Syntheses and stereochemical revision of pseudopterosin G - J aglycon and helioporin E

Article abstract of DOI:10.1021/ol006192k

(equation presented) Revised structures are proposed for pseudopterosin G - J aglycon and helioporin E.

Full text of DOI:10.1021/ol006192k

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2389-2392
Syntheses and Stereochemical Revision
of Pseudopterosin G−J Aglycon and
Helioporin E
Scott E. Lazerwith, Ted W. Johnson, and E. J. Corey*
Department of Chemistry and Chemical Biology HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received June 12, 2000
ABSTRACT
Revised structures are proposed for pseudopterosin G−J aglycon and helioporin E.
We recently reported an especially simple and direct route
for the synthesis of antiinflammatory pseudopterosins such
as pseudopterosin A (1) and pseudopterosin E (2) from
inexpensive (S)-(-)-limonene.1 The synthetic strategy used
involved an aromatic annulation process to form the ben-
zenoid ring and a cationic cyclization to generate the third
ring of the aglycon intermediate 3.2
(1) Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777.
(2) For other synthetic routes to the pseudopterosin family, see: (a)
Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53, 1584. (b)
Corey, E. J.; Carpino, P. J. Am. Chem. Soc. 1989, 111, 5472. (c) Corey, E.
J.; Carpino, P. Tetrahedron Lett. 1990, 31, 3857. (d) McCombie, S. W.;
Cox, B.; Lin, S.-I.; Ganguly, A. K.; McPhail, A. T. Tetrahedron Lett. 1991,
32, 2083. (e) McCombie, S. W.; Ortiz, C.; Cox, B.; Ganguly, A. K. Synlett
1993, 541. (f) Buszek, K. R. Tetrahedron Lett. 1995, 36, 9125. (g) Buszek,
K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129. (h) Gill, S.; Kocienski,
P.; Kohler, A.; Pontiroli, A.; Qun, L. J. Chem. Soc., Chem. Commun. 1996,
1743. (i) Majdalani, A.; Schmalz, H.-G. Tetrahedron Lett. 1997, 38, 4545.
(j) Majdalani, A.; Schmalz, H.-G. Synlett 1997, 1303. (k) Kato, N.; Zhang,
C.-S.; Matsui, T.; Iwabachi, H.; Mori, A.; Ballio, A.; Sassa, T. J. Chem.
An interesting discovery made during this study was the
finding that either the pseudopterosin A-F system or the
Soc., Perkin Trans. 1 1998, 2475.
(3) In these cases, the peak shapes are similar broad doublets with
couplings of approximately 9 Hz.
(4) 3 arises from the deprotection of 6 (see ref 1).
(8) For isolation and original structural determination of the helioporins,
see: Tanaka, J.-i.; Ogawa, N.; Liang, J.; Higa, T.; Gravalos, D. G.
Tetrahedron 1993, 49, 811. For structural revision of helioporin C and D,
see: (a) Geller, T.; Schmalz, H.-G.; Bats, J. W. Tetrahedron Lett. 1998,
39, 1537. (b) Ho¨rstermann, D.; Schmalz, H.-G.; Kociok-Ko¨hn, G. Tetra-
hedron 1999, 55, 6905.
(5) 15 arises via the deprotection of 7 (see Schemes 2 and 3 below).
(6) Roussis, V.; Wu, Z.; Fenical, W.; Strobel, S. A.; Van Duyne, G. D.;
Clardy, J. J. Org. Chem. 1990, 55, 4916.
(7) Pseudopterosins G-J were originally assigned to be C(7) diastere-
omers of pseudopterosins A-F by NOE experiments. See ref 6.
10.1021/ol006192k CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

C(1)-diastereomeric analogues could be accessed depending
on the intermediate used for the cationic closure of the third
ring. As shown in Scheme 1, ring closure of mesylate 4
Scheme 1
Figure 1. Spectral comparison of pseudopterosin A-F aglycon
3, pseudopterosin G-J aglycon 15, and monomethylated aglycon
14 derived from pseudopterosin I (1H NMR, 500 MHz, CDCl3).
produced the pseudopterosin A-F system (6), whereas
cyclization of the corresponding tert-butyldimethylsilyl ether
5 afforded selectively the C(1)-diastereomeric product 7.
These results are readily understood in terms of two
different reaction pathways. In the synthesis of 6, the six-
membered ring is likely formed by direct electrophilic attack
by the intermediate allyl cation 8 on the benzenoid ring at
the carbon para to benzyloxy. On the other hand, the
transformation 5 f 7 probably occurs from 8 via the spiro
Careful comparisons of the 1H NMR data in Figure 1 for
3 and 15 with the data reported for pseudopterosins G-J6
suggested that these pseudopterosins might correspond
stereochemically to 15.7 This hypothesis is consistent with
recent synthetic work by Schmalz and co-workers which
showed that the stereochemistry of at least two members of
the helioporins, a class of biologically active diterpenoids,
were similarly misassigned at C(7).8 These discoveries left
the stereochemical configurations of both helioporin A and
helioporin E ambiguous. Analysis of the 1H NMR spectrum
reported for helioporin E (11) suggested that it too might
correspond stereochemically with 15.
1
intermediate 9. The H NMR spectra of 6 and 7 display a
few small but characteristic differences with respect to the
protons attached to C(1) and C(14). As expected, the
pseudoaxial C(1) proton in 7 shows large couplings and
resembles a broad doublet of doublets. In contrast, the
pseudoequatorial C(1) proton in 6 shows small couplings
and appears as a compressed multiplet. In addition, the proton
attached to C(14) has a chemical shift of 4.97 ppm in 7,
whereas the corresponding C(14) proton in 6 appears at 5.11
ppm.3 These differences are especially apparent from the 1H
NMR data for the fully deprotected cyclization products,
aglycons 34 and 155 as shown in Figure 1.
To test these proposals, cyclization product 7 was con-
verted into its monomethyl ether 14 by the following
sequence: (1) desilylation using Bu4NF in THF, (2) careful
preparative TLC purification to give phenol 12 in >25:1
purity at C(1), (3) alkylation of the C(10) oxygen using
methyl iodide under phase-transfer conditions, and (4)
treatment with lithium di-tert-butylbiphenylide (LDBB)9 to
effect debenzylation (i.e. 12 f 13 f 14, Scheme 2).
1
In this paper we show that these H NMR data, which
When monomethyl ether 14 prepared in this way was
compared with the corresponding methylated aglycon derived
from pseudopterosin I,10 the samples were found to be
clearly distinguish the known structures 3 and 15, allow a
reassignment of stereochemistry to the previously reported
pseudopterosins G-J6,7 and also helioporin E.8 The aglycon
corresponding to these previously reported structures for
pseudopterosins G-J, which is pictured as 10 in Figure 2,
differs from the pseudopterosin A-F aglycon 3 at the C(7)
stereocenter. Similarly, the structure previously ascribed to
helioporin E (formula 11 in Figure 2) also differs from 3
with regard to configuration at C(7).
(9) Shimshock, S. J.; Waltermire, R. E.; DeShong, P. J. Am. Chem. Soc.
1991, 113, 8791.
(10) A natural sample of pseudopterosin I was generously donated by
Professor William Fenical. It was converted into its methylated aglycon by
(1) treatment with methyl iodide and potassium carbonate in hot acetone
to afford a mixture of methylated products (arising from acetyl migration
in the sugar portion of the molecule) and (2) deglycosylation with HCl
(aq) in methanol. See ref 6.
Figure 2. Originally reported structures for the pseudopterosin G-J
aglycon 10 and helioporin E (11).
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Org. Lett., Vol. 2, No. 15, 2000

the revised structure of helioporin E (16 as shown in Scheme
3) also differs at both C(1) and C(7) as compared with the
reported structure (see Figure 2).16
Scheme 2
Finally, to provide conclusive proof for the stereochemical
reassignment for both pseudopterosin G-J aglycon 15 and
helioporin E (16), the p-bromobenzoate 17 of synthetic
intermediate phenol 12 was prepared, crystallized,17 and
subjected to analysis which unambiguously yielded the
structure shown in Figure 3.18
identical by 1H NMR, 13C NMR, FTIR, and high-resolution
mass spectroscopy.11 Thus, the tricyclic core of pseudopterosins
G-J must correspond stereochemically with cyclization
product 7 and are not diastereomeric at C(1) and C(7) as
1
reported (see Figure 2).12 The H NMR spectrum for the
naturally derived version of monomethyl ether 14 is dis-
played in Figure 1 above. Its correspondence with synthetic
aglycon 15 is evident.
Figure 3. X-ray crystal structure of p-bromobenzoate 17.
The original stereochemical assignment of helioporin E
wasbasedprimarilyonspectralcomparisonswithpseudopterosins
G-J,13 which implies that helioporin E had been similarly
misassigned. To prove this, phenol 12 was converted into
the corresponding acetal 16 (Scheme 3). This was ac-
To summarize, by exploiting the versatile acid-catalyzed
cyclization of dienes such as 4 and 5, selective syntheses of
both pseudopterosin G-J aglycon 15 and the potent cytotoxic
agent helioporin E (16) were accomplished. These syntheses
provided the first compelling evidence that these compounds
are diastereomeric at C(1) relative to the pseudopterosins
A-F, not at C(7) as originally reported. Thus, the stereo-
chemical configurations of pseudopterosin G-J aglycon and
helioporin E are best represented by 15 and 16.
Scheme 3
It is possible that the reported structure (18, Figure 4) for
complished by boron tribromide-mediated debenzylation of
12 to give pseudopterosin G-J aglycone 15, which was
methylenated with methylene chloride and cesium fluoride
in DMF at 110 °C for 45 min14 to produce the desired acetal
1
16, which was found to be identical to helioporin E by H
NMR, FTIR, and high-resolution mass spectroscopy.15 Thus,
Figure 4. Revised structures for the pseudopterosin G-J aglycon
15 and helioporin E (16) and the reported structure for pseudopterox-
azole 18.
(11) Synthetic methyl ether 14: [R]2D5 +90 (c 0.05, CHCl3). Methyl
ether 14 derived from pseudopterosin I: [R]2D5 +98 (c 0.050, CHCl3).
(12) Professor Fenical and co-workers independently discovered indirect
evidence for this stereochemical reassignment, but lacked experimental proof
(personal communication).
the related natural product pseudopteroxazole19 may also
require revision in line with 15 and 16. Synthetic studies
are ongoing in this laboratory to shed light on this matter.
(13) Stereochemical assignments for pseudopterosins G-J were made
by NOE. See ref 6.
(14) Clark, J. H.; Holland, H. L.; Miller, J. M. Tetrahedron Lett. 1976,
38, 3361.
(15) We are grateful to Professor Tatsuo Higa for copies of the 1H NMR
spectrum of helioporin E (16).
(16) A similar reassignment was hypothesized by Schmalz and co-
workers. See ref 8b.
Org. Lett., Vol. 2, No. 15, 2000
2391

Acknowledgment. This research was assisted financially
by a graduate fellowship from the Eli Lilly Corporation
(S.E.L.) and postdoctoral fellowship from the National
Institutes of Health (T.W.J.) as well as a grant from the
National Science Foundation. Also, special thanks are
extended to Eduardo J. Martinez for solving the crystal
structure of 17 and to Professor Fenical for his help and
advice.
(17) p-Bromobenzoate 17 was prepared from phenol 12 by treatment
with excess p-bromobenzoyl chloride and DMAP in CH2Cl2, followed by
preparative TLC purification. Recrystallization from methanol afforded
X-ray quality crystals, mp 140-144 °C.
(18) Detailed X-ray crystallographic data are available from the Cam-
bridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ,
U.K.
Supporting Information Available: Experimental pro-
cedures and spectral characterization for compounds 7 and
12-17. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Rodr´ıguez, A. D.; Ram´ırez, C.; Rodr´ıguez, I. I.; Gonza´lez, E. Org.
Lett. 1999, 1, 527.
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