Total synthesis of (+)-Manzamine A

Article abstract of DOI:10.1021/ja103721s

A novel synthetic route to (+)-manzamine A was developed. It highlights an amazingly efficient construction of a highly strained 15-membered ring across a cyclohexenone ring with the aim of installing the requisite functionalities in a completely stereocontrolled manner. Other key features include a stereoselective Diels-Alder reaction of an optically active butenolide, construction of the 15-membered ring by intramolecular Mitsunobu reaction of a nosyl amide, [3,3]-sigmatropic rearrangement of allyl cyanate for stereoselective introduction of nitrogen functionality at a sterically congested position, and a ring-closing metathesis in the presence of labile functional groups.

Full text of DOI:10.1021/ja103721s

Published on Web 07/13/2010
Total Synthesis of (+)-Manzamine A
Tatsuya Toma, Yoichi Kita, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 9, 2010; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1
Abstract: A novel synthetic route to (+)-manzamine A was
developed. It highlights an amazingly efficient construction of a
highly strained 15-membered ring across a cyclohexenone ring
with the aim of installing the requisite functionalities in a com-
pletely stereocontrolled manner. Other key features include a
stereoselective Diels-Alder reaction of an optically active buteno-
lide, construction of the 15-membered ring by intramolecular
Mitsunobu reaction of a nosyl amide, [3,3]-sigmatropic rearrange-
ment of allyl cyanate for stereoselective introduction of nitrogen
functionality at a sterically congested position, and a ring-closing
metathesis in the presence of labile functional groups.
Manzamine A (1), which has been isolated from marine sponges
of the genera Haliclona1 and Pellina,2 exhibits broad biological
activity, including cytotoxic,1 antibacterial,2 antimalarial,3 insec-
ticidal,4 anti-inflammatory,5 and anti-HIV.6 The combination of the
outstanding biological activity and unique structure of manzamine
A has driven a number of synthetic studies aimed at the construction
of the pentacyclic core skeleton7 of ircinal A (2), a known precursor
of 1.8 Despite intensive investigations, including those conducted
in our laboratories,9e only three total syntheses have been reported
to date.9 Herein, we report a total synthesis of (+)-1 in which a
unique 15-membered ring intermediate was employed.
As illustrated in our retrosynthetic analysis (Scheme 1), we
envisioned that the bicyclic ketone 3 would be ideal for controlling
the stereochemistry of all of the stereogenic centers on ring B and
for stereoselective introduction of a C1 unit to build ring A. A
powerful nosyl chemistry could be applied for the construction of
the strained 15-membered ring.10 Ring B in turn would be
constructed by the Diels-Alder reaction between butenolide 4,
which is readily available in almost optically pure form,11 and
siloxydiene 5.
Execution of the above strategy required the preparation of
vinylogous ester 9 (Scheme 2). Alcohol 7, prepared from known
bromide 6,12 was converted to diol 8 in a three-step sequence
involving iodination, alkylation with methyl acetoacetate, and
reduction of both carbonyl groups. Dess-Martin oxidation of the
1,3-diol in the presence of t-BuOH, which promoted the second
oxidation, and subsequent one-pot esterification afforded 9. Initial
attempts to perform the Diels-Alder reaction between siloxydiene
5, which was readily prepared from 9, and 4 met with limited
success because of the extreme lability of 5 to moisture. However,
addition of a solid base such as sodium acetate and molecular sieves
proved to block hydrolysis of 5, affording 10 in 97% yield.
Methanolysis of acetoxylactone 10 gave a mixture of hydroxylac-
tone and aldehyde, but they were converted to the same methyl
ester 11 by a one-pot Wittig reaction and methylation.
12. Introduction of an amine functional group by Mitsunobu reaction
followed by a one-pot deprotection of the Boc group and the PMP
group afforded 13. With alcohol 13 in hand, we next focused on
the formation of the 15-membered ring by performing an intramo-
lecular Mitsunobu reaction. Although the target molecule was a
highly strained 15-membered ring containing a cyclohexenone ring
and an alkyne, the macrocyclization proceeded smoothly without
the need for high dilution, affording 3 in good yield.
Our next challenge was to construct the quaternary stereogenic
center. Initial attempts to construct ring A from the amine derived
from 3 by means of Mannich reaction with formaldehyde13 met
with failure, primarily because of steric problems. In another
approach, conversion of 3 to the corresponding ꢀ-ketoester followed
by direct introduction of ring E was attempted. However, the
reactivity of the ꢀ-ketoester was so poor that allyl iodides were
the only electrophiles that could be used in practice. Thus, we
decided to pursue a [3,3]-sigmatropic rearrangement of allyl cyanate
for stereoselective introduction of the nitrogen functionality (Scheme
4).14 Allyl iodide 18 was chosen as a key electrophile for accessing
the substrate for the sigmatropic rearrangement (Scheme 3).
Enantioselective addition of diethylzinc15 to known aldehyde 1416
afforded the desired alcohol 16 in 93% ee. Introduction of a
carbamate group and then deprotection and iodination of the primary
alcohol followed by recrystallization afforded enantiomerically pure
iodide 18. According to Mander’s protocol,17 ketone 3 was
converted to a ꢀ-ketoester, which was subjected to allylation with
18 (Scheme 4). As expected, stereoselective alkylation occurred
from the sterically less crowded R-face to give a single product.18
Similarly, treatment with TBHP and Triton B afforded epoxyketone
19 as a single diastereomer.19 Upon dehydration of 19 with TFAA
and Et3N,20 the critical [3,3]-sigmatropic rearrangement proceeded
even at 0 °C to give the corresponding isocyanate with complete
control of the stereochemistry. For construction of ring C, the
Reduction of the methyl ester, protection of the resulting alcohol,
hydrolysis of the enol ethers, and then selective NaBH(OAc)3
reduction of the aldehyde in the presence of the enone afforded
9
10.1021/ja103721s  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10233–10235 10233

C O M M U N I C A T I O N S
Scheme 2a
Scheme 4a
a Reaction conditions: (a) n-BuLi, THPO(CH2)2CCH, TMEDA, n-Bu4NI,
THF/HMPA, -78 °C to rt, 91%. (b) CSA, MeOH, rt, 93%. (c) I2, PPh3,
imidazole, CH3CN/Et2O, 0 °C to rt, 97%. (d) Methyl acetoacetate, NaH,
THF, reflux, 86%. (e) LiAlH4, THF, rt, 91%. (f) Dess-Martin periodinane,
t-BuOH, CH2Cl2, rt; p-TsOH·H2O, Na2SO4, MeOH, rt, 66%. (g) TBSOTf,
Et3N, Et2O, 0 °C. (h) 4, NaOAc, toluene, MS3A, reflux, 97% (two steps,
endo/exo ) 2:1). (i) Et3N, MeOH, rt; evaporation; MeOCH2PPh3Cl,
KHMDS, THF, -78 to 0 °C; MeI, i-Pr2NEt, DMF, 0 °C, 89% (E/Z ) 1:1
for endo, 1:4 for exo). (j) LiAlH4, Et2O, 0 °C, 99%. (k) TBDPSCl, imidazole,
CH2Cl2, rt, 99%. (l) p-TsOH·H2O, acetone, rt, 97%. (m) NaBH(OAc)3,
AcOH, benzene, 40 °C, 88%. (n) NsNHBoc, DEAD, PPh3, benzene, rt,
97%. (o) TFA, rt; evaporation; CAN, CH3CN/H2O, 0 °C, 81%. (p) DEAD,
PPh3, toluene (0.01M), rt, 85%.
a Reaction conditions: (a) LHMDS, THF, -78 °C; NCCO2Me, -78 °C
to rt. (b) 18, K3PO4, DMF, rt, 69% (two steps). (c) TBHP, Triton B, CH3CN/
benzene, rt, 62%. (d) TFAA, Et3N, CH2Cl2, 0 °C; evaporation; AcOH,
Mg(ClO4)2, benzene, 40 °C. (e) NaBH(OCOCF3)3, THF, rt; TFA; 5-hexenoyl
chloride, Et3N, 0 °C, 80% (two steps). (f) LiAlH4, AlCl3, Et2O, -20 to
-10 °C, 93%. (g) IBX, t-BuOH, 70 °C. (h) PhSH, Cs2CO3, CH3CN, 50 °C;
NaBH(OCOCF3)3, THF, rt, 89% (two steps). (i) 24 (1.0 equiv), PMPOH,
CH2Cl2 (1 mM), rt, 41%. (j) TBAF, THF, 50 °C; evaporation; H2, Lindlar’s
catalyst, quinoline, MeOH, rt, 84%. (k) Dess-Martin periodinane, CH2Cl2,
rt, 87%.
Scheme 3a
reaction for construction of ring E was attempted. Unfortunately,
because of the rapid isomerization of the terminal alkene, the ring-
closing metathesis reaction of substrate 21 afforded a significant
amount of the undesired seven-membered ring. Thus, we decided
to construct ring A prior to formation of ring E. While ring A was
constructed by lactamization, all attempts to reduce the lactam were
unsuccessful because of steric congestion. A reductive amination
was therefore employed to form ring A. In the event, the methyl
ester and amide groups were simultaneously reduced with a
combination of lithium aluminum hydride and aluminum chloride
to preserve the nitro group in the nosyl amide. IBX oxidation of
22 in tert-butyl alcohol,22 removal of the nosyl group, and reduction
of the resultant hemiaminal afforded diamine 23. The last crucial
step of the synthesis was the ring-closing metathesis reaction of
diamine 23. Although isomerization of the terminal alkene was not
observed, participation of the tertiary amines23 and the alkyne were
the major problems. After extensive efforts, reproducible results
were obtained when complex 2424 was utilized in the presence of
p-methoxyphenol,25 giving the eight-membered ring 25 in 41%
yield. With the pentacyclic core constructed, simple functional group
a Reaction conditions: (a) 15 (8 mol %), Et2Zn, hexane/toluene, -10 °C,
75%, 93% ee. (b) Cl3CCONCO, CH2Cl2, 0 °C; evaporation; Et3N, MeOH,
rt; evaporation; TBAF, THF, 50 °C, 99%. (c) MsCl, Et3N, CH2Cl2, 0 °C.
(d) NaI, acetone, 50 °C, 51% (two steps), >99% ee.
resultant isocyanate had to be converted to imine 20 under
anhydrous conditions because 20 was susceptible to hydrolysis even
under neutral conditions, triggering irreversible lactamization with
the methyl ester. After extensive experimentation, we found that
treatment of the isocyanate with AcOH and magnesium perchlorate
in the presence of molecular sieves enabled the desired transformation.
Subsequent reduction of imine 20 and acylation with 5-hexenoyl
chloride21 afforded amide 21. At this stage, a ring-closing metathesis
9
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C O M M U N I C A T I O N S
Scheme 5a
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Acknowledgment. We thank J. Kobayashi (Hokkaido Univer-
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Grants-in-Aid (15109001, 16073205, and 20002004) from the
Ministry of Education, Culture, Sports, Science and Technology
of Japan (MEXT). T.T. is a Research Fellow of the Japan Society
for the Promotion of Science (JSPS).
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Supporting Information Available: Experimental details and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA103721S
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