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. 2016 May 4;138(17):5467-78.
doi: 10.1021/jacs.6b02019. Epub 2016 Apr 26.

Enantioselective Alcohol C-H Functionalization for Polyketide Construction: Unlocking Redox-Economy and Site-Selectivity for Ideal Chemical Synthesis

Jiajie Feng  1 , Zachary A Kasun  1 , Michael J Krische  1
Affiliations

Enantioselective Alcohol C-H Functionalization for Polyketide Construction: Unlocking Redox-Economy and Site-Selectivity for Ideal Chemical Synthesis

Jiajie Feng et al. J Am Chem Soc. .

Abstract

The development and application of stereoselective and site-selective catalytic methods that directly convert lower alcohols to higher alcohols are described. These processes merge the characteristics of transfer hydrogenation and carbonyl addition, exploiting alcohols and π-unsaturated reactants as redox pairs, which upon hydrogen transfer generate transient carbonyl-organometal pairs en route to products of C-C coupling. Unlike classical carbonyl additions, stoichiometric organometallic reagents and discrete alcohol-to-carbonyl redox reactions are not required. Additionally, due to a kinetic preference for primary alcohol dehydrogenation, the site-selective modification of glycols and higher polyols is possible, streamlining or eliminating use of protecting groups. The total syntheses of several iconic type I polyketide natural products were undertaken using these methods. In each case, the target compounds were prepared in significantly fewer steps than previously achieved.

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Figures

Figure 1
Figure 1
Economic selective pressure as a driver for synthetic efficiency and the technological gap vis-à-vis methods for complex molecule construction.
Figure 2
Figure 2
Selected polyketide natural products and semi-synthetic congeners used in human medicine.
Figure 3
Figure 3
First-generation methods for polyketide construction and new capabilities availed by direct alcohol C-C coupling.
Figure 4
Figure 4
General mechanism for iridium catalyzed C-C coupling of primary alcohols and selected transformations applicable to polyketide construction: allylation, crotylation, tert-prenylation and tert-(hydroxy)prenylation.
Figure 5
Figure 5
Formal syntheses of rifamycin S and scytophycin C via enantioselective C-H crotylation of 2-methyl-1,3-propane diol.a aFor graphical summaries of prior total syntheses, see Supporting Information.
Scheme 1
Scheme 1
Enantioselective ruthenium catalyzed alcohol C-H crotylation.
Scheme 2
Scheme 2
Prior total syntheses of selected erythromycin family members and total synthesis of 6-deoxyerythronolide B via enantioselective alcohol C-H crotylation.a aFor graphical summaries of prior total syntheses, see Supporting Information. LLS = Longest Linear Sequence; TS = Total Steps.
Scheme 3
Scheme 3
Total synthesis of (+)-zincophorin methyl ester via enantioselective alcohol C-H crotylation.a aFor graphical summaries of prior total syntheses, see Supporting Information.
Scheme 4
Scheme 4
Formal synthesis of premisakinolide A and C(19)–C(32) of swinholide A via site-selective C-H allylation and crotylation of unprotected diols.a aFor graphical summaries of prior syntheses, see Supporting Information.
Scheme 5
Scheme 5
Direct generation of an acetate-based triketide motif via bidirectional enantioselective C-H allylation of 1,3-propane diol.a aFor further experimental details, see references , , , .
Scheme 6
Scheme 6
Total synthesis of the oxo-polyene macrolide (+)-roxaticin via enantioselective alcohol C-H allylation and crotylation.a aFor graphical summaries of prior total syntheses, see Supporting Information.
Scheme 7
Scheme 7
Total syntheses of cyanolide A, neopeltolide, psymberin (irciniastatin A), mandelalide and cryptocaryol A via bidirectional enantioselective alcohol C-H allylation.a aFor graphical summaries of prior total syntheses, see Supporting Information.
Scheme 8
Scheme 8
Total synthesis of bryostatin 7 via hydrogenative and transfer hydrogenative carbonyl addition.a aFor graphical summaries of prior total syntheses, see Supporting Information.
Scheme 9
Scheme 9
Total synthesis of trienomycin A and F via hydrogenative and transfer hydrogenative carbonyl addition.a aFor graphical summaries of prior total syntheses, see Supporting Information.
Scheme 10
Scheme 10
Total synthesis of oridamycin A via enantioselective alcohol C-H tert-(hydroxy)prenylation.a aFor graphical summaries of prior total syntheses, see Supporting Information.
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