Enantioselective total synthesis of bistramide A

Article abstract of DOI:10.1021/ja057686l

The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments. Copyright

Full text of DOI:10.1021/ja057686l

Published on Web 03/29/2006
Enantioselective Total Synthesis of Bistramide A
Michael T. Crimmins* and Amy C. DeBaillie
Department of Chemistry, Venable and Kenan Laboratories of Chemistry,
UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received November 11, 2005; E-mail: crimmins@email.unc.edu
Bistramide A1 (1) is a member of a new class of bioactive
molecules isolated from the marine ascidian Lissoclinum bistratum.
The bistramides demonstrate significant neuro- and cytotoxic
properties as well as profound effects on cell cycle regulation.2 In
particular, bistramide A has an IC50 of 0.03-0.32 µg/mL for the
P388/dox, B16, HT29, and NSCLC-N6 cell lines.3 Studies have
shown that bistramide A is cell permeable, blocks sodium channels,4
and induces highly selective activation of a single protein kinase
C (PKC) isotype δ.5 The biological activity of bistramide A, as
well as the other bistramides, has rendered them potential candidates
for the treatment of slowly evolving tumors, such as nonsmall cell
pulmonary carcinoma.2
From the time of their original isolation,1a the bistramides have
presented a challenging stereochemical conundrum. Synthetic efforts
toward the bistramides6 were hampered by the lack of information
regarding their relative and absolute configuration prior to Wipf’s
theoretical and synthetic studies.6d,g Kozmin and co-workers7 have
recently reported the first total synthesis of bistramide A, thus
confirming Wipf’s prediction of the stereochemical assignment of
bistramide C.6d,g
Figure 1. Retrosynthesis of bistramide A.
Scheme 1. Synthesis of Pyran 2a
Herein we disclose a convergent, enantioselective, total synthesis
of bistramide A. At the onset of this project, the absolute
configuration of bistramide A had not been established. Therefore,
our goal was to devise a strategy that would allow either enantiomer
of the three key subunits to be prepared, with the added requirement
that either configuration at C39 could be accessed. Hence, it was
envisioned that bistramide A would derive from three fragments:
pyran 2, carboxylic acid 3, and spiroketal fragment 4 (Figure 1).
The pyran fragment 2 was constructed as shown in Scheme 1.
Exposure of aldehyde 58 to the chlorotitanium enolate of N-
propionyl thiazolidinethione 69 proceeded smoothly (87%) with
excellent diastereoselectivity (>98:2 dr). The chiral auxiliary was
reductively cleaved, and the resulting aldehyde was exposed to
Ph3PdCHCO2Et to give R,â-unsaturated ethyl ester 8 in 78% yield
over two steps. Hydrogenation of the resulting alkene provided the
saturated ethyl ester, which was converted to the lactone in the
presence of PPTS. Reductive acylation10 of the lactone delivered
acetate 9 as an inconsequential 7:1 mixture of anomers. Treatment
of acetate 9 with the 2-trimethylsilyloxy-1,3-pentadiene,11 in the
presence of TMSOTf, installed the R,â-unsaturated ketone moiety
of pyran 10 in 87% yield (9:1 dr). The TIPS ether was removed,
and the resulting primary alcohol was oxidized to the acid.6f
Esterification of the acid with hydroxysuccinimide gave pyran 2.
The synthesis of carboxylic acid 3 began by transformation of
allylic alcohol 1112 to the epoxy alcohol in 95% yield (98% ee)
via a Sharpless asymmetric epoxidation13 (Scheme 2). Treatment
of the epoxy alcohol with lithium dimethylcuprate yielded the 1,3-
diol accompanied by the undesired 1,2-diol (6:1). The minor isomer
was readily removed by treating the mixture with sodium periodate
to yield 1,3-diol 12 in 71% yield. Protection of diol 12 as the bis-
silyl ether followed by oxidative cleavage of the PMB ether
a Conditions: (a) TiCl4, NMP, (-)-sparteine, CH2Cl2, -78 °C, 6, 87%;
(b) i-Bu2AlH, THF, -78 °C; (c) Ph3PdCHCO2Et, CH2Cl2, 78% (two steps);
(d) H2, Raney Ni, EtOH; (e) PPTS, CH2Cl2, 40 °C, 81% (two steps); (f)
i-Bu2AlH, pyridine, DMAP, Ac2O, CH2Cl2, -78 to -20 °C, 96%; (g) Et3N,
TMSOTf, 3-penten-2-one, CH2Cl2, 0 °C then -78 °C, then add acetate 9,
87%, 9:1 dr; (h) H2SiF6, CH3CN, 0 °C, 75%; (i) H5IO6/CrO3, CH3CN, 77%;
(j) N-hydroxysuccinimide, EDC‚HCl, CH2Cl2, 100%.
Scheme 2. Preparation of Carboxylic Acid Fragment 3a
a Conditions: (a) L-(+)-DET, Ti(Oi-Pr)4, t-BuOOH, CH2Cl2, 4 Å sieves,
-20 °C, 95%, 98% ee; (b) Me2CuLi, Et2O, -50 °C to 25 °C, 6:1 of 1,3-
to 1,2-diol; NaIO4, H2O, 71%; (c) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C,
97%; (d) DDQ, pH 7 buffer, CH2Cl2, 0 °C, 98%; (e) DEAD, PPh3,
(PhO)2PON3, THF, 0 °C, 90%; (f) CSA, MeOH, CH2Cl2, 0 °C, 85%; (g)
NaClO2, TEMPO, CH3CN, 35 °C, 95%; (h) HF/pyr., THF, 70%; (i) H2,
Pd/C, Fmoc-OSu, THF, 70%.
provided alcohol 13 in 95% yield over two steps. The azide moiety
was then installed via a Mitsunobu reaction14 with diphenylphos-
phoryl azide, whereupon the primary TBS ether was selectively
cleaved with CSA in methanol to yield alcohol 14. Oxidation15 of
the primary alcohol to the carboxylic acid, followed by deprotection
of the TBS ether, gave the hydroxy acid in 66% yield over two
steps. The azide moiety was readily reduced to the primary amine
9
4936
J. AM. CHEM. SOC. 2006, 128, 4936-4937
10.1021/ja057686l CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Synthesis of Bistramide Aa
Scheme 3. Preparation of Spiroketal Fragment 4a
a Conditions: (a) MeOH, MeNH2, 65 °C; (b) PyBOP, 3, DIEA, DMF
88% (two steps); (c) Et2NH, DMF; (d) 2, DMF 82% (two steps).
was identical in all respects (1H, 13C, [R]D, MS) to the natural
product. The synthesis was completed with a longest linear sequence
of 18 steps (Scheme 4).
a Conditions: (a) NaHMDS, allyl iodide, THF, PhMe, -78 to -45 °C,
81%; (b) LiBH4, MeOH, Et2O, 98%; (c) Et3N, DMSO, (COCl)2, CH2Cl2,
-78 to 25 °C, 98%; (d) LiHMDS, THF, sulfone 17, then aldehyde 16,
-78 to -20 °C, 87%; (e) Cl2(Cy3P)(IMes)RudCHPh, methyl acrylate,
CH2Cl2, 40 °C, 87%; (f) H2, Pd/C, EtOAc; (g) p-TSA, benzene, 80 °C,
70% (two steps); (h) alkyne 20, n-BuLi, -78 °C, then lactone 19; (i) H2,
Pd/C, MeOH, EtOAc, 83% (two steps); (j) PPh3, DEAD, phthalimide, THF,
0 °C; (k) HF/pyr., THF, 84% (two steps); (l) Dess-Martin periodinane,
CH2Cl2, pyr., 92%; (m) Ba(OH)2, THF, MeCOCH(Me)P(O)(OEt)2 (23),
58%; (n) (R)-CBS, catecholborane, toluene, -78 °C, 65%, >98:2 dr.
Acknowledgment. Financial support from the National Cancer
Institute (CA63572) is gratefully acknowledged. Thanks also to
Professors P. Wipf and S. Kozmin for helpful discussions.
Supporting Information Available: Experimental procedures as
well as 1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
with hydrogen and Pd/C followed by in situ acylation to yield the
desired carboxylic acid fragment 3.
References
Construction of the spiroketal fragment 4 began with an
asymmetric glycolate alkylation16 of the sodium enolate of imide
15 with allyl iodide to produce the allylated acyl oxazolidinone in
81% yield (>98:2 dr; Scheme 3). Reductive cleavage of the
auxiliary, followed by oxidation of the resulting primary alcohol
under Swern17 conditions, gave aldehyde 16. Subjection of aldehyde
16 to a modified Julia reaction18 with sulfone 17 gave diene 18 as
a 60:40 mixture of E:Z isomers. A cross-metathesis reaction of diene
18 with methyl acrylate provided the unsaturated methyl ester in
87% yield. Hydrogenation of the two alkenes resulted in concomi-
tant cleavage of the benzyl ether, whereupon treatment with acid
gave lactone 19 (70% yield, two steps). Addition of lactone 19 to
the lithium acetylide of alkyne 20 produced a keto alcohol, which
was immediately exposed to hydrogen and Pd/C at 50 psi. As
anticipated, the resulting trihydroxy ketone spontaneously cyclized
to exclusively produce spiroketal 21 in 83% yield over two steps.
Installation of the phthalimide under Mitsunobu14 conditions,
followed by deprotection of the TBDPS ether, gave alcohol 22 in
84% yield over two steps. Treatment of alcohol 22 with the Dess-
Martin reagent19 provided the aldehyde, which was subjected to a
Horner-Wadsworth-Emmons olefination20 with phosphonate 23
to install the E-olefin (C36-C37). The completed spiroketal
fragment 4 was then obtained by stereoselective reduction of the
resulting ketone with Corey’s oxazoborolidine21 to establish the
C39 stereogenic center.
(1) (a) Gouiffes, D.; Moreau, S.; Helbecque, N.; Bernier, J. L.; Henichart, J.
P.; Barbin, Y.; Laurent, D.; Verbist, J. F. Tetrahedron 1988, 44, 451. (b)
Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey, E. J.; Parry, D.
L.; Watters, D. J. J. Med. Chem. 1989, 32, 1354.
(2) Biard, J. F.; Roussakis, C.; Kornprobst, J. M.; Gouiffesbarbin, D.; Verbist,
J. F.; Cotelle, P.; Foster, M. P.; Ireland, C. M.; Debitus, C. J. Nat. Prod.
1994, 57, 1336.
(3) Johnson, W. E.; Watters, D. J.; Suniara, R. K.; Brown, G.; Bunce, C. M.
Biochem. Biophys. Res. Commun. 1999, 260, 80.
(4) Sauviat, M. P.; Gouiffesbarbin, D.; Ecault, E.; Verbist, J. F. Biochim.
Biophys. Acta 1992, 1103, 109.
(5) Frey, M. R.; Leontieva, O.; Watters, D. J.; Black, J. D. Biochem.
Pharmacol. 2001, 61, 1093.
(6) (a) Foster, M. P.; Mayne, C. L.; Dunkel, R.; Pugmire, R. J.; Grant, D.
M.; Kornprobst, J. M.; Verbist, J. F.; Biard, J. F.; Ireland, C. M. J. Am.
Chem. Soc. 1992, 114, 1110. (b) Solladie, G.; Bauder, C.; Biard, J. F.
Tetrahedron Lett. 2000, 41, 7747. (c) Gallagher, P. O.; McErlean, C. S.
P.; Jacobs, M. F.; Watters, D. J.; Kitching, W. Tetrahedron Lett. 2002,
43, 531. (d) Wipf, P.; Uto, Y.; Yoshimura, S. Chem.-Eur. J. 2002, 8,
1670. (e) Wipf, P.; Hopkins, T. D. Chem. Commun. 2005, 3421. (f) Lowe,
J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231. (g) Zuber, G.; Goldsmith,
M.-R.; Hopkins, T. D.; Beratan, D. N.; Wipf, P.; Org. Lett. 2005, 7, 5269.
(7) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126,
9546.
(8) Hamdouchi, C.; Sanchez-Martinez, C. Synthesis 2001, 833.
(9) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894.
(10) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(11) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717.
(12) Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.;
Kawamoto, T.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997, 38,
7887.
(13) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(14) Mitsunobu, O. Synthesis 1981, 1.
(15) Zhao, M. Z.; Li, J.; Mano, E.; Song, Z. G.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564.
With the three required fragments in hand, their assembly to
bistramide A was undertaken. Cleavage of the phthalimide protect-
ing group of 4 with methanol and methylamine gave the amine,
which was immediately exposed to a PyBOP-mediated condensation
with acid 3 delivering amide 24 in 88% yield over two steps.
Removal of the Fmoc group with subsequent exposure of the
unpurified amine to ester 2 provided synthetic bistramide A, which
(16) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165.
(17) Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem. 1978, 43, 2480.
(18) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(19) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(20) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774.
(21) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1987.
JA057686L
9
J. AM. CHEM. SOC. VOL. 128, NO. 15, 2006 4937