Synthesis of a ring-expanded bryostatin analogue

Article abstract of DOI:10.1021/ja067305j

A ring-expanded bryostatin analogue was synthesized by utilizing a Ru-catalyzed tandem tetrahydropyran formation, a Pd-catalyzed tandem dihydropyran formation, and a ring-closing metathesis (RCM) as key steps. The analogue possesses potent antitumor activ

Full text of DOI:10.1021/ja067305j

Published on Web 02/06/2007
Synthesis of a Ring-Expanded Bryostatin Analogue
Barry M. Trost,* Hanbiao Yang, Oliver R. Thiel, Alison J. Frontier, and Cheyenne S. Brindle
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received October 11, 2006; E-mail: bmtrost@stanford.edu
Scheme 2 a
The bryostatins are a family of marine natural products that
display a wide range of biological activities, most notably their
anticancer activity in vivo.1 This effect is attributed to their ability
to modulate the functions of protein kinase C isozymes within cells.
One of the members of this family, bryostatin 1, is currently in
several phase I and phase II clinical trials for the treatment of several
cancers.2 The syntheses of bryostatins and their analogues have
been an active research area since the structure elucidation of
bryostatin 1 in 1982.3 To date, three total and one formal syntheses
have been reported,4-7 and potent bryostatin analogues8 have been
identified. In the analogue synthesis front, efforts have been centered
on the simplification of the 26-membered macrolactone backbone.
Herein, we report the synthesis of a ring-expanded analogue 1
(Scheme 1), which retains all the functionalities in the bryostatins,
and their biological activities against several cancer cell lines.
Scheme 1
a Reagents and conditions: (a) TBSOTf, Et3N, -78 °C, 94%; (b) 9-BBN,
then H2O2, NaOAc, 93%; (c) TEMPO, KBr, NaOCl, CH2Cl2/H2O; (d) Ti(O-
i-Pr)2Cl2, 11, toluene, -78 °C, 69% over two steps, ∼10:1 dr at C(5); (e)
Me4NBH(OAc)3, AcOH/CH3CN, -35 °C, 96%, 15:1 dr at C(3); (f) 10 mol
% of Otera’s catalyst 13, hexane, reflux; (g) TBDPSCl, imidazole, DMF,
50 °C, quantitative; (h) AcOH/H2O (4:1), 69%; (i) Dess-Martin oxidation;
(j) allyl iodide, In, DMF, rt, 66% over two steps; (k) Dess-Martin oxidation,
85%; (l) 10 mol % of [CpRu(CH3CN)3]PF6, acetone, rt, 56% yield, dr 9:1;
(m) NBS, DMF, 93%; (n) BF3‚OEt2, 1,3-propanedithiol, CH2Cl2, 0 °C, 98%;
(o) PPTS, CH3OH, CH(OCH3)3, reflux, 71%; (p) TESCl, DMAP, then
pyridine, Ac2O, 92%; (q) PPTS, MeOH, rt, 85%; (r) DMSO, (COCl)2, Et3N,
CH2Cl2, -78 °C to rt; (s) Ph3PCH3Br, n-BuLi, 63% over two steps; (t)
TBAF, THF, rt, 82%; (u) Me3SnOH, DCE, 140 °C, microwave, 82%; (v)
Pd(PPh3)4, CO, DMF/CH3OH, 85 °C, 94%; (w) TESOTf, 2,6-lutidine,
CH2Cl2, 68%.
stage, a â,γ-unsaturated ketone was introduced to give 5. The key
Ru-catalyzed tandem coupling between enone 5 and homopropar-
gylic alcohol 4 furnished tetrahydropyran 15 in 56% yield as a 9:1
cis:trans diastereomeric mixture, and no double bond isomer was
observed. Although excess 5 (2.2 equiv) was used in the reaction,
Shown in Scheme 1 is our retrosynthetic analysis. Inspired by
the B-ring and C-ring segments, we developed a Ru-catalyzed
tandem process9 for the synthesis of 4-methylene-cis-2,6-tetra-
hydropyran and a Pd(II)-catalyzed tandem reaction10 for the
synthesis of dihydropyrans. Since our Pd(II) catalysis necessitates
an early installation of the sensitive R,â-unsaturated methyl ester
at C(13), we decided to evaluate a ring-closing metathesis (RCM)
approach for the formation of the macrocycle.11,12 The steric
hindrance of the C(16)-C(17) double bond (bryostatin numbering)
made this approach risky, but we were encouraged by the potential
to access ring-expanded analogues.13
1.2 equiv was recovered and recycled. Subsequent bromination and
deprotection gave the corresponding diol, which was subjected to
a tandem lactone methanolysis-ketalization to afford 16. Com-
pound 16 was converted to vinyl bromide 16 and then the northern
hemisphere 2 in eight steps.
Our synthesis of the southern hemisphere 3 commenced with
D-glactonic acid 1,4-lactone (Scheme 3). Epoxide opening of 1817
with methyl propionate delivered methyl ynoate 19, which was
coupled with alkyne 2018 under our tandem Pd(II) catalysis
conditions to give dihydropyran 21 in 55% yield.19 At this stage,
the vicinal oxygens at C(19) and C(20) were introduced via an
epoxidation. Unfortunately, the stereochemistry of the newly
introduced C(20) hydroxyl group was the opposite of that required
for our synthesis. This undesired selectivity was overcome by a
Dess-Martin oxidation20/Luche reduction21 sequence. After intro-
Our synthesis of the northern hemisphere 2 is outlined in Scheme
2. The alcohol 914 was converted to the hydroxyketone 12 following
a procedure5 from Evans. Subsequent hydroxyl-directed anti-
reduction,15 lactonization,16 and protection gave lactone 14. At this
9
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J. AM. CHEM. SOC. 2007, 129, 2206-2207
10.1021/ja067305j CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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a Reagents and conditions: (a) n-BuLi, methyl propionate, BF3‚OEt2,
THF, -78 °C, 92%; (b) Pd(OAc)2, tris(2,6-dimethoxyphenyl)phosphine,
20, benzene, then Pd(O2CCF3)2, rt, 55%; (c) trifluoroperacetic acid,
Na2HPO4, CH2Cl2/CH3CN/CH3OH, 0 °C; (d) Dess-Martin oxidation; (e)
NaBH4, CeCl3‚7H2O, -30 °C; (f) Ac2O, pyridine, DMAP, CH2Cl2, rt, 45%
over four steps; (g) Et3N‚3HF, THF, rt, 54-77%; (h) Dess-Martin
oxidation, 94%; (i) CrCl2, CHI3, THF, rt, 26% (47% BRSM); (j) Pd(PPh3)4,
22, THF, rt, 68%; (k) AcOH/H2O (3:1); (l) TESCl, TEA, DMF, -35 to
-15 °C, 60% over two steps; (m) Et3N, DMAP, 2-methyl-6-nitrobenzoic
acid anhydride, CH2Cl2, 51%; (n) benzene, 50-80 °C, 17 mol % of
Grubbs-Hoveyda catalyst, 80%, 1:1 E:Z mixture; (o) PPTS, MeOH, rt,
36% of 1, 46% of 27.
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(11) The Julia olefination, a well-established method in the previous three total
syntheses for the construction of the macrocycle, is unlikely to work for
our system due to the basicity of this procedure; see ref 5b.
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ducing a terminal olefin via a Takai olefination22 and a Negishi
cross-coupling,23 the resulting triene 24 was hydrolyzed and
monosilylated to give the southern hemisphere 3, which was then
coupled with 2 in the presence of 2-methyl-6-nitrobenzoic acid
anhydride24 to give 25. Gratifyingly, treatment of 25 with Grubbs-
Hoveyda catalyst25 gave 31-membered lactone 26 as an inseparable
1:1 E:Z mixture in 80% yield.26 Final deprotection gave triols 1
and 27, which were separated by preparative TLC.
The compounds 1 and 27 were tested against several cancer cell
lines. Particularly impressive and interesting is the ability of 1 to
inhibit the growth of NCI-ADRsa breast cancer cell line with added
multi-drug-resistant pumpsswith an IC50 of 123 nM.27
(13) Our efforts to construct the bryostatin macrocycle via a RCM reaction
met with no success; details will be reported in full account of our work.
For another RCM approach by Thomas and co-workers, see ref 3f.
(14) (a) Shiina, I.; Shibata, J.; Ibuka, R.; Imai, Y.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 2001, 74, 113. (b) Blakemore, P. R.; Browder, C. C.; Hong, J.;
Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White,
J. D. J. Org. Chem. 2005, 70, 5449.
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(18) Synthesized in three steps from 3-methyl-2-butanone. See Supporting
Information for details.
In summary, a ring-expanded bryostatin analogue 1 with potent
antitumor activity against the NCI-ADR cancer cell line was
synthesized. Notable features include a Ru-catalyzed tandem
tetrahydropyran formation, a Pd-catalyzed tandem dihydropyran
formation, and a ring-closing metathesis. The chemistry reported
herein should be applicable to future syntheses of the bryostatins
and their analogues.
(19) This reaction is reproducible at 0.3 mmol scale. For large-scale reactions,
a two-step procedure of Pd(OAc)2-catalyzed cross-coupling of 17 and 18
to form a ene-yne adduct followed by PdCl2(CH3CN)2-catalyzed cyclo-
isomerization was performed. See Supporting Information for details.
(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(21) Luche, J. L.; Rodriguez-Hahn, L.; Crabbe, P. Chem. Commun. 1978, 601.
(22) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
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(24) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004,
69, 1822.
Acknowledgment. We thank NIH General Medical Science
(GM 13598), NSF, and fellowships from Amgen (H.Y.), Bristol-
Myers Squibb (H.Y.), the Alexander-von-Humboldt foundation
(O.R.T.), NIH (A.J.F.), NSF (C.S.B.), and ARCS (C.S.B.) for their
generous financial support. We thank Dr. Hugo Menzella from
Kosan Biosciences for testing the biological activities of compounds
1 and 27, and Dr. Yong Li for helpful discussions. We thank
Professor Deryn Fogg, Jay Conrad, Professor Robert Grubbs, and
Dr. Tobias Ritter for providing samples of catalysts and Johnson
Matthey for a gift of Pd salts. Mass spectra were provided by the
Mass Spectrometry Regional Center of the UCSF, supported by
the NIH Division of Research Resources.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168.
(26) Under this and several other conditions, relay ring-closing metathesis
(RRCM) did not occur. For a leading reference on RRCM, see: Hoye, T.
R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem.
Soc. 2004, 126, 10210.
(27) Compound 27 is about 9-fold less active than 1 against NIC-ADR cell
line. Epothilone D and discodermolide display IC50 values of 10 and 240
nM, respectively, in the same assay; see: (a) Hearn, B. R.; Zhang, D.;
Li, Y.; Myles, D. C. Org. Lett. 2006, 8, 3057. (b) Shaw, S. J.; Sundermann,
K. F.; Burlingame, M. A.; Myles, D. C.; Freeze, B. S.; Xian, M.; Brouard,
I.; Smith, A. B., III. J. Am. Chem. Soc. 2005, 127, 6532.
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