Catalytic asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with N-Boc-protected imines

Article abstract of DOI:10.1002/anie.201202442

Crossed: A catalyst system has been developed that allows the direct asymmetric coupling of aliphatic aldehydes and N-Boc-protected imines in a cross-aza-benzoin reaction (see scheme; Boc=tert-butoxycarbonyl). The active catalyst is shown to react rapidly with the imine, however, the presence of an acid as co-catalyst renders this process reversible and allows the regeneration of the catalyst. Copyright

Full text of DOI:10.1002/anie.201202442

Angewandte
Chemie
DOI: 10.1002/anie.201202442
Synthetic Methods
Catalytic Asymmetric Cross-Aza-Benzoin Reactions of Aliphatic
Aldehydes with N-Boc-Protected Imines**
Daniel A. DiRocco and Tomislav Rovis*
The benzoin reaction has been studied for more than
a century, since the initial report by Wçhler and Liebig in
1832.[1,2] Nature has long utilized the concept of “umpolung”
(reversal of polarity) in the form of thiamine-dependent
enzymes, which are required for life.[3] However, a general
method for the asymmetric cross-benzoin reaction has not yet
been discovered.[4] The inherent problem with this trans-
formation lies in the lack of chemoselectivity between
are used as substrates, negating the requirement for a slow
addition protocol.
With the assumption that a less activated system would
lead to increased stability of the newly formed stereocenter as
well as a more synthetically valuable product, we began to
evaluate the addition of butanal 1a to N-Boc-protected imine
2a. In our study of aza-Breslow intermediates we found acetic
acid to be a competent catalyst for the regeneration of the
active carbene. Acetate salts have been used as bases in
a variety of processes catalyzed by N-heterocyclic carbene
(NHC), and their implementation in this system would
generate catalytic amounts of the required acid in situ.[15]
We were pleased to find that catalyst 3c in combination
with cesium acetate provides the desired a-amido ketone 4a
in good yield (89%) and excellent enantioselectivity (96%;
Table 1). Amine bases, such as diisopropylethylamine, are not
effective, except when catalytic amounts of acid are added to
aldehyde partners.
A few elegant methodologies have
addressed this problem, thus making the synthesis of enan-
tioenriched hetero-benzoin products possible.[5,6]
Related to the cross-benzoin reaction of aldehydes is the
cross-aza-benzoin reaction of aldehydes and imines.[7] This
concept has a variety of advantages. The difference in
reactivity between an aldehyde and an imine is inherently
greater but can also be tuned because of the trivalency of
nitrogen. Furthermore, a-amido ketones represent an impor-
tant class of medicinal agents and are a synthon for the
ubiquitous 1,2-amino-alcohol motif.[8,9]
Table 1: Reaction optimization.[a]
Murry, Frantz, and co-workers reported the first example
of an aldehyde–imine cross-benzoin reaction catalyzed by
thiazolylidene carbenes, using arylsulfonylamides as imine
precursors.[10,11] Later, Miller and co-workers disclosed an
asymmetric variant of this work by implementing their
peptide-derived thiazolium salt as a precatalyst to deliver
aryl aldehyde derived a-amido ketones.[12] They further noted
some epimerization of the newly formed stereocenter when
they used more activated coupling partners.
The speculation about the reversibility of active catalyst
addition to an imine has led to the dogma that slow in situ
generation of the imine or attenuation of its electrophilicity
would be necessary for catalyst turnover.[13] We have recently
disclosed a study of aza-Breslow intermediates derived from
the interaction of one of our chiral triazolylidene carbenes
with iminium salts.[14] This study showed that addition of these
carbene species to an iminium salt is facile and leads to
a stable intermediate; however, in the presence of a weak acid
this process is highly reversible. We wondered if we could take
advantage of this reversibility when electrophilic acyl imines
Entry
Cat.
T [8C]
Base
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
3c
3c
3c
3c
3c
3c
3c
3a
3b
0
0
0
À10
À20
À25
À30
À20
À20
iPr2NEt
iPr2NEt
NaOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
none
AcOH
none
4 ꢀ M.S.
4 ꢀ M.S.
4 ꢀ M.S.
4 ꢀ M.S.
4 ꢀ M.S.
4 ꢀ M.S.
<5%
91
33
83
89
68
61
38
51
n.a.
90
99
90
96
97
98
25
87
[a] Reactions conducted with 1a (1.5 equiv) and 2a (1.0 equiv). [b] Yield
of isolated product after purification by column chromatography.
[c] Enantiomeric excess determined by HPLC analysis on a chiral
stationary phase. Optimized reaction conditions in bold. Boc=tert-
butoxycarbonyl, M.S.=molecular sieves, n.a.=not available.
[*] D. A. DiRocco, Prof. T. Rovis
Department of Chemistry, Colorado State University
Fort Collins, CO 80526 (USA)
E-mail: rovis@lamar.colostate.edu
[**] We thank the NGIMS for generous support of this research (GM
72586), and Donald Gauthier (Merck) for a gift of aminoindanol.
T.R. thanks Amgen and Roche for support. Boc=tert-butoxycar-
bonyl.
the reaction.[16] Addition of 4 ꢀ molecular sieves is necessary
to suppress imine hydrolysis, likely because of the hygroscopic
nature of cesium acetate, while lowering the temperature led
to a significant reduction in post reaction epimerization.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202442.
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
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With an efficient catalyst system in hand, we evaluated the
scope of this transformation (Scheme 1). A variety of
aliphatic aldehydes, which contained a diverse range of
functionality, were examined. Straight-chain aldehydes pro-
duced the desired products in high yield (71–93%) and
excellent enantioselectivity (84–93% ee), while b-branched
aldehydes gave the desired products with excellent enantio-
selectivity (98% ee), but in lower yields (33%).[17] Hetero-
atoms could be incorporated into the tether without delete-
rious impact on yield or enantioselectivity, thus allowing the
incorporation of functionality, such as thioethers, imides, and
esters. Currently, a-branched aldehydes do not participate in
the reaction. The scope of the imine partner was assessed by
using N-Boc-protected imines of varying electronic nature.
Electron-rich and electron-poor aryl derivatives gave the
products in comparable yields (72–74%), despite some small
variation in enantioselectivity (90–94% ee). The common
methylenedioxyphenyl motif could be incorporated with high
selectivity (94% ee); heterocycles, such as furan, could also be
incorporated, but with lower selectivity (60% ee). Ortho-
substituted aryl derivatives led to an unexpected loss of
reactivity.
The a-amido ketone products are useful intermediates in
the synthesis of 1,2-aminoalcohols. Reduction of 3a provided
the anti-1,2-aminoalcohol as the sole diastereomer in quanti-
tative yield (Scheme 2).[18]
Scheme 2. Diastereoselective reduction of amidoketones.
Upon devoloping an efficient catalyst system, we were
interestested in probing the interaction between N-Boc-
protected imines and our active carbene to gain further
evidence for the reversible formation of an aza-Breslow
intermediate in the catalytic cycle. Subjection of precatalyst
3c to an excess of KOtBu shows clean formation of carbene 5
1
by H NMR spectroscopy. Addition of 1.0 equivalent of N-
Boc-protected imine 2a immediately produces a bright yellow
solution and shows the formation of a new species, which was
1
assigned as aza-Breslow intermediate 6 by H NMR spec-
troscopy and HRMS (Scheme 3).[19] To test the reversibility of
this process under the reaction conditions, 6 was treated with
an excess of AcOH, leading to the regeneration of a colorless
Scheme 3. NMR Studies of catalyst–substrate interaction.
1
solution. H NMR analysis confirmed the disappearance of
intermediate 6 but neither carbene 5 nor imine 2a could be
identified, thus suggesting that the carbene may not be the
resting state under these conditions.[20]
In conclusion, we have developed a highly enantioselec-
tive cross-aza-benzoin reaction of aliphatic aldehydes and N-
Boc-protected imines. This transformation provides access to
useful 1,2-amino alcohol synthons in a single step. Crucial
insight pertaining to the reversible formation of aza-Breslow
intermediates in the catalytic cycle has enabled the direct
implementation of highly reactive imines as substrates, thus
negating the requirement for a slow-addition protocol.
Scheme 1. Reaction scope. Reactions conducted with 1.5 equiv 1 and
1.0 equiv 2. Yields of isolated products after column chromatography.
Enantiomeric excesses determined by HPLC analysis on a chiral sta-
tionary phase. Absolute stereochemistry of products assigned by
analogy; see the Supporting Information.
2
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Chemie
[6] For an asymmetric cross-benzoin reaction of aldehydes with
Experimental Section
trifluoromethylketones, see: D. Enders, A. Grossmann, J.
Fronert, G. Raabe, Chem. Commun. 2010, 46, 6282 – 6284.
[7] For a homo-aza-benzoin reaction, see: B. J. E. Reich, A. K.
Justice, B. T. Beckstead, J. H. Reibenspies, S. A. Miller, J. Org.
Chem. 2004, 69, 1357 – 1359.
[8] A. Lee, L. Huang, J. Ellman, J. Am. Chem. Soc. 1999, 121, 9907 –
9914.
[9] D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835 –
876.
[10] J. A. Murry, D. E. Frantz, A. Soheili, R. Tillyer, E. J. J. Grabow-
ski, P. J. Reider, J. Am. Chem. Soc. 2001, 123, 9696 – 9697.
[11] For other examples using imines or iminium ions as acceptors,
see: a) J. Castells, F. Lꢃpez-Calahorra, M. Bassedas, P. Urrios,
Synthesis 1988, 314 – 315; b) G.-Q. Li, L.-X. Dai, S.-L. You,
Chem. Commun. 2007, 852 – 854; c) D. Enders, A. Henseler, S.
Lowins, Synthesis 2009, 4125 – 4128.
Triazolium salt precatalyst 3c (26 mg, 0.058 mmol, 0.2 equiv), cesium
acetate (55 mg, 0.29 mmol, 1.0 equiv), activated molecular sieves
(4 ꢀ, 8–12 mesh, 5–10 beads) and dichloromethane (1.5 mL) were
added to a dry 4 mL vial equipped with a magnetic stirrer bar. Under
constant stirring, the vial was placed in a cooling bath (À208C) and
purged with argon. After 5 min, the aldehyde (0.43 mmol, 1.5 equiv)
was added through a syringe, followed by a solution of the imine
(0.28 mmol, 1.0 equiv) in dichloromethane (0.5 mL). The reaction
was stirred at À208C for 24 h, then acetic acid (50 mL) was added, and
the mixture was directly purified by column chromatography on silica
gel with a mixture of hexanes:EtOAc (typically 20:1). The desired
amido-ketone was obtained as a white amorphous solid.
Received: March 29, 2012
Published online: && &&, &&&&
[12] S. M. Mennen, J. D. Gipson, Y. R. Kim, S. J. Miller, J. Am. Chem.
Soc. 2005, 127, 1654 – 1655.
[13] M. He, J. W. Bode, Org. Lett. 2005, 7, 3131 – 3134.
[14] D. A. DiRocco, K. M. Oberg, T. Rovis, J. Am. Chem. Soc. 2012,
134, 6143 – 6145.
Keywords: benzoin reaction · carbenes · imines ·
organocatalysis · umpolung
.
[15] a) S. P. Lathrop, T. Rovis, J. Am. Chem. Soc. 2009, 131, 13628 –
13630; b) K. E. Ozboya, T. Rovis, Chem. Sci. 2011, 2, 1835 –
1838; c) X. Zhao, D. A. DiRocco, T. Rovis, J. Am. Chem. Soc.
2011, 133, 12466 – 12469; d) G. Liu, P. D. Wilkerson, C. A. Toth,
H. Xu, Org. Lett. 2012, 14, 858 – 861; e) D. A. DiRocco, E. L.
Noey, K. N. Houk, T. Rovis, Angew. Chem. 2012, 124, 2441 –
2444; Angew. Chem. Int. Ed. 2012, 51, 2391 – 2394.
[16] We observed increased reactivity when the aldehyde was not
distilled prior to use, which we attribute to the presence of
carboxylic acid impurities.
[1] J. Liebig, F. Wçhler, Ann. Pharm. 1832, 3, 249 – 282.
[2] For reviews of NHC catalysis, including the benzoin reaction,
see: a) J. Moore, T. Rovis, Top. Curr. Chem. 2009, 291, 77 – 144;
b) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107,
5606 – 5655.
[3] U. Nilsson, L. Meshalkina, Y. Lindqvist, G. Schneider, J. Biol.
Chem. 1997, 272, 1864.
[4] For seminal work on the cross-benzoin reaction, see: H. Stetter,
G. Dꢁmbkes, Synthesis 1977, 403 – 404; for select recent results,
see: M. Y. Jin, S. M. Kim, H. Han, D. H. Ryu, J. W. Yang, Org.
Lett. 2011, 13, 880 – 883; C. A. Rose, S. Gundala, C.-L. Fagan,
J. F. Franz, S. J. Connon, K. Zeitler, Chem. Sci. 2012, 3, 735 – 740.
[5] For the first example of an asymmetric cross-benzoin reaction
using enzyme catalysis, see: a) P. Dꢂnkelmann, D. Kolter-Jung,
A. Nitsche, A. S. Demir, P. Siegert, B. Lingen, M. Baumann, M.
Pohl, M. Mꢂller, J. Am. Chem. Soc. 2002, 124, 12084 – 12085; for
the asymmetric cross-silyl-benzoin reaction catalyzed by metal-
lophosphites, see: b) X. Linghu, J. R. Potnick, J. S. Johnson,
J. Am. Chem. Soc. 2004, 126, 3070 – 3071.
[17] Aromatic aldehydes do not provide adduct under these con-
ditions.
[18] M. K. Ghorai, A. Kumar, D. P. Tiwari, J. Org. Chem. 2010, 75,
137 – 151.
[19] See the Supporting Information for details.
[20] In parallel work, we have found that the coupling of aldehydes
with in situ generated iminium electrophiles leads to generation
of aza-Breslow intermediates in situ, the formation of which is
reversible under the reaction conditions; D. A. DiRocco, T.
Rovis, J. Am. Chem. Soc., DOI: 10.1021/ja3030164.
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Angewandte
Communications
Communications
Synthetic Methods
D. A. DiRocco, T. Rovis*
&&&& — &&&&
Catalytic Asymmetric Cross-Aza-Benzoin
Reactions of Aliphatic Aldehydes with N-
Boc-Protected Imines
Crossed: A catalyst system has been
developed that allows the direct asym-
metric coupling of aliphatic aldehydes
and N-Boc-protected imines in a cross-
aza-benzoin reaction (see scheme; Boc=
tert-butoxycarbonyl). The active catalyst is
shown to react rapidly with the imine,
however, the presence of an acid as co-
catalyst renders this process reversible
and allows the regeneration of the cata-
lyst.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
These are not the final page numbers!