Enantioselective Total Synthesis of Batzelladine F
A R T I C L E S
Scheme 1
Scheme 2
was incorrect, leading to a new proposal for the structure of
batzelladine F (Section V). In the following contribution, we
detail our synthesis of this new structure, and studies that define
all aspects of the structure of batzelladine F.9
which had been defined by total synthesis.5,6 The configuration
of the left-hand tricyclic portion (C1 through C9) was assigned
on the basis of NOE data.7 The length of the nonyl chain at
C25, and the length of the chain connecting the tricyclic
guanidines were assigned by MS fragmentation patterns, but
this analysis was not discussed, nor were the data presented.
There was no information that related the relative configurations
of the two tricyclic guanidine fragments, specified the config-
uration at C16, or defined the absolute configuration.
Results and Discussion
I. Synthesis of 2a,8a-Anti-decahydrotriazaacenaphthalenes
Corresponding to the Originally Proposed Structure of
Batzelladine F. Believing that both tricyclic guanidine frag-
ments of batzelladine F possessed the same anti relationship
between the angular hydrogens at carbons 4 and 7, and carbons
20 and 23 (batzelladine numbering), we conceived of a divergent
strategy that would allow us to construct each half of the
molecule from a common intermediate. We chose the ester bond
as a logical first disconnection, thus, generating alcohol 5 and
acid 6 as synthetic objectives. Each of these intermediates was
conceived as arising from an intermediate such as 7a or 7b,
which differ in the side chain at C9. Employing a disconnection
developed during our total synthesis of batzelladine D,6
intermediates 7a and 7b were simplified to a common precursor
8 bearing a masked aldehyde that would allow for attachment
of different side chains by olefination reactions. Anti amino
alcohol 8 was seen as arising from â-hydroxy ester 9.
The preparation of common intermediate 8 began with
Weinreb amide 10,10 to which Grignard reagent 1111 was added
to afford â-hydroxy ketone 12 in 76% yield (Scheme 2). This
intermediate was subjected to Evans’ variant of the Tishchenko
reduction to set the 1,3-stereorelationship and differentiate the
hydroxyl groups of the resulting 1,3-diol.12 In this way,
monoprotected diol 13 was obtained in 92% yield from ketone
precursor 12 as a single stereoisomer. Nitrogen was installed
In 1999, Snider and Murphy independently published syn-
theses of tricyclic guanidines related to the left-hand portion of
batzelladine F that have a syn relationship of the methine
hydrogens flanking the pyrrolidine nitrogen.8 The 13C NMR data
of these analogues supported a revision of the configuration of
the natural product at C4 and C7 from anti to syn. However,
rigorous verification of this proposal would require the synthesis
of a related anti-fused tricyclic guanidine and the demonstration
that its spectra were distinct from those of the natural product.
In this contribution, we first describe our synthesis of 2a,-
8a-anti tricyclic guanidines corresponding to the originally pro-
posed relative configuration of these units of batzelladine F and
proof that the original configurational assignment of the left-
hand guanidine fragment of this alkaloid was incorrect (Section
I). We then describe our preparation of analogous 2a,8a-syn
tricyclic guanidines (Section II) and the evolution of our strategy
for the total synthesis of linked tricyclic guanidines correspond-
ing to the proposed constitution and revised relative configu-
ration of batzelladine F (Sections III-IV). We then demonstrate
that the originally reported connectiVity of the natural product
(5) Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A. J. Tetrahedron Lett. 1996,
37, 6977-6980.
(9) (a) Our synthesis of the natural product has been outlined: Cohen, F.;
Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782-10783. (b) Cohen,
F.; Overman, L. E. J. Am. Chem. Soc. 2006, 128, 2604-2608.
(10) Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Stappenbeck, F. J. Am.
Chem. Soc. 1999, 121, 6944-6945.
(11) Lee, T. V.; Porter, J. R. Org. Synth. 1995, 72, 189-195.
(12) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-6449.
(6) Cohen, F.; Overman, L. E.; Sakata, S. K. L. Org. Lett. 1999, 1, 2169-
2172.
(7) These data were not presented in the paper or the Supporting Information.
(8) (a) Snider, B. B.; Busuyek, M. V. J. Nat. Prod. 1999, 62, 1707-1711. (b)
Black, G. P.; Murphy, P. J.; Thornhill, A. J.; Walshe, N. D. A.; Zanetti, C.
Tetrahedron 1999, 55, 6547-6554.
9
J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006 2595