Highly chemo- and enantioselective cross-benzoin reaction of aliphatic aldehydes and α-ketoesters

Article abstract of DOI:10.1021/ol400769t

An electron-deficient, valine-derived triazolium salt is shown to catalyze a highly chemo- and enantioselective cross-benzoin reaction between aliphatic aldehydes and α-ketoesters. This methodology represents the first high yielding and highly enantioselective intermolecular cross-benzoin reaction using an organocatalyst (up to 94% ee). Further diastereoselective reduction of the products gives access to densely oxygenated compounds with high chemo- and diastereoselectivity.

Full text of DOI:10.1021/ol400769t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Chemo- and Enantioselective
Cross-Benzoin Reaction of Aliphatic
Aldehydes and r‑Ketoesters
Karen Thai,† Steven M. Langdon,† Franc-ois Bilodeau,‡ and Michel Gravel*,†
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon,
SK S7N 5C9, Canada, and Research and Development, Boehringer Ingelheim (Canada),
Ltd., 2100 rue Cunard, Laval, QC, H7S 2G5, Canada
michel.gravel@usask.ca
Received March 21, 2013
ABSTRACT
An electron-deficient, valine-derived triazolium salt is shown to catalyze a highly chemo- and enantioselective cross-benzoin reaction between
aliphatic aldehydes and R-ketoesters. This methodology represents the first high yielding and highly enantioselective intermolecular cross-
benzoin reaction using an organocatalyst (up to 94% ee). Further diastereoselective reduction of the products gives access to densely oxygenated
compounds with high chemo- and diastereoselectivity.
N-Heterocyclic carbene (NHC) catalysis with its attrac-
tive ability to invert the reactivity of aldehydes (umpolung)
has led to intensive research in the area.1 Although the
NHC-catalyzed benzoin reaction dates back to 1943,2 the
chemo- and enantioselective coupling of two different
aldehydes still remains elusive. Despite the recent advances
in the field in which highly enantioselective intermolecular
homocoupling of aldehydes has been achieved,3 the study
of the chemo- and enantioselective coupling of acyl anion
equivalents with different carbonyl partners remains in its
infancy.4,5 Indeed, such transformations have only re-
cently been achieved with varying levels of success. Pio-
neering work on the intramolecular cross coupling of
† University of Saskatchewan.
‡ Boehringer Ingelheim.
(1) For recent reviews on NHC-catalyzed transformations, see: (a)
Enders, D.; Balensiefer, T.; Niemeier, O.; Christmann, M. In Enantio-
selective Organocatalysis: Reactions and Experimental Procedures;
Dalko, P. I., Ed.; Wiley-VCH: Weinheim, Germany, 2007; pp 331À355.
(b) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606.
(c) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2009, 291, 77. (d) Chiang,
P.-C.; Bode, J. W. In N-Heterocyclic Carbenes: From Laboratory
(4) For selected examples on the chemoselective, intermolecular
€
cross-benzoin reaction, see: (a) Stetter, H.; Dambkes, G. Synthesis
1977, 403. (b) Mennen, S. M.; Miller, S. J. J. Org. Chem. 2007, 72,
5260. (c) Rose, C. A.; Gundala, S.; Connon, S. J.; Zeitler, K. Synthesis
2011, 190. For cross-benzoin reactions employing O-silylcarbinols, see:
(d) Mathies, A. K.; Mattson, A. E.; Scheidt, K. A. Synlett 2009, 377. For
an example of a cross-benzoin reaction between R-ketoesters and
R-diketones as acyl anion surrogates, see: (e) Bortolini, O.; Fantin, G.;
Fogagnolo, M.; Giovannini, P. P.; Venturi, V.; Pacifico, S.; Massi, A.
Tetrahedron 2011, 67, 8110. For cross-benzoin reactions employing
acylsilanes, see: (f) Tarr, J. C.; Johnson, J. S. J. Org. Chem. 2010, 75,
3317 and references therein.
ꢀ
Curiosities to Efficient Synthetic Tools; Dıez-Gonzalez, S., Ed.; Royal
´
Society of Chemistry: Cambridge, United Kingdom, 2010; pp 339À445.
(e) Campbell, C. D.; Ling, K. B.; Smith, A. D. In N-Heterocyclic
Carbenes in Transition Metal Catalysis and Organocatalysis; Cazin,
C. S. J., Ed.; Springer: Dortrecht, Germany, 2011; Vol. 32, pp 263À297.
(f) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511.
(2) Ukai, T.; Tanaka, S.; Dokawa, S. J. Pharm. Soc. Jpn. 1943, 63,
269.
(5) Enantio- and chemoselective cross-benzoin reactions: (a) Enders,
D.; Grossmann, A.; Fronert, J.; Raabe, G. Chem. Commun. 2010, 46,
6282. (b) O’Toole, S. E.; Rose, C. A.; Gundala, S.; Zeitler, K.; Connon,
S. J. J. Org. Chem. 2011, 76, 347. (c) Jin, M. Y.; Kim, S. M.; Han, H.;
Ryu, D. H.; Yang, J. W. Org. Lett. 2011, 13, 880. (d) Rose, C. A.;
Gundala, S.; Fagan, C. -L.; Franz, J. F.; Connon, S. J.; Zeitler, K. Chem.
Sci. 2012, 3, 735. Enzymatic coupling employing R-diketones: (e)
Giovannini, P. P.; Fantin, G.; Massi, A.; Venturi, V.; Pedrini, P. Org.
Biomol. Chem. 2011, 9, 8038.
(3) For recent examples on the enantioselective homocoupling of
aldehydes, see: (a) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002,
41, 1743. (b) Ma, Y.; Wei, S.; Wu, J.; Yang, F.; Liu, B.; Lan, J.; Yang, S.;
You, J. Adv. Synth. Catal. 2008, 350, 2645. (c) Enders, D.; Han, J.
Tetrahedron: Asymmetry 2008, 19, 1367. (d) Baragwanath, L.; Rose,
C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74, 9214. (e) Soeta,
T.; Tabatake, Y.; Inomata, K.; Ukaji, Y. Tetrahedron 2012, 68, 894.
r
10.1021/ol400769t
XXXX American Chemical Society

aldehydes with ketones was reported by the groups of
Enders and Suzuki, in which high yields as well as high
diastereo- and enantioselectivities were achieved.6 In con-
trast, chemo- and enantioselective intermolecular cross-
benzoin reactions using a small molecule organocatalyst
we pursued our studies with the aim of uncovering such
a reaction.
Scheme 1. Cross-Benzoin Reaction between Aldehydes and
Ketones
have proven difficult, and only a few reports have been
€
5
published (Scheme 1). In related work, Muller and co-
workers reported the use of ThDP-dependent enzymes to
achieve the decarboxylative coupling of R-ketoacids and
carbonyl compounds, as well as the chemo- and enantio-
selective coupling between aromatic aldehydes.7 Very re-
´ ´
cently, Domınguez de Marıa and co-workers disclosed
an enzyme-catalyzed diastereoselective coupling between
aromatic and aliphatic aldehydes.8
Despite these advances, the intermolecular cross-
benzoin reaction is still limited by a narrow reaction scope,
moderate enantioselectivities, or both. Importantly, only
enzyme-catalyzed intermolecular cross-benzoin reactions
have achieved high enantioselectivities (>90% ee) to date.
Aliphatic aldehydes in particular are challenging coupling
partners in NHC-catalysis because of their low reactivity
and the presence of enolizable protons under basic con-
ditions.9 On the basis of our previous success utilizing
R-ketoesters as useful Stetter acceptors,10 we hypothesized
that the combination of these highly reactive substrates11
and aliphatic aldehydes as coupling partners could be used
in cross-benzoin reactions. As our studies were in progress,
the groups of Connon and Zeitler jointly disclosed their
results in the cross-benzoin reaction using R-ketoesters and
an achiral catalyst. Although this detailed report firmly
established the use of a variety of functionalized aldehydes
as coupling partners, a general and highly enantioselective
version of the reaction remained elusive. In one example,
moderate yield and moderate enantioselectivity was
achieved at ambient temperature (Scheme 1b).5d In view of
the current absence of highly enantioselective intermolec-
ular cross-benzoin reactions utilizing organocatalysts,
A brief catalyst screen was performed with various
chiral electron-deficient triazolium derived carbenes
8aÀe (Table 1, entries 1À5). Triazolium precatalyst 8a12
furnished the desired cross-benzoin product in good yield
and good enantioselectivity (entry 1). In contrast to the
long reaction times required under the conditions reported
by Connon, Zeitler, and co-workers,5d good conversion
was observed after a few hours (4 h). The use of Rovis’
aminoindanol-derived precatalyst 8b13 led to a decrease
in both the yield and enantioselectivity of the reaction
(entry 2). However, the use of a closely related triazolium
salt 8c10 furnished the cross-benzoin product in moderate
yield and improved enantioselectivity (entry 3). Inan effort
to increase the steric bulk near the reactive center, di-
methyl-substitutedtriazolium salt8d10 was used. However,
this modification resulted in complete suppression of
reactivity since neither desired cross-benzoin nor homo-
benzoin products were observed (entry 4). Use of valine-
derived triazolium salt 8e14 resulted in increased enantios-
electivity, albeit at the expense of yield (entry 5). Addition
of molecular sieves had a beneficial effect on the yield and
was accompanied by a slight reduction in the observed
enantioselectivity (entry 6). Further efforts showed a
strong influence of the ester moiety on the outcome of
the reaction (entries 7À8). Aiming to improve the enan-
tioselectivity of the reaction with NHC precatalyst 8e,
substrate 3 bearing a bulky tert-butyl ester moiety was
synthesized. Surprisingly, the reaction suffered from a
decrease in both the reactivity and enantioselectivity
(entry 7) compared to that using ethyl R-ketoester 2. In
light of this result, the use of a substituent smaller than the
(6) For examples on the intramolecular cross-benzoin reaction be-
tween aldehydes and ketones, see: (a) Hachisu, Y.; Bode, J. W.; Suzuki,
K. J. Am. Chem. Soc. 2003, 125, 8432. (b) Enders, D.; Niemeier, O.
Synlett 2004, 2111. (c) Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006,
2431. (d) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int.
Ed. 2006, 45, 1463. (e) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki,
K. Angew. Chem., Int. Ed. 2006, 45, 3492. (f) Takikawa, H.; Suzuki, K.
Org. Lett. 2007, 9, 2713. (g) Li, Y.; Feng, Z.; You, S.-L. Chem. Commun.
2008, 2263. (h) Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T.
Org. Lett. 2009, 11, 4866. (i) Takada, A.; Hashimoto, Y.; Takikawa, H.;
Hikita, K.; Suzuki, K. Angew. Chem., Int. Ed. 2011, 50, 2297.
€
(7) (a) Pohl, M.; Lingen, B.; Muller, M. Chem.;Eur. J. 2002, 8, 5288.
€
(b) Dunkelmann, P.; Kolter-Jung, D.; Nitsche, A.; Demir, A. S.; Siegert,
P.; Lingen, B.; Baumann, M.; Pohl, M.; Muller, M. J. Am. Chem. Soc.
€
€
2002, 124, 12084. (c) Lehwald, P.; Richter, M.; Rohr, C.; Hung-wen, L.;
€
Muller, M. Angew. Chem., Int. Ed. 2010, 49, 2389. Beigi, M.; Waltzer, S.;
€
Fries, A.; Eggeling, L.; Sprenger, G. A.; Muller, M. Org. Lett. 2013, 15,
452.
€
ꢀ
ꢀ
(8) Muller, C.; Perez-Sanchez, M.; Domınguez de Marıa, P. Org.
´ ´
Biomol. Chem. 2013, 11, 2000.
(9) Rovis and co-workers have shown efficient, enantioselective
transformations with aliphatic aldehydes for the NHC-catalyzed Stetter
and aza-benzoin reactions. (a) DiRocco, D. A.; Noey, E. L.; Houk,
K. N.; Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 2391. (b) DiRocco,
D. A.; Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 5904.
(12) DiRocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
Chem. Soc. 2009, 31, 10872.
ꢀ
(10) Sanchez-Larios, E.; Thai, K.; Bilodeau, F.; Gravel, M. Org. Lett.
(13) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5726.
(14) An analogous N-Ph salt has been reported: Kerr, M. S.; Read de
Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298.
2011, 13, 4942.
(11) Cohen, D. T.; Cardinal-David, B.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2011, 50, 1678.
B
Org. Lett., Vol. XX, No. XX, XXXX

ethyl group present in 2 was then considered. Gratifyingly,
the methyl ester substrate underwent the reaction with an
improvement in both the yield and enantioselectivity
(entry 6 vs entry 8). The use of a lower catalyst loading
led to decreased yields.
Scheme 2. Scope of the Cross-Benzoin Reactiona
Table 1. Reaction Optimizationa
entry substrate NHC precat additive yield (%)b ee (%)c
1
2
3
4
5
6
7
8
2
8a
8b
8c
8d
8e
8e
8e
8e
none
none
none
none
none
77
22
55
0
80
74
89
À
2
2
2
2
27
61
22
80
91
89
74
91
˚
2
4 A M.S.
˚
3
4 A M.S.
˚
a All reactions were performed by the addition of iPr2NEt (1 equiv)
to a solution of aldehyde 1 (1.5 equiv), R-ketoester 4 (1 equiv), powdered
4 A M.S. (1:1 w/w with respect to 4) and precatalyst 8e (0.1 equiv) in dry
CH2Cl2 (0.2 M) under inert atmosphere at 23 °C. b Performed with
30 mol % catalytic loading.
4a
4 A M.S.
a Unless otherwise noted, all reactions were performed by the addi-
tion of iPr2NEt (1 equiv) to a solution of aldehyde 1a (1.5 equiv),
R-ketoester (1 equiv), and precatalyst (0.1 equiv) in dry CH2Cl2 under
inert atmosphere at 23 °C. b Yield of isolated product. c Enantiomeric
excess determined by HPLC analysis on chiral stationary phase. M.S. =
molecular sieves.
possible. As can be seen in Scheme 2, various aryl-
substituted R-ketoester acceptors furnished the desired cross-
benzoin products with moderate to good yields and en-
antioselectivities (products 7g16À7k). Excellent reactivity
was observed with the 3-pyridyl R-ketoester acceptor,
which was however accompanied by a small decrease in
the enantioselectivity (7g). The use of a large naphthalene
substituent led to a significant decrease in the yield and a
slight decrease in the enantiomeric excess of the cross-
benzoin product (7h). In contrast, the use of a p-tolyl-
R-ketoester acceptor led to the corresponding cross-
benzoin product 7i in excellent enantioselectivity, albeit
in moderate yield. Reactions performed with electron-
poor aryl substituents also afforded the products with very
good enantioselectivity (7j and 7k). Alkyl-substituted
R-ketoester acceptors did not participate in the reaction
under these conditions. Nevertheless, the excellent reactiv-
ity observed between various aliphatic aldehydes and
aryl-substituted R-ketoester acceptors is noteworthy, as
all reactions were completed within 3À24 h.
Having established optimal conditions, the scope of the
cross-benzoin reaction was then investigated. Aliphatic
aldehydes of varying chain length were explored (Scheme 2).
The use of hydrocinnamaldehyde 1a furnished the de-
sired cross-benzoin product 7a in good yield and good
enantioselectivity (80% yield, 91% ee). Short linear alde-
hydes such as propanal 1b and butanal 1c led to the
corresponding cross-benzoin products 7b and 7c, respec-
tively, in good yields and good enantiomeric excess. With
longer linear carbon chain aldehydes, such as octanal 1d,
the high enantioselectivity was preserved to furnish 7d in
excellent yield (98% yield, 93% ee). The presence of esters
was also found to be compatible under the optimized
conditions, furnishing the desired cross-benzoin product
7e in moderate yield and excellent enantioselectivity (56%
yield, 94% ee). The introduction of a substituent at the b
position of the aldehyde provided 7f with good enantios-
electivity, albeit at the expense of reactivity (43% yield,
88% ee). On the other hand, R-branched aliphatic alde-
hydes and aromatic aldehydes did not undergo any reac-
tion under these conditions, presumably as a result of steric
hindrance.15 Some modifications on the acceptor are also
Cross-benzoin products 7 could be reduced with very
high chemo- and diastereoselectivity, as shown in Scheme 3.
Reduction using 1 equiv of sodium borohydride in the
presence of zinc chloride cleanly afforded the correspond-
ing syn diols. This simple cross-benzoin/reduction sequence
(15) Similar limitations in the aldehyde partner were found using
an amino indanol-derived triazolium salt for aza-benzoin reactions; see
ref 9b.
(16) Because of the ease of preparation of 4b, the ethyl ester substrate
was used instead of the methyl ester counterpart.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Diastereoselective Reduction of Cross-Benzoin
Products to Access syn Diols
thus affords densely oxygenated products with high chemo-,
diastereo-, and enantioselectivity. The minor anti diaste-
reomer obtained from the reduction of 7c was used to
determine its absolute configuration. The absolute con-
figuration of all other cross-benzoin products (7aÀk)
was assigned by analogy (see Supporting Information
for details).
Figure 1. Proposed rationale for the stereochemical outcome.
The stereochemical outcome of the cross-benzoin reac-
tion can be rationalized by a five-membered transi-
tion state featuring a hydrogen bonding interaction
(Figure 1).17 The favored transition state (TS-1) has the
large aryl substituent oriented away from the carbene
catalyst. The transition state that leads to the formation
of the minor enantiomer (TS-2) orients the large aryl
substituent beneath the catalyst framework, causing steric
repulsion. In both cases, the acceptor approaches from the
face opposite the isopropyl substituent.
An enantioselective cross-benzoin reaction has been
realized through the development of a new valine-derived
triazolium catalyst. Excellent enantioselectivity is observed
with aliphatic aldehydes and various aryl R-ketoester
acceptors. This transformation provides access to enantio-
merically enriched tertiary alcohols in two steps from
readily accessible starting materials. Furthermore, the
cross-benzoin products were conveniently reduced to syn
diols with excellent diastereoselectivity. Further work on
cross-benzoin and other NHC-catalyzed reactions is on-
going in our laboratories.
Acknowledgment. Dedicated to the memory of Louis
Morency. We thank Boehringer Ingelheim (Canada), Ltd.,
for an Industrial Cooperative Research Scholarship in
Synthetic Organic Chemistry (to K.T.), the Natural
Sciences and Engineering Research Council of Canada,
the Canada Foundation for Innovation, and the Univer-
sity of Saskatchewan for financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data and NMR spectra for
all new compounds; HPLC chromatograms for cross-
benzoin products 7 and diols 9a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Dudding, T.; Houk, K. N. Proc. Natl. Acad. Sci. U. S. A.
2004, 101, 5770. (b) Enders, D.; Niemeier, O.; Balensiefer, T. Angew.
Chem., Int. Ed. 2006, 45, 1463.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX