introduction of intended functionality and the dienic
appendage would follow its course as shown in Figure 2.
The feasibility of this plan was put to the test while being
cognizant of the importance of ensuring orthogonal reac-
tivity and/or compatibility in the choice of reagents and
reactions.
The readily available N-Boc-D-serine 1 was converted in
two steps to the N,O-protected Weinreb amide derivative6
2 in an overall yield of 81% (Scheme 1). Treatment with
MeLiledtothe methylketone3,8 which wassubjected to an
9
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acetylide extension according to Joullie and co-workers
with the corresponding Grignard reagent to give 4 as the
major diastereomer in excellent yield (dr >10:1). Hydroxyl-
assisted partial reduction afforded the allylic alcohol 5,
which was dihydroxylated with AD-Mix-β10 to give the
triol 6 as the major diastereomer in 80% yield (dr >5:1).
Conversion to the O-TBDPS/BOM derivative, followed
by separation of isomers, gave intermediate 7 in 78% yield.
Treatment with NaHMDS afforded the cyclic carbamate 8
in 81% yield.
Cleavage of the acetal, oxidation of the primary alcohol
under Dess-Martin conditions11 and then treatment with
methylenetriphenylphosphorane led to the terminal alkene
9 in an overall yield of 62%. N-Alkylation with 3-buten-1-
ol triflateester12 gave10in 78% yield, whichwasconverted
to the primary alcohol by treating with TBAF and then
subjected to ring closing metathesis with Grubbs’ II
catalyst13 to afford 11 in excellent yield.
In order to elaborate the remaining steps, it was neces-
sary to hydrolyze the cyclic carbamate and protect the
resulting 3,4-unsaturated piperidine with an Fmoc group
to give 12. Oxone-induced epoxidation14 gave 13 as the
major diastereomer in 83% yield (dr > 20:1), which was
oxidized to the aldehyde 14 under Dess-Martin conditions.
Our attempts to couple the aldehyde 14 with the entire
cyclopropyl diene unit as the vinyl iodide A (Figure 2)
under Nozaki-Hiyama-Kishi conditions,15 or by halogen-
metal exchange using tBuLi and then transmetalation with
iPrMgCl16 and tBuLi, were not successful, mainly because
of the difficulty in the isolation and purification of the
Figure 1. Structures of cyclizidine and indolizomycin.
was the product of a genetically engineered protoplast fusion
technique from two microorganisms.5
Herein we describe the first total synthesis of (þ)-cyclizi-
dine, the enantiomer of the levorotatory natural product
(Figure 1). This choice was initially guided by the three-
dimensional ORTEP representation portrayed in the ori-
ginally published report for the levorotatory product.1
Analysis of the structural features of cyclizidine reveals a
number of challenges that are heightened by the presence
of the C7/C8 epoxide, as part of six contiguous stereogenic
centers extending to C3 of the indolizidine core structure.
In addition, we were aware that the order of introducing
the required functional groups in a regio- and stereocon-
trolled manner with control of absolute stereochemistry on
a given core motif was critical. We visualized D-serine as a
hidden chiron, which would accommodate the C8a stereo-
chemistry and the position of the nitrogen atom (Figure 2).
Key bond forming sequences would be executed starting
with a N,O-protected D-serine ester which would be trans-
formed to a methylketone and further elaborated to the
tertiary alcohol via an acetylide anion addition. Systematic
(7) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis
1998, 1707–1709.
(8) See Supporting Information for details.
ꢀ
(9) Li, P.; Evans, C. D.; Wu, Y.; Cao, B.; Hamel, E.; Joullie, M. M.
J. Am. Chem. Soc. 2008, 130, 2351–2364.
(10) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.;
Xu, D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768–2771.
(11) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
(12) 3-Buten-1-ol triflate ester was prepared as described by:
Hanessian, S.; Tremblay, M; Petersen, J. F. W. J. Am. Chem. Soc.
2004, 126, 6064–6071.
(13) Scholl, M.; Ding, S.; Lee, W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(14) (a) Yang, D.; Wong, M. K.; Yip, Y. C. J. Org. Chem. 1995, 60,
3887–3889. (b) Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. Org. Chem.
2010, 75, 815–824.
(15) (a) Haolun, J.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem.
Soc. 1986, 108, 5644–5646. (b) Takai, K.; Kimura, K.; Kuroda, T.;
Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281–5284.
(16) (a) Hanessian, S.; Guesne, S.; Chenard, E. Org. Lett. 2010, 8,
1816–1819. (b) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K.
J. Org. Chem. 2001, 66, 4333–4339.
Figure 2. Key disconnections toward cyclizidine.
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