A stereoselective synthesis of the C-10 to C-18 (right-half) fragment of mycalamides employing lewis acid promoted intermolecular aldol reaction.

Article abstract of DOI:10.1021/ol000072v

[reaction: see text] Beginning with D-mannitol, a stereoselective synthesis of the right-half segment of the mycalamides has been accomplished by employing Lewis acid catalyzed intermolecular aldol reaction and oxypalladation as the key steps.

Full text of DOI:10.1021/ol000072v

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2031-2034
A Stereoselective Synthesis of the C-10
to C-18 (Right-Half) Fragment of
Mycalamides Employing Lewis Acid
Promoted Intermolecular Aldol Reaction
Masahiro Toyota,* Masako Hirota, Hitomi Hirano, and Masataka Ihara*
Department of Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai, 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received April 3, 2000
ABSTRACT
Beginning with D-mannitol, a stereoselective synthesis of the right-half segment of the mycalamides has been accomplished by employing
Lewis acid catalyzed intermolecular aldol reaction and oxypalladation as the key steps.
Mycalamides A (1)1 and B (2),2 isolated from a New Zealand
sponge of the genus Mycale, are potent antiviral and
antitumor compounds (Figure 1).3 On top of that, mycala-
mides A (1) and B (2) show strong immunosuppressive
activity.4 The mycalamides are structurally related to onna-
mides5 and theopederins6 and have a highly functionalized
system in which an exo-olefinic tetrahydropyran connects
with a trioxa-cis-decalin ring through a hydroxyacetamide
moiety. The unique structural features of the mycalamides
coupled with their biological properties have provided
(1) Perry, N. B.; Blunt, J. W.; Munro, M. H. G. J. Am. Chem. Soc. 1988,
110, 4850.
(2) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson, A. M. J.
Org. Chem. 1990, 55, 223.
Figure 1.
(3) (a) Burres, N. S.; Clement, J. J. Cancer Res. 1989, 49, 2935. (b)
Ogawara, H.; Higashi, K.; Uchino, K.; Perry, N. B. Chem. Pharm. Bull.
1991, 39, 2152.
(4) Galvin, F.; Freeman, G. J.; Razi-Wolf, Z.; Benacerraf, B.; Nadler,
L.; Reiser. H. Eur. J. Immunol. 1993, 23, 283.
(5) (a) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T. J. Am.
Chem. Soc. 1988, 110, 4852. (b) Matsunaga, S.; Fusetani, N.; Nakano, Y.
Tetrahedron 1992, 48, 8369.
(6) (a) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992,
57, 3828. (b) Tsukamoto, S.; Matsunaga, S.; Fusetani, N.; Toh-e, A.
Tetrahedron 1999, 55, 13697.
motivation for the development of synthetic strategies toward
these marine natural products.7 Herein we would like to
present a stereoselective synthesis of the right segment
(C-10 to C-18) of the mycalamides.
(7) Total syntheses of the mycalamides: (a) Hong, C. Y.; Kishi, Y. J.
Org. Chem. 1990, 55, 4242. (b) Nakata, T.; Matsukura, H.; Jian, D.;
Nagashima, H. Tetrahedron Lett. 1994, 35, 8229. (c) Kocienski, P. J.;
Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. T. Synlett 1998, 869.
10.1021/ol000072v CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

Our retrosynthetic analysis for the right segment, 3, of the
mycalamides is shown in Scheme 1. The first key reaction
Scheme 2a
Scheme 1. Retrosynthetic Analysis for Right Segment of
Mycalamides
a Reagents and conditions: (a) OsO4 (cat.), NMO (100%, R:â
) 8:1); (b) t-Bu(Ph)2SiCl, DMAP, Et3N (51% after recrystalliza-
tion); (c) AcOH-THF-H2O (3:1:1), 55 °C (98%); (d) t-BuCOCl,
pyridine (89%); (e) (MeO)2CH2, P2O5 (88%); (f) DIBALH, 0 °C
(99%); (g) (COCl)2, DMSO, Et3N, -78 to -40 °C.
of 10 mol % of Yb(OTf)3 (Table 1, entry 1). Under the above
conditions, TMS ether 13 was obtained in 62% yield, as a
major product, together with alcohol 14 (15% yield). When
of the synthesis is the oxypalladation of 5 for the stereo-
selective construction of the trioxa-cis-decalin ring system
4, which already has the right-half skeleton 3 of the
mycalamides and suitable functionalities. A series of func-
tional group modifications in 6 would lead to 5. The second
key step of the present synthesis is the Lewis acid promoted
intermolecular aldol reaction of aldehyde 7 with dimeth-
ylketene methyl trimethylsilyl acetal.
Table 1. Lewis Acid Promoted Intermolecular Aldol Reactiona
The requisite aldehyde 12 for a Lewis acid promoted
intermolecular aldol reaction was prepared in a stereoselec-
tive manner as depicted in Scheme 2. Thus, dihydroxylation
of olefin 8,8 synthesized from D-mannitol, with a catalytic
amount of osmium tetroxide in the presence of N-methyl-
morpholine oxide (1.5 equiv) afforded the corresponding diol
(R: â ) 8:1),9 which was subjected to monosilylation to
produce the desired R-alcohol 9 as a single stereoisomer after
recrystallization. Hydrolysis of the acetal group of 9 followed
by monoesterification with pivaloyl chloride furnished
compound 10, which was transformed into alcohol 11 by
1,3-dioxane formation10 and DIBALH reduction of the
pivaloate ester. Alcohol 11 was oxidized to aldehyde 12
without epimerization under Swern conditions.11
equiv-
alent
13, R2 14, R2
temp, °C ) TMSb ) Hb
entry Lewis acid
12c
1
2
3
4
5
Yb(OTf)3 10 mol % rt
Sc(OTf)3 10 mol % -78 to rt
Cu(OTf)3 10 mol % rt
62%
41%
15%
19% 19%
41% 25%
21%
InCl3
TiCl4
10 mol % rt
150 mol % -78
63%
a R1 ) Si(Ph)2t-Bu. b Yield for 2 steps from the alcohol 11. c Recovered
starting material.
Sc(OTf)3 and Cu(OTf)2 were used as Lewis acid, a consider-
able amount of the starting material 12 was recovered in
addition to 14 (entries 2 and 3). Subjecting 12 to InCl3 at
room temperature led to the coupled products (13 and 14,
with a combined yield greater than 60% yield, entry 4).
Unlike the above results, only 14 was isolated when
employing TiCl4 as Lewis acid13 (entry 5).
We initially investigated the intermolecular aldol reaction12
of aldehyde 12 with the dimethylketene acetal in the presence
(8) Nokami, J.; Ogawa, H.; Miyamoto, S.; Mandai, T.; Wakabayashi,
S.; Tsuji, J. Tetrahedron Lett. 1988, 29, 5181.
(9) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(10) Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276.
(11) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
The stereochemistry of hydroxyester 14 was determined
after the conversion of 14 to the bicyclic compound 19 as
(13) We evaluated Lewis acids such as TMSOTf, Eu(OTf)3, Gd(OTf)3,
and Y(OTf)3; however, all the Lewis acids tested gave low yields.
(12) Review: Kobayashi, S. Synlett 1994, 689.
2032
Org. Lett., Vol. 2, No. 14, 2000

shown in Figure 3. The stereochemical outcome of the
present aldol reaction might be rationalized by nucleophilic
attack from less hindered face (Figure 2). With stereoselective
Table 2. Intramolecular Oxypalladation of the Compound 16a
entry
Pd
additive
CuCl, O2 DMF-H2O 67% 22% trace
DMSO 84% 9%
solvent
17
18
19
1
2
PdCl2
Pd(Oac)2
a R ) CH2OSi(Ph)2t-Bu.
Figure 2.
led to 18 (84%) together with 19 (9%). The structures of 18
and 19 were confirmed by their NOE experiments as shown
in Figure 3. Since the formation of the second ring proved
induction of the side chain established, we next focused on
the formation of the second ring of 4 (Scheme 1). The
required substrate 16 for oxypalladation14 was readily
prepared via a six-step sequence from 14 (Scheme 3).
Scheme 3a
Figure 3.
to be more difficult than expected,16 we decided to apply
the experimental result (entry 1) of the oxypalladation of
compound 16 to the construction of enol ether 17. After
transformation of 15 into the requisite substrate in three steps
(74% overall yield), the oxypalladation was carried out under
the reaction conditions similar to those of entry 1 (Table 2)
to provide the desired enol ether 20 in 83% yield.
a Reagents and conditions: (a) NaH, MeI, 0 °C to rt (95%); (b)
DIBALH, 0 °C (100%); (c) SO3‚Py DMSO, Et3N (97%); (d)
Ph3PEtBr, BuLi, 0 °C (100%); (e) liquid NH3, Li, -78 °C; (f) DDQ
(73% for two steps).
With the skeletal framework assembled, completion of the
synthesis of the right segment of the mycalamides would
require the installation of the side chain and the carbamate
group. Compound 20 was subjected to ozonolysis followed
by DIBALH reduction and acetylation, generating the
corresponding lactol, which was exposed to allyltrimethyl-
silane in the presence of BF3‚Et2O to give rise to the allylated
trioxadecalin 21 as a single stereoisomer (Scheme 4).17
Asymmetric dihydroxylation18 of 21 gave a mixture of diol
isomers (â: R ) 3.6:1), which were easily separated after
conversion to the cyclic carbonate with triphosgene. The
major product was treated with tetrabutylammonium fluoride
Methylation of alcohol 14 followed by DIBALH reduction
and oxidation provided aldehyde 15, which was allowed to
undergo a Wittig reaction to give the corresponding olefin.
After reductive deprotection of the benzyl group, the phenyl
moiety on the silicon, partially reduced, was reoxidized with
DDQ to afford 16.
Upon treatment of olefin 16 with PdCl2 in the presence
of CuCl in a mixture of DMF and water under a oxygen
atmosphere, the oxypalladation proceeded smoothly, produc-
ing cyclized products (17 and 18), in 89% yield, as a 3:1
separable mixture (Table 2). The result from the next
(16) Although we tried to construct directly the second ring system of
the right-half segment using 14 and 15, the desired bicyclic compounds
were not formed in considerable yield.
15
example was intriguing. Switching catalyst to Pd(OAc)2
(14) Review: Hosokawa, T.; Murahashi, S. Acc. Chem. Res. 1990, 23,
49.
(17) Breitfelder, S.; Schlapbach, A.; Hoffmann, R. W. Synthesis 1998,
468.
(15) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M. Tetrahedron
Lett. 1989, 30, 4925.
(18) Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, B. Chem.
ReV 1994, 94, 2483.
Org. Lett., Vol. 2, No. 14, 2000
2033

presence of 2-(trimethylsilyl)ethanol to furnish carbamate 23.
The stereochemistry of 21 and 23 was established by
the NOE experiments as shown in Figure 4. Finally, to
Scheme 4a
Figure 4.
confirm the structure of 23 by direct comparison, cyclic
carbonate 23 was transformed into compound 37c in three
steps.
In conclusion, a stereoselective synthesis of the right half
of the mycalamides has been demonstrated by employing
Lewis acid promoted intermolecular aldol reaction and
oxypalladation as the key steps. This route would be
adaptable to the preparation of onnamides and theopederins.
a Reagents and conditions: (a) Ph3PMeBr, BuLi, 0 °C to rt
(100%); (b) liquid NH3, Li, -78 °C; (c) DDQ (74% for two steps);
(d) PdCl2, CuCl, O2, DMF-H2O (83%); (e) O3, -78 °C, then Me2S
(80%); (f) DIBALH, -78 °C; (g) Ac2O, pyridine (96% for two
steps); (h) allyltrimethylsilane, BF3‚Et2O, 4 Å molecular sieves, 0
°C; (i) K2OsO4‚2H2O, dihydroquinone 9-phenanthryl ether,
K3Fe(CN)6, K2CO3 (96%, R:â ) 1:3.6); (j) triphosgene, Et3N (72%);
(k) Bu4NF (92%); (l) Jones reagent; (m) (PhO)2P(O)N3, Et3N,
2-(trimethylsilyl)ethanol, 4 Å molecular sieves, 65 °C (70% for
two steps); (n) LiOH‚H2O, MeOH (76%); (o) TBDMSCl, DMAP,
Et3N (100%); (p) CF3SO3Me, 2,6-di-tert-butyl-4-methylpyridine, 70
°C (66%).
Acknowledgment. We thank Professor P. J. Kocienski
for providing us with the spectral data of compound 3.
OL000072V
to yield alcohol 22, which was subjected to Jones oxidation
followed by a Curtius rearrangement reaction19 in the
(19) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203.
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Org. Lett., Vol. 2, No. 14, 2000