The first total synthesis of nakadomarin A

Article abstract of DOI:10.1021/ja034464j

(-)-Nakadomarin A is a member of manzamine alkaloid isolated from a marine sponge and have a unique hexacyclic structure. The first total synthesis of (+)-nakadomarin A, an enantiomer of natural product, has been accomplished from stereochemically defined 4-oxopiperidin-3-carboxylic acid derivative. The synthesis established the structure of nakadomarin A including absolute configuration. Copyright

Full text of DOI:10.1021/ja034464j

Published on Web 05/29/2003
The First Total Synthesis of Nakadomarin A
Toshiaki Nagata, Masako Nakagawa,† and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received February 3, 2003; E-mail: nishida@p.chiba-u.ac.jp
Scheme 1. Biosynthsis of Nakadomarin A from Ircinal
Nakadomarin A (1) was first isolated from a marine sponge
collected at Okinawa by Kobayashi and co-workers.1 Its structure
was elucidated by exhaustive NMR study and shown to have a
unique hexacyclic skeleton. Nakadomarin A was thought to be a
member of the manzamine family,2 and an interesting biogenetic
pathway from ircinal A (2) was proposed (Scheme 1).1,3 Although
some biological activities of 1 have been reported, including
cytotoxicity, antimicrobial activities, and inhibitory activity against
cyclin-dependent kinase 4, its limited availability has prevented a
complete survey of its biological activity.1 Synthetic studies4,5 of
this molecule have been reported by Fu¨rstner, Magnus, and us.
However, no total synthesis of 1 has yet been reported. In
connection with our synthetic study of manzamine alkaloids,6 we
started a total synthesis of 1 to confirm its structure, including its
absolute stereochemistry, and to prepare enough natural naka-
domarin A and its analogues for further biological testing.
A retrosynthetic analysis of nakadomarin A showed that both
15- and 8-membered azacycles could be obtained by ring-closing
metathesis (RCM) (Scheme 2).7 To construct strained ABCD core
ring system 5, a novel intramolecular Mannich-type cyclization of
a furan to an iminium cation in 6 was attractive as a potential route
in considering the proposed biogenetic pathway. The N-acyliminium
ion 68 could be obtained from spiro-γ-lactam 7, which could be
prepared by Suzuki-Miyaura coupling of 89 and 9 followed by
hydrogenation. Further retrosynthetic analysis of the key intermedi-
ate 9 led to unsaturated ester 10.
Condensation of (R)-(-)-115,10 with benzylamine, followed by
catalytic dihydroxylation and oxidative cleavage of the 1,2-diol,
gave aldehyde 12, which was immediately converted to R,â-
unsaturated ester 13 by Wittig olefination. Intramolecular Michael
addition11 of 13 upon treatment with DBU in EtOH gave the desired
spirolactam as a major product (3.3:1) in an inseparable mixture
of the diastereomers. The mixture was then hydrolyzed to acids to
remove less polar impurities, including phosphine oxide, and re-
esterified to give 14. Reduction of 14 gave the separable alcohol
15 in 54% yield [eight steps from (R)-11]. Deprotection of the ketal
group with 70% HClO4 gave keto alcohol 16. Its primary alcohol
was selectively protected as THP ether to prevent intermolecular
acetal formation. The ketone 17 was converted to the enol triflate
18. Due to steric hindrance of the N-benzyl group, Suzuki-Miyaura
coupling of 18 with furan-3-boronic ester 89 proceeded under strong
basic conditions12 using PdCl2(dppf) to give the coupling product
in 95% yield. Stereoselective hydrogenation13 occurred from the
â-side (vide infra) to give 19 (5.7:1), as expected from a previous
model study.5
Scheme 2. Retrosynthetic Analysis of Nakadomarin A
the furan ring was reduced with LiBH4. The N-benzyl group in 20
was converted to a Boc group by deprotection-protection proce-
dures to give 21. Next, reduction of both Boc imide and carbonates
with DIBALH, followed by treatment with Ac2O/pyridine, gave
the ester 22 as a 3:2 inseparable mixture of the two diastereomers
in 62% yield (six steps from 19). No over-reduction was observed
even when a large excess of DIBALH was used. Treatment of 22
with p-TsOH, followed by deprotection of the THP ether, gave the
desired tetracyclic product 23 in 87% yield as a single isomer. In
the next phase of the synthesis, 23 was elaborated to set the stage
for the formation of the 15- and 8-membered rings by sequential
RCM reactions, where the sequence began with the parallel
refunctionalization of the two protected primary alcohols. Selenation
of 23 followed by oxidation of the selenide resulted in the formation
of 24. Deprotection of the Boc followed by N-acylation gave the
diene 25 (54% from 23). When 25 was exposed to the second-
generation Grubbs catalyst 26,14 a facile RCM reaction ensued to
furnish azocine lactam 27 in 70% yield. The same reaction using
30 afforded 27 in only 15% yield after 48 h with recovery of 25
(36%).15 Hydrolytic removal of acetate followed by oxidation
furnished an aldehyde that underwent a Wittig reaction under salt-
free conditions to give 28 (53%, three steps), which was character-
ized by X-ray crystallography.9 Reductive removal of the sulfon-
amide from 28 and N-acylation gave 29 (77%, two steps). When
the diene 29 was exposed to the Grubbs ruthenium catalyst 30,16
the second RCM reaction occurred to give a mixture of geometrical
isomers (Z/E ) ca. 2:3 by NMR) from which (24Z)-31 was isolated
in 26% yield. Reduction of bislactam (24Z)-31 with Red-Al resulted
The stage was now set for the crucial construction of ring B by
cyclization to iminium cation. Before this crucial transformation,
a protecting benzyl group on a nitrogen in ring D was converted to
a Boc group, since carbamate protection is essential for the efficient
reduction of lactams to cyclic aminals. First, an ester side chain in
† Present address: Department of Chemistry, Faculty of Science, Kanagawa
University, Hiratsuka, Kanagawa 259-1293, Japan.
in the first total synthesis of (+)-nakadomarin A (free), 1, [R]20
D
9
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J. AM. CHEM. SOC. 2003, 125, 7484-7485
10.1021/ja034464j CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
a Conditions: (a) BnNH2, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC)‚HCl, HOBt, DMF, 91%; (b) cat. OsO4, NMO, aq THF, rt; (c) NaIO4,
CH2Cl2:H2O (2:1), rt; (d) Ph3PdCHCO2Et, CH2Cl2, reflux; (e) DBU, EtOH; (f) 2 N NaOH, MeOH; (g) AcCl, EtOH, 54% (8 steps); (h) LiBH4, MeOH,
THF, 99%; (i) 70% HClO4, CH2Cl2, rt, 91%; (j) DHP, cat. CSA, 91%; (k) i) LiN(TMS)2, THF, -78 °C, ii) PhNTf2, 87%; (l) 8, PdCl2(dppf), K3PO4, 80 °C,
3 h, 95%; (m) i) H2, 10% Pd-C, MeOH, rt, 1.5 h, 71% (8R-H:8â-H ) 1:5.7), ii) PPTS, EtOH, iii) separation of diastereomers, (iv) DHP, cat. CSA, 69%;
(n) LiBH4, MeOH, THF, 99%; (o) Li, liq. NH3; (p) PhSO2Cl, aq NaHCO3, 80% (2 steps); (q) (Boc)2O, Et3N, cat. DMAP, 98%; (r) DIBALH, CH2Cl2,
toluene; (s) Ac2O, pyridine, 80% (2 steps); (t) p-TsOH, CH2Cl2; (u) 1 N HCl, THF, 87% (2 steps); (v) 2-nitrophenylselenocyanate, n-Bu3P; (w) mCPBA,
aq K2HPO4; (x) TFA, CH2Cl2; (y) 5-hexenoic acid, WSC‚HCl, HOBt, 73% (4 steps); (z) 26 (20 mol %), CH2Cl2, 2 mM, 50 °C, 1.5 h; (aa) 2 N NaOH,
MeOH, rt, 1.5 h, 64% (2 steps); (bb) Dess-Martin periodinane, 80%; (cc) Ph3PdCH2, 72%; (dd) Na, naphthalene; (ee) 5-hexenoic acid, WSC‚HCl, HOBt,
77% (2 steps); (ff) 30 (15 mol %), CH2Cl2, 0.5 mM, 50 °C, 24 h, 26% (24Z), 44% (24E); (gg) Red-Al, toluene, reflux.
) +79.2 (c 0.12, MeOH), in 86% yield (Scheme 3). The same
reduction of (24E)-31 gave (+)-(24E)-nakadomarin A in 63% yield.
Although the H NMR spectrum of synthetic (+)-nakadomarin
spectra for selected compounds (PDF). X-ray crystallographic data in
CIF format. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
A was similar to that of natural (-)-1 reported by Kobayashi, the
vinylic protons in the eight-membered ring and the methylene and
methine protons connected to two tertiary amines of natural (-)-1
References
(1) (a) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem.
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1
were shifted downfield. Therefore, the H NMR spectra of both
natural and synthetic (+)-1 were measured again in the presence
of HCl under the same conditions by Professors Kobayashi and
Tsuda. Those spectra clearly showed that these compounds were
identical.9 Furthermore, a careful comparison of the specific rotation
[synthetic (+)-nakadomarin A (2HCl salt), 1, [R]20 +45 (c 0.13,
D
(5) Nagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42, 8345.
MeOH)] showed that the absolute configuration of all stereo centers
in natural 1 [[R]20D -16 (c 0.12, MeOH)] could be assigned to be
R.17
In summary, the first total synthesis of ent-(+)-nakadomarin A
was completed from the readily available chiral 11. The absolute
configuration of natural 1 was assigned to be R. Finally, the
procedure described here provides an access to structural analogues
of nakadomarin A for further study, including biological evaluation.
(6) (a) Uchida, H.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 1999, 40,
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(9) See the Supporting Information for complete experimental details and
crystallographic, spectroscopic, and analytical data.
(10) The racemic acid 11, which was prepared in >75% yield from com-
mercially available methyl 4-oxopiperidinecarboxylate, was resolved to
give the (R)-11 in 99.6% ee using (+)-cinchonine. The absolute stereo-
chemistry of (R)-11 was determined by X-ray analysis of its cinchoninium
salt.9
Acknowledgment. This research was supported by a Grant-in-
Aid for Scientific Research of Priority Areas (A) “Exploitation of
Multi-Element Cyclic Molecules” from the Ministry of Education,
Culture, Sports, Sciences, and Technology. Financial support from
the Uehara Memorial Foundation is also gratefully acknowledged.
We thank Professors J. Kobayashi and M. Tsuda (Hokkaido
University) for their help in identifying natural 1 and synthetic ent-
1. We also thank Dr. K. Yamaguchi for X-ray analysis and Ms. R.
Hara for MS at the Analytical Center, Chiba University.
(11) Littel, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. In
Organic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1995; p 315.
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(14) Scholl, M.; Ding. S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
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Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584.
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(17) The difference between these values is likely attributable to a difference
in purity or partial racemization of 1 in its biosynthesis. Tsuda, M.; Inaba,
K.; Kawasaki, N.; Honma, K.; Kobayashi, J. Tetrahedron 1996, 52, 2319.
Supporting Information Available: Schemes for the preparation
of 8 and rac-11; experimental procedures and characterization data for
all new compounds reported in Scheme 3; copies of 1H and 13C NMR
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