Concise synthesis of the bryostatin A-ring via consecutive C-C bond forming transfer hydrogenations

Article abstract of DOI:10.1021/ol901096d

Under the conditions of C-C bond forming transfer hydrogenation, 1,3-propanediol 1 engages in double asymmetric carbonyl allylation to furnish the C2-symmetric diol 2. Double ozonolysis of 2 followed by TBS protection delivers aldehyde 3, which is subject

Full text of DOI:10.1021/ol901096d

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3108-3111
Concise Synthesis of the Bryostatin
A-Ring via Consecutive C-C Bond
Forming Transfer Hydrogenations
Yu Lu and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received May 19, 2009
ABSTRACT
Under the conditions of C-C bond forming transfer hydrogenation, 1,3-propanediol 1 engages in double asymmetric carbonyl allylation to
furnish the C2-symmetric diol 2. Double ozonolysis of 2 followed by TBS protection delivers aldehyde 3, which is subject to catalyst directed
carbonyl reverse prenylation via transfer hydrogenation to deliver neopentyl alcohol 4 and, ultimately, the bryostatin A-ring 7. Through use
of two consecutive C-C bond forming transfer hydrogenations, the Evans’ bryostatin A-ring 7 is prepared in less than half the manipulations
previously reported.
Originally isolated from the bryozoan Bugula neritina,1 the
bryostatins are a family of over 20 marine natural products
that possess a polyacetate backbone and differ largely on
the basis of substitution at C7 and C21 (Figure 1, top).2 The
bryostatins exhibit a remarkable range of biological effects,
including antineoplastic activity against diverse tumor cell
lines, immunopotentiating activity, restoration of apoptotic
function, and the ability to act synergistically with other
chemotherapeutic agents.3 More recently, the bryostatins
have been found to exhibit exciting neurological effects,
including activity against Alzheimer’s disease,4 neural growth
and repair, and the reversal of stroke damage,5 as well as
memory enhancement.6
The natural abundance of bryostatins is insufficient to
advance clinical studies and elucidate their precise mecha-
nism of action.7 Consequently, the de noVo synthesis of
various bryostatins and the design and preparation of non-
natural functional analogues has been the topic of intensive
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Frigerio, M. Nat. Prod. Rep. 2002, 19, 413. (b) Kortmansky, J.; Schwartz,
G. K. Cancer InVest. 2003, 21, 924. (c) Wender, P. A.; Baryza, J. L.;
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Ross, J. T.; Lebherz, W. B.; Reeves, M. P.; Eberwein, R. M.; Rodgers,
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10.1021/ol901096d CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

Figure 1. (Top) Structures of bryostatins 1-17. (Bottom) Selected bryostatin analogues and binding affinities for PKCR.
investigation. To date, total syntheses of bryostatin 2,
bryostatin 3, bryostatin 7, and bryostatin 16 have been
reported by Evans,8 Yamamura,9 Masamune,10 and Trost,11
respectively. A formal synthesis of bryostatin 7 was reported
by Hale.12 Finally, several creative synthetic approaches to
bryostatin fragments are reported by Hale,13 Thomas,14
Hoffman,15 Vandewalle,16 Burke,17 and the present author.18
Although impressive, these syntheses do not represent a
practical source of material for clinical study. Hence, efforts
led by Wender,19,20 Keck,21 and Hale13b have focused on
the design of simplified structural analogues that possess
enhanced functional capability and provide insight into key
structural features of the bryostatins that confer unique
biological activity (Figure 1, bottom).
As part of a broad program aimed at the development of
hydrogen-mediated C-C bond formations,22 enantioselective
carbonyl allylations,23a-c,f crotylations,23d and reverse prenyl-
ations23e were recently achieved under the conditions of
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Charette, A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37, 2354. (b)
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.;
Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540.
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Lett. 1991, 32, 2821. (b) De Brabander, J.; Vandewalle, M. Synlett 1994,
231. (c) De Brabander, J.; Vandewalle, M. Synthesis 1994, 855. (d) De
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Asymmetry 1997, 8, 1721.
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Bull. Chem. Soc. Jpn. 2004, 77, 875.
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J. C. Org. Lett. 2006, 8, 4581. (c) Wender, P. A.; Horan, J. C.; Verma,
V. A. Org. Lett. 2006, 8, 5299. (d) Wender, P. A.; Verma, V. A. Org. Lett.
2008, 10, 3331. (e) Wender, P. A.; DeChristopher, B. A.; Schreier, A. J.
J. Am. Chem. Soc. 2008, 130, 6658.
(12) Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.;
Aliev, A. E.; Hale, K. J. Org. Lett. 2006, 8, 4477.
(13) Review: (a) Hale, K. J.; Hummersone, M. G.; Cai, J.; Manavaiazar,
S.; Bhatia, G. S.; Lennon, J. A.; Frigerio, M.; Delisser, V. M.; Chumnong-
saksarp, A.; Jogiya, N.; Lemaitre, A. Pure Appl. Chem. 2000, 72, 1659.
(b) Hale, K. J.; Frigerio, M.; Manaviazar, S.; Hummersone, M. G.;
Fillingham, I. J.; Barsukov, I. G.; Damblon, C. F.; Gescher, A.; Roberts,
G. C. K. Org. Lett. 2003, 5, 499. (c) Hale, K. J.; Frigerio, M.; Manaviazar,
S. Org. Lett. 2003, 5, 503. (d) Hale, K. J.; Frigerio, M.; Manaviazar, S.
Org. Lett. 2001, 3, 3791. (e) Hale, K. J.; Lennon, J. A.; Manaviazar, S.;
Javaid, M. H.; Hobbs, C. J. Tetrahedron Lett. 1995, 36, 1359. (f) Hale,
K. J.; Hummersone, M. G.; Bhatia, G. S. Org. Lett. 2000, 2, 2189.
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Germay, O.; Oller, P. C.; Kumar, N.; Martin, N.; O’Brien, M.; Omori, H.;
Moore, C.; Thomas, E. J. Pure Appl. Chem. 2005, 77, 103. (b) Green, A. P.;
Hardy, S.; Thomas, E. J. Synlett 2008, 2103.
(20) Reviews: (a) Wender, P. A.; Martin-Cantalejo, Y.; Carpenter, A. J.;
Chiu, A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.; Koehler, M. F. T.;
Lippa, B.; Morrison, J. A.; Mu¨ller, S. G.; Mu¨ller, S. N.; Park, C.-M.;
Shiozaki, M.; Siedenbiedel, C.; Skalitsky, D. J.; Tanaka, M.; Irie, K. Pure
Appl. Chem. 1998, 70, 539. (b) Wender, P. A.; Hinkle, K. W.; Koehler,
M. F. T.; Lippa, B. Med. Res. ReV. 1999, 19, 388. (c) Wender, P. A.; Baryza,
J. L.; Brenner, S. E.; Clarke, M. O.; Gamber, G. G.; Horan, J. C.; Jessop,
T. C.; Kan, C.; Pattabiraman, K.; Williams, T. J. Pure Appl. Chem. 2003,
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Keck, G. E.; Poudel, Y. B.; Welch, D. S.; Kraft, M. B.; Truong, A. P.;
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Org. Lett., Vol. 11, No. 14, 2009
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Scheme 1. Synthesis of the Bryostatin A-Ring Employing Consecutive C-C Bond Forming Transfer Hydrogenations
iridium catalyzed transfer hydrogenation. A long-term goal
of these studies resides in defining a departure from
preformed organometallic reagents in carbonyl and imine
addition, thereby circumventing the excessive preactivation
and waste generation associated with their use. Furthermore,
the ability to achieve asymmetric carbonyl addition directly
from the alcohol oxidation level, as established by the
aforementioned processes, is inherently more redox-economic
and, hence, step-economic than classical protocols. Given
the longstanding challenges associated with defining concise
routes to the bryostatins, this class of natural products was
deemed an ideal vehicle to benchmark the utility of C-C
bond forming hydrogenations and transfer hydrogenations
developed in our laboratory. In prior work, enantioselective
hydrogen-mediated alkyne-carbonyl reductive coupling was
applied to the construction of the bryostatin C-ring. Here,
using two different C-C bond forming transfer hydrogena-
tions, we disclose a synthetic route to a known bryostatin
A-ring fragment in less than half the steps previously
required.8
acetone.25 Notably, this particular carbonyl allylation cannot
be achieved directly from the aldehyde oxidation level due
to the instability of malondialdehyde. The C2-symmetric diol
2 was subjected to double ozonolysis followed by protection
in situ as the bis-TBS ether to deliver aldehyde 3. Because
the transient dialdehyde moieties that arise upon ozonolysis
are homotopic, pyran 3 appears as a single isomer (Scheme
1).
The stage was now set for catalyst-directed prenylation
of aldehyde 3 under previously disclosed transfer hydrogena-
tion conditions.23e Upon exposure of aldehyde 3 to 1,1-
dimethylallene and isopropanol in the presence of the iridium
C,O-benzoate generated in situ from allyl acetate, m-
nitrobenzoic acid, and (R)-SEGPHOS,26 a 92% isolated yield
of the prenylated adduct 4 was obtained as a 1:11 (S:R) ratio
of epimers at 60 °C. Using the catalyst derived from (S)-
SEGPHOS under otherwise identical conditions, the preny-
lated adduct 4 was obtained as a 16:1 (S:R) ratio of epimers.
These data suggest that the catalysts derived from (R)- and
(S)-SEGPHOS are mismatched and matched, respectively,
with regard to the inherent diastereofacial bias of aldehyde
3. Indeed, upon use of the corresponding achiral iridium
complex derived from BIPHEP, the prenylated adduct 4 was
obtained as a 1.4:1 (S:R) ratio of epimers corroborating a
fortuitous bias of the substrate toward formation of the (S)-
epimer. By isolating the catalyst derived from (S)-SEGPHOS
and employing it at slightly lower temperature (50 °C), the
prenylated adduct 4 was obtained in 90% isolated yield as a
Our initial step toward the bryostatin A-ring employs the
double asymmetric carbonyl allylation of 1,3-propanediol 1
to furnish the C2-symmetric diol 2,23c which is obtained in
>99% ee as the minor enantiomer of the monoadduct is
converted to the meso-isomer of the bis-adduct.24 Identical
material was previously prepared in four steps from acetyl-
(22) For selected reviews on C-C bond forming hydrogenation and
transfer hydrogenation, see: (a) Ngai, M.-Y.; Kong, J. R.; Krische, M. J. J.
Org. Chem. 2007, 72, 1063. (b) Skucas, E.; Ngai, M.-Y.; Komanduri, V.;
Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. (c) Shibahara, F.; Krische,
M. J. Chem. Lett. 2008, 37, 1102. (d) Bower, J. F.; Kim, I. S.; Patman,
R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34.
1
single (S)-epimer as determined by H NMR (Scheme 2).
Transformation of the neopentyl alcohol 4 to the bryostatin
A-ring was accomplished in five manipulations. In ac-
cordance with literature precedent,27 the neopentyl alcohol
4 was converted to the corresponding p-methoxybenzyl ether
in 78% isolated yield. Selective removal of the lactol TBS
(23) (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6340. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 14891. (c) Lu, Y.; Kim, I.-S.; Hassan, A.; Del Valle, D. J.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 5018. (d) Kim, I. S.; Han,
S.-B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514. (e) Han, S.-B.;
Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 6916. (f)
For a report on carbonyl allylations, see: Hassan, A.; Lu, Y.; Krische, M. J.
Org. Lett. 2009, DOI: (10.1021/ol901136w).
(24) This mechanism for enantiomeric enrichment is documented by
Eliel and Midland: (a) Kogure, T.; Eliel, E. L. J. Org. Chem. 1984, 49,
576. (b) Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1144.
(25) Rychnovsky, S. D.; Griesgraber, G.; Powers, J. P. Org. Synth. 2000,
77, 1.
(26) SEGPHOS: Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo,
N.; Miura, T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(27) Wipf, P.; Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346.
3110
Org. Lett., Vol. 11, No. 14, 2009

To summarize, it is well-appreciated that new synthetic
methods beget new synthetic strategies that can dramatically
simplify the preparation of target substances. Here, through
consecutive use of C-C bond forming transfer hydrogena-
tions, a remarkably concise synthesis of a known bryostatin
A-ring fragment was achieved in less than half the manipula-
tions previously required. In earlier work utilizing hydrogen-
mediated alkyne-carbonyl reductive coupling, a route to the
bryostatin C-ring was established.18 Future studies will focus
on total syntheses of the bryostatins and simplified structural
analogues that possess enhanced functional capability, taking
advantage of the simplifications availed through C-C bond
forming hydrogenation and transfer hydrogenation.
Scheme 2. Catalyst-Directed Diastereoselectivity in the Transfer
Hydrogenative Reverse Prenylation of Aldehyde 3
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation and the NIH-NIGMS (RO1-
GM069445) for partial support of this research. Dr. Oliver
Briel of Umicore is thanked for the generous donation of
[Ir(cod)Cl]2. Takasago is thanked for the generous donation
of SEGPHOS.
ether was achieved using TBAF-AcOH, also in 78% isolated
yield.28 Finally, Jones oxidation of the lactol delivers lactone
5 in 81% isolated yield.29 Ring-opening of lactone 5 mediated
by AlMe3-PhNH2 provides anilide 6 in 84% isolated yield,8
which upon ozonolysis furnishes the previously reported
bryostatin A-ring fragment 78 in a total of eight manipula-
tions from 1,3-propanediol 1 (Scheme 1).30 Notably, this
material was prepared previously in 12 steps from 2,2-
dimethyl-4,4-diphenyl-3-butenal, which itself is prepared in
five steps from 3-chloro-2-methylpropene,31 thus representing
a total of 17 steps from 3-chloro-2-methylpropene.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901096D
(30) With regard to the assignment of relative and absolute stereochem-
istry, the optical rotation of C2-symmetric diol 2 was correlated with reported
data (see ref 25 and Supporting Information). In the reverse prenylation of
3, the undesired diastereomer of adduct 4 obtained using (R)-SEGPHOS
1
as ligand was used to complete the A-ring. As anticipated, the H NMR
data did not match the reported data. In contrast, the A-ring diastereomer
obtained using (S)-SEGPHOS as ligand in the prenylation step matches
the reported data, notwithstanding a small difference in the ratio of
diastereomers at C9.
(31) (a) Julia, M.; Baillarge, M. Bull. Soc. Chim. Fr. 1966, 734. (b)
Zimmerman, H. E.; Pratt, A. C. J. Am. Chem. Soc. 1970, 92, 6259.
(28) Orgueira, H. A.; Bartolozzi, A.; Schell, P.; Litjens, R. E.; Palmacci,
E. R.; Seeberger, P. H. Chem. Eur. J. 2003, 9, 140.
(29) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc.
1996, 118, 11054.
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