Total Synthesis of (+)-Macquarimicin A

Article abstract of DOI:10.1021/ja038732p

The first total synthesis of (+)-macquarimicin A (1), a novel inhibitor of neutral sphingomyelinase (N-SMase) with antiinflammatory activity, has been accomplished. The present work determined the absolute configuration of (+)-1 and revised the C(2)?C(3)

Full text of DOI:10.1021/ja038732p

Published on Web 11/08/2003
Total Synthesis of (+)-Macquarimicin A
Ryosuke Munakata, Hironori Katakai, Tatsuo Ueki, Jun Kurosaka, Ken-ichi Takao, and
Kin-ichi Tadano*
Department of Applied Chemistry, Keio UniVersity, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Received September 25, 2003; E-mail: tadano@applc.keio.ac.jp
Scheme 1. Retrosynthetic Analysis for (+)-Macquarimicin A (1)
(+)-Macquarimicin A (1) was isolated from Micromonospora
chalcea by researchers at Abott in 1995.1 Later, researchers at
Sankyo found that 1 is a selective inhibitor of membrane-bound
neutral sphingomyelinase (N-SMase) and exhibits antiinflammatory
activity in vivo.2 The structure of 1 is characterized by a unique
tetracyclic framework, which comprises a cis-tetrahydroindanone
ring, a â-keto-δ-lactone ring, and a 10-membered carbocycle.1b
Scheme 2. Preparation of the (Z)-Stannylalkene 7a
As closely related natural products, an antitumor antibiotic
cochleamycin A (2)3 and a microtubule-stabilizing agent FR182877
(3)4 have been isolated. This class of natural products shares a
biogenetic hypothesis that involves the intramolecular Diels-Alder
(IMDA) reaction of polyketide intermediates.5 This intriguing
feature, combined with biological activities and a formidable
molecular architecture, makes them highly attractive synthetic
targets.6 In 2002, Sorensen et al.7 and Evans and Starr8 achieved
enantioselective total syntheses of (+)- and (-)-3, respectively.
Very recently, Tatsuta et al.9 disclosed the total synthesis of (+)-
2. Herein, we describe the first total synthesis of (+)-1, determi-
nation of its absolute configuration, and revision of the proposed
structure concerning the C(2)-C(3) geometry.10
Scheme 3. Preparation of the (E)-Iodoalkene 8a
The retrosynthetic analysis is outlined in Scheme 1.11 The
tetracyclic framework of 1 was projected to arise from the
transannular Diels-Alder (TADA) reaction12 of 5. The macrocycle
5 could be elaborated through the intramolecular Trost-Tsuji
reaction of 6, which in turn would be available via the Stille
coupling of (Z)-stannylalkene 7 and (E)-iodolalkene 8.
(Z)-Stannylalkene 7 was synthesized in two steps from dibro-
moalkene 911 (Scheme 2). The application of Uenishi’s method13
to 9 generated (Z)-bromoalkene 10 exclusively. The halogen-
lithium exchange of 10 followed by treatment with Bu3SnCl
produced 7.
the resulting diol and conversion to bromoalkyne 16 followed by
one-pot hydrostannylation-iodination17 produced (E)-iodoalkene
8.
The synthesis of the other coupling substrate 8 started from (R)-
epichlorohydrin (11) via known acetylenic compound 1214 (Scheme
3). The conversion of 12 to aldehyde 13 was conducted in a
straightforward manner and proceeded in 84% yield from 11. The
vinylogous Mukaiyama aldol reaction between 13 and 1415 gave a
1:1 diastereomeric mixture of the adducts, which was converted to
â-hydroxyketone 15 in two steps. The diastereoselective reduction16
of 15 gave the desired syn-1,3-diol exclusively. The protection of
With stannane 7 and iodide 8 in hand, assembly was undertaken
(Scheme 4). The cuprous chloride-promoted Stille coupling18,19
(97%), followed by selective deprotection20 of the TBDPS group
(94%), afforded 17. Conversion of 17 to the methyl carbonate
followed by thermolysis in toluene/MeOH furnished the â-keto ester
6. Macroallylation21 was successfully carried out to form a 17-
membered macrocycle 18 (ca. 3:2 diastereomeric mixture) in 84%
yield using Pd(PPh3)4/dppe (1:1) as a catalyst. After removal of
9
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J. AM. CHEM. SOC. 2003, 125, 14722-14723
10.1021/ja038732p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4 . Total Synthesis of (+)-1 via TADA of 5a
C(3) geometry. Further study for the syntheses of the other members
of this class of natural products is currently underway.
Acknowledgment. This research was supported by Grants-in-
Aid for Scientific Research on Priority Areas (A) “Targeted Pursuit
of Challenging Bioactive Molecules” and for the 21st Century COE
program "KEIO LCC” from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. We thank Dr. Takeshi
Ogita (Sankyo Co., Ltd.) for providing us with a sample and
spectroscopic data of macquarimicin A, and Daiso Co., Ltd. for
providing (R)-epichlorohydrin.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds and details on the
determination of the C(2)-C(3) geometry (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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Hensey, D. M.; Humphrey, P. E.; Swanson, S. J.; Barlow, G. J.;
Premachandran, U.; McAlpine, J. B. J. Antibiot. 1995, 48, 462. (b)
Hochlowski, J. E.; Mullally, M. M.; Henry, R.; Whittern, D. M.; McAlpine,
J. B. J. Antibiot. 1995, 48, 467.
(2) Tanaka, M.; Nara, F.; Yamasato, Y.; Masuda-Inoue, S.; Doi-Yoshioka,
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(4) (a) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.; Hino,
M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123. (b) Yoshimura,
S.; Sato, B.; Kinoshita, T.; Takase, S.; Terano, H. J. Antibiot. 2002, 55,
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(5) (a) Shindo, K.; Sakakibara, M.; Kawai, H.; Seto, H. J. Antibiot. 1996, 49,
249. (b) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J.
Am. Chem. Soc. 2003, 125, 5393. (c) Recent review on the topic: Stocking,
E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42, 3078.
(6) Synthetic studies: (a) Cochleamycin A: Chang, J.; Paquette, L. A. Org.
Lett. 2002, 4, 253. (b) FR182877: ref 5b and references therein.
(7) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc.
2002, 124, 4552. See also ref 5b for total synthesis of (-)-3.
(8) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002, 41, 1787.
(9) Tatsuta, K.; Narazaki, F.; Kashiki N.; Yamamoto, J.; Nakano, S. J. Antibiot.
2003, 56, 584.
(10) Macquarimicin A was originally reported to have E geometry concerning
the C(2)-C(3) double bond. However, we assumed the correct structure
of macquarimicin A to be 1 on the basis of the spectroscopic similarity
to 2.
(11) Preliminary study on our IMDA approach: Munakata, R.; Ueki, T.;
Katakai, H.; Takao, K.; Tadano, K. Org. Lett. 2001, 3, 3029.
(12) Recent review on TADA: Marsault, E.; Toro´, A.; Nowak, P.; Deslong-
champs, P. Tetrahedron 2001, 57, 4243.
(13) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998,
63, 8965.
(14) Takano, S.; Kamikubo, T.; Sugihara, T.; Suzuki, M.; Ogasawara, K.
Tetrahedron: Asymmetry 1993, 4, 201.
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Org. Chem. 1991, 56, 91.
(16) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155.
(17) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans. 1
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the TBS groups in 18, the formation of the â-keto-δ-lactone ring
under basic conditions followed by a double-bond introduction was
carried out to afford 5 as a mixture of C(2)-C(3) geometrical
isomers.22
The stage was set for the key TADA reaction. Under thermal
conditions (130 °C), the cycloaddition of 5 furnished the desired
diastereomer 4 as a sole cycloadduct. In this reaction, the (Z,E)-
geometry of the reacting diene is the origin of endo selectivity,11
while the lactone ring restricts conformation to control the diaste-
reofacical selectivity completely.23
The cycloadduct 4 was converted to (+)-1 as follows. Silylation
and removal of the MPM group, followed by Dess-Martin
oxidation, gave 14-O-TES-1. Finally, PPTS-catalyzed cleavage of
the TES ether afforded (+)-1. Spectral properties (1H and 13C NMR
and IR) of synthetic (+)-1 were completely identical to those of a
natural sample, and optical rotation of synthetic (+)-1 ([R]23
)
D
+270; c 0.20, MeOH) established the absolute configuration of
natural (+)-1 ([R]25 ) +285.6; c 0.2, MeOH). Furthermore,
D
(18) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600.
(19) Extensive investigation on the coupling reaction revealed that the use of
CuCl and the protection of the primary alcohol are essential to suppress
the intramolecular Heck-type reaction of the (Z)-alkenylstannane.
(20) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177.
(21) Review: Trost, B. M. AnVew. Chem., Int. Ed. Engl. 1989, 28, 1173.
(22) Compound 5 gave a complicated 1H NMR spectrum, making elucidation
of the E/Z ratio difficult. We attribute the complication to the tautomer-
ization of 5 (such as ketalization), in addition to the geometry of the C(2)-
C(3) double bond.
extensive NOE experiments on synthetic (+)-1 revealed that the
C(2)-C(3) geometry must be Z, not E as reported1b (see Supporting
Information for details).
In conclusion, the first total synthesis of (+)-macquarimicin A
(1) has been accomplished with 27 linear steps from 11 in 9.9%
overall yield (92% average yield per step). The synthesis features
the transannular Diels-Alder reaction, which constructed the
tetracyclic framework of 1 stereoselectively. Also, the present work
established the absolute configuration of (+)-1 and revised its C(2)-
(23) A TADA substrate without the lactone ring did not afford the desired
cycloadduct.
JA038732P
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