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

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 [alpha],[omega]-di-, tri-, or tetrasubstituted cumulenes, i.e., [R.sup.1][R.sup.2]C=C=C=C=[sub.n-2]C[R.sup.3][R.sup.4], 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. Natta (11) 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 France (16) 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.

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

Encouraged by the discovery and development of the alkyne carboalumination reaction catalyzed by [Cp.sub.2]Zr[Cl.sub.2] (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)

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 carbometalation (78) are representative. For favorable results, all of the side reactions shown in the red frame of Scheme 4 must be effectively suppressed.

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)Zr[Cl.sub.2] (79) and its partially hydrogenated derivatives (80) were less effective. The most effective among those tested is Erker's [(NMI).sub.2]Zr[Cl.sub.2]. (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)


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-[10.sup.3] to [greater than or equal to] [10.sup.3]-[10.sup.4] 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)


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).sub.2] as an additive, (ii) Pd(DPEphos)[Cl.sub.2] and [sup.i][Bu.sub.2]AlH (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[degrees]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 [alpha],[omega]-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)

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 stereo-controlled [sp.sup.3]-[sp.sup.3] cross-coupling reactions (89) 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).



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 ZAC A 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 [greater than or equal to] 98% ee is limited to 50% or, more specifically [less than or equal to] 25% if E = 10, [less than or equal to] 35% if E = 20, and [less than or equal to] 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 [greater than or equal to] 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 [greater than or equal to] 99% pure acetates would be [less than or equal to] 1-2% (E [less than or equal to] 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 [greater than or equal to] 99% pure acetates of (S)-2-methyl-1-alkanols can be predicted as follows: [less than or equal to] 80% if the initial [ee.sub.o] is 70% and E is 50; [less than or equal to] 85% if [ee.sub.o] is 80% and E is 30; [less than or equal to] 95% if [ee.sub.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 [greater than or equal to] 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 [greater than or equal to] 70% ee and (ii) the E values are sufficiently high, preferably [greater than or equal to] 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 :-bonds or heterofunctional groups, have been efficiently synthesized in [greater than or equal to] 98% ee by ZACA--lipase-catalyzed acetylation sequential protocol. (92)



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 [greater than or equal to] 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 [greater than or equal to] 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)

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 [greater than or equal to] 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 NaCl[O.sub.2] in the presence of catalytic amounts of NaClO and 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO). Thus, a highly enantioselective ([greater than or equal to] 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)

(S)-2-Methyl-3-iodo-1-propanol 6 of [greater than or equal to] 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 Pd[Cl.sub.2](DPEphos)-catalyzed Negishi coupling reactions where the second Negishi coupling proceeding with a clean stereoinversion (Scheme 12). (87)

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 [gamma]- and more-remotely chiral alcohols of high enantiomeric purity through simple paradigm shift, as summarized in Scheme 13. (96)

Having developed a widely applicable route to various [gamma]- 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 [gamma] or [delta] position relative to the OH group, the enantiomeric purities of [greater than or equal to] 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 (M[alpha]NP), which had been used in determining the absolute configuration of chiral secondary alcohols. (98),(99) Presumably the naphthyl ring of MoNP esters would exert greater anisotropic shielding effects than [alpha]-methoxy-[alpha]-trifluoromethylphenylacetic acid (MTPA) phenyl group. Indeed, the two terminal methyl groups of the diastereomeric MaNP ester (R,R)- and (R,S)-13, derived from [epsilon]-chiral alcohol (R)-11, showed completely separate [sup.1]H NMR signals, while the diastereomeric MTPA ester 12 showed no separation (Scheme 14). The M[alpha]NP ester analysis was also successfully applied to chiral discrimination of other [delta]- and [epsilon]-chiral primary alcohols, which demonstrated surprising long-range anisotropic differential shielding effects. It should be noted that the diastereotopic chemical shift differences of MoNP esters were affected by NMR solvent and resonance frequency (MHz) of NMR. d-Acetonitrile, d-acetone, d-methanol and/or CD[Cl.sub.3] have been shown to be suitable solvents. The higher the resonance frequency, the better discrimination of chemical shifts obtained.



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 [C.sub.15] vitamin E side-chain 19 (Scheme 15). (100) The key [alpha],[omega]-dioxyfunctional [C.sub.5] synthon 15 ([greater than or equal to] 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 [C.sub.5] iodide 16 were employed as the key steps for preparing the [C.sub.15] vitamin E side-chain 19, which was shown to be >99% ee by [sup.1]H NMR analysis of its M[alpha]NP ester (Scheme 16). (100)





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 ([greater than or equal to] 99% ee) and catalytic synthesis of various 1-alkanols of isotopomeric "cryptochirality" (Scheme 17). (104)


Three deuterium-substituted [delta]-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 [O.sub.2] provided intermediate (S)-25 of 85% ee in 67% yield. This crude (S)-25 was readily purified to the level of [greater than or equal to] 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 [alpha],[omega]-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 [greater than or equal to] 99% ee through lipase-catalyzed acetylation of a racemic mixture of 25.

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 C[H.sub.3] vs. CD[H.sub.2], C[H.sub.3]C[H.sub.2] vs. [CD.sub.3]C[H.sub.2], and C[H.sub.3]C[H.sub.2]C[H.sub.2] vs. C[H.sub.3][CD.sub.2]C[H.sub.2]. Enantiomeric purities ([greater than or equal to] 99% ee) of [beta]- and [gamma]-chiral isotopomers, e.g., (S)-21, were successfully determined by [sup.1]H 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 [gamma]-chiral alkanol (S)-21, showed completely separate [sup.1]H NMR signals. The enantiomeric purities of more remotely chiral, e.g., [delta]- and [epsilon]-chiral, isotopomers have been determined by the M[alpha]NP ester analysis.


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.





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 "Zr[Cp.sub.2]", 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.


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(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-[gamma]-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 [Q.sub.10]. 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 ([+ or -])-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 [C.sub.1]-[C.sub.17] and [C.sub.18]-[C.sub.25] fragments of bafilomycin [A.sub.1]. 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) Carboalu mination/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 (D)-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 (D)-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 multi-component 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 (D)-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 electro philes 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., Wingbermuhle, D., Kurger, 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 [alpha],[omega]-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 [gamma]-, [delta]-, and [epsilon]-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 [sup.1]H 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 M[alpha]NP esters, powerful chiral resolution and [sup.1]H NMR anisotropy tools-aromatic geometry and solvent effects on [DELTA][delta] 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) Enantiose lective 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 [alpha],[omega]-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 (D)-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 stereo selective 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 (D)-bistramide C. Chem. Commun. 27, 3421-3423.

(Received May 22, 2015; accepted July 22, 2015)


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.


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.

By Ei-ichi NEGISHI * [1], [[dagger]] and Shiqing XU * [1]

(Communicated by Ryoji NOYORI, M.J.A.)

* [1] Herbert C. Brown Laboratories of Chemistry, Purdue University, Indiana, U.S.A.

[[dagger]] Correspondence should be addressed: E. Negishi, Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, U.S.A. (e-mail:

doi: 10.2183/pjab.91.369
Table 1. Some representative examples of natural products
synthesized by using Zr-catalyzed carboalumination of

Year        Name of Natural Product                     Reference

2005        bis-Deoxylophotoxin                         25
2006        N-Acetylcysteamine thioester of             26
            Carbazomadurin B                            27
            1,22-Dihydroxynitianes                      28
            (+)-Epolactaene                             29
            Aurisides A and B                           30
            (3S)-Oxidosqualene (analogs)                31
            Dolabelide C (C1-C15 fragment)              32
2007        Amphidinolide X and Y (C12-C21 fragment)    33
            Dechloroansamitocin P-3                     34
            Iromycins                                   35
            Nakiterpiosin                               36
            Coenzyme Q10                                37
            (-)-Reidispongiolide A                      38
            Iridal's core structure                     39
            ([+ or -])-Phomactin B2                     40
            Amphidinolide H and G                       41
2008        Callipeltoside Aglycone                     42
            Bafilomycin A1 (C1-C17 and C18-C25          43
            Nafuredinmilbemycin O3, and                 44
              (-)-bafilomycin A1 (key
            (-)-Reidispongiolide A                      45
2009        Amphidinolides B1, B4, G1, H1, and H2       46
            Phomactins                                  47
            Verticipyrone                               48
            (+)-Myrrhanol A                             49
            Plaunotol                                   50
            Marinomycin A (monomeric counterpart)       51
2010        Carbazomadurin A                            52
            Meiogynin A                                 53
            Maytansinoids                               54
            Ansamitocins P-2 to P-4                     54
2011-2015   Mycolactones A and B                        55
            Leiodermatolide (macrocyclic core)          56
            N-acetyl-S-farnesyl-L-cysteine              57
            FTPA triazole I                             58
            (+)-Concanamycin F                          59
            Bafilomycin A1                              60
            Palmerolide (C16-C24 fragment)              61
            Carbazomadurin A                            62
            (S)-(+)-Carbazomadurin B                    62
            Leiodolide A (C22-C31 fragment)             63
            Celastrol                                   64
            Enokipodin B                                65
            24-Fluorinated Bafilomycin (analog)         66
            Ieodomycins A and B                         67
            Amphidinolides C, C2, and C3                68
              (C-18-C-34 Fragment)
            Verrillin (functionalized core)             69
            (+)-Myrrhanol C                             70
            Myceliothermophins C, D, and E              71

Table 2. Statistical enantiomeric amplification
in iterative enantioselective process

ee in step or   ee in step or    Overall ee
species I (%)   species II (%)      (%)

70                    70            94.0
80                    80            97.6
90                    80            98.8
90                    90            99.4
99                    99           99.995

Table 3. Significance of high initial enantiomeric excess
([ee.sub.o]) and selectivity factor (E) on the maximally
attainable yields of (S)-2-alkyl-1-alkanols of >98% ee

Initial [ee.sub.o] (%)   E [a]         Max. yield (%)

0 (racemic)               100    [less than or equal to] 2
                          90                 0

20                        100    [less than or equal to] 35
                          80                ~20
                          60                 0

50                        100    [less than or equal to] 70
                          50                ~55
                          40                ~25
                          30                 0

60                        100    [less than or equal to] 80
                          50                ~65
                          30                ~25
                          20                 0

70                        100    [less than or equal to] 85
                          50                ~80
                          30                ~60
                          20                ~25
                          10                 0

80                        100    [less than or equal to] 90
                          30                ~85
                          20                ~70
                          10                 0

90                        100    [less than or equal to] 95
                          20                <95
                          10                 80
                           5                 0
[a] E (enantiomeric ratio or selectivity factor) =
ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)]

C and ee are the extent of conversion and the enantiomeric
excess of the unreacted alcohol, respectively d (%)

Table 4.

ZACA--lipase-catalyzed acetylation processes for the
synthesis of 2-methyl-1-alkanols

R                   Initial    Intial   Enzyme      Solvent
                   Yield (%)   ee (%)

Ph                    85         89     Amano PS      THF/

                                        Amano PS      THF/

                                        PPL           THF/

PhC[H.sub.2]          85         76     PPL           THF/

                                        Amano PS      THF/

Ph[(C[H.sub.2]).      85         78     PPL           THF/
sub.2]                                             [H.sub.2]O

                                        Amano PS      THF/

[FORMULA NOT          76         75     Amano PS   C[H.sub.2]
REPRODUCIBLE                                       [Cl.sub.2]

n-Hex                 71         72     Amano PS   C[H.sub.2]

R                  Enzyme         Temp

Ph                 Amano PS        23

                   Amano PS        23

                   PPL             23

PhC[H.sub.2]       PPL             23

                   Amano PS        23

Ph[(C[H.sub.2]).   PPL             23
                   Amano PS        23

[FORMULA NOT       Amano PS        0

n-Hex              Amano PS        0

R                  Enzyme     Conversion

Ph                 Amano PS       22

                   Amano PS       50

                   PPL            31

PhC[H.sub.2]       PPL            48

                   Amano PS       40

Ph[(C[H.sub.2]).   PPL            30
                   Amano PS       38

[FORMULA NOT       Amano PS       16

n-Hex              Amano PS       38

R                  Enzyme     Recovery

Ph                 Amano PS      68

                   Amano PS      43

                   PPL           62

PhC[H.sub.2]       PPL           51

                   Amano PS      59

Ph[(C[H.sub.2]).   PPL           64
                   Amano PS      56

[FORMULA NOT       Amano PS      80

n-Hex              Amano PS      60

R                  Enzyme     Final
                              ee (%)

Ph                 Amano PS     93

                   Amano PS     96

                   PPL          99

PhC[H.sub.2]       PPL          77

                   Amano PS     99

Ph[(C[H.sub.2]).   PPL          99
                   Amano PS     99

[FORMULA NOT       Amano PS     98

n-Hex              Amano PS     98

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

Entry   Chiral Compounds of     Structure        Total or Fragment
        Biological and                           Synthesis
        Medicinal Interest

(1)     vitamin E (2001 and     [FORMULA NOT     total
          2002) (82), (105)       REPRODUCIBLE
                                  IN ASCII]
(2)     vitamin K (2001 and     [FORMULA NOT     total
          2007) (92), (105)       REPRODUCIBLE
                                  IN ASCII]
(3)     phytol (2001) (105)     [FORMULA NOT     total
                                  IN ASCII]
(4)     scyphostatin (2004,     [FORMULA NOT     sidechain
          2010 and 2012)          REPRODUCIBLE     (106), (107)
          (106)-(108)             IN ASCII]        and total
(5)     TMC-151A-F C11-C20      [FORMULA NOT     C11-C20 fragment
          fragment (2004)         REPRODUCIBLE
          (83)                    IN ASCII]
(6)     siphonarienal           [FORMULA NOT     total
          (2004) (109)            REPRODUCIBLE
                                  IN ASCII]
(7)     siphonarienone          [FORMULA NOT     total
          (2004) (109)            REPRODUCIBLE
                                  IN ASCII]
(8)     siphonarienolone        [FORMULA NOT     total
          (2004) (109)            REPRODUCIBLE
                                  IN ASCII]
(9)     (+)-sambutoxcin         [FORMULA NOT     C9-C18 fragment
          C9-C18 fragment         REPRODUCIBLE
          (2004) (109)            IN ASCII]
(10)    6,7-dehydrostipiamide   [FORMULA NOT     total
          (2004) (110)            REPRODUCIBLE
                                  IN ASCII]
(11)    ionomycin C1-C10        [FORMULA NOT     C1-C10 fragment
          fragment (2005)         REPRODUCIBLE
          (86)                    IN ASCII]
(12)    borrelidin              [FORMULA NOT     C3-C11 fragment
          C3-C11 fragment         REPRODUCIBLE
          (2005) (86)             IN ASCII]
(13)    preen gland wax of      [FORMULA NOT     total

          the graylag groose,     REPRODUCIBLE
          Anser anser (2006)      IN ASCII]
(14)    doliculide C1-C9        [FORMULA NOT     C1-C9 fragment
          fragment (2006)         REPRODUCIBLE
          (87)                    IN ASCII]
(15)    (+)-stellattamide A     [FORMULA NOT     sidechain
          (2007) (92)             REPRODUCIBLE
                                  IN ASCII]
(16)    (+)-stellattamide B     [FORMULA NOT     C5-C11 sidechain
          (2007) (92)             REPRODUCIBLE
                                  IN ASCII]
(17)    (-)-spongidepsin        [FORMULA NOT     total
          (2007) (111)            REPRODUCIBLE
                                  IN ASCII]
(18)    (D)-discodermolide      [FORMULA NOT     C11-C17 fragment
          (2007) (112)            REPRODUCIBLE
                                  IN ASCII]
(19)    (-)-callystatin A       [FORMULA NOT     C1-C11 fragment
          (2007) (112)            REPRODUCIBLE
                                  IN ASCII]
(20)    archazolides A and      [FORMULA NOT     C7-C15 fragment
          B (2007) (112)          REPRODUCIBLE
          A: R = Me               IN ASCII]
          B: R = H
(21)    nafuredin (2008) (44)   [FORMULA NOT     C9-C18 fragment
                                  REPRODUCIBLE     (formal total)
                                  IN ASCII]
(22)    milbemycin              [FORMULA NOT     C1-C13 fragment
          [[beta].sub.3]          REPRODUCIBLE
          (2008) (44)             IN ASCII]
(23)    bafilomycin [A.sub.1]   [FORMULA NOT     C1-C11 fragment
          (2008) (44)             REPRODUCIBLE
                                  IN ASCII]
(24)    fluvirucinin            [FORMULA NOT     total
          [A.sub.1] (2008)        REPRODUCIBLE
          (113)                   IN ASCII]
(25)    4,6,8,10,16,18-         [FORMULA NOT     total
          hexamethyldocosane      REPRODUCIBLE
          (2008) (114)            IN ASCII]
(26)    yellow scale            [FORMULA NOT     total
          pheromone (2008)        REPRODUCIBLE
          (115)                   IN ASCII]
(27)    (R)- and (S)-arundic    [FORMULA NOT     total
          acids (2012) (93)       REPRODUCIBLE
                                  IN ASCII]
(28)    phthioceranic acid      [FORMULA NOT     total
          (2015) (88)             REPRODUCIBLE
                                  IN ASCII]
(29)    (7S,10R)-pitiamide A    [FORMULA NOT     total
          (2000) (116)            REPRODUCIBLE
                                  IN ASCII]
(30)    (7R,10R)-pitiamide A    [FORMULA NOT     total
          (2000) (116)            REPRODUCIBLE
                                  IN ASCII]
(31)    (+)-bistramide C        [FORMULA NOT     total
          (2005) (117)            REPRODUCIBLE
                                  IN ASCII]

Scheme 7. "One-pot" ZACA Pd-catalyzed vinylation tandem process.

Additive (equiv)     Solvent      Temp.

Zn[Br.sub.2](1)      THF       60

Zn[Br.sub.2](1)      DMF       120

Zn[Br.sub.2](3)      DMF       120

Zn[(OTf).sub.2](1)   DMF       70

Additive (equiv)     Solvent   Catalyst (%)                 Yield

Zn[Br.sub.2](1)      THF       Pd[(P[Ph.sub.3]).sub.4](5)   14

Zn[Br.sub.2](1)      DMF       [Cl.sub.2]Pd(DPEphos)(5) +   36

Zn[Br.sub.2](3)      DMF       [Cl.sub.2]Pd(DPEphos)(5) +   63

Zn[(OTf).sub.2](1)   DMF       [Cl.sub.2]Pd(DPEphos)(3) +   71
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Author:Negishi, Ei-ichi; Xu, Shiqing
Publication:Japan Academy Proceedings Series B: Physical and Biological Sciences
Article Type:Report
Date:Aug 1, 2015
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