Stereoselective construction of the azabicyclic core applicable to the biologically important polyguanidinium alkaloids batzelladine A and D using a free radical cyclization

Article abstract of DOI:10.1016/S0040-4039(01)01340-5

The intramolecular addition of the free radical derived from the alkyl bromide 13 provides an expeditious and stereoselective approach to the azabicyclic core 14, which is applicable to the biologically important polyguanidinium alkaloids batzelladine A (1) and D (2).

Full text of DOI:10.1016/S0040-4039(01)01340-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6637–6640
Stereoselective construction of the azabicyclic core applicable to
the biologically important polyguanidinium alkaloids batzelladine
A and D using a free radical cyclization
P. Andrew Evans* and Thara Manangan
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
Received 22 June 2001; revised 20 July 2001; accepted 23 July 2001
Abstract—The intramolecular addition of the free radical derived from the alkyl bromide 13 provides an expeditious and
stereoselective approach to the azabicyclic core 14, which is applicable to the biologically important polyguanidinium alkaloids
batzelladine A (1) and D (2). © 2001 Published by Elsevier Science Ltd.
The batzelladines are a growing family of novel and
highly complex polyguanidinium alkaloids that were
isolated from the Caribbean sponge Batzella sp. by
Patil and Faulkner.1,2 Batzelladine A (1, Fig. 1) is
particularly pertinent because it competitively inhibits
the binding of the HIV envelope protein gp-120 to the
human CD4 receptor with micromolar affinity. Since
acquired immunodeficiency syndrome (AIDS) is associ-
ated with the progressive decline in the number of
CD4+ cells, which in turn leads to the failure of the
immune system and ultimately death through suscepti-
bility to infection, this relationship is clearly important
and mechanistically intriguing. Hence, the therapeutic
significance of the batzelladines coupled with their
unique and complex skeletal composition has stimu-
lated significant synthetic attention.3–5 The stereochemi-
cal revision of batzelladine A and D by Snider and
co-workers to an anti-relationship of the angular
hydrogens flanking the pyrrolidine nitrogen, allowed
Overman and co-workers to accomplish the first asym-
metric total synthesis of batzelladine D.6,7
We have recently demonstrated that oxauracil and
oxathymine provide excellent free radical acceptors for
a variety of radical cyclization reactions.8 This type of
approach, with 5-(hydroxymethyl)uracil, was expected
to provide a diastereoselective route to an intermediate,
which would be applicable to the guanidinium core of
batzelladine A and D. Furthermore, this strategy would
circumvent the problem associated with controlling the
C-5 carboxylate stereochemistry (thymine numbering).
Herein, we now describe an adaptation to our previous
studies, which provides both an expeditious and
diastereoselective route to the azabicyclic core of these
important natural products.
Scheme 1 summarizes the synthetic routes utilized for
the preparation of the prerequisite alkyl bromides 6a/c
and acyl selenides 6b/d for our initial study. Treatment
of the secondary alcohol 4 with 3-N-benzoyl protected
uracil and thymine 3a/b under Mitsunobu conditions
furnished 5a and 5b in 81% and 72% yield, respec-
tively.9,10 The alkyl halides 6a/c were then prepared via
the acid-catalyzed hydrolysis of the tert-butyl-
dimethylsilyl group 5a/b, and treatment of the resulting
primary alcohol with N-bromosuccinimide and
triphenylphosphine.11 The acyl radical cyclization reac-
tions were examined for comparative purposes, in
which additional functionality was expected to be use-
ful for analog studies. Oxidation of the primary tert-
butyldimethylsilyl ethers 5a/b with Jones reagent
+
Me
NH2
NH
( )8
O
H
NH
NH
C9H19
N
RO
R1 =
R2 =
N
+
H
R2O2C
H
+
NH2
Batzelladine A (1) R = R1
Batzelladine D (2) R = R2
H2N
N
( )2
H
Figure 1.
Keywords: radical cyclization; natural products; batzelladine A and
D; anti-HIV.
* Corresponding author. E-mail: paevans@indiana.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01340-5

6638
P. A. E6ans, T. Manangan / Tetrahedron Letters 42 (2001) 6637–6640
R
R
R
TBSO
DEAD, PPh3
Br
5
1. cat. p-TsOH
THF/H2O
O
O
O
4, THF
HN
N
N
2
N
N
N
Bz
Bz
Bz
0 °C to RT
Bz = PhCO-
2. NBS, PPh3
0 °C to RT
Me
Me
O
O
O
3
5
6
a R = H
b R = Me
a R = H 81%
b R = Me 72%
a R = H 79%
c R = Me 59%
1. Jones Oxidation
OH
-10 °C to RT
2. Et3N, RT, 30 min.
PhSeBr, nBu3P
4
Me
OTBS
R
O
SePh
N
O
N
Bz
Me
O
6
b R = H 71%
d R = Me 59%
Scheme 1.
furnished the corresponding carboxylic acids, which
were converted using the Crich protocol to the acyl
selenides 6b/d in good yield.12,13
reduction at C-5. Treatment of 6c/d under analogous
reaction conditions furnished the azabicycles 7c/d with
]19:1 diastereoselectivity at C-5/6 (entries 3–4). The
origin of diastereocontrol at C-5 is presumably a conse-
quence of the conformational bias of the azabicyclic
core derived after the cyclization, which results in
reduction from the more accessible convex face of the
molecule, as illustrated in Fig. 2.18
Table 1 summarizes the results for the alkyl and acyl
radical cyclization reactions. Treatment of 6a/b with
tris(trimethylsilyl)silane and triethylborane, in the pres-
ence of air, furnished the corresponding azacycles 7a/b
with ]19:1 diastereoselectivity (entries 1–2).15,16 The
origin of the trans-diastereoselectivity was attributed to
non-bonding interactions between the C-2 carbonyl of
uracil and the incipient a-amino stereogenic center.8,17
The synthesis of the batzelladines using this strategy
requires the introduction of an additional stereogenic
center at C-5.
Favored
Me
O
H
Bz
H
N
N
H
O
H
Me
Disfavored
We envisioned that thymine would serve as a useful
model to examine the stereoselectivity of a radical
Figure 2.
Table 1. Intramolecular alkyl and acyl radical additions with uracil and thymine derivatives14
O
O
O
R
Y
Bz
O
R
H
Bz
O
R
H
Bz
O
N
N
N
(TMS)3SiH, Et3B
PhH, RT, Air
5
4
5
4
2
+
X
X
N
N
N
X = O, Y = SePh
X = H2, Y = Br
X
Me
Me
Me
6
7
8
Bz = PhCO
Entry
Radical precursor 6a
Conc. (M)
Ratio of 7/8b
Yield (%)c
R=
X=
Y=
1
2
3
4
a
b
c
H
H
Me
Me
H2
O
H2
O
Br
SePh
Br
0.02
0.02
0.02
0.02
]19:1
]19:1
]19:1
]19:1
78
70
72
81
d
SePh
a All reactions were carried out on a 0.5 mmol reaction scale.
b Ratios of diastereoisomers were determined by 400 MHz 1H NMR integration.
c Isolated yields.

P. A. E6ans, T. Manangan / Tetrahedron Letters 42 (2001) 6637–6640
6639
Scheme 2 outlines the preparation of alkyl bromide 13
Acknowledgements
required for the batzelladine polycyclic guanidinium
core.14 Selective protection of 5-(hydroxymethyl)uracil
9 with benzoyl chloride and pyridine followed by purifi-
cation on a silica gel, furnished bis-N,O-benzoyl-5-
(hydroxymethyl)uracil 10 in 82% overall yield. The
alkyl bromide 13 was then prepared in an analogous
fashion to 6a, albeit with an enantiomerically enriched
secondary alcohol 11 derived from (R)-malic acid.19
We sincerely thank the National Institutes of Health
(GM58877) for generous financial support. We also
thank Eli Lilly for a Young Faculty Grantee Award
GlaxoWellcome for a Chemistry Scholar Award and
Novartis Pharmaceuticals for an Academic Achievement
Award. The Camille and Henry Dreyfus Foundation is
thanked for a Camille Dreyfus Teacher-Scholar Award
(P.A.E.), and the Development and Promotion of Sci-
ence and Technology Talents Project (DPST)-Thailand
for a Graduate Fellowship (T.M.).
Treatment of 13 under the standard free radical cycliza-
tion conditions furnished the azabicycle 14 as the major
diastereoisomer (Scheme 3).14 The stereochemistry of 14
was confirmed with the aid of an NOE NMR experi-
ment, which established the syn-relationship of the
protons at C-5/6 (thymine numbering).
References
1. For the isolation and biological evaluation of batzella-
dines A–E, see: Patil, A. D.; Kumar, N. V.; Kokke, W.
C.; Bean, M. F.; Freyer, A. J.; DeBrosse, C.; Mai, S.;
Truneh, A.; Faulkner, D. J.; Carte´, B.; Breen, A. L.;
Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.; Potts,
B. C. M. J. Org. Chem. 1995, 60, 1182.
2. For the isolation and biological evaluation of batzella-
dines F–I, see: Patil, A. D.; Freyer, A. J.; Taylor, P. B.;
Carte´, B.; Zuber, G.; Johnson, R. K.; Faulkner, D. J. J.
Org. Chem. 1997, 62, 1814.
In conclusion, we have demonstrated that intramolecular
addition of alkyl and acyl radicals to uracil, thymine
and 5-(hydroxymethyl)uracil derivatives provides a
diastereoselective route to 5,6-azabicycles, in which
the latter is applicable to the polycyclic guani-
dinium core of batzelladine A and D. Furthermore,
the azabicyclic cores represent unnatural nucleo-
side analogs that may serve as useful mechanistic
probes.
3. For a short review on the batzelladines, see: Berlinck, R.
G. S. Nat. Prod. Rep. 1999, 339.
4. For synthetic approaches to the batzelladines, see: (a)
Rao, A. V. R.; Gurjar, M. K.; Vasudevan, J. J. Chem.
Soc., Chem. Commun. 1995, 1369; (b) Louwrier, S.;
Ostendorf, M.; Tuynman, A.; Hiemstra, H. Tetrahedron
Lett. 1996, 37, 905; (c) Snider, B. B.; Chen, J. Tetra-
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Mackin, G. H.; Overman, L. E.; Shaka, A. J. J. Org.
Chem. 1999, 64, 1512; (e) Black, G. P.; Murphy, P. J.;
Thornhill, A. J.; Walshe, N. D. A.; Zanetti, C. Tetra-
hedron 1999, 55, 6547; (f) Nagasawa, K.; Koshino, H.;
Nakata, T. Tetrahedron Lett. 2001, 42, 4155 and perti-
nent references cited therein.
O
O
Bz
O
i. BzCl, Pyr., MeCN
HO
NH
BzO
N
ii. Silica Gel
82%
N
H
O
N
H
9
10
OH
11, DEAD
OTPS
TBSO
71% PPh3, THF
11
iPr2CHOH, ∆
5. For the synthesis and determination of the absolute
configuration of the batzelladine A (1) side chain, see:
Duron, S. G.; Gin, D. Y. Org. Lett. 2001, 3, 1551.
6. For the revision of the stereochemistry of batzelladines A
and D, see: Snider, B. B.; Chen, J.; Patil, A. D.; Freyer,
A. J. Tetrahedron Lett. 1996, 39, 6977.
7. For the first enantioselective total synthesis of batzel-
ladine D, see: Cohen, F.; Overman, L. E.; Ly Sakata, S.
K. Org. Lett. 1999, 1, 2169.
BzO
BzO
1. cat. p-TsOH
THF/H2O
Br
TBSO
O
O
2. NBS, MeCN
0 °C to RT
80%
N
N
N
N
Bz
Bz
O
O
TPSO
TPSO
13
12
Scheme 2.
BzO
H
O
N
BzO
H
O
N
BzO
Br
O
N
N
H
H
Bz
Bz
Bz
N
N
5
6
5
6
(TMS)3SiH, Et3B
PhH, RT, Air
77%
+
O
O
O
OTPS
OTPS
OTPS
13
14
14 : 15 22 : 1
determined by HPLC
15
Scheme 3.

6640
P. A. E6ans, T. Manangan / Tetrahedron Letters 42 (2001) 6637–6640
8. Evans, P. A.; Manangan, T.; Rheingold, A. L. J. Am.
59.52 (o), 56.29 (o), 46.97 (o), 32.01 (e), 26.75 (o), 25.78
(e), 19.17 (e); HRMS (CI, M+) calcd for C39H40N2O6Si
660.2656, found 660.2662.
Chem. Soc. 2000, 122, 11009.
9. For the preparation of 3-N-benzoyluracil and thymine,
see: Cruickshank, K. A.; Jiricny, J.; Reese, C. B. Tetra-
hedron Lett. 1984, 25, 681.
10. For a recent review on the Mitsunobu reaction, see:
Hughes, D. L. Org. React. 1992, 42, 335. For a related
example using maleimide, see: Walker, M. A. J. Org.
Chem. 1995, 60, 5352.
11. Yuasa, Y.; Kano, S.; Shibuya, S. Heterocycles 1991, 32,
2311.
12. Evans, P. A.; Roseman, J. D.; Garber, L. T. Synth.
Commun. 1996, 26, 4685.
15. For a recent reviews on this reagent, see: (a) Chat-
gilialoglu, C. Acc. Chem. Res. 1992, 25, 188; (b) Chat-
gilialoglu, C.; Ferreri, C.; Gimisis, T. In The Chemistry of
Organic Silicon Compounds; Rappoport, S.; Apeloig, Y.,
Eds.; Wiley: London, 1998; Vol. 2, Chapter 25, p. 1539.
16. For related examples of the intramolecular addition of
aryl and alkyl radicals to uracil derivatives, see: (a)
Yoshimura, Y.; Otter, B. A.; Ueda, T.; Matsuda, A.
Chem. Pharm. Bull. 1992, 40, 1761; (b) Zhang, W.; Pugh,
G. Tetrahedron Lett. 1999, 40, 7591 and pertinent refer-
ences cited therein.
17. For a related example of a stereoselective free radical
cyclization where a similar nonbonding interaction is
invoked to rationalize the trans-diastereoselectivity, see:
(a) Hart, D. J.; Kanai, K. J. Am. Chem. Soc. 1983, 105,
1255; (b) Beckwith, A. L. J.; Joseph, S. P.; Mayadunne,
R. T. A. J. Org. Chem. 1993, 58, 4198.
18. For recent reviews on alkyl and acyl radicals in synthesis,
see: (a) Curran, D. P. In Comprehensive Organic Synthe-
sis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
1992; Vol. 4; (b) Chatgilialoglu, C.; Crich, D.; Komatsu,
M.; Ryu, I. Chem. Rev. 1999, 99, 1991 and pertinent
references cited therein.
19. McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke,
S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998,
120, 7647.
13. Batty, D.; Crich, D. Synthesis 1990, 273.
1
14. All new compounds exhibited spectroscopic (IR, H and
13C NMR) and analytical (HRMS) data in accord with
the assigned structure. Representative data given for
compound 14: [h]1D9 +1.52 (c=1.1, CHCl3); IR (CDCl3)
3018 (m), 2957 (m), 2930 (m), 2858 (m), 1752 (s), 1706 (s),
1
1662 (s) cm−1; H NMR (400 MHz, CDCl3) l 7.99–7.20
(m, 4H), 7.59–7.51 (m, 6H), 7.41–7.29 (m, 8H), 7.24–7.20
(m, 2H), 4.82 (dd, J=3.5, 11.8, 1H), 4.77 (dd, J=4.2,
11.8, 1H), 4.30 (dd, J=3.6, 10.4, 1H), 4.19–4.07 (m, 2H),
3.57 (dd, J=1.6, 10.4 Hz, 1H), 2.94 (dt, J=3.8, 12.2 Hz,
1H), 2.58–2.51 (m, 1H), 2.25–2.13 (m, 2H), 1.84–1.73 (m,
1H), 0.97 (s, 9H); 13C NMR (100 MHz, CDCl3) l 169.45
(e), 168.28 (e), 166.10 (e), 148.85 (e), 135.52 (o), 135.44
(o), 134.55 (o), 133.38 (e), 132.86 (e), 132.64 (e), 132.51
(e), 130.19 (o), 129.84 (o), 129.71 (o), 129.30 (e), 129.01
(o), 128.50 (o), 127.78 (o), 127.74 (o), 62.95 (e), 59.94 (e),