A concise, selective synthesis of the polyketide spacer domain of a potent bryostatin analogue

Article abstract of DOI:10.1021/ol0272390

(Matrix presented) A concise, asymmetric synthesis of the polyketide spacer domain portion (C1-C13) of a highly potent bryostatin analogue was developed. The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters,

Full text of DOI:10.1021/ol0272390

ORGANIC
LETTERS
2003
Vol. 5, No. 3
277-279
A Concise, Selective Synthesis of the
Polyketide Spacer Domain of a Potent
Bryostatin Analogue
Paul A. Wender,* Alexander V. W. Mayweg, and Christopher L. VanDeusen
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
wenderp@leland.stanford.edu
Received November 5, 2002
ABSTRACT
A concise, asymmetric synthesis of the polyketide spacer domain portion (C1−C13) of a highly potent bryostatin analogue was developed.
The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters, while a substrate directed syn reduction
sets the C9 stereocenter. The spacer domain 1 is obtained in 10 steps with a 25% overall yield and is readily incorporated into the synthesis
of 2.
The bryostatins are a family of structurally novel and
complex marine macrolides exhibiting a unique set of
biological activities, including induction of apoptosis, reversal
of multidrug resistance, and immune system enhancement.
They also synergize the effect of other cancer therapeutic
agents.1 Bryostatin 1 is in phase I and phase II clinical trials
due to its promising antineoplastic activity, both as a single
agent and in combination with other agents.2 However, the
low abundance and difficult isolation of bryostatin 1 has
significantly limited its supply as well as access to potentially
superior clinical derivatives.1 To circumvent these problems,
we have been involved in the de novo design and synthesis
of simplified bryostatin analogues. Recently, this effort has
resulted in the identification and synthesis of a bryostatin
analogue 2 (Figure 1) that exhibits in vitro and in vivo
biological activities comparable to or better than bryostatin
1 in various assays.3,4
Our previous synthesis of 2 was based on the two-step
combination of the polyketide spacer domain 3 and recogni-
tion domain 4 (Figure 1). The route to 3 in turn was designed
(1) (a) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8, 1841-1860.
(b) Pettit, G. R. J. Nat. Prod. 1996, 59, 812-821. (c) Hale, K. J.;
Hummersone, M. G.; Manaviazar, S.; Frigerio, M. Nat. Prod. Rep. 2002,
19, 413-453.
Figure 1. Convergent assembly of analogue 2 from spacer domain
3 and recognition domain 4.
(2) For current information, see: http://clinicaltrials.gov
10.1021/ol0272390 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/09/2003

to allow rapid access to structures needed to test our
pharmacophore hypothesis and proceeded in 11 linear steps
and 11% yield, affording 3, but with only 60% selectivity.3
With the potency of analogue 2 now established, our attention
turned to an improvement of its synthesis with respect to
overall yield, selectivity, and scalability. This has led to a
new strategy for the synthesis of a spacer domain in the form
of 1 (Scheme 1) and its conversion to 2.
Scheme 2. Synthesis of Spacer Domain 1a
Scheme 1. Retrosynthetic Analysis of Modified Spacer
Domain 1
The strategy for accessing our new spacer domain (Scheme
1: 1) is based on the conjunction and asymmetric elaboration
of three commercially available building blocks. Our syn-
thesis started with the acylation of the anion of commercially
available 4-benzyloxy-2-butanone with the commercially
available acid chloride 8, which afforded diketone 7 in 68%
yield (Scheme 2).
At this stage, in one of the key transformations of this
sequence, the C3 and C5 stereocenters were set through a
Noyori asymmetric diketone hydrogenation that proceeded
in excellent yield and in greater than 95:5 enantioselectivity
(as determined by Mosher’s ester analysis) and complete syn
selectivity to provide diol 9.5,6 The secondary alcohols in 9
were then differentiated through a lactonization of the C5
alcohol with the proximate ester group, affording after C3
protection, lactone 6.
a Reagents and conditions: (a) LDA, 4-benzyloxy-2-butanone,
-78 °C, 10 min, 68%; (b) Ru-(S)-BINAPCl2, MeOH, H2, (95 atm),
30 °C, 78 h, 92% (97% BORSM); (c) silica, PhMe, 12 h, reflux,
95%; (d) TBDPSCl, imidazole, DMF, 2 h, 85%; (e) ethylaceto-
acetate, LDA (2 equiv), -78 °C; (f) Et3SiH, TFA, -30 °C, 4 h,
70% over two steps; (g) Ru-(R)-BINAPCl2, EtOH, H2 (78 atm),
96 h, 91%; (h) H2, Pd(OH)2, Et2O, 1 h, then LiBH4, 1 h, 96%; (i)
2,2-dimethoxypropane, TsOH, DMF, then silica, DCM, 4 h, 93%;
(j) TEMPO, NaOCl, NaClO2, MeCN, 50 °C, 4 h, 92%.
stereocenter was set through a second asymmetric hydroge-
nation, affording the hydroxyester 5 in excellent yield and
greater than 99% de.8 It was found that 5 can be transformed
to the corresponding triol in a one-operation procedure
involving a hydrogenolysis with Pd/C under 1 atm of
hydrogen followed by a LiBH4 reduction. Protection of the
triol as the acetonide 13 followed by oxidation of the alcohol
with the Merck TEMPO/NaOCl/NaClO2 procedure afforded
the new spacer domain 1 in 10 steps, 25% overall yield, and
greater than 95:5 selectivity.9
The new spacer domain 1, incorporating a simpler diol
protecting group relative to 3 (acetone in 1 vs menthone in
3), was then tested as a substrate for coupling to the
recognition domain 4 (Scheme 3). Toward this end, 1 was
first coupled to 4 by using a PyBroP-mediated esterification
to afford the richly functionalized ester 14.10 Gratifyingly,
The third set of backbone carbons (C10-C13) of the
spacer domain were then introduced by addition of the
dianion of ethyl acetoacetate to lactone 6. The resultant lactol
11 was subsequently reduced without further purification,
thus setting the C9 stereocenter and providing the desired
syn tetrahydropyran 12 in good yield.7 At this stage, the C11
(3) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner, S.
E.; Clarke, M. O.; Horan, J. C.; Kan, C.; LaCote, E.; Lippa, B. S.; Nell, P.
G.; Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648-13649.
(4) (a) Wender, P. A.; Hinkle, K. W.; Koehler, M. F. T.; Lippa, B. Med.
Res. ReV. 1999, 19, 388-407. (b) Wender, P. A.; MartinCantalejo, Y.;
Carpenter, A. J.; Chiu, A.; DeBrabander, J.; Harran, P. G.; Jimenez, J. M.;
Koehler, M. F. T.; Lippa, B.; Morrison, J. A.; Muller, S. G.; Muller, S. N.;
Park, C. M.; Shiozaki, M.; Siedenbiedel, C.; Skalitzky, D. J.; Tanaka, M.;
Irie, K. Pure Appl. Chem. 1998, 70, 539-546. (c) Unpublished results.
(5) (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumabayashi,
H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc.
1988, 110, 629-631. (b) For general reviews on 1,3-dicarbonyl reductions
with ruthenium biarylbisphosphine catalysts see: (i) Noyori, R.; Kitamura,
M.; Ohkuma, T. Asymmetric Hydrogenation. In Catalytic Asymmetric
Synthesis, 2nd ed.: Ojima, I., Ed.; Wiley-VCH: New York, 2000. (ii) Ager,
D. J.; Laneman, S. A. Tetrahedron: Asymmetry 1997, 8, 3327-3355.
(6) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(7) (a) The selectivity of this step was determined to be greater than
95:5 by 1H NMR. (b) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem.
Soc., Chem. Commun. 1986, 1568-1569.
(8) (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856-
5858. (b) We believe this to be one of the more complex examples of a
reduction of this type.
(9) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566.
(10) Coste, J.; Fre´rot, E.; Jouin, P. J. Org. Chem. 1994, 59, 2437-2446.
278
Org. Lett., Vol. 5, No. 3, 2003

spacer domain with the existing synthesis of analogue 2. It
also provides a further example of the generality of this
macroacetalization strategy in which C3 and C26 are
deprotected and the stereochemistry at C15 is set under
thermodynamic control in one operation in the presence of
a diverse array of functionality.
Scheme 3. Synthesis of Analogue 2 from New Spacer Domain
1 and Recognition Domain 4a
In summary, a selective and concise new strategy for the
synthesis of the polyketide-like spacer domain of our
bryostatin analogue 2 has been realized. The synthesis utilizes
three commercially available building blocks to establish the
13-carbon backbone of the spacer domain and asymmetric
hydrogenation to control its relative and absolute stereo-
chemistry. This approach offers enhanced efficiency and
selectivity over the previous route to 2 and potential cost
and scalability benefits. This spacer domain is currently being
paired with new modified recognition domains. Further
results will be reported in due course.
Acknowledgment. Support of this work through a grant
(CA31845) provided by the NIH and fellowship support from
GlaxoSmithKline (A.V.W.M.) and Roche BioScience (CVD)
is gratefully acknowledged. HRMS analyses were performed
at UCSF.
a Reagents and conditions: (a) PyBroP, Hu¨nig’s base, recognition
domain 4, DMAP, DCM, 70%; (b) HF‚py, THF, 16 h, 90%.
Supporting Information Available: Experimental condi-
tions and spectral data for compounds1, 2, and 5-14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
this ester efficiently underwent deprotection and macro-trans-
acetalization upon exposure to HF/pyridine, affording the
desired analogue 2, identical (1H NMR, HPLC, MS) with a
sample of the analogue obtained with use of the previous
spacer domain. This establishes the compatibility of the new
OL0272390
Org. Lett., Vol. 5, No. 3, 2003
279