Stereoselective synthesis of the ABC ring system of norzoanthamine

Article abstract of DOI:10.1021/ol036492c

(Equation presented) An efficient synthesis of enone 4, representing the ABC ring motif of norzoanthamine, is presented. The crucial C22 quaternary center was introduced via a stereoselective methylation of enone 8. The trans-anti-trans relative configura

Full text of DOI:10.1021/ol036492c

ORGANIC
LETTERS
2
004
Vol. 6, No. 6
41-944
Stereoselective Synthesis of the ABC
Ring System of Norzoanthamine
9
Subhash Ghosh, Fatima Rivas, Derek Fischer, Miguel A. Gonz a´ lez, and
Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@chem.ucsd.edu
Received December 23, 2003
ABSTRACT
An efficient synthesis of enone 4, representing the ABC ring motif of norzoanthamine, is presented. The crucial C22 quaternary center was
introduced via a stereoselective methylation of enone 8. The trans-anti-trans relative configuration of the ABC framework of 4 was installed
via a sequence of reactions that included a hydroboration and a modified Robinson annulation.
The zoanthamine alkaloids constitute a distinctive family of
significantly, norzoanthamine (2) represents a promising
marine metabolites that have been isolated during the last
candidate for an antiosteoporotic drug due to its IL-6
inhibitory profile.
1
1,7
20 years from colonial zoanthids of the genus Zoanthus sp.
These natural products are characterized by a densely
functionalized and stereochemically rich framework, as
The combination of such challenging molecular architec-
tures and potent biological profiles has spurred the develop-
ment of novel synthetic strategies that rest primarily on
Diels-Alder cycloaddition reactions. Nevertheless, despite
such an effort none of these natural products has yet
2
exemplified by the structures of zoanthamine (1), norzoan-
3
4
8
thamine (2), and zoanthamide (3) (Figure 1), as well as by
5
a wide spectrum of interesting biological activities. For
example, compounds 1 and 3 were shown to inhibit phorbol
myristate acetate (PMA)-induced inflammation in mouse
ear,4 while 2 reportedly inhibits the growth of P-388 murine
,6
3
b
leukemia cells with an IC50 value of 24 µg/mL. More
(
1) For selected reviews on this topic, see: (a) Rahman, A.-U.;
Choudhary, M. I. In Alkaloids; Academic Press: New York, 1999; Vol.
2, pp 233-260. (b) Kuramoto, M.; Yamaguchi, K.; Tsuji, T.; Uemura, D.
5
Zoanthamines, Antiosteoporotic Alkaloids. In Drugs from the Sea; Fusetani,
N., Ed.; Karger: Basel, 2000; pp 98-106. (c) Yamada, K.; Kuramoto, M.;
Uemura, D. Rec. Res. DeVel. Pure Appl. Chem. 1999, 3, 245-254. (d)
Fern a´ ndez, J. J.; Souto, M. L.; Daranas, A. H.; Norte, M. Curr. Topics
Phytochem. 2000, 4 105-119.
(2) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M.; Faulkner, D. J.; Chen, M. H. M.; Clardy, J. J. Am. Chem.
Soc. 1984, 106, 7983-7984.
(3) (a) Kuramoto, M.; Hayashi, K.; Fujitani, Y.; Yamaguchi, K.; Tsuji,
T.; Yamada, K.; Ijuin, Y.; Uemura, D. Tetrahedron Lett. 1997, 38, 5683-
686. (b) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatsu, A.; Yamada,
K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207-214.
4) Rao, C. B.; Anjaneyulu, A. S. R.; Sarma, N. S.; Venkatateswarlu,
Y.; Rosser, R. M.; Faulkner, D. J. J. Org. Chem. 1985, 50, 3757-3760.
5
(
Figure 1. Selected structures of the zoanthamine alkaloids.
1
0.1021/ol036492c CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/12/2004

Scheme 1. Synthesis of Ketone 6a
Figure 2. Retrosynthetic analysis of fragment 4.
9
succumbed to a total synthesis. Herein we report a new
synthetic strategy for these natural products. Our approach
provides an efficient and stereoselective entry into the
tricyclic ABC ring system of these complex alkaloids
(
represented as 4, Figure 2) and paves the way toward their
a
Reagents and conditions: (a) 1.1 equiv of LDA, 1.5 equiv of
total synthesis.
1
2, -78 °C, 1 h, 72%; (b) Jones [O], 0-25 °C, 2 h, 60%; (c) 1.1
equiv of 10, 1 equiv of 9, 2.2 equiv of KF, MeOH, 25 °C, 24 h,
74%; (d) 0.25 equiv of NaBH , EtOH, 0.5 h, -78 °C, 90%; (e) 1.5
equiv of TBSCl, 3.0 equiv of NH
f) 1.1 equiv of t-BuOK, 5.0 equiv of CH
3
h, 68%; (g) 2 equiv of LiAlH
of 2,2-dimethoxypropane, 0.01 equiv of CSA, CH
C, 95%; (i) 1.5 equiv of BH
The retrosynthetic approach toward fragment 4 is shown
in Figure 2. We envisioned that construction of the fully
functionalized A ring of 4 could invoke conjugate reduction
of enone 5 followed by functionalization of the C15 and C17
centers (zoanthamine numbering). Enone 5 could be formed
from fragment 6, representing the BC ring system, by
4
4
NO
3
, DMF, 30 h, 0-25 °C, 99%;
I, benzene, 0-25 °C, 12
, THF, 0 °C, 2 h 85%; (h) 3.0 equiv
Cl , 0.5 h, 0-25
‚THF, THF, 24 h, 0 °C, 90% (3:2 in
(
4
2
2
°
3
10
implementing a Robinson annulation strategy. The trans
decalin motif of 6 was projected to arise from hydroboration/
favor of 15); (j) 3.0 equiv of MOMCl, 4.0 equiv of DIPEA, 0-25
°C, 24 h, 90%; (k) 2.0 equiv of TBAF, THF, 48 h, 50 °C, 95%; (l)
.0 equiv of IBX, CH Cl /DMSO (10:1), 48 h, 0-25 °C, 97%.
2 2
2
(
5) For other alkaloids of the zoanthamine family, see: Rahman, A.-U.;
Alvi, K. A.; Abbas, S. A.; Choudhary, M. I.; Clardy, J. Tetrahedron Lett.
989, 30, 6825-6828. Daranas, A. H.; Fern a´ ndez, J. J.; Gavin, J. A.; Norte,
1
oxidation of alkene 7 which, in turn, suggested enone 8 as
its synthetic precursor. The latter structure can be formed
by annealing 2-methyl-1,3-cyclohexanedione (9) with Naz-
M. Tetrahedron 1998, 54, 7891-7896. Nakamura, H.; Kawase, Y.;
Maruyama, K.; Murai, A. Bull. Chem. Soc. Jpn. 1998, 71, 781-787.
Venkateswarlu, Y.; Reddy, N. S.; Ramesh, P.; Reddy, P. S.; Jamil, K.
Heterocycl. Commun. 1998, 4, 575-580.
1
1
arov reagent (10). Herein, we disclose the results of our
studies based on such strategic bond disconnections.
Our synthetic studies commenced with construction of
enone 8, which was formed by a KF-induced condensation
of ketoester 10 with diketone 9 as previously described
(
6) Rao, C. B.; Rao, D. V.; Raju, V. S. N. Heterocycles 1989, 28, 103-
09.
7) Yamaguchi, K.; Yada, M.; Tsuji, T.; Kuramoto, M.; Uemura, D. Biol.
1
(
Pharm. Bull. 1999, 22, 920-928. Kuramoto, M.; Hayashi, K.; Yamaguchi,
K.; Yada, M.; Tsuji, T.; Uemura, D. Bull. Chem. Soc. Jpn. 1998, 71, 771-
7
79. Villar, R. M.; Gil-Longo, J.; Daranas, A. H.; Souto, M. L.; Fern a´ ndez,
J. J.; Peixinho, S.; Barral, M. A.; Santaf e´ , G.; Rodriguez, J.; Jim e´ nez, C.
1
2
Bioorg. Med. Chem. 2003, 11, 2301-2306.
(Scheme 1). Stereoselective reduction of the C13 carbonyl
(
8) Tanner, D.; Andersson, P. G.; Tedenborg, L.; Somfai, P. Tetrahedron
13
group of 8 and silylation of the resulting alcohol gave rise
1
994, 50, 9135-9144. Tanner, D.; Tedenborg, L.; Somfai, P. Acta Chem.
to enone 13 (two steps, 89% overall yield). When this
silylation was performed in the presence of conventional
bases, such as imidazole or pyridine, silyl ether 13 was
Scand. 1997, 51, 1217-1223. Williams, D. R.; Brugel, T. A. Org. Lett.
2
000, 2, 1023-1026. Sakai, M.; Sasaki, M.; Tanino, K.; Miyashita, M.
Tetrahedron Lett. 2002, 43, 1705-1708. Nielsen, T. E.; Tanner, D. J. Org.
Chem. 2002, 67, 6366-6371.
(9) For approaches toward the aminal motif of zoanthamines, see: Hikage,
N.; Furukawa, H.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1998, 39,
(10) For a general review in annulation chemistry, see: Jung, M. E.
Tetrahedron 1976, 32, 3-31.
(11) Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch. Khim. 1953, 23, 1703;
Engl. Trans. 1953, 23, 1793-1794; Chem. Abstr. 1954, 48, 13667h. Zibuck,
R.; Streiber, J. M. Org. Synth. 1993, 71, 236-241.
6
237-6240. Hikage, N.; Furukawa, H.; Takao, K.; Kobayashi, S. Tetra-
hedron Lett. 1998, 39, 6241-6244. Williams, D.; Cortez, G. S. Tetrahedron
Lett. 1998, 39, 2675-2678. Hikage, N.; Furukawa, H.; Takao, K.;
Kobayashi, S. Chem. Pharm. Bull. 2000, 48, 1370-1372.
942
Org. Lett., Vol. 6, No. 6, 2004

contaminated with a disilylated adduct arising from con-
comitant reaction with the enone functionality. However, use
Scheme 2. Synthesis of Enone 4a
4 3
of NH NO in combination with TBSCl led to exclusive
1
4
formation of 13, which was isolated in 99% yield. Treat-
ment of enone 13 with potassium tert-butoxide produced the
extended enolate that upon reaction with methyl iodide
formed compound 7 as a single isomer at the C22 center
(
zoanthamine numbering) (68% yield). The â-ketoester
1
5
4
functionality of 7 was then reduced with LiAlH , and the
resulting diol was converted to the corresponding acetonide
4 (two steps, 81% combined yield). Hydroxylation of the
C20-C21 double bond (BH ‚THF/H ) occurred predomi-
1
3
2 2
O
nantly from the more accessible â-face of 14 and afforded
the desired trans-fused bicyclic motif of 15 together with its
16
cis isomer (3:2 isomeric ratio in favor of 15). Gratifyingly,
the two isomers were easily separable by column chroma-
tography and the relative stereochemistry of the major
product 15 was unequivocally confirmed by X-ray analysis
(
Scheme 1; for clarity, only the hydrogens at chiral centers
1
7
are shown). Treatment of 15 with MOMCl and DIPEA
produced adduct 16 that after desilylation and oxidation gave
rise to ketone 6 (three steps, 83% combined yield).
The conversion of ketone 6 to enone 4 is highlighted in
Scheme 2. Our initial plan to alkylate the enolate of 6 with
methyl vinyl ketone en route to a Robinson annulation
sequence gave rise to a mixture of products, including
isomers at the C18 center. This problem was circumvented
by alkylating 6 with methyl formate to produce the â-keto-
carbonyl adduct 17, which underwent a smooth Michael
addition in the presence of methyl vinyl ketone and triethy-
lamine. Subsequent treatment with NaOMe led to a
Robinson annulation with concomitant removal of the formyl
group, thereby affording 5 as a single isomer at the C18
center (72% combined yield). Reduction of enone 5 with
lithium in liquid ammonia gave rise to ketone 18 (90% yield).
Unambiguous structural proof of compound 18 was obtained
after derivatization to the corresponding p-bromobenzoate
a
2
Reagents and conditions: (a) 2.0 equiv of NaH, HCO Me
(excess), THF/PhMe (1:1), 0-25 °C, 24 h; (b) 1.5 equiv of
MeCOCHdCH , 4.0 equiv of Et N, CH Cl , 2 h; (c) 5.0 equiv of
NaOMe, MeOH, 0-25°C, 24 h, 72% (three steps); (d) 3.0 equiv
of Li, liq NH , EtOH, THF, -78 °C, 4 h, 90%; (e) 2.0 equiv of
NaBH , EtOH, 0 °C, 0.5 h, 95% (4:1); (f) 1.5 equiv of
p-BrC COCl, 2.5 equiv of Et N, DMAP (cat.), CH Cl , 0-25
°C, 1 h, 90%; (g) 1.2 equiv of NaHMDS, 1.1 equiv of PhSeCl,
-78 °C, 75%; (h) 2.0 equiv of NaIO , H O/THF (1:2), 25 °C, 92%;
i) 1.2 equiv of MeLi, Et O, 0 °C, 0.5 h, 90%; (j) 2 equiv of PCC,
Å MS, CH Cl , 2 h, 0 °C, 78%.
2
3
2
2
1
8
3
4
H
6 4
3
2
2
4
2
(
3
2
2
2
19, which upon recrystallization from methanol/water yielded
(
12) Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong, B. G.; Palladino,
crystals suitable for X-ray analysis (Scheme 2; for clarity,
only the hydrogens at chiral centers are shown). This study
confirmed the desired trans-anti-trans stereorelation of the
tricyclic motif of 19.
M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843-8853. Zhou, G.;
Gao, X.; Li, W. Z.; Li, Y. Tetrahedron Lett. 2001, 42, 3101-3103. Inayama,
S.; Shimizu, N.; Ohkura, T.; Akita, H.; Oishi, T.; Itaka, Y. Chem. Pharm.
Bull. 1989, 37, 712-717. Ling, T.; Kramer, B. A.; Palladino, M. A.;
Theodorakis, E. A. Org. Lett. 2000, 2, 2073-2076.
17
(13) Spencer, T. A.; Weaver, T. D.; Greco, W. J., Jr. J. Org. Chem.
Introduction of the desired functionalities on the A ring
of 18 was accomplished by a NaHMDS-promoted phenylse-
lenylation followed by oxidation and elimination of the
resulting selenide to produce enone 20 in 69% yield.19 The
latter compound was treated with methyllithium and the
resulting tertiary alcohol was subjected to a PCC-mediated
oxidative rearrangement to produce enone 4 (two steps, 70%
1
965, 30, 3333-3336. Pelletier, S. W.; Chappel, R. L.; Prabhakar, S. J.
Am. Chem. Soc. 1968, 90, 2889-2895. Banerjee, A. K.; Pena Matheud, C.
A.; Hurtado S.; Hector, E.; Diaz, M. G. Heterocycles 1986, 24, 2155-
2
3
(
15) Bhandaru, S.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 8347-8350.
(16) The functionality at the C13 center was found to be crucial to the
diastereomeric outcome of this hydroxylation reaction. For example, the
cis decalin was obtained as a major product upon hydroxylating a substrate
having a ketal functionality at the C13 center. See also: Gool, M. V.;
Vandewalle, M. Eur. J. Org. Chem. 2000, 3427-3431.
2
0
combined yield), which represents a fully functionalized
ABC tricyclic motif of norzoanthamine.
In summary, we present herein an efficient synthesis of
the ABC ring framework 4 of norzoanthamine. The approach
(17) CCDC-226516 (15) and CCDC-226517 (19) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge
CB21EZ, UK; fax: (+44)1223-336-033; or deposit@ccdc.cam.ac.uk).
(19) Kende, A. S.; Roth, B. Tetrahedron Lett. 1982, 23, 1751-1754.
(20) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682-685.
Moens, L.; Baizer, M. M.; Little, R. D. J. Org. Chem. 1986, 51, 4497-
4499. Ling, T.; Rivas, F.; Theodorakis, E. A. Tetrahedron Lett. 2002, 43,
9019-9022.
(18) Spencer, T. A.; Friary, R. J.; Schmiegel, W. W.; Simeone, J. F.;
Watt, D. S. J. Org. Chem. 1967, 33, 719-726. Spencer, T. A.; Smith, R.
A. J.; Storm, D. L.; Villarica, R. M. J. Am. Chem. Soc. 1971, 93, 4856-
4
864.
Org. Lett., Vol. 6, No. 6, 2004
943

rests upon a stereocontrolled methylation of â-ketoester 13,
that establishes the critical C22 quaternary center. Other key
steps include a stereoselective hydroxylation of alkene 14
and a modified Robinson annulation that set the desired
relative stereochemistry of this scaffold.
and Fondo Social Europeo for a postdoctoral Fellowship to
M.A.G. We are thankful to Dr. L. N. Zakharov (UCSD,
X-ray Facility) for the reported crystallographic studies.
Supporting Information Available: Synthetic procedures
1
13
and spectroscopic data, including H and C NMR spectra,
for compounds 4-8 and 13-20. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the NIH
(CA086079) is gratefully acknowledged. We also thank the
NIH for a Graduate Fellowship to F.R. (F31 GM067444)
and the Secretaria de Estado de Educaci o´ n y Universidades
OL036492C
944
Org. Lett., Vol. 6, No. 6, 2004