Nature's vast collection of polyketide natural products comprises thousands of compounds incorporating polyacetate derived 1,3-diol or higher 1,3-polyol substructures. While numerous protocols for the synthesis of these ubiquitous structural motifs have been advanced,[1] the iterative allylmetallation of aldehydes has found exceptionally broad use.

The electrophilic cyclization of N,N-diethyl 4-N,N-(dimethylamino)-2-(3-N,N-dimethyldimethylaminophenylchalcogeno)benzamides 7 with POCl3 and triethylamine in CH2Cl2 or with POCl3 in acetonitrile gave excellent yields (77−97% in CH2Cl2, 73−77% in acetonitrile) of the corresponding 2,7-bis-N,N-dimethylaminochalcogenoxanthen-9-ones 6. 3-Methoxyphenylchalcogo-substituted benzamide derivatives were much less reactive toward POCl3 and phenylchalcogeno-substituted benzamide derivatives gave no reaction with POCl3 after 48 h.

The triene-containing C17-benzene ansamycins trienomycins A and F are prepared in 16 steps (longest linear sequence, LLS) and 28 total steps. The C11-C13 stereotriad is prepared via enantioselective ruthenium catalyzed alcohol CH-syn-crotylation followed by chelation-controlled carbonyl dienylation. Enantioselective rhodium catalyzed acetylene-aldehyde reductive coupling mediated by gaseous hydrogen forms a diene that ultimately is subjected to diene-diene ring closing metathesis to form the macrocycle. The present approach is 14 steps shorter (LLS) than the prior syntheses of trienomycins A and F, and 8 steps shorter (LLS) than any prior synthesis of a triene-containing C17-benzene ansamycin.

Natures vast collection of polyketide natural products comprises thousands of compounds incorporating polyacetate-derived 1,3-diol or higher 1,3-polyol substructures. Although numerous procedures for the synthesis of these ubiquitous structural motifs have been advanced, [1] the iterative allylmetallation of aldehydes has found exceptionally broad use. [1][2][3][4][5][6] For example, asymmetric iterative allylchromation (Nozaki-Hiyama coupling), [2] allyltitanation, [3] allylstannation, [4] allylsilation, [5] and allylboration [6] have been employed in synthetic approaches to 1,3-diols and higher homologues. Browns allylborane (n-C 3 H 5 )Ipc 2 B (Ipc = isopinocampheyl) [7] has found the most extensive use in iterative asymmetric carbonyl allylation.[6] Although superstoichiometric generation of isopinocampheol poses a barrier to large-volume applications, [8] both enantiomers of a-pinene are available at low cost and excellent levels of stereocontrol are observed, making the Brown method attractive for use in academic laboratories. However, use of traditional allylmetallation procedures in iterative two-directional syntheses of 1,3-polyol substructures is prohibited by the instability of malondialdehyde.In connection with efforts to exploit catalytic hydrogenation in C À C couplings beyond hydroformylation, [9] we have developed an enantioselective method for carbonyl allylation from the alcohol oxidation level under the conditions of iridium-catalyzed transfer hydrogenation that employ allyl acetate as an allyl donor.[10] The reactant alcohol serves both as a source of hydrogen and as an aldehyde precursor, enabling formation of highly optically enriched homoallylic alcohols directly from the alcohol oxidation level by way of a transient aldehyde. Whereas reductive coupling of allylic carboxylates, alcohols, or ethers to carbonyl partners is typically achieved using metallic reductants, such as SmI 2 , SnCl 2 , Et 2 Zn, or Et 3 B, [11][12][13][14][15] transfer-hydrogenative carbonyl allylation precludes the use of any stoichiometric metallic reagents. Here, using a chiral iridium C,O-benzoate complex modified by 4-chloro-3-nitrobenzoic acid and (R)-or (S)-Cl,MeO-biphep (2,2'-bis(diphenylphosphino)-5,5'-dichloro-6,6'-dimethoxy-1,1'-biphenyl), we report an iterative twodirectional bis allylation of glycols. The method is demonstrated by the rapid assembly of protected 1,3-polyol substructures with exceptional levels of enantiocontrol and catalyst-directed diastereoselectivity.[16] Notably, this process successfully exploits 1,3-diols as synthetic equivalents to unstable malondialdehydes.Although malondialdehyde can be generated through the hydrolysis of 1,1,3,3-tetramethoxypropane, capture of this dialdehyde is impeded by the fact that it is highly unstable and is generated under aqueous conditions, which promote hydration, oligomerization, and self-condensation, and preclude the use of most organometallic reagents. The ability to bypass stoichiometric pre-formation of aldehyde electrophiles, as in carbonyl allyl...

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