Studies directed toward the synthesis of nakadomarin A

Article abstract of DOI:10.1016/j.tetlet.2010.11.134

The application of a Pummerer-initiated tandem reaction cascade leads to the highly stereoselective formation of the tetracyclic core of nakadomarin A.

Full text of DOI:10.1016/j.tetlet.2010.11.134

Tetrahedron Letters 52 (2011) 2162–2164
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies directed toward the synthesis of nakadomarin A
Thomas Haimowitz , Mark E. Fitzgerald à, Jeffrey D. Winkler
⇑
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 9 December 2010
The application of a Pummerer-initiated tandem reaction cascade leads to the highly stereoselective for-
mation of the tetracyclic core of nakadomarin A.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Pummerer
Tandem reactions
Nakadomarin
Manzamine
Nakadomarin A 1 (Fig. 1) was first isolated from the Okinawan
marine sponge Amphimedon sp. by Kobayashi in 1997.1 The struc-
ture of 1 was elucidated spectroscopically and consists of an
unprecedented hexacyclic ring system (8/5/5/5/15/6). Kobayashi
has proposed an interesting biogenetic transformation for the con-
version of ircinal A 2, the precursor to manzamine A 3,2 to naka-
domarin A 1, underscoring the striking structural similarities
among this compound class.3
and
11
a
Gram-positive bacterium (Cornebacterium xerosis, MIC
l
g/mL). However, its limited availability from natural sources
(1.8 ꢀ 10ꢁ3% of sponge wet weight) has prevented a complete
study of its biological activity. The structural complexity of naka-
domarin A coupled with its intriguing and as yet not fully explored
biological activity led to considerable effort directed toward the
synthesis of 1, culminating in a series of elegant total syntheses.4
We describe herein a conceptually novel approach to the synthesis
of manzamine core based on a Pummerer-initiated tandem reac-
tion cascade.5
Nakadomarin A 1 demonstrates a range of promising biological
activities including cytotoxic activity against murine lymphoma
L1210 cells (IC50 1.3
dependent kinase
against a fungus (Trichophyton mentagrophytes, MIC 23
l
g/mL), inhibitory activity against cyclin
We envisioned that the ABCDE pentacyclic core 4 of nakadom-
arin A 1 could be obtained by global reduction of bislactam sulfide
5, which we envisioned as the product of a Pummerer-initiated
4
(IC50 9.9 g/mL), anti-microbial activity
l
lg/mL),
N
N
CHO
H
H
H
H
H
OH
OH
O
N
N
N
H
N
N
N
H
H
H
1
2
3
Figure 1. Nakadomarin A 1, ircinal A 2, and manzamine A 3.
⇑
Corresponding author.
E-mail address: winkler@sas.upenn.edu (J.D. Winkler).
Present address: TetraLogic Pharmaceuticals, 343 Phoenixville Pike, Malvern, PA 19355, United States.
Present address: Chemical Biology Platform, The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, United States.
à
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.134

T. Haimowitz et al. / Tetrahedron Letters 52 (2011) 2162–2164
2163
H
SEt
N
SEt
N
R'
R'
R'
C
A
RN
RN
RN
B
O
O
O
D
O
O
H
H
H
N
H
H
O
O
14
E
5
6
4
COOH
EtS
RN
SEt
N
O
SEt
EtS
D
O
H
H2N
N
C
H
O
O
14
O
E
8
7
9
Scheme 1. Retrosynthetic analysis for the synthesis of the pentacyclic core 4 of nakadomarin A.
tandem reaction cascade of 7 via the intermediacy of thionium ion
6 (Scheme 1). We note that the elegant studies of Martin,2b Mu-
kai,4g and Zhai6 suggest that the C-14 stereocenter would lead to
the desired diastereoselectivity in the cascade cyclization reaction
via approach of the thionium ion 6 from the a-face of the pyrroline
D-ring to give 5. We anticipated that the requisite cyclization sub-
hydrazine and reductive alkylation with p-bromobenzaldehyde
gave secondary amine 14, which was coupled with acid chloride
152b to give the cascade cyclization substrate 16. Exposure of 16
to dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)9 led
to the exclusive formation of the desired tetracycle 17, the struc-
ture of which was unambiguously confirmed via X-ray crystallo-
graphic analysis of the hydrochloride salt of the derived tertiary
amine 18, as shown in Scheme 2.10
The extension of these results to a substrate containing the C-14
stereocenter is outlined in Scheme 3. Reaction of the known acid
192b with the p-methoxybenzyl amine 20 (obtained from 13 by
reductive alkylation) gave amide 21. While the reaction of 21 with
DMTSF resulted in extensive decomposition of the starting
material without the formation of the desired product, we were
delighted to find that exposure of the corresponding benzoate 22
to DMTSF led to the formation of the desired cyclization product
23 in 50% yield, which was fully characterized as the corresponding
Cbz analog 24.11 The stereoselective formation of 23 is consistent
strate 7 could be prepared via coupling of 8 and 9.
To examine the feasibility of the key cascade sequence, we
examined the reaction in the simpler model system 16,7 lacking
the C-14 stereocenter, as outlined in Scheme 2. Metalation of
10,8 based on the work of Das, and the reaction of the derived an-
ion with ethylene oxide delivered alcohol 11, which on Mitsunobu
reaction with phthalimide afforded 12. Deprotection of 12 with
ClOC
O
O
N
n-BuLi
with the addition of the thionium ion from the
a-face of the
EtS
SEt
SEt
EtS
H
THF -78oC
59%
pyrroline ring, as noted in related systems by Zhai6 and Martin.2b
Further support for this stereochemical assignment, albeit indirect,
was obtained by cyclization of 24 to the cyclic urethane 25, which
revealed no NOE between the two methines (C-6 and C-14 using
15
OtBu
R
90%
O
O
PhthNH
PPh3/DIAD
10
11 R=OH
100%
NH2NH2
MeOH/CH2Cl2
95%
12 R=NPhth
13 R=NH2
EtS
SEt
PMBN
O
1) 4-BrPhCHO
14 R=p-Br-PhNH
EtS
DMTSF
MeNO2
COOH
PMBHN
2) NaBH4
SEt
95% overall yield
20
-30oC--25oC
O
O
DMTSF
MeNO2
50%
50% yield
N
HATU
DIEA
83%
N
p-Br-PhN
O
p-Br-PhN
O
Boc
Boc
EtS
OR
SEt
OTBDPS
1) TBAF
O
O
21 R=OTBDMS
22 R=(p-Br)PhCO
14
2) pBrPhCOCl
TEA/DMAP
89% overall
19
H
N
N
R
Boc
17 R=H
PhCHO
NaBH(OAc)3
60%
16
K2CO3
MeOH
75%
18 R=Bn
PMBN
O
PMBN
6
O
O
O
14
H
H
H
N
R
N
OCOPh(p-Br)
O
O
25
CbzCl
23 R=H
24 R=CBz
DIEA
DMAP
62%
Scheme 3. Synthesis of tetracyclic model system 23.
Scheme 2. Synthesis of the tetracyclic core 17.

2164
T. Haimowitz et al. / Tetrahedron Letters 52 (2011) 2162–2164
Ed. 2004, 43, 2020–2023; (d) Young, I.; Kerr, M. J. Am. Chem. Soc. 2007, 129,
1465–1469; (e) Jakubec, P.; Cockfield, D.; Dixon, D. J. Am. Chem. Soc. 2009, 131,
16632–16633; (f) Nilson, M.; Funk, R. Org. Lett. 2010, 12, 4912–4915; For a
formal synthesis of nakadomarin A, see: (g) Inagaki, F.; Kinebuchi, M.;
Miyakoshi, N.; Mukai, C. Org. Lett. 2010, 12, 1800–1803.
the numbering of the nakadomarin ring system) of the pyrrolidine
ring of 25.12
We have developed an alternative strategy to the elegant work
of Zhai6 on the use of the glutamate-derived stereochemistry to
control the establishment of the key stereochemical relationships
of the core structure of nakadomarin A. In both Zhai’s work and
the current study, a single stereocenter leads to the establishment
of all of the key stereochemical relationships of the nakadomarin
tetracyclic core. Further studies on the application of this strategy
to the synthesis of biologically relevant systems are underway in
our laboratories and our results will be reported in due course.
5. For recent reviews, see: Padwa, A. J. Org. Chem. 2009, 74, 6421–6441; Bur, S.;
Padwa, A. Adv. Heterocycl. Chem. 2007, 94, 1–105; Bur, S.; Padwa, A. Chem. Rev.
2004, 104, 2401–2403.
6. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791–1793.
7. All new compounds were fully characterized by 1H and 13C NMR, IR, and high
resolution mass spectrometry.
8. Das, B.; Ramyu, R.; Reddy, M.; Mahender, G. Synthesis 2005, 250–254.
9. Trost, B.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529–6530.
10. CCDC 796390 Cambridge Crystallographic Data Centre.
11. Characterization data for 24: ½a D24:1
ꢂ
+83.36, c 1.00 (CDCl3); 1H NMR (500 MHz,
CDCl3, 335 K) d 7.87 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.47 (br s, 1H),
7.46–7.28 (m, 5H), 7.16 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.2 Hz, 2H), 6.32 (d,
J = 1.6 Hz, 1H), 5.76 (s, 1H), 5.70 (d, J = 5.0 Hz, 1H), 5.28 (d, J = 2.4 Hz, 2H), 4.91
(d, J = 13.5 Hz, 1H), 4.73 (dd, J = 4.7, 10.5 Hz, 1H), 4.63 (t, J = 9.4 Hz, 1H), 4.35
(br, 1H), 4.33 (d, J = 14.3 Hz, 1H), 4.03 (d, J = 17.3 Hz, 1H), 3.74 (dd, J = 6.2,
17.4 Hz, 1H), 3.69 (s, 3H), 2.44 (d, J = 13.7 Hz, 1H), 2.21 (dd, J = 8.6, 13.7 Hz,
1H); 13C NMR (125 MHz, CDCl3, 335 K) d 171.0, 165.3, 159.4, 148.9, 136.5,
131.7, 131.3, 129.5, 129.2, 128.4, 128.2, 127.9, 124.2, 114.4, 109.0, 105.0, 67.6,
64.5, 62.0, 58.3, 55.2, 50.0, 47.5, 38.1, 29.7; IR (neat) 2917, 2850, 2253, 1714,
Acknowledgments
This Letter is dedicated with deep gratitude to Professor Harry
Wasserman, a scientist who has taught us so much about the art
of organic synthesis. We would like to thank the NIH (CA134983)
for their generous support of this work.
1698, 1652, 1590, 1514, 1486, 1404, 1354, 1272, 1248, 1175, 1118, 1030 cmꢁ1
;
HRMS (ESI) m/z calcd for C36H31BrN2NaO7 [MNa+] 705.1212, obsd 705.1236.
References and notes
12. Characterization data for 25: ½a D24:2
ꢂ
+122.85, c 1.00 (CDCl3); 1H NMR (500 MHz,
CDCl3) d 7.49–7.45 (m, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.88–6.81 (m, 2H), 6.35 (d,
J = 1.9 Hz, 1H), 5.94 (s, 1H), 5.72 (dd, J = 2.0, 6.5 Hz, 1H), 4.61 (d, J = 14.4 Hz,
1H), 4.54 (d, J = 14.4 Hz, 1H), 4.48 (dd, J = 7.4, 8.9 Hz, 1H), 4.17 (dd, J = 2.3,
9.1 Hz, 1H), 4.01–3.93 (m, 2H), 3.79 (s, 3H), 3.75 (dd, J = 6.5, 17.3 Hz, 1H), 2.36
(dd, J = 7.1, 12.8 Hz, 1H), 2.00 (dd, J = 9.1, 12.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 170.5, 159.4, 159.2, 159.1, 149.8, 136.5, 129.6, 128.9, 127.0, 114.2,
109.8, 105.5, 67.7, 66.9, 62.9, 58.0, 55.3, 49.4, 47.8, 44.0; IR (neat) 2969, 2925,
1. Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem. 1997, 62,
9236–9239.
2. For the total synthesis of manzamine A, see: (a) Winkler, J. D.; Axten, J. M. J. Am.
Chem. Soc. 1998, 120, 6425–6426; (b) Martin, S. F.; Humphrey, J. M.; Ali, A.;
Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866–867; (c) Toma, T.; Kita, Y.;
Fukuyama, T. J. Am. Chem. Soc. 2010, 132, 10233–10235.
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4. For a recent review, see: (a) Martin, D.; Vanderwal, C. Angew. Chem., Int. Ed.
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2856, 1750, 1646, 1611, 1510, 1398, 1375, 1248, 1222, 1178, 1029 cmꢁ1
;
HRMS (ESI) m/z calcd for C22H21N2O5 [MH+] 392.1372, obsd 392.1348.