Organocatalytic kinetic resolution cascade reactions: New mechanistic and stereochemical manifold in diphenyl prolinol silyl ether catalysis

Article abstract of DOI:10.1002/chem.201104029

A new cascade reaction involving an iminium-catalyzed intramolecular oxa-Michael addition followed by an enamine-catalyzed intermolecular Michael addition is reported herein. This cascade reaction generates enantiopure, highly functionalized tetrahydropyrans and tetrahydrofurans in a one-pot reaction and in up to 89 % combined yield and up to 99 % ee. This cascade reaction is catalyzed by diaryl prolinol silyl ethers, which are a privileged class of catalysts. The stereochemical outcome of these cascade reactions is unprecedented. Computational studies indicate that this stereochemical outcome arises from nonclassical hydrogen-bonding interactions between the electrophile and the substrate, and from entropic considerations of preorganization. The unprecedented configurations of the cascade products, combined with the computational models, reveal for the first time that asymmetric induction by diaryl prolinol silyl ether catalysts is not always exclusively reagent controlled. The stereochemical outcome also arises from a kinetic resolution or dynamic kinetic resolution of the β-stereocenter through an enamine-catalyzed intermolecular reaction. This unprecedented organocascade reaction mechanism may be adaptable to diaryl prolinol silyl ether-catalyzed cascade reactions, in which both the iminium- and enamine-catalyzed steps are intermolecular, an underdeveloped type of cascade reaction. A new resolution for 2012: A cascade reaction generating enantiopure, highly functionalized tetrahydropyrans and -furans in a one-pot reaction is described. The stereochemical outcome of this cascade reaction is unprecedented. The cascade reaction also proceeds by an unprecedented mechanism, in which a kinetic resolution or dynamic kinetic resolution of the β-stereocenter occurs, mediated by the enamine-catalyzed intermolecular reaction (see scheme). Copyright

Full text of DOI:10.1002/chem.201104029

FULL PAPER
DOI: 10.1002/chem.201104029
Organocatalytic Kinetic Resolution Cascade Reactions: New Mechanistic and
Stereochemical Manifold in Diphenyl Prolinol Silyl Ether Catalysis
Patrick G. McGarraugh,[a] Ryne C. Johnston,[b] Aurora Martꢀnez-MuÇoz,[c]
Paul Ha-Yeon Cheong,*[b] and Stacey E. Brenner-Moyer*[a]
Abstract: A new cascade reaction in-
volving an iminium-catalyzed intramo-
lecular oxa-Michael addition followed
by an enamine-catalyzed intermolecu-
lar Michael addition is reported herein.
This cascade reaction generates enan-
tiopure, highly functionalized tetrahy-
dropyrans and tetrahydrofurans in
a one-pot reaction and in up to 89%
combined yield and up to 99% ee. This
cascade reaction is catalyzed by diaryl
prolinol silyl ethers, which are a privi-
leged class of catalysts. The stereo-
chemical outcome of these cascade re-
actions is unprecedented. Computa-
tional studies indicate that this stereo-
chemical outcome arises from nonclass-
ical hydrogen-bonding interactions
between the electrophile and the sub-
strate, and from entropic considera-
tions of preorganization. The unprece-
dented configurations of the cascade
products, combined with the computa-
tional models, reveal for the first time
that asymmetric induction by diaryl
prolinol silyl ether catalysts is not
always exclusively reagent controlled.
The stereochemical outcome also arises
from a kinetic resolution or dynamic
kinetic resolution of the b-stereocenter
through an enamine-catalyzed intermo-
lecular reaction. This unprecedented
organocascade reaction mechanism
may be adaptable to diaryl prolinol
silyl ether-catalyzed cascade reactions,
in which both the iminium- and enam-
ine-catalyzed steps are intermolecular,
an underdeveloped type of cascade re-
action.
Keywords: cascade
reactions
·
domino reactions · kinetic resolu-
tion · organocatalysis
Introduction
Since they were first reported in 2005, diaryl prolinol silyl
ethers (1, Scheme 1) have fast become a privileged class of
organocatalysts.[1] While they have proven effective in the
production of a diverse array of enantioenriched monofunc-
tionalized saturated aldehydes through enamine or iminium
catalysis, arguably their most impressive feat is the catalysis
of cascade reactions.[2] Cascade reactions are an efficient
green chemical method for rapidly building molecular com-
plexity, in which enamine- and iminium-catalyzed reactions
are combined to generate highly functionalized enantiopure
Scheme 1. Model for cascade reactions catalyzed by 1.
aldehydes from simple achiral starting materials in a single
flask.
In the most common class of cascade reactions catalyzed
by 1,[3–5] an a,b-unsaturated aldehyde 2 reacts with 1 to form
a conjugated iminium ion, 3. Conjugate addition of a nucleo-
phile (Nu) to 3 occurs from the face opposite the bulky
groups of the catalyst. The direct product of this conjugate
addition is an enamine, 4, which can react with an electro-
phile (E) that approaches from the face opposite the bulky
groups of the catalyst. The vast majority of cascade reac-
tions of this type involve nucleophiles that are tethered to
electrophiles, rendering the enamine-catalyzed step intramo-
lecular, generating cyclic products. Subsequent hydrolysis of
the catalyst reveals a chiral, vicinally functionalized alde-
hyde, 5, with the indicated absolute (at the b position) and
relative (i.e., a,b-syn) configurations. This simple stereo-
chemical model, in which asymmetric induction in reactions
catalyzed by 1 is entirely reagent-controlled, rationalizes
this stereochemical outcome, which is uniformly observed
[a] P. G. McGarraugh, Prof. S. E. Brenner-Moyer
Department of Chemistry
Brooklyn College of the City University of New York
2900 Bedford Avenue, Brooklyn NY 11210 (USA)
Fax : (+1)718-951-4607
E-mail: SBrenner@brooklyn.cuny.edu
[b] R. C. Johnston, Prof. P. H.-Y. Cheong
Department of Chemistry
Oregon State University
153 Gilbert Hall, Corvallis, OR 97331 (USA)
Fax : (+1)541-737-2062
E-mail: paulc@science.oregonstate.edu
[c] A. Martꢀnez-MuÇoz
Departmento de Quꢀmica Orgꢁnica
Universidad de Sevilla
41012 Sevilla (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201104029.
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regardless of the nature of the nucleophile and electrophile,
or whether they are tethered or untethered.[3–5]
trans. These products were initially formed in an approxi-
mately 1:1 ratio, and in good (in the case of the cis-product)
to excellent (in the case of the trans-product) selectivities.
There was, however, a strong thermodynamic preference for
the (all-equatorial) cis-product. This led to rapid epimeriza-
tion of 13-trans at the b position, thereby generating ent-13-
cis, which increased the cis/trans ratio while decreasing the
ee of 13-cis.
We recently began investigating the cascade reaction illus-
trated in Scheme 2.[6] We were interested in this cascade re-
action for several reasons. First, it would entail a novel oxa-
Michael addition (8!9). Second, it would be a rare example
of a cascade reaction catalyzed by 1 in which the nucleo-
phile (i.e., OH) and electrophile (E) are untethered. Finally,
it would generate both 2,5-cis- and trans-tetrahydrofurans
(10, n=1) and 2,6-cis- and trans-tetrahydropyrans (10, n=
2), all of which are prevalent substructures in bioactive com-
plex natural products.
Cascade reaction with tetrahydropyran-forming substrates:
In the presence of catalyst 1 and b-nitrostyrene as an exter-
nal electrophile, a kinetic resolution of racemic substrates 6
resulted (Scheme 4). Substrates 6 underwent an oxa-Michael
addition, initially forming 13-cis and -trans. The latter rapid-
ly epimerized to ent-13-cis, thereby generating a racemic
mixture of cis-tetrahydropyrans, rac-13-cis. One enantiomer,
ent-13-cis, underwent a subsequent enamine-catalyzed Mi-
chael addition to b-nitrostyrene to produce, after reduction,
cascade product 15. The rate of this reaction of the other
enantiomer, 13-cis, was substantially diminished, and 13-cis
was largely recovered (as 14, after reduction).
Scheme 2. Proposed cascade reaction.
During the course of these investigations, we observed
a dramatic difference in the behavior of substrates of type 6
and that of substrates of type 7 in both steps of this cascade
reaction. Additionally, none of the cascade products arising
from either 6 or 7 had the expected absolute (at the b posi-
tion) and relative (i.e., a,b-syn) configurations that are typi-
cal of cascade products generated using 1 (i.e., those of 10).
These results, presented herein, provide new insight into the
stereochemical and mechanistic models for cascade reac-
tions employing this popular class of organocatalysts.
Scheme 4. Organocascade kinetic resolution. a) 6 (0.44 mmol), b-nitro-
styrene (0.88 mmol), 1 (0.088 mmol), PhCO2H (0.088 mmol), toluene
(1.1 mL), ꢁ308C, then THF·BH3 (1m in THF, 0.5 mL) or NaBH4
(2 mmol), MeOH (4.4 mL).
Results and Discussion
This was, in fact, a rare example of a kinetic resolution by
enamine catalysis.[6] Moreover, the resolved intermediates
are useful synthons; one was readily transformed in ꢀ three
steps into known intermediates in the total synthesis of (ꢁ)-
dactylolide and leucascandrolide A.[6]
Arguably more notable than the kinetic resolution is the
stereochemical outcome of this transformation. The absolute
(at the b position) and relative (at the a vs. b positions) con-
figurations of the cascade products 15 were opposite those
that normally arise from use of catalyst 1 (i.e., 15 vs. 5). This
unprecedented stereochemical outcome can be accounted
for by the proposed stereochemical and mechanistic models
for this kinetic resolution, discussed in later sections.
Oxa-Michael addition of tetrahydropyran-forming sub-
strates: In the presence of catalyst 1, racemic substrates of
type 6a undergo an intramolecular oxa-Michael addition via
iminium 11 (Scheme 3). Conjugate addition of the hydroxyl
group from the face opposite the bulky groups of the cata-
lyst directly produces enamine 12, which, upon hydrolysis,
yields cis- and trans-tetrahydropyran products, 13-cis and 13-
This methodology was also compatible with other b-nitro-
styrene substrates, including electron-rich and -poor b-nitro-
styrenes (Scheme 5). Use of diethylazodicarboxylate or ni-
trosobenzene as alternative electrophiles in this kinetic reso-
lution, however, was not successful. This may be because
these electrophiles lack suitably acidic hydrogens that can
Scheme 3. Oxa-Michael addition of tetrahydropyran-forming substrates.
a) 6a, 1 (10 mol%), PhCO2H (10 mol%), toluene (0.4m), 08C.
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Scheme 5. Other b-nitrostyrene substrates.
participate in nonclassical hydrogen-bonding interactions
(see below).
Scheme 6. An organocascade dynamic kinetic resolution.
Although a variety of substrates were tolerated in this ki-
netic resolution, several substrates were not successfully re-
solved under these conditions (Figure 1). These included
substrates with sterically less demanding R groups, such as
6b and 6c, which contain sp2- and sp-hybridized carbons, re-
spectively, directly bound to the resulting tetrahydropyran
ring. For these substrates, the trans-tetrahydropyran oxa-Mi-
chael adduct (13-trans) persisted, likely due to the reduced
thermodynamic preference for the (all-equatorial) cis-tetra-
hydropyran. Multiple cascade products were also observed,
several of which presumably arose from the trans-tetrahy-
dropyran oxa-Michael adduct.
which (even more slowly) went on to ultimately produce 17,
although it should be noted that we did not allow complete
consumption of 13-cis to test this hypothesis.
Finally, substrate 6 f, without an R group, formed two cas-
cade products, 18 and 15 f, arising from Michael addition of
both enantiomers of rac-13 f to b-nitrostyrene (Scheme 7).
This result demonstrated that, for the tetrahydropyran-form-
ing substrates, the R group is necessary for the kinetic reso-
lution of oxa-Michael adducts, rac-13-cis.
Scheme 7. R group controls outcome of enamine-catalyzed Michael addi-
tion.
Figure 1. Other substrates for the organocascade kinetic resolution.
Substrates 6d and 6e[7] formed one predominant cascade
product, and the reactions were quenched when a good
crude yield of this cascade product 17 and of the oxa-Mi-
chael adduct 13-cis was achieved and when their ratio was
approximately 1:1 (Scheme 6). For all substrates in
Scheme 4, this led to high ee values of both the cascade
product and of the oxa-Michael adduct. For substrates 6d
and 6e, the cascade reaction was exceedingly sluggish (13–
35 d) and 13-cis was recovered (as its corresponding alcohol)
in low ee. While all substrates of type 13 can epimerize at
the 2-, or b position (as in the conversion of 13-trans to ent-
13-cis), only 13d and 13e have a mechanism by which they
can also epimerize at the 6-position. Substrate 13d-cis can
form a benzylic cation stabilized through resonance with the
electron-rich benzene ring. Substrate 13e-cis can undergo
a b-alkoxide elimination to form an enone, which could be
facilitated by deprotonation of the indicated acidic protons
by the secondary amine catalyst. We therefore believe that
these two substrates were slowly undergoing a dynamic ki-
netic resolution; 13-cis was slowly converting to ent-13-cis,
Oxa-Michael addition of tetrahydrofuran-forming sub-
strates: In the presence of catalyst 1, racemic substrates of
type 7a also undergo an intramolecular oxa-Michael addi-
tion (Scheme 8). As in the case of tetrahydropyran-forming
Scheme 8. Oxa-Michael addition of tetrahydrofuran-forming substrates.
substrate 6a, this addition appears to be iminium-catalyzed,
as it does not occur on this time scale in the absence of cata-
lyst, nor in the presence of base (Et3N) or acid (PhCO2H)
alone. Also like the tetrahydropyran-forming substrates, cis-
and trans-tetrahydrofuran products, 19a-cis and -trans, are
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initially formed in an approximately 1:1 ratio. Unlike the
tetrahydropyran-forming substrates, however, both the cis-
and trans-tetrahydrofuran products are formed completely
nonselectively, in <1% ee. Moreover, the approximately 1:1
cis/trans ratio persists over time, possibly due to the reduced
thermodynamic preference for a configuration that enables
an all-(pseudo)equatorial conformation.
chael addition, to epimerize the b position of either oxa-Mi-
chael adduct 19a (R) (to form 19a (S)) or of enamine 21 (to
form 23), occurs. Oxa-Michael adducts 19a-cis and -trans,
with R configuration at the b position, would thereby ulti-
mately be converted to enamine 23, with S configuration at
the b position, which does react with b-nitrostyrene, and
which can alternatively form directly from reaction of the
catalyst with ent-19a-cis and -trans (i.e., 19 (S)).
Cascade reaction with tetrahydrofuran-forming substrates:
In the presence of catalyst 1 and b-nitrostyrene (16c) as an
external electrophile, cascade products, 20a-cis and 20a-
trans, with cis- and trans-tetrahydrofuran rings, respectively,
were generated (Scheme 9). This was not entirely surprising
As indicated in Scheme 11, a variety of substrates afford-
ed similar outcomes to that of 7a in this cascade, including
alcohols with adjacent sterically demanding alkyl substitu-
ents (7d), silyl protecting groups (7 f), sp2-hybridized car-
bons (7g, 7h), and stereocenters (7i, 7j), as well as sub-
strates containing other reactive functional groups (7e).
More specifically, in all cases, cascade products 20-cis and
20-trans, with cis- and trans-tetrahydrofuran rings, respec-
tively, were generated in >95% ee and in an approximately
1:1 ratio. Interestingly, there was a slight preference for the
trans-tetrahydrofuran cascade products in all cases, which
contrasts with the initial oxa-Michael addition that slightly
favored formation of the cis-tetrahydrofuran (Scheme 8).
In substrates 20i and 20j, the presence of the additional,
adjacent stereocenter did impact the outcome of the cascade
reaction. While the cis/trans ratio did not change or changed
only modestly, the d.r. of the cis- and trans-products changed
dramatically. Compounds 20i-cis and 20j-cis formed without
diastereoselectivity, while 20i-trans and 20j-trans were
formed in outstanding d.r. Additionally, an oxepane-forming
substrate readily decomposed under these reaction condi-
tions.
The configuration of cascade products 20a-cis and 20a-
trans at the 5-position was established by running the cas-
cade reaction with the pure R and pure S enantiomers of
substrate 7a. The remaining stereocenters in 20a-cis and
20a-trans were established by X-ray crystallography.[8] The
stereochemistry of all other cascade products of type 20 was
assigned by analogy.
As with the tetrahydropyran-containing cascade products,
15, all tetrahydrofuran-containing cascade products, 20, con-
tain absolute (b position) and relative (a vs. b positions)
configurations that are opposite those that normally arise
from use of catalyst 1 (i.e., 20 vs. 5). This unprecedented ste-
reochemical outcome can be accounted for by the proposed
stereochemical and mechanistic models for this cascade re-
action, discussed in the next two sections.
Scheme 9. Cascade reaction with tetrahydrofuran-forming substrates.
in light of the fact that, as discussed in the preceding section,
both cis- and trans-tetrahydrofuran rings (i.e., 19a-cis and
19a-trans) arose from, and persisted in, the iminium-cata-
lyzed oxa-Michael addition. What was surprising, however,
was that while racemic cis- and trans-tetrahydrofuran rings
arose from the iminium-catalyzed oxa-Michael addition, the
subsequent enamine-catalyzed Michael addition to b-nitro-
styrene generated cis- and trans-tetrahydrofuran ring-con-
taining cascade products in >99% ee.
This is indicative of a dynamic kinetic resolution of the b-
stereocenter (Scheme 10). Oxa-Michael adducts, 19a-cis and
-trans, with R configuration at the b position (i.e., 19a (R)),
can react with the catalyst to generate enamine 21, which
evidently does not react with b-nitrostyrene (16c). Instead,
a retro-oxa-Michael addition followed by a forward oxa-Mi-
Unlike the tetrahydropyran-forming substrates, 6, the R
group in the tetrahydrofuran-forming substrates, 7, did not
influence the reactivity of the oxa-Michael adducts in the
enamine-catalyzed Michael addition to b-nitrostyrene. Evi-
dence in support of this is the formation of cascade products
(20a–j) with both R and S configurations at the 5-position.
All cascade products do, however, have the same configura-
tion at the b position. This suggests that, in contrast to sub-
strates of type 6, it is the configuration at the b position that
dictates the reactivity of the oxa-Michael adducts arising
from substrates 7 in the enamine-catalyzed Michael addition
to b-nitrostyrene. Further evidence in support of this is that
Scheme 10. Dynamic kinetic resolution with respect to configuration at
b position.
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Scheme 12. b-Group, not R group, controls outcome of enamine-cata-
lyzed Michael addition.
substrate 7k, without an R group, forms a single cascade
product (Scheme 12).
Proposed model for stereochemical outcome of cascade re-
actions: All cascade products generated in these studies (15
and 20) possess S configuration at the b position. This con-
figuration effectively arises from the approach of the alcohol
from the same face as the bulky groups of the catalyst in the
initial iminium-catalyzed oxa-Michael addition. As men-
tioned, this is not typically observed in reactions catalyzed
by 1, and results in cascade products with unprecedented ab-
solute (at the b position) and relative (a vs. b positions) con-
figurations.
With the current understanding of the selectivities of reac-
tions catalyzed by 1, such stereochemical outcomes could
only arise if the second step (Michael addition to b-nitro-
styrene) was rate- and stereodetermining. The former sup-
position is supported by experimental data: in all cases, the
1
oxa-Michael addition was observed by H NMR to be com-
plete within 12 h, while a further 2–35 d was required for
completion of the Michael addition to b-nitrostyrene. Transi-
ꢁ
tion states (TSs) of the carbon carbon bond-forming event
involving b-nitrostyrene and the catalyst-enamine of sub-
strates 6a (TS-IV), 6 f (TS-II), 7a (TS-III), and 7k (TS-I)
were, therefore, computed in order to quantify the stereo-
controlling elements. Exhaustive DFT conformational
ꢁ
searches of the C C bond-forming transition states were
performed. Structures and thermodynamic corrections were
computed using B3LYP/6-31G* in toluene (PCM), as imple-
mented in the Gaussian 09 suite of programs. Energies were
refined using SCS-MP2/cc-pVTZ, as implemented in the Q-
Chem 4.0.[9] Although the ubiquitous B3LYP/6-31G* often
overestimates activation barriers and reaction endergonicity
due to poor treatment of dispersion interactions, we at
Oregon State have recently discovered that SCS-MP2 single
point energies correct for the lack of dispersion in B3LYP/6-
31G* results, leading to a remarkable accuracy in barrier
heights and stereoselectivities where other methods have
failed.[10]
The lowest energy conformations of the transition states
for the Michael addition to b-nitrostyrene are shown for
each stereoisomer in Figure 2.[11] The R or S labels refer to
the stereochemistry at the b position of the enamine sub-
strate. All transition-state conformations are remarkably
Scheme 11. Scope of cascade reaction with tetrahydrofuran-forming sub-
strates.[a–e] a) 7 (0.44 mmol), 16c (0.88 mmol), 1 (0.088 mmol), PhCO2H
(0.088 mmol), toluene (1.1 mL), ꢁ308C, then NaBH4 (2 mmol), MeOH
(4.4 mL), ꢁ308C. b) Yield=combined isolated yield of 20-cis and -trans.
1
c) d.r. of the 20-cis and -trans products was determined by H NMR spec-
troscopy and is defined as the ratio of the amount of the major cascade
product to the sum of the amounts of the minor cascade products, usually
three, arising from the R and S enantiomers, respectively, of 7. d) ee
values of alcohol determined by chiral phase HPLC. e) All reaction
times were 6 d.
ꢁ
similar, with forming C C bond lengths around 2.1 ꢃ. Al-
though the orientations of the catalyst side chain vary be-
tween the different transition states, the energetic differen-
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S. E. Brenner-Moyer, P. H.-Y. Cheong et al.
ces between these conformations are small, around 0.5 kcal
molꢁ1.[12b] The lowest energy conformations have the devel-
oping bond between the enamine and b-nitrostyrene occur-
ring from the sterically accessible face of the enamine, oppo-
site the bulky groups of the catalyst side chain. Additionally,
the conformation around the b-stereocenters is such that it
minimizes the steric and torsional interactions with the ap-
proaching b-nitrostyrene electrophile.
There is good agreement between the computed selectivi-
ties and experiments. DFT geometry optimizations in sol-
vent (toluene) in conjunction with SCS-MP2 energetics was
critical in reproducing the stereoselectivity trends, namely,
that the TS-I, TS-III, and TS-IV series are much more selec-
tive than TS-II. B3LYP gas-phase results erroneously predict
that TS-II is the most selective (>2 kcalmolꢁ1), and geome-
try optimizations in solvent erroneously predict the same
level of stereoselectivity for TS-II and TS-IV (DDG° =
1.2 kcalmolꢁ1), in disagreement with experiments that
showed no selectivity for the TS-II series (DDG° =0.0 kcal
molꢁ1).
The stereoselectivity of the Michael addition to b-nitro-
styrene is controlled by three factors: a) the anti versus syn
catalyst-enamine preference; b) the Re or Si facial selectivi-
ty of the nitrostyrene electrophile; and c) the effect of the
stereochemistry of the b position of the enamine substrate.
Prolinol catalysts are known to favor the anti-orientation of
ꢁ
Figure 2. C C Bond-forming transition structures between b-nitrostyrene and the catalyst–enamine of substrates 6a (TS-IV), 6 f (TS-II), 7a (TS-III), and
7k (TS-I). Experimentally, substrates 6a, 7a, and 7k show greater selectivity than 6 f, and the computed results are consistent in that they show that the
TS-I, TS-III, and TS-IV are much more selective than the TS-II series.
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the nucleophilic double bond with respect to the catalyst
side chain, both in the enamine ground state and the Mi-
chael transition states.[12] The nitrostyrene facial selectivity is
governed by electrostatic contact between the developing
negative charge of the nitro group and the developing posi-
tive charge of the enamine in the Michael transition state.[1b]
The Si face attack guarantees maximal electrostatic contact
and stabilization, and therefore is favored. In all cases, the
shortest distance between the nitro group and the enamine
nitrogen is >3 ꢃ, indicating nonbonding interaction is in
effect, rather than covalent.
While the first two factors are well understood, the effect
of the stereochemistry of the b position of the enamine sub-
strate is poorly understood. Initially, in seeking an explana-
tion for this unprecedented stereochemical outcome, we
proposed that this might result from differential shielding of
enamine faces by the b-stereocenter in the enamine-cata-
lyzed Michael addition to b-nitrostyrene.[6] However, DFT
(B3LYP/6-31G*) modeling of various enamine intermedi-
ates revealed no pronounced facial discrimination of the cat-
alyst enamines arising from the b-stereocenter.
to the tune of 0.4 kcalmolꢁ1. This entropic penalty is halved
in the methyl-substituted case (TS-IV) because the equatori-
al preference of the methyl diminishes the entropic penalty
for conformational preorganization of the pyran. This leads
to a scenario in which the enthalpic and free energy selectiv-
ity are much more similar (DDH° =1.3 and DDG° =0.9 kcal
molꢁ1).
In unsubstituted (TS-I) and methyl-substituted (TS-III)
furans, the opposite scenario occurs - the free energy prefer-
ence (DDG°) of (S)-TSs over (R) is greater than the en-
thalpic preference (DDH°). For an example, in TS-I, the
DDH° is 0.5 kcalmolꢁ1, while the free energy preference is
1.1 kcalmolꢁ1. This heightened free energy preference signi-
fies that the (R)-TS is conformationally more rigid (preor-
ganized) than the (S)-TS. This is due to an enthalpic stereo-
ꢁ
electronic preference for the furan C O bond to be anti-per-
ꢁ
iplanar to the forming C C bond with the incoming electro-
phile (anti-periplanar atoms circled in Figure 3). Only in the
ꢁ
(R)-TS, can this anti-periplanar arrangement of a C O bond
ꢁ
with respect to the forming C C bond be realized, leading
to transition state preorganization and thus entropic penalty.
ꢁ
The examination of the computed nitrostyrene transition
structures reveals that the b-stereocenter of the catalyst–en-
amine controls the stereoselectivity in two ways: a) enthalp-
ic stabilization from nonclassical hydrogen bonds and b) en-
tropic penalty from preorganization of the reactants in the
transition states.
In the (S)-TS, the forming C C bond is anti-periplanar to
ꢁ
a ring C C bond, an arrangement with much weaker elec-
tronic bias and therefore weaker entropic penalization. In-
terestingly, this anti-periplanar arrangement between the
ꢁ
ꢁ
forming C C bond and the heterocycle C O bond only
occurs for the (R)-TS of furans (TS-I and TS-III), but not
the pyrans (TS-II and TS-IV). In the furan series, this ar-
rangement is clearly anti (~1778), while in the pyran series,
it is not (~1658), as shown in Figure 3. This explains why the
entropic enhancement of selectivity only occurs in the furan
series.
Earlier this year, the Blackmond and Armstrong groups
published a seminal mechanistic study of 1-catalyzed enam-
ine-mediated conjugate addition of achiral aldehydes to b-
nitrostyrene.[14] In this report, they found that the resting
state of the catalyst was a cyclobutane intermediate arising
from the condensation of the nitroenolate and the catalyst
iminium immediately following the Michael addition. Al-
though we cannot rule out a role for analogous cyclobutane
species or other stable downstream intermediates in the
stereo-determining step, the currently available experimen-
tal and computational data are consistent with the hypothe-
sis that the carbon-carbon bond forming step is stereodeter-
mining.
This proposed model accounts for the selectivities of all
substrates examined experimentally. Importantly, the unpre-
cedented stereochemical outcome of these 1-catalyzed cas-
cade reactions combined with the proposed enthalpic and
entropic stereocontrolling elements that rationalize this out-
come together suggest that the accepted stereochemical
model for asymmetric induction in reactions catalyzed by
1 as being entirely reagent-controlled is an oversimplifica-
tion. Evidently, there is a more complex relationship be-
tween the role of the substrate and that of the catalyst in
asymmetric induction in reactions catalyzed by 1 than has
previously been suggested.
Enthalpic stabilization of (S)-TSs from nonclassical hydro-
gen bonds: Energetically, at least half of the stereocontrol
arises from stabilizing nonclassical hydrogen bonds (electro-
static contacts) between the heterocycle of the catalyst-en-
amine and the incoming electrophile. Specifically, the (S)-
TSs are stabilized through nonclassical hydrogen bonds be-
tween the approaching b-nitrostyrene benzylic hydrogen
and the oxygen of the enamine heterocycle (distances ca.
2.5 ꢃ, indicated by thin lines, Figure 2).[13] In the disfavored
(R)-TSs, this stabilizing electrostatic contact is replaced by
a repulsive electrostatic interaction between a methylene
and the b-nitrostyrene benzylic hydrogen. This enthalpic
preference is worth 0.5 and 1 kcalmolꢁ1 for unsubstituted
furan and pyran substrates (TS-I and TS-II), respectively.
However, inclusion of the methyl group (TS-III and TS-IV)
slightly increases the selectivity, possibly through inductive
effects that strengthen the basicity of the heterocycle
oxygen.
Entropic penalty of preorganization: Entropic penalties ac-
company preorganization. In this particular study, we have
discovered that the entropic considerations play a significant
role in determining the stereoselectivity.
In unsubstituted pyrans (TS-II), the enthalpic preference
(DDH°) for the (S)-TS over the (R) is 1.0 kcalmolꢁ1. How-
ever, the conformational preorganization that arises from
the nonclassical hydrogen bonds in the (S)-TS is entropically
disfavored. Therefore, the free energy preference (DDG°) is
smaller in magnitude compared to the enthalpic preference,
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S. E. Brenner-Moyer, P. H.-Y. Cheong et al.
ꢁ
Figure 3. Side views of the C C bond-forming transition structures between b-nitrostyrene and the catalyst–enamine of substrates 6 f (TS-II) and 7k (TS-
ꢁ
ꢁ
I) shown in Figure 2. In the furan series, for an example the TS-I series, the C O bond of the heterocycle is antiperiplanar to the forming C C bond,
while in the pyran series, for an example the TS-II series, it is not. The four atoms involved in this relationship are circled, and the associated dihedral
angles reveal that the TS-I transition structures are anti (ꢂ1778), whereas the analogous angles in TS-II transition structures are not (ꢂ1658).
Proposed mechanistic model of cascade reactions: The pro-
posed mechanistic model for these cascade reactions is illus-
trated in Scheme 13. As discussed previously, the initial oxa-
Michael addition is reversible and ultimately generates race-
mic oxa-Michael adducts 25 (cis only for n=2, cis and trans
for n=1). Oxa-Michael adducts possessing S configuration
at the b-carbon react with the catalyst to form enamine 26,
while those possessing R configuration at the b-carbon react
with the catalyst to form enamine 9.
favorable entropic considerations, result in a relatively rapid
reaction with an electrophile that approaches from the back
face of the enamine, generating cascade products of type 27.
Entropic penalties and/or the absence of this synergism in
enamine 9, account for its relative unreactivity and for the
observation of, in most cases, only trace formation of cas-
cade products of type 28.
If a retro-oxa-Michael addition/forward oxa-Michael addi-
tion to epimerize (R)-25 or 9 at the b position can occur,
then a dynamic kinetic resolution of the b-stereocenter is
possible. This occurs with all tetrahydrofuran-forming sub-
strates (25, n=1), and both (S)-25 and (R)-25 generate cas-
cade products of type 27, with the S configuration at the
b position. As mentioned, we also suspect this occurs with
tetrahydropyran-forming substrates 6d and 6e.
If a retro-oxa-Michael addition/forward oxa-Michael addi-
tion to epimerize (R)-25 or 9 at the b position is not possi-
ble, then a kinetic resolution occurs. This occurs with the
tetrahydropyran-forming substrates (25, n=2), because epi-
merization of enamine 9a (or its corresponding aldehyde) at
the b position would generate a thermodynamically disfa-
vored trans-tetrahydropyran ring, 26a, in which one of the
substituents on the ring must occupy an axial position
(Scheme 14). Thus, for tetrahydropyran-forming substrates,
enamine 26 produces a cascade product, 27, whereas enam-
ine 9 cannot readily convert to cascade product 28 nor to
enamine 26, and so simply reverts back to (R)-25.
Scheme 13. Proposed mechanistic model.
As discussed in the preceding section, synergism between
the blocking effects of the catalyst side chain and the direct-
ing effects of the nonclassical hydrogen-bond capabilities of
the substrate in enamine 26, in conjunction with relatively
This mechanistic model accounts for the different reactivi-
ty of the tetrahydropyran- and -furan-forming substrates. It
also presents an interesting possibility. A general strategy to
obtain products with high selectivity in cascade reactions ini-
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Organocatalytic Kinetic Resolution Cascade Reactions
FULL PAPER
ed steps are intermolecular, a class of cascade reactions that
has thus far been considerably limited in scope.
Experimental Section
General information: All chemicals and solvents were purchased from
Scheme 14. Epimerization at b position generates the trans-tetrahydro-
pyran ring.
1
Sigma–Aldrich, Fisher Scientific or VWR International. H and 13C NMR
spectra were collected using a Bruker 400 MHz Biospin. The NMR data
herein uses the following abbreviations: s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet, dd=doublet of doublets, td=triplet of dou-
blets, dt=doublet of triplets, ddt=doublet of doublet of triplets. Enantio-
meric excesses were determined using a Perkin–Elmer Series 200 HPLC
with Daicel Chemical Industries, LTD. Chiralpak AD-H (0.46ꢄ25 cm),
Chiralpak OD-H (0.46ꢄ25 cm), and Chiralpak AS-H (0.46ꢄ25 cm) col-
umns. Enantiomeric excesses were determined by comparison to a race-
mic sample (prepared with the corresponding racemic catalyst). Optical
rotations were determined using a Jasco P-1020 polarimeter. IR spectra
were collected using a Nicolet 6700 FT-IR. High resolution mass spectra
were collected using an Agilent 6520 Q-TOF. Flash chromatography was
carried out with Merck, grade 9385, 230–400 mesh, 600 ꢃ silica gel and
with Merck, silica 60F-254 on glass, 250 mm layer TLC plates with fluo-
rescent indicator. Solvents were dried and kept air free in a solvent pu-
rification unit. Solvents were evaporated using a standard rotovapor and
a high vacuum. All reactions were carried out in oven dried glassware
and conducted under an argon atmosphere. In all cases, yield refers to an
isolated yield, unless otherwise indicated.
tiated by reversible iminium-catalyzed conjugate additions
has been to compensate for the reversible conjugate addi-
tion to prevent racemization of conjugate addition products
at the b position. This has most often been done using an
enamine-catalyzed intramolecular reaction. As a result, as
mentioned earlier, the vast majority of cascade reactions
catalyzed by 1 employ nucleophiles tethered to electrophilic
centers, forming cyclic products. In so doing, a reversible
iminium-catalyzed conjugate addition can be compensated
for via: A) an intramolecular enamine-catalyzed reaction
that is more rapid than the retro-conjugate addition reac-
tion, or B) a dynamic kinetic resolution of the b-stereocen-
ter of racemic conjugate addition products via an intramo-
lecular enamine-catalyzed reaction. Our data reveals for the
first time that the latter scenario is also possible through in-
termolecular enamine-catalyzed reactions. Thus, using ap-
propriately chosen untethered nucleophiles and electro-
philes, it may be possible to develop cascade reactions, in
which both steps are intermolecular, and which take advant-
age of the reversibility of iminium-catalyzed conjugate addi-
tions to obtain cascade products with high selectivity
through a dynamic kinetic resolution process. Cascade reac-
tions of this type would generate enantiopure, highly func-
tionalized acyclic products, possibly with configurations
analogous to those reported herein. Moreover, cascade reac-
tions of this type would lead to an expansion of the limited
scope of cascade reactions catalyzed by 1 in which both the
iminium- and enamine-catalyzed steps are intermolecular.
Characterization and supporting information for previously published
compounds: Full characterization of compounds of type 6, 14 and 15
(Scheme 4) as well as copies of 1H NMR spectra, 13C NMR spectra, and
HPLC chromatograms is contained in the Supporting Information for
reference [6].
General procedure for the organocascade reaction of pyrans and furans:
Catalyst 1 (28.6 mg, 0.088 mmol) and PhCO2H (10.7 mg, 0.088 mmol)
were dissolved in dry toluene (1.1 mL) and cooled to ꢁ308C. Substrate 6
or 7 (0.44 mmol) was added in one portion. Compound 16 (131.2 mg,
0.88 mmol) was added after 5 min and the reaction was stirred at ꢁ308C.
The reaction was monitored by 1H NMR. (Note: for the furan forming
reactions, two identical reactions were setup.)
For the pyran reactions (14, 15 and 18): Once the resolution was judged
to be complete (the corresponding aldehyde of 14 and the corresponding
aldehyde of 15 are present in the reaction mixture in roughly equal
amounts, as determined by 1H NMR of the reaction mixture), the crude
yield of 14 was determined by 1H NMR of the crude reaction mixture
using an internal standard. The d.r. of 15 was also determined by
1H NMR of the crude reaction mixture. The d.r. of 15 was calculated by
integration of the aldehyde peaks of all diastereomers of the correspond-
ing aldehyde of 15 resulting from the S enantiomer of 6. An in situ reduc-
tion was performed using conditions A or B below.
Conclusion
In summary, we have developed novel cascade reactions
that lead to enantiopure tetrahydropyran and tetrahydrofur-
an substrates. Notably, all of the cascade products manifest
unusual, unprecedented stereochemical configurations oppo-
site of what has been previously reported for diphenyl proli-
nol silyl ether catalysts. This observation, in conjunction
with computational studies, is evidence of a more complex
relationship between the role of the substrate and that of
the catalyst in asymmetric induction in reactions catalyzed
by this privileged class of catalysts than has previously been
disclosed. The mechanistic implications of the cascade reac-
tions discussed herein may be amenable to other cascade re-
actions involving an intermolecular enamine-catalyzed step.
This may aid in the development of cascade reactions cata-
lyzed by 1 in which both the iminium- and enamine-mediat-
Reduction conditions A: For reactions with substrates 6a, 6d, and 6 f,
BH3·THF (1.0m in THF, 0.50 mL) was added dropwise to the reaction
mixture and the reaction was allowed to warm to 08C over 30 min. The
reaction was quenched by adding 1.0m aqueous HCl (4 mL). The aque-
ous layer was extracted with CH2Cl2 (2ꢄ15 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated.
Reduction conditions B: For reaction with substrate 6e the reaction mix-
ture was diluted with MeOH (4.4 mL), and NaBH4 (75.7 mg, 2.0 mmol)
was added. The reaction was stirred at ꢁ308C for 15 min and was
quenched by slowly adding saturated aqueous NH4Cl (5 mL). The aque-
ous layer was extracted with CH2Cl2 (2ꢄ15 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated.
Both oxa-Michael product 14 and cascade product 15 were purified from
the residue by column chromatography (EtOAc/petroleum ether 30:70).
For the furan reactions (20a–j cis and trans, and 20k): Upon complete
conversion to the cis and trans cascade products, one of the two reactions
was reduced using Reduction conditions B. Products 20-cis and 20-trans
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S. E. Brenner-Moyer, P. H.-Y. Cheong et al.
were purified from the residue by column chromatography (EtOAc/
CH2Cl2 2:98) and an isolated yield was determined. The major 20-cis dia-
stereomer was isolated in this way. The major 20-trans diastereomer was
further purified by prep TLC (EtOAc/petroleum ether 25:75).
ACHTUNGTRENNUNG
For products 20a–h and 20k: Upon complete conversion to the cis and
trans cascade products, the other reaction was directly purified by
column chromatography (EtOAc/petroleum ether 15:85), isolating all
diastereomeric aldehyde products together as a mixture. This diastereo-
meric mixture was used for the determination of the diastereomeric ratio.
To 0.05 mmol of all diastereomeric aldehyde products, was added 0.5 mL
CDCl3. The d.r. of 24-cis and 24-trans were calculated by integration of
the aldehyde peaks of all diastereomers of the corresponding aldehydes
of 24-cis and 24-trans arising from the R and S enantiomers, respectively,
of 7.
21.3 ppm; IR (thin film, KBr): n˜
= 3441, 2964, 1640, 1552, 1261,
1023 cmꢁ1; the enantiomeric excess was determined by HPLC with an
AS-H column (n-hexane/iPrOH 90:10), 0.5 mLminꢁ1; major enantiomer
tR =21.7 min, minor enantiomer tR =26.7 min; HRMS (ESI): m/z: calcd
for C15H21NO4: 279.1471; found: 279.1475 [M+].
Full characterization of compounds of type 6b–e, 7a–k, 14b, 14d, 14e,
15b, 15d–f, 18, 20b–j-cis, 20b–j-trans, and 20k as well as copies of
1H NMR spectra, 13C NMR spectra, and HPLC chromatograms is con-
tained in the Supporting Information.
The 24-cis/24-trans ratio for some products had to be determined in the
presence of a chiral shift reagent, (ꢁ)-Eu
tion of CDCl3 (0.5 mL) and Eu(hfc)3 (15 mg) was prepared. The CDCl3
solution of all diastereomeric aldehyde products 24 was titrated with the
Eu(hfc)3 solution, adding 50 mL at a time, until the aldehyde proton
ACHUTGTNERN(GUN hfc)3 or (+)-EuACHTUNGTRENN(UGN hfc)3. A solu-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
peaks for the corresponding aldehydes of 24-cis and 24-trans were separa-
ble and could be accurately integrated to determine the 24-cis/24-trans
ratio. Titration with (+)-EuACHTNUGTRENNUNG
Acknowledgements
This work was supported by the National Science Foundation (CHE-
1148295, S.E.B.M.). The authors acknowledge Dr. Cliff Soll (City Univer-
sity of New York) for assistance with mass spectrometry, and Dr. William
Brennessel (University of Rochester) for assistance with X-ray crystallog-
raphy.
24e, and 24h. Titration with (ꢁ)-Eu
ACHTUNGTRENNUNG
24g. No chiral shift reagent was required for products 24 f and 24k.
For product 20i: The d.r. and 20-cis/20-trans ratio for 20i were deter-
mined by chiral HPLC of the mixture of all diastereomers of 20i (AD-H
column, n-hexane/iPrOH 90:10, 1.0 mLminꢁ1).
For product 20j: The d.r. and 20-cis/20-trans ratio for 20j were deter-
mined by isolated yield of the different diastereomers of 20j after chro-
matography.
[1] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. 2005, 117, 804–807; Angew. Chem. Int. Ed. 2005, 44,
794–797; b) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew.
Chem. 2005, 117, 4284–4287; Angew. Chem. Int. Ed. 2005, 44, 4212–
4215.
Representative data for pyrans
2-((2R,6R)-6-Methyltetrahydro-2H-pyran-2-yl)ethanol (14a):[6] colorless
oil; [a]2D3 =ꢁ18.6 (c=2.00 in CHCl3, 90% ee); 1H NMR (400 MHz,
CDCl3): d=3.80 (m, 2H), 3.59 (m, 1H), 3.49 (m, 1H), 3.15 (bs, 1H),
1.87–1.63 (m, 3H), 1.62–1.45 (m, 3H), 1.47–1.20 (m, 2H), 1.18 ppm (d,
J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=78.9, 74.1, 61.9, 37.9,
33.0, 31.3, 23.4, 22.2 ppm; IR (thin film, KBr): n˜ = 3390, 2970, 2934, 2860,
1372, 1202, 1081, 1044, 754 cmꢁ1; HRMS (ESI): m/z: calcd for C8H16O2:
144.115;, found: 144.1148 [M+].
[2] For a recent review of organocascade reactions, see: C. Grondal, M.
Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–178.
[3] For 1-catalyzed cascade reactions involving only C C s bond forma-
ꢁ
tion, see, for example: a) H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J.
Am. Chem. Soc. 2007, 129, 10886–10894; b) L. Zu, H. Li, H. Xie, J.
Wang, W. Jiang, Y. Tang, W. Wang, Angew. Chem. 2007, 119, 3806–
3808; Angew. Chem. Int. Ed. 2007, 46, 3732–3734; Angew. Chem.
2007, 119, 3806–3808; c) I. Ibrahem, G.-L. Zhao, R. Rios, J. Vesely,
H. Sundꢅn, P. Dziedzic, A. Cꢆrdova, Chem. Eur. J. 2008, 14, 7867–
7879; d) G.-L. Zhao, I. Ibrahem, P. Dziedzic, J. Sun, C. Bonneau, A.
Cꢆrdova, Chem. Eur. J. 2008, 14, 10007–10011; e) J. Zhang, Z. Hu,
L. Dong, Y. Xuan, C. Lou, M. Yan, Tetrahedron: Asymmetry 2009,
20, 355–361; f) M. Rueping, A. Kuenkel, F. Tato, J. W. Bats, Angew.
Chem. 2009, 121, 3754–3757; Angew. Chem. Int. Ed. 2009, 48, 3699–
3702; Angew. Chem. 2009, 121, 3754–3757; g) A. Ma, D. Ma, Org.
Lett. 2010, 12, 3634–3637; h) S. Anwar, H.-J. Chang, K. Chen, Org.
Lett. 2011, 13, 2200–2203; i) B.-C. Hong, A. A. Sadani, R. Y. Nimje,
N. S. Dange, G.-H. Lee, Synthesis 2011, 1887–1895.
ACHTUNGTRENNUNG
=
CHCl3, 99% ee); 1H NMR (400 MHz, CDCl3): d=7.26–7.17 (m, 2H),
7.09–6.97 (m, 2H), 5.02 (dd, J=12.4, 4.6 Hz, 1H), 4.80 (dd, J=12.4,
10.9 Hz, 1H), 4.16 (d, J=12.6 Hz, 1H), 4.04 (td, J=10.5, 4.6 Hz, 1H),
3.64 (m, 1H), 3.27–3.13 (m, 3H), 1.80 (m, 1H), 1.66–1.50 (m, 3H), 1.38
(m, 1H), 1.30–1.10 (m, 2H), 1.19 ppm (d, J=6.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=163.3, 160.9, 134.6, 134.6, 129.8, 129.7, 115.9,
115.7, 79.1, 78.7, 75.1, 59.5, 47.2, 42.4, 33.0, 29.0, 23.4, 22.2 ppm; IR (thin
film, KBr): n˜ = 3507, 2935, 2864, 1553, 1511, 1380, 1225, 1087, 1043,
838 cmꢁ1; the enantiomeric excess was determined by HPLC with an AS-
H column (n-hexane/iPrOH 90:10), 0.5 mLminꢁ1; major enantiomer tR =
15.9 min, minor enantiomer tR =18.1 min; HRMS (ESI): m/z: calcd for
C16H22FNO4: 311.1533; found: 311.1528 [M+].
[4] For 1-catalyzed cascade reactions involving C-heteroatom bond for-
mation see, for example: a) M. Marigo, J. Franzꢅn, T. B. Poulsen, W.
Zhuang, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 6964–6965;
b) S. Brandau, E. Maerten, K. A. Jørgensen, J. Am. Chem. Soc.
2006, 128, 14986–14991; c) J. Vesely, I. Ibrahem, G.-L. Zhao, R.
Rios, A. Cꢆrdova, Angew. Chem. 2007, 119, 792–795; Angew.
Chem. Int. Ed. 2007, 46, 778–781; Angew. Chem. 2007, 119, 792–
795; d) H. Li, L. Zu, H. Xie, J. Wang, W. Jiang, W. Wang, Org. Lett.
2007, 9, 1833–1835; e) G.-L. Zhao, J. Vesely, R. Rios, I. Ibrahem, H.
Sundꢅn, A. Cꢆrdova, Adv. Synth. Catal. 2008, 350, 237–242; f) H.
Li, L. Zu, H. Xie, J. Wang, W. Wang, Chem. Commun. 2008, 5636–
5638; g) E. Reyes, G. Talavera, J. L. Vicario, D. Badꢀa, L. Carrillo,
Angew. Chem. 2009, 121, 5811–5814; Angew. Chem. Int. Ed. 2009,
48, 5701–5704; Angew. Chem. 2009, 121, 5811–5814; h) P. Kotame,
B.-C. Hong, J.-H. Liao, Tetrahedron Lett. 2009, 50, 704–707; i) J.-Y.
Bae, H.-J. Lee, S.-H. Youn, S.-H. Kwon, C.-W. Cho, Org. Lett. 2010,
12, 4352–4355.
Representative data for furans
ACHTUNGTRENNUNG(2R,3S)-2-((2S,5S)-5-Methyltetrahydrofuran-2-yl)-4-nitro-3-phenylbutan-
1-ol (20a-cis): colorless amorphous solid; [a]2D1 = +21.2 (c = 2.00 in
CHCl3, >99% ee); 1H NMR (400 MHz, CDCl3): d=7.40–7.25 (m, 5H),
5.05 (dd, J=12.6, 4.7 Hz, 1H), 4.94 (dd, J=12.6, 10.7 Hz, 1H), 4.06 (dd,
J=12.4, 1.6 Hz, 1H), 3.97–3.82 (m, 3H), 3.70 (dd, J=12.4, 3.7 Hz, 1H),
3.21 (brs, 1H), 1.98 (m, 1H), 1.93–1.79 (m, 2H), 1.72 (m, 1H), 1.48 (m,
1H), 1.29 ppm (d, J=6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
138.7, 128.9, 128.2, 127.7, 81.0, 78.4, 76.0, 59.3, 46.3, 44.7, 32.8, 29.8,
21.1 ppm; IR (thin film, KBr): n˜ =3455, 2970, 1637, 1552, 1380, 702 cmꢁ1
;
the enantiomeric excess was determined by HPLC with an AS-H column
(n-hexane/iPrOH 97:3), 0.3 mLminꢁ1; major enantiomer tR =73.7 min,
minor enantiomer tR =83.5 min; HRMS (ESI): m/z: calcd for C15H21NO4:
279.1471, found: 279.1472 [M+].
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Organocatalytic Kinetic Resolution Cascade Reactions
FULL PAPER
[5] For 1-catalyzed cascade reactions involving untethered nucleophiles
and electrophiles, see: a) M. Marigo, T. Schulte, J. Franzꢅn, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 15710–15711; b) H. Jiang,
J. B. Nielsen, M. Nielsen, K. A. Jørgensen, Chem. Eur. J. 2007, 13,
9068–9075; c) C. Appayee, S. E. Brenner-Moyer, Org. Lett. 2010,
12, 3356–3359; d) A. Quintard, A. Alexakis, Chem. Commun. 2011,
47, 7212–7214.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian,
Inc., Wallingford CT, 2009; b) S. Grimme, J. Comput. Chem. 2003,
24, 1529–1537; c) M. Gerenkamp, S. Grimme, Chem. Phys. Lett.
2004, 392, 229–235; d) T. H. Dunning Jr., J. Chem. Phys. 1989, 90,
1007–1023.
[10] M. D. Pierce, R. C. Johnston, S. Mahapatra, H. Yang, R. G. Carter,
P. H.-Y. Cheong, J. Am. Chem. Soc., DOI 10.1021/ja3018219).
[11] Side views of all transition structures in Figure 2 can be found in the
Supporting Information.
[6] P. G. McGarraugh, S. E. Brenner-Moyer, Org. Lett. 2011, 13, 6460–
6463 and references therein.
[7] Substrate 6e could not be synthesized in uncyclized form, and was
thus subjected to cascade reaction conditions as the corresponding
racemic cis-tetrahydropyran.
[8] CCDC-855353 (20a-cis), -855354 (32a-trans), contain the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
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Received: December 23, 2011
Revised: March 27, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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S. E. Brenner-Moyer, P. H.-Y. Cheong et al.
Organocatalysis
P. G. McGarraugh, R. C. Johnston,
A. Martꢀnez-MuÇoz, P. H.-Y. Cheong,*
S. E. Brenner-Moyer* . . . . . . . &&&& — &&&&
A new resolution for 2012: A cascade
reaction generating enantiopure,
ceeds by an unprecedented mecha-
nism, in which a kinetic resolution or
dynamic kinetic resolution of the b-ste-
reocenter occurs, mediated by the
enamine-catalyzed intermolecular
reaction (see scheme).
Organocatalytic Kinetic Resolution
Cascade Reactions: New Mechanistic
and Stereochemical Manifold in
highly functionalized tetrahydropyrans
and -furans in a one-pot reaction is de-
scribed. The stereochemical outcome
of this cascade reaction is unprece-
dented. The cascade reaction also pro-
Diphenyl Prolinol Silyl Ether Catalysis
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www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!