Scheme 1. Retrosynthetic Analysis of AMMTD
Figure 1. Microsclerodermins A and B.
The first step involved formation of benzyl ether 2 by
reaction of 1 with benzyl 2,2,2-trichloroacetimidate, fol-
lowed by reduction to aldehyde 3 (Scheme 2).15 The crude
aldehyde was transfomed into (E,E)-diene 5 through
(E)-selective HornerÀWadsworthÀEmmons reaction with
phosphonate 4. We found that the desired olefination
proceeded efficiently utilizing 2 equiv of phosphonate and
LDA at À20 °C. This allowed for the formation of diene 5
in good yield (67%, three steps) as an (inseparable)
(E,E)/(E,Z) 9:1 mixture and as a single enantiomer
(ee >90%, by Mosher’s ester analysis).
contiguous stereocenters and variation in the degree of
unsaturation in the side-chain tail. Early studies on the
microsclerodermins by Shioiri10 were followed by Ma who
reported the only total synthesis of any microsclerodermin
(E, containing a β-amino acid with four contiguous stereo-
centers).11 Shioiri12 and Chandrasekhar13 reported the
synthesis of protected variants of the β-amino acid in
microscleroderminsA and B(AMMTD), whilethesimpler
β-amino acid of microsclerodermins C and D (APTO) and
E (AETD) have received the most attention.14
It was essential that our approach to AMMTD (Scheme 1)
produced the target in a form that would permit conjuga-
tion to other amino acids, ultimately allowing a total
synthesis of the microsclereodermins. Another funda-
mental part of our design was late-stage introduction of
the aliphatic tail, to allow access to multiple members of
the family. We envisaged side-chain installation via organo-
cuprate addition to functionalized electrophile III. The key
aminohydroxyl unit at C2,C3 could be installed via a regio-
and stereoselective aminohydroxylation of an olefin via TA
reaction of II. Precursor II could arise from manipulation
of a diol, generated by dihydroxylation (AD) of R,β,γ,δ-
unsaturated ester I. In turn diene I should be readily
prepared as a single enantiomer from (S)-Roche ester.
Scheme 2. Construction of Diene 5
Installation of the C4,C5 diol proceeded via regio- and
stereoselective dihydroxylation of diene 5 under Sharpless
AD conditions, exploiting preferential reaction at the more
electron rich alkene (Scheme 3).16 Reaction of 5 with AD
mix-R gave diol 6 as a single diastereoisomer17 (stereo-
selectivity assigned by the Sharpless mnemonic18). The
preferential rate of dihydroxylation of (E)-1,2- over
(8) (a) Bewley, C. A.; Debitus, C.; Faulkner, D. J. J. Am. Chem. Soc.
1994, 116, 7631. (b) Qureshi, A.; Colin, P. L.; Faulkner, D. J. Tetra-
hedron 2000, 56, 3679. (c) Schmidt, E. W.; Faulkner, D. J. Tetrahedron
1998, 54, 3043.
(9) Zhang, X.; Jacob, M. R.; Rao, R. R.; Wang, Y. H.; Agarwal,
A. K.; Newman, D. J.; Khan, I. A.; Clark, A. M.; Li, X. C. Research
Reports in Medicinal Chemistry 2012, 2, 7.
(10) (a) Shioiri, T.; Sasaki, S.; Hamada, Y. ARKIVOC 2003, 103. (b)
Sasaki, S.; Hamada, Y.; Shioiri, T. Synlett 1999, 453.
(11) Zhu, J.; Ma, D. Angew. Chem., Int. Ed. 2003, 42, 5348.
(12) (a) Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1999,
40, 3187. (b) Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1997,
38, 3013.
(15) An alternative route that involved over-reduction of 2 to the
primary alcohol (LiBH4) and oxidation under ParikhÀDoering condi-
tions formed 5 in 75% yield from 1; see Supporting Information.
(16) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc.
1992, 114, 7570.
(13) Chandrasekhar, S.; Sultana, S. S. Tetrahedron Lett. 2006, 47,
7255.
(17) For comparison we also dihydroxylated the diene using the same
conditions but with diastereomeric ligand (DHQD)2PHAL (AD mix-β)
to give the diastereomeric diol, again as a single diastereomer (>20:1).
(18) For a review, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless,
K. B. Chem. Rev. 1994, 94, 2483.
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Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2013, 78, 2500. (b)
Hjelmgaard, T.; Faure, S.; Lemoine, P.; Viossat, B.; Aitken, D. J. Org.
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(19) Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115,
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B
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