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Review
. 2014 Apr;31(4):504-13.
doi: 10.1039/c3np70076c. Epub 2014 Feb 11.

Polyketide construction via hydrohydroxyalkylation and related alcohol C-H functionalizations: reinventing the chemistry of carbonyl addition

Anne-Marie R Dechert-Schmitt  1 , Daniel C Schmitt, Xin Gao, Takahiko Itoh, Michael J Krische
Affiliations
Review

Polyketide construction via hydrohydroxyalkylation and related alcohol C-H functionalizations: reinventing the chemistry of carbonyl addition

Anne-Marie R Dechert-Schmitt et al. Nat Prod Rep. 2014 Apr.

Abstract

Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via"C-C bond forming transfer hydrogenation" provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of the respective natural product families.

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Figures

Figure 1
Figure 1
Representative polyketide natural products isolated from soil bacteria used in human medicine.
Figure 2
Figure 2
General catalytic mechanism and survey of selected bond lengths from a series of π-allyliridium C,O-benzoate complexes.
Scheme 1
Scheme 1
Enantioselective iridium catalyzed alcohol C-H allylation.a aI = (R)-Cl,MeO-BIPHEP, II = (R)-TMBTP, III = (R)-BINAP
Scheme 2
Scheme 2
Generation of polyacetate substructures via 1- and 2-directional chain elongation.
Scheme 3
Scheme 3
Asymmetric iridium catalyzed C-H allylation of chiral β-stereogenic alcohols.
Scheme 4
Scheme 4
Enantioselective iridium catalyzed alcohol C-H crotylation.
Scheme 5
Scheme 5
Total synthesis of the oxo-polyene macrolide (+)-roxaticin.
Scheme 6
Scheme 6
Asymmetric double anti-crotylation of 2-methyl-1,3-propanediol: formal syntheses of rifamycin S and scytophycin C.
Scheme 7
Scheme 7
Ruthenium catalyzed syn-diastereo- and enantioselective crotylation via hydrohydroxyalkylation of 2-silyl-butadienes. a Chiral Ligand = (R)-DM-SEGPHOS. b Chiral Ligand = (R)- SEGPHOS.
Scheme 8
Scheme 8
Total syntheses of trienomycins A and F via ruthenium catalyzed syn-diastereo- and enantioselective hydrohydroxyalkylation of 2-silyl-butadienes.
Scheme 9
Scheme 9
Inversion of diastereoselectivity in enantioselective ruthenium catalyzed crotylation via butadiene hydrohydroxyalkylation.
Scheme 10
Scheme 10
Total synthesis of 6-deoxyerythronlide B via diastereo- and enantioselective alcohol C-H crotylation.
Scheme 11
Scheme 11
Enantioselective iridium catalyzed alcohol C-H reverse prenylation.
Scheme 12
Scheme 12
Total synthesis of bryostatin 7 via C-C bond forming hydrogenation and transfer hydrogenation.
Scheme 13
Scheme 13
Total synthesis of cyanolide A via enantioselective double allylation of neopentyl glycol.
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References

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