Simple and efficient synthesis of (+)-methyl 7-benzoylpederate, a key intermediate toward the mycalamides

Article abstract of DOI:10.1021/ol990936g

(equation presented) A simple and efficient method for the synthesis of (+)-methyl 7-benzoylpederate, the left half of pederin, mycalamides, onnamides, and theopederins, was developed. The key reactions include the Evans asymmetric aldol reaction, a thioa

Full text of DOI:10.1021/ol990936g

ORGANIC
LETTERS
1
999
Vol. 1, No. 6
57-959
Simple and Efficient Synthesis of
9
(+)-Methyl 7-Benzoylpederate, a Key
Intermediate toward the Mycalamides
Nicholas S. Trotter, Shunya Takahashi, and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research),
Wako-shi, Saitama 351-0198, Japan
nakata@postman.riken.go.jp
Received August 12, 1999
ABSTRACT
A simple and efficient method for the synthesis of (+)-methyl 7-benzoylpederate, the left half of pederin, mycalamides, onnamides, and
theopederins, was developed. The key reactions include the Evans asymmetric aldol reaction, a thioacetalization−lactonization, a stereoselective
Claisen condensation, and a Takai−Nozaki olefination. The synthesis requires only nine steps and proceeds in 26% overall yield.
1
3
4
5
Mycalamide A (1; Figure 1), isolated from a New Zealand
fuscipes. The onnamides and theopederins, which are
structurally related compounds, were isolated from a Japanese
marine sponge of the genus Theonella. Their unique structure
and potent biological activity have attracted the attention of
marine sponge of the genus Mycale, exhibits in vivo potent
antitumor and antiviral activity and immunosuppressive
6-15
numerous synthetic organic chemists:
been reported for pederin,
onnamide A, and theopederin D.13 As all of these natural
total syntheses have
mycalamides A9,10 and B,
6
-8
9,11
1
2
(
2) (a) Burres, N. S.; Clement, J. J. J. Cancer Res. 1989, 49, 2935. (b)
Ogawara, H.; Higashi, K.; Uchino, K.; Perry, N. B. Chem. Pharm. Bull.
991, 39, 2152. (c) Galvin, F.; Freeman, G. J.; Razi-Wolf, Z.; Benacerraf,
B.; Nadler, L.; Reiser, H. Eur. J. Immunol. 1993, 23, 283.
3) (a) Cardani, C.; Ghiringhelli, D.; Mondelli, R.; Quilico, A. Tetra-
1
(
hedron Lett. 1965, 2537. (b) Matsumoto, T.; Yanagiya, M.; Maeno, S.;
Yasuda, S. Tetrahedron Lett. 1968, 6297. (c) Furusaki, A.; Watanabe, T.;
Matsumoto, T.; Yanagiya, M. Tetrahedron Lett. 1968, 6301.
(4) (a) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T. J. Am.
Chem. Soc. 1988, 110, 4851. (b) Matsunaga, S.; Fusetani, N.; Nakao, Y.
Tetrahedron 1992, 48, 8369. (c) Kobayashi, J.; Itagaki, F.; Shigemori, H.,
Sasaki, T. J. Nat. Prod. 1993, 56, 976.
Figure 1. Structures of mycalamide A (1) and pederin (2).
(
5) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992, 57,
828.
6) (a) Tsuzuki, K.; Watanabe, T.; Yanagiya, M.; Matsumoto, T.
Tetrahedron Lett. 1976, 4745. (b) Yanagiya, M.; Matsuda, K.; Hasegawa,
K.; Matsumoto, T. Tetrahedron Lett. 1982, 23, 4039. (c) Matsumoto, T.;
Matsuda, F.; Hasagawa, K.; Yanagiya, M. Tetrahedron 1984, 40, 2337.
3
(
2
action via inhibition of T-cell activation. Structure elucida-
tion revealed its striking resemblance to the unique structure
of pederin (2), a strong insect toxin isolated from Paederus
(
d) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T. Tetrahedron
1
988, 44, 7063.
(1) (a) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K. J.
(7) (a) Nakata, T.; Nagao, S.; Mori, N.; Oishi, T. Tetrahedron Lett. 1985,
Am. Chem. Soc. 1988, 110, 4850. (b) Perry, N. B.; Blunt, J. W.; Munro,
M. H. G.; Thompson, A. M. J. Org. Chem. 1990, 55, 223.
26, 6461. (b) Nakata, T.; Nagao, S.; Oishi, T. Tetrahedron Lett. 1985, 26,
6465.
1
0.1021/ol990936g CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/03/1999

compounds contain an identical pederic acid (3a) as the left
half, various methods for the syntheses of pederic acid
Scheme 2a
6-8,14
derivatives 3 have been reported in these synthetic studies.
However, more efficient syntheses of pederic acid derivatives
are still required for further studies on the total synthesis
3
of this mycalamide family and detailed examination of their
biological activity. We herein describe a substantially
improved, simple, and highly efficient synthesis of (+)-
methyl 7-benzoylpederate (3b), which is the key intermediate
in our total synthesis of 1.10
Our synthetic strategy for 3b is outlined in Scheme 1. The
C4-exo-methylene unit is introduced to the ketone 4 at the
Scheme 1
a
Reagents and conditions: (a) Bu
°C; MeCHO, -78 to 0 °C (91%); (b) NaOMe, MeOH, 0 °C
70%); (c) LDA, t-BuOAc, THF, -78 to -15 °C (94%); (d)
BF ‚Et O, HSCH CH SH, CH Cl , -40 °C to room temperature
90%); (e) LDA, MeOC(Me) OCH CO Me, THF, HMPA, ZnCl
ether, -78 to -40 °C; (f) CSA, CH(OMe) , MeOH, CH Cl , room
temperature (82% from 5); (g) PhCOCl, DMAP, pyridine, room
temperature (98%); (h) (CF CO IPh, MeCN, H O, -5 °C to room
temperature (80%); (i) Zn, CH , TiCl , THF, room temperature
79%).
2 2 2 3
BOTf, CH Cl , Et N, -78 to
0
(
final stage. The key step involves the construction of the
C6-C7 bond with concomitant control of the C6 and C7
stereochemistry via a diastereoselective Claisen condensation
of the δ-lactone 5 and a glycolate unit. The δ-lactone 5 can
be prepared from the optically active 2,3-syn-hydroxy ester
3
2
2
2
2
2
(
2
2
2
2
-
3
2
2
3
2
)
I
2
2
2
2
4
(
6.
The synthesis of (+)-methyl 7-benzoylpederate (3b) started
with an Evans asymmetric aldol reaction using chiral
1
6
propionimide 7 derived from L-valine (Scheme 2). Reaction
of the boron enolate of 7 with acetaldehyde provided the
2
(8) (a) Willson, T. M.; Kocienski, P.; Jarowicki, K.; Isaac, K.; Faller,
,3-syn-alcohol 8 with excellent stereoselectivity in 91%
yield. Treatment of 8 with NaOMe in MeOH effected the
A.; Campbell, S. F.; Bordner, J. Tetrahedron 1990, 46, 1757. (b) Willson,
T. M.; Kocienski, P.; Jarowicki, K.; Isaac, K.; Hitchcock, P. M.; Faller,
A.; Campbell, S. F. Tetrahedron 1990, 46, 1767. (c) Kocienski, P.;
Jarowicki, K.; Marczak, S. Synthesis 1991, 1191.
17
alcoholysis to give methyl ester 6 without any racemization
in 70% yield. Reaction of the ester 6 with the lithium enolate
of tert-butyl acetate at -15 °C afforded a 10:1 equilibrium
mixture of â-keto ester 9 and its enol tautomer in 94% yield.
The mixture was converted into the desired δ-lactone 5 in
one step: upon treatment with 1,2-ethanedithiol in the
(
(
9) Hong, C. Y.; Kishi, Y. J. Org. Chem. 1990, 55, 4242.
10) (a) Nakata, T.; Matsukura, H.; Jian, D. L.; Nagashima, H.
Tetrahedron Lett. 1994, 35, 8229. (b) Nakata, T.; Fukui, H.; Nakagawa,
T.; Matsukura, H. Heterocycles 1996, 42, 159. Synthesis of artificial
analogues of mycalamide A: (c) Fukui, H.; Tsuchiya, Y.; Fujita, K.;
Nakagawa, T.; Koshino, H.; Nakata, T. Bioorg. Med. Chem. Lett. 1997, 7,
2
081.
11) (a) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle,
presence of BF
3
2 2 2
‚Et O in CH Cl , thioacetalization and
(
1
8
F. T. Synlett 1998, 869. Synthesis of 18-O-methyl mycalamide B: (b)
Kocienski, P.; Raubo, P.; Davis, J. K.; Boyle, F. T.; Davies, D. E.; Richter,
A. J. Chem. Soc., Perkin Trans. 1 1996, 1797.
lactonization took place simultaneously, giving a 17:1
mixture of 5 and its C3 epimer in 90% yield. The δ-lactone
5 has an ideal structure toward the target compound 3b: it
retains the 2,3-syn-dimethyl substituents, it possesses a
masked ketone for introduction of the exo-methylene unit,
and it has a lactone carbonyl group for introduction of the
glycolate unit in the development of the side chain.
(
12) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.
(13) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. T.
Synlett 1998, 1432.
14) Synthesis of pederic acid derivatives: (a) Adams, M. A.; Duggan,
(
A. J.; Smolanoff, J.; Meinwald, J. J. Am. Chem. Soc. 1979, 101, 5364. (b)
Isaac, K.; Kocienski, P.; Campbell, S. J. Chem. Soc., Chem. Commun. 1983,
2
49. (c) Roush, W. R.; Marron, T. G.; Pfeifer, L. A. J. Org. Chem. 1997,
6
2, 474. (d) Toyota, M.; Hirota, M.; Nishikawa, Y.; Fukumoto, K.; Ihara,
M. J. Org. Chem. 1998, 63, 5895.
15) Synthetic studies of mycalamides: (a) Roush, W. R.; Marron, T.
(16) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G.
J. Am. Chem. Soc. 1984, 106, 1154.
(17) Tai, A.; Imaida, M. Bull. Chem. Soc. Jpn. 1978, 51, 1114.
(18) (a) Nakata, T.; Takao, S.; Fukui, M.; Tanaka, T.; Oishi, T.
Tetrahedron Lett. 1983, 24, 3873. (b) Nakata, T.; Nagao, S.; Yakao, S.;
Tanaka, T.; Oishi, T. Tetrahedron Lett. 1985, 26, 73.
(
G. Tetrahedron Lett. 1993, 34, 5421. (b) Marron, T. G.; Roush, W. R.
Tetrahedron Lett. 1995, 36, 1581. (c) Roush, W. R.; Pfeifer, L. A.; Marron,
T. G. J. Org. Chem. 1998, 63, 2064. (d) Hoffmann, R. W.; Schlapbach, A.
Tetrahedron Lett. 1993, 34, 7903. (e) Hoffmann, R. W.; Breitfelder, S.;
Schlapbach, A. HelV. Chim. Acta 1996, 79, 346.
958
Org. Lett., Vol. 1, No. 6, 1999

In most previous syntheses of pederic acid derivatives 3,
the glycolate units were introduced to the corresponding
PhCOCl and catalytic DMAP in pyridine gave the benzoate
10b in 98% yield. Dethioacetalization of 10b with bis-
(trifluoroacetoxy)iodobenzene in aqueous MeCN20 cleanly
afforded ketone 4 in 80% yield. Finally, introduction of an
δ-lactone derivatives with low stereoselectivity of the C7-
hydroxyl group:6
a,7b,8a,14a,b
therefore, oxidation followed by
stereoselective reduction of the resulting ketone was neces-
sary for the stereoselection.6 With the δ-lactone 5 in hand,
our attention was focused on introduction of a methyl
glycolate unit to 5 with direct stereocontrol of the C7-
hydroxyl group. After several attempts, we found that in the
Claisen-type condensation of 5 and a methyl glycolate
exo-methylene to the labile ketone 4 was achieved by a
a,7b
14c,21
Takai-Nozaki olefination:
CH , and TiCl
7-benzoylpederate (3b) in 79% yield.
treatment of 4 with Zn,
2
I
2
4
in THF-CH
2
Cl provided (+)-methyl
2
2
2,23
The spectral data
1
13
( H, C NMR, and [R]
D
) of the synthetic 3b were identical
1
0b
with those of the authentic sample prepared previously
derivative, addition of ZnCl
2
improved both the yield and
the stereoselectivity. The condensation of 5 with the lithium
enolate of MeOC(Me) OCH CO Me in THF was undertaken
in the presence of HMPA and ethereal ZnCl at -78 to -40
C for 19 h to afford the coupling product. Subsequent
by this group.
19
In summary, we have developed a very simple and
efficient synthesis of (+)-methyl 7-benzoylpederate (3b), the
left half of the mycalamide family, in only nine steps and
with 26% overall yield from chiral propionimide 7.24
2
2
2
2
°
treatment with CSA and CH(OMe)
3
2 2
in MeOH-CH Cl gave
Acknowledgment. This work was supported in part by
Special Project Funding for Basic Science (Multibioprobe)
from RIKEN. We thank Ms. K. Harata for the mass spectral
measurements.
the desired 7R-hydroxy ester 10a as the single isomer in 82%
yield (two steps) along with recovered 5 (8%). In the absence
of HMPA, the coupling reaction was interminably slow, and
elevation of the reaction temperature beyond -30 °C led to
significant substrate destruction. The present reaction would
proceed with excellent stereoselection via the thermodynami-
cally stable zinc-chelated intermediate i as shown in Figure
Supporting Information Available: Full experimental
details and product characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
9
2,
in which the C7 substituent occupies an equatorial
OL990936G
position.
(19) Unrelated studies on the aldol condensation of ketones and aldehydes
by House et al. showed that addition of an ethereal solution of ZnCl2 to a
preformed lithium enolate effected an increase in the yield and significant
stereocontrol: House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead,
H. D. J. Am. Chem. Soc. 1973, 95, 3310.
(
20) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(21) (a) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1
985, 26, 5579. (b) Okazoe, T.; Hibino, J.; Takai, K.; Nozaki, H.
Tetrahedron Lett. 1985, 26, 5581. (c) Erdik, E. Tetrahedron 1987, 43, 2203.
d) Achyutha Rao, S.; Knochel, P. J. Am. Chem. Soc. 1991, 113, 5735.
22) Treatment of 3b with n-PrSLi in HMPA produced 7-benzoylpederic
(
(
acid (3c) (R1 ) H, R2 ) COPh) (96%), which was employed as the left
half in our total synthesis of mycalamide A.1
0b
+
-
(
23) The Wittig reaction of 4 using PhP3P MeI and n-BuLi produced
6
a,7b
methyl pederate (3d; R1 ) Me, R2 ) H)
(31%) and R,â-unsaturated
Figure 2.
ketone (17%) by elimination of MeOH.
(24) Our previous procedure for the synthesis of 3b needed 21 steps
and resulted in 17% overall yield starting from Evans chiral propionimide
derived from D-valine.7
b,10b
Other recent procedures for the synthesis of
Completion of the synthesis of (+)-methyl 7-benzoylped-
erate (3b) was achieved via introduction of the C4-exo-
methylene unit as follows. Protection of the alcohol 10a with
pederic acid derivatives starting from Evans chiral propionimides: Roush
group, synthesis of 3e (R1 ) H, R2 ) DMPM), 14% overall yield in 15
14c
steps; Toyota-Ihara group, synthesis of 3d (R1 ) Me, R2 ) H), 6%
overall yield in 21 steps.1
4d
Org. Lett., Vol. 1, No. 6, 1999
959