Development of an asymmetric trimethylenemethane cycloaddition reaction: Application in the enantioselective synthesis of highly substituted carbocycles

Article abstract of DOI:10.1021/ja207550t

A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures, is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored, and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.

Full text of DOI:10.1021/ja207550t

ARTICLE
pubs.acs.org/JACS
Development of an Asymmetric Trimethylenemethane Cycloaddition
Reaction: Application in the Enantioselective Synthesis of Highly
Substituted Carbocycles
Barry M. Trost,* Steven M. Silverman,# and James P. Stambuli§
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
ABSTRACT: A protocol for the enantioselective [3+2] cy-
cloaddition of trimethylenemethane (TMM) with electron-
deficient olefins has been developed. The synthesis of novel
phosphoramidite ligands was critical in this effort, and the
preparation and reactivity of these ligands is detailed. The
evolution of the ligand design, commencing with acyclic
amine-derived phosphoramidites and leading to cyclic pyrroli-
dine and azetidine structures, is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsi-
lylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes
with high levels of enantioselectivity. The donor scope was also explored, and substituted systems were tolerated, including one
bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing
three stereocenters in high enantioselectivity and complete diastereoselectivity.
Scheme 1. Catalytic Cycle for the Pd-TMM Cycloaddition
’ INTRODUCTION
The transition-metal-catalyzed [3+2] trimethylenemethane
(TMM) cycloaddition reaction (eq 1) is a versatile method for
the chemo-, regio-, and diastereoselective construction of highly
substituted five-membered rings.1 Utilization of Pd-TMM com-
plexes derived from 3-acetoxy-2-trimethylsilylmethyl-1-propene
(1) has resulted in the efficient catalytic syntheses of carbocycles2
and heterocycles.3 Although this methodology was disclosed
over 30 years ago by our laboratory,4 a general asymmetric
variant of the cycloaddition remained elusive until 2006.5 In this
full account, we will describe the development of the asymmetric
TMM reaction and its application in the synthesis of complex
carbocycles.
isomerization of the exocyclic olefin to give the internal alkene,
depending on the reaction conditions.
The catalytic cycle for the TMM reaction of silyl allylic
acetates (Scheme 1) was proposed early and has withstood the
test of time.6 The zwitterionic Pd-TMM intermediate 2 is
generated in situ by metal-promoted ionization of the allylic
acetate functionality in 1, followed by desilylation promoted by
the displaced acetate. Complex 2 is nucleophilic in nature and
can add to electron-deficient systems, including olefins, alde-
hydes, and imines. Addition of the nucleophilic Pd-TMM com-
plex to the olefin gives intermediate 3, which is followed by
collapse of the zwitterionic intermediate via intramolecular attack
of the soft carbon nucleophile onto the π-allylpalladium. This
affords the desired product 4, which can undergo a base-promoted
The mechanism in Scheme 1 illustrates the difficulty in the
development of an asymmetric variant of the TMM reaction.
Nucleophilic addition is the enantiodiscriminating step. The
coordinated chiral ligands on the palladium are spatially remote
to the reaction center, and this distance likely decreases their
ability to transfer stereochemical information during the addition.
Evidence for a distal approach was obtained in early mechanistic
studies.7 Accordingly, prior to 2006, attempts to induce asymmetry
Received: August 10, 2011
Published: September 22, 2011
r
2011 American Chemical Society
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Scheme 2. Hayashi’s Catalytic, Asymmetric Methylenecyclopentane Synthesis
Scheme 3. Initial Discovery of the Phosphoramidite-Catalyzed Asymmetric TMM Reaction
into the TMM reaction had largely been limited to the use of
chiral auxiliaries on the acceptor;8 chiral catalysis was largely
unsuccessful. In fact, for several years, a single example of a
catalytic, asymmetric TMM reaction stood alone in the
literature: Hayashi disclosed an asymmetric [3+2] cycloaddi-
tion of 2-(sulfonylmethyl)-2-propenyl carbonate with simple
esters and ketones in 1989 (Scheme 2).9 While the acceptor
scope was limited to methyl vinyl ketone and methyl acrylate,
and multiple equivalents were required, this represented an
important advance in the development of the asymmetric
reaction.
’ DESIGN AND APPLICATION OF ACYCLIC AMINE
PHOSPHORAMIDITE LIGANDS TO THE ASYMMETRIC
TRIMETHYLENEMETHANE CYCLOADDITION REACTION
Of the diverse transformations promoted by phosphorami-
dites, afairlysubstantialnumberrelyonafewrelativelysimilarligand
structures, specifically containing a BINOL backbone and secondary
amine. This, in conjunction with a 2005 report from Alexakis which
details the effects of structural changes to the amine segment of
the phosphoramidite ligand on iridium-catalyzed asymmetric
allylic alkylation,15 prompted us to study the effect of modifications
of the amine on the TMM reaction.
In the Trost group, work toward the development of an
asymmetric reaction spanned more than two decades, and thus
a comprehensive discussion is outside the scope of this account.
It should be noted that the potential of phosphoramidite ligands
in the asymmetric transformation was recognized by our group
early after applications of this class of ligand began to appear in
the literature. While conventional wisdom states that bidentate
ligands provide the highest levels of reactivity and selectivity in
asymmetric catalysis, an increasing body of literature demon-
strates the utility of chiral monodentate phosphorus ligands.10
Indeed, in many asymmetric reactions, these structures have
proven to be superior to bidentate ligands. Phosphoramidite
ligands are one such class of privileged structures.11 Initially
disclosed as a derivatization method for the determination of
enantiomeric excesses (ee's) of chiral amines,12 phosphorami-
dites were soon recognized as competent additives in catalytic,
asymmetric conjugate additions13 and numerous other reac-
tions.11 Due to the success of both phosphites and hexa-
methylphosphorus triamide as ligands in the achiral TMM
reaction, we saw potential in the unique phosphoramidite
ligand class containing both axial and point chiral elements.
Our initial hit is shown in Scheme 3. Use of Feringa ligand L1
with the parent donor 1 provided the desired cycloadduct 6 of
the unsaturated oxazolidinone 5 in 69% yield and 29% ee.14
After further experimentation, it became clear that ligand
optimization would be required to reach the desired enantio-
selectivity level.
For our initial studies (Scheme 4), we chose benzylidene
acetone 7 as the TMM acceptor. Initially we chose a 4:1 ligand:
palladium ratio, but we quickly found that a 2:1 ratio gave the
same product selectivity. Our standard reaction time was 4 h,
though the reaction was generally complete within 1ꢀ2 h as
determined by gas chromatography (GC). As a basis for com-
parison, we first screened ligand L1. Under our standard condi-
tions, we observed a 75% conversion and 33% ee at room temper-
ature. We were pleased to quickly observe that small structural
changes did in fact produce significant variation in reactivity and
selectivity. Installation of a single ortho-methyl group (L2),
1-naphthyl (L3), or 2-naphthyl (L4) gave cyclopentane 8a with
ee values comparable to that obtained with the Feringa ligand but
different levels of conversion. Replacing the ortho alkyl group with
an alkoxy as in L5 or L6 led to a very quick reaction with high
conversion but similar ee. We speculate that this may be due to a
hemilabile coordination between the oxygen and palladium, provid-
ing a more active catalyst system. Increasing the steric bulk around
both phenyl rings (L7) provided a nearly inactive catalyst system, in
contrast to the work of Alexakis.15 The conversion was restored with
bis-methoxy ligand L8, perhaps due to a hemilabile coordination.
While electronic effects of the system appear to be
responsible for conversion, we speculated that steric factors
may be the primary dictator of enantioselectivity. In order to
test this, we first removed a methyl group entirely, as in
L9ꢀL12. No reactivity was observed in any case, and it
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Scheme 4. Initial Screen of Acyclic Amine Phosphoramidite Ligands
became clear that catalyst decomposition with these ligands
was very fast. Changing the relative stereochemistry of the
chiral amine subunit, as in L13ꢀL20, had a significant
impact. Inversion of the stereocenter adjacent to the unsub-
stituted ring (L13) was not beneficial, but inversion of the
stereocenter proximal to the substituted ring (L14ꢀL18)
substantially improved the ee. The presence of a hemilabile
alkoxy group again improved reactivity with L17, giving the
product in 84% ee and 92% conversion at ꢀ25 °C. Interest-
ingly, all of these ligands give product of the same absolute
configuration, indicating that the BINOL is responsible for
the overall product stereochemistry. Increasing the bulk
closer to phosphorus (L19, L20) gave good conversion but
decreased enantioselectivity.
evaluated under the same conditions (Figure 1). In no case were
satisfactory results obtained. While reasonable ee was ob-
served with ligand L24 containing only a single stereocenter
on the amine portion of the ligand, conversion was unaccep-
tably low. Self-adapting catalyst L25, which proved useful in
conjugate additions,16 showed no reactivity in the TMM
cycloaddition. TADDOL-derived phosphoramidite L26 was
also unreactive.
’ DESIGN AND APPLICATION OF A PYRROLIDINE
PHOSPHORAMIDITE LIGAND TO THE ASYMMETRIC
CYCLOADDITION REACTION
While modification of the acyclic amines led to respectable
levels of enantioselectivity, we felt that more significant structural
changes would be necessary to further elevate selectivity to the
In addition to the ligands shown in Scheme 4, other catalysts
not containing the bis-benzylic and (R)-BINOL motifs were
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desired levels. As steric factors clearly play a significant role in
both the conversion and enantioselectivity, we envisioned re-
stricting the flexibility of the amine fragment through constraint
to a pyrrolidine, as this could eliminate conformations that lead
to lower levels of selectivity. Additionally, the pyrrolidine is less
sterically demanding. Since we previously observed that very
bulky systems show decreased reactivity, this could provide a
more active catalyst system. We first targeted diphenylpyrroli-
dine ligand L27, which had been synthesized previously and
utilized in asymmetric conjugate addition reactions.17 We were
gratified to observe an immediate jump in both reactivity and
selectivity using this ligand, as compared to the majority of the
acyclic amine-derived ligands. Under the standard conditions,
the starting material was completely consumed within 30 min at
room temperature to give the product in 76% isolated yield and
72% ee, which increased to 82% ee at ꢀ25 °C (Scheme 5).
The pyrrolidine-based catalyst system L27 represented the
most general and selective one for the cycloaddition to date. The
substrate scope is shown in Table 1. To avoid confusion, it should
be noted that these experiments were conducted using (S,S,S)-
L27 unless otherwise stated. The absolute stereochemistry has
been confirmed by analogy to a crystal structure obtained of a
derivative of the cycloadduct of β-nitrostyrene with the parent
donor.18 The reaction proved general for a variety of systems.
Both aliphatic (entries 1ꢀ3) and aromatic (entries 4ꢀ6) ketones
functioned in the reaction. As can be seen in entry 3, aliphatic
groups on the olefin were also tolerated. The yields were good in
all cases, with enantioselectivities ranging from moderate to good
in these systems. The reaction performed well at temperatures as
low as ꢀ25 °C, with an increase in enantioselectivity of approxi-
mately 10% being observed upon lowering the temperature
from 23 to ꢀ25 °C (entries 1ꢀ3). Esters (entry 7) and nitriles
(entry 8) were tolerated, albeit with reduced enantioselectivity.
Substituted tetralones proved to be excellent substrates for this
reaction (entries 9ꢀ13) allowing the formation of an all-carbon
quaternary center in enantioselectivities as high as 92%. We
believe the increase in selectivity for these substrates has to do with
their steric bulk, which most likely causes increased discrimination
in the approach of the substrate to the palladiumꢀligandꢀdonor
complex and, therefore, the initial bond-forming event.
We also evaluated the effect of solvent on the asymmetric
reaction (Table 2). Although toluene and THF have been the
solvents of choice in the achiral reaction, we felt that an examination
of solvent effect on yield and selectivity of this process using the new
catalyst system was warranted. Reactions conducted in THF, diethyl
ether, and DME gave good yields with modest ee values slightly
lower than those observed in toluene (entries 2ꢀ4), while reactions
in DCM, CH3CN, DMF, and dioxane gave low conversion to the
cyclopentane product. Thus, toluene appears optimal.
’ FURTHER MODIFICATION OF THE PYRROLIDINE
PHOSPHORAMIDITE LIGAND AND EXPANDED SUB-
STRATE SCOPE
With the discovery that the diphenylpyrrolidine moiety was
very important for both selectivity and reactivity, we wanted to
determine if modifications of the backbone could further im-
prove the reaction. Ligands L28ꢀL33 (Figure 2) were prepared
and tested using benzylidene acetone as the acceptor under the
standard conditions (5 mol % Pd(dba)2, 10 mol % ligand, 23 °C,
toluene). Removal of the axial chirality element through use of a
catechol (L28) or biphenyl (L29) backbone gave inactive
catalysts. We tested a ligand containing a partially hydrogenated
BINOL backbone (L30) with the hope that the increased bulk of
the system would provide additional enantiodiscrimination and
make the reaction more selective. Unfortunately, while full
conversion was observed, the ee dropped to 61% from the 72%
afforded by the fully unsaturated system. Under identical condi-
tions, reversal of the BINOL enantiomer gave an inactive catalyst
(L31), as did methyl and phenyl substitutions at the aryl moiety
3- and 30-positions (L32, L33). We suspected that substitution at
both the 3- and 30-positions may increase the steric bulk to such
an extent that substrate approach is prohibited.
Due to our earlier success in improving the reaction selectivity
by changes to the amine segment of the ligand, we hoped
alteration of the pyrrolidine would also prove fruitful. Synthesis
of the modified pyrrolidines was challenging, as low solubility of
intermediates prevented their preparation in a manner analogous
to the method used to prepare the diphenylpyrrolidine.17 We
decided to develop a new route to the desired 2,5-disubstituted
pyrrolidines which would allow for maximum diversity, including
preparation of unsymmetrically substituted compounds. In
2006, Campos disclosed a one-pot, sequential chiral lithiation,
Figure 1. Additional acyclic amine ligands evaluated in the [3+2]
cycloaddition.
Scheme 5. Reaction of Benzylidene Acetone and TMS Propenyl Acetate Using Ligand (R,R,R)-L27
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Table 1. Initial Substrate Scope of the [3+2] Cycloadditiona
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Table 1. Continued
a All reactions were performed at 0.2 M in toluene with 5% Pd(dba)2, 10% ligand, and 1.6 equiv of donor 1, and stirred for 2ꢀ24 h as monitored by GC
for disappearance of the acceptor. Yields are isolated values; ee’s were determined by chiral HPLC or chiral GC. b Reaction performed with (R,R,R)-L27.
Table 2. Solvent Effects on the Asymmetric [3+2] Cycloaddition
entry
solvent
toluene
yield (%)
ee (%)
1
2
3
4
5
6
7
8
80
68
80
69
10
0
58
48
53
55
32
0
THF
DME
diethyl ether
DCM
CH3CN
DMF
0
0
dioxane
35
39
Figure 2. Pyrrolidine phosphoramidite ligands with modified backbones.
transmetalation, and Negishi coupling of N-Boc pyrrolidine which
could be used to efficiently generate substituted pyrrolidines.19
While the authors include only a single example of the prepara-
tion of a disubstituted pyrrolidine, we hoped that we could make
this a general process.
Our revised strategy for ligand synthesis is shown in Scheme 6.
Carbamate protection of pyrrolidine proceeds in high yield and is
followed by installation of the first aryl group. As shown in
Table 3, the results are good, proceeding in high yields and ee's
(>93%). This is not surprising, as the enantiodiscriminating
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Scheme 6. General Method for Synthesis of Pyrrolidine-Derived Phosphoramidite Ligands
performed the final step of the sequence at 60 °C. This
immediately solved the lack of reactivity and produced the
desired products (entries 1ꢀ4) in good yield. The diastereo-
selectivity was excellent, giving almost exclusively the desired
trans-pyrrolidines. A second problem arose when we moved to
bulkier substrates. We observed that the solubility of the anion in
TBME was not very high, as substantial precipitate was observed
during the deprotonation step. Using our previous conditions,
bis-2-naphthyl pyrrolidine 11ca was obtained in only 26% yield,
and many other disubstituted pyrrolidines did not form, even in
trace quantities. To aid in the anion solubility, we added 10ꢀ30
vol % toluene relative to TBME and found that yields increased
substantially with no loss of diastereoselectivity. Using these
conditions, we were able to form sterically bulkier products
including bis-2-naphthyl pyrrolidine 11ca (entry 6), mixed
1-naphthyl-2-naphthyl pyrrolidine 11cb (entry 7), mixed
2-naphthyl-3,5-tert-butylphenyl pyrrolidine 11cc (entry 8), bis-
3-biphenyl pyrrolidine 11d (entry 9), and the very bulky bis-3,5-
diphenylphenyl pyrrolidine 11e (entry 10), all in good yields and
excellent diastereoselectivities. Significant quantities of the mono-
substituted pyrrolidines could be recovered after the reaction, but
the ee was considerably lower than that of the starting material,
indicating competitive deprotonation between the disubstituted and
more acidic (and more hindered) trisubstituted centers. Most likely,
the transmetalation or Negishi coupling fails on the trisubstituted
center for steric reasons, leading to nonselective protonation during
workup and recovery of the pyrrolidine.
Having successfully generalized Campos’s lithiation strategy
to form disubstituted pyrrolidines in high yields and selectivities,
we wanted to further elaborate the structures to phosphoramidite
ligands (Table 4). After deprotection (20 equiv of TFA/CH2Cl2,
4 h, 23 °C), the free pyrrolidines 12aꢀg could easily be
transformed into the desired ligands. A 0.5 M solution of (R)-
BINOL chlorophosphite 13 was added to the pyrrolidine,
DMAP, and triethylamine in toluene to form the ligands.
Monosubstituted pyrrolidine ligand L34 was prepared from
the corresponding amine to determine if both substitutions are
in fact necessary. The yields for the ligand synthesis were generally
good, regardless of the bulk of the pyrrolidine.
Table 3. Synthesis of Mono- and Disubstituted Pyrrolidines
yield ee
yield
entry
R1
C6H5
ref (%) (%)
R2
ref (%)
dr
1
2
3
4
5
6
7
8
10a 81
93 C6H5
2-MeOC6H4 11ab
2-naphthyl 11ac
93 2-MeOC6H4 11ba
11aa
51 24:1
44 24:1
45 > 50:1
37 16:1
2-MeOC6H4 10b 77
C6H5
95 2-naphthyl
1-naphthyl
3,5-t-
11ab 33a 21:1
11ca
50b > 50:1
11cb 45b > 50:1
2-naphthyl
10c 75
11cc
61b > 50:1
BuC6H3
9
3-biphenyl
10d 86
ND 3-biphenyl
11d
49b > 50:1
48b > 50:1
23b,c > 50:1
10
11
12
13
3,5-PhC6H3 10e 70
ND 3,5-PhC6H3 11e
94 4-biphenyl 11f
10g 83 >93d 1-naphthyl
10h 54 ND 3,5-t-
BuC6H3
4-biphenyl
1-naphthyl
3,5-t-
10f 82
11g NDb,e ND
11h
0
BuC6H3
a Reaction performed at 23 °C. b With toluene cosolvent. c After
recrystallization from CH2Cl2:pentane. d Some overlap in HPLC trace.
e Could not completely purify by column chromatography; purified after
deprotection.
event is the lithiation step, and thus the final value is independent
of the identity of the aryl bromide utilized.
Installation of the second aryl group proved more challeng-
ing (Table 3). While we were able to repeat the synthesis of
diphenylpyrrolidine 11aa at room temperature (entry 1), the
reaction failed when attempting to form o-methoxyphenyl pyr-
rolidine 11ab or 2-naphthyl pyrrolidine 11ac. In fact, significant
reaction was only observed at ambient temperature in the
synthesis of 11ab when the unsubstituted phenyl group was
installed second (entry 5). In this case, the yield was only 33%.
We suspected that the low solubility of the organozinc inter-
mediate in ethereal solvents, in combination with the slower rate
of oxidative addition of palladium to the more electron-rich aryl
rings in the Negishi coupling, might be the cause and accordingly
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Table 4. Deprotection of N-Boc Pyrrolidines and Phosphoramidite Synthesis
entry
N-Boc pyrrolidine
R1
R2
pyrrolidine
yield (%)
ligand
yield (%)
1
10a
C6H5
H
12a
92
97
L34
L35
L36
L37
L38
L39
L40
L41
L42
L43
L44
38
81
82
41
84
77
68
40
68
82
60
2
11ab
11ac
11ba
11ca
11cb
11cc
11d
C6H5
2-OMeC6H4
2-naphthyl
2-MeOC6H4
2-naphthyl
1-naphthyl
3,5-t-BuC6H3
3-biphenyl
3,5-PhC6H3
4-biphenyl
1-naphthyl
12ab
12ac
12ba
12ca
12cb
12cc
12d
3
C6H5
100
71
4
2-MeOC6H4
2-naphthyl
2-naphthyl
2-naphthyl
3-biphenyl
3,5-PhC6H3
4-biphenyl
1-naphthyl
5
98
6
100
86
7
8
97
9
11e
12e
92
10
11f
12f
99
10a
11
11g
12g
a Isolated yield for two steps from 10g.
Scheme 7. Selected Pyrrolidine and Azetidine Phosphoramidite Ligand Results
With the series of cyclic amine-derived phosphoramidites in
hand, we wanted to compare the levels of reactivity and
selectivity with what we had observed in our previously explored
catalyst systems (Scheme 7). We used conditions identical to
those used to screen the acyclic systems. As was observed with
the acyclic structures, ligands containing methylene centers
adjacent to nitrogen, as in L34, are unproductive in the cycload-
dition. We immediately observed that the disubstituted cyclic
systems were far superior to the acyclic systems in terms of
reactivity. Even at ꢀ25 °C, complete conversion was observed in
every case. The electronic nature of the aromatic rings proved to
be less important than was previously observed in the acyclic
systems. Installation of a single o-methoxy group (L35) showed
essentially the same selectivity as the parent diphenyl ligand.
A second methoxy substitution (L37) raised the selectivity by a
small amount. Steric factors turned out to be differential in
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Table 5. Substrate Scope of the [3+2] Cycloaddition with L38a
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Table 5. Continued
a All reactions were performed at 0.2 M in toluene with 5% Pd(dba)2, 10% ligand, and 1.6 equiv of donor 1, and stirred for 2ꢀ24 h as monitored by GC
c
for disappearance of the acceptor. Yields are isolated values; ee’s were determined by chiral HPLC or chiral GC. b Conversion. ee obtained by
conversion to the corresponding methyl ester using Otera’s catalyst (6 mol % catalyst, 60 equiv of CH3OH, 0.1 M PhCH3, 15 h, 12% conversion).
improving enantioselectivity. While the biphenyl system L43
gave only a small increase in ee, installation of a naphthyl group
(L36) had a significant effect, increasing the ee to 84% at room
temperature and 91% at ꢀ25 °C. This is the first time we had
observed such a high selectivity in this system. The bis-1-
naphthyl ligand L44 gave a 91% ee at room temperature, and
bis-2-naphthyl ligand L38 showed the best results in the series,
giving the cyclopentane product in 98% ee at room temperature.
We also wanted to test the effect of ring size on reactivity and
selectivity, and therefore we screened the azetidine phosphor-
amidite L45. The lower steric demand led to a catalyst of higher
reactivity, giving complete conversion in less than 15 min, but in
only 52% ee. Clearly, steric factors are the most important in
determining the enantioselectivity of these catalyst systems.
With ligand L38 in hand, we proceeded to examine the scope
of the asymmetric TMM reaction. Gratifyingly, this ligand
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Scheme 8. Synthesis of Cyano-Substituted TMM Donor 17
proved superior to those previously studied systems in terms of
scope and selectivity. The substrate range was considerably
broader and where comparisons were obtained, enantioselec-
tivities were uniformly higher (Table 5). Both aliphatic and
aromatic ketones performed well in the reaction (entries 1ꢀ3),
providing the respective cyclopentanes in good yields and
enantioselectivities of greater than 90%. In cases where conver-
sion was low, the temperature of the reaction could be raised,
generally with the effect of substantially increasing conversion
with only a minor drop in enantioselectivity. The tolerance of this
catalyst to elevated temperatures may explain the increased
substrate scope using the naphthyl ligand. Esters were tolerated
(entries 4 and 5) and led to ee values more than 30% higher than
those obtained with the diphenyl ligand. An unsaturated nitrile
gave good yield and selectivity (entry 6). Thioesters functioned
well (entry 7), as did a Weinreb amide (entry 8). Conversion was
reduced in the latter case, though the enantioselectivity remained
high at temperatures as high as 75 °C. Oxazolidinones could
be used in the reaction (entries 9 and 10), but the enantio-
selectivity dropped. Unfortunately, a cis-olefin gave no product
(entry 11).
Acylpyrroles represent a very interesting class of alkene
acceptors, as they are formally at the carboxylic acid oxidation
state but have reactivity profiles similar to those of ketones. They
are susceptible to nucleophilic attack and can be converted to a
number of different products at various oxidation states. The
chemistry of α,β-unsaturated acylpyrroles has been studied in
conjugate additions,20 asymmetric epoxidations and cyclopropa-
nations.21 A series of these compounds was prepared to examine
the scope of this class of compounds in the TMM reaction. They
were synthesized in the manner described by Shibasaki,22 and it
was quickly discovered that they performed very well in the
asymmetric cycloaddition reaction. Full conversion was obtained
at room temperature, and the reaction is tolerant of both
aromatic (entries 12ꢀ17) and aliphatic (entry 18) groups. Steric
bulk (entry 13), electron-withdrawing groups (entry 14), elec-
tron-donating groups (entry 15), and heterocyclic aromatic
groups (entries 16 and 17) all gave high levels of conversion,
although the ee dropped considerably with use of the 2-furyl
substituent but not the 3-furyl system. A cyclohexyl substrate was
tolerated (entry 18), and although conversion was low at 45 °C,
the reaction went to completion at 75 °C without any deleterious
effect on the enantioselectivity. Many of these products contain
functional groups that can be further manipulated to generate
cyclopentanes with high levels of molecular complexity.
Figure 3. LUMO energies of α,β-unsaturated ketones and carboxylic
acid derivatives.
oxindoles and oxobenzofurans provided interesting insight into
the TMM reaction and yielded a strategy for the facile construc-
tion of spirocyclic systems containing multiple adjacent stereo-
genic centers.23 To expand the scope of the reaction, we hoped to
find a more general acceptor. We sought to find a system that,
through subsequent synthetic manipulations, would allow access
to an even wider range of cyclopentane-containing structures.
Our early studies focused on cyano donor 17, the synthesis of
which is detailed in Scheme 8. Oxidation of key alcohol 15 with
manganese dioxide gave aldehyde 16, and subsequent reaction
with pyruvonitrile provided the donor 17 in a single step from the
aldehyde in 58% yield.
We began to examine our cyano donor in the context of other
electron-deficient olefins. Unfortunately, our initial efforts were
met with frustration, with both benzylidene acetone and methyl
cinnamate showing no reactivity. The tetralone substrates that
had performed well with the diphenyl phosphoramidite ligand
were also unreactive. Interestingly, GC-MS analysis of the crude
reaction mixture seemed to indicate the presence of the cycload-
duct between the dibenzylidene acetone ligand and the cyano
donor. In light of this result, we began to look at the electronic
properties of the substrates we were hoping to operate on. Speci-
fically, we looked at orbital energies. In his studies of lanthanide-
catalyzed nucleophilic epoxidation reactions, Shibasaki observed
a direct correlation between reaction rate and lowest unoccupied
molecular orbital (LUMO) energy.22 He found that little, if any,
conversion was observed with the morpholine amide 18 (<10%
after 1 h). The conversion increased substantially with decreasing
LUMO energies, and under identical conditions, conversions of
approximately 40% and 60% were seen with the acylpyrrole 21
and chalcone 22, respectively. As Figure 3 shows, the LUMO
energies of methyl cinnamate (19) and benzylidene acetone (7)
are comparatively high (ꢀ1.72 and ꢀ1.88 eV, respectively),
whereas dibenzylidene acetone would be expected to lie con-
siderably lower, near that of chalcone. The oxazolidinones,
acylpyrroles, and chalcones all have low-lying LUMOs. The
acylpyrroles were the most attractive acceptors because of their
’ EXPANSION OF THE SCOPE: ASYMMETRIC CYCLO-
ADDITIONS WITH SUBSTITUTED TMM DONORS
With our robust catalyst system in hand, we next turned our
attention toward expansion of the TMM donor component of
the reaction. Our studies of cycloadditions with substituted
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Table 6. Substrate Scope of the TMM Reaction of Acylpyrroles with Nitrile Donor 17
a All reactions were performed at 0.2 M in toluene with 5% Pd(dba)2, 10% ligand L38, and 1.5 equiv of 17 and stirred for 3 h; yields are combined isolated
yields; ee’s were determined by HPLC with a chiral stationary phase column. b Reaction performed at 50 °C.
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Scheme 9. Generation of Palladium-TMM Complex 26
Figure 5. The structure indicates that one of the aryl rings of the
BINOL could act as a wall such that the substrate approaches as
depicted in Figure 5a; approach as depicted in Figure 5b would
lead to significant steric interactions. While this model is not to
be taken as definitive evidence in the absence of a crystal struc-
ture, it does serve as a reasonable rationalization and accurately
depicts the absolute and relative stereochemistry observed in this
series, as well as that observed with oxindole, ketimine,25 and
tropone26 acceptors.
The excellent reactivity of this specific substrate class in the
TMM cycloaddition is very fortuitous. Because the nitrogen lone
pair of an acylpyrrole is delocalized through the aromatic ring,
there is little delocalization into the carbonyl. As a result, the
compound, while formally at the carboxylic oxidation level, displays
a reactivity profile similar to that of a ketone but can be further
transformed through synthetic manipulations common to the
ester oxidation level. This leads to a wide range of accessible
structures.
Figure 4. Confirmation of relative stereochemistry by NOE.
versatility in further transformations and excellent performance
with the parent TMM donor.
Gratifyingly, application of our standard reaction conditions to
cyano donor 17 and acylpyrroles using ligand L38 gave us a
single product in excellent yield and enantioselectivity (Table 6).
The substrate scope was found to be very general. A diverse range
of sterically and electronically different aryl- and heteroaryl-
substituted acceptors performed well (entries 1ꢀ7). A diene
acceptor reacted regioselectively with the 2,3-double bond only
(entry 8). Substrates bearing saturated alkyl substituents were
also reactive (entries 9 and 10), not requiring elevated tempera-
tures as in the case of the parent donor (entry 10). Perhaps the
most striking feature about this reaction was the diastereoselec-
tivity. None of the trans,trans-diastereomer was observed in any
case. In fact, the only evidence that small amounts may form was
found in the case of 23c (entry 3). Trace quantities of the
tautomerized product were obtained. We would expect the ee to
remain unchanged if it were simply the desired product isomer-
ization. However, the observed ee was 84%, indicating that the
isomerized material may potentially arise from the other diaster-
eomer, which had lower ee, and that the rate of isomerization of
this diastereomer is considerably higher, such that we do not
observe any of the exocyclic olefin.
Another interesting feature of this reaction is the regioselec-
tivity. Generation of the active Pd-TMM species occurs as shown
in Scheme 9. Palladium-mediated ionization of 17 gives π-allyl
24, which after acetate-mediated desilylation gives TMM com-
plex 25. While this initial ionization places the anion distal to the
nitrile, the regioselectivity shown in the products above is derived
exclusively from the donor species 26, in which the anion is
adjacent to the nitrile. This anion is expected to be favored on
both thermodynamic grounds, as the anion proximal to the nitrile
is resonance-stabilized, and steric grounds, as this form places the
bulk of the palladium-ligand complex distal to the donor sub-
stituent. The TMM species is dynamic in nature, and 25 and 26
are readily interchangeable by πꢀσꢀπ isomerization, which in
this case occurs faster than attack of the anion to the olefin
acceptor.24
’ CONCLUSION
In summary, we have discovered and developed the first highly
enantioselective asymmetric cycloadditions of trimethylene-
methane. These transformations utilize a series of novel ligands
which evolved from secondary amine-based phosphoramidites to
a series of pyrrolidine-derived ligands during our studies. Se-
quential chiral lithiation, transmetalation, and Negishi coupling
steps provided a general, efficient method that could be used in
ligand preparation. Studies of the newly developed catalysts have
culminated in the development of a robust synthetic method
which can be used to prepare highly substituted cyclopentane
scaffolds containing three contiguous stereocenters in high enantio-
selectivity and complete regio- and diastereoselectivity. The
methodology is tolerant of a wide variety of electron-deficient
olefins, including ketones, esters, nitriles, thioesters, and amides.
Furthermore, the use of acylpyrrole substituents with substituted
donors gives our method additional synthetic utility because it
allows a good deal of flexibility in subsequent transformations.
Applications of this novel methodology in the synthesis of
complex molecules are highly anticipated.
’ EXPERIMENTAL SECTION
O,O0-(R)-(1,10-Dinaphthyl-2,20-diyl)-N-((R,R)-2,5-di(2-
naphthyl)pyrrolidine) Phosphoramidite (L38). (R)-tert-Butyl
2-(Naphthalen-2-yl)pyrrolidine-1-carboxylate (10c). A solution of N-
Boc pyrrolidine (4.9 g, 28.5 mmol, 1.2 equiv) and (ꢀ)-sparteine (6.5 mL,
28.5 mmol, 1.2 equiv) in tert-butyl methyl ether (60 mL) was cooled
to ꢀ78 °C, and s-BuLi (28.5 mmol, 1.2 equiv, 27.1 mL of a 1.05 M
solution in cyclohexane) was added dropwise over 15 min. The pale
yellow solution was stirred at this temperature for 3 h, at which point
ZnCl2 (17.1 mmol, 0.72 equiv, 17.1 mL of a 1.0 M solution in diethyl
ether) was added dropwise slowly over 15 min. The solution was stirred
at ꢀ78 °C for 30 min and then allowed to warm to room temperature and
The relative and absolute stereochemistry were assigned by
analogy to our previously disclosed acceptors,23 for which absolute
stereochemistry has been confirmed by X-ray crystallography.
Relative stereochemistry was also confirmed by NOE analysis of
23j (Figure 4). In addition, a geometry optimization of the
palladium-ligand-TMM complex performed at the PM3 level using
Spartan yielded the energy-minimized conformation shown in
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Figure 5. Spartan-minimized (PM3) Pd-TMM complex.
stir for an additional 30 min. 2-Bromonaphthalene (4.92 g, 23.75 mmol,
1.0 equiv) was added, followed by Pd(OAc)2 (256 mg, 1.14 mmol,
0.048 equiv) and t-Bu3P-HBF4 (413 mg, 1.42 mmol, 0.06 equiv), and the
solution was stirred overnight at room temperature. After 12 h aqueous
ammonia (2.5 mL) was added, and the mixture was stirred for 1 h. At this
time, the mixture was filtered through Celite to remove salts and washed
with tert-butyl methyl ether. The filtrate was washed with 1 N HCl and
water, dried over MgSO4, filtered, and concentrated. The product was
purified by flash chromatography on silica gel (90% methylene chloride in
petroleum ether) to give the desired product as a white solid (5.3 g, 75%).
1H NMR (400 MHz, CDCl3): δ 7.82ꢀ7.77 (m, 3H), 7.58 (s, 1H), 7.45
(br s, 2H), 7.31 (d, J = 8.4 Hz, 1H), 5.11 (s, 0.3H), 4.96 (s, 0.7H),
3.70ꢀ3.54 (m, 2H), 2.38 (br s, 1H), 1.99ꢀ1.87 (m, 3H), 1.50ꢀ1.43 (m,
3H), 1.14 (s, 6H). Chiral HPLC (Chiralcel AD column, 1% isopropanol
in heptane, 1.0 mL/min, λ = 254 nm): tR = 15.06 (major), 16.65 (minor).
(2R,5R)-tert-Butyl 2,5-Di(naphthalen-2-yl)pyrrolidine-1-carboxy-
late (11ca). A solution of 10c (1.70 g, 5.7 mmol, 1.2 equiv) and (ꢀ)-
sparteine (1.31 mL, 5.7 mmol, 1.2 equiv) in tert-butyl methyl ether
(12 mL) was cooled to ꢀ78 °C. Toluene (3 mL) was added to aid in
solubility. s-BuLi (5.7 mmol, 1.2 equiv, 4.45 mL of a 1.28 M solution in
cyclohexane) was added dropwise over 15 min to give a dark yellow
solution. The solution was stirred at this temperature for 3 h, at which
point ZnCl2 (3.42 mmol, 0.72 equiv, 3.42 mL of a 1.0 M solution in
diethyl ether) was added dropwise slowly over 15 min. The solution was
stirred at ꢀ78 °C for 30 min and then allowed to warm to room
temperature and stir for an additional 30 min. 2-Bromonaphthalene
(984 mg, 4.75 mmol, 1.0 equiv) was added, followed by Pd(OAc)2
(51 mg, 0.228 mmol, 0.048 equiv) and t-Bu3P-HBF4 (83 mg, 0.285
mmol, 0.06 equiv), and the solution was stirred overnight at 60 °C.
After 12 h, the solution was cooled to room temperature, aqueous
ammonia (500 μL) was added, and the mixture was stirred for 1 h. At
this time, the mixture was filtered through Celite to remove salts and
washed with tert-butyl methyl ether. The filtrate was washed with 1 N
HCl and water, dried over MgSO4, filtered, and concentrated. The
product was purified by flash chromatography on silica gel (10% ethyl
acetate in petroleum ether) to give the desired product as a white solid
(1.01 g, 50%). 1H NMR (400 MHz, CDCl3): δ 7.86ꢀ7.82 (m, 6H), 7.69
(d, J = 9.2 Hz, 2H), 7.52ꢀ7.38 (m, 6H), 5.56 (d, J = 7.2 Hz, 1H), 5.41 (d,
J = 7.6 Hz, 1H), 2.62ꢀ2.51 (m, 2H), 1.88ꢀ1.79 (m, 2H), 1.11 (s, 9H).
(2R,5R)-2,5-Di(naphthalen-2-yl)pyrrolidine (12ca). A solution of
11ca (1.06 g, 2.5 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was cooled to
0 °C, and TFA (3.71 mL, 50 mmol, 20.0 equiv) was added. The mixture
was stirred for 4 h at room temperature and then concentrated. Ethyl
acetate was added, followed by 2 N NaOH (20 mL). Triethylamine
(5 mL) was added. The organic phase was separated, dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatogra-
phy on silica gel (10% ethyl acetate in pentane) gave the product
as a white solid (795 mg, 98%). 1H NMR (400 MHz, CDCl3): δ
7.88ꢀ7.82 (m, 8H), 7.58 (dd, J = 8.6, 1.6 Hz, 2H), 7.50ꢀ7.43 (m, 4H),
4.80 (t, J = 7.0 Hz, 2H), 2.58ꢀ2.47 (m, 2H), 2.10ꢀ2.00 (m, 2H).
13C NMR (100 MHz, CDCl3): δ 143.2, 133.4, 132.6, 128.3, 127.8, 127.6,
126.0, 125.5, 125.0, 124.5, 62.5, 35.5.
O,O0-(R)-(1,10-Dinaphthyl-2,20-diyl)-N-((R,R)-2,5-di(2-naph-
thyl)pyrrolidine) Phosphoramidite (L38). To a suspension of
(R)-1,10-binaphthyl-2,20-diol (2.86 g, 10.0 mmol, 1.0 equiv) in PCl3
(14.0 mL, 160 mmol, 16 equiv) was added N-methylpyrrolidone (three
drops). The mixture was stirred at 60 °C for 15 min, cooled, and carefully
concentrated to give a yellow, foamy solid. The residue was twice
azeotroped with toluene (10 mL) and finally dissolved in toluene
(20 mL) to make a 0.5 M stock solution of chlorophosphite 13, which
could be stored for several days at ꢀ15 °C. The intermediate was
observed to be air sensitive, but the brief exposure during this procedure
resulted in no more than 5% oxidation products (as judged by
31P NMR), which did not effect the subsequent reaction. 31P NMR
(162 MHz, CDCl3): δ 179.0. A solution of BINOL chlorophosphite
(1.56 mmol, 1.2 equiv, 3.12 mL of a 0.5 M in solution in toluene) was
added dropwise to a mixture of pyrrolidine 12ca (420 mg, 1.30 mmol,
1.0 equiv), triethylamine (903 μL, 6.5 mmol, 5.0 equiv), and DMAP
(31.7 mg, 0.26 mmol, 0.2 equiv) in toluene (8 mL) at 0 °C. The mixture
was stirred overnight at room temperature and the ligand purified by
flash chromatography on silica gel (25% dichloromethane in hexanes
with 1% triethlyamine) to give the product as a white solid (694 mg,
1
84%) after trituration from hexanes. H NMR (400 MHz, CDCl3): δ
7.94ꢀ7.80 (m, 9H), 7.57ꢀ7.52 (m, 5H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H),
7.32ꢀ7.28 (m, 3H), 7.23ꢀ7.09 (m, 5H), 6.59 (d, J = 8.8 Hz, 1H), 5.86
(dd, J = 8.8, 0.8 Hz, 1H), 5.38 (d, J = 7.2 Hz, 2H), 2.59ꢀ2.48 (m, 2H),
1.84ꢀ1.76 (m, 2H). 31P NMR (162 MHz, CDCl3): δ 145.5. 13C NMR
(100 MHz, CDCl3): δ 149.4 (d, J = 9.8 Hz), 149.0, 143.3 (d, J = 4.5 Hz),
133.4, 132.8, 132.7, 132.1, 131.2, 130.2, 129.9, 128.5, 128.2, 128.1, 128.0,
127.9, 127.7, 127.1, 126.9, 126.2, 125.8, 125.7, 125.4, 125.3, 125.2, 124.6,
124.0, 122.0, 121.9, 120.8 (d, J = 3.1 Hz), 62.7 (d, J = 12.9 Hz), 33.2. IR
(neat): ν 3054, 3008, 2970, 2933, 2870, 1619, 1591, 1507, 1463, 1326,
1230, 1068, 946, 818, 748. [α]D = ꢀ117.8 (c 0.34, PhCH3), ꢀ1.3
24
(c 2.51, CHCl3). HRMS (ESI): calcd for C44H32NNaO2P [M+Na]+,
660.2068; found, 660.2075.
General Procedure for Palladium-Catalyzed Asymmetric
TMM Cycloaddition. A flask containing Pd(dba)2 (2.9mg, 0.005mmol,
0.05 equiv), 2-naphthyl pyrrolidine phosphoramidite (L38, 6.4 mg,
0.01 mmol, 0.10 equiv), and (E)-3-(4-bromophenyl)-1-(1H-pyrrol-1-yl)-
prop-2-en-1-one (27.6 mg, 0.1 mmol, 1.0 equiv) was evacuated and purged
with argon. Toluene (0.5 mL) was added and the mixture stirred for 5 min
at room temperature. Nitrile TMM donor 17 (35 μL, 0.15 mmol, 1.5 equiv)
was added, and the solution was stirred at room temperature for 3 h. The
mixture was loaded directly onto a silica gel column and purified by flash
chromatography on silica gel (15% ethyl acetate in hexanes) to give the
desired product as a white solid (35.5 mg, quantitative).
23f: 1H NMR (400 MHz, CDCl3): δ 7.49 (dd, J = 8.8, 2.4 Hz, 2H),
7.30ꢀ7.22 (m, 2H), 7.19ꢀ7.15 (m, 2H), 6.32 (dd, J = 2.8, 2.4 Hz, 2H),
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5.44ꢀ5.42 (m, 1H), 5.33ꢀ5.31 (m, 1H), 4.07ꢀ4.05 (m, 1H), 3.99ꢀ
3.95 (m, 1H), 3.86ꢀ3.81 (m, 1H), 3.15ꢀ3.08 (m, 1H), 2.93ꢀ2.85
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 170.4, 142.9, 136.6, 132.2,
129.5, 122.3, 119.1, 117.8, 114.1, 112.6, 49.4, 47.5, 41.0, 35.6. IR (neat):
ν 2961, 2916, 2849, 2243, 1704, 1665, 1467, 1261, 1070, 901, 800.
[α]D26 = 3.9 (c 0.41, CHCl3). HRMS (ESI): calcd for C18H15BrN2NaO
[M+Na]+, 377.0265; found, 377.0255. Chiral HPLC (Chiralpak IA
column, 5% isopropanol in heptane, 1.0 mL/min, λ = 254 nm): tR =
16.25 (minor), 29.06 (major).
(14) Trost, B. M.; Yamano, M. Unpublished results.
(15) Alexakis, A.; Polet, D. Org. Lett. 2005, 7, 1621.
(16) Wakabayashi, K.; Aikawa, K.; Kawauchi, S.; Mikami, K. J. Am.
Chem. Soc. 2008, 130, 5012.
(17) Choi, Y. H.; Choi, J. Y.; Yang, H. Y.; Kim, Y. H. Tetrahedron:
Asymmetry 2002, 13, 801.
(18) Trost, B. M.; Bringley, D. A. Unpublished results.
(19) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C.-Y. J. Am. Chem. Soc. 2006, 128, 3538–3539.
(20) (a) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 514. (b) Vakulya, B.; Varga, S.; Soos, T. J. Org. Chem.
2008, 73, 3475. (c) Shaghafi, M. B.; Kohn, B. L.; Jarvo, E. R. Org. Lett.
2008, 10, 4743.
(21) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 13410.
(22) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki,
M. J. Am. Chem. Soc. 2004, 126, 7559.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental details,
b
compound characterization data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(23) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396.
’ AUTHOR INFORMATION
(24) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1981, 103, 5972.
(25) Trost, B. M.; Silverman, S. M. J. Am. Chem. Soc. 2010,
132, 8238.
Corresponding Author
bmtrost@stanford.edu
(26) Trost, B. M.; McDougall, P. J.; Hartmann, O.; Wathen, P. T.
J. Am. Chem. Soc. 2008, 130, 14960.
Present Addresses
#Bristol-Myers Squibb, One Squibb Dr., New Brunswick,
NJ 08903
§Department of Chemistry, The Ohio State University, 100 West
18th Ave., Columbus, OH 43210
’ ACKNOWLEDGMENT
We thank the NSF and NIH (Grant GM13598) for their
generous support of our programs. S.M.S. thanks Eli Lilly and
Roche for graduate fellowships. We thank Johnson-Matthey for
their generous gifts of palladium salts.
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