Synthesis of the C(43)-C(67) fragment of amphidinol 3

Article abstract of DOI:10.1021/ol052322j

(Chemical Equation Presented) A synthesis of the C(43)-C(67) fragment of amphidinol 3 (AM3) has been accomplished by a route that features the use of a double allylboration reaction for synthesis of 1,5-diol 4b, which serves as a precursor to dihydropyran

Full text of DOI:10.1021/ol052322j

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5509-5512
Synthesis of the C(43)
of Amphidinol 3
−C(67) Fragment
Jacqueline D. Hicks,† Eric M. Flamme,† and William R. Roush*,‡
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109, and
Department of Chemistry, Scripps-Florida, Jupiter, Florida 33485
roush@scripps.edu
Received September 24, 2005
ABSTRACT
A synthesis of the C(43)−C(67) fragment of amphidinol 3 (AM3) has been accomplished by a route that features the use of a double allylboration
reaction for synthesis of 1,5-diol 4b, which serves as a precursor to dihydropyran 11.
The amphidinols are a class of natural products isolated from
the marine dinoflagelates Amphidinium sp. that display
antifungal, hemolytic, cytoxic, and ichthyotoxic activities.1
Of the 13 polyketide metabolites in this family, amphidinol
3 (AM3) is one of the most biologically active, with
antifungal activity against Aspergillus niger and hemolytic
activity on human erythrocytes.1c AM3 effects cholesterol-
dependent membrane disruption, leading to speculation that
its mode of action may, in part, be due to disruption of cell
membranes.1c
25 stereocenters on a contiguous 67 carbon backbone. Since
Murata’s assignment of the absolute configuration of AM3
appeared in 1999,2 a number of synthetic studies toward AM3
have been disclosed, including reports from Cossy,3 Rych-
novsky,4 Paquette,5 and our laboratory.6 Herein, we describe
a synthesis of the protected C(43)-C(67) fragment 1 of AM3
via the intermediacy of pyran 3, which will also serve as a
precursor to the stereochemically identical C(32)-C(39)
tetrahydropyran unit.
Analysis of the C(44)-C(51) and C(32)-C(39) tetrahy-
dropyran units of AM3 reveals these fragments to be
identical, suggesting that they should be synthesized from a
common intermediate (Figure 1). Disconnection of the
C(42)-C(43) and the C(25)-C(26) bonds gives major
fragments 1 and 2 (plus the C(1)-C(25) polyol fragment
previously synthesized in our group; not shown).6 Intermedi-
ates 1 and 2 can be simplified to the tetrahydropyran 3, which
The complex structure of AM3 makes it an interesting
synthetic target. It contains a C(52)-C(67) skipped polyene
chain, a series of 1,5-diols within the C(2)-C(15) region,
two highly substituted tetrahydropyran units, and a total of
† University of Michigan.
‡ Scripps-Florida.
(1) (a) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J.
Am. Chem. Soc. 1991, 113, 9859. (b) Paul, G. K.; Matsumori, N.; Murata,
M.; Tachibana, K. Tetrahedron Lett. 1995, 36, 6279.(c) Paul, G. K.;
Matsumori, N.; Konoki, K.; Sasaki, M.; Murata, M.; Tachibana, K. In
Harmful and Toxic Algal Blooms. Proceeding of the SeVenth International
Conference on Toxic Phytoplankton; Yasumoto, T., Oshima, Y., Fukuyo,
Y., Eds.; UNESCO: Sendai, Japan, 1996; p 503. (d) Paul, G. K.; Matsumori,
N.; Konoki, K.; Murata, M.; Tachibana, K. J. Mar. Biotech. 1997, 5, 124.
(e) Echigoya, R.; Rhodes, L.; Oshima, Y.; Satake, M. Harmful Algae 2005,
4, 383.
(2) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana,
K. J. Am. Chem. Soc. 1999, 121, 870.
(3) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451.
(4) de Vicente, J.; Betzemeier, B.; Rychnovsky, S. D. Org. Lett. 2005,
7, 1853.
(5) Paquette, L. A.; Chang, S. Org. Lett. 2005, 7, 3111.
(6) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411.
10.1021/ol052322j CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/22/2005

Figure 1. Retrosynthetic analysis.
contains all of the stereocenters present in 1 and 2. We
envisioned that tetrahydropyran 3 could be accessed via
dehydrative cyclization7 of syn-1,5-diol 4b, which in turn
would be synthesized by using the double allylboration
reaction methodology developed in this laboratory.8
a 70-80% yield of syn-1,5-diol 4b was obtained with an
overall reaction selectivity of 9:1 dr after the second
allylboration reaction. Because attempts to accomplish the
selective mesylation of 4b were unsuccessful, we pursued
the stepwise functionalization approach that we recently
reported.7 Thus, treatment of 4b with TESCl (1.05 equiv),
imidazole, and DMAP at -78 °C provided the mono-TES
ether 9 in 81% yield, with >20:1 regioselectivity for
silylation of the allylic alcohol. The homoallylic hydroxyl
group was then functionalized as a mesylate and the allylic
Our initial goal was to prepare a differentially function-
alized derivative of 4b that would serve as a precursor to
pyran 3. Accordingly, we targeted an intermediate such as
hydroxy mesylate 10 to serve as the immediate precursor of
3 (Scheme 1).7 In initial studies, in situ generated γ-boryl-
substituted allylborane 68 was treated with aldehyde 5a9 (0.8
equiv) at -78 °C. After the first allylboration was allowed
to proceed to completion at -78 °C, D-glyceraldehyde
acetonide10 was added and the reaction mixture was allowed
to warm to ambient temperature overnight. This sequence
provided the syn-1,5-diol 4a in 57% yield and 4:1 dr.
Investigation of the selectivity of each allylation reaction (by
isolating the intermediate allylboronate 7 in Scheme 1)
revealed that the initial reaction of aldehyde 5a and allyl-
borating reagent 6 is stereochemically mismatched.11 For-
tunately, use of acetonide-protected aldehyde 5b12 in place
of 5a resulted in significantly improved mismatched double
diastereoselectivity in the first allylboration step; ultimately,
Scheme 1. Synthesis of Mesylate 10
(7) Flamme, E. M.; Roush, W. R. Beilstein J. Org. Chem. 2005, 1, 7.
(8) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
(9) Aldehyde 5a was made starting from diisopropyl D-tartrate. See the
Supporting Information for details.
(10) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J. Org. Chem.
1991, 56, 4056.
(11) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1.
(12) Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org.
Chem. 1997, 62, 8095.
5510
Org. Lett., Vol. 7, No. 24, 2005

TES group removed under acidic conditions to give cycliza-
tion precursor 10 (93% yield from 9).
Table 2. Dihydroxylation of Dihydropyran 11
With hydroxy mesylate 10 in hand, we turned our attention
to the cyclization of 10 to dihydropyran 11. This transforma-
tion was complicated by a competing elimination pathway
(Table 1). Initial attempts to effect the cyclization of 11 using
entry
conditions
yield (%)
dr
Table 1. Cyclization of Mesylate 10 to Dihydropyran 11
1
2
OsO4, NMO, acetone-H2O
K2OsO2(OH)4, DHQD-IND, K3FeCN6,
K2CO3, t-BuOH-H2O
80
97
1.6:1
3:1
3
OsO4, TMEDA, CH2Cl2, -78 °C
75
9:1
DHQD-IND ligand,16 provided a slight increase in selectivity
(dr 3:1). We found, however, that the diastereoselectivity
could be further improved through the use of stoichiometric
OsO4 and TMEDA in CH2Cl2 -78 °C,17 which provided
tetrahydropyran 3 in 75% yield and with 9:1 diastereo-
selectivity (entry 3, Table 2).
Synthesis of the C(43)-C(67) polyene fragment was
initiated by protection of 3 as the bis-PMB ether followed
by deprotection of the TBDPS group, which delivered
primary alcohol 13 in 94% yield (Scheme 2). Oxidation of
yield of
entry
conditions
10/11/12a 11 (%)
1
2
3
4
5
KHMDS, THF, -78 °C
26:0:74
74:0:26
30:54:16
23:50:27
0:85:15
(Bu3Sn)2O, benzene; DMF 80 °C
(Bu3Sn)2O, benzene; NMP 150 °C
KOtBu, t-BuOH; 40 °C (0.05 M)
KOtBu, t-AmOH, 0 °C (0.03 M)
36
41
80
1
a Ratio determined by H NMR analysis.
Scheme 2. Synthesis of Aldehyde 15
a strong base such as KHMDS resulted in exclusive
formation of diene 12 (entry 1, Table 1). We anticipated7
that use of the less basic tributylstannyl ether13 generated
from alcohol 10 would minimize elimination and favor the
cyclization to dihydropyran 11. However, the requisite
tributylstannyl ether, prepared by treatment of 10 with (Bu3-
Sn)2O in benzene, was not sufficiently nucleophilic to
undergo cyclization at 80 °C. Although the cyclization
occurred at higher temperatures (150 °C), significant de-
composition was observed and only poor yields of 11 were
obtained (entry 3, Table 1). After examining a number of
other bases, we discovered that KO-t-Bu in protic solvents,
under high dilution conditions, gave attractive mixtures
(2:1) of 11 relative to the diene 12. Further optimization of
the reaction solvent (tert-amyl alcohol), temperature (0 °C),
and concentration (0.03 M) provided 11 and 12 with 85:15
selectivity (entry 5, Table 1). Dihydropyran was obtained in
80% isolated yield under these conditions.
13 using the Swern protocol18 and treatment of the resulting
aldehyde with vinylmagnesium bromide gave allylic alcohol
14 in 91% yield as a 2:1 mixture of diastereomers. Subjection
of this mixture to a Johnson ortho ester Claisen rearrange-
ment19 followed by DIBAL reduction of the resulting ester
provided aldehyde 15 in 70% yield.
We turned next to the dihydroxylation reaction required
to set the final stereocenters in tetrahydropyran 3. Unfortu-
nately, only a slight preference for dihydroxylation on the
bottom face of 11 was observed (dr 1.6:1) under standard
OsO4/NMO conditions (entry 1, Table 2).14 Attempts to
improve the facial selectivity, through the use of the
Sharpless asymmetric dihydroxylation protocol15 with the
(15) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(16) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568.
(17) (a) Tomioka, K.; Nakajima, M.; Koga, K. J. Am. Chem. Soc. 1987,
109, 6213. (b) Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992,
57, 468. (c) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N.
J. Tetrahedron Lett. 1997, 38, 5027.
(13) (a) Davies, A. G. Organotin Chemistry; Wiley-VCH: Weinheim,
1997. (b) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
(14) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(18) Tidwell, T. T. Org. React. 1990, 39, 297.
Org. Lett., Vol. 7, No. 24, 2005
5511

Scheme 3. Synthesis of the C(43)-C(67) Fragment of AM3
Our plan was to subject pyran 15 to a Horner-
aldehyde 15. Use of the more reactive diethyl phosphonate
21 led to the isolation of 1 in 66% yield, but with diminished
selectivity (86:14 E/Z).
Wadsworth-Emmons olenfination reaction with dienylic
phosphonate 20 or 21 to complete the synthesis of the
C(43)-C(67) fragment 1 (Scheme 3). The synthesis of
phosphonates 20 and 21 commenced with the homologation
of (E)-hepta-4,6-dienal (16)20 with commerically available
phosphonate 17, thereby providing tetraene 18. DIBAL
reduction of 18 afforded alcohol 19, which was converted
to the primary bromide upon treatment with CBr4 and PPh3.
The sensitive dienylic bromide was immediately treated with
either sodium diisopropyl phosphite or triethyl phosphite to
give 20 and 21, respectively. Olefination of aldehyde 15 with
diisopropyl phosphonate 20 proceeded with 90:10 E/Z
selectivity,21 albeit in only 22% yield (best under the various
conditions examined), owing to oligomerization of the
In summary, we have synthesized the C(43)-C(67)
fragment 1 of AM3 via the intermediacy of tetrahydropyran
3, an intermediate that we plan also to elaborate into the
C(26)-C(42) tetrahydropyran fragment 2. Tetrahydropyran
3 was synthesized in six steps (30% yield) from aldehyde
5b via a sequence featuring the double-allylboration reaction
with 6 and the base-mediated cyclization of hydroxy mesylate
10 to dihydropyran 11. Further progress on the synthesis of
AM3 will be reported in due course.
Acknowledgment. This work was supported by the
National Institutes of Health (GM 38436).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T.; Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741.
(20) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 15878.
(21) Roush, W. R.; Peseckis, S. M.; Walts, A. E. J. Org. Chem. 1984,
49, 3429.
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Org. Lett., Vol. 7, No. 24, 2005