Enantioselective reductive coupling of alkynes and α-keto aldehydes via rhodium-catalyzed hydrogenation: An approach to bryostatin substructures

Article abstract of DOI:10.1021/ol052976s

Hydrogen-mediated reductive coupling of glyoxal 2 and 1,3-enyne 3 provides α-hydroxy ketone 4 in 70% yield and 91% enantiomeric excess. Notably, the benzylic ether and diene side chain of 4 remain intact under the conditions of hydrogen-mediated coupling.

Full text of DOI:10.1021/ol052976s

ORGANIC
LETTERS
2006
Vol. 8, No. 5
891-894
Enantioselective Reductive Coupling of
Alkynes and -Keto Aldehydes via
Rhodium-Catalyzed Hydrogenation: An
Approach to Bryostatin Substructures
r
Chang-Woo Cho and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received December 8, 2005
ABSTRACT
Hydrogen-mediated reductive coupling of glyoxal 2 and 1,3-enyne 3 provides
r-hydroxy ketone 4 in 70% yield and 91% enantiomeric excess.
Notably, the benzylic ether and diene side chain of 4 remain intact under the conditions of hydrogen-mediated coupling. In four steps,
ketone 4 is converted to pyrans 8 and 9, which embody key structural features of the bryostatin recognition domain.
r-hydroxy
The bryostatins are a family of marine natural products
possessing a polyacetate backbone that were originally
isolated from the bryozoan Bugula neritina.1 Presently, 20
naturally occurring bryostatins are known, which differ
primarily on the basis of substitution at C7 and C21 (Figure
1).2 The bryostatins and related structural analogues exhibit
a range of extraordinary biological properties, which include
antineoplastic activity against a broad range of tumor cell
lines, immunopotentiating activity, the restoration of apop-
totic function, and the ability to act synergistically with other
chemotherapeutic agents.3 While the mechanism of action
of the bryostatins remains unclear, it is believed that the
ability of the bryostatins to inhibit protein kinase C without
tumor promotion plays an important role.3h Due to these
remarkable features, clinical evaluation of bryostatin 1 is
currently in progress.
The total synthesis of bryostatin 2, bryostatin 3 and
bryostatin 7 have been reported by Evans,4 and Yamamura,5
and Masamune,6 respectively. Though impressive, these
syntheses require over 60 steps and, hence, do not represent
an effective source of material for clinical study. This fact,
coupled with the low natural abundance of the bryostatins,
has stimulated efforts toward the preparation and evaluation
of simplified analogous by Wender7 and Keck.8 Finally, a
Frigerio, M. Nat. Prod. Rep. 2002, 19, 413. (e) Clamp, A.; Jayson, G. C.
Anti-Cancer Drugs 2002, 13, 673. (f) Kortmansky, J.; Schwartz, G. K.
Cancer InVest. 2003, 21, 924. (g) Hofmann, J. Curr. Cancer. Drug Targets
2004, 4, 125. (h) Grant, S. Comb. Canc. Ther. 2005, 61.
(4) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; 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.
(5) (a) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290. (b) Ohmori, K. Bull.
Chem. Soc. Jpn. 2004, 77, 875.
(6) Kageyama, M.; Tamura, T.; Nantz, M.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407.
(1) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold,
E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846.
(2) (a) Pettit, G. R. J. Nat. Prod. 1996, 59, 812. (b) Lopanik, N.;
Gustafson, K. R.; Lindquist, N. J. Nat. Prod. 2004, 67, 1412.
(3) For reviews encompassing the biological properties of the bryostatins,
see: (a) Kraft, A. S. J. Natl. Cancer Inst. 1993, 85, 1790. (b) Petit, G. R.
J. Nat. Prod. 1996, 59, 812. (c) Mutter, R.; Wills, M. Bioorg. Chem. Lett.
2000, 8, 1841. (d) Hale, K. J.; Hummersone, M.. G.; Manaviazar, S.;
10.1021/ol052976s CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/31/2006

Figure 1. Structure of bryostatins 1-17.
number of creative synthetic approaches to various bryostatin
fragments are reported by Hale,9 Thomas,10 Hoffman,11
Vandewalle,12 and Burke.13
As part of a broad program in hydrogen-mediated C-C
bond formation,14 the catalytic reductive coupling of con-
jugated alkynes with carbonyl14f,g,k and imine14j partners was
recently reported from our laboratory. This reductive cou-
pling method was deemed applicable to the synthesis of the
bryostatin C-ring derivatives 8 and 9 on the following
basis: (a) the reductive coupling of 1,3-enynes to glyoxals
provides â,γ-unsaturated R-hydroxy ketonessan oxidation
pattern matching that found in C19-C21 of bryostatin 1 and
the majority of other bryostatins; (b) the geometry of the
trisubstituted alkene derived upon enyne-glyoxal reductive
coupling is consistent with the geometry of the alkylidene
moiety at C21 of the bryostatin C-ring; and finally, (c) through
the use of chirally modified rhodium catalysts, it should be
possible to address absolute stereochemistry. The following
retrosynthetic analysis, which involves the reductive coupling
of gloxal 2 to enyne 3 to afford the â,γ-unsaturated
R-hydroxy ketone 4, illustrates these features (Scheme 1).
(7) 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,
75, 143.
Scheme 1. Retrosynthetic Analysis of the Bryostatin C-Ring
via Hydrogen-Mediated Reductive Coupling
(8) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153.
(9) Review: 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.
(10) Review: Baron, A.; Ball, M.; Bradshaw, B.; Donnelly, S.; 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.
(11) (a) Lampe, T. F. J.; Hoffman, H. M. R. Chem. Commun. 1996, 1931.
(b) Lampe, T. F. J.; Hoffman, H. M. R. Tetrahedron Lett. 1996, 37, 7695.
(c) Weiss, J.; Hoffman, H. M. R. Tetrahedron: Asymmetry 1997, 8, 3913.
(d) Vakalopoulos, A.; Lampe, T. F. J.; Hoffman, H. M. R. Org. Lett. 2001,
3, 929. (e) Seidel, M. C.; Smits, R.; Stark, C. B. W.; Frackenpohl, J.;
Gaertzen, O.; Hoffman, H. M. R. Synthesis 2004, 1391.
(12) (a) De Brabander, J.; Vanhessche, K.; Vandewalle, M. Tetrahedron
Lett. 1991, 32, 2821. (b) De Brabander, J.; Vandewalle, M. Synlett 1994,
231. (c) De Brabander, J.; Vandewalle, M. Synthesis 1994, 855. (d) De
Brabander, J.; Kulkarni, A.; Garcia-Lopez, R.; Vandewalle, M. Tetrahe-
dron: Asymmetry 1997, 8, 1721.
To explore the feasibility of an enantioselective variant,
the reductive coupling of glyoxal 215 to enyne 3 using Rh-
(COD)2OTf (5 mol %) and Ph3CCO2H (5 mol %) as additive
at ambient temperature and pressure was performed in the
presence of assorted chiral phosphine ligands (Table 1).
Among the chiral ligands assayed, (R)-Tol-BINAP proved
superior. Through variation of the reaction temperature, 65
°C was identified as the ideal temperature, affording a 58%
yield of 4 in 78% enantiomeric excess (Table 1, entry 6).
Interestingly, a striking dependence of enantiomeric excess
upon the reaction temperature was observed. This result may
be explained by a Curtin-Hammett-type effect akin to that
observed in the asymmetric hydrogenation of dehydro-R-
amino acids, which also employs a cationic rhodium
catalyst.16 While use of Ph3CCO2H as a substoichiometric
(13) (a) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org.
Lett. 2004, 6, 4045. (b) Voight, E. A.; Roethle, P. A.; Burke, S. D. J. Org.
Chem. 2004, 69, 4534.
(14) For hydrogen-mediated C-C bond formations developed in our
laboratory, see: (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am.
Chem. Soc. 2002, 124, 15156. (b) Huddleston, R. R.; Krische, M. J. Org.
Lett. 2003, 5, 1143. (c) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6,
691. (d) Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J. J. Org.
Chem. 2004, 69, 1380. (e) Jang, H.-Y.; Huddleston, R. R.; Krische, M.
Angew. Chem., Int. Ed. 2003, 42, 4074. (f) Jang, H.-Y.; Huddleston, R. R.;
Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4664. (g) Huddleston, R. R.;
Jang, H.-Y. Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488. (h) Jang,
H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875. (i) Jang, H.-Y.;
Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. Am.
Chem. Soc. 2005, 127, 6174. (j) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J.
Am. Chem. Soc. 2005, 127, 11269. (k) Kong, J.-R.; Ngai, M.-Y.; Krische,
M. J. J. Am. Chem. Soc. 2006, 128, 718.
(15) The R-keto aldehyde 2 was prepared via oxidation of the corre-
sponding methyl ketone. See the Supporting Information for detailed
experimental procedures.
892
Org. Lett., Vol. 8, No. 5, 2006

Scheme 2. Synthesis of Ketal 6 via Acid-Catalyzed TBS
Deprotection-Cyclization of 5a
Table 1. Enantioselective Hydrogen-Mediated Reductive
Coupling of Glyoxal 2 to 1,3-Enyne 3a
a See the Supporting Information for detailed experimental
procedures.
as the configuration of this position is ultimately established
by the anomeric effect under conditions of thermodynamic
control in bryostatin and related structures.
To complete the preparation of bryostatin C-ring deriva-
tives 8 and 9, a regioselective oxidative cleavage of the diene
moiety is required. Whereas ozonolytic cleavage gives a
complex distribution of products,19 exposure of 6 to sub-
stoichiometric quantities of OsO4 in the presence of NaIO4
provides the desired enal product 7 in 83% yield.20 Oxidation
of the enal 7 with manganese oxide and sodium cyanide in
methanol gave the methyl enoate 8 in 72% yield. Sodium
borohydride reduction of enal 7, carried out with in ethanol
at 0 °C, provides the allylic alcohol 9 in 86% yield (Scheme
3).
a The cited yields are of pure material isolated by silica gel chromatog-
raphy. See the Supporting Information for detailed experimental procedures.
additive has been found to accelerate the reaction rate in the
Rh-catalyzed reductive coupling of conjugated alkynes and
carbonyl partners,14k it was speculated that an acidic species
of this type may deprotect the TBS groups of enyne 3 or the
coupling product 4. Indeed, when the loading of Ph3CCO2H
is decreased to 1.5 mol %, the coupling product 4 is obtained
in 70% isolated yield and 91% enantiomeric excess (Table
1, entry 8). Under otherwise identical conditions, but in the
absence of Ph3CCO2H, the reductive coupling product 4 was
obtained in only 32% yield and 90% enantiomeric excess
(Table 1, entry 9).
Hydrogen-mediated C-C bond formation enables direct
reductive coupling of highly functionalized π-unsaturated
Scheme 3. Synthesis of the Enoate 8 and the Enol 9 via
Regioselective Oxidation of Diene of 6a
Elaboration of coupling product 4 to bryostatin C-ring
derivatives 8 and 9 is achieved in four steps. Esterification
of the reductive coupling product 4 with C7H15CO2H using
diisopropylcarbodiimide and DMAP in dichloromethane17
provides the ester 5 in 92% yield. An initial attempt to
achieve the direct conversion of ester 5 to cyclic ketal 6
involved exposure of 5 to p-TsOH‚H2O (5 mol %) and CH-
(OCH3)3 (350 mol %) in methanol.18 Under these conditions,
deprotection of the TBS ether of ester 5 occurs in situ and
the resulting primary alcohol spontaneously cyclizes to give
the ketal 6 in 48% yield as a 4:1 mixture of diastereomers.
Under otherwise identical conditions, but using of 20 equiv
of CH(OCH3)3, the ketal 6 is obtained in 70% yield (Scheme
2). The stereochemistry at the anomeric carbon is irrelevant,
(16) (a) Brown, J. M.; Chaloner, P. A. J. Chem. Soc., Chem. Commun.
1980, 344. (b) Brown, J. M.; Chaloner, P. A.; Morris, G. A. J. Chem. Soc.,
Chem. Commun. 1983, 664.
(17) 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.; Nell, P. G.;
Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648.
a See Supporting Information for detailed experimental proce-
dures.
(18) Baxter, J.; Mata, E. G.; Thomas, E. J. Tetrahedron 1998, 54, 14359.
Org. Lett., Vol. 8, No. 5, 2006
893

substrates to carbonyl and imine acceptors, providing access
to functional group arrays that are otherwise difficult to
prepare.14 To highlight the synthetic utility of hydrogen-
mediated C-C bond formation, the first highly enantiose-
lective reductive coupling of glyoxals and enynes was
developed and applied strategically in a concise approach
to C17-C23 of the bryostatin recognition domain. Future
studies will be devoted to the discovery and development
of new reductive C-C bond formations mediated by
hydrogen.
Acknowledgment is made to the Research Corporation
Cottrell Scholar Program, the Sloan Foundation, the Dreyfus
Foundation, the Robert A. Welch Foundation, Eli Lilly,
Johnson & Johnson, Merck, Boehringer-Ingelheim, and the
NIH-NIGMS (RO1-GM69445) for partial support of this
research.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, and HRMS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005,
127, 7014.
(20) Sakya, S. M.; Suarez-Contreras, M.; Dirlam, J. P.; O’Connell, T.
N.; Hayashi, S. F.; Santoro, S. L.; Kamicker, B. J.; George, D. M.; Ziegler,
C. B. Bioorg. Med. Chem. Lett. 2001, 11, 2751.
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