VB12的不对称全合成

The Asymmetric Total Synthesis of Vitamin B12 Nathan S. Werner Denmark Group Meeting September 28th, 2010 The most advanced synthetic intermediate as of 1968 Biology of Vitamin B12 •Vitamin B12, common name cobalamin, is a water soluble molecule produced by bacteria and algae •It is involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation •Vitamin B12 deficiency can potentially cause sever and irreversible damage to the nervous system Brown, K. L. Chem. Rev. 2005, 2075–2149 The Pigments of Life Vitamin B12 corrin, 1973 Heme porphin, 1929 Chlorophyll A chlorin, 1960 Woodward, R.B. Pure Appl. Chem. 1973, 145–177 Fischer, H. et al. Justus Liebigs Ann. Chem. 1929, 468 R. B. Woodward et al. J. Am. Chem. Soc. 1960, 3800 X-Ray Crystal Structure Hodgkin, D. C.; et al. Nature 1956, 1032–1033 X-Ray Crystal Structure Solved 1956 Structural Analysis •Cobalt complex •15-membered macrocycle •4 heterocyclic rings •9 stereogenic centers •6 contiguous stereogenic centers •4 quaternary carbon atoms •6 amide side chains •1 carboxylic acid side chain •Direct linkage between A-D rings Bernhauer, K.; et al. Helv. Chim. Acta 1960, 704–712Mulzer, J. Eur. J. Org. Chem. 2005, 30–45 Retrosynthetic Analysis Bernhauer, K.; et al. Helv. Chim. Acta 1960, 704–712 Woodward, R.B. Pure Appl. Chem. 1968, 519–520 Woodward, R.B. Pure Appl. Chem. 1971, 283–304 Woodward, R.B. Pure Appl. Chem. 1973, 145–177 b-Corrnorsterone Retrosynthetic Analysis Woodward, R.B. Pure Appl. Chem. 1968, 519–520 Woodward’s Western Fragment Synthesis Woodward, R.B. Pure Appl. Chem. 1968, 519–520 The (-)-enantiomer was used to test synthetic routes “our experience has been such that this is just about the only kind of model study which we regard as wholly reliable” –R. B. Woodward Preparation of Pentacyclenone Preparation of Beckmann Precursor wrong epimer Preparation of b-Corrnorsterone Corrnorsterone •corr for corrin •norsterone for norsteroid •cornerstone (Slurvian) Equilibration of Corrnorsterones Brominated ent-b-corrnorsterone First Generation A-D Ring Synthesis CONH2 CONH2 CONH2 COOH 1. O3 2. CH2N2 1. NaBH4 2. Ms2OLiBr The Solution to Side-Chain Differentiation UV Complete C–O bond cleavage observed CF3CO2H Preparation of A-D Ring Cyanobromide Oxidation at sulfur is observed with other thiols Thioester vs Ester •Similar reactivity O-bases •Less reactive to acid hydrolysis •More reactive to N-nucleophiles Thiodextrolin Retrosynthetic Analysis Eschenmoser Synthesis of B-Ring Arndt-Eistert Homologation Preparation of the C-Ring Rings B and C can be prepared from a common intermediate Group Question ? ? Please provide a mechanism for the formation of 52 and 55. Zn, MeOH work-up step work-up step Vinylogous Amidine The condensation of enamines with iminoesters was successfully used in simple model systems, but failed with complex intermediates Eschenmoser, A. Pure Appl. Chem. 1969, 1–23Eschenmoser, A. Pure Appl. Chem. 1963, 297–316 Eschenmoser Sulfide Contraction Eschenmoser, A. Pure Appl. Chem. 1969, 1–23 Preparation of Thiodextrolin East Meets West Secocorrin to Corrin Outline of the Utopian Synthesis Eschenmoser, A.; et al. Science 1977, 1410–1420 1. Produce all four rings from a common racemic starting material 2. Secocorrin → corrin metal- templated ring closure Retrosynthetic Analysis Eschenmoser, A.; et al. Science 1977, 1410–1420 Synthesis of the A-Ring Synthesis of the D-Ring Attachment of D-Ring Attachment of A-Ring The cadium complex is helically labile Woodwood & Hoffman’s Prediction Eschenmoser, A.; et al. Science 1977, 1410–1420 Eschenmoser, A. Pure Appl. Chem. 1969, 1–23 Woodward, R. B. Angew. Chem. Int. Ed. 1969, 781–853 Secocorrin → Corrin Remaining Challenges Eschenmoser, A.; et al. Science 1977, 1410–1420 Selective Methylation Me+ Me+ Me+ Application of Selective Methylation End-Game 78:28 epi/nat 70–80% Eschenmoser’s Amide Solution Eschenmoser, A.; et al. Science 1977, 1410–1420 Woodward, R.B. Pure Appl. Chem. 1973, 145–177 “a diabolically clever scheme” –R. B. Woodward Conclusions For additional analysis and references: Nicolaou, K.C.; Sorensen, E. J. Vitamin B12. Classics in Total Synthesis, VCH: New York, 2003; 100–136 For additional references on the chemistry of corrins: Eschenmoser, A. Pure Appl. Chem. 1963, 297–316 Eschenmoser, A. Angew. Chem. Int. Ed. 1988, 5–39 •The asymmetric total synthesis of Vitamin B12 stands as one of the most significant achievements in organic chemistry. •Produced chemical understanding in the form of: •Synthetic Strategy & Methods •Physical Organic Chemistry •The Woodward-Hoffman Rules •Corrin Chemistry •Diastereoselective Synthesis •Remains unrivaled even after almost 40 years