An organocascade kinetic resolution

Article abstract of DOI:10.1021/ol2027587

Products of a novel iminium-catalyzed oxa-Michael addition undergo a kinetic resolution by a subsequent enamine-catalyzed intermolecular reaction. This is a rare example of kinetic resolution by enamine catalysis and the first organocascade kinetic resolution. This resolution produces enantioenriched 2,6-cis-tetrahydropyrans and, notably, cascade products with absolute and relative configurations normally not observed using this diphenyl prolinol silyl ether. This resolution thus provides new insight into asymmetric induction in reactions employing this catalyst.

Full text of DOI:10.1021/ol2027587

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6460–6463
An Organocascade Kinetic Resolution
Patrick G. McGarraugh and Stacey E. Brenner-Moyer*
Department of Chemistry, Brooklyn College and the City University of New York,
2900 Bedford Avenue, Brooklyn, New York 11210, United States
SBrenner@brooklyn.cuny.edu
Received October 13, 2011
ABSTRACT
Products of a novel iminium-catalyzed oxa-Michael addition undergo a kinetic resolution by a subsequent enamine-catalyzed intermolecular
reaction. This is a rare example of kinetic resolution by enamine catalysis and the first organocascade kinetic resolution. This resolution produces
enantioenriched 2,6-cis-tetrahydropyrans and, notably, cascade products with absolute and relative configurations normally not observed using
this diphenyl prolinol silyl ether. This resolution thus provides new insight into asymmetric induction in reactions employing this catalyst.
Efficient enantioselective oxa-Michael additions of alco-
hols are complicated by their reversibility, which can lead
to low yields and selectivities.1 Organocatalytic oxa-
Scheme 1. Organocatalytic Oxa-Michael Additions of Alcohols
Michael additions of alcohols have relied primarily on
two strategies to overcome this issue and as a result, with
few exceptions,2,4e,5b,6f,6l generate structures of type 2
(Scheme 1). Intramolecular oxa-Michael additions (i.e., of 1)
catalyzed by chiral phosphoric acid,2 guanidine,3 cinchona
alkaloid,4 and thiourea5 organocatalysts generate pro-
Alternatively, by tethering a nucleophilic alcohol to an
electrophilic center, as in 3, intermolecular oxa-Michael
additions are followed by intramolecular reactions, lead-
ing to cascade products in high yields and selectivities
by a combination of iminium and enamine catalysis.6
We sought to develop the enantioselective oxa-Michael
ducts in high yields, because the equilibrium of these
reactions lies largely to the right. Only a few examples
were both highly diastereo- and enantioselective.2,4g,5
(1) Kano, T.; Tanaka, Y.; Maruoka, K. Tetrahedron 2007, 63, 8658–
8664.
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T. Eur. J. Org. Chem. 2008, 2759–2766. (b) Das, B. C.; Mohapatra, S.;
Campbell, P. D.; Nayak, S.; Mahalingam, S. M.; Evans, T. Tetrahedron
Lett. 2010, 51, 2567–2570.
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2000, 41, 10229–10232. (b) Tanaka, T.; Kumamoto, T.; Ishikawa, T.
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T.; Tanaka, T.; Ikeda, T.; Ishikawa, T. J. Org. Chem. 2004, 69, 2760–2767.
(d) Merschaert, A.; Delbeke, P.; Daloze, D.; Dive, G. Tetrahedron Lett.
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H.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2007, 48, 2181–2184.
(c) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W.
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Chem. Commun. 2007, 507–509. (d) Sunden, H.; Ibrahem, I.; Zhao,
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G.-L.; Eriksson, L.; Cordova, A. Chem.;Eur. J. 2007, 13, 574–581.
(e) Xu, D.-Q.; Wang, Y.-F.; Luo, S.-P.; Zhang, S.; Zhong, A.-G.; Chen,
H.; Xu, Z.-Y. Adv. Synth. Catal. 2008, 350, 2610–2616. (f) Reyes, E.;
Talavera, G.; Vicario, J. L.; Badıa, D.; Carrillo, L. Angew. Chem., Int.
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Ed. 2009, 48, 5701–5704. (g) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Org.
Lett. 2009, 11, 1627–1630. (h) Kotame, P.; Hong, B.-C.; Liao, J.-H.
Tetrahedron Lett. 2009, 50, 704–707. (i) Hong, B.-C.; Kotame, P.; Tsai,
C.-W.; Liao, J.-H. Org. Lett. 2010, 12, 776–779. (j) Xia, A.-B.; Xu,
D.-Q.; Luo, S.-P.; Jiang, J.-R.; Tang, J.; Wang, Y.-F.; Xu, Z.-Y.
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G.; Hintermann, L. Eur. J. Org. Chem. 2007, 5886–5898. (g) Wang, H.-F.;
Cui, H.-F.; Chai, Z.; Li, P.; Zheng, C.-W.; Yang, Y.-Q.; Zhao, G.
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129, 3830–3831. (b) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem.
Soc. 2008, 130, 46–48.
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r
10.1021/ol2027587
Published on Web 11/15/2011
2011 American Chemical Society

addition depicted in Table 1 (5af8-cis and -trans). If
successful, this transformation would be the first example
ofa highlyselective iminium-catalyzedMichael additionof
an alcohol that was not part of a cascade reaction.7 More-
over, it would provide a new, green chemical method for
accessing enantioenriched 2,6-cis- and trans-tetrahydro-
pyrans, both of which are prevalent in natural products.
During studies toward this new oxa-Michael reaction, an
unanticipated organocascade kinetic resolution was ob-
served and is described herein.
We wondered whether it would be possible to trap
enamine intermediate 9 (Scheme 2) with an external elec-
trophile (“E”) to prevent retro-oxa-Michael addition and,
in turn, the conversion of 8-trans to epi-8-cis. As alluded to
earlier, it is a common practice to trap enamine intermedi-
ates arising from oxa-Michael additions by subsequent
intramolecular reactions, as occurs when an oxa-Michael
donor is tethered to an electrophilic center, as in 3.6
Trapping enamine intermediates arising from oxa-Michael
additions using intermolecular reactions has not been
reported and would generate cis- and trans-tetrahydropy-
ran cascade products 10-cis and -trans, with a syn relation-
ship between substituents at the R- and β-positions.
Table 1. Development of a Novel Oxa-Michael Additiona
Scheme 2. Cascade by Enamine-Catalyzed Intermolecular Re-
action
time
yieldb
(%)
drc
% eed
% eed
entry
cat.
(min)
(cis/trans)
(cis)
(trans)
1
2
3
4
5
6
7
8f
Et3N
45
45
1
À
À
6
À
Using β-nitrostyrene (11) as the external electrophile,
and a 5 mol % catalyst loading at À30 °C, trace conversion
was observed (entry 1, Table 2). When the catalyst loading
was increased, an unanticipated kinetic resolution was
observed (entry 2). The enamine-catalyzed intermolecular
reaction was slower than the retro-oxa-Michael, as 8-trans
had completely converted to epi-8-cis, resulting in a race-
mic intermediate, rac-8-cis. Thus, no trans-tetrahydropyr-
an cascade product was observed. One enantiomer, epi-
8-cis, underwent an enamine-catalyzed intermolecular
Michael addition to furnish cascade product 12, with an
anti relationship between its R- and β-substituents, in 42%
conversion (maximum theoretical conversion = 50%), 9:1
dr, and 99% ee. The other enantiomer, 8-cis, underwent
the subsequent enamine-catalyzed intermolecular Michael
addition at a considerably retarded rate (only 11% con-
version) and could be recovered in 90% ee. This kinetic
resolution is highly solvent-dependent. In THF, neither
enantiomer of rac-8-cis underwent the enamine-catalyzed
intermolecular Michael addition, whereas in CHCl3 both
enantiomers did (entries 3 and 4).
A variety of different substrates underwent a kinetic
resolution using these conditions (Scheme 3). In all cases a
small amount of cascade product arising from 8-cis was
generated; however, alcohols 13 and 14 were produced,
following an in situ reduction, in generally good to excel-
lent yields and selectivities. Regardless of the steric bulk of
the R group, products were obtained in excellent yield and
selectivity (compounds aÀd). Other reactive functional
groups and adjacent heteroatoms were also well tolerated,
as was an sp2 hybridized R group (compounds eÀg).
44
68
70
70
80
73
54/46
59/41
62/38
82/18
62/38
63/37
68
57
46
17
52
53
95
96
6
5
6
10
45
20
180
96
6
89
6e
6
>99
>99
a Reaction conditions: 5a (1 equiv), cat. (10 mol %), PhCO2H (10
mol %), toluene (0.4 M), 0 °C. b Yield of corresponding alcohol
generated by in situ reduction. c Dr of corresponding alcohols deter-
mined by 1H NMR. d % ee of para-nitrobenzoate derivative of corre-
sponding alcohol determined by chiral phase HPLC. e 5 mol % 6 and 5
mol % PhCO2H used. f Reaction run at À30 °C.
This intramolecular oxa-Michael addition was not
base- or acid-catalyzed but was rapidly iminium-catalyzed
(entries 1 and 2 vs 3À8). By stopping this reaction at
various time points (entries 3À6), two trends became
apparent. First, the trans-tetrahydropyran product can
be obtained in excellent ee. Second, although the initial
oxa-Michael addition is selective, a plot of these data
revealed that 8-trans converts to epi-8-cis over time, which
erodes both the trans/cis ratio and the ee of 8-cis.8 Ex-
tensive optimizations8 revealed that lower catalyst load-
ings (5 mol %) and temperatures (À30 °C) led to the
highest yield and ee >99% of the trans-product (entries
7 and 8). Thus, although it is possible to stop this reaction
at a time point at which the trans-product can be isolated in
high yield and ee, at all time points, and even at incomplete
conversions (entries 3 and 4), the trans/cis ratio was <1.
(7) (a) For a nonhighly selective version, see: Dı
´
ꢀ~
ez, D.; Nunez, M.-G.;
ꢀ
Beneitez, A.; Moro, R.-F.; Marcos, I. S.; Basabe, P.; Broughton, H. B.;
Urones, J. G. Synlett 2009, 390–394. (b) For a version using peroxyal-
cohols, see: Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem.
Soc. 2008, 130, 8134–8135.
(9) Substrates 5h and 5i could not be synthesized in uncyclized form
and were, thus, subjected to cascade reaction conditions as the corre-
sponding racemic cis-tetrahydropyrans.
(8) See Supporting Information for full details.
Org. Lett., Vol. 13, No. 24, 2011
6461

Importantly, substrates that generate tetrahydropyrans
with substitution at the 4-position are amenable to this ki-
netic resolution.9 Tetrahydropyran products with a dithiane
ring at the 4-position were generated in good ee, but with a
slightly lower dr (compound h). A reaction with a substrate
producing tetrahydropyrans with an olefin at the 4-position
could be readily scaled up to a 1.1 g scale (compound i).
8-trans to epi-8-cis may occur via a high energy Z-iminium
species 7-Z.10
Scheme 3. A General Organocascade Kinetic ResolutionaÀd
Table 2. An Organocascade Kinetic Resolutiona
% convb
% eec
% convb,d
drb
% eed,e
entry solvent
(8-cis)
(8-cis)
(12)
(12)
(12)
1f
2
toluene
toluene
THF
À
N/A
90
À
N/A N/A
45
69
À
42(11)
À
9:1
99 (nd)
3
0
N/A N/A
4
CHCl3
N/A
39 (38)
2:1
99 (99)
a Reaction conditions: 5a (1 equiv), 11 (2 equiv), 6 (20 mol %),
PhCO2H (20 mol %), solvent (0.4 M), À30 °C. b Determined by 1H
NMR of crude reaction mixture. c % ee of para-nitrobenzoate derivative
of corresponding alcohol determined by chiral phase HPLC. d Number
in parentheses is for cascade product derived from 8-cis. e % ee of
corresponding alcohol determined by chiral phase HPLC. f 5 mol % 6
and 5 mol % PhCO2H used.
The absolute configuration of 13a was established by
comparison of data for a known compound.8 The absolute
configuration of 14a at the 6-position of the tetrahydro-
pyran was established by running this organocascade re-
action with the pure R and pure S enantiomers of 5a.8 The
configurations of the remaining stereocenters in 14a were
established by X-ray crystallography of its para-nitro-
benzoate derivative.8
Our working stereochemical model for this organocas-
cade kinetic resolution is illustrated in Scheme 4. Racemic
alcohol 5a reacts with catalyst 6 to form E-iminium 7-E.
The hydroxyl group approaches from the face opposite the
bulky groups of the catalyst, generating oxa-Michael
products 8-trans and 8-cis. Oxa-Michael product 8-trans
is highly unstable because one of the substituents must
occupy an axial position on the tetrahydropyran ring.
Therefore, 8-trans undergoes a rapid retro-oxa-Michael/
oxa-Michael addition to generate the thermodynamically
favored, all-equatorial epi-8-cis. Although we could not
isolate 8-trans to test the mechanism of the retro-oxa-
Michael, we know that, in the forward direction, the oxa-
Michael addition isiminium-catalyzed (and, as mentioned,
not simply base- or acid-catalyzed) and that nucleophiles
reacting with iminium ions formed from catalyst 6 gener-
ally approach from the face opposite the bulky groups
of this catalyst. It is therefore possible that conversion of
a Reaction conditions:5a(0.44mmol), 11 (0.88 mmol), 6 (0.088 mmol),
PhCO2H (0.088 mmol), toluene (1.1mL), À30°C, thenTHF BH3 (1M in
3
THF, 0.5 mL) or NaBH4c(2 mmol), MeOH (4.4 mL). bConv and dr
determined by 1H NMR. Yield = yield of isolated product. dEe’s of
alcohol or of para-nitrobenzoate derivative of alcohol determined by
chiral phase HPLC. eReaction run on 4 mmol scale.
Intermediates 8-cis and epi-8-cis can react with catalyst 6
to form enamines 16 and 15, respectively. In enamine 15,
the bulky groups of the catalyst and the substituents at the
β- and 6-positions all block the top face of the enamine.
These synergistic blocking effects evidently result in rapid
reaction with an electrophile that approaches from the
bottom face of the enamine, generating cascade product
12. In enamine 16, the bulky groups of the catalyst shield
the top face of the enamine, while the substituents at the
β- and 6-positions shield the bottom face. These opposing
blocking effects may account for the relative unreactivity
of enamine 16.
Thus, formation of epi-8-cis, which effectively arises
from the approach of the alcohol from the same face as
the bulky groups of the catalyst in iminium species 7-E,
is disfavored in the initial oxa-Michael addition, in accord
with the accepted model for asymmetric induction of
(10) Z-Iminium species have been invoked in olefin isomerizations;
for example, see: Yang, J. W.; Fonseca, M. T. H.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2005, 44, 108–110.
6462
Org. Lett., Vol. 13, No. 24, 2011

Scheme 4. Proposed Mechanism of Organocascade Kinetic Resolution
catalyst 6. However, epi-8-cis is matched for the subsequent
enamine-catalyzed intermolecular reaction. This is indica-
tive of a more complex relationship between the role of
steric influences of the substrate and that of the catalyst
(discussed in the preceding paragraph) in asymmetric in-
duction in reactions catalyzed by 6 than has previously
been proposed. Notably, this also results in the formation
of cascade products, 12, with the opposite absolute (i.e.,
S configuration at the β-position) and relative (i.e., anti
relationship between R- and β-substituents) configuration
to those of cascade products normally arising from use of
catalyst 6.
Scheme 5. Synthetic Utility of Resolved Oxa-Michael Adducts
Moreover, this is a rare example of a kinetic resolution
byenamine catalysis. While there are many examples ofthe
use of enamine/iminium catalysis in dynamic kinetic asym-
metric transformations,11 there are only isolated examples
of their use in kinetic resolutions.12
The products of this kinetic resolution are synthetically
useful. Alcohol 13i was readily transformed into inter-
mediates in the total syntheses of two complex natural
products, as outlined in Scheme 5.13,14
In conclusion, we have developed an organocascade ki-
netic resolution, which provides access to enantioenriched,
functionalized tetrahydropyrans. The organocascade is
initiated by a novel oxa-Michael addition that is highly
selective but rapidly reversible. In a rare demonstration of
the use of enamine catalysis in a kinetic resolution, an
intermolecular reaction has, for the first time, been used
to resolve racemic oxa-Michael adducts. The experimental
(i.e., solvent dependency) and stereochemical insights
presented herein may facilitate the broader application of
enamine catalysis in kinetic resolutions, as well as other
new applications of these catalysts. Further investigations
into this, and related, organocascade kinetic resolutions
are presently underway, and results will be reported in due
course.
Acknowledgment. This work was supported by the
National Institutes of Health (1SC3GM095404). The
authors acknowledge Dr. Cliff Soll (City University of
New York) for assistance with mass spectrometry, and
Dr. Christopher Incarvito (Yale University) for assis-
tance with X-ray crystallography.
(11) For a recent review of organocatalyzed DYKAT, including
those involving enamine/iminium catalysis, see: Pellissier, H. Adv. Synth.
Catal. 2011, 353, 659–676.
(12) (a) Carpenter, R. D.; Fettinger, J. C.; Lam, K. S.; Kurth, M. J.
Angew. Chem., Int. Ed. 2008, 47, 6407–6410. (b) Lv, J.; Zhang, J.; Lin, Z.;
Wang, Y. Chem.;Eur. J. 2009, 15, 972–979. (c) Shimada, N.; Ashburn,
B. O.; Basak, A. K.; Bow, W. F.; Vicic, D. A.; Tius, M. A. Chem.
Commun. 2010, 46, 3774–3775. (d) Quintard, A.; Alexakis, A.; Mazet, C.
Angew. Chem., Int. Ed. 2011, 50, 2354–2358. (e) Reddy, R. J.; Chen, K.
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Supporting Information Available. General experi-
mental conditions and full characterization data for
compounds 5aÀi, 13aÀi, 14aÀi, 18, 19, and the cor-
responding alcohols of 8-cis and -trans. This material -
is available free of charge via the Internet at http://
pubs.acs.org.
(13) Louis, I.; Hungerford, N. L.; Humphries, E. J.; McLeod, M. D.
Org. Lett. 2006, 8, 1117–1120.
(14) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343–
347.
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