Enantioselective linchpin catalysis by SOMO catalysis: An approach to the asymmetric a-chlorination of aldehydes and terminal epoxide formation

Article abstract of DOI:10.1002/anie.200901855

Time for SOme MOre: For the first time SOMO (singly occupied molecular orbital) activation has been exploited to allow a new approach to the α-chlorination of aldehydes. This transformation can be readily implemented as part of a linchpin catalysis approach to the enantioselective production of terminal epoxides.

Full text of DOI:10.1002/anie.200901855

Angewandte
Chemie
DOI: 10.1002/anie.200901855
Organocatalysis
Enantioselective Linchpin Catalysis by SOMO Catalysis: An Approach
to the Asymmetric a-Chlorination of Aldehydes and Terminal Epoxide
Formation**
Muriel Amatore, Teresa D. Beeson, Sean P. Brown, and David W. C. MacMillan*
Over the last 40 years, research strategies in the field of
asymmetric catalysis have been founded upon the direct
production of enantioenriched synthons which typically exist
within a unique structural class (e.g. epoxide, aziridine, 1,2-
diol, amino acid, etc.).[1] Whereas the collective value of these
individual transformations is beyond measure, it is intriguing
to consider that such synthon-specific studies do not often
provide generic lessons that can be translated into other
reaction classes (e.g. epoxidation catalysts are not employed
in amino acid synthesis). Recently, we became interested in
the concept of “linchpin” catalysis (Scheme 1), an alternative
strategy for reaction design wherein the key induction step
does not lead to a unique end-point, but instead, to an
enantioenriched reactive intermediate that can be rapidly
converted (in situ) into a broad range of valuable structural
motifs.[2] As one example, we hypothesized that simple
aldehydes might be readily transformed into a variety of
fundamental organic building blocks including epoxides,[3a,b]
Scheme 1. Linchpin catalysis using a-chloroaldehydes to access many
aziridines,[3b] or a-amino acids[3c] by the asymmetric produc-
synthons.
tion and in situ derivation of a-formyl chlorides, a versatile
sp3-carbon electrophile.[4–6] Towards this goal, we report a new
mechanistic approach to the enantioselective a-chlorination
of aldehydes using organo-SOMO catalysis (SOMO = singly
occupied molecular orbital),[7] a novel transformation that
employs LiCl as a chlorine source and a simple amine catalyst.
As a first example of our linchpin catalysis strategy, we
document a pragmatic and inexpensive protocol for the in situ
conversion of aldehydes into enantioenriched terminal epox-
ides, a motif that remains elusive to direct catalysis technol-
ogies.[8,9]
From the outset, we realized that the success of our
multisynthon strategy would require the development of a
linchpin formyl/chlorination reaction which is highly selective
at room temperature yet inexpensive, nontoxic, and opera-
tionally trivial to perform.[10] Whereas studies from the group
of Jørgensen and our own group have shown that such a-
halocarbonyl products can be furnished by enamine cataly-
sis,[11] we recognized that organo-SOMO activation of alde-
hydes using a chiral amine catalyst might allow low-molecular
weight, feedstock reagents such as LiCl or NaCl to be used as
suitable chlorine sources (Scheme 2).[7a,12] The proof of
principle experiments with octanal, catalyst 1, and LiCl
demonstrated the feasibility of this approach, albeit using a
Ce(IV) oxidant and cryogenic conditions (Scheme 2). More-
over, we found that the same protocol performed at 238C
resulted in a dramatic drop in enantioselectivity, which was
not within the expected Boltzman distribution. Indeed,
subsequent control experiments revealed that the enantioin-
[*] Dr. M. Amatore, T. D. Beeson, S. P. Brown, Prof. D. W. C. MacMillan
Merck Center for Catalysis at Princeton University
Washington Road, Princeton NJ 08544-1009 (USA)
Fax: (+1)609-258-5922
E-mail: dmacmill@princeton.edu
Homepage: http://www.princeton.edu/~dmacgr/
[**] Financial support was provided by the NIHGMS (R01 GM078201-
01-01), the French Ministry of Foreign Affairs (EGIDE, Lavoisier
fellowship for M.A.), Merck and Amgen. The would like to thank
J. W. L. Hammett for help with the described racemization studies.
SOMO=singly occupied molecular orbital.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901855.
Scheme 2. SOMO catalysis at ambient temperature and using
inexpensive chlorine sources.
Angew. Chem. Int. Ed. 2009, 48, 5121 –5124
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5121

Communications
tegrity of the product is rapidly compromised by catalyst 1 at
catalyst system will effectively shield the Re face of the radical
cation, leaving the Si face exposed for enantioselective
chlorination. With respect to post-reaction racemization, we
anticipated that catalyst 2 would exist in a ground state (DFT-
2) wherein the nitrogen lone pair of electrons is eclipsed by
the adjacent tert-butyl substituent, a structural feature that
will impede the rate of iminium formation (k1) with the a-
chloro product (and thereafter enamine formation k2).
Indeed, control experiments revealed that 2-chlorooctanal
does not undergo an erosion of optical purity when exposed to
catalyst 2 for 6 hours at 238C (Scheme 3).[15]
room temperature, presumably through an iminium–enamine
equilibration mechanism (Scheme 3). On this basis we
recognized that our linchpin strategy would require the de
The proposed SOMO a-formyl chlorination was first
examined at room temperature using octanal and LiCl, with
imidazolidinone catalysts 1 and 2, and a series of stoichio-
metric oxidants (not shown).[16] As revealed in Table 1,
excellent levels of reaction efficiency and enantiocontrol
(Table 1, entry 1) were accomplished using catalyst 2 in the
Table 1: Effect of the oxidant, halide source, and catalyst loading on the
reaction.
Scheme 3. Amine catalyst mediated racemization of a-chloroalde-
hydes. The data was recorded for the reaction run at 238C in acetone.
Entry[a] Catalyst
CuX2
MCl
t
[h]
Conv. ee
[%][a]
[%][b]
novo design of a 238C enamine SOMO catalyst which
1) could provide high levels of kinetic enantiocontrol in the
1
2
3
4
2 (20 mol%) Cu(TFA)2 LiCl
4
4
4
4
5
5
91
92
94
82
88
67
94
10
89
91
94
95
97
ꢀ
C Cl bond-forming event yet 2) be inert to enamine forma-
1 (20 mol%) Cu(TFA)2 LiCl
[c]
tion with the a-chloro product, thereby avoiding a post-
product racemization pathway. On the basis of DFT calcu-
lations, we proposed that the imidazolidinone catalyst 2[13]
should selectively form the SOMO-activated radical cation 5
(DFT-5) which projects the 3p-electron system away from the
bulky tert-butyl group, whereas the carbon-centered radical
atom will selectively populate an E configuration to minimize
nonbonding interactions with the imidazolidinone ring
(Scheme 4).[14] In this topography, the methyl group on the
2 (20 mol%) CuCl2
LiTFA
2 (20 mol%) Cu(TFA)2 NaCl
5
2 (5 mol%)
2 (1 mol%)
Cu(TFA)2 LiCl
Cu(TFA)2 LiCl
6
7[d]
2 (20 mol%) Cu(TFA)2 LiCl
4 (108C) 94
[a] Conversion determined by GLC analysis using an internal standard.
[b] Enantiomeric excess determined by chiral GLC analysis. [c] Using
stoichiometric CuCl2. [d] Using 2.2 equivalents of H2O as an additive.
presence of an oxidant combination consisting of sodium
persulfate and catalytic copper(II) trifluoroacetate [Cu-
(TFA)2] in CH3CN.[17] As expected, post-product racemiza-
tion was only observed when the same protocol was employed
with catalyst 1 (Table 1, entry 2). We have found that both
LiCl and NaCl can be used successfully in this reaction, an
important consideration given the low molecular weight and
cost of both halide sources (Table 1, entries 1 and 4).[10]
Moreover, CuCl2 can be used as both a stoichiometric oxidant
and a halide source in the presence of lithium trifluoroacetate
(Table 1, entry 3). The effect of the catalyst loading on
reaction efficiency was also evaluated. Whereas 20 mol% of
imidazolidinone 2 was routinely employed in this investiga-
tion, it appears that catalyst loadings as low as 1 mol%
provide useful levels of enantioselectivity (Table 1, compare
entries 1 and 6). Lastly, higher levels of enantiocontrol are
observed when the transformation is performed at 108C in the
presence of 2.2 equivalents of H2O (Table 1, entry 7). The
superior levels of induction and efficiency exhibited by amine
salt 2 in CH3CN at 108C to afford (S)-2-chlorooctanal in
97% ee and 94% conversion prompted us to select these
catalytic conditions for additional exploration.
Scheme 4. Comparison of catalysts 1 and 2 in the SOMO catalysis.
5122
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5121 –5124

Angewandte
Chemie
We next examined the scope of the aldehyde component
in this enantioselective a-chlorination protocol. As high-
lighted in Table 2, a wide range of functional groups, including
olefins, esters, amines, carbamates, and aryl rings can be
readily tolerated on the aldehydic substrate (Table 2,
entries 2–4 and 6–8). Moreover, considerable variation in
the steric demand of the aldehyde component (Table 2,
entries 1, 7, and 9) is possible without loss in efficiency or
enantiocontrol (ꢁ 89% yield, 95–96% ee). These mild cata-
lytic conditions are also tolerant of both oxidation and acid-
sensitive functionalities such as indoles and acetals, respec-
tively (Table 2, entries 5 and 6). Notably, a catalyst exposure
study has revealed that product racemization is not observed
over the indicated reaction time (4 h) for any case shown in
Table 2. These results serve to illustrate the remarkable
capacity of amine catalyst 2 to successfully differentiate
between the aldehyde a-methylene substrates and the a-
chloroaldehyde products.
design criteria, we restricted our studies to reaction conditions
that could be telescoped into a single vessel without the need
for solvent switching or reagent quenching (i.e. the overall
transformation would involve only the sequential addition of
reagents over a predetermined time frame). As highlighted in
Table 3, we have found that the exposure of a series of
aldehydes to our new SOMO-activation, a-chlorination
conditions and subsequent in situ treatment with NaBH4
and then KOH shortly thereafter (15 min) allows the
formation of a range of terminal epoxides with high levels
of reaction efficiency and enantiocontrol. Once again, these
mild reaction conditions tolerate electron-rich p systems
which are typically prone to oxidation under many epoxida-
tion conditions (Table 3, entry 6). Moreover, acid-sensitive
functionalities such as tert-butylcarbamates are tolerated with
good levels of reaction efficiency and high levels of enantio-
Having successfully developed a new room-temperature,
a-chlorination reaction, we directed our efforts to exploiting
this asymmetric mechanism in our linchpin catalysis strategy.
As a first example, we sought to rapidly convert simple
aldehydes into enantioenriched terminal epoxides in a one-
flask, three-stage operation that would incorporate an a-
chlorination/reduction/ring-closure sequence. As a central
Table 3: Aldehydes converted into enantioenriched terminal epoxides:
Scope.
Entry Aldehyde
1
Product
Yield [%] ee [%][a]
Table 2: Enantioselective a-formyl chlorination: Substrate scope.
85
80
95
95
2
3
Entry
1
Product[a,b]
Entry
2
Product[a,b]
80
77
84
95
95
94
4
5
90% yield, 96% ee
81% yield, 95% ee
89% yield, 96% ee
91% yield, 94% ee
3
5
4
6
6
7
89
92
93
94
84% yield, 94% ee
89% yield, 95% ee
75% yield, 91% ee
95% yield, 95% ee
7
9
8
8
9
77
82
95
94
10
10
73
94
89% yield, 96% ee
95% yield, 95% ee
[a] Yield and enantioselectivity obtained after NaBH4 reduction to the
corresponding alcohol. [b] Enantiomeric excess determined by SFC
analysis. MOM=methoxymethyl ether, Boc=tert-butoxycarbonyl.
[a] Enantiomeric excess determined by HPLC analysis after expoxide opening
with 2-naphthyl thiol. TFA=trifluoroacetate, Bn=benzyl.
Angew. Chem. Int. Ed. 2009, 48, 5121 –5124
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5123

Communications
references [11a–d]), linchpin catalysis provides a strategy that
enables the direct in situ conversion of simple aldehydes into
these valuable synthons (in one reaction vessel) without the
isolation or purification of the intermediate.
meric excess (Table 3, entries 9 and 10). Importantly, the
enantioselectivities achieved in the a-chlorination step were
comprehensively maintained throughout this epoxide forma-
tion sequence. Furthermore, this complete aldehyde!termi-
nal epoxide sequence is accomplished in less than five hours,
using inexpensive, nontoxic reagents and catalysts, at temper-
atures between 0 and 238C for all of the examples shown in
Table 3.
In summary, we report a new SOMO-activated aldehyde
a-chlorination reaction which can be exploited as part of a
linchpin-catalysis approach to the enantioselective produc-
tion of terminal epoxides. Application of this strategy to the
asymmetric synthesis of aziridines and a-amino acids will be
disclosed shortly.
[7] a) T. D. Beeson, A. Mastracchio, J.-B. Hong, K. Ashton, D. W. C.
MacMillan, Science 2007, 316, 582; b) H.-Y. Jang, J.-B. Hong,
D. W. C. MacMillan, J. Am. Chem. Soc. 2007, 129, 7004; c) H.
Kim, D. W. C. MacMillan, J. Am. Chem. Soc. 2008, 130, 398;
d) T. H. Graham, C. M. Jones, N. T. Jui, D. W. C. MacMillan, J.
Am. Chem. Soc. 2008, 130, 16494.
[8] Hydrolytic kinetic resolution: a) D. A. Annis, E. N. Jacobsen, J.
Am. Chem. Soc. 1999, 121, 4147; b) S. E. Schaus, B. D. Brandes,
J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould, M. E.
Furrow, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 1307;
c) L. P. C. Nielsen, C. P. Stevenson, D. G. Blackmond, E. N.
Jacobsen, J. Am. Chem. Soc. 2004, 126, 1360. Organocatalytic
epoxidation of styrenes: d) H. Tian, X. She, X. Jiaxi, Y. Shi, Org.
Lett. 2001, 3, 1929; e) H. Tian, X. She, H. Yu, L. Shu, Y. Shi, J.
Org. Chem. 2002, 67, 2435.
Received: April 6, 2009
Published online: June 12, 2009
[9] Organocatalytic epoxidation of a,b-unsaturated carbonyls, see:
a) E. J. Corey, F.-Y. Zhang, Org. Lett. 1999, 1, 1287; b) M.
Marigo, T. B. Poulsen, W. Zhang, K. A. Jørgensen, J. Am. Chem.
Soc. 2005, 127, 6964.
[10] Price per 100 mmol and molecular weight of chlorine sources in
previous and the present study: 2,3,4,5,6,6-hexachloro-2,4-cyclo-
hexadien-1-one (MW= 300.8 gmolꢀ1), $301; N-chlorosuccin-
imide (MW= 133.5 gmolꢀ1), $1.64; LiCl (MW= 42.4 gmolꢀ1),
$0.77; NaCl (MW= 58.4 gmolꢀ1), $0.27 (based on Sigma–
Aldrich or Acros Organics pricing for 2009).
[11] a) M. P. Brochu, S. P. Brown, D. W. C. MacMillan, J. Am. Chem.
Soc. 2004, 126, 4108; b) N. Halland, A. Braunton, S. Bachmann,
M. Marigo, K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 4790;
c) M. Marigo, S. Bachmann, N. Halland, A. Braunton, K. A.
Jørgensen, Angew. Chem. 2004, 116, 5623; Angew. Chem. Int.
Ed. 2004, 43, 5507; d) N. Halland, M. A. Lie, A. Kjærsgaard, M.
Marigo, B. Schiøtt, K. A. Jørgensen, Chem. Eur. J. 2005, 11, 7083.
Application in cascade catalysis e) Y. Huang, A. M. Walji, C. H.
Larsen, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 15051.
[12] LiCl in oxidative cyclizations: B. B. Snider, Chem. Rev. 1996, 96,
339.
Keywords: epoxidation · enantioselectivity ·
asymmetric catalysis · organocatalysis
.
[1] a) Comprehensive Asymmetric Catalysis, Vols. 1–3 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999;
b) Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen,
A. Pfaltz, H. Yamamoto), Springer, Berlin, 2004, Supplement 1 –
2.
[2] For pioneering work on transition-metal-mediated linchpin
catalysis, see: H. E. Burks, J. P. Morken, Chem. Commun.
2007, 4717.
[3] a) Q.-H. Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, K.-X. Su, Chem.
Rev. 2005, 105, 1603; b) Aziridines and Epoxides in Organic
Synthesis (Ed.: A. K. Yudin), Wiley-VCH, Weinheim, 2006;
c) C. Nꢀjera, J. M. Sansano, Chem. Rev. 2007, 107, 4584.
[4] N. De Kimpe, R. Verhꢁ in The Chemistry of a-Haloketones, a-
Haloaldehydes and a-Haloimines (Eds.: S. Patai, Z. Rappoport),
Wiley, Chichester, 1988.
[5] Reviews and recent examples of enantioselective a-chlorina-
tions: a) H. Kotsuki, H. Ikishima, A. Okuyama, Heterocycles
2008, 75, 757; b) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List,
Chem. Rev. 2007, 107, 5471; c) M. Marigo, K. A. Jørgensen,
Chem. Commun. 2006, 2001; d) M. Oestreich, Angew. Chem.
2005, 117, 2376; Angew. Chem. Int. Ed. 2005, 44, 2324; e) S.
France, A. Weatherwax, T. Lectka, Eur. J. Org. Chem. 2005, 475;
f) H. Ibrahim, A. Togni, Chem. Commun. 2004, 1147; g) E. C.
Lee, K. M. McCauley, G. C. Fu, Angew. Chem. 2007, 119, 995;
Angew. Chem. Int. Ed. 2007, 46, 977.
[13] The capability of 2 to catalyze photoredox enamine trans-
formations at room temperature has already been shown: D. A.
Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77.
[14] DFT calculations performed using B3LYP/6-311 + G(2d,p)//
B3LYP/6-31G(d).
[15] Similar results were obtained using CH3CN/H2O.
[16] See the Supporting Information for details.
[17] For pioneering work on the mechanism of radical species in the
presence of copper salts, see: J. K. Kochi, Acc. Chem. Res. 1974,
7, 351.
[6] While it has been established that aldehydes can be converted
into epoxides, a-amino acids etc., over several discrete steps (see
5124
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5121 –5124