An approach to the total synthesis of the marine ascidian metabolite perophoramidine via a halogen-selective tandem heck/carbonylation strategy

Article abstract of DOI:10.1021/ol034314d

(Matrix presented) A halogen-selective tandem intramolecular Heck/carbonylation reaction has been developed for the construction of the C,E,F-ring system and the C20 quaternary center found in perophoramidine (1). This process can be effected in good yiel

Full text of DOI:10.1021/ol034314d

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1523-1526
An Approach to the Total Synthesis of
the Marine Ascidian Metabolite
Perophoramidine via a
Halogen-Selective Tandem Heck/
Carbonylation Strategy
Gerald D. Artman III and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
Received February 21, 2003
ABSTRACT
A halogen-selective tandem intramolecular Heck/carbonylation reaction has been developed for the construction of the C,E,F-ring system and
the C20 quaternary center found in perophoramidine (1). This process can be effected in good yields in the presence of both the chlorine and
bromine atoms found in the natural product. In addition, it is possible to introduce the quaternary center at C4 in a stereoselective manner
by a lactone enolate alkylation, using NaH and allyl bromide.
Marine ascidians are a rich source of diverse natural products
that display a wide range of biological activity. A recent
investigation of the Philippine ascidian Perophora namei by
Ireland and co-workers resulted in the isolation of the
reversed between the two quaternary centers at C4,C20 for
perophoramidine (1) and C7,C13 for 2 and 3. A preliminary
1
metabolite perophoramidine (1).1 With use of H and 13C
NMR correlation experiments, a hexacyclic framework
containing three halogens, two amidine moieties, and two
adjacent quaternary centers was elucidated for the natural
product. Interestingly, perophoramidine (1) is structurally
similar to the previously reported communesin A (2) and B
(3).2-4 However, the relative stereochemical relationship is
(1) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.;
Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(2) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami,
Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett.
1993, 34, 2355.
(3) Recently, Hemscheidt and co-workers reported isolation of nomo-
fungin, whose structure was misassigned and which proved to be identical
to communesin B (2). (a) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S.
L.; Hemscheidt, T. K. J Org. Chem. 2001, 66, 8717. (b) Ratnayake, A. S.;
Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J Org. Chem. 2003,
68, 1640.
biological assay of 1 showed it to possess moderate cyto-
toxicity against the human carcinoma cell line HCT116 (IC50
) 60 µM). The inherent difficulties in constructing two
adjacent quaternary centers and a functionally complex ring
10.1021/ol034314d CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/08/2003

Scheme 1
system like that found in perophoramidine makes it a
found in 1. Although one would expect that oxidative
insertion of palladium into an aryl iodine bond would be
faster than that into aryl chlorine or bromine bonds, we were
unable to find any examples of an intramolecular Heck
reaction with this type of internal competition where different
types of halogens are present in the same molecule.9 In
addition, we needed to test the compatibility of a C ring ortho
substituent with our key transformation, and to investigate
the introduction of the second quaternary center at C4 with
the requisite stereochemistry.
We began our study by attempting a Heck/carbonylation
reaction in the presence of the two chlorines needed for the
F ring of 1 and an ortho C-ring methoxy substituent.10
Synthesis of two Heck precursors was initiated by a
stereoselective Wittig olefination between the known γ-lac-
tone ylide11 4 and o-anisaldehyde (5) to afford the meth-
oxybenzylidene lactone 6 in 98% yield exclusively as the E
isomer (Scheme 1).12 Ring opening of the lactone 6 with
the aluminum amide13 derived from commercially available
2,4-dichloro-6-iodoaniline (7) proceeded smoothly to give
the iodo acrylamide 8 in 95% yield. The primary alcohol
functionality of iodo acrylamide 8 was then converted to the
TBS ether 9 in 98% yield. The iodo amide 9 was N-alkylated
with MeI to give iodo N-methyl amide 10 and, to have a
removable protecting group, with MOMCl to give iodo
N-MOM amide 11 in good yields.
challenging synthetic target. In this Letter we report our
efforts toward a total synthesis of perophoramidine (1) via
a key halogen-selective tandem intramolecular Heck/carbo-
nylation sequence for the efficient construction of the C20
quaternary center and the C,E,F-ring system.
The Heck reaction has proven to be a powerful tool for
the coupling of aryl and vinyl halides with a variety of
olefins.5 In particular, Overman has extensively used the
intramolecular Heck reaction6 as a means to construct
quaternary centers and to control absolute stereochemistry
in such systems.7 Recently, tandem intramolecular Heck
reactions have been developed by removing the opportunity
for â-hydride elimination and thus the resulting palladium
intermediate can undergo subsequent coupling with organo-
stannanes, organoboronates, or carbon monoxide providing
entry to highly functionalized systems.8 Our synthetic
strategy for perophoramidine is based on effecting a tandem
Heck/carbonylation reaction in the presence of the halogens
(4) For a biogenetically patterned approach to the communesins, see:
May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203.
(5) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Heck, R. F. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, UK, 1991; Vol. 4, p 833. (c) Beletskaya, I. D.; Cheprakov,
A. V. Chem. ReV. 2000, 100, 3009. (d) Whitecombe, N. J.; Hii, K. K.;
Gibson, S. E. Tetrahedron 2001, 57, 7449. (e) Genet, J. P.; Savignac, M.
J. Organomet. Chem. 1999, 576, 305. (f) Amatore, C.; Jutard, A. J.
Organomet. Chem. 1999, 576, 254.
The key tandem Heck/carbonylation reaction was explored
by using Pd(OAc)2 as a palladium source, P(o-Tol)3 as a
ligand, Bu4NBr as an additive, and triethylamine as the base.
(6) For a recent review of the intramolecular Heck reaction, see: Link,
J. T. Org. React. 2002, 60, 157.
(7) (a) Oestrich, M.; Dennison, P. R.; Kodanko, J. J.; Overman, L. E.
Angew. Chem., Int. Ed. 2001, 48, 1439. (b) Ashimori, A.; Overman, L. E.
J. Synth. Org. Chem. Jpn. 2000, 58, 718. (c) Asimori, A.; Bachand, B.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 2000, 122, 192. (d) Link,
J. T.; Overman, L. E. CHEMTECH 1998, 28, 19. (e) Ashimori, A.; Bachand,
B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477. (f)
Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488. (g) Overman, L. E. Pure
Appl. Chem. 1994, 66, 1423.
(9) For a halogen-selective intermolecular Suzuki-Miyaura coupling
involving 1-bromo-3-chloro-5-iodobenzene, see: Hensel, V.; Schluter, A.
D. Eur. J. Org. Chem. 1999, 451 and references cited.
(10) This particular substituent was chosen based upon the putative
structure for nomofungin, which had not been retracted at the start of this
work.3
(8) (a) Grigg, R.; Millington, E. L.; Thornton-Pett, M. Tetrahedron Lett.
2002, 43, 2605. (b) Brown, S.; Clarkson, S.; Grigg, R.; Thomas, W. A.;
Sridharan, V.; Wilson, D. M. Tetrahedron 2001, 57, 1347. (c) Anwar, U.;
Casaschi, A.; Grigg, R.; Sansano, J. M. Tetrahedron 2001, 57, 1361. (d)
de Meijere, A.; Bra¨se, S. J. Organomet. Chem. 1999, 576, 88. (e) Poli, G.;
Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959. (f) Negishi,
E.; Ma, S.; Amanfu, J.; Cope´ret, C.; Miller, J. A.; Tour, J. M. J. Am. Chem.
Soc. 1996, 118, 5919.
(11) (a) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron
1992, 48, 9373. (b) McCort, G.; Hoornaert, C.; Aletru, M.; Denys, C.;
Duclos, O.; Cadilhac, C.; Guilpain, E.; Dellac, G.; Janiak, P.; Galzin, A.-
M.; Delahaye, M.; Guilbert, F.; O’Connor, S. Bioorg. Med. Chem. 2001,
9, 2129.
(12) The E geometry of benzylidene lactone 6 was established by nOe
NMR experiments.
(13) Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1979, 59, 49.
1524
Org. Lett., Vol. 5, No. 9, 2003

Scheme 2
Scheme 3
The reactions were heated in a 2:1 mixture of DMA and
MeOH under a balloon atmosphere of CO. Acrylamides 8
and 9 were first exposed to the Heck conditions, but no
reaction occurred and only the starting amides were recov-
ered unchanged. We believe this lack of reactivity is due to
a low population of the rotamer needed for the initial Heck
reaction to occur. On the other hand, the iodo N-methyl
amide 10 readily cyclized under these conditions to yield
the desired N-methyl lactam 12 in 74% yield (Scheme 2).
Similarly, the iodo N-MOM amide 11 also underwent the
desired Heck/carbonylation reaction to afford the N-MOM
lactam 13 in slightly better yield. Both lactams 12 and 13
were isolated as single diastereoisomers having the stereo-
chemistry shown (vide infra). This stereochemistry is the
result of a net syn addition of the aryl palladium intermediate
and CO across the E olefin. The N-methyl amide 12 was
converted to the lactone 14 by using TBAF/NH4F14 to first
remove the silyl protecting group followed by heating the
alcohol ester with TsOH in benzene to give the lactone in
80% yield as a 3:1 â/R mixture of C4 epimers. nOe
experiments established the conformation and configuration
of the major epimer of lactone 14 to be as shown.
Alternatively, using HCl in MeOH to remove the TBS group
from N-MOM amide 13, followed by heating with TsOH in
benzene, afforded MOM lactone 15 in 79% yield as a single
diastereoisomer. The conformation and configuration of 15
were proven by X-ray crystallography, where the lactone ring
exists as a half-chair with the lactam carbonyl in a pseudo-
axial position and the C4 methoxyarene in an equatorial
position (see Supporting Information).
olefination of the ylide 4 with 4-bromobenzaldehyde in 84%
yield (Scheme 3). Ring opening of the lactone 16 with iodo
aniline 7 in the presence of trimethyl aluminum afforded
acrylamide 17 in 67% yield. Conversion of the primary
alcohol functionality of acrylamide 17 to its TBS ether and
N-alkylation with MeI yielded the iodo N-methyl amide 18
in 65% overall yield. We were pleased to find that exposure
of the bromo iodo amide 18 to our optimized tandem Heck
conditions resulted in clean formation of the desired bromo
dichlorolactam 19 in 77% yield as a single stereoisomer. As
was done for Heck product 15, bromo dichlorolactam 19
was cyclized to the bromo lactone 20 in 80% yield as an
inseparable 5:1 â/R mixture of C4 epimers.
At this stage, the installation of the quaternary center at
C4 of perophoramidine (1) was explored. Alkylation of the
lactone 15 with various amide bases and allyl bromide at
room temperature in THF proved sluggish. However, using
NaH in DMF at 70 °C overnight resulted in the allylated
lactone 23 in 65% yield as a single diastereomer along with
a trace of starting material. Decoupling and nOe NMR
experiments (H3 vs H18 enhancement) showed that the
allylation product had the correct stereochemistry for pero-
phoramidine (1).
At this point we can only speculate as to the reasons for
this stereochemical outcome. Allylation of the two half-chair
forms of the enolates 21 and 22 might occur via axial attack
by the electrophile to afford the observed product 23 and
the C4 epimer 24, respectively. One possibility is that the
direction of attack in this slow allylation process reflects
product stability.15 In fact, calculations show 23 to be >2
We have also explored the feasibility of having a
potentially labile bromine present in the C ring of pero-
phoramidine (1) during the cyclization. To that end, we
prepared E-4-bromobenzylidene lactone 16 by a Wittig
(14) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817.
Org. Lett., Vol. 5, No. 9, 2003
1525

reasonable based on the X-ray structure of lactone 15, where
the distance between the oxygen lone pair and the lactone
carbonyl carbon is about 2.8 Å, and the corresponding angle
is approximately 110°.
Scheme 4
In conclusion, we have developed an efficient approach
to the synthesis of perophoramidine (1) via a halogen-
selective tandem Heck/carbonylation sequence. We have
demonstrated that the presence of the chlorines and bromine
atoms and an ortho C ring substituent do not adversely affect
the desired transformation. In addition, we have shown that
the second quaternary center at C4 can be introduced in a
stereoselective manner providing the requisite stereochem-
istry for the metabolite. Application of this strategy to a total
synthesis of perophoramidine (1) is underway.
Acknowledgment. We are grateful to the National
Institutes of Health (CA-34303) for financial support of this
research, Professor Ray Funk for many helpful discussions,
and Dr. Hemant Yennawar for the crystal structure of lactone
15. We also wish to acknowledge NSF grant CHE-0131112
for the purchase of an X-ray diffractometer.
Supporting Information Available: Experimental pro-
cedures for preparation of new compounds including spectral
data, and X-ray data for compound 15 in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034314D
(15) Evans, D. A. Stereoselective Alkylation Reactions of Chiral Metal
Enolates. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press:
New York, 1983; Vol. 3, p 28.
(16) Molecular modeling calculations were performed with Serena
Software PC Model 7.5.
(17) The boat conformers resulting from “equatorial” allylation of the
enolates 21 and 22 were considerably higher in energy.
(18) (a) Bu¨rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973,
95, 5065. (b) Bu¨rgi, H. B.; Lehn, J. M.; Wipff, G. J. Am. Chem. Soc. 1974,
96, 1956. (c) Bu¨rgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron
1974, 30, 1563. See also: (d) Nishide, K.; Hagimoto, Y.; Hasegawa, H.;
Shiro, M.; Node, M. Chem. Commun. 2001, 2394.
kcal/mol more stable than 24.16,17 In addition, allylation
product 23 may gain additional stabilization via a Bu¨rgi-
Dunitz interaction18 between a lactam oxygen lone pair and
the π* orbital of the lactone carbonyl group, which is not
possible in isomer 24. This type of interaction seems
1526
Org. Lett., Vol. 5, No. 9, 2003