Phosphoramidite gold(I)-catalyzed diastereo- and enantioselective synthesis of 3,4-substituted pyrrolidines

Article abstract of DOI:10.1021/ja200084a

In this article the utility of phosphoramidite ligands in enantioselective Au^I catalysis was explored in the development of highly diastereo- and enantioselective Au^I-catalyzed cycloadditions of allenenes. A Au^I-catalyzed synthesis of 3,4-disubstituted pyrrolidines and γ-lactams is described. This reaction proceeds through the enantioselective Au^I-catalyzed cyclization of allenenes to form a carbocationic intermediate that is trapped by an exogenous nucleophile, resulting in the highly diastereoselective construction of three contiguous stereogenic centers. A computational study (DFT) was also performed to gain some insight into the underlying mechanisms of these cycloadditions. The utility of this new methodology was demonstrated through the formal synthesis of (-)-isocynometrine.(Figure Presented)

Full text of DOI:10.1021/ja200084a

ARTICLE
pubs.acs.org/JACS
Phosphoramidite Gold(I)-Catalyzed Diastereo- and Enantioselective
Synthesis of 3,4-Substituted Pyrrolidines
Ana Z. Gonzꢀalez,† Diego Benitez,‡ Ekaterina Tkatchouk,‡ William A. Goddard, III,‡ and F. Dean Toste*,†
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125,
United States
S Supporting Information
b
ABSTRACT: In this article the utility of phosphoramidite
ligands in enantioselective AuI catalysis was explored in the
development of highly diastereo- and enantioselective AuI-
catalyzed cycloadditions of allenenes. A AuI-catalyzed synthesis
of 3,4-disubstituted pyrrolidines and γ-lactams is described.
This reaction proceeds through the enantioselective AuI-cata-
lyzed cyclization of allenenes to form a carbocationic inter-
mediate that is trapped by an exogenous nucleophile, resulting
in the highly diastereoselective construction of three contiguous
stereogenic centers. A computational study (DFT) was also
performed to gain some insight into the underlying mechanisms of these cycloadditions. The utility of this new methodology was
demonstrated through the formal synthesis of (ꢀ)-isocynometrine.
Scheme 1. AuI-Catalyzed Cycloadditions of Allenenes
1. INTRODUCTION
The enantioselective synthesis of functionalized pyrrolidines
has attracted significant interest due to their abundance in
bioactive natural and unnatural products and use as chiral ligands
and organocatalysts.1 Their importance has inspired the devel-
opment of diverse methods for their enantioselective construc-
tion including transition-metal-catalyzed hydroamination,2
cycloaddition,3 and cycloisomerization reactions.4 Despite
these advances, enantioselective access to 3,4-substituted
pyrrolidines5 remains a synthetic challenge. Over the past
decade, homogeneous AuI catalysis has opened the door to a
plethora of highly complex molecular frameworks.6 The
operational simplicity and stability of AuI complexes to air
and moisture has made them, arguably, a leading contender in
the field of asymmetric catalysis. As a result, we sought a
diastereo- and enantioselective AuI-catalyzed entry into 3,
4-substituted pyrrolidines.
We had previously observed the formation of pyrrolidines
during the investigation of the mechanism of the AuI-catalyzed [2
þ 2]-cycloaddition of allenenes. These studies suggested that the
trans-3,4-substituted pyrrolidines derived from kinetically gener-
ated cationic intermediate A (Scheme 1);7 however, attempts to
trap A with MeOH using chiral biaryl bisphosphine ligands (4)
tendency has been extended to the field of enantioselective
that had been successfully employed in the enantioselective [2 þ
2]-cycloadditions of allenenes provided methoxycyclization8
product 3a as a racemate.
gold(I) catalysis10 despite the pronounced preference of gold(I)
to form two-coordinate linear complexes rather than the
Initially introduced by Kagan and Dang in 1971, bidentate
chiral phosphines have remained the ligands of choice on many
metal-catalyzed synthetic transformations.9 Expectedly, this
Received: January 4, 2011
Published: March 23, 2011
r
2011 American Chemical Society
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bidentate complexes typical formed with these ligands.11,12
These ancillary ligands are also expensive and difficult to
synthesize, thwarting optimization efforts.
Table 1. Ligand Optimization for Phosphoramidite AuI-
Catalyzed [2 þ 2]-Cycloaddition of 1ba
Recently we and others have shown the utility of tunable
monodentate phosphite and phosphoramidite AuI catalysts in
mediating enantioselective cycloadditions.13 First introduced to
the asymmetric catalysis community in 1994, monodentate chiral
phosphoramidites have remained useful ancillary ligands in many
transformations.12 We initially became interested in this ligand
class because their modular framework is readily constructed
from commercially available enantiomerically pure compounds,
thereby allowing for the straightforward preparation of large
ligand libraries. We first reported the use of a MonoPhosꢀ
AuOTf complex on the enantioselective Conia-Ene reaction in
2005 without success.14 It was not until we explored the enantio-
selective intramolecular AuI-catalyzed formal DielsꢀAlder
cycloadditions of allene-dienes that a true need for the development
of chiral phosphoramidite AuI catalysts transpired. An inspec-
tion of the MonoPhosꢀAuCl complex in its solid state suggested
that ortho-substitution of its BINOL moiety would provide for a
more defined steric environment.13a This idea was pursued with
success, resulting in the chemoselective synthesis of the desired
[4 þ 2]-cycloadducts in excellent enantioselectivities (eq 1).
entry
Cat.
yield (%)b
ee (%)c
1
(S,S,S)-5a
(S,S,S)-5b
(S,S,S)-5c
(S,S,S)-6
81
91
67
34
81
77
86
73
87
22
88
66
---
34(þ)
14(þ)
56(þ)
60(þ)
70(þ)
64(ꢀ)
90(þ)d
52(ꢀ)
32(þ)
4(þ)
2
3
4
5
(S,S,S)-7
6
(R,R,R)-8
(R,R,R)-9a
(S,R,R)-9a
(R,R,R)-9b
(R,R,R)-9c
(R)-9d
7
8
9
10
11
12
13
32(þ)
56(ꢀ)
---
(R,R,R)-10a
(R,R,R)-10b
a Reaction conditions: Cat. (5 mol %), AgBF4 (5 mol %), dichloro-
methane, 25 °C, 24 h. Only one diastereoisomer was observed in
all cases. b Isolated yields after silica gel flash column chromatography.
c Enantiomeric excess determined by enantiodiscriminating HPLC (see
Supporting Information). d The enantioselectivity was increased to 99%
ee after a simple crystallization.
Consequently, we focus our studies on the AuI-catalyzed reactions
of allenene 1a with this ligand class. Through these studies we
uncovered two highly stereoselective phosphoramidite AuI catalysts
expanding our repertoire of reagents and advancing our efforts in the
enantioselective catalytic arena.
entries 1ꢀ3). Exploring other backbones in our screen
showed that VANOL-derived catalyst 7 produced 2b in a
promising 70% ee (entry 5). However, attempts to improve
this result by using what we thought would be a more hindered
VAPOL backbone (8) instead resulted in a lower enantios-
electivity (entry 6). However, complex 9a, containing a
simpler spirobiindane-derived phosphoramidite, gave a pro-
mising hit (entry 7). Employing its diastereomer (S,R,R)-9a
gave 2b in lower enantioselectivity confirming that (R,R,R)-9a
corresponds to the match case. We then decided to explore the
effect of the amine moiety of 9 on the product’s enantioselec-
tivity, and catalysts 9bꢀd were synthesized and tested. Repla-
cing the bis(1-phenylethyl)amine group for its pyrrolidine
counterpart and utilizing a larger amine or a smaller alcohol
moiety proved to be ineffective (entries 9ꢀ11).
2. RESULTS AND DISCUSSION
2.1. Enantioselective AuI-Catalyzed [2 þ 2]-Cycloaddi-
tions of Allenenes. Scope and Limitations. We began our
catalyst screen with BINOL-derived phosphoramidite cata-
lysts 5. Employing unsubstituted complex (S,S,S)-5a resulted
in low enantioinduction, and contrary to our expectations,
introducing substituents in the 3,30-positions on the BINOL
moiety did not significantly improve the selectivity (Table 1,
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Table 2. Ligand Optimization for Phosphoramidite AuI-
Catalyzed [2 þ 2]-Cycloaddition of 1 with (R,R,R)-9aa
entry
2
X
R
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9d
a
b
c
d
e
f
C(CO2Me)2
N-Ts
Ph
Ph
Ph
Ph
75
86
82
52
82
80
72
87
67
14
94
85
81
80
91
80
97
90
C(SO2Ph)2
N-Boc
N-Ts
2-OMe-C6H4
3-OMe-C6H4
4-OMe-C6H4
4-Cl-C6H4
Ph
N-Ts
Figure 1. Structure of complex (R,R,R)-9a in the solid state. Ellipsoids
are drawn at the 50% probability level.
g
h
b
N-Ts
N-Ts
N-Ts
An inspection of complex 9a (Figure 1) in its solid state
suggested that employing 6,60-disubstituted spirobiindane
phosphoramidite ligands might provide a steric environment
similar to that found with catalysts 5.15 To access our 6,60-
disubstituted spirobiindane phosphoramidite gold(I) complexes
we chose to employ a variation of the BellerꢀK€ockritz Suzuki
protocol which circumvents the protection and subsequent
deprotection of both of SPINOL’s alcohol moieties (see Sup-
porting Information for additional details).16 Unfortunately,
utilizing catalysts 10 on the cycloaddition of allenene 1b did
not result in improved enantioselectivities.
a Reaction conditions: Cat. (5 mol %), AgBF4 (5 mol %), dichloro-
methane, 25 °C, 24 h. Only one diastereoisomer was observed in all
cases. trans-2 was used in all cases except for those noted. b Isolated yields
after silica gel flash column chromatography. c Enantiomeric excess
determined by enantiodiscriminating HPLC (see Supporting In-
formation). d From cis-1b.
mechanism where the alkene adds to the gold-coordinated
allene, leading to a vinyl-gold in a concerted fashion. There are
two stereochemical arrangements for the relative position of the
substituents on the formed cyclopentane ring: cis (in red) and
trans (in blue) (Figure 2). Both pathways lead to intermediates
where we found (in the most stable conformation) an interaction
between the carbocation and gold that forms a five-membered
metallacycle. This electrostatic interaction results in carbocation
stabilization by the full d-shell of the electron-rich gold. On the cis
pathway the metallacycle ruptures to form the cyclobutane ring,
effecting demetalation. Experimentally, exposing isolated 2a to
(PhO)3PAuBF4 in the presence of MeOH did not give the
alkoxycyclization product 3a, demonstrating that the formation
of 2a is irreversible under these reaction conditions (Scheme 2).
This result contrasts with F€urstner’s findings that when exposed
to an NHCꢀAuCl complex (NHC = N-heterocyclic carbene),
compound 2a underwent rearrangement to the thermodynami-
cally favored ring-expanded products, a process that was hy-
pothesized to occur through the regeneration of an A-type
carbocation.19
The trans pathway exhibits a similar cyclization leading to a
five-membered ring and a carbocation, notably, with a lower
barrier than that for the cis pathway (trans: 10.4 kcal/mol vs cis:
13.3 kcal/mol). Moreover, we found a barrier for the addition of
MeOH and demetalation20 which is lower than the rate-
determining barrier for the formation of product via the cis
pathway. The absence of deuterium loss in the AuI-catalyzed
formation of d-3a from d-1a suggests that the alkoxycycliza-
tion product is not formed from the addition of the MeOH to
the styrene moiety of a 1,4-diene (B) but from a cationic
intermediate A in agreement with our computational studies
(Scheme 2).
We then decided to examine the scope of the [2 þ 2]-
cycloadditions of various allenenes with 9a. Catalyst 9a proved
to be selective for several allenenes with varying tethers (Table 2,
entries 2ꢀ4). Notably, bis-sulfone tethered 2c was obtained in
85% ee (entry 3), a large improvement when compared to that
synthesized with 4 (Scheme 1). Nonetheless, catalyst 9a was
unselective toward 1a, showing a complementary reactivity to 4.
Both electron-withdrawing and -donating substituents as well as
distinct substitution patterns on the arene moiety were well
tolerated (entries 5ꢀ8). Interestingly cis-1b (entry 9) afforded
the same enantiomer as that obtained from its trans counter-
part in identical selectivity albeit in lower yield. This provides
further evidence of the initial formation of A (Scheme 1),
which, in the absence of an exogenous nucleophile, undergoes
cycloreversion forming the more thermodynamically stable
trans-1b. We decided to take a closer look at the hypothesized
mechanism by means of a quantum mechanical study using the
M06 functional17 of the density functional theory (DFT)
which has been shown18 to be adequate for the description
of organogold catalytic reactions. In doing so, we also hoped
to gain some insight into the factors governing the alkoxycy-
clization reaction pathway leading to the formation of 3,4-
substituted pyrrolidines.
2.2. Computational Analysis on the AuI-Catalyzed Cy-
cloadditions of Allenenes. The potential energy surface was
computed using the model phosphoramidite catalyst (MeO)2-
(Me2N)PAuþ as shown in Figure 2. Consistent with our previous
predictions,18c our present computational study found a stepwise
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Figure 2. DFT profile for the potential free energy surface for the cis (red) and trans (blue) cyclization pathways at the M06/LACV3P**þþ level of
theory corrected for CH2Cl2 as solvent in kcal/mol. L = P(OMe)2(NMe2).
Scheme 2. AuI-Cycloadditions of Allenenes
substituents at the 3 and 30 positions of the binaphthol moiety
increased the enantiomeric excess (entries 5ꢀ11), with 1-pyr-
enyl-disubstituted catalyst 5c providing 3b in up to 76% ee
(entry 6). Attempts to improve this result by varying the
solvent were unsuccessful (entry 7).21 Employing the H8-
BINOL-analog 5c substantially improved the selectivity and
the reaction yield each to 82%. The structures of the AuI
complexes 5c and 11a in the solid state help rationalize this
boost in enantioselectivity. The larger dihedral angle of 11a
(57.75°) compared to 5c (53.39°) produces a shortening of the
AuꢀC3BINOL distance to 3.49 Å from 3.63 Å, thereby placing
the Au-center in closer proximity to the chiral information
(Figure 3). An examination of the solid state structure of 11a
also led us to believe that a 4-pyrenyl moiety instead of its
1-pyrenyl isomer in 11a would extend the chiral pocket further
outward. Indeed, 11b (Figure 3) catalyzed the cycloaddition/
MeOH trapping of 1b with increased selectivity (88% ee, entry
13). We installed electron-deficient arenes on the 4-pyrenyl
moiety of 11b in an effort to improve efficiency. We came to
this hypothesis from the observed high reactivity of 5e, which
allowed us to carry out the reaction at lower temperatures
(entries 9ꢀ10). Although 11c mediated the formation of 1a
with better selectivity even at room temperature (92% ee, entry
14), running the reaction at a lower temperature (0 °C)
produced superior results (entry 15).22 The improved selec-
tivity of 11c when compared to 11b at room temperature might
be due to an increased bite angle (58.2°) as observed in its solid
state (Figure 3).
In order to examine the scope of the reaction, a variety of
allenenes were synthesized and subjected to the optimized
conditions for trapping with various alcohols (Table 4). Both
electron-donating (entries 1ꢀ3) and -withdrawing (entry 4)
substituents on the aromatic moiety were well tolerated, as
were ortho-, meta-, and para-substituents (entries 1ꢀ3).23 The
expected cycloadducts were obtained in high yield and en-
antioselectivity when trapping 1b with several primary
(entries 5ꢀ7) and secondary (entry 8) alcohols as nucleo-
philes. We were pleased to find that even water was a suitable
trapping agent and alcohol 3l was isolated in good yield and
enantioselectivity (entry 9). Even a tertiary ether could be
synthesized from a trisubstituted olefin in excellent diastereo-
(>98:2) and enantioselectivity (92%) (entry 12). The allene
moiety was also varied with similar success (entry 13).
Our results suggest that both cis and trans pathways are
competitive, but in the presence of a nucleophile (MeOH), the
trans pathway is preferred. On the other hand, in the absence of a
viable nucleophile, the cis pathway is operative. These findings
also suggest that a more polar solvent, such as MeNO2, could
further increase the preference for the trans pathway, an
observation that has been confirmed experimentally (see
section 2.3). In addition, we speculate that the interaction
between the carbocation and gold may serve to direct the attack
of the nucleophile from the opposite side. With a clear view of
the underlying mechanism on the AuI-catalyzed cycloadditions
of allenenes we took a closer look at their enantioselective
alkoxycyclization.
2.3. Enantioselective Synthesis of 3,4-Disubstituted Pyr-
rolidines. We first inspected the selectivity of catalyst 9a on the
alkoxycyclization of 1b with MeOH; alas 3b was obtained in low
selectivity (Table 3, entry 1). Even though the yield was improved
by carrying the reaction in MeNO2, the enantiomeric excess
remained low (entry 2). We then decided to test BINOL-derived
phosphoramidites 5. Catalysts 5a gave 3b with low enantioselec-
tivity; however, we found (S,S,S)-5a to be more selective than its
diastereomer (R,S,S)-5a (Table 3, entries 3ꢀ4). Introducing
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Table 3. Ligand Optimization for the AuI-Catalyzed Cy-
cloaddition/Alkoxylation of Allenenesa
for which the nature of the nucleophile significantly affects
enantioselectivity.8b,24b
Additionally, 3,4-disubstituted γ-lactams 13a and 13b could
be accessed through this methodology in high enantioselectivity
(eq 3). The observed reactivity with an amide substrate (12)
prompted us to examine this alkoxycyclization reaction toward
the synthesis of (ꢀ)-isocynometrine.
entry
catalyst
temp
rt
yield (%)b
ee (%)c
2.4. Formal Synthesis of (ꢀ)-Isocynometrine. The utility of
this methodology is exemplified by the synthesis of (ꢀ)-iso-
cynometrine, an imidazole alkaloid isolated from the Cynomera
species, known for its antitussive and analgesic properties.26 This
alkaloid was first synthesized by Xu and co-workers through a Pd-
catalyzed enyne cycloaddition introducing two of the three
contiguous stereogenic centers in 53% ee.4e The third stereo-
center was then installed by reduction of a phenyl ketone to its
secondary carbinol in 2.5:1 dr. In our approach allenene 14 was
subjected to the optimized reaction conditions in the presence of
water yielding γ-lactam 15 in 83% yield and 86% ee (Scheme 3).
The resulting secondary alcohol in 15 was then converted to its
benzoyl ester and the trisubstituted olefin was oxidatively cleaved
with ozone yielding 17 in 80% yield (two steps). The synthesis
could then be completed as previously established in the
literature to give (ꢀ)-isocynometrine.
1d
2
(R,R,R)-9a
(R,R,R)-9a
(R,S,S)-5a
(S,S,S)-5a
(R,R,R)-5b
(S,S,S)-5c
(S,S,S)-5c
(S,S,S)-5d
(R,R,R)-5e
(R,R,R)-5e
(R,R,R)-5f
(R,R,R)-11a
(S,S,S)-11b
(S,S,S)-11c
(S,S,S)-11c
42
72
41
74
75
80
75
17
84
86
87
82
86
86
95
20(þ)
28(þ)
10(ꢀ)
19(þ)
38(þ)
76(ꢀ)
70(ꢀ)
34(ꢀ)
53(þ)
70(þ)
49(þ)
82(þ)
88(ꢀ)
92(ꢀ)
94(ꢀ)
rt
3
rt
4
rt
5
rt
6
7d
rt
rt
8
rt
9
rt
10
11
12
13
14
15
ꢀ15 °C
rt
rt
rt
rt
2.5. Computational Study on the Origin of Enantioselec-
tivity. Having established the general mechanism using a model
ligand, we used molecular mechanics27 to investigate the con-
formational landscape starting from the X-ray structure of ligand
(S,S,S)-11c on the fixed coordinates of the intermediates and
transition structures. Ligand (S,S,S)-11c is composed of a (S,S)-
bis(1-phenylethyl)amine fragment and a 3,30-functionalized (S)-
octahydro-BINOL. Upon visual analysis of the catalystꢀsub-
strate complex, the octahydro BINOL group provides the axial
chirality to the catalyst, while the bis(1-phenylethyl)amine group
adds steric bulk, increasing the helical pitch. We performed a
study of the possible relative rotational orientations of the
phosphoramidite ligand and the substrate. Our conformational
analysis suggests that the specific stereochemistry of the pheny-
lethyl groups in (S,S)-bis(1-phenylethyl)amine may not effect
direct enantiomeric discrimination but may be critical in lever-
aging the performance of the BINOL moiety. Following our
classical mechanics analysis, we subjected two pairs of selected
conformations of the full structures of the enantiodetermining
transition structures to DFT geometry optimization at the M06/
LACVP* level of theory with a CꢀC distance constraint (1.994 Å
0 °C
a Reaction conditions: LAuCl (5 mol %), AgBF4 (5 mol %), MeOH (9
equiv), nitromethane, rt, 24 h. In all experiments a small amount (<9%)
of the corresponding [2 þ 2]-cycloaddition product was also produced.
The diastereoselectivity was >98:2 in all cases. b Isolated yields after silica
gel flash column chromatography. c Enantiomeric excess determined by
enantiodiscriminating HPLC (see Supporting Information). d Reaction
run in dichloromethane.
Accordingly, electron-rich aryl nucleophiles24 could be em-
ployed in this transformation, producing the FriedelꢀCrafts
product 3p in good yield (73%) and enantioselectivity (97%,
eq 2).25
Interestingly, cis-substituted allenene (cis-1b) afforded the
same 2b isomer as its trans-1b counterpart, albeit in lower yield
and enantioselectivity (entries 10ꢀ11). This observation and the
conservation of enantioselectivity regardless of the nucleophile
used (Table 4, entries 5ꢀ10) suggest that the cyclization is the
enantiodetermining step. These findings are in stark contrast
with the related 5-exodig cyclization/trapping of 1,6-enynes
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Figure 3. ORTEP representations of complexes 5c and 11aꢀc. Ellipsoids are drawn at the 50% probability level.
Table 4. Substrate Scope for AuI-Catalyzed Cycloaddition/Alkoxylation of Allenenes with 11ca
a Reaction conditions: 11c (6 mol %), AgBF4 (5 mol %), trapping agent (Nu) (9 equiv), 24 h. For entries 5ꢀ10 the reaction was run at 0 °C; all others
were run at room temperature. In all experiments a small amount (<9%) of the corresponding [2 þ 2]-cycloaddition product was also produced. The
diastereoselectivity was >98:2 in all cases. Isolated yields after silica gel flash column chromatography. Enantiomeric excess determined by
enantiodiscriminating HPLC (see Supporting Information).
as found for the model ligand) (Figure 4). This methodology is
thought to exhibit enough accuracy to visualize the key structural
factors that govern the enantioselectivity.
while the styrenyl and dimethylallyl groups point toward the
H8-BINOL; alternatively, on the other orientation, the styr-
enyl and dimethylallyl groups point toward the bis(1-pheny-
lethyl)amine group, while the N-tosyl pyrrolidine fragment
points in the direction of the H8-BINOL. The enantioselec-
tivity originates from the relative interactions between these
groups. We identified the following key ligand structural
directives: (1) the aligning of the substrate by the 3,30-BINOL
substituents, (2) the steric interactions provided by the bis(1-
phenylethyl)amine group, and the (3) steric interactions
provided by the “downward” facing H4-naphthyl group. We
Our structural analysis suggests that the groups at the 3,30-
positions on BINOL serve to orient the substrate by flanking
it. This could explain the increase in enantioselectivity using
pyrenyl substituents. The parallel placement of the pyrenyl
groups forms a channel in which the substrate can adopt two
complementary orientations that lead to the different enan-
tiomers. In one of these orientations, the N-tosyl pyrrolidine
fragment points toward the bis(1-phenylethyl)amine group
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Scheme 3. Enantioselective Synthesis of (ꢀ)-
to be highly selective for the [2 þ 2]-cycloadditions of
allenenes. Importantly, catalyst 9a was particularly selective toward
nitrogen and bis-sulfone tethered substrates, both of which
underwent this transformation with previously reported bis-
phosphine-derived 4 in low enantioselectivity. This report also
describes a new AuI-catalyzed cyclization/alkoxylation for the
conversion of allenenes to trans-3,4-disubstituted pyrrolidines
and γ-lactams. The reaction allows for the highly diastereo- and
enantioselective synthesis of these heterocycles containing three
contiguous stereocenters. Central to the success of this effort was
the use of bulky monophosphorusꢀAuI complex 11c. We also
studied these reactions computationally using the M06 func-
tional (DFT) to gain insight into key factors determining the
mechanism and the enantioselectivity. The utility of this meth-
odology is demonstrated by the formal synthesis of (ꢀ)-
isocynometrine.
Isocynometrine
’ ASSOCIATED CONTENT
S
Supporting Information. Computational details, experi-
b
mental procedures, and compound characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge funding from the National Insti-
tute of General Medical Services (GM073932) and Amgen. A.Z.
G. thanks the NIH for a postdoctoral fellowship. We thank
Vincent Medrꢀan and Pablo Mauleꢀon for preliminary experiments
and Johnson Matthey for a gift of AuCl3. We would also like to
thank Dr. Antonio DiPasquale for his assistance in collecting and
analyzing crystallographic data. Computational resources were
partially funded as part of the Center for Catalytic Hydrocarbon
Functionalization, an Energy Frontier Research Center funded
by the U.S. Department of Energy, Office of Science, Office of
Basic Energy Sciences under Award Number DE-SC0001298.
’ REFERENCES
Figure 4. Views for the matched (top) and mismatched (bottom)
(1) (a) The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 2000; Vol. 54. (b) O’Hagan, D. Nat.
Prod. Rep. 2000, 17, 435.(c) Schomaker, J. M.; Bhattacherjee, J. Y.;
Borhan, B. J. Am. Chem. Soc. 2007, 129, 1996 and references cited
therein. (d) Hanessian, S.; Yun, H.; Tintelnot-Blomley, M. J. Org. Chem.
2005, 70, 6746.
(2) For selected recent examples of enantioselective synthesis of
pyrrolidines, see: (a) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. Org.
Lett. 2007, 9, 2887. (b) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste,
F. D. Science 2007, 317, 496. (c) LaLonde, R. L.; Sherry, B. D.; Kang,
E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (d) Shen, X.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564. (e) Mai, D. N.;
Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157.
(3) (a) Cabrera, S.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc.
2005, 127, 16394. (b) Saito, S.; Tsibogo, T.; Kobayashi, S. J. Am. Chem.
Soc. 2007, 129, 5364. (c) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X.
J. Am. Chem. Soc. 2007, 129, 750. (d) Najera, C.; Retamosa, M. G.;
Sansano, J. M. Angew. Chem., Int. Ed. 2008, 47, 6055. (e) Wang, C.-J.;
Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250. (f)
structures minimized at the M06/LACVP* level of theory.
also recognized that a higher dihedral angle of the BINOL
group increases the steric interaction of the enantiodiscriminating
H4-naphthyl group, which could explain why increasing the
dihedral correlated with higher enantioselectivities.
3. CONCLUSIONS
The successful development of newly AuI-catalyzed transfor-
mations depends largely on the ability to design inexpensive
ligands that are easy to prepare and tune for a specific chemical
transformation. Within this context, this report serves to further
demonstrate the potential utility of phosphoramidite ligands in
enantioselective AuI catalysis. We uncovered two new highly
selective catalysts for the cycloadditions of allenenes. Commer-
cially available, small, SIPHOS-PE-derived catalyst 9a proved
5506
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Journal of the American Chemical Society
ARTICLE
Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc.
2010, 132, 9688.
2010, 49, 1949. (c) Alonso, I.; Trillo, B.; Lꢀopez, F.; Montserrat, S.;
Ujaque, G.; Castedo, L.; Lledꢀos, A.; Mascareꢁnas, J. L. J. Am. Chem. Soc.
2009, 131, 13020.
(14) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168.
In 2005 Echavarren et al. also showed an unsuccessful (2% ee) example
of the use of a phosphoramidite Au(I) catalyst: see ref 8b.
(15) Yang, Y.; Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, Zhou, Q.-
L. J. Am. Chem. Soc. 2007, 129, 2248.
(16) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; K€ockritz,
A.; Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008, 64, 1316.
(17) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
(18) (a) Torker, S.; Merki, D.; Chen, P. J. Am. Chem. Soc. 2008,
130, 4808. (b) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y. M.;
Goddard, W. A.; Toste, F. D. Nat. Chem. 2009, 1, 482. (c) Benitez, D.;
Tkatchouk, E.; Gonzalez, A. Z.; Goddard, W. A.; Toste, F. D. Org. Lett.
2009, 11, 4798. (d) Wang, Z. J.; Benitez, D.; Tkatchouk, E.; Goddard,
W. A.; Toste, F. D. J. Am. Chem. Soc. 2010, 132, 13064.
(19) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; F€urstner, A.
Angew. Chem., Int. Ed. 2010, 49, 2542.
(4) (a) Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104. (b)
Lei, A.; Waldrich, J. P.; He, M.; Zhang, X. Angew. Chem., Int. Ed. 2002,
41, 4527. (c) Chakrapani, H.; Liu, C.; Widenhoefer, R. A. Org. Lett. 2003,
5, 157. (d) Jang, H.-Y.; Hughes, F. W.; Gong, H.; Zhnag, J.; Brodbelt,
J. S.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 6174. (e) Xu, W.; Kong,
A.; Lu, X. J. Org. Chem. 2006, 71, 3854. (f) Rhee, J. U.; Krische, M. J.
J. Am. Chem. Soc. 2006, 128, 10674. (g) Nicolaou, K. C.; Li, A.; Ellery,
S. P.; Edmonds, D. J. Angew. Chem., Int. Ed. 2009, 48, 6293.
(5) 3,4-Substituted pyrrolidines comprise a structural motif com-
monly found in natural products and biologically active molecules: (a)
Farwick, A.; Helmchen, G. Org. Lett. 2010, 12, 1108. (b) Ohki, S.;
Nagasaka, T.; Matsuda, H.; Ozawa, N.; Hamaguchi, F. Chem. Pharm.
Bull. 1986, 34, 3606. (c) Okazaki, Y.; Ishizuka, A.; Ishihara, A.; Nishioka,
T.; Iwamura, H. J. Org. Chem. 2007, 72, 3830. (d) Yu, S.; Qin, D.;
Shangary, J. C.; Wang, G.; Ding, K.; McEachern, D.; Qiu, S.; Nikolovska-
Coleska, Z.; Miller, R.; Kang, S.; Yang, D.; Wang, S. J. Med. Chem. 2009,
52, 7970. (d) Ali, A.; Ahmad, V. U.; Ziemer, B.; Liebscher, J. Tetrahedron:
Asymmetry 2000, 11, 4365. (e) Clayden, J.; Knowles, F. E.; Menet, C. J.
Tetrahedron Lett. 2003, 44, 3397. (f) Cook, G. R.; Sun, L. Org. Lett. 2004,
6, 2481. (g) Lian, G.-Y.; Yu, J.-D.; Yang, H.-F.; Lin, F.; Gao, Q.; Zhang,
D.-W. Chem. Lett. 2007, 36, 408. (h) Han, X.; Luo, J.; Liu, C.; Lu, Y.
Chem. Commun. 2009, 2044.
(20) We also found a barrier of 22.9 kcal/mol for the formation of a
cyclobutane ring via the trans pathway.
(21) For a full account of all catalysts screened and different reaction
conditions used, refer to the Supporting Information.
(22) Varying the counterion (OTf, SbF6, PF6) proved to be incon-
sequential to the enantioselectivity of the reaction.
(6) For a review on enantioselective Au-catalysis, see: (a) Wide-
nhoefer, R. A. Chem.—Eur. J. 2008, 14, 5382. For recent reviews on
gold-catalyzed reactions, see:(b) F€urstner, A. Chem. Soc. Rev. 2009,
38, 3208. (c) Shen, H. C. Tetrahedron 2008, 64, 7847. (d) Gorin, D. J.;
Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (e) Li, Z.;
Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (f) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395. (g) Hashmi, A. S. K.; Hutchings, G. J.
Angew. Chem., Int. Ed. 2006, 45, 7896.
(23) An aryl substituent on the substrate’s olefinic moiety proved to
be necessary to achieve reactivity in the [2 þ 2]-cycloaddition and
alkoxycyclization reactions. For example, independent reaction of a
dimethyl-substituted olefin-containing substrate with 9a and 11c (in the
presence of MeOH) in dichloromethane (12 h, rt) resulted in the
recovery of the starting material.
(24) For a Pt- and Au-catalyzed enantioselective cyclization/
hydroalkylation, see: (a) Toullec, P. Y.; Chao, C.-M.; Chen, Q.; Gladiali,
S.; Genet, J. P.; Michelet, V. Adv. Synth. Catal. 2008, 350, 2401. (b)
Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genet, J.-P.; Michelet, V.
Chem.—Eur. J. 2009, 15, 1319.
(25) We attempted to recover both 9a and 11c after their use as
catalysts in the corresponding [2 þ 2]-cycloaddition and alkoxycycliza-
tion reactions of 1b without success. For successful recycling of related
catalysts, see ref 13a.
(7) Luzung, M. R.; Mauleon, P.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 12402.
(8) For examples of Pt- and Au-catalyzed enantioselective alkoxycy-
clization reactions of enynes, see: (a) Charrualt, L.; Michelet, V.; Taras,
R.; Gladiali, S.; Genet, J. P. Chem. Commun. 2004, 850. (b) Muꢁnoz,
M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005,
24, 1293. (c) Michelet, V.; Charrualt, L.; Gladiali, S.; Genet, J. P. Pure
Appl. Chem. 2006, 78, 397. (d) Martinez, A.; Garcia-Garcia, P.;
Fernandez-Rodriguez, M. A.; Rodriguez, F.; Sanz, R Angew. Chem., Int.
Ed. 2010, 49, 4633. (e) Sethofer, S. G.; Mayer, T.; Toste, F. D. J. Am.
Chem. Soc. 2010, 132, 8276. (f) Chao, C.-M.; Genin, E.; Toullec, P. Y.;
Genet, J.-P.; Michelet, V. J. Organomet. Chem. 2009, 694, 538.
(9) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
(10) For the use of bisphosphine gold(I) catalysts in enantioselective
transformations, see: (a) Melhado, A. D.; Amarante, G. W.; Wang, Z. J.;
Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 3517. (b) Yao, L.-
F.; Wei, Y.; Shi, M. J. Org. Chem. 2009, 74, 9466. (c) LaLonde, R. L.;
Wang, Z. J.; Mba, M.; Lackner, A. D. Angew. Chem., Int. Ed. 2010, 49, 598.
(d) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178. (e)
Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009,
131, 5372. (f) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 3464. (g) Watson, I. D. G.; Ritter, S.; Toste,
F. D. J. Am. Chem. Soc. 2009, 131, 2056. (h) Chao, C.-M.; Vitale, M. R.;
Toullec, P. Y.; Gen^et, J.-P.; Michelet, V. Chem ꢀ Eur. J. 2009, 15, 1319.
(i) Luzung, M. R.; Mauleꢀon, P.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 12402. (j) Tarselli, M. A.; Chianese, A. R.; Lee, S. J.; Gagnꢀe, M. R.
Angew. Chem., Int. Ed. 2007, 46, 6670. (k) Liu, C.; Widenhoefer, R. A. Org.
Lett. 2007, 9, 1935. (l) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 2452. (m) Zhang, Z.; Widenhoefer, R. A.
Angew. Chem., Int. Ed. 2007, 46, 283. (n) Johansson, M. J.; Gorin, D. J.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002.
(26) (a) Chiaroni, A.; Riche, C.; Tchissambou, L.; Khuong-Huu, F.
J. Chem. Res. (S) 1981, 182. (b) Tchissambou, L.; Benechie, M.;
Khuong-Huu, F. Tetrahedron 1982, 38, 2687.
(27) Halgren, T. A. J. Comput. Chem. 1996, 17, 490.
(11) (a) F€urstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007,
46, 3410. (b) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675.
(12) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(13) (a) Gonzꢀalez, A. Z.; Toste, F. D. Org. Lett. 2010, 12, 200. (b)
Teller, H.; Flugge, S.; Goddard, R.; F€urstner, A. Angew. Chem., Int. Ed.
5507
dx.doi.org/10.1021/ja200084a |J. Am. Chem. Soc. 2011, 133, 5500–5507