Reductive aldol coupling of divinyl ketones via rhodium-catalyzed hydrogenation: Syn-diastereoselective construction of β-hydroxyenones

Article abstract of DOI:10.1021/ol0624023

Catalytic hydrogenation of divinyl ketones 1a and 1e in the presence of diverse aldehydes 2a-e at ambient temperature and pressure using cationic rhodium catalysts ligated by tri-2-furyl phosphine enables formation of aldol products 3a-e and 5a-e, respect

Full text of DOI:10.1021/ol0624023

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5657-5660
Reductive Aldol Coupling of Divinyl
Ketones via Rhodium-Catalyzed
Hydrogenation: syn-Diastereoselective
Construction of
â-Hydroxyenones
Soo Bong Han and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin,
Texas 78712
mkrische@mail.utexas.edu
Received September 29, 2006
ABSTRACT
Catalytic hydrogenation of divinyl ketones 1a and 1e in the presence of diverse aldehydes 2a−e at ambient temperature and pressure using
cationic rhodium catalysts ligated by tri-2-furyl phosphine enables formation of aldol products 3a−e and 5a−e, respectively, with high levels
of syn diastereoselection. Through an assay of counterions (Rh(COD)2X), Rh(COD)2SbF6 is identified as the optimum precatalyst for reductive
aldol couplings of this type. For para-substituted styryl vinyl ketones 1b
releasing para substituents.
−e, a progressive increase in isolated yield is observed for electron-
Following seminal studies by Revis (1987),1a the catalytic
reductive coupling of R,â-unsaturated carbonyl compounds
and aldehydes to form aldol products, termed the “reductive
aldol reaction”, has been the subject of intensive investiga-
tion. To date, catalysts for reductive aldol coupling based on
rhodium,1,2 cobalt,3 iridium,4a palladium,4b copper,4c-g and
indium4h have been described. Further, highly diaster-
eo-1c,2e,3b-d,4e,h,i and enantioselective1d,g,h,4a,f,g variants have
been achieved.
The majority of catalytic systems for reductive aldol
coupling employs acrylate pronucleophiles in combination
with hydrosilanes as the terminal reductant. We have
developed conditions for hydrogen-mediated reductive aldol
(2) For rhodium-catalyzed reductive aldol reaction mediated by hydrogen,
see: (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 15156-15157. (b) Huddleston, R. R.; Krische, M. J. Org. Lett.
2003, 5, 1143-1146. (c) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6,
691-694. (d) Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J.
J. Org. Chem. 2004, 69, 1380-1382. (e) Jung, C.-K.; Garner, S. A.; Krische,
M. J. Org. Lett. 2006, 8, 519-522.
(3) For cobalt-catalyzed reductive aldol reaction, see: (a) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 2005-2008. (b) Baik, T.-G.; Luis, A.
L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112-5113.
(c) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang,
X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448-9453. (d) Lam, H.
W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto, O.; Luebbers,
T. Org. Lett. 2006, 8, 3729-3732.
(1) For rhodium-catalyzed reductive aldol reaction mediated by silane
or other reductants, see: (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987,
28, 4809-4812. (b) Matsuda, I.; Takahashi, K.; Sata, S. Tetrahedron Lett.
1990, 31, 5331-5334. (c) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc.
1999, 121, 12202-12203. (d) Taylor, S. J.; Duffey, M. O.; Morken, J. P.
J. Am. Chem. Soc. 2000, 122, 4528-4529. (e) Emiabata-Smith, D.;
McKillop, A.; Mills, C.; Motherwell, W. B.; Whitehead, A. J. Synlett 2001,
1302-1304. (f) Freir´ıa, M.; Whitehead, A. J.; Tocher, D. A.; Motherwell,
W. B. Tetrahedron 2004, 60, 2673-2692. (g) Fuller, N. O.; Morken, J. P.
Synlett 2005, 1459-1461. (h) Nishiyama, H.; Siomi, T.; Tsuchiya, Y.;
Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972-6973. (i) Willis, M. C.;
Woodward, R. L. J. Am. Chem. Soc. 2005, 127, 18012-18013.
10.1021/ol0624023 CCC: $33.50
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Published on Web 10/21/2006

coupling that are applicable to commercially available methyl
and ethyl vinyl ketones (MVK and EVK).2a,e Furthermore,
upon the use of cationic rhodium catalysts ligated by tri-2-
furylphosphine, exceptionally high levels of syn-diastereo-
selection are observed.2e,5
hydroxyenone 3a in 72% isolated yield with an 8:1 syn/anti
ratio (Table 1, entry 1). In the hope of improving chemical
Table 1. Counterion Effects in the Hydrogen-Mediated
Reductive Aldol Coupling of Divinyl Ketone 1a to
p-Nitrobenzaldehyde 2a Employing Cationic Rhodium
Precatalytsa
Remarkably, under the conditions of hydrogen-mediated
aldol coupling, functional groups borne by the aldehyde that
are generally considered “hydrogen labile” (alkynes, alkenes,
benzylic ethers, and nitroarenes) remain intact.2e These results
support the feasibility of couplings involving vinyl ketones
that incorporate unsaturated functional groups. Here, we
report the first reductive aldol couplings of diVinyl ketones.
Specifically, catalytic hydrogenation of crotyl vinyl ketone
1a or para-(dimethylamino)styryl vinyl ketone 1e in the
presence of assorted aldehydes results in reductive coupling
of the less-substituted vinyl moiety to furnish the corre-
sponding syn-aldols 3a-e and 5a-e, respectively.6,7 Ad-
ditionally, we describe studies of the reductive coupling of
various para-substituted styryl vinyl ketones 1b-e, wherein
progressive increases in isolated yields are observed for
electron-releasing para substituents. These studies offer
further insight into the structural and interactional features
of the catalytic system required for efficient hydrogen-
mediated aldol coupling and provide access to â-hydroxy-
enones, which are important precursors to dihydropyridinones
(Scheme 1).7
entry
rhodium precatalyst
yield
dr (syn/anti)
1
2
3
4
Rh(COD)2OTf
Rh(COD)2BARF
Rh(COD)2BF4
Rh(COD)2SbF6
72%
55%
61%
82%
8:1
17:1
9:1
13:1
a Cited yields are of material isolated by SiO2 chromatography. Diaster-
eomeric ratios were determined by 1H NMR analysis of the crude reaction
mixtures. See Supporting Information for detailed experimental procedures.
yield and diastereoselectivity, alternate rhodium precatalysts
were screened. Upon use of Rh(COD)2BARF (BARF )
{3,5-(CF3)2C6H3}4Bθ), a substantial increase in diastereose-
lectivity is observed, but the isolated yield of hydroxyenone
3a is diminished considerably (Table 1, entry 2). Similarly,
upon use of Rh(COD)2BF4, a 61% isolated yield of coupling
product 3a is obtained with a 9:1 diastereomeric ratio (Table
1, entry 3). Gratifyingly, upon use of Rh(COD)2SbF6 as the
precatalyst, hydroxyenone 3a is produced in 82% isolated
yield with a 13:1 diastereomeric ratio, representing an
improvement in both yield and stereoselectivity in compari-
son to the reaction employing Rh(COD)2OTf as the precata-
lyst (Table 1, entry 4).
Scheme 1. Catalytic Reductive Aldol Coupling of Divinyl
Ketones Mediated by Hydrogen
Our initial studies focused on the reductive coupling of
crotyl vinyl ketone 1a to p-nitrobenzaldehyde. Using our
previously developed conditions for syn-selective aldol
coupling,2e crotyl vinyl ketone 1a (200 mol %) was subjected
to hydrogenation at ambient temperature and pressure in the
presence of p-nitrobenzaldehyde 2a (100 mol %) to furnish
Under optimized conditions using Rh(COD)2SbF6 as the
precatalyst and (2-Fur)3P as the ligand, the hydrogen-
mediated aldol coupling of crotyl vinyl ketone 1a to diverse
aldehydes 2a-e was conducted at ambient temperature and
pressure (Figure 1, top). High levels of syn-diastereoselection
were observed using aromatic aldehydes (3a, 82% yield, 13:1
dr), R-heteroatom-substituted aldehydes (3b, 80% yield, 9:1
dr; 3c, 85% yield, 13:1 dr), heterocyclic aromatic aldehydes
(3d, 94% yield, 11:1 dr), and R,â-unsaturated aldehydes (3e,
75% yield, 12:1 dr). Notably, the unsaturated products 3a-e
are not subject to overreduction under the conditions of
hydrogen-mediated coupling, presumably due to a diminished
rate of conjugate reduction in response to â-substitution of
the enone moiety. Generally, reactions are complete within
(4) For reductive aldol coupling catalyzed by other metals, see the
following. Iridium: (a) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken,
J. P. Org. Lett. 2001, 3, 1829-1831. Palladium: (b) Kiyooka, S.; Shimizu,
A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237-5238. Copper: (c) Ooi, T.;
Doda, K.; Sakai, D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2133-2136.
(d) Lam, H.-W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225-4228. (e) Lam,
H.-W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743-5746. (f) Zhao,
D.; Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403-
1407. (g) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292-1297. Indium: (h) Shibata, I.; Kato, H.;
Ishida, T.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 711-
714. (i) Miura, K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004,
1985-1989.
(5) For tri-2-furylphosphine effects in metal-catalyzed reactions, see: (a)
Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595. (b)
Farina, V. Pure Appl. Chem. 1996, 68, 73-78. (c) Anderson, N. G.; Keay,
B. A. Chem. ReV. 2001, 101, 997-1030.
(6) To date, a single study of catalyzed aldol additions involving aldol
donors incorporating an enone moiety has been reported: Trost, B. M.;
Shin, S.; Sclafani, J. A. J. Am. Chem. Soc. 2005, 127, 8602-8603.
(7) For noncatalyzed aldol additions of preformed enolates derived from
methyl enones, see: (a) Patterson, I.; Osborne, S. Tetrahedron Lett. 1990,
31, 2213-2216. (b) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004,
6, 91-94. (c) Baker-Glenn, C.; Hodnett, N.; Reiter, M.; Ropp, S.; Ancliff,
R.; Gouverneur, V. J. Am. Chem. Soc. 2005, 127, 1481-1486. (d) Reiter,
M.; Turner, H.; Mills-Webb, R.; Gouverneur, V. J. Org. Chem. 2005, 70,
8478-8485. (e) Gao, B.; Yu, Z.; Fu, Z.; Feng, X. Tetrahedron Lett. 2006,
47, 1537-1539.
5658
Org. Lett., Vol. 8, No. 24, 2006

Figure 1. Hydrogen-mediated aldol coupling of crotyl vinyl enone 1a (top) and styryl vinyl enone 5a (bottom) to assorted aldehydes.
1
Cited yields are of isolated material. Diastereomeric ratios were determined by H NMR analysis of the crude reaction mixtures. Ar )
b
c
d
p-dimethylaminophenyl. Enone loadings of 150 mol % were employed. Enone loadings of 200 mol % were employed. Enone loadings
of 300 mol % were employed. See Supporting Information for detailed experimental procedures.
7 h, as determined by consumption of the aldehyde. If the
couplings are allowed to continue beyond this point, product
overreduction becomes evident. As a control experiment,
hex-4-en-3-one and p-nitrobenzaldehyde were exposed to
standard coupling conditions. The aldol addition product 3a
was not formed. Finally, upon reexposure of aldol addition
product 3a to standard coupling conditions, 3a may be
recovered in high yield without any noticeable erosion in
diastereoselectivity. This latter experiment suggests that
hydrogen-mediated aldol addition is irreversible.
formation occurs with high levels of kinetic stereospecificity
by way of internal hydride delivery to the enone s-cis
Table 2. Reductive Aldol Coupling of Styryl Vinyl Ketonesa
As one would anticipate, crotyl vinyl ketone 1a is
somewhat unstable with respect to polymerization and must
be used immediately upon isolation. Accordingly, crystalline
divinyl ketones of enhanced stability were sought, which led
to the preparation of para-substituted styryl vinyl enones 1b-
e. With the exception of 1c, these compounds are crystalline
materials that may be stored for prolonged periods of time
in the dark. To evaluate their reactivity in the reductive aldol
coupling, styryl vinyl enones 1b-e (150 mol %) were
hydrogenated in the presence of p-nitrobenzaldehyde (100
mol %) at ambient temperature and pressure using Rh-
(COD)2SbF6 as the precatalyst (Table 2). As reflected by
the isolated yield of aldol coupling products 4b-e, it was
found that the reaction responds remarkably to the effect of
remote electron-withdrawing or -releasing groups. For ex-
ample, whereas para-nitrostyryl vinyl enone 1b provides only
a 44% isolated yield of aldol coupling product 4b (Table 2,
entry 1), the corresponding para-(dimethylamino)styryl vinyl
enone 1e furnishes aldol coupling product 4e in 93% yield
under identical coupling conditions (Table 2, entry 4). These
effects may be attributed to modulation of the HOMO
energies of the intermediate rhodium enolates, with more
reactive rhodium enolates being derived from precursors
possessing electron-releasing p-styryl substituents. It is also
interesting to note that diastereoselectivity decreases with
increasing enolate reactivity, presumably due to intervention
of boatlike transition structures, or increased isomerization
of enolate geometry in advance of aldol coupling. As
previously hypothesized,2e it is believed that Z-(O)-enolate
entry
styryl vinyl ketone, Ar1
yield
dr (syn/anti)
1
2
3
4
1b, p-nitrophenyl
1c, phenyl
1d, p-methoxyphenyl
1e, p-(dimethylamino)phenyl
44%
50%
64%
93%
16:1
12:1
11:1
10:1
a Cited yields are of material isolated by SiO2 chromatography. Diaster-
eomeric ratios were determined by 1H NMR analysis of the crude reaction
mixtures. See Supporting Information for detailed experimental procedures.
conformer through a six-centered transition structure.8 Ad-
dition of the Z-(O)-enolate to the aldehyde through a
Zimmerman-Traxler-type transition structure would then
account for the observed syn-diastereoselectivity.9
Under standard conditions using Rh(COD)2SbF6 as the
catalyst precursor and Fur3P as the ligand, the hydrogen-
mediated aldol coupling of para-(dimethylamino)styryl vinyl
ketone 1e to aldehydes 2a-e was conducted at ambient
temperature and pressure (Figure 1, bottom). Again, highly
syn-diastereoselective coupling is observed for aromatic
aldehydes (5a, 93% yield, 10:1 dr), R-heteroatom-substituted
aldehydes (5b, 90% yield, 10:1 dr; 5c, 81% yield, 17:1 dr),
heterocyclic aromatic aldehydes (5d, 87% yield, 11:1 dr),
(8) Enones constrained in the s-trans configuration, such as cyclohex-
enone, do not participate in hydrogen-mediated reductive aldol coupling.
(9) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920-1923. See also: Evans, D. A.; Nelson, J. V.; Taber, T. R. Top.
Stereochem. 1982, 13, 1-115.
Org. Lett., Vol. 8, No. 24, 2006
5659

of 13:1.10 Access to the corresponding anti-1,3-diol 6b is
achieved upon treatment of 3b with NaHB(OAc)3.11 Here, a
diastereomeric ratio of 10:1 is observed. As illustrated by
the conversion of 6a to 6c, the crotyl residue may serve as
a masked aldehyde, enabling entry into higher polyols.
Finally, oxidative cyclization catalyzed by palladium permits
direct conversion of 3b to dihydropyranone 6d (Scheme
2).7b-d
Scheme 2. Elaboration of Aldol Adduct 3b to Diverse
Building Blocks for Polypropionate Constructiona
In summary, rhodium-catalyzed hydrogenation of divinyl
ketones 1a and 1e in the presence of aldehydes 2a-e results
in highly syn-diastereoselective reductive aldol coupling to
afford the R,â-unsaturated coupling products 3a-e and 5a-
e, respectively, without overreduction. As revealed by a
survey of counterions (Rh(COD)2X, where X ) OTf, BF4,
SbF6, BARF ) {3,5-(CF3)2C6H3}4B), Rh(COD)2SbF6 is
identified as the optimum precatalyst for reductive aldol
couplings of this type. Finally, for para-substituted styryl
vinyl ketones 1b-e, a progressive increase in isolated yield
in response to the presence of electron-releasing para
substituents is observed. These studies offer further insight
into the structural and interactional features of the catalytic
system required for efficient hydrogen-mediated aldol cou-
pling and provide new methods for the construction of natural
products that incorporate polypropionate motifs.
Acknowledgment. Acknowledgment is made to the
Research Corporation Cottrell Scholar Program, the Sloan
Foundation, the Dreyfus Foundation, the Robert A. Welch
Foundation, Johnson & Johnson, and the NIH-NIGMS (RO1-
GM69445) for partial support of this research.
a Cited yields are of material isolated by SiO2 chromatography.
Diastereomeric ratios were determined by 1H NMR analysis of the
crude reaction mixtures. See the experimental section for detailed
procedures.
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.
and R,â-unsaturated aldehydes (5e, 71% yield, 13:1 dr).
Unlike adducts 3a-e, the para-(dimethylamino)styryl-
containing adducts 5a-e are far less susceptible to overre-
duction under the conditions of hydrogen-mediated C-C
coupling. Additionally, for couplings that employ 1e, lower
loadings of a pronucleophile may be used.
To illustrate the relevance of this methodology with respect
to the synthesis of polypropionate-derived substructures, aldol
coupling product 3b was subjected to several different
transformations. Exposure of 3b to conditions for syn-
diastereoselective hydroxy-directed reduction affords the syn-
1,3-diol containing stereotriad 6a with a diastereomeric ratio
OL0624023
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5660
Org. Lett., Vol. 8, No. 24, 2006