FR900482 has been studied extensively, resulting in five
total,7-11 and several formal, syntheses,12-14 the shortest of
which was reported by Williams and requires 29 linear steps
(33 total). We reasoned that uniting a suitable aromatic frag-
ment with aziridine 4 would allow for convergent access to
both series, leaving only changes in oxidation state to com-
plete the synthesis (Scheme 1). Beginning with chemistry
reported in this group,15 we envisioned that aziridine fragment
4 could be assembled in an efficient manner. Finally, this
approach introduces several polar functional groups late in
the synthesis and avoids multiple protecting group manipula-
tions.
Scheme 3. Preparation of the Aziridine Fragment
Preparation of the aryl fragment 8 (Scheme 2) began with
the known triflate 5,12 which is prepared in three steps from
Scheme 2. Preparation of the Aryl Fragment
and Supporting Information). Thus, it appears that double
inversion occurs via neighboring group participation of the
tert-butyl carbamate placing the vinyl group cis to the
aziridine.
The single carbon-carbon bond formation of our synthesis
proceeds via Heck coupling17 to produce the exocyclic olefin
17 and construct the “mitomycin” skeleton of the natural
product. No detectable double bond isomerization is observed
in this step, even though such a process would lead to
aromatization, via formation of an indole.
Inspired by the pioneering works of Dmitrienko18 and
Ziegler,19 we envisioned that a Polonovski reaction, followed
by a subsequent oxidative ring expansion, might afford the
commercially available 5-nitrovanillin as reported previously.
The aryl triflate 5 is converted to an aryl iodide (6) via
nucleophilic aromatic substitution with sodium iodide in
DMF. Oxidation of aldehyde 6 with NIS and K2CO3 in
methanol affords the methyl benzoate 7. This substrate is
subjected to iron mediated reduction yielding aniline 8
without undesirable reduction of the aryl iodide.
(7) Fukuyama, T.; Xu, L.; Goto, S. J. Am. Chem. Soc. 1992, 114, 383.
(8) Schkeryantz, J. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117,
4722.
The requisite aziridine 4 is prepared in eight steps from
divinyl carbonate 9 (Scheme 3). First, a palladium-catalyzed
DYKAT (dynamic catalytic asymmetric transformation)
reaction15 yields amino-alcohol 10 as a single stereoisomer.
Following TBS protection, diene 11 is submitted to Sharpless
dihydroxylation,16 yielding the diol 12 with excellent chemo-
and diastereoselectivity. The phthalimide group contained
in amino-alcohol 12 is exchanged for a tert-butyl carbamate
yielding diol 13. Selective silylation and mesylation, followed
by exposure of the crude mesylate to cesium carbonate in
warm DMF affords the aziridine 14. Finally, removal of the
TBDPS group and Dess-Martin oxidation yields the com-
pleted aziridine fragment 4.
Reductive amination between the aziridine 4 and aniline
8 affords the coupled product 15 (Scheme 4). Removal of
the allylic TBS group and activation of the resulting alcohol
with triflic anhydride yields the pyrrolidine 16. Simple
inversion at C-8 was initially expected; however, NOE
analysis of intermediate 18 and its epimer reveals strong
correlations between the C-8 and C-9 protons (Scheme 4
(9) (a) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron 1997,
53, 10229. (b) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh,
T.; Terashima, S. Tetrahedron 1997, 53, 10239. (c) Katoh, T.; Nagata, Y.;
Yoshino, T.; Nakatani, S.; Terashima, S. Tetrahedron 1997, 53, 10253.
(10) (a) Judd, T. C.; Williams, R. M. Angew. Chem., Int. Ed. 2002, 41,
4683. (b) Judd, T. C.; Williams, R. M. J. Org. Chem. 2004, 69, 2825.
(11) (a) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukuyama, T. Angew.
Chem., Int. Ed. 2002, 41, 4686. (b) Suzuki, M.; Kambe, M.; Tokuyama,
H.; Fukuyama, T. J. Org. Chem. 2004, 69, 2831.
(12) Fellows, I. M.; Kaelin, D. E.; Martin, S. F. J. Am. Chem. Soc. 2000,
122, 10781.
(13) Paleo, M. R.; Aurrecoechea, N.; Jung, K. Y.; Rapoport, H. J. Org.
Chem. 2003, 68, 130.
(14) Ducray, R.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2002, 41, 4688.
(15) Trost, B. M.; Aponick, A. J. Am. Chem. Soc. 2006, 128, 3931.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(17) Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am. Chem. Soc.
1990, 112, 6959.
(18) (a) Dmitrienko, G. I.; Denhart, D.; Mithani, S.; Prasad, G. K. B.;
Taylor, N. J. Tetrahedron Lett. 1992, 33, 5705. (b) Mithani, S.; Drew, D.
M.; Rydberg, E. H.; Taylor, N. J.; Mooibroek, S.; Dmitrienko, G. I. J. Am.
Chem. Soc. 1997, 119, 1159.
(19) (a) Ziegler, F. E. Belema, M. J. Org. Chem. 1994, 59, 7962. (b)
Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62, 1083.
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