Stereoselective synthesis of tricyclic guanidine, the key component of the batzelladine alkaloids

Article abstract of DOI:10.1016/S0040-4039(02)01371-0

Stereoselective and efficient synthesis of tricyclic guanidine, the key component of batzelladines A and D, was accomplished based on successive 1,3-dipolar cycloadditions and successive cyclizations for the construction of the tricyclic guanidine ring.

Full text of DOI:10.1016/S0040-4039(02)01371-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6383–6385
Stereoselective synthesis of tricyclic guanidine, the key
component of the batzelladine alkaloids
Kazuo Nagasawa,a,* Takanori Ishiwata,c Yuichi Hashimotoa and Tadashi Nakatab,c
aInstitute of Molecular and Cellular Biosciences, Univeristy of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan
bRIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan
cGraduate School of Science and Engineering, Saitama University, Shimokubo, Saitama 338-8570, Japan
Received 7 June 2002; revised 28 June 2002; accepted 5 July 2002
Abstract—Stereoselective and efficient synthesis of tricyclic guanidine, the key component of batzelladines A and D, was
accomplished based on successive 1,3-dipolar cycloadditions and successive cyclizations for the construction of the tricyclic
guanidine ring. © 2002 Elsevier Science Ltd. All rights reserved.
Batzelladines A–E, members of a novel class of guanidine
alkaloids containing a tricyclic guanidine unit, were
isolated from the Caribbean sponge Batzella sp.1 Later,
four further metabolites, termed batzelladines F–I, were
obtained from the same source.2 Batzelladines A (1) and
B inhibit the binding of HIV glycoprotein gp-120 to the
human CD4 receptor,1 while batzelladines F (3), G, H,
and I induce the dissociation of protein kinase p56lck
from CD4.2 Inspired by the novel structures of the
batzelladines and their potential clinical importance in
AIDS treatment, several synthetic studies have been
reported.3–9 In 1998, Snider’s group succeeded in the total
synthesis of batzelladine E; this was the first successful
synthesis in this class of natural products.5b In 1999 and
2001, Overman’s group accomplished the first total
synthesis of batzelladines D (2)7c and F (3),7d respectively,
which have the same tricyclic guanidine structure con-
taining five stereogenic centers as batzelladine A. Though
several total syntheses and other synthetic studies leading
toward batzelladines have been reported, control of the
stereochemistry on the tricyclic guanidine system is still
an issue. In this communication, we report the synthesis
of the tricyclic guanidine 4, the key component of
batzelladines, with complete stereocontrol of its five
stereogenic centers by way of successive 1,3-dipolar
cycloadditions and tricyclic guanidine formation by
utilizing the Mitsunobu reaction conditions and an SN2
type reaction.
NH
O
N
O
H
H2N
N
H
O
O
H
N
H
H
H
H
H
H
H
H
H2N
O
N
O
N
NH
NH
Me
N
N
H
C9H19
Me
N
N
H
C9H19
NH2
Batzelladine D (2)
Batzelladine A (1)
H
H
H
H
H
H
H
MeO2C
Me
N
Me
O
N
H
H
H
Me
N
N
H
O
N
N
N
H
C9H19
H
Me
N
N
H
C7H15
4
H
Batzelladine F (3)
* Corresponding author. Tel.: +81-3-5841-7848; fax: +81-3-5841-8495; e-mail: nagasawa@iam.u-tokyo.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01371-0

6384
K. Nagasawa et al. / Tetrahedron Letters 43 (2002) 6383–6385
be obtained. By means of this strategy, synthesis of the
tricyclic guanidine 4, a common key component of
batzelladines A (1), D (2), and F (3), was achieved as
shown in Scheme 2.
Recently, we have developed an efficient strategy for
stereoselective construction of the 3,6-anti- or 3,6-syn-
fused tricyclic guanidine compound 11.10 Our strategy
features 1) successive 1,3-dipolar cycloadditions to give
2,5-disubstituted pyrrolidine (5 to 9), 2) guanidine for-
mation of 2,5-disubstituted pyrrolidine with a protected
thiourea reagent (9 to 10), and 3) construction of the
tricyclic guanidine by utilizing the Mitsunobu reaction
and/or an SN2 type reaction (10 to 11) (Scheme 1). In
this protocol, the stereochemistry at C1 and C3 of 11 is
controlled by the 1,3-dipolar cycloaddition reaction.
Thus, if the unsaturated ester 12, instead of the olefin 6,
is used for the 1,3-dipolar cycloaddition with 5, the
fully stereocontrolled cyclic guanidine compound 4 can
1,3-Dipolar cycloaddition of the nitrone 5 and methyl
crotonate (14) in toluene gave the isoxazoline 15 in 82%
yield.11 The ester group of 15 was reduced with LiAlH4
and subsequent protection of the hydroxyl group with
t-BuMe2SiCl gave 16 in 95% yield. The oxidation of the
isoxazoline 16 with mCPBA12 effected regioselective
ring cleavage to give the nitrone 17, which was subse-
quently subjected to a second 1,3-dipolar cycloaddition
with 1-undecene (18) to give 19 in 76% yield (two
OH
R1
3
1) oxidation
3
reduction
6
N
R1
N
N
H
3
6
N
1
1
HO
R1
OH
R1
2)
O
8
O
O
R1
1
R1
CO2R3
7
R1
5
8
9
6
R2
12
3
steps
3
6
3
R3O2C
N
N
N
HO
R1
OH
R1
2
4
1
O
1
R1
N
N
H
R1
N
P
N
8
1
R2
P
13
11
10
P = protective group
Scheme 1.
H
H
H
3
b,c
d
a
MeO2C
N
N
N
2
N
O
TBSO
TBSO
O
O
O
OH
Me
Me
Me
h
11
15
5
16
17
Me
H
H
6
H
H
6
e
f,g
N
AcO
N
1
TBSO
8
O
H
8
HO
OH
C9H19
1
TBSO
Me
H
C9H19
H
20
19
AcO
AcO
Me
OH
HO
H
H
H
H
H
H
j
i
Me
TBSO
N
N
C9H19
Me
N
H
H
N
N
C9H19
TBSO
N
NH
Cbz Cbz
TBSO HN
Cbz
N
C9H19
Cbz Cbz
22
24
23
H
H
H
H
H
H
6
n
k
l,m
MeO2C
Me
TBSO
N
N
4
2
8
Me
N
N
C9H19
N
N
C9H19
H
H
Cbz
Cbz
25
26
Scheme 2. Reagents and conditions: (a) methyl crotonate (14), toluene, 100°C, 82%; (b) LiAlH4, Et2O, 0°C; (c) TBDMSCl,
imidazole, CH2Cl2, rt, 95% (two steps); (d) mCPBA, CH2Cl2, 0°C; (e) 1-undecene (18), toluene, 110°C, 76% (two steps); (f) Ac2O,
Py, rt; (g) Pd/C, H2, EtOH, rt, 98% (two steps); (h) bis-Cbz-2-methyl-2-thiopseudourea (21), HgCl2, Et3N, DMF, 0°C to rt, 52%;
(i) DEAD, PPh3, THF, rt, 58%; (j) NaH, THF–MeOH (1:1), rt, 80%; (k) MsCl, Et3N, CH2Cl2, 0°C, 82%; (l) Jones’ reagent,
acetone, 0°C; (m) TMSCHN2, PhH–MeOH (7:2), rt, 47% (two steps); (n) Pd/C, H2, EtOH, rt, 85%.

K. Nagasawa et al. / Tetrahedron Letters 43 (2002) 6383–6385
6385
steps). In this cycloaddition, 1-undecene (18)
approached 17 from the less-hindered side (b-face) in
the exo-mode, and the newly generated stereochemistry
of 19 at C6 and C8 was satisfactorily controlled.10,13
After protection of the hydroxyl group of 19 with Ac2O
in pyridine, the NꢀO bond was reduced with hydrogen
in the presence of 10% Pd/C to give the trans-2,5-disub-
stituted-b-hydroxypyrrolidine 20 in 98% yield. Treat-
ment of 20 with bis-Cbz-2-methyl-2-thiopseudourea
(21) in the presence of mercury (II) chloride14 generated
the guanylated pyrrolidine 22 in 51% yield. Treatment
of 22 under the Mitsunobu reaction conditions15
effected cyclization with inversion of the stereochem-
istry at C8 to give the bicyclic guanidine 23 in 58%
yield. Deprotection of one of the Cbz groups and the
acetyl group of 23 took place simultaneously with
sodium hydride in MeOH–THF (1:1)16 to give 24 in
80% yield. The tricyclic guanidine was formed on treat-
ment of 24 with methanesulfonyl chloride in the pres-
ence of triethylamine to give 25 in 82% yield.
Deprotection of the TBS ether of 25 and oxidation of
the resulting primary alcohol were simultaneously car-
ried out with Jones reagent to give the carboxylic acid,
which was treated with trimethylsilyldiazomethane to
give the methyl ester 26 in 47% yield. Finally, deprotec-
tion of the Cbz group was accomplished with hydrogen
over 10% Pd/C to give 4 in 85% yield. The spectral data
of 4 (1H, 13C NMR in CD3OD, and high-resolution
mass spectrum)17 were consistent with the data reported
by Overman.7a
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In conclusion, we have succeeded in the stereoselective
synthesis of the tricyclic guanidine 4, the key compo-
nent of batzelladines, based on successive 1,3-dipolar
cycloadditions and successive cyclizations for the con-
struction of tricyclic guanidine ring. This method
should be applicable to various types of tricyclic
guanidine class compounds. Efforts towards the synthe-
sis of batzelladines A (1) D (2) and F (3) are in progress
in our laboratories.
12. (a) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybul-
ski, E. J.; Wong, S. C.; Ali, S.k. A. J. Am. Chem. Soc.
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hedron Lett. 1986, 27, 1489; (c) Ali, S.k. A.; Wazeer, M.
I. M. Tetrahedron Lett. 1993, 34, 137.
13. Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.;
Kita, T.; Hashimoto, Y. Org. Lett. 2002, 4, 177.
14. (a) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677;
(b) Iwanowicz, E. J.; Poss, M. A.; Lin, J. Syn. Commun.
1993, 23, 1443.
Acknowledgements
15. Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994,
35, 977.
K.N. thanks Toray Co., Ltd. for an Award in Synthetic
Organic Chemistry, Japan and the Pharmacy Research
Encouragement Foundation for their financial support.
This research was also supported in part by a Grant-in-
Aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
16. McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett.
2000, 41, 1849.
1
17. Spectral data for 4: H NMR (CD3OD, 400 MHz) l 3.94
(m, 1H), 3.83 (m, 1H), 3.72 (s, 3H), 3.54 (m, 2H), 3.15 (t,
J=3.4 Hz, 1H), 2.35 (ddd, J=12.2, 4.0, 2.1 Hz, 1H), 2.21
(m, 2H), 1.50–1.64 (m, 4H), 1.29 (brs, 14H), 1.25 (d,
J=6.3 Hz, 3H), 0.89 (t, J=6.4 Hz, 3H); 13C NMR
(CD3OD, 100 MHz) 171.0, 151.5, 57.8, 57.3, 53.2, 49.9,
45.4, 37.0, 34.3, 33.0, 31.4, 30.6 (2 carbons), 30.4, 29.3,
26.2, 23.7, 18.4, 14.4 ppm; HRMS (FAB, MH+) calcd for
C21H38N3O2: 364.2964, found: 364.2963.
References
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