Scheme 1. Retrosynthesis Analysis for Dragmacidin E
Scheme 2. Key Witkop/Dieckmann Sequence To Fashion the
Cycloheptannelated Indole Core
proximity, and so, not surprisingly, irradiation of a 5.0 mM
solution of 8 in CH3CN led to reasonably efficient conversion
into the C(4)-cyclized species 9. Yields in the Wipkop
procedure rarely exceed 50%, and it is possible that the added
benefit of a second radical stabilizing chloride within 8
contributed to the relatively higher yield with this substrate.
Presumably, an unobserved intermediate C(5′′′)-methyl,
-chloride-bearing species is formed en route to 9, but a
second photochemically mediated dehydrochlorination in-
tervenes to deliver the alkene of the product. Similar
chemistry has been reported in related systems.5c Conversion
of the cyclooctanoid skeleton of 9 into the carbocyclic
cycloheptanoid bridge of the target occupied a second pivotal
role in the synthesis strategy. Although several routes could
be envisioned, after much experimentation, an efficient and
scalable sequence, which featured treatment of an N-BOC
derivative of the enone 9 with a hydride source, was
identified. Presumably, the unobserved enolate 10, derived
from conjugate addition of [H-], played a central role in this
transformation. Dieckmann closure into the proximal ester
moiety then completes the preparation of 11. This Dieckmann
cyclization lacks the usually cited driving force associated
with high-yielding conversion (deprotonation of an acidic
product), but it likely benefits from relief of steric compres-
sion as the endo-disposed ester unit is incorporated into the
molecular framework. The imide BOC group is cleaved
during this transformation, but it can be readily reinstalled
in the next step. An alternative route to 11, which involved
initial hydrogenation of the alkene within the N-BOC
derivative of 9 to afford an R-methyl ketone and then
treatment with base, was explored briefly but offered no
advantage.
attempts to prepare lower homologues largely met with
failure.5b Thus, application of this useful C(4) functional-
ization reaction to the dragmacidin E problem would require
some modification or extension of the basic transform in
order to secure the desired cycloheptannelated structure of
1.
This line of reasoning led to the retrosynthesis shown in
Scheme 1, wherein dragmadicin E (1) was envisioned to
derive from a cyclocondensation between aminoketone 2 and
the ketoamide 3. The aminoketone 2 embodies appropriate
functionality and stereochemistry along its periphery to
deliver the requisite guanidine unit of the natural product.
The C(6′′′) quaternary center of 2 might be introduced by
formal Strecker chemistry on the ketone within 4, the pivotal
cycloheptannelated indole intermediate. In the key sequence
of a projected synthesis of 2, this cycloheptane ring might
originate from an unusual Dieckmann cyclization within the
cyclooctanoid construct 6, an obvious target for Witkop
photocyclization chemistry.
Synthesis of the model dragmacidin E tetracycle 18
commenced with the dichloroamide derivative 8 of tryp-
tophan methyl ester, available by simple acylation of the
parent amine (97%) (Scheme 2). This Witkop reaction
substrate contains both the N-unprotected indole electron
donor unit and chlorocarbonyl electron acceptor in close
(5) (a) Beck, A. L.; Mascal, M.; Moody, C. J.; Slawin, A. M. Z.;
Williams, D. J.; Coates, W. J. J. Chem. Soc., Perkin Trans. 1 1992, 797-
811. (b) Beck, A. L.; Mascal, M.; Moody, C. J.; Coates, W. J. J. Chem.
Soc., Perkin Trans. 1 1992, 813-820. (c) Mascal, M.; Moody, C. J.; Slawin,
A. M. Z.; Williams, D. J. J. Chem. Soc., Perkin Trans. 1 1992, 823-830.
(6) (a) Nagata, R.; Endo, Y.; Shudo, K. Chem. Pharm. Bull. 1993, 41,
369-372. (b) Mascal, M.; Moody, C. J.; Morrell, A. I.; Slawin, A. M. Z.;
Williams, D. J. J. Am. Chem. Soc. 1993, 115, 813-814. (c) Mascal, M.;
Wood, I. G.; Begley, M. J.; Batsanov, A. S.; Walsgrove, T.; Slawin, A. M.
Z.; Williams, D. J.; Drake, A. F.; Siligardi, G. J. Chem. Soc., Perkin Trans.
1 1996, 2427-2433. (d) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.; Bosch,
J. Heterocycles 1996, 43, 1959-1966. (e) Ruchkina, E. L.; Blake, A. J.;
Mascal, M. Tetrahedron Lett. 1999, 40, 8443-8445. (f) Bremner, J. B.;
Russell, H. F.; Skelton, B. W.; White, A. H. Heterocycles 2000, 53, 277-
296.
Two more operations of note were required to process 11
into 18: (1) installation of the spiroimidazolone ring at C(6′′′)
and (2) scission of the imide bridge. A priori, it was not
clear if any benefit attended sequencing step (1) before step
(2) or vice versa, and so the former course was selected for
study first (Scheme 3). The bridging amide 11 could be
5450
Org. Lett., Vol. 7, No. 24, 2005