Horn,  D.E. and  Yoshida,  T. (1985) Carbometallation reaction of alkynes with organoalane-zirconocene derivatives as a route to stereo- and regio-defined trisubstituted alkenes. J. Am. Chem. Soc. 107, 6639–6647.
• 22)   Negishi,  E. (2007) Transition metal-catalyzed organometallic reactions that have revolutionized organic synthesis. Bull. Chem. Soc. Jpn. 80, 233–257.
• 23)   Negishi,  E. and  Owczarczyk,  Z. (1991) Highly selective synthesis of vitamin A and its derivatives. Critical comparison of some known palladium-catalyzed alkenyl-alkenyl coupling reactions. Tetrahedron Lett. 32, 6683–6686.
• 24)   Zeng,  F. and  Negishi,  E. (2001) A novel, selective, and efficient route to carotenoids and related natural products via Zr-catalyzed carboalumination and Pd- and Zn-catalyzed cross coupling. Org. Lett. 3, 719–720.
• 25)   Cases,  M.,  Gonzalez-Lopez de Turiso,  F.,  Hadjisoteriou,  M.S. and  Pattenden,  G. (2005) Synthetic studies towards furanocembrane diterpenes. A total synthesis of bis-deoxylophotoxin. Org. Biomol. Chem. 3, 2786–2804.
• 26)   Frenzel,  T.,  Bruenjes,  M.,  Quitschalle,  M. and  Kirschning,  A. (2006) Synthesis of the N-acetylcysteamine thioester of seco-proansamitocin. Org. Lett. 8, 135–138.
• 27)   Knoell,  J. and  Knoelker,  H.-J. (2006) First total synthesis and assignment of the absolute configuration of the neuronal cell protecting alkaloid carbazomadurin B. Synlett 4, 651–653.
• 28)   Wilson,  M.S.,  Woo,  J.C.S. and  Dake,  G.R. (2006) A synthetic approach toward nitiol: construction of two 1,22-dihydroxynitianes. J. Org. Chem. 71, 4237–4245.
• 29)   Tan,  Z. and  Negishi,  E. (2006) Selective synthesis of epolactaene featuring efficient construction of methyl (Z)-2-iodo-2-butenoate and (2R,3S,4S)-2-trimethylsilyl-2,3-epoxy-4-methyl-γ-butyrolactone. Org. Lett. 8, 2783–2785.
• 30)   Suenaga,  K.,  Hoshino,  H.,  Yoshii,  T.,  Mori,  K.,  Sone,  H.,  Bessho,  Y.,  Sakakura,  A.,  Hayakawa,  I.,  Yamada,  K. and  Kigoshi,  H. (2006) Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin. Tetrahedron 62, 7687–7698.
• 31)   Winne,  J.M.,  Guang,  B.,  D’Herde,  J. and  De Clercq,  P.J. (2006) Application of the B-alkyl Suzuki–Miyaura cross-coupling reaction to the stereoselective synthesis of analogues of (3S)-oxidosqualene. Org. Lett. 8, 4815–4818.
• 32)   Vincent,  A. and  Prunet,  J. (2006) Enantioselective synthesis of the C1–C15 fragment of dolabelide C. Synlett 14, 2269–2271.
• 33)   Rodriguez-Escrich,  C.,  Olivella,  A.,  Urpi,  F. and  Vilarrasa,  J. (2007) Toward a total synthesis of amphidinolide X and Y. The tetrahydrofuran-containing fragment C12–C21. Org. Lett. 9, 989–992.
• 34)   Meyer,  A.,  Bruenjes,  M.,  Taft,  F.,  Frenzel,  T.,  Sasse,  F. and  Kirschning,  A. (2007) Chemoenzymatic approaches toward dechloroansamitocin P-3. Org. Lett. 9, 1489–1492.
• 35)   Shojaei,  H.,  Li-Boehmer,  Z. and  Von Zezschwitz,  P. (2007) Iromycins: A new family of pyridone metabolites from streptomyces sp. II. Convergent total synthesis. J. Org. Chem. 72, 5091–5097.
• 36)   Ito,  T.,  Ito,  M.,  Arimoto,  H.,  Takamura,  H. and  Uemura,  D. (2007) Studies toward the total synthesis of nakiterpiosin: construction of the CDE ring system by a transannular Diels–Alder strategy. Tetrahedron Lett. 48, 5465–5469.
• 37)   Lipshutz,  B.H.,  Butler,  T.,  Lower,  A. and  Servesko,  J. (2007) Enhancing regiocontrol in carboaluminations of terminal alkynes. Application to the one-pot Synthesis of coenzyme Q₁₀. Org. Lett. 9, 3737–3740.
• 38)   Paterson,  I.,  Ashton,  K.,  Britton,  R.,  Cecere,  G.,  Chouraqui,  G.,  Florence,  G.J. and  Stafford,  J. (2007) Total synthesis of (−)-reidispongiolide A, an actin-targeting marine macrolide. Angew. Chem. Int. Ed. 46, 6167–6171.
• 39)   Corbu,  A.,  Gauron,  G.,  Castro,  L.M.,  Dakir,  M. and  Arseniyadis,  S. (2007) A domino-based approach toward stereodefined heavily functionalized cyclohexanes: synthesis of iridal’s core structure. Org. Lett. 9, 4745–4748.
• 40)   Huang,  J.,  Wu,  C. and  Wulff,  W.D. (2007) Total synthesis of (±)-phomactin B2 via an intramolecular cyclohexadienone annulation of a chromium carbene complex. J. Am. Chem. Soc. 129, 13366–13367.
• 41)   Fuerstner,  A.,  Bouchez,  L.C.,  Funel,  J.-A.,  Liepins,  V.,  Poree,  F.-H.,  Gilmour,  R.,  Beaufils,  F.,  Laurich,  D. and  Tamiya,  M. (2007) Total syntheses of amphidinolide H and G. Angew. Chem. Int. Ed. 46, 9265–9270.
• 42)   Marshall,  J.A. and  Eidam,  P.M. (2008) A formal synthesis of the callipeltoside aglycone. Org. Lett. 10, 93–96.
• 43)   Yadav,  J.S.,  Reddy,  K.B. and  Sabitha,  G. (2008) Stereoconvergent synthesis of C₁–C₁₇ and C₁₈–C₂₅ fragments of bafilomycin A₁. Tetrahedron 64, 1971–1982.
• 44)   Zhu,  G. and  Negishi,  E. (2008) 1,4-Pentenyne as a five-carbon synthon for efficient and selective syntheses of natural products containing 2,4-dimethyl-1-penten-1,5-ylidene and related moieties by means of Zr-catalyzed carboalumination of alkynes and alkenes. Chemistry 14, 311–318.
• 45)   Paterson,  I.,  Ashton,  K.,  Britton,  R.,  Cecere,  G.,  Chouraqui,  G.,  Florence,  G.J.,  Knust,  H. and  Stafford,  J. (2008) Total synthesis of (−)-reidispongiolide A, an actin-targeting macrolide isolated from the marine sponge Reidispongia coerulea. Chem. Asian J. 3, 367–387.
• 46)   Fuerstner,  A.,  Bouchez,  L.C.,  Morency,  L.,  Funel,  J.-A.,  Liepins,  V.,  Poree,  F.-H.,  Gilmour,  R.,  Laurich,  D.,  Beaufils,  F. and  Tamiya,  M. (2009) Total syntheses of amphidinolides B1, B4, G1, H1 and structure revision of amphidinolide H2. Chemistry 15, 3983–4010.
• 47)   Blackburn,  T.J.,  Helliwell,  M.,  Kilner,  M.J.,  Lee,  A.T.L. and  Thomas,  E.J. (2009) Further studies of an approach to a total synthesis of phomactins. Tetrahedron Lett. 50, 3550–3554.
• 48)   Lipshutz,  B.H. and  Amorelli,  B. (2009) Carboalumination/Ni-catalyzed couplings. A short synthesis of verticipyrone. Tetrahedron Lett. 50, 2144–2146.
• 49)   Domingo,  V.,  Silva,  L.,  Dieguez,  H.R.,  Arteaga,  J.F.,  Quilez del Moral,  J.F. and  Barrero,  A.F. (2009) Enantioselective total synthesis of the potent anti-inflammatory (+)-myrrhanol A. J. Org. Chem. 74, 6151–6156.
• 50)   Hirata,  Y.,  Yukawa,  T.,  Kashihara,  N.,  Nakao,  Y. and  Hiyama,  T. (2009) Nickel-catalyzed carbocyanation of alkynes with allyl cyanides. J. Am. Chem. Soc. 131, 10964–10973.
• 51)   Amans,  D.,  Bareille,  L.,  Bellosta,  V. and  Cossy,  J. (2009) Synthesis of the monomeric counterpart of marinomycin A. J. Org. Chem. 74, 7665–7674.
• 52)   Hieda,  Y.,  Choshi,  T.,  Kishida,  S.,  Fujioka,  H. and  Hibino,  S. (2010) A novel total synthesis of the bioactive poly-substituted carbazole alkaloid carbazomadurin A. Tetrahedron Lett. 51, 3593–3596.
• 53)   Fotsop,  D.F.,  Roussi,  F.,  Leverrier,  A.,  Breteche,  A. and  Gueritte,  F. (2010) Biomimetic total synthesis of meiogynin A, an inhibitor of Bcl-xL and Bak interaction. J. Org. Chem. 75, 7412–7415.
• 54)   Harmrolfs,  K.,  Bruenjes,  M.,  Draeger,  G.,  Floss,  H.G.,  Sasse,  F.,  Taft,  F. and  Kirschning,  A. (2010) Cyclization of synthetic seco-proansamitocins to ansamitocin macrolactams by actinosynnema pretiosum as biocatalyst. ChemBioChem 11, 2517–2520.
• 55)   Wang,  G.,  Yin,  N. and  Negishi,  E. (2011) Highly selective total synthesis of fully hydroxy-protected mycolactones A & B and their stereoisomerization upon deprotection. Chemistry 17, 4118–4130.
• 56)   Paterson,  I.,  Paquet,  T. and  Dalby,  S.M. (2011) Synthesis of the macrocyclic core of leiodermatolide. Org. Lett. 13, 4398–4401.
• 57)   Bergman,  J.A.,  Hahne,  K.,  Hrycyna,  C.A. and  Gibbs,  R.A. (2011) Lipid and sulfur substituted prenylcysteine analogs as human Icmt inhibitors. Bioorg. Med. Chem. Lett. 21, 5616–5619.
• 58)   Bergman,  J.A.,  Hahne,  K.,  Song,  J.,  Hrycyna,  C.A. and  Gibbs,  R.A. (2012) S-Farnesyl-thiopropionic acid triazoles as potent inhibitors of isoprenylcysteine carboxyl methyltransferase. ACS Med. Chem. Lett. 3, 15–19.
• 59)   Paterson,  I.,  Steadman nee Doughty,  V.A.,  McLeod,  M.D. and  Trieselmann,  T. (2011) Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones. Tetrahedron 67, 10119–10128.
• 60)   Kleinbeck,  F.,  Fettes,  G.J.,  Fader,  L.D. and  Carreira,  E.M. (2012) Total synthesis of bafilomycin A₁. Chemistry 18, 3598–3610.
• 61)   Lisboa,  M.P.,  Jeong-Im,  J.H.,  Jones,  D.M. and  Dudley,  G.B. (2012) Toward a new palmerolide assembly strategy: synthesis of C16–C24. Synlett 23, 1493–1496.
• 62)   Hieda,  Y.,  Choshi,  T.,  Fujioka,  H. and  Hibino,  S. (2013) Total synthesis of the neuronal cell-protecting carbazole alkaloids carbazomadurin A and (S)-(+)-carbazomadurin B. Eur. J. Org. Chem. 2013, 7391–7401.
• 63)   Zhang,  X.,  Liu,  J.,  Sun,  X. and  Du,  Y. (2013) An efficient cis-reduction of alkyne to alkene in the presence of a vinyl iodide: stereoselective synthesis of the C22–C31 fragment of leiodolide A. Tetrahedron 69, 1553–1558.
• 64)   Kaiser,  T.M.,  Huang,  J. and  Yang,  J. (2013) Regiochemistry discoveries in the use of isoxazole as a handle for the rapid construction of an all-carbon macrocyclic precursor in the synthetic studies of celastrol. J. Org. Chem. 78, 6297–6302.
• 65)   McGrath,  K.P. and  Hoveyda,  A.H. (2014) A multicomponent Ni-, Zr-, and Cu-catalyzed strategy for enantioselective synthesis of alkenyl-substituted quaternary carbons. Angew. Chem. Int. Ed. 53, 1910–1914.
• 66)   Shibata,  H.,  Tsuchikawa,  H.,  Matsumori,  N.,  Murata,  M. and  Usui,  T. (2014) Design and synthesis of 24-fluorinated bafilomycin analogue as an NMR probe with potent inhibitory activity to vacuolar-type ATPase. Chem. Lett. 43, 474–476.
• 67)   Das,  S. and  Goswami,  R.K. (2013) Stereoselective total synthesis of ieodomycins A and B and revision of the NMR spectroscopic data of ieodomycin B. J. Org. Chem. 78, 7274–7280.
• 68)   Clark,  J.S.,  Yang,  G. and  Osnowski,  A.P. (2013) Synthesis of the C-18–C-34 Fragment of Amphidinolides C, C2, and C3. Org. Lett. 15, 1464–1467.
• 69)   Saitman,  A. and  Theodorakis,  E.A. (2013) Synthesis of a highly functionalized core of verrillin. Org. Lett. 15, 2410–2413.
• 70)   Domingo,  V.,  Lorenzo,  L.,  Quilez del Moral,  J.F. and  Barrero,  A.F. (2013) First synthesis of (+)-myrrhanol C, an anti-prostate cancer lead. Org. Biomol. Chem. 11, 559–562.
• 71)   Nicolaou,  K.C.,  Shi,  L.,  Lu,  M.,  Pattanayak,  M.R.,  Shah,  A.A.,  Ioannidou,  H.A. and  Lamani,  M. (2014) Total synthesis of myceliothermophins C, D, and E. Angew. Chem. 126, 11150–11154.
• 72)   Negishi,  E. (1999) Principle of activation of electrophiles by electrophiles through dimeric association — Two is better than one. Chemistry 5, 411–420.
• 73)   Kondakov,  D. and  Negishi,  E. (1995) Zirconium-catalyzed enantioselective methylalumination of monosubstituted alkenes. J. Am. Chem. Soc. 117, 10771–10772.
• 74)   Kondakov,  D. and  Negishi,  E. (1996) Zirconium-catalyzed enantioselective alkylalumination of monosubstituted alkenes proceeding via noncyclic mechanism. J. Am. Chem. Soc. 118, 1577–1578.
• 75)  For a recent ZACA review, see:  Negishi,  E. (2011) Discovery of ZACA reaction: Zr-catalyzed asymmetric carboalumination of alkenes. ARKIVOC viii, 34–53.
• 76)   Negishi,  E. and  Yoshida,  T. (1980) A novel zirconium-catalzyed hydroalumination of olefins. Tetrahedron 21, 1501–1504.
• 77)  For a recent review, see:  Alt,  H.G. and  Koppl,  A. (2000) Effect of the nature of metallocene complexes of group IV metals on their performance in catalytic ethylene and propylene polymerization. Chem. Rev. 100, 1205–1222.
• 78)   Takahashi,  T.,  Seki,  T.,  Nitto,  Y.,  Saburi,  M.,  Rousset,  C.J. and  Negishi,  E. (1991) Remarkably “pair”-selective and regioselective carbon–carbon bond forming reaction of zirconacylclopentane derivatives with Grignard reagents. J. Am. Chem. Soc. 113, 6266–6268.
• 79)   Wild,  F.R.W.P.,  Zsolnai,  L.,  Huttner,  G. and  Brintzinger,  H.H. (1982) ansa-Metallocene derivatives: IV. Synthesis and molecular structures of chiral ansa-titanocene derivatives with bridged tetrahydroindenyl ligands. J. Organomet. Chem. 232, 233–247.
• 80)   Wild,  F.R.W.P.,  Wasiucionek,  M.,  Huttner,  G. and  Brintzinger,  H.H. (1985) ansa-Metallocene derivatives: VII. Synthesis and crystal structure of a chiral ansa-zirconocene derivative with ethylene-bridged tetrahydroindenyl ligands. J. Organomet. Chem. 288, 63–67.
• 81)   Erker,  G.,  Aulbach,  M.,  Knickmeier,  M.,  Wingbermühle,  D.,  Kürger,  C.,  Nolte,  M. and  Werner,  S. (1993) The role of torsional isomers of planarly chiral nonbridged bis(indenyl)metal type complexes in stereoselective propene polymerization. J. Am. Chem. Soc. 115, 4590–4601.
• 82)   Huo,  S.,  Shi,  J. and  Negishi,  E. (2002) A new protocol for the enantioselective synthesis of methyl-substituted alkanols and their derivatives through a hydroalumination/zirconium-catalyzed alkylalumination tandem process. Angew. Chem. Int. Ed. 41, 2141–2143.
• 83)   Negishi,  E.,  Tan,  Z.,  Liang,  B. and  Novak,  T. (2004) A new, efficient, and general route to reduced polypropionates via Zr-catalyzed asymmetric C–C bond formation. Proc. Natl. Acad. Sci. U.S.A. 101, 5782–5787.
• 84)  For review articles, see:  Hanessian,  S.,  Giroux,  S. and  Mascitti,  V. (2006) The iterative synthesis of acyclic deoxypropionate units and their implication in polyketide-derived natural products. Synthesis 7, 1057–1076.
• 85)   ter Horst,  B.,  Feringa,  B.L. and  Minnaard,  A.J. (2010) Iterative strategies for the synthesis of deoxypropionates. Chem. Commun. 46, 2535–2547.
• 86)   Novak,  T.,  Tan,  Z.,  Liang,  B. and  Negishi,  E. (2005) All-catalytic, efficient, and asymmetric synthesis of α,ω-diheterofunctional reduced polypropionates via “one-pot” Zr-catalyzed asymmetric carboalumination–Pd-catalyzed cross-coupling tandem process. J. Am. Chem. Soc. 127, 2838–2839.
• 87)   Liang,  B.,  Novak,  T.,  Tan,  Z. and  Negishi,  E. (2006) Catalytic, efficient, and syn-selective construction of deoxypolypropionates and other chiral compounds via Zr-catalyzed asymmetric carboalumination of allyl alcohol. J. Am. Chem. Soc. 128, 2770–2771.
• 88)   Xu,  S.,  Oda,  A.,  Bobinski,  T.,  Li,  H.,  Matsueda,  Y. and  Negishi,  E. (2015) Highly efficient, convergent, and enantioselective synthesis of phthioceranic acid. Angew. Chem. Int. Ed. 54, 9319–9322.
• 89)   Yang,  C.-T.,  Zhang,  Z.-Q.,  Liang,  J.,  Liu,  J.-H.,  Lu,  X.-Y.,  Chen,  H.-H. and  Liu,  L. (2012) Copper-catalyzed cross-coupling of nonactivated secondary alkyl halides and tosylates with secondary alkyl Grignard reagents. J. Am. Chem. Soc. 134, 11124–11127.
• 90)   Chen,  C.S.,  Fujimoto,  Y.,  Girdaukas,  G. and  Sih,  C.J. (1982) Quantitative analyses of biochemical kinetic resolutions of enantiomers. J. Am. Chem. Soc. 104, 7294–7299.
• 91)   Chen,  C.S. and  Sih,  C.J. (1989) General aspects and optimization of enantioselective biocatalysis in organic solvents: The use of lipases. Angew. Chem. Int. Ed. Engl. 28, 695–707.
• 92)   Huang,  Z.,  Tan,  Z.,  Novak,  T.,  Zhu,  G. and  Negishi,  E. (2007) Zirconium-catalyzed carboaluminumination of alkenes: ZACA–lipase-catalyzed acetylation synergy. Adv. Synth. Catal. 349, 539–545.
• 93)   Xu,  S.,  Lee,  C.-T.,  Wang,  G. and  Negishi,  E. (2013) Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1-alkanols by zirconium-catalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling. Chem. Asian J. 8, 1829–1835.
• 94)   Tateishi,  N.,  Mori,  T.,  Kagamiishi,  Y.,  Satoh,  S.,  Katsube,  N.,  Morikawa,  E.,  Morimoto,  T.,  Matsui,  T. and  Asano,  T. (2002) Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: Suppression of astrocytic activation by a novel agent (R)-(−)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J. Cereb. Blood Flow Metab. 22, 723–734.
• 95)   Sorbera,  L.A. and  Castaner,  J. (2004) Arundic acid–Astrocyte-modulating agent treatment of stroke treatment of neurodegeneration. Drugs Future 29, 441–448.
• 96)   Xu,  S.,  Oda,  A.,  Kamada,  H. and  Negishi,  E. (2014) Highly enantioselective synthesis of γ-, δ-, and ε-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling. Proc. Natl. Acad. Sci. U.S.A. 111, 8368–8373.
• 97)   Dale,  J.A. and  Mosher,  H.S. (1973) Nuclear magnetic resonance enantiomer regents. Configurational correlations via nuclear magnetic resonance chemical shifts of diastereomeric mandelate, O-methylmandelate, and alpha-methoxy-alpha-trifluoromethylphenylacetate (MTPA) esters. J. Am. Chem. Soc. 95, 512–519.
• 98)   Harada,  N.,  Watanabe,  M.,  Kuwahara,  S.,  Sugio,  A.,  Kasai,  Y. and  Ichikawa,  A. (2000) 2-Methoxy-2-(1-naphthyl)propionic acid, a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the ¹H NMR anisotropy method. Tetrahedron Asymmetry 11, 1249–1253.
• 99)   Kasai,  Y.,  Sugio,  A.,  Sekiguchi,  S.,  Kuwahara,  S.,  Matsumoto,  T.,  Watanabe,  M.,  Ichikawa,  A. and  Harada,  N. (2007) Conformational analysis of MαNP esters, powerful chiral resolution and ¹H NMR anisotropy tools–aromatic geometry and solvent effects on Δδ values. Eur. J. Org. Chem. 1811–1826.
• 100)   Matsueda,  Y.,  Xu,  S. and  Negishi,  E. (2015) A novel highly enantio- and diastereoselective synthesis of vitamin E side-chain. Tetrahedron Lett. 56, 3346–3348.
• 101)   Mislow,  K. and  Bickart,  P. (1976) An epistemological note on chirality. Isr. J. Chem. 15, 1–6.
• 102)  Mislow, K. (1997) Fuzzy restrictions and inherent uncertainties in chirality studies. In Fuzzy Logic in Chemistry (ed. Rouvray, D.H.). Academic press, San Diego, pp. 65–90.
• 103)   Mislow,  K. (2003) Absolute asymmetric synthesis: a commentary. Collect. Czech. Chem. Commun. 68, 849–864.
• 104)   Xu,  S.,  Oda,  A. and  Negishi,  E. (2014) Enantioselective synthesis of chiral isotopomers of 1-alkanols by a ZACA–Cu-catalyzed cross-coupling protocol. Chemistry 20, 16060–16064.
• 105)   Huo,  S. and  Negishi,  E. (2001) A convenient and asymmetric protocol for the synthesis of natural products containing chiral alkyl chains via Zr-catalyzed asymmetric carboalumination of alkenes. Syntheses of phytol and vitamins E and K. Org. Lett. 3, 3253–3256.
• 106)   Tan,  Z. and  Negishi,  E. (2004) An efficient and general method for the synthesis of α,ω-difunctional reduced polypropionates by Zr-catalyzed asymmetric carboalumination: synthesis of the scyphostatin sidechain. Angew. Chem. Int. Ed. 43, 2911–2914.
• 107)   Xu,  S.,  Lee,  C.-T.,  Rao,  H. and  Negishi,  E. (2011) Highly (>98%) stereo- and regioselective trisubstituted alkene synthesis of wide applicability via 1-halo-1-alkyne hydroboration–tandem Negishi–Suzuki coupling or organoborate migratory insertion. Adv. Synth. Catal. 353, 2981–2987.
• 108)   Pitsinos,  E.,  Athinaios,  N.,  Xu,  Z.,  Wang,  G. and  Negishi,  E. (2010) Total synthesis of (+)-scyphostatin featuring an enantioselective and highly efficient route to the side-chain via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA). Chem. Commun. 46, 2200–2202.
• 109)   Magnin-Lachaux,  M.,  Tan,  Z.,  Liang,  B. and  Negishi,  E. (2004) Efficient and selective synthesis of siphonarienolone and related reduced polypropionates via Zr-catalyzed asymmetric carboalumination. Org. Lett. 6, 1425–1427.
• 110)   Zeng,  X.,  Zeng,  F. and  Negishi,  E. (2004) Efficient and selective synthesis of 6,7-dehydrostipiamide via Zr-catalyzed asymmetric carboalumination and Pd-catalyzed cross-coupling of organozincs. Org. Lett. 6, 3245–3248.
• 111)   Zhu,  G. and  Negishi,  E. (2007) Fully reagent-controlled asymmetric synthesis of (−)-spongidepsin via the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction). Org. Lett. 9, 2771–2774.
• 112)   Huang,  Z. and  Negishi,  E. (2007) Highly stereo- and regioselective synthesis of (Z)-trisubstituted alkenes via 1-bromo-1-alkyne hydroboration–migratory insertion–Zn-promoted iodinolysis and Pd-catalyzed organozinc cross-coupling. J. Am. Chem. Soc. 129, 14788–14792.
• 113)   Liang,  B. and  Negishi,  E. (2008) Highly efficient asymmetric synthesis of fluvirucinine A₁ via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–lipase-catalyzed acetylation tandem process. Org. Lett. 10, 193–195.
• 114)   Zhu,  G.,  Liang,  B. and  Negishi,  E. (2008) Efficient and selective synthesis of (S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyldocosane via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA) reaction. Org. Lett. 10, 1099–1101.
• 115)   Xu,  Z. and  Negishi,  E. (2008) Efficient and stereoselective synthesis of yellow scale pheromone via alkyne haloboration, Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction), and Pd-catalyzed tandem Negishi coupling. Org. Lett. 10, 4311–4314.
• 116)   Ribe,  S.,  Kondru,  R.K.,  Beratan,  D.N. and  Wipf,  P. (2000) Optical rotation computation, total synthesis, and stereochemistry assignment of the marine natural product pitiamide A. J. Am. Chem. Soc. 122, 4608–4617.
• 117)   Wipf,  P. and  Hopkins,  T.D. (2005) Total synthesis and structure validation of (+)-bistramide C. Chem. Commun. 27, 3421–3423.