Synthesis of the C11-C29 fragment of amphidinolide F

Article abstract of DOI:10.1021/ol048381z

(Chemical Equation Presented) An efficient synthesis of the C(11)-C(29) fragment 31 of amphidinolide F has been accomplished via a diastereoselective [3 + 2]-annulation reaction of allylsilane 5 and ethyl glyoxylate to prepare the key tetrahydrofuran 15 a

Full text of DOI:10.1021/ol048381z

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3865-3868
Synthesis of the C11
Amphidinolide F
−C29 Fragment of
J. Brad Shotwell and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received August 13, 2004
ABSTRACT
An efficient synthesis of the C(11)
reaction of allylsilane 5 and ethyl glyoxylate to prepare the key tetrahydrofuran 15 and a highly stereoselective methyl ketone aldol reaction
to generate the C(11) C(16) segment.
−C(29) fragment 31 of amphidinolide F has been accomplished via a diastereoselective [3 + 2]-annulation
−
The amphidinolides are a structurally diverse group of
bioactive secondary metabolites isolated from the symbiotic
marine dinoflagellate Amphidinium sp. Kobayashi and co-
workers have published numerous spectroscopic and semi-
synthetic studies relating to various members of this class,
culminating in relative and/or absolute stereochemical as-
signments for most members of the amphidinolide family.1
Importantly, Kobayashi has also demonstrated that many am-
phidinolides possess extremely potent antineoplastic activity.1
The combination of structural diversity and potent cytotox-
icity has led to interest in both the biosynthesis and mode(s)
of action of these compounds. Accordingly, total syntheses
of various members of this class (amphidinolides A,2 K,3
P,4 J,5 R,6 T1,7 T2-T5,7a,c and W8) have been reported,
several resulting in reassignments in relative and/or absolute
configuration for certain members of the family.2d,3,4,8
The 25-membered macrocycle possessing two embedded
trans-tetrahydrofuran moieties is unique to amphidinolides
F9 (1) and C10 (2) (Figure 1). While amphidinolide C (2)
possesses potent cytotoxic activity against murine lymphoma
L1210 and epidermoid carcinoma KB cells in vitro (IC50
)
0.0058 and 0.0046 µg mL-1, respectively), amphidinolide F
displays much more modest activity (1.5 and 3.2 µg mL-1,
respectively).9,10 Kobayashi has reported partial syntheses of
the C(19)-C(26) and C(1)-C(8) portions of 1 and 2 in
connection with stereochemical assignments.11 We report
herein our synthetic studies on 1 and 2, resulting in the
synthesis of the C11-C29 fragment 31 corresponding to
amphidinolide F (1).
A retrosynthetic analysis of 1 and 2 is presented in Figure
1. A variety of metal-mediated processes could allow the
late-stage union of functionalized tetrahydrofurans 3 and 4.
(5) Williams, D.; Kissel, W. J. Am. Chem. Soc. 1998, 120, 11198.
(6) Kissel, W. Ph.D. Dissertation, Indiana University, Bloomington, IN,
1998.
(7) (a) Fu¨rstner, A.; Aissa, C.; Riveiros, R.; Ragot, J. Angew. Chem.,
Int. Ed. 2002, 41, 4763. (b) Ghosh, A.; Liu, C. J. Am. Chem. Soc. 2003,
125, 2374. (c) Aiessa, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem.
Soc. 2003, 125, 15512. (d) Colby, E.; O’Brien, K.; Jamison, T. J. Am. Chem.
Soc. 2004, 126, 998.
(8) Ghosh, A.; Gong, G. J. Am. Chem. Soc. 2004, 126, 3704.
(9) Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu, T.;
Hirota, H.; Sasaki, T. J. Antibiot. 1991, 44, 1259.
(10) Kobayashi, J.; Ishibashi, M.; Wa¨lchli, M.; Nakamura, H.; Hirata,
Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490.
(11) (a) Ishiyama, H.; Ishibashi, M.; Kobayashi, J. Chem. Pharm. Bull.
1996, 44, 1819. (b) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001,
3, 1363. (c) Kubota, T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59,
1613.
(1) For recent reviews, see: (a) Kobayashi, J.; Ishibashi, M. Chem. ReV.
1993, 93, 1753. (b) Chakraborty, T.; Das, S. Curr. Med. Chem.: Anti-
Cancer Agents 2001, 1, 131. (c) Kobayashi, J.; Shimbo, K.; Kubota, T.;
Tsuda, M. Pure Appl. Chem. 2003, 75, 337. (d) Kobayashi, J.; Tsuda, M.
Nat. Prod. Rep. 2004, 21, 77.
(2) (a) Pattenden, G.; Lam, H. Angew. Chem., Int. Ed. 2002, 41, 508.
(b) Maleczka, R.; Terrell, L.; Geng, F.; Ward, J. Org. Lett. 2002, 4, 2841.
(c) Trost, B.; Chisholm, J.; Wrobleski, S.; Jung, M. J. Am. Chem. Soc.
2002, 124, 12420. (d) Trost, B.; Harrington, P. J. Am. Chem. Soc. 2003,
126, 5028.
(3) Williams, D.; Meyer, K. J. Am. Chem. Soc. 2001, 123, 765.
(4) Williams, D.; Myers, B.; Mi, L. Org. Lett. 2000, 2, 945.
10.1021/ol048381z CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/15/2004

Scheme 1. Synthesis of the C(20)-C(23) Tetrahydrofuran
Studies of the eventual protiodesilylation reaction that
would be used to excise the PhMe2Si- substituent of
15-17 revealed that a dithiane carbonyl protecting group
would survive the harsh basic reaction conditions anticipated
for the C(sp3)-SiMe2Ph bond cleavage (vida infra).19 Ac-
cordingly, alkylation of iodide 17 with dithiane 2020 (Scheme
2) afforded 21 as a mixture of silylated and desilylated
Figure 1. Retrosynthetic analysis.
Of current interest to our laboratory is the convergent
synthesis of substituted tetrahydrofurans via the stereocon-
trolled [3 + 2]-annulation of aldehydes and allylsilanes.12
Accordingly, we anticipated that the C(20)-C(23) and
C(3)-C(6) tetrahydrofuran units of 3 and 4 would be
constructed via chelate-controlled [3 + 2]-annulations of
chiral allylic silanes 5 and 6.13 Further examination of 1 and
2 reveals the opportunity for formation of the C(13)-C(14)
bond via a methyl ketone aldol reaction (Figure 1). To
achieve Felkin-type selectivity in the aldol step, replacement
of the C(15) ketone with a (S)-hydroxyl group (as in 3 and
7) reveals a 1,3-diol that could derive from â-hydroxy ketone
8. In the forward sense, intermediate 8 could result from a
matched double-asymmetric aldol reaction (i.e., 9 + 10 f
8).14 Stereochemical information could then be effectively
relayed to C(13) in 7 via an Evans-Tishchenko reduction.15
Efforts toward the key C(20)-C(23) tetrahydrofuran began
with known aldehyde 11.16 Silylallylboration of 11 with
(+)-pinene-derived silylallyborane 1217 followed by TBS-
protection afforded R-hydroxylallylsilane 5 in 57% overall
yield (91% ee). Treatment of 5 with ethyl glyoxylate (13)
and SnCl4 gave [3 + 2]-annulation adduct 15 (consistent with
syn-synclinal transition state 14)12c in 62% yield as a single
diastereomer.18 Subsequent standard manipulations of 15
provided iodide 17 in excellent yield.
Scheme 2. Preparation of Propargyl Alcohol 22
terminal alkynes (i.e., R ) TES and H, ca. 4:1). Subsequent
exposure of the crude reaction mixture to tetrabutylammo-
nium fluoride in THF at 0 °C gave propargyl alcohol 22 in
97% yield from iodide 17.
Allyl- and crotylsilanes have proven to be powerful
intermediates for the convergent preparation of stereodefined
3866
Org. Lett., Vol. 6, No. 21, 2004

tetrahydrofurans, as illustrated in the present work for the
rapid construction of the C(20)-C(23) tetrahydrofuran
moiety of amphidinolides C/F. However, this method neces-
sarily generates tetrahydrofurans with silicon substitution on
the newly formed tetrahydrofuran ring. In the current case,
where an unsubstituted tetrahydrofuran is required, a sub-
sequent protiodesilylation step is used to remove the di-
methylphenylsilyl substituent. Early efforts on the protiode-
silylation reaction of C(sp3)-SiMe2Ph units in our labora-
tory12c,21 made use of a modified Hudrlik reaction,22 in which
TBAF was added to Hudrlik’s standard conditions for this
reaction (5% KOtBu, 18-crown-6, DMSO-H2O, 95 °C) to
effect in situ deprotection of the proximal TBS ether to give
the free hydroxyl group, which was believed to be required
for the subsequent protiodesilylation step.22 Unfortunately,
application of this protocol to 21 or 22 proved to be quite
problematic, requiring rigorous degassing and extended
reaction times to generate protiodesilylated adduct 24 in low
yield (entry 1, Table 1). Prolonged exposure of 20 to these
During the course of efforts to optimize this experiment,
we discovered that intermediate silanol 23 was generated
rapidly and in good yield upon exclusion of 18-crown-6 from
the reaction mixture (entry 2, Table 1).23 Additionally, it was
found that 23 converted to 24 upon exposure to standard
conditions with added 18-crown-6 (cf. entry 1, Table 1).
Hypothesizing that the conversion of silanol 23 to protiode-
silylated 24 might proceed via the intermediacy of the
corresponding siloxane, we treated 22 with TBAF in DMF,
conditions known to effect the protiodesilylation of isolated
siloxanes24 (entries 3 and 4, Table 1). Under optimal
conditions (entry 4), 24 was obtained in 90% yield from 22.
This result indicates that the “naked” alkoxides presumably
generated upon treatment of 21/22 with 18-crown-6/KOtBu
mixtures are not required for the efficient protiodesilylation
of C(sp3)-SiMe2Ph bonds (entry 4, Table 1). The TBAF-
mediated protiodesilylation of 22 proceeds via the interme-
diacy of isolable silanol 23 (entry 3, Table 1) in THF/DMF
solvent mixtures in excellent isolated yield.25 With efficient
Scheme 3. Synthesis of â-Hydroxyketone 27
Table 1. Optimization of a C(sp3)-SiMe2Ph Protiodesilylation
isolated yield (%)
conditions
substrate 22
21 or 23
23
24
(1) 5% KOtBu, DMSO/H2O, 95 °C,
3 days, 18-crown-6, TBAF
(2) 5% KOtBu, DMSO/H2O, 95 °C,
TBAF, 4 h
<30
21
92
(3) TBAF, THF/DMF, 85 °C, 4 h
(4) TBAF, THF/DMF, 85 °C, 24 h
(5) Bu4NOH, THF/DMF, 85 °C, 36 h 22
22
22
56
<5
35
90
80
protiodesilylation conditions led to no appreciable decom-
position, suggesting the propargylic alcohol unit in 21 and
22 was the offending functionality.
access to the protiodesilylated C(15)-C(26) fragment 24
secured, we next focused on the stereoselective formation
of the C(11)-C(16) polyketide segment of amphidinolides
C/F. Protection of the C(24) hydroxyl as the corresponding
TBS ether, DDQ-mediated deprotection of the -OPMB
protecting group,26 and Parikh-Doering oxidation27 of the
derived primary alcohol afforded aldehyde 25 in excellent
(12) (a) Panek, J.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. (b)
Panek, J.; Beresis, R. J. Org. Chem. 1993, 58, 809. (c) Micalizio, G.; Roush,
W. Org. Lett. 2000, 2, 461.
(13) (a) Davies, H.; Hansen, T.; Rutberg, J.; Bruzinski, P. Tetrahedron
Lett. 1997, 38, 1741. (b) Bulugahapitiya, P.; Landais, Y.; Parra-Rapado,
L.; Planchenault, D.; Weber, V. J. Org. Chem. 1997, 62, 1630.
(14) (a) Paterson, I.; Goodman, J.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R.
Tetrahedron Lett. 1995, 36, 3443. (c) Roush, W. R.; Dilley, D. J.
Tetrahedron Lett. 1999, 40, 4955.
(15) Evans, D.; Hoveyda, A. J. Am. Chem. Soc. 1990, 112, 6447.
(16) Nicolaou, K.; Murphy, F.; Barluenga, S.; Ohshima, T.; Wei, H.;
Xu, J.; Gray, D.; Baudoin, O. J. Am. Chem. Soc. 2000, 122, 3830.
(17) Roush, W.; Pinchuk, A.; Micalizio, G. Tetrahedron Lett. 2000, 41,
9413.
(18) Stereochemistry of 15 was assigned by NOE studies of the derived
alcohol 16 and chemical correlation with a known compound (see
Supporting Information).
(22) (a) Hudrlik, P.; Hudrlik, A.; Kulkarni, A. J. Am. Chem. Soc. 1982,
104, 6809. (b) Hudrlik, P.; Holmes, P.; Hudrlik A. Tetrahedron Lett. 1988,
29, 6395. (c) Hudrlik, P.; Gebreselassie, P.; Tafesse, L.; Hudrlik, A.
Tetrahedron Lett. 2003, 44, 3409.
(23) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.;
Andersson, P.; Ito, Y. J. Am. Chem. Soc. 1995, 115, 6487. For a related
fluoride-mediated process involving C(sp2)-SiMe2Ph bond cleavage, see:
Anderson, J.; Flaherty, A. J. Chem. Soc., Perkin Trans. 1 2000, 3025.
(24) Hale, M.; Hoveyda, A. J. Org. Chem. 1992, 57, 1643.
(25) Subsequent experimentation has revealed that the adjacent hydroxyl
group is not required for efficient protiodesilylation in related systems,
suggesting that siloxane intermediates may not be involved in this case.
The present process seems to be fluoride mediated (entry 5, Table 1), in
contrast to similar transformations reported by Hudrlik. Further optimization/
study of this transformation will be reported in due course.
(19) Greene, T.; Wuts, P. ProtectiVe Groups in Organic Synthesis; Wiley
& Sons: New York, 1999.
(20) Derived in one step from known iodide 18: Walkup, R.; Boatman,
D.; Kane, R.; Cunningham, R. Tetrahedron Lett. 1991, 32, 3937.
(21) Micalizio, G.; Roush, W. Org. Lett. 2001, 3, 1949.
Org. Lett., Vol. 6, No. 21, 2004
3867

yield (94%, three steps). Treatment of aldehyde 25 with the
dicyclohexylboron enolate derived from known methyl ke-
tone 2628 afforded â-hydroxy ketone 27 as a single diaste-
reomer in excellent yield (93%). The stereochemistry of the
C(15)-OH group of aldol 27 was assigned by using the
modified Mosher method,29 which revealed the (S)-config-
uration at this center. This stereochemistry is fully consistent
with the anticipated Felkin addition in the aldol step. Evans-
Tishchenko reduction of â-hydroxy ketone 27 afforded an
11:1 mixture of diastereomers with anti-1,3-benzoate 28
predominating.30
Scheme 4. Completion of the C(11)-C(29) Fragment 31
Silylation of 28 followed by a two-step stannylation-
iododestannylation sequence31 afforded (E)-vinyl iodide 29.
This intermediate (29) represents a key point of divergence
for the synthesis of a variety of amphidinolide C/F C(25)
side-chain analogues from a common precursor. For example,
Stille cross-coupling32 with known vinylstannane 3033 af-
forded diene 31, corresponding to the full amphidinolide F
C(11)-C(29) fragment. Stille-coupling with a variety of other
vinylstannanes could give rise to intermediates suitable for
advancement to amphidinolide C (2) or any of a variety of
nonnatural amphidinolide C/F congeners.
C(20)-C(23) tetrahydrofuran fragment of 29 was ac-
complished via the chelation controlled [3 + 2]-annulation
reaction of allylsilane 5 and ethyl glyoxylate, which provided
15 with excellent stereochemical control. Additionally, the
C(11)-C(16) polyketide region has been stereoselectively
synthesized via the highly selective aldol reaction of aldehyde
25 with the dicyclohexylboron enolate derived from methyl
ketone 26. Continued advancement of these intermediates
toward the eventual total syntheses of 1 and 2 will be reported
in due course.
In summary, the C(11)-C(29) fragment (31) (18 steps,
9.7% overall yield from 11) of amphidinolide F (1) has been
synthesized via vinyl iodide 29. Intermediate 29 (17 steps,
18% overall yield from 11) should also be suitable for
advancement to amphidinolide C (2). Generation of the
Acknowledgment. This work was supported by the
National Institutes of Health (GM 38907). J.B.S. gratefully
acknowledges the National Cancer Institute for a postdoctoral
fellowship (CA 103339).
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(30) Hydrolysis of the benzoate ester and formation of the corresponding
acetonide indicated that the C(13,15) diol has anti stereochemistry:
Rychnovsky, S.; Rogers, B.; Richardson, T. Acc. Chem. Res. 1998, 31, 9.
(31) Zhang, H.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.
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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.
OL048381Z
(33) Saihi, M.; Pereyre, M. Bull. Soc. Chim. Fr. 1977, 1251.
3868
Org. Lett., Vol. 6, No. 21, 2004