A new strategy for highly concise, convergent, and enantioselective access to polydeoxypropionates has been developed. ZACA-Pd-catalyzed vinylation was used to prepare smaller deoxypropionate fragments, and then two key sequential Cu-catalyzed stereocontrolled sp³–sp³ cross-coupling reactions 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 full stereocontrol.

A new strategy for highly concise, convergent, and enantioselective access to polydeoxypropionates has been developed. ZACA-Pd-catalyzed vinylation was used to prepare smaller deoxypropionate fragments, and then two key sequential Cu-catalyzed stereocontrolled sp³–sp³ cross-coupling reactions 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 full stereocontrol.

Chiral compounds arising from the replacement of hydrogen atoms by deuterium are very important in organic chemistry and biochemistry. Some of these chiral compounds have a non-measurable specific rotation, owing to very small differences between the isotopomeric groups, and exhibit cryptochirality. This particular class of compounds is difficult to synthesize and characterize. Herein, we present a catalytic and highly enantioselective conversion of terminal alkenes to various β and more remote chiral isotopomers of 1-alkanols, with ≥99 % enantiomeric excess (ee), by the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA) and Cu-catalyzed cross-coupling reactions. ZACA-in situ iodinolysis of allyl alcohol and ZACA-in situ oxidation of TBS-protected ω-alkene-1-ols protocols were applied to the synthesis of both (R)- and (S)-difunctional intermediates with 80–90 % ee. These intermediates were readily purified to provide enantiomerically pure (≥99 % ee) compounds by lipase-catalyzed acetylation. These functionally rich intermediates serve as very useful synthons for the construction of various chiral isotopomers of 1-alkanols in excellent enantiomeric purity (≥99 % ee) by introducing deuterium-labeled groups by Cu-catalyzed cross-coupling reactions without epimerization.

A highly enantioselective and widely applicable method for the synthesis of various chiral 2-alkyl-1-alkanols, especially those of feeble chirality, has been developed. It consists of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and palladium- or copper-catalyzed cross-coupling. By virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1-alkanols (1), 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)-1 or (R)-2 for introduction of various primary, secondary, and tertiary carbon groups with retention of all carbon skeletal features. These chiral tertiary alkyl-containing alcohols can be further converted into the corresponding acids with full retention of the stereochemistry. The synthetic utility of this method has been demonstrated in the highly enantioselective (≥99 % ee) and efficient syntheses of (R)-2-methyl-1-butanol and (R)- and (S)-arundic acids.

(Z)-1-Halo-1-alkenylboranes (7), preparable in 80–90% yields as ≥98% isomerically pure compounds via hydroboration of 1-halo-1-alkynes, have been converted to a wide range of trisubstituted alkenes via three different routes in the tail-to-head (T-to-H) direction, i.e., (i) palladium-catalyzed Negishi–Suzuki tandem alkenylation, (ii) treatment with organolithium or Grignard reagents to generate α-bromo-1-alkenylboronate complexes that can undergo migratory insertion of a carbon group (R²) to form (E)-alkenylboranes with inversion of alkene configuration (≥98% inversion), followed by fluoride-promoted Suzuki alkenylation, and (iii) Negishi coupling to generate (Z)-alkenylboranes in ≥98% retention of configuration, followed by treatment with organolithium or Grignard reagents to produce trisubstituted alkenes with reversed stereo configurations. The synthetic utility of the present methodology has been demonstrated in the highly selective synthesis of the side chain of scyphostatin in 28% yield over nine steps in the longest linear sequence from allyl alcohol. Thus, this new tandem protocol has been emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to prepare.

Unprecedentedly efficient and highly (≥98 %) stereoselective syntheses of mycolactones A and B side chains relied heavily on Pd-catalyzed alkenylation (Negishi version) and were completed in 11 longest linear steps from ethyl (S)-3-hydroxybutyrate in 12 % and 11 % overall yield, respectively, roughly corresponding to an average of 82 % yield per step. The synthesis of mycolactone core was realized by using Pd-catalyzed alkenylallyl coupling and an epoxide-opening reaction with a trialkylalkenylaluminate as key steps. Fully hydroxy-protected mycolactones A and B of ≥98 % isomeric purity were synthesized successfully for the first time. However, unexpected 4:3–5:4 inseparable mixtures of mycolactones A and B were obtained upon deprotection.

The hitherto unprecedented palladium-catalyzed cross-coupling of (Z)-β-bromo-β-arylethenylboranes can be made to proceed satisfactorily through (1) the use of highly catalytically active bis(tri-tert-butylphosphine)palladium or dichloro[N,N-bis-(2,6-diisopropylphenyl)imidazol-2-yl](m-chloropyridine)palladium and (2) conversion of the dibromoboryl group to the (pinacol)boryl group. Thus, a wide variety of carbon groups can be used to substitute bromine in ≥98% stereo- and regioselectivity, while suppressing the otherwise dominant β-debromoboration. Together with the alkylethyne-based protocols, the alkyne bromoboration–Negishi coupling tandem process has emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to access.

(Z)-β-bromo-1-propenyl(pinacol)borane (4), recently made available in 85 % yield as a ≥98 % isomerically pure compound via bromoboration of 1-propyne, has been converted to β-alkyl-, aryl-, and alkenyl-substituted (Z)-2-methyl-1-alkenyl(pinacol)boranes (2a) in ca. 75 % yield based on propyne via Pd-catalyzed Negishi alkenylation with suitable organozinc bromide. The previously sluggish and modest-yielding Suzuki alkenylation of β,β-disubstituted alkenylboranes has been significantly promoted by fluorides, especially nBu₄NF(TBAF) or CsF, to give trisubstituted alkenes, i.e., (Z)-β-Me-substituted 3-i–3-xi and (E)-β-Ph-substituted 2b–i and 2b–ii. In all cases, each alkene product was formed in a ≥98 % stereoselectivity. The propyne-based protocol nicely complements the widely used Zr-catalyzed alkyne methylalumination–Pd-catalyzed alkenylation by providing a highly stereoselective(≥98 %) route to (Z)-Me-substituted alkenes.

Zr-catalyzed methylalumination of 3-butyn-1-ols followed by AlCl₃-promoted stereoisomerization at 50 °C for 6 h provides 4-iodo-3-methyl-3-buten-1-ols 2b and 6 (≥98 % Z configuration) in 87 and 67 % yields, respectively. (Z)-1,4-Diiodo-2-methyl-1-butene (1b) obtainable by iodination of 2b is a valuable synthon for efficient and selective syntheses of (Z)-alkene-containing isoprenoids.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Two highly efficient protocols for enantioselective synthesis of 2,4-dimethyl-1-penten-1,5-ylidene derivatives involve the combined use of the Zr-catalyzed methylalumination of alkynes (ZMA) and the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA). The ZMA/ZACA protocol has been applied to the synthesis of a nafuredin intermediate 14 and a potential intermediate 18 for milbemycin β₃, while the ZACA/ZMA protocol has been applied to the synthesis of a (−)-bafilomycin A₁ intermediate 25.