A novel face specific Mannich closure providing access to the saframycin-ecteinascidin series of piperazine based alkaloids

Article abstract of DOI:10.1016/S0040-4039(00)00106-4

The Mannich-like closure of 10→6 directly provides the backbone stereochemistry required for the titled alkaloids, in contrast to the stereochemical outcome in a related earlier case (3→4). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00106-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2043–2046
A novel face specific Mannich closure providing access to the
saframycin-ecteinascidin series of piperazine based alkaloids
Bishan Zhou,a Jinsong Guo a and Samuel J. Danishefsky a,b,∗
aThe Department of Chemistry, Columbia University, Havemeyer Hall, New York, NY 10027, USA
bThe Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Ave., New York,
NY 10024, USA
Received 7 July 1999; revised 17 December 1999; accepted 19 December 1999
Abstract
The Mannich-like closure of 10→6 directly provides the backbone stereochemistry required for the titled
alkaloids, in contrast to the stereochemical outcome in a related earlier case (3→4). © 2000 Elsevier Science
Ltd. All rights reserved.
In the previous letter1 we described the synthesis of two building blocks (vide infra) which would
be merged and interlocked as part of a synthetic entry to the saframycin series antibiotic antitumor
alkaloids (see representative structures 2, Scheme 1).2 Our underlying targets in this program are the
ecteinascidins,3 a family of highly potent cytotoxic agents (see representative ET structure 1). The total
synthesis of 1 by Corey and co-workers was the first and only synthesis of an ecteinascidin.4
In addition to the incentives for total synthesis, driven by the novel structures and highly potent
antitumor properties of ET (1),5 another interest in the group of piperazine based alkaloids arose from
our total synthesis of quinocarcinol 5.6 The key to that construction, conducted long before the ET series
was known, was a Mannich-like envelopment strategy (see 3→4). In proposing to apply that lesson to the
ET-saframycin family, we were not unaware that the anti backbone relationship between C3 and C11 in
4, produced from 3, required a stereochemical correction to reach the syn series of quinocarcinol. Such a
C3–C11 syn relationship also pertains in 1 and 2. We set as our goal compound 6. In doing so, we would
be revisiting the question of the reasons for the outcome of the backbone stereochemistry in the Mannich
closure sequence.
Coupling of 7 and 8 via amide bond formation was accomplished through the action of BOPCl,7
as shown, in 60–65% yield (Scheme 2). Oxidation of the diastereomeric alcohol functions gave rise to
9 (75–80%) as a homochiral entity. To set the stage for the envisaged annulation, it was necessary to
expose the aryl aldehyde function from its protected benzyl alcohol precursor. Following deprotection
and oxidation, the homochiral 10, bearing the strategic aldehyde,8 was in hand.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00106-4
tetl 16385

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Scheme 1.
Scheme 2. (a) 1.1 equiv. BOPCl, 2.5 equiv. Et3N, CH2Cl2, 10 h, 63%; (b) 1.5 equiv. Dess–Martin periodinate, CH2Cl2, 30 min,
78%; (c) 1.5 equiv. DDQ, CH2Cl2–buffer 7.0–H2O (20:1:1), 3 h, 84%; (d) 2 equiv. NMO, cat. TPAP, m.s. 4 Å, CH2Cl2, 30 min,
84%; (e) formic acid, reflux, 10 h, 75% for 6, 17% for 11; (f) formic acid, reflux
In the event, exposure of compound 10 to the action of formic acid accomplished cleavage of the
tBoc group, thereby triggering Mannich-like double closure to produce 6 (75%) and 11 (17%). These
products differ only in the ‘solvolytic’ state of the primary center. In a subsequent step, 6 was converted
to 11. Characterization of 6 and 11 by extensive NMR measurements (including COSY, ROESY,
HMQC and HMBC techniques) established an unexpected and most welcome result. Not only had
cyclization occurred, but also the piperazinone ring had been elaborated with the syn C3–C11 backbone
stereochemical relationship required for 1 and 2.9
It is appropriate to conjecture about the strikingly different outcome in the seemingly similar ring
closure steps of 3→4 and 10→6 (Scheme 3). We focus on the hypothetical iminium ions 13 and 15 which
presumably appear in the two progressions. In each case, the system has been programmed such that

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attack of the nucleophile can only occur from one face of the iminium electrophile (β-as drawn). The
interesting issue arises with respect to the stereochemistry of the reaction of the nucleophile. If the enol
is attacked from its α-face, the anti backbone will be produced (cf. 3→4). Alternatively, attack from the
β-face of the enol would give rise to a syn backbone product (10→6).
Scheme 3.
Aside from issues of steric hindrance, there is a potentially important stereoelectronic consideration. In
modeling the closure reaction, it is seen that the coplanarity of the amide substituents can be maintained
only if the enol is attacked from its β-face. By contrast, attack at the α-face of the enol seems to require
rotation about the amide in the direction of orthogonalization. From this perspective the syn backbone
cyclization product would be expected (see stereostructure 15, which leads to 6).
Comparable modeling soon reveals that in the case of hypothetical stereostructure 14, which could
also arise from 3, attack at the β-face of the enol, though favored from the perspective of maximal
maintenance of amide coplanarity, would incur a serious steric interaction between ring B and the two
carbon bridge. This hindrance would be compounded by a particularly close abutment between the β-
disposed vinyl and carbomethoxy groups if cyclization leading to the hypothetical 16 were to ensue.
Hence, 4 rather than 16 is produced. By contrast, in 15, where the six-membered iminium ring contains
two additional sp2 centers, the steric problems arising from the emerging syn backbone bridged system
are perhaps reduced. In summary, it is proposed that cyclization of 10 (by way of stereostructure 15) is
governed by the stereoelectronic factor (maintenance of amide coplanarity), while cyclization of 3 (by
way of stereostructure 13), is dictated by an overriding steric hindrance effect, leading to 4.
Research directed to testing our proposal on the interplay of the stereoelectronic and steric effects that

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govern the critical Mannich step is ongoing in the context of our total synthesis and analog construction
programs.10
Acknowledgements
This work was supported by the National Institutes of Health (Grant Nos CA-28824 and HL-25848
(S.J.D.). B.Z. gratefully acknowledges the Pharmacia-Upjohn Corporation for a predoctoral Fellowship.
We thank Vinka Parmakovich and Barbara Sporer (Columbia University) for mass spectral analyses.
Dedication. We dedicate this paper to Professor E. J. Corey and co-workers for their groundbreaking
synthesis of Ecteinascidin 743 and for bringing this problem to our attention.
References
1. Zhou, B.; Edmondson, S.; Padron, J.; Danishefsky, S. J. Tetrahedron Lett. 2000, 41, 2039.
2. (a) Arai, T.; Takahashi, K.; Kubo, A. J. Antibiot. 1977, 30, 1015. (b) Arai, T.; Takahashi, K.; Ishiguro, K.; Mikami, T. Gann.
1980, 71, 790.
3. Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, A. Proc. Natl. Acad. Sci. USA 1992, 89, 11456.
4. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202.
5. For recent reviews, see: (a) Pommier, Y.; Kohlhagen, G.; Bailly, C.; Waring, M.; Mazumder, A.; Kohn, K. Biochemistry
1996, 35, 13303. (b) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc. Natl. Acad. Sci. USA 1999, 96, 3496.
6. Danishefsky, S. J.; Harrison, P. J.; Webb, R. R.; O’Neill, B. T. J. Am. Chem. Soc. 1985, 107, 1421.
7. Cabre-Castellvi, J.; Polomo-Coll, A.; Palomo-Coll, A. C. Synthesis 1981, 616.
8. Attempts to reach 6 by means of a 3-point attachment of a formic acid equivalent were unsuccessful. Only with the aromatic
aldehyde in place was cyclization realized.
9. The stereochemistry assigned to 6 and 11 was verified by a crystallographic determination at a later stage of the synthetic
sequence.
10. Subsequent studies reveal that the stereochemical outcome of the Mannich closure step is also a function of the substitution
pattern on the aldehyde-containing aromatic ring that enters into the cyclization event. These matters will be discussed in a
fuller treatment of the subject.