Total synthesis of (+)-mycalamide A

Article abstract of DOI:10.1021/ol052943c

A convergent total synthesis of (+)-mycalamide A is described. A Yb(OTf)₃-TMSCl catalytic system is used to synthesize a trioxadecalin ring system, which contains the right segment of mycalamide A. In addition, a tetrahydropyran ring, which is

Full text of DOI:10.1021/ol052943c

ORGANIC
LETTERS
2006
Vol. 8, No. 5
875-878
Total Synthesis of (+)-Mycalamide A
Natsuko Kagawa,† Masataka Ihara,‡ and Masahiro Toyota*,†
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan, and Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
toyota@c.s.osakafu-u.ac.jp
Received December 5, 2005
ABSTRACT
A convergent total synthesis of (
system, which contains the right segment of mycalamide A. In addition, a tetrahydropyran ring, which is the left segment, is constructed with
use of a novel one-pot -lactonization protocol. Both segments are prepared from a common starting material, -mannitol. These segments
+)-mycalamide A is described. A Yb(OTf)3−TMSCl catalytic system is used to synthesize a trioxadecalin ring
δ
D
are then coupled and the functional groups are transformed to synthesize (+)-mycalamide A.
Mycalamide A (1a) was initially isolated from a New
Zealand marine sponge in 1988.1 This natural product blocks
T-cell activation and exhibits a more effective immunosup-
pressive activity than FK-506.2 Additionally, 1a is reported
to show potent antitumor and antiviral activities. The unique
structure of 1a has attracted the attention of synthetic
chemists since it has a tetrahydropyran ring and a trioxa-
decalin ring system bridged by an N-acyl aminal bond.3
Numerous compounds which resemble mycalamide A (1a)
have been isolated. For example, the hydroxyl group at C-17
of mycalamide A (1a) is replaced by a methoxy group in
mycalamide B (1b).4 Also, theopederins5 and onnamides6
have structures similar to the mycalamides, except for the
C-15 side chain fragments. Interestingly, each natural product
shows a strong cytotoxic property. Kocienski’s convergent
† Osaka Prefecture University,
‡ Tohoku University.
(1) Perry, N. B.; Blunt, J. W.; Munro, M. H. G. J. Am. Chem. Soc. 1988,
110, 4850-4851.
(2) Garvin, F.; Freeman, G. J.; Razi-Wolf, Z.; Benacerraf, B.; Nadler,
L.; Reiser, H. Eur. J. Immunol. 1993, 23, 283-286.
(3) Total synthesis of (+)-mycalamide A: (a) Hong, C. Y.; Kishi, Y. J.
Org. Chem. 1990, 55, 4242-4245. (b) Nakata, T.; Fukui, H.; Nakagawa,
T.; Matsukura, H. Heterocycles 1996, 42, 159-164. (c) Roush, W. R.;
Pfeifer, L. A. Org. Lett. 2000, 2, 859-862. (d) Sohn, J.-H.; Waizumi, N.;
Zhong, H. M.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 7290-7291.
Formal synthesis of (+)-mycalamide A: Nakata, T.; Matsukura, H.; Jian,
D.; Nagashima, H. Tetrahedron Lett. 1994, 35, 8229-8232. Formal
synthesis of (-)-mycalamide A: Trost, B. M.; Tang, H.; Probst, G. D. J.
Am. Chem. Soc. 2004, 126, 48-49. Total synthesis of (+)-onnamide A:
Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693-9694. Other
synthetic studies: Breitfelder, S.; Schlapbach, A.; Hoffmann, R. W. Synthesis
1998, 468-478 and references therein. Toyota, M.; Hirota, M.; Hirano,
H.; Ihara, M. Org. Lett. 2000, 2, 2031-2034.
Figure 1. Structures of mycalamides A (1a) and B (1b).
protocol7 is adopted in our total synthesis of mycalamide A
(1a). However, our efforts have focused on the asymmetric
synthesis of both right and left segments of mycalamide A
(1a). Scheme 1 summarizes our retrosynthetic analysis of
the right segment of 1a. The stereochemistry of the aminal
10.1021/ol052943c CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/01/2006

Reduction of 15 with DIBAL-H (98% yield) followed by
Swern oxidation produces aldehyde 16, which is a key
intermediate for the cross-aldol reaction. Table 1 shows the
Scheme 1. Retrosynthetic Analysis of the Right Segment 2 of
Mycalamide A (1a)
Scheme 2. Stereoselective Synthesis of Aldehyde 16
at the C-10 position in the right segment 2 is due to a Curtius
rearrangement of the corresponding carboxylic acid, which
is derived from alcohol 3. The allyl group at C-15 can be
stereoselectively introduced in the presence of a Lewis acid.
Compound 3 is formed by the cyclization of aldol product 4
and subsequent acetylation. It should be noted that novel
cross-aldol reaction conditions without epimerization of the
aldehyde 5 must be created for this stage. Finally, 5 is derived
from D-mannitol through alcohol 6. Both the right and left
segments are synthesized from D-mannitol since it is a very
inexpensive chiral starting material.
Mulzer’s protocol8 is adopted to synthesize (3R,4R)-3-
benzyloxy-4,5-isopropylidenedioxypentene 11. Consequently,
acetate 8 (52% yield from 7) and alcohol 9 (41% yield from
7) are respectively isolated by silica gel column chromatog-
raphy. Each compound is converted to alcohol 10 by using
the following methods. Acetate 8 is directly hydrolyzed to
provide 10 in 98% yield. On the other hand, alcohol 9 (41%
yield from 7) is subjected to the Mitsunobu reaction followed
by hydrolysis to give 10 (2 steps, 81% yield). Treating 10
with LiAlH4 and benzylation of the corresponding alcohol
afforded benzyl ether 11 in 98% overall yield. Then the olefin
moiety of 11 is diastereoselectively dihydroxylated. As
expected, the major product is desired diol 12.9 Compound
12 is converted to 15 through alcohol 13 and diol 14.
remarkable effects of a Lewis acid in the cross-aldol reaction.
When Yb(OTf)3 is used as the Lewis acid, desired com-
pounds 17a and 17b are obtained in 59% total yield along
with the epimers 18a and 18b (entry 1). Using titanium
tetrachloride or indium trichloride gives the desired aldol
products in moderate yields (entries 2 and 3), which is similar
to the results with Yb(OTf)3. As shown in entry 5, a
stoichiometric amount of TMSCl dramatically improves the
yield of the silyl aldol product 17a, while shortening the
reaction time. Interestingly, a catalytic amount of TMSCl
does not affect the reaction (entry 4). Furthermore, a catalytic
amount of TMSOTf decreases the yield of 17a (entry 6).
The stereochemical outcome of this aldol reaction can be
rationalized as a nucleophilic attack on the chelated confor-
mation A from the less hindered face as depicted in Figure
2. Consequently, the major products are the desired aldols
17a and 17b. Enolization of 16 easily occurs at this stage.
Therefore, compounds 18a and 18b are generated from the
epimerized aldehyde epi-16. Thus, the addition of a sto-
ichiometric amount of TMSCl to Yb(OTf)3 improves the total
(4) (a) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson, A. M.
J. Org. Chem. 1990, 55, 223-227. (b) Simpson, J. S.; Garson, M. J.; Blunt,
J. W.; Munro, M. H. G.; Hooper, J. N. A. J. Nat. Prod. 2000, 63, 704-
706.
(5) (a) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992,
57, 3828-3832. (b) Tsukamoto, S.; Matsunaga, S.; Fusetani, N.; Toh-E,
A. Tetrahedron 1999, 55, 13697-13702.
(6) (a) Sakemi, S.; Ichiba, T.; Kohmoto, G.; Saucy, G.; Higa, T. J. Am.
Chem. Soc. 1988, 110, 4851-4853. (b) Matsunaga, S.; Fusetani, N.; Nakano,
Y. Tetrahedron 1992, 48, 8369-8376.
(7) Total synthesis of mycalamide B and theopederin D: Kocienski, P.;
Narquizuan, R.; Raubo, P.; Smith, C.; Farrugia, L. J.; Muir, K.; Boyle, E.
T. J. Chem. Soc., Perkin Trans. 1 2000, 2357-2384.
(8) Mulzer, J.; Greifenberg, S.; Beckstett, A.; Gottwald, M. Liebigs Ann.
Chem. 1992, 1131-1135.
876
Org. Lett., Vol. 8, No. 5, 2006

Table 1. Lewis Acid-Promoted Cross-Aldol Reactiona
Scheme 3. Preparation of the Right Segment 2
yield (%)b
(h) 17a 17b 18a 18b
Lewis acid
(mol %)
additive
(mol %)
time
entry
1
2c
3
4
5
6
Yb(OTf)3 (10) none
48
1
43
1
1
21
51
8
63
25
5
TiCl4 (150)
InCl3 (10)
none
none
41 21
46
79 10
27 24 13
Yb(OTf)3 (10) TMSCI (10)
Yb(OTf)3 (10) TMSCI (100)
Yb(OTf)3 (10) TMSOTf (10)
9
29
3
a Methyl trimethylsilyl dimethylketene acetal was used as a nucleophile.
b Two-step yield from the corresponding alcohol. c All reactions were carried
out at room temperature in CH2Cl2 except entry 2 (-78 °C).
yield of this aldol reaction by accelerating the reaction rate
prior to the enolization of 16.10
steps, 99% yield). Treating 22 with allyltrimethylsilane in
the presence of BF3‚Et2O produces the corresponding allyl
product as a single diastereoisomer. To prepare the aminal
Scheme 4. Retrosynthetic Analysis of the Left Segment 26 of
Mycalamide A (1a)
Figure 2. Plausible stereochemical rationale.
Both 17a and 17b are treated with CSA in MeOH to give
the corresponding alcohol (3 steps, 84% yield), which is
subsequently treated with MeI in the presence of NaH to
provide methyl ether 19 (95% yield). Ester 19 is converted
to 20 in three steps. An unexpected overreduction of the
diphenyl groups on the silicon atom of 20 accompanies the
removal of the benzyl ether under Birch reduction conditions.
Hence, reoxidation of the crude products with DDQ provides
21 (2 steps, 74% yield). Oxidative cleavage of the olefin
moiety of 21 followed by acetylation affords acetate 22 (2
(9) Cha, J. K.; Christ, W. H.; Kishi, Y. Tetrahedron 1984, 40, 2247-
moiety, alcohol 23, which is obtained from 22 in 86% overall
yield, is oxidized with Jones’ reagent to provide the
corresponding carboxylic acid. A Curtius rearrangement11
2255.
(10) Kagawa, N.; Toyota, M.; Ihara, M. J. Aust. Chem. 2004, 57, 655-
657 and references therein.
Org. Lett., Vol. 8, No. 5, 2006
877

is converted to diol 36 through mesylate 35. Diol 36 is
transformed into olefin 37 by oxidative cleavage and a Wittig
reaction (2 steps, 69% yield). Finally, CuOTf is used to
conduct an intermolecular cyclopropanation reaction to give
cyclopropane derivative 38 as a 3:1 mixture of the diaste-
reoisomers in 81% yield. After deprotection of the benzyl
moiety, a novel δ-lactone generation reaction is conducted
with diphenyldiselenide and NaBH4 in EtOH at 80 °C.13 The
Krapcho reaction14 of the crude product provides lactone 27,
which is then transformed into the corresponding enol triflate.
The enol triflate is subsequently converted to vinyltin 26 by
using the standard method15 (Scheme 5).
Scheme 5. Synthesis of the Left Segment 26
The left and right segments are coupled by transmetalation
of 26 followed by regioselective nucleophilic addition of the
resulting vinyl anion to the ester group of 2 and produce
adduct 39 in 50% yield. Functional group manipulations of
39, as shown in Scheme 6, provide (+)-mycalamide A (1a).
Scheme 6. Synthesis of Mycalamide A (1a)
with diphenylphosphoryl azide in the presence of TMS
ethanol provides carbamate 24 (2 steps, 78% yield). The
spectral data of 24 are identical with those reported by
Kocienski.7 Carbamate 24 is transformed into the desired
N-acyl product 25 in 78% yield. The synthesis of the right
segment 2 is completed by removing the trimethylsi-
lylethoxycarbonyl (Teoc) group with TBAF (93% yield)
(Scheme 3).
Scheme 4 shows the retrosynthetic analysis for the left
segment 26. Vinyltin species 26 is derived from lactone 27.
The phenylselenide group is introduced by a nucleophilic
ring opening of the cyclopropane unit of 28, which is
prepared by using an intermolecular cyclopropanation reac-
tion between dimethyl diazomalonate and chiral olefin 29.
Finally, 29 is derived from D-mannitol through a regiose-
lective reduction and regioselective methylation.
The spectroscopic properties of synthetic mycalamide A (1a)
are identical with those reported for the natural product.
Acknowledgment. The authors are indebted to Professor
T. Nakata (Tokyo University of Science) for providing copies
of the 1H NMR spectra of mycalamide A. We thank
Professor M. Suginome (Kyoto University) and Ms. H.
Ushitora (Kyoto University) for their assistance with the FAB
mass spectral analyses. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas
17035007 from The Ministry of Education, Culture, Sports,
Science and Technology (MEXT).
Supporting Information Available: Experimental condi-
tions and spectral data for compounds reported in this paper.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Starting with D-mannitol, R,â-unsaturated ester 32 is
synthesized as described in the literature.12 The reduction
of 32 with DIBAL-H followed by Sharpless’ asymmetric
epoxidation gives epoxy alcohol 33 (2 steps, 88% yield),
which is converted to TBDPS ether 34 via protection of the
primary alcohol and regioselective methylation. Alcohol 34
OL052943C
(13) A representative review: Wong, H. N. C.; Hon, M.-Y.; Tse, C.-
W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165-198.
(14) Krapcho, A. P. Synthesis 1982, 805-822 and 893-914.
(15) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
(11) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34, 5421-
5424.
(12) Takano, S.; Kurotaki, M.; Takahashi, M.; Ogasawara, K. Synthesis
1986, 403-406.
878
Org. Lett., Vol. 8, No. 5, 2006