Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond, and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.

Eight P-chiral monodentate ferrocenyl phosphines (1a-h) were prepared in high enantiomeric excess (>95% ee in most cases) by way of an ephedrine-based oxazaphospholidine borane complex. Primary alkyl, secondary alkyl, and substituted aromatic substituents were successfully introduced at the phosphorus center, along with ferrocenyl and phenyl groups, generating phosphines of the general structure FcP(Ph)(R) (Fc = ferrocenyl, R = aryl, alkyl). The synthetic route employed provides facile access to a previously undeveloped class of chiral monophosphines. These compounds were evaluated as ligands in asymmetric catalytic reductive coupling of alkynes and aldehydes and were found to provide the desired chiral allylic alcohols with good regioselectivity and ee in many cases and with complete (E)-selectivity (>98:2) in all cases.

Two nickel-catalyzed reductive coupling reactions of alkynes were instrumental in a modular, stereoselective synthesis of amphidinolide T1 (1). The C13-C21 fragment was prepared from two simple starting materials that were joined in a catalytic alkyne-epoxide fragment coupling operation, whereas an intramolecular aldehyde-alkyne reductive coupling simultaneously formed the final carbon-carbon bond of the macrocycle and established the C13 carbinol configuration with complete selectivity in the desired fashion.

Nickel-catalyzed reductive coupling reactions of 1,3-enynes and aromatic aldehydes efficiently afford conjugated dienols in excellent regioselectivity and modest enantioselectivity when conducted in the presence of catalytic amounts of a monodentate, P-chiral ferrocenyl phosphine ligand. 1-(Trimethylsilyl)-substituted enynes are shown to be effective coupling partners in these reactions, and the dienol products thus formed readily undergo protiodesilylation under mild conditions. Keywords: allylic alcohols; asymmetric catalysis; C À C bond formation; nickel; reductive coupling 1,3-Dienes are important and versatile intermediates in organic synthesis. They are able participants in an array of cycloaddition reactions, most notably the Diels-Alder reaction, [1 -3] and there are a variety of efficient methods for preparing them.[4] Many of these, such as olefination reactions, [5,6] cross-couplings, [7,8] alkene/ enyne metathesis, [9] and other transformations, [10] facilitate convergent synthesis because they simultaneously construct a new carbon-carbon bond. Recently, our laboratory [11] and others [12] reported a new strategy for the synthesis of 1,3-dienes via transition metal-catalyzed reductive coupling reactions of 1,3-enynes and aldehydes. In addition to forming a new carbon-carbon bond, these methods also generate a stereogenic center, [13] allowing for efficient construction of chiral 1,3-dienes that have been widely employed in diastereoselective Diels-Alder reactions. [14,15] We now report the first enantioselective examples of catalytic reductive coupling reactions of 1,3-enynes, promoted by sub-stoichiometric amounts of a monodentate, P-chiral ferrocenyl phosphine ligand.Previous work from our laboratory has shown that nickel-catalyzed reductive couplings of aryl-substituted alkynes (Ar À C C À R) and aldehydes are highly enantioselective when ( þ )-neomenthyldiphenylphosphine (NMDPP) is employed as a chiral ligand (Scheme 1).[16]We have also described a class of P-chiral, monodentate ferrocenyl phosphines (e.g., 1a, 1b; Figure 1) that are efficient promoters of related couplings of aliphatic internal alkynes (Alkyl À C C À Alkyl') and aldehydes, [17] and of multi-component coupling reactions of alkynes, imines, and organoboron reagents. [18] Reductive coupling reactions of 2-methyl-1-hexen-3-yne and benzaldehyde in the presence of catalytic amounts of Ni(cod) 2 and ( þ )-NMDPP, and a stoichiometric quantity of triethylborane (Et 3 B), afforded dienol 2a in low yield and low enantioselectivity, but with high regioselectivity (Table 1, entry 1). Ferrocenylphosphine 1a maintained this high regioselectivity but enhanced both the efficacy and enantioselectivity of the transformation (entry 2). ortho-Isopropylphenyl-substiScheme 1. Asymmetric, nickel-catalyzed reductive coupling of arylalkynes and aldehydes. tuted-ferrocenylphosphine 1b provided even higher levels of both reactivity and enantioselectivity (entry 3). A variety of aromatic aldehydes undergo reductive coupling with 2-methyl-1-hexen-3...

In this article we compare and contrast the strategies and tactics used in the syntheses of the amphidinolide T family of natural products that have been reported by Fürstner, Ghosh and ourselves. Similar approaches to the trisubstituted THF ring present in the targets are utilized in all of the syntheses, but each strategy showcases a different means of macrocyclization.

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Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.