Synthetic studies on (+)-manzamine A: Stereoselective synthesis of the tetracyclic core framework

Article abstract of DOI:10.1021/ol801111r

(Chemical Equation Presented) The stereoselective synthesis of the tetracyclic intermediate 3 for (+)-manzamine A (1) has been achieved. The key features of this stereoselective synthesis of 3 are the Rh-catalyzed asymmetric hydrogenation and a diastereoselective intermolecular Diels-Alder reaction. The 8-membered ring is efficiently constructed utilizing our Ns-strategy.

Full text of DOI:10.1021/ol801111r

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3251-3253
Synthetic Studies on (+)-Manzamine A:
Stereoselective Synthesis of the
Tetracyclic Core Framework
Yoichi Kita,† Tatsuya Toma,† Toshiyuki Kan,‡ and Tohru Fukuyama*,†
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, Japan, and School of Pharmaceutical Sciences, UniVersity of
Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan
kant@u-shizuoka-ken.ac.jp; fukuyama@mol.f.u-tokyo.ac.jp
Received May 14, 2008
ABSTRACT
The stereoselective synthesis of the tetracyclic intermediate 3 for (+)-manzamine A (1) has been achieved. The key features of this stereoselective
synthesis of 3 are the Rh-catalyzed asymmetric hydrogenation and a diastereoselective intermolecular Diels-Alder reaction. The 8-membered
ring is efficiently constructed utilizing our Ns-strategy.
Manzamine A (1), a naturally occurring ꢀ-carboline alkaloid
isolated from a sponge of genus Haliclona by Higa1 and
from genus Pellina by Kobayashi,2 has shown numerous
biological activities, including cytotoxic,1 antibacterial,2
antimalarial,3 insecticidal,4 anti-inflammatory,5 and anti-HIV6
activities. The remarkable biological activities coupled with
its highly complex structure have made it an attractive total
synthesis target, and several synthetic studies on this family
of compounds have been published.7 However, only three
total syntheses8 have been reported to date. The crucial step
in the synthesis of 1 should be the construction of the
complex pentacyclic skeleton because the ready conversion
from its biosynthetic precursor ircinal A (2) to 1 is known.9
Herein, we report the stereocontrolled synthesis of tetracyclic
intermediate 3 for the total synthesis of (+)-1 (Scheme 1).
We envisioned that formation of the D ring and addition
of the C1 unit to the vinylogous ester 3 could be achieved
† University of Tokyo.
‡ University of Shizuoka.
(1) (a) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
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of the Pharmaceutical Society of Japan, Sendai, 2006; 028[F]-031.
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M. T Heterocycles 2007, 71, 245.
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10.1021/ol801111r CCC: $40.75
Published on Web 07/03/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis
Scheme 2. Synthesis of the Quinone
in a later stage of the synthesis. Further disconnection led
to tricyclic compound 4. The C ring would form via SN2
reaction from the secondary amine, and the A ring would
result from conversion of the cyclohexenone. We assumed
that asymmetric Diels-Alder reaction of quinone 5 and
butadiene derivative was a key step for construction of the
cis-decalin skeleton including quarternary carbon center. It
seemed that an Ns-strategy10,11 was suitable for formation
of the remaining E ring. An asymmetric hydrogenation of
an enamide ester mediated DuPHOS catalyst12 would be
suitable to prepare optically active 5 on a large scale.
As shown in Scheme 2, synthesis of 5 was commenced
with commercially available o-vanillin (6). After protecting
the phenol of 6 with a mesyl group, the aldehyde was
subjected to Horner-Emmons reaction with a phosphonate13
to give (Z)-dehydrophenylalanine derivative 7. Catalytic
asymmetric hydrogenation of 7 proceeded smoothly in the
presence of [((COD)-(R,R)-Et-DuPHOS)Rh]+OTf- under
1000 psi of hydrogen to afford the amino ester 8. After
treating 8 with DIBAL, the resulting aldehyde was subjected
to the Wittig reaction to predominantly afford the cis-alkene
9. After switching from the Boc group of 9 to the Ns group
and upon treating 10 with DEAD and PPh3, the desired
cyclization reaction proceeded smoothly to afford 8-mem-
bered ring 11 in excellent yield.14 Removal of the Ms group
was achieved by treatment with LHMDS15 because utilizing
basic hydrolysis conditions, such as KOH in MeOH, resulted
in the ꢀ-elimination of the Ns group by deprotonation the
allylic hydrogen. Subsequent oxidation of 12 with Fremy’s
salt16 furnished quinone 5 in good yield.
With desired quinone 5 in hand, we then focused on the
stereoselective construction of the tetracyclic ring system of
3, as shown in Scheme 3. The critical intermolecular
Diels-Alder reaction was achieved by utilizing optically
active diene 13 reported by Rawal.17 Upon treatment of diene
13 and quinone 5, a facial selective Diels-Alder reaction
proceeded smoothly at room temperature to provide 14 as a
single isomer in 92% yield. Successively treating ketone 14
with NaBH4 enabled the diastereoselective reduction from
the less hindered exo-face of the molecule to afford the
alcohol as a single product. In this reaction, undesired
reduction of the vinylogous ester was not observed. Subse-
quent removal of the TBS group by TBAF and simultaneous
elimination of oxazolidinone proceeded to afford enone 4
in good yield.
(10) For a review on Ns chemistry, see: (a) Kan, T.; Fukuyama, T. J.
Syn. Org. Chem., Jpn. 2001, 59, 779. (b) Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 1204
.
The next challenge in the synthesis was oxidative cleavage
of the opening reaction cyclohexenone skeleton 4 to convert
(11) (a) Fukuyama, T.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831. (c) Fukuyama, T.; Cheung, M.; Kan,
T. Synlett 1999, 1301. (d) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth.
2002, 79, 186
.
(15) Similar deprotection of Ms group by LDA, see: (a) Ritter, T.;
Stanek, K.; Larrosa, I.; Carreira, E. M. Org. Lett. 2004, 6, 1513.
(16) For a review, see: Zimmer, H.; Lankin, D. C.; Horgan, S. W Chem.
ReV. 1971, 71, 229.
(12) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125.
(13) Schmidt, U; Lieberknecht, A; Wild, J. Synthesis 1984, 53.
(14) For construction of 8-membered ring by Ns-strategy, see: (a) Kan,
T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697.
(17) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org. Chem.
2000, 65, 9059.
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Org. Lett., Vol. 10, No. 15, 2008

Scheme 3. Synthesis of the Tetracyclic Core of Manzamine A
to the piperidine ring without affecting the reactive double
bond of the E ring. Epoxy ketone 15 was converted by
stereoselective oxidation of enone 4 with TBHP in the
presence of Triton B and subsequent protection with acetate.
Upon treatment of 15 and nosyl hydrazide in acidic condi-
tions, the desired Eshcenmoser-Tanabe fragmentation oc-
curred smoothly to give the desired alkyne, and subsequent
reduction of the resulting aldehyde and protection with TES
group afforded 16. Chemoselective conversion from alkyne
16 to N-tosylimide 17 was performed according to Chang’s
protocol.18 Upon treatment with 16 and tosyl azide in the
presence of copper iodide, the desired cycloaddition reaction
and rearrangement proceeded smoothly to give 17. Because
the direct ammonolysis of Ts-imide 17 was difficult, N-
methylation and subsequent treatment with excess ammonia
gave primary amide 18. After one-pot switching from the
TES ether to mesylate, treating the amide with PhI(OAc)2
in the presence of allyl alcohol enabled the crucial Hofmann
rearrangement to proceed smoothly to afford 19. The
piperidine ring was constructed by treating allyl carbamate
19 with potassium carbonate and concomitant of hydrolysis
of the Ac group to give 20. Due to its steric hindrance,
removing the Ns group was extremely troublesome under
typical conditions.11d After several attempts, it was found
that a combination of thioglycolic acid and LHMDS allowed
a smooth deprotection reaction to provide 21. Upon treatment
with 21 with dimethylphenylphosphine19 in carbon tetra-
chloride, the cyclization reaction proceeded to provide 3 in
excellent yield.
In conclusion, an enantioselective ABCE ring of Man-
zamine A (1) has been accomplished in 24 steps from
o-vanillin (6). Our stereoselective synthesis features a
DuPHOS-mediated catalytic asymmetric hydrogenation, ef-
ficient construction of the E ring by employing our Ns-
strategy, and a diastereoselective Diels-Alder reaction to
construct a functionalyzed cis-decalin skeleton. Sequential
Eschenmoser-Tanabe fragmentation, Chang’s amide forma-
tion, and Hofmann rearrangement converted piperidine 20
from cyclohexanone 4 even in the presence of the labile
double bond of the E-ring. Further investigation of the total
synthesis of Manzamine A (1) by introducing the C1 unit at
the vinylogous ester and constructing the D ring are currently
underway in our laboratory.
Acknowledgment. This work was financially supported
in part by Grant-in-Aid for Scientific Research on Priority
Areas 16073205 and 17025011 from The Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
of Japan.
Supporting Information Available: Available detailed
experimental procedures and spectroscopic data. This mate-
rialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
(18) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046. (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007,
46, 1897.
(19) Utilizing other phosphines or employing typical Mitsunobu condi-
tions did not provide the desired product.
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