Despite recent advances of asymmetric synthesis, the preparation of enantiomerically pure (≥99% ee) compounds remains a challenge in modern organic chemistry. We report here a strategy for a highly enantioselective (≥99% ee) and catalytic synthesis of various γ-and more-remotely chiral alcohols from terminal alkenes via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)-Cu-or Pd-catalyzed cross-coupling. ZACA-in situ oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols produced both (R)-and (S)-α,ω-dioxyfunctional intermediates (3) in 80-88% ee, which were readily purified to the ≥99% ee level by lipase-catalyzed acetylation through exploitation of their high selectivity factors. These α,ω-dioxyfunctional intermediates serve as versatile synthons for the construction of various chiral compounds. Their subsequent Cu-catalyzed cross-coupling with various alkyl (primary, secondary, tertiary, cyclic) Grignard reagents and Pd-catalyzed cross-coupling with aryl and alkenyl halides proceeded smoothly with essentially complete retention of stereochemical configuration to produce a wide variety of γ-, δ-, and e-chiral 1-alkanols of ≥99% ee. The MαNP ester analysis has been applied to the determination of the enantiomeric purities of δ-and e-chiral primary alkanols, which sheds light on the relatively undeveloped area of determination of enantiomeric purity and/or absolute configuration of remotely chiral primary alcohols.A symmetric synthesis remains as a significant challenge to synthetic organic chemists as the demand for enantiomerically pure compounds continues to increase. Chirality plays a vital role in chemical, biological, pharmaceutical, and material sciences. The US Food and Drug Administration requires that all chiral bioactive molecules have to be as pure as possible, containing a single pure enantiomer, because chirality significantly influences drugs' biological and pharmacological properties. As a consequence, development of new methods for asymmetric synthesis of enantiomerically pure compounds (≥99% ee) continues to be increasingly important (1-5). We recently reported a highly selective and efficient method (6) for the preparation of 2-chirally substituted 1-alkanols via a sequence consisting of (i) Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction hereafter) (7-10)-in situ iodinolysis of allyl alcohol, (ii) enantiomeric purification by lipase-catalyzed acetylation (11, 12) of both (S)-and (R)-ICH 2 CH (R)CH 2 OH (1), the latter obtained as acetate, i.e., (R)-2, and (iii) Cu-or Pd-catalyzed cross-coupling (13, 14) (Scheme 1).As satisfactory as the procedure shown in Scheme 1 is, however, 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 came up with a strategy shown in Scheme 2, which, in principle, should be applicable to the synthesis of γ-and more-remotely chiral alcohols of high enantiomeric purity. In contrast to Scheme 1, the alkylalane int...
The Pd-or Ni-catalyzed cross-coupling reactions of organometals containing Zn, Al, Zr, and B as well as related reactions of those containing Mg and several other metals collectively have emerged as arguably the most widely applicable organic skeleton construction method discovered and developed over the past several decades, allowing synthetic chemists to prepare practically all types of organic compounds. In this chapter, some of the seminal and critically important discoveries and early developments in the 1970s as well as their current scope are briefly discussed. Some of the notable discoveries and developments include (i) identification of superior properties of Pd as a critical element for crosscoupling relative to Ni, (ii) the broad scope of Pd-or Ni-catalyzed cross-coupling with respect to metal countercations including Zn, Al, Zr, B, and Mg, (iii) the hydrometallation-Pd-catalyzed cross-coupling sequential processes for selective syntheses of alkenes, dienes, oligoenes, and oligoenynes, (iv) double metal catalysis involving Pd or Ni and added metal compounds containing Zn, In, Li, and others, and (v) realization of high turnover numbers (TONs) (≥10 3 -10 9 ) through the use of chelating phosphines, such as bis-[2-(diphenylphosphino)phenyl] ether (DPEphos) and 1,1 -Bis(diphenylphosphino)ferrocene (dppf).The Zr-catalyzed alkyne carboalumination and the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction) have provided efficient and selective routes to (E)-trisubstituted alkenylalanes and 2-substituted chiral alkylalanes, respectively. These reactions provide two additional examples of prototypical transition metal-catalyzed organometallic reactions. Significantly, they can be readily combined with the Pd-or Ni-catalyzed cross-coupling for the synthesis of trisubstituted alkenes embracing a wide variety of natural products, such as terpenoids, carotenoids, and others, as well as various chiral organics including deoxypolypropionates and saturated terpenoids. The Zr-catalyzed alkyne carboalumination has been applied to the synthesis of a large number (>100) of natural products, while the ZACA reaction has been transformed from a mere scientific novelty to a full-fledged asymmetric synthetic method that is catalytic in both transition metal (Zr) and chiral auxiliaries through a series of breakthroughs.
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