Expedient synthesis of the tetracyclic core of ent-nakadomarin a

Article abstract of DOI:10.1021/ol800579j

An efficient eight-step assembly of the tetracyclic core (ABCD rings) of ent-(+)-nakadomarln A, a bloactlve hexacyclic marine alkaloid, has been realized with Sonogashlra coupling, platinum(ll)-promoted cascade cycllzatlons, and saturation of a challenging carbon-carbon double bond through a hydroboratlon/oxldatlon/xanthate formation/Barton-McComble deoxygenatlon sequence as key transformations.

Full text of DOI:10.1021/ol800579j

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1791-1793
Expedient Synthesis of the Tetracyclic
Core of ent-Nakadomarin A
Haibing Deng,† Xiaobao Yang,†,‡ Zhaolong Tong,† Zhong Li,‡ and Hongbin Zhai*,†
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, China 200032, and School of
Pharmacy, East China UniVersity of Science and Technology, Shanghai, China 200237
zhaih@mail.sioc.ac.cn
Received March 13, 2008
ABSTRACT
An efficient eight-step assembly of the tetracyclic core (ABCD rings) of ent-(+)-nakadomarin A, a bioactive hexacyclic marine alkaloid, has
been realized with Sonogashira coupling, platinum(II)-promoted cascade cyclizations, and saturation of a challenging carbon-carbon double
bond through a hydroboration/oxidation/xanthate formation/Barton-McCombie deoxygenation sequence as key transformations.
Marine natural products, perpetually manufactured by the
oceans, have received immense popularity owing to their
diverse and distinct structures and important physiological
activities. (-)-Nakadomarin A (1), native to sea sponge
Amphimedon sp. (SS-264) collected off the Kerama Islands,
Okinawa, was first isolated and characterized through
extensive NMR analyses by Kobayashi and co-workers a
decade ago.1 This manzamine-related marine alkaloid with
remarkable architectural intricacy and intrinsic beauty fea-
tures an unprecedented 8/5/5/5/15/6 hexacyclic framework
that comprises four densely imbedded carbon-based stereo-
centers (including a quaternary one, i.e., C-7) and especially
a furan moiety. (-)-Nakadomarin A was cytotoxic against
murine lymphoma L1210 cells and displayed antimicrobial
and CDK4-inhibitory activities.2 The impressive structural
features and valuable pharmacological profiles prompted
global scientists to develop efficient and economical chemical
syntheses based upon rational synthetic designs, which would
in turn fuel further biological screening. Hitherto, several
laboratories have communicated their synthetic studies,3
culminating in three total syntheses of 1 and/or ent-1.4
An original asymmetric synthesis project for nakadomarin
A was launched in 2003. The hexacyclic skeleton of this
(3) (a) Furstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc.
1999, 121, 11108. (b) Furstner, A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl,
M.; Gabor, B.; Mynott, R. Chem. Eur. J. 2001, 7, 4811. (c) Nagata, T.;
Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42, 8345. (d) Magnus,
P.; Fielding, M. R.; Wells, C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947.
(e) Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171. (f) Ahrendt, K. A.;
Williams, R. M. Org. Lett. 2004, 6, 4539. (g) Young, I. S.; Williams, J. L.;
Kerr, M. A. Org. Lett. 2005, 8, 953. (h) Nilson, M. G.; Funk, R. L. Org.
Lett. 2006, 8, 3833.
† Shanghai Institute of Organic Chemistry.
‡ East China University of Science and Technology.
(1) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem.
1997, 62, 9236.
(2) Kobayashi, J.; Tsuda, M.; Ishibashi, M. Pure Appl. Chem. 1999,
71, 1123.
10.1021/ol800579j CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

marine alkaloid was considered as a strained tetracyclic core
(ABCD rings) flanked with a fused eight-membered ring (E
ring) and a bridged 15-membered ring (F ring). Both E and
F rings should be accessible through ring-closing metathesis
(RCM), as has been demonstrated by Nishida and Kerr,
respectively. Our study was focused on the construction of
tetracycle 2 (Scheme 1), a core structure of (+)-nakadomarin
A (ent-1).
accessible through the above-mentioned platinum(II)-
promoted tandem reactions from substrate 4, a reductive
adduct of amine 5 and aldehyde 6.
As delineated in Scheme 2, the synthesis of tetracycle 2
was commenced from Pd(PPh3)2Cl2/CuI-catalyzed Sono-
gashira coupling of carbamate 711 with 3-iodofuran (8) in
degassed Et3N/THF at room temperature, where 8 was
generated in situ from 3-bromofuran following Negishi’s
procedure12 (i.e., through halogen-lithium exchange fol-
lowed by nucleophilic substitution with I2 at -78 °C).
Internal alkyne 9 was obtained as an orange solid (79%).
Scheme 1. Retrosynthetic Analysis of 2
Scheme 2. Synthesis of 2 and X-ray Structure of 10b
Tandem reactions5 are advantageous in the total synthesis
of structurally complex natural products owing to their
intrinsic superb synthetic efficacies manifested by the forma-
tion of two or more rings within one operational step.
Meanwhile, application of strongly electrophilic metal spe-
cies, notably platinum(II)6 and gold(I) and (III) salts,7 has
brought forth numerous efficient organic transformations
including tandem reactions8 and skeletal rearrangements.9
In 2007, Dake and co-workers developed a novel platinu-
m(II)-catalyzed cyclization method to generate quaternary
carbon centers using enesulfonamides, enecarbamates, or
enamides as nucleophiles.10 We envisioned that this might
serve as an alternative in the total synthesis of nakadomarin
A to our initially adopted tandem Pummerer/N-acyliminium
ion cyclization strategy. The retrosynthetic analysis (Scheme
1) shows that core 2 may be derived by saturation of the
carbon-carbon double bond in 3, which in turn may be
(4) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003,
125, 7484. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int.
Ed. 2004, 43, 2020. (c) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007,
129, 1465.
(5) For a review on tandem reactions in total synthesis of natural
products, see: Parson, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996,
96, 195.
However, no coupling product was formed if 3-bromofuran
was used instead of 8. Carbamate 9 was converted into
sulfonamide 4 in 54% overall yield after a three-step reaction
sequence: (1) removal of the Boc group to form the HCl
salt of 5, (2) reductive amination with unsaturated aldehyde
(6) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 3700.
(7) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
Lalonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991.
(8) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250.
(9) (a) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023. (b) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317.
(10) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9,
367.
(11) Wu, J.; Fang, F.; Lu, W.-Y.; Hou, J.-L.; Li, C.; Wu, Z.-Q.; Jiang,
X.-K.; Li, Z.-T.; Yu, Y.-H. J. Org. Chem. 2007, 72, 2897.
(12) Liu, F.; Negishi, E. J. Org. Chem. 1997, 62, 8591.
1792
Org. Lett., Vol. 10, No. 9, 2008

613 to afford a secondary amine, and (3) N-sulfonylation with
TsCl. Here the reductive amination was conducted in a
stepwise fashion. If MeOH was used in the imine formation
step, the overall yield for the secondary amine dramatically
dropped because acetalization of 6 took place prominently.
Acetalization can be inhibited using CH2Cl2 as solvent, but
imine formation was also shut off. As all of the enecarbam-
ate, alkyne, and arene functionalities are arranged in ap-
propriate positions in the same molecule, compound 4 is
ready for the cascade reactions promoted by platinum(II)
chloride. Indeed, treatment of 4 with PtCl2 (18 mol %) in
toluene at reflux effected the desired tandem reaction
sequence in an apparently regiospecific (6-endo versus 5-exo)
and stereospecific manner since spiro-fused tetracyclic
heterocycle 3 was obtained exclusively. The starting material
seemed to be susceptible to decomposition at the reaction
temperature. Therefore, a syringe pump was used for addition
of the substrate to secure a better yield (see experimental
procedures in Supporting Information). In contrast, under
Dake’s conditions (i.e., reaction with PtCl2 in toluene in a
sealed tube heated at 110 °C) the reaction produced 3 in
only 38% yield. The cascade sequence presumably consists
of the following steps: (1) nucleophilic attack of enecar-
bamate on the PtCl2-activated alkyne, (2) interception of the
intermediate azacarbenium ion by the proximate furan moiety
at the R-position, and (3) rearomatization of the dihydro-
furanyl cation to furan and release of a proton leading to
the desired product and regeneration of the platinum catalyst.
Compared to the target 2, tetracycle 3 possesses extra
unsaturation in the A ring, which needs to be hydrogenated
or reduced to generate an additional stereogenic center at
C-8 (a fused point between A and B rings). This seemingly
simple task represented a major challenge to the synthetic
strategy. Standard hydrogenation (H2, Pd/C) of 3 was totally
infeasible because the trisubstituted double bond was less
reactive toward hydrogenation than the tetrasubstituted
double bond in the furan moiety in such a constrained
environment, similar to Nishida’s findings during their
synthetic studies on nakadomarin A.3c Other methods such
as TFA/Et3SiH or hydroboration followed by protonation
(with HBr or HOAc) also were not successful. However,
we were eventually delighted to discover that 3 could be
converted to alcohol 10a in moderate yield (71%) via
stereoselective hydroboration (BH3·SMe2) followed by oxida-
tion (H2O2, NaOH). Barton-McCombie alcohol deoxygen-
ation14 (nBu3SnH, AIBN, toluene, reflux) with precedent
xanthate formation (NaH, CS2, MeI, THF, room temperature)
afforded the desired tetracyclic core structure 2 as a white
solid (mp 78-80 °C; [R]22D -94.8 (c 1.15, CHCl3)) in 72%
yield over two steps from 10a. In the meantime, alcohol 10a
was acylated (p-O2N-PhCOCl, Et3N, DMAP, CH2Cl2, room
temperature, 2 h) to give ester 10b as colorless crystals in
good yield (81%). The structure of 10b was unambiguously
confirmed by X-ray crystallographic analysis.
In summary, we have accomplished the construction of
the tetracyclic core (ABCD rings, see 2) of ent-(+)-
nakadomarin A in high efficiency (8 steps; 10.9% overall
yield). Key transformations of the present synthesis involved
(i) platinum(II)-promoted cascade reaction sequence, (ii)
Sonogashira coupling of 3-iodofuran, and (iii) saturation of
an otherwise difficult carbon-carbon double bond in A ring
of 3 through a hydroboration/oxidation/xanthate formation/
Barton-McCombie deoxygenation sequence. Development
of other cyclization methods for assembly of the tetracyclic
core and completion of the total synthesis of nakadomarin
A are currently underway and will be disclosed in due course.
Acknowledgment. Financial support was provided by
grants from NSFC (90713007; 20772141; 20625204;
20632030).
Supporting Information Available: Experimental pro-
1
cedures, analytical data, and copies of H and 13C NMR
(13) For preparation of racemic aldehyde 6, see: (a) Shono, T.;
Matsumura, Y.; Tsubata, K.; Sugihara, Y. Tetrahedron Lett. 1982, 23, 1201.
(b) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1998, 39, 4789. (c)
Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org. Chem.
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1999, 64, 6646. The enatiopure (5S)-6 {[R]23.6 -41.2 (c 1.34, CHCl3)}
D
was synthesized via Vilsmeier formylation13d (DMF, POCl3, CH2C12,
0 °C) from the known enecarbamate.13c (d) Shono, T.; Matsumura, Y.;
Tsubata, K.; Sugihara, Y.; Yamane, S.; Kanazawa, T.; Aoki, T. J. Am. Chem.
Soc. 1982, 104, 6697.
OL800579J
(14) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574. (b) Hong, F.-T.; Paquette, L. A. Chemtracts 1998, 11, 67.
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