Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres

Article abstract of DOI:10.1038/nchem.1796

The development of a general catalytic method for the direct and stereoselective construction of contiguous all-carbon quaternary stereocentres remains a formidable challenge in chemical synthesis. Here, we report a highly enantio- and diastereoselective [3+2] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalysed by a palladium complex bearing a newly devised phosphine ligand with a chiral ammonium salt component, which enables the single-step construction of three contiguous stereocentres, including vicinal all-carbon quaternary stereocentres, in a five-membered heterocyclic framework. This stereoselective cycloaddition protocol relies on the remarkable ability of the chiral ligand to rigorously control the absolute stereochemistry of each chiral centre associated with the multiple bond-forming events, and provides a reliable catalytic process for the asymmetric synthesis of densely functionalized pyrrolidines.

Full text of DOI:10.1038/nchem.1796

ARTICLES
PUBLISHED ONLINE: 24 NOVEMBER 2013 | DOI: 10.1038/NCHEM.1796
Ligand-enabled multiple absolute stereocontrol in
metal-catalysed cycloaddition for construction of
contiguous all-carbon quaternary stereocentres
Kohsuke Ohmatsu1,2, Naomichi Imagawa2 and Takashi Ooi1,2
*
The development of a general catalytic method for the direct and stereoselective construction of contiguous all-carbon
quaternary stereocentres remains a formidable challenge in chemical synthesis. Here, we report a highly enantio- and
diastereoselective [312] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalysed by a
palladium complex bearing a newly devised phosphine ligand with a chiral ammonium salt component, which enables
the single-step construction of three contiguous stereocentres, including vicinal all-carbon quaternary stereocentres, in a
five-membered heterocyclic framework. This stereoselective cycloaddition protocol relies on the remarkable ability of the
chiral ligand to rigorously control the absolute stereochemistry of each chiral centre associated with the multiple
bond-forming events, and provides
functionalized pyrrolidines.
a reliable catalytic process for the asymmetric synthesis of densely
contiguous array of all-carbon quaternary stereocentres is vicinal all-carbon quaternary stereocentres in a single synthetic
found in many complex natural products, and it is often operation remains largely unexplored14,16–21
crucial for the expression of their biological activities. Transition-metal-catalysed intermolecular cycloadditions for the
.
A
Accordingly, the establishment of reliable methodologies for the rapid assembly of cyclic molecular frameworks have been studied
efficient stereoselective construction of this structural motif extensively22,23. Among the wide range of useful variations, catalytic
represents a significant and highly important task, but is among annulation mediated by a zwitterionic p-allylpalladium intermedi-
the most challenging objectives in organic synthesis1–6. In principle, ate is one of the most powerful tools for the stereoselective synthesis
the prospective molecular transformations for the construction of a of highly substituted cyclic compounds from relatively simple
contiguous array of chiral quaternary carbons can be classified into materials24–29. The overall bond connection in this system is believed
two general schemes. One is asymmetric addition to tetrasubstituted to take place in a stepwise manner. When a readily accessible trisub-
alkenes (Fig. 1a), wherein regiochemical control is indispensable to stituted alkene is used as an electrophilic coupling partner, the
ensure the structural integrity of the product, and the relative stereo- initial intermolecular addition of the allylpalladium species affords
chemistry of the two resulting chiral centres is highly dependent on the zwitterionic intermediate possessing a trisubstituted carbanionic
the geometry of the starting alkenes. As such, the development of site (Fig. 1c). If the subsequent ring closure is fast enough to allow
this mode of reaction requires geometrically pure alkenes in order retention of the stereochemical information from the parent alkene
to achieve rigorous stereocontrol. This approach is thus hindered geometry in the generated carbanion, enantiofacial discrimination
by the difficulty associated with selective preparation of tetrasubsti- of the alkene in the intermolecular addition step would enable the
tuted alkenes7. The other scheme is the asymmetric coupling of stereoselective construction of not only the trisubstituted chiral
trisubstituted carbon nucleophiles and electrophiles (Fig. 1b). centre, but also the adjacent quaternary carbon stereocentre.
Although the complicated stereochemical presetting of substrates Moreover, employment of a precursor with a tetrasubstituted
is not essential, bond formation between the sterically congested, chiral carbon for the generation of the 1,1-disubstituted allylpalla-
prochiral carbons of these species is inherently unfavourable, and dium species allows for the introduction of an additional quaternary
achievement of the requisite high level of absolute and relative stereocentre in the second ring-closing event. Importantly, control
stereocontrol through the simultaneous yet precise recognition of of the isomerization of the planar chiral p-allylpalladium via
their intricate stereochemistries poses a formidable challenge. As a p–s–p interconversion is necessary to accomplish the stereo-
means of addressing this long-standing problem, intramolecular selective construction of this chiral carbon centre29–31. To achieve
processes are considered to be advantageous, particularly in terms such double absolute stereocontrol, that is, the discrimination of
of circumventing the steric constraints on the reactivity by the prochiral trisubstituted alkene and control of the planar chirality
exploiting the enforced proximity of the two reactive sites. In fact, of the p-allylpalladium, in a single cycloaddition process, we
as previously reported, a limited number of approaches mostly devised a new type of phosphine ligand with a pendant chiral
rely on intramolecular reactions such as polyene cyclization8,9, ammonium salt (Fig. 1d)32,33. It was hypothesized that each struc-
sigmatropic rearrangement10–14 and intramolecular cycloaddi- tural component of this onium–phosphine hybrid ligand (arylphos-
tions15. However, although substrate-directed diastereoselective phine, chiral ammonium ion and counterion) would play a pivotal
methods have been well documented, the development of catalytic role in a cooperative manner through the generation of a doubly
asymmetric protocols for the direct and selective generation of ion-pairing intermediate, in which the remote anionic site of the
1Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya 464-8602, Japan, 2Department of Applied Chemistry, Graduate School
of Engineering, Nagoya University, Nagoya 464-8603, Japan. e-mail: tooi@apchem.nagoya-u.ac.jp
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1796
ARTICLES
a
b
d
δ+
C2
Ar1
Z–
C2
δ–
C1
–
+
C1
Me
+
N
Geometrically pure
tetrasubstituted alkene
Prochiral
trisubstituted carbons
Ar22P
Ar1
c
Discrimination of prochiral face
of trisubstituted alkene
–
N +
X–
[Pd]
+
Me
+
O
X
X
Z–
PdL
+
X–
X
O
[Pd]
P
+
PdL
Control of planar chirality
of π-allylpalladium
Racemic
Figure 1 | Overview of stereoselective construction of contiguous all-carbon quaternary stereocentres. a, Reaction of tetrasubstituted alkenes. b, Reaction
between prochiral trisubstituted carbon reagents. c, Concept of multiple absolute stereocontrol in palladium-catalysed cycloaddition for asymmetric
construction of contiguous stereocentres. d, Structure of chiral onium–phosphine hybrid ligand and proposed doubly ion-pairing intermediate.
zwitterionic constituent could be recognized by the chiral the use of a phosphine ligand incorporating a quaternary
ammonium ion moiety of the ligand coordinated to the cationic ammonium halide component, not only to assist the preferable
palladium centre. Here, we report the highly enantio- and diastereo- halide–palladium contact but also to recognize the anionic site via
selective construction of contiguous all-carbon quaternary stereo- facile pairing with the ammonium ion. Accordingly, the reaction
.
centres based on this strategy. Specifically, a palladium-catalysed with o-diphenylphosphinobenzylammonium bromide 1 Br,
a
asymmetric [3þ2] annulation reaction of 5-vinyloxazolizinones ligand recently developed in our laboratory32,33, was evaluated. As
and activated trisubstituted alkenes was developed, thereby offering anticipated, bond formation reached completion within 1 h, afford-
a reliable catalytic process for the asymmetric synthesis of densely ing 5 quantitatively (entry 3). Notably, replacement of the bromide
substituted pyrrolidines34–36
.
ion of the ligand by the acetate ion resulted in a substantial decrease
Results and discussion
Table 1 | Optimization of catalytic system for cycloaddition
of 5-vinyloxazolidinone 3 with benzylidenemalononitrile 4.
The studies initially focused on the development of an effective
ligand for promoting the palladium-catalysed asymmetric [3þ2]
cycloaddition. For this purpose, N-(4-nitrobenzenesulfonyl)-5,5-
divinyloxazolidin-2-one (3) and 2-benzylidenemalononitrile (4)
were selected as model substrates for the following reasons: (i)
these compounds can be readily prepared from a commercially
available glycine derivative and malononitrile, respectively; (ii) the
enantioselectivity of the cycloadduct would be a suitable parameter
for evaluating the ability of the chiral onium–phosphine hybrid
ligand to discriminate prochiral 4 in the conjugate addition of the
anionic site of the allylpalladium species generated from 3; (iii)
this transformation could provide straightforward access to optically
active, highly functionalized chiral pyrrolidines, which are ubiqui-
tous structural cores in biologically relevant natural products and
O
Ph
CN
CN
Pd2(dba)3·CHCl3
(Pd 2.5 mol%)
Ligand (5 mol%)
O
NosN
CN
NosN
+
Ph
CN
Toluene, r.t., 1 h
3
4
5
(Nos = 4-NO2C6H4SO2)
Ar1
Z–
2a·Z (Ar1 = Ar2 = Ph)
Me
2b·Z (Ar1 = β-Naph, Ar2 = Ph)
PPh2
NMe3
N
2c·Z (Ar1 = Ph, Ar2 = 4-CF3C6H4)
2d·Z (Ar1 = β-Naph, Ar2 = 4-CF3C6H4)
+
Z–
pharmaceuticals37–39
.
Ar22P
Ar1
1·Z
The reaction of 3 with 4 was first attempted under the influence
of the catalyst generated in situ from the tris(dibenzylideneacetone)-
dipalladium–chloroform complex [Pd2(dba)3 CHCl3] and triphe-
Entry
Ligand
Yield (%)*
e.e. (%)†
.
1
PPh3
PPh3
43
79
99
49
94
99
99
99
99
99
99
–
–
–
–
63
63
57
75
72
90
92
2‡
3
nylphosphine (PPh3) as a ligand in toluene at room temperature.
After stirring for 1 h, the desired N-protected pyrrolidine 5 was
obtained in moderate yield (Table 1, entry 1). This insufficient reac-
tivity was ascribed to the reluctant addition of the sulfonamide ion
moiety of the zwitterionic allylpalladium to 4, probably due to the
internal association of this weak nucleophile with the cationic palla-
dium centre. This unproductive interaction could be suppressed by
the addition of an external anion with strong coordinating affinity
for palladium such as a halide ion40, as previously observed by
Knight and Aggarwal in related reaction systems35,36. Indeed, in
the presence of a catalytic amount of tetrabutylammonium
bromide, the cycloaddition proceeded much faster under otherwise
identical conditions to give 5 in 79% yield (entry 2). This obser-
vation led us to envision further enhancement of the reactivity by
.
1 Br
.
4
5
6
7
8
9
10
11§
1 OAc
.
2a Br
.
2b Br
.
2c Br
.
2d Br
.
2d Cl
.
2d I
.
2d I
Unless otherwise noted, reactions were carried out with 0.10 mmol of 3 and 0.12 mmol of 4 in the
.
presence of Pd2(dba)3 CHCl3 (Pd, 2.5 mol%) and ligand (5 mol%) in 1.0 ml of toluene at room
temperature for 1 h. *Isolated yield. †Determined by high-performance liquid chromatography
(HPLC) analysis. ‡Performed with 5 mol% of tetrabutylammonium bromide (TBAB). §Carried out
at 0 8C for 3 h.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1796
ARTICLES
stereo-directing ability of the ligand. The use of the chloride
variant (2d Cl) subtly affected the selectivity (entry 9), whereas a
a
O
Ph
CN
CO2Et
Pd2(dba)3·CHCl3
(Pd 2.5 mol%)
2d·I (5 mol%)
.
O
NosN
CN
NosN
dramatic improvement in the enantioselectivity was achieved
.
+
Ph
when the counterion was substituted with iodide (2d I) (entry
Toluene
CO2Et
10). This correlation supports the claim that the halide ion
experiences intimate contact with positively charged palladium in
the transition state, and has a critical effect on stereocontrol
as well as the catalytic efficiency, in concert with the chiral
ammonium ion component, which is a distinctive feature of this
new chiral onium phosphine ligand. Finally, lowering the reaction
temperature to 0 8C allowed the quantitative isolation of 5 with
92% e.e. (entry 11).
0 °C, 24 h
3
6a (3 equiv.)
7
99% yield, d.r. = >20:1, 93% e.e.
b
O
CO2t-Bu
Pd2(dba)3·CHCl3
O
CO2t-Bu
(Pd 2.5 mol%)
NosN
CO2t-Bu
NosN
Me
2d·I (5 mol%)
Me
+
CO2t-Bu
Toluene
0 °C, 8 h
Having established the optimal ligand structure and reaction
conditions for realizing precise discrimination of prochiral alkene
4 in the cycloaddition, this catalytic system was extended to the
stereoselective construction of all-carbon quaternary stereocentres
using a trisubstituted alkene with different geminal substituents as
an electrophilic substrate. Thus, the reaction of oxazolidinone 3
with (E)-ethyl 2-cyano-3-phenylacrylate (6a) was conducted
under optimized conditions to furnish diastereomerically pure pyr-
rolidine 7 in quantitative yield with excellent enantioselectivity
10
99% yield, 94% e.e.
8a
Racemic
9 (3 equiv.)
Figure 2 | Examinations of individual absolute stereocontrol. a, Reaction to
generate an all-carbon quaternary stereocentre at the C3 position of
pyrrolidine. b, Reaction to generate an all-carbon quaternary stereocentre at
the C4 position of pyrrolidine.
.
in reactivity, giving credence to the postulate that the coordinating (Fig. 2a). The potential ability of ligand 2d I to control the planar
ability of the anion is crucial to the catalytic performance (entry chirality of p-allylpalladium through the p–s–p isomerization
.
4). Based on the prime efficacy of 1 Br as a ligand for promoting process was also evaluated by using racemic 5-methyl-5-vinyloxazo-
the zwitterionic allylpalladium-mediated cycloaddition, this ligand lidinone 8a in combination with 2-methylidenemalonate 9 for
was evolved into chiral ammonium phosphines with the capacity similar annulation. To our delight, this trial efficiently produced
for rigorous control of the absolute stereochemistry at the initial pyrrolidine 10 in a stereoconvergent manner with 94% e.e.
conjugate addition stage of the present system. This strategy (Fig. 2b). These data strongly suggest that chiral ammonium phos-
involved the introduction of a chiral 1,1′-binaphthyl-derived azepi- phine 2d I should pave the way to achieving individual yet simul-
.
nium skeleton41 into the ammonium ion component; the effective- taneous absolute stereocontrol during the plural bond-forming
′
.
ness of 2a Br, having simple phenyl appendages at the 3,3 -positions events involved in the palladium-catalysed asymmetric
of the binaphthyl unit (Ar1) as well as the phosphorus centre (Ar2), cycloaddition reaction.
was immediately evident, thus inducing an appreciable level of
On the basis of this prospect, the viability of the asymmetric
enantiocontrol on 5 without detrimental impact on the reactivity construction of contiguous all-carbon quaternary stereocentres via
profile (entries 5–8). The subsequent structural modifications of the [3þ2] annulations of racemic oxazolidinones 8 with trisubsti-
1
the aromatic substituents of 2 Br (Ar and Ar2) revealed that tuted alkenes 6 was assessed (Table 2). Subjection of oxazolidinone
.
.
.
2d Br was a promising candidate for further optimization. 8a and 2-cyano-3-phenylacrylate 6a to catalysis by Pd2(dba)3 CHCl3
Interestingly, the identity of the halide ion, a remaining structural and 2d I in toluene at 0 8C gave rise to the desired densely substi-
.
parameter to be varied, appeared to have a profound effect on the tuted pyrrolidine 11a in a stereochemically pure form (entry 1).
Table 2 | Asymmetric construction of contiguous all-carbon quaternary stereocentres through palladium-catalysed
cycloaddition.
O
R2
Pd2(dba)3·CHCl3
(Pd 2.5 mol%)
2d·I (5 mol%)
CN
CO2Et
O
NosN
CN
NosN
R1
R1
R2
+
CO2Et
Toluene
8
6
11
Racemic
Entry
R1
8
R2
6
Temperature
11
Yield (%)*
d.r.†
e.e. (%)‡
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Et
i-Bu
PhCH2
i-Pr
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
Ph
6a
6b
6c
6d
6e
6a
6a
6a
6a
6a
6a
6a
0 8C
0 8C
0 8C
0 8C
0 8C
0 8C
0 8C
0 8C
r.t.
11a
11b
11c
11d
11e
11f
11g
11h
11i
98
99
99
94
99
99
99
99
70
99
94
97
.20:1:,1:ND
17:1:,1:ND
98
97
99
99
97
98
99
95
94
93
94
95
4-Br-C6H4
4-MeO-C6H4
2-naphthyl
2-furyl
Ph
Ph
Ph
Ph
Ph
.20:1:,1:ND
.20:1:,1:ND
.20:1:,1:ND
.20:1:,1:ND
.20:1:,1:ND
.20:1:,1:ND
.20:1:,1:ND
9.8:1:,1:ND
8.6:1:,1:ND
9.3:1:,1:ND
9§
10
11
12
Ph
r.t.
r.t.
r.t.
11j
11k
11l
4-Cl-C6H4
4-MeO-C6H4
8g
8h
Ph
Ph
.
.
Unless otherwise noted, reactions were carried out with 0.10 mmol of 8 and 0.30 mmol of 6 in the presence of Pd2(dba)3 CHCl3 (Pd, 2.5 mol%) and 2d I (5 mol%) in 1.0 ml of toluene. For reaction time, see
Supplementary pages 11-14. *Isolated yield of the mixture of diastereomers. †Determined based on 1H NMR analysis of crude reaction mixture. ND, not detected. ‡Enantiomeric excesses of the major
diastereomer are indicated, which were analysed by chiral stationary-phase HPLC. Absolute configurations of 11a and 11j were confirmed by X-ray diffraction analysis, and the stereochemistries of other
examples were assumed by analogy. §Reaction was performed with Pd2(dba)3 CHCl3 (Pd, 5 mol%) and 2d I (10 mol%). r.t., room temperature.
.
.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1796
ARTICLES
O
Ph
with 4-methoxybenzylamine followed by the intramolecular
Mitsunobu reaction, furnishing 19 as an essentially single stereoisomer.
In conclusion, a highly enantio- and diastereoselective [3þ2]
annulation reaction of 5-vinyloxazolidinones and activated trisub-
stituted alkenes catalysed by a palladium complex bearing a newly
devised phosphine ligand with a chiral ammonium salt component
was developed, which allows for the single-step construction of three
contiguous stereocentres, including vicinal all-carbon quaternary
stereocentres, on the pyrrolidine core. This system relies heavily
on the remarkable ability of the chiral onium–phosphine hybrid
ligand to facilitate the intermolecular cycloaddition with precise
CO2Et
NO2
Me
Pd2(dba)3·CHCl3
(Pd 2.5 mol%)
O
NosN
NO2
CO2Et
NosN
Ligand (5 mol%)
Me
Ph
+
Toluene
8a
Racemic
12 (3 equiv.)
(E/Z = 1:2)
13
Ligand = 1·Br, r.t., 24 h
Ligand = 2d·I, 0 °C, 8 h
27% yield, d.r. = 5:8:3:1
99% yield, d.r. = 11:1.4:1:<1
95% e.e. (for major isomer)
Figure 3 | [312] cycloaddition of oxazolidinone and nitroacrylate. Chiral
.
ligand 2d I enabled multiple local stereocontrol in a [3þ2] cycloaddition
a
O
Ph
CN
CO2Et
Me
between oxazolidinone 8a and a nitroacrylate 12 (which was used as a
Pd2(dba)3·CHCl3
(Pd 0.5 mol%)
2d·I (1 mol%)
O
mixture of geometric isomers).
NosN
CN
NosN
Me
Ph
+
CO2Et
Toluene
0 °C, 48 h
99%
Parallel results were obtained with other 2-cyanoacrylates bearing
different aromatic or heteroaromatic substituents at their 3-pos-
itions (entries 2–5). This virtually complete stereocontrol was also
feasible in the cycloaddition between oxazolidinones 8 with
various 5-alkyl substituents, including branched variations, and 6a
(entries 6–9). Notwithstanding the requirement for a higher reac-
tion temperature, 5-aryl-substituted oxazolidinones were tolerated
with preservation of high levels of diastereo- and enantiocontrol
(entries 10–12).
The potential of the present strategy was further extended to
achieve multiple absolute stereocontrol in the reaction of 8a with
ethyl 2-nitro-3-phenylacrylate (12; E/Z ¼ 1:2) (Fig. 3). Exposure of
these substrates to similar conditions resulted in smooth cyclo-
addition to furnish the corresponding adduct 13 quantitatively
with high diastereoselectivity (11:1.4:1:,1) and excellent enantio-
selectivity (95% e.e.), despite the use of an isomeric mixture of 12.
The E/Z ratio of the remaining 12 was confirmed to be almost
unchanged. It is of fundamental importance to note that 13 was
obtained as a 5:8:3:1 mixture of the four diastereomers when the
reaction was implemented using achiral ammonium phosphine
8a
Racemic
3.1 g (10 mmol)
6a
11a
d.r. = >20:1:<1:ND, 95% e.e.
4.7 g (10 mmol)
b
Ph
Ph
Ph
CN
(ii) Cs2CO3
CN
CN
OH
OH
(i) DIBAL-H
n-C12H15SH
CO2Et
Me
HN
NosN
NosN
Me
Me
CH3CN
(64%)
CH2Cl2
(62%)
11a
14
15
d.r. = >20:1:<1:ND
98% e.e.
Ph
Ph
O
CN
CN
(iii) O3
then Me2S
(iv) DIBAL-H
THF
CO2Et
Me
NosN
NosN
O
(v) TFA
CH2Cl2
CH2Cl2
(97%)
CHO
16
Me
17
(95% for 2 steps)
.
1 Br as a ligand. These results clearly indicate that catalyst control
overrides the geometrical nature of the trisubstituted alkene, and
also demonstrate the inherent power of the chiral ammonium–phos-
phine hybrid ligand 2d I to enable efficient individual stereocontrol
Ph
O
(vii) DEAD
Ph3P
Ph
O
CN
CN
PMB
(vi) PMBNH2
.
N
NosN
N
PMB
NosN
H
CH3CN
(91%)
for the construction of the array of three contiguous chiral carbons in
this single annulation process (Supplementary Figs 2 and 3).
The synthetic versatility of the present catalytic system was next
demonstrated through a large-scale reaction and the product deriva-
tizations (Fig. 4). The reaction of 8a with 6a on a 10 mmol scale was
found to be completed in 48 h, even with a reduced amount of
catalyst, yielding 4.7 g of cycloadduct 11a without a notable decrease
in stereoselectivity (Fig. 4a). Cycloadduct 11 can be readily trans-
formed into N-unprotected pyrrolidines. For instance, the selective
reduction of the ethyl ester moiety of 11a by treatment with diiso-
butylaluminum hydride (DIBAL-H) and subsequent deprotection
of the 4-nitrobenzenesulfonyl (Nos) group42 under well-established
conditions afforded the corresponding pyrrolidine 15 (Fig. 4b). In
addition, 11a was successfully converted into the densely substituted
bicyclic lactam 19, which is the core structure of the analogue of
THF
(88%)
Me
Me
OH
19
18
d.r. = >20:1:<1:ND
98% e.e.
c
NH
H2N
O
O
O
N
R
R1
N
R2
thrombin inhibitors43–45. Thrombin is a key serine protease in the Figure 4 | Synthetic versatility of the present catalytic system. a, Scale-up
blood coagulation cascade, and a series of lactams with a tricyclic of the cycloaddition process. b, Derivatization of cycloaddition product 11a to
core have been developed as non-peptidic, high-affinity inhibitors unprotected pyrrolidine 15 and multi-substituted bicyclic lactam 19. Reagents
(Fig. 4c). The synthetic sequence from 11a depicted in Fig. 4b and conditions: (i) diisobutylaluminum hydride (DIBAL-H) (2 equiv.),
could offer access to the previously elusive analogues bearing carbo- CH2Cl2, 278 8C, 30 min then 0 8C, 1 h; (ii) Cs2CO3 (2 equiv.), n-C12H25SH
genic substituents at the core. Thus, ozonolysis of the vinyl function (2 equiv.), CH3CN, r.t., 4 h; (iii) O3, CH2Cl2, 278 8C, 10 min, then Me2S
in 11a led to the corresponding aldehyde 16. The formyl group of 16 (10 equiv.), 278 8C to r.t., 2 h; (iv) DIBAL-H (2 equiv.), THF, 278 8C, 2 h;
could be selectively reduced to the primary alcohol by treating with (v) trifluoroacetic acid (TFA)/CH2Cl2 ¼ 1:1, r.t., 7 h; (vi) 4-methoxybenzylamine
DIBAL-H in tetrahydrofuran (THF), and subsequent exposure to (PMBNH2) (2 equiv.), CH3CN, reflux, 6 h; (vii) diethyl azodicarboxylate
TFA gave the bicyclic lactone 17. Eventually, the transformation (DEAD) (1.1 equiv.), Ph3P (1.1 equiv.), THF, r.t., 10 h. c, R1 ¼ R2 ¼ H; known
of lactone to lactam was executed by the transient opening of 17 thrombin inhibitor. R1, R2 ¼ alkyl; previously elusive analogues.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1796
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26. Trost, B. M. & Silverman, S. M. Enantioselective construction of pyrrolidines by
palladium-catalyzed asymmetric [3þ2] cycloaddition of trimethylenemethane
with imines. J. Am. Chem. Soc. 134, 4941–4954 (2012).
control of the individual absolute stereochemistry across multiple
bond formation, and represents a reliable catalytic process for the
asymmetric synthesis of densely functionalized pyrrolidines and
their derivatives.
27. Shintani, R., Park, S., Shirozu, F., Murakami M. & Hayashi, T. Palladium-
catalyzed asymmetric decarboxylative lactamization of g-methylidene-d-
valerolactones with isocyanates: conversion of racemic lactones to
enantioenriched lactams. J. Am. Chem. Soc. 130, 16174–16175 (2008).
28. Trost, B. M., Lam, T. M. & Herbage, M. A. Regio- and enantioselective synthesis
of pyrrolidines bearing a quaternary center by palladium-catalyzed asymmetric
[3þ2] cycloaddition of trimethylenemethanes. J. Am. Chem. Soc. 135,
2459–2461 (2013).
Received 16 August 2013; accepted 11 October 2013;
published online 24 November 2013
References
1. Peterson, E. A. & Overman, L. E. Natural product synthesis special feature. Proc.
Natl Acad. Sci. USA 101, 11943–11948 (2004).
29. Trost, B. M., Morris, P. J. & Sprague, S. J. Palladium-catalyzed diastereo- and
enantioselective formal [3þ2]-cycloadditions of substituted vinylcyclopropanes.
J. Am. Chem. Soc. 134, 17823–17831 (2012).
2. Trost, B. M. & Jiang, C. Catalytic enantioselective construction of all-carbon
quaternary stereocenters. Synthesis 369–396 (2006).
30. Du, C., Li, L., Li, Y. & Xie, Z. Construction of two vicinal quaternary carbons
by asymmetric allylic alkylation: total synthesis of hyperolactone C and
(2)-biyouyanagin A. Angew. Chem. Int. Ed. 48, 7853–7856 (2009).
31. Trost, B. M. & Fandrick, D. R. Palladium-catalyzed dynamic kinetic asymmetric
allylic alkylation with the DPPBA ligands. Aldrichimica Acta 40, 59–72 (2007).
32. Ohmatsu, K., Ito, M., Kunieda, T. & Ooi, T. Ion-paired chiral ligands for
asymmetric palladium catalysis. Nature Chem. 4, 473–477 (2012).
33. Ohmatsu, K., Ito, M., Kunieda, T. & Ooi, T. Exploiting the modularity of ion-
paired chiral ligands for palladium-catalyzed enantioselective allylation of
benzofuran-2(3H)-ones. J. Am. Chem. Soc. 135, 590–593 (2013).
34. Aoyagi, K., Nakamura, H. & Yamamoto, Y. Palladium-catalyzed aminoallylation
of activated olefins with allylic halides and phthalimide. J. Org. Chem. 67,
5977–5980 (2002).
3. Hawner, C. & Alexakis, A. Metal-catalyzed asymmetric conjugate addition
reaction: formation of quaternary stereocenters. Chem. Commun. 46,
7295–7306 (2010).
4. Das, J. P. & Marek, I. Enantioselective synthesis of all-carbon quaternary
stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).
5. Mitsunuma, H., Shibasaki, M., Kanai, M. & Matsunaga, S. Catalytic asymmetric
total synthesis of chimonanthine, folicanthine, and calycanthine through double
Michael reaction of bisoxindole. Angew. Chem. Int. Ed. 51, 5217–5221 (2012).
6. Trost, B. M. & Osipov, M. Palladium-catalysed asymmetric construction of
vicinal all-carbon quaternary stereocenters and its application to the synthesis of
cyclotryptamine alkaloids. Angew. Chem. Int. Ed. 52, 9176–9181 (2013).
7. Flynn, A. B. & Ogilvie, W. W. Stereocontrolled synthesis of tetrasubstituted
olefins. Chem. Rev. 107, 4698–4745 (2007).
35. Knight, J. G., Stoker, P. A., Tchabanenko, K., Harwood, S. J. & Lawrie, K. W. M.
Synthesis of highly substituted pyrrolidines via palladium-catalyzed cyclization of
5-vinyloxazolidinones and activated alkenes. Tetrahedron 64, 3744–3750 (2008).
36. Lowe, M. A. et al. Palladium-mediated annulation of vinyl aziridines with
Michael acceptors: stereocontrolled synthesis of substituted pyrrolidines and its
application in a formal synthesis of (2)-a-kainic acid. Angew. Chem. Int. Ed. 50,
6370–6374 (2011).
8. Fish, P. V. & Johnson, W. S. The first examples of nonenzymic, biomimetic
polyene pentacyclizations. Total synthesis of the pentacyclic triterpenoid
sophoradiol. J. Org. Chem. 59, 2324–2335 (1994).
9. Corey, E. J. & Lin, S. A short enantioselective total synthesis of dammarenediol
II. J. Am. Chem. Soc. 118, 8765–8766 (1996).
10. Gilbert, J. C. & Selliah, R. D. Enantioselective synthesis of (2)-trichodiene.
J. Org. Chem. 58, 6255–6265 (1993).
37. O’Hagan, D. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids.
Nat. Prod. Rep. 17, 435–446 (2000).
38. Michael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep. 22,
603–626 (2005).
39. Blanco-Ania, D. et al. Synthesis of dihydrouracils spiro-fused to pyrrolidines:
druglike molecules based on the 2-arylethyl amine scaffold. Molecules 15,
2269–2301 (2010).
11. Lemieux, R. M. & Meyers, A. I. Asymmetric synthesis of (2)-trichodiene.
Generation of vicinal stereogenic quaternary centers via the thio-Claisen
rearrangement. J. Am. Chem. Soc. 120, 5453–5457 (1998).
12. Gu, Z., Herrmann, A. T., Stivala, C. E. & Zakarian, A. Stereoselective
construction of adjacent quaternary chiral centers by the Ireland–Claisen
rearrangement: stereoselection with esters of cyclic alcohols. Synlett.
1717–1722 (2010).
40. Fagnou, K. & Lautens, M. Halide effects in transition metal catalysis. Angew.
Chem. Int. Ed. 41, 26–47 (2002).
41. Ooi, T., Kameda, M. & Maruoka, K. Design of N-spiro C2-symmetric chiral
quaternary ammonium bromides as novel chiral phase-transfer catalysts:
synthesis and application to practical asymmetric synthesis of a-amino acids.
J. Am. Chem. Soc. 125, 5139–5151 (2003).
13. Shimizu, Y., Shi, S-L., Usuda, H., Kanai, M. & Shibasaki, M. Catalytic
asymmetric total synthesis of ent-hyperforin. Angew. Chem. Int. Ed. 49,
1103–1106 (2010).
14. Uyeda, C., Ro¨theli, A. R. & Jacobsen, E. N. Catalytic enantioselective Claisen
rearrangements of O-allyl b-ketoesters. Angew. Chem. Int. Ed. 49,
9753–9756 (2010).
42. Kan, T. & Fukuyama, T. Ns strategies: a highly versatile synthetic method for
amines. Chem. Commun. 353–359 (2004).
43. Scha¨rer, K., Morgenthaler, M., Seiler, P. & Diederich, F. Enantiomerically pure
thrombin inhibitors for exploring the molecular-recognition features of the
oxyanion hole. Helv. Chim. Acta 87, 2517–2538 (2004).
44. Fokkens, J. & Klebe, G. A simple protocol to estimate differences in protein
binding affinity for enantiomers without prior resolution of racemates. Angew.
Chem. Int. Ed. 45, 985–989 (2006).
45. Nicolotti, O. et al. Screening of benzamidine-based thrombin inhibitors via a
linear interaction energy in continuum electrostatics model. J. Comput. Aided
Mol. Des. 24, 117–129 (2010).
15. Stafford, J. A. & Heathcock, C. H. Daphniphyllum alkaloids. Part 8. Asymmetric
total synthesis of (2)-secodaphniphylline. J. Org. Chem. 55, 5433–5434 (1990).
16. Doyle, M. P., Zhou, Q-L., Charnsangavej, C. & Longoria, M. A. Chiral catalysts
for enantioselective intermolecular cyclopropanation reactions with methyl
phenyldiazoacetate. Origin of the solvent effect in reactions catalyzed by
homochiral dirhodium(II) prolinates. Tetrahedron Lett. 37, 4129–4132 (1996).
17. Gao, L., Hwang, G-S. & Ryu, D. H. Oxazaborolidinium ion-catalysed
cyclopropanation of a-substituted acroleins: enantioselective synthesis of
cyclopropanes bearing two chiral quaternary centers. J. Am. Chem. Soc. 133,
20708–20711 (2011).
18. Cao, Z-Y. et al. Highly stereoselective olefin cyclopropanation of diazooxindoles
catalyzed by a C2-symmetric spiroketal bisphosphine/Au(I) complex. J. Am.
Chem. Soc. 135, 8197–8200 (2013).
19. Payette, J. N. & Yamamoto, H. Regioselective and asymmetric Diels–Alder
reaction of 1- and 2-substituted cyclopentadienes catalysed by a Brønsted acid
activated chiral oxazaborolidine. J. Am. Chem. Soc. 129, 9536–9537 (2007).
20. Trost, B. M., Cramer, N. & Silverman, S. M. Enantioselective construction
of spirocyclic oxindolic cyclopentanes by palladium-catalyzed
trimethylenemethane-[3þ2]-cycloaddition. J. Am. Chem. Soc. 129,
12396–12397 (2007).
21. Zhang, H., Hong, L., Kang, H. & Wang, R. Construction of vicinal all-carbon
quaternary stereocenters by catalytic asymmetric alkylation reaction of
3-bromooxindoles with 3-substituted indoles: total synthesis of
(þ)-perophoramidine. J. Am. Chem. Soc. 135, 14098–14101 (2013).
22. Lautens, M., Klute, W. & Tam, W. Transition metal-mediated cycloaddition
reactions. Chem. Rev. 96, 49–92 (1996).
23. Fru¨hauf, H-W. Metal-assisted cycloaddition reactions in organotransition metal
chemistry. Chem. Rev. 97, 523–596 (1997).
24. Kobayashi, S. & Jorgensen, K. A. (eds) Cycloaddition Reactions in Organic
Synthesis (Wiley, 2002).
Acknowledgements
This paper is dedicated to Professor Keiji Maruoka on the occasion of his 60th birthday.
Financial support was provided by NEXT program, the Program for Leading Graduate
Schools ‘Integrative Graduate Education and Research Program in Green Natural Sciences’
in Nagoya University, and the Uehara Memorial Foundation.
Author contributions
K.O. and T.O. conceived and designed the study, and co-wrote the paper. K.O. and N.I.
performed the experiments, and analysed the data. All authors discussed the results and
commented on the manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to T.O.
25. Wang, C. & Tunge, J. A. Asymmetric cycloadditions of palladium-polarized
aza-o-xylylenes. J. Am. Chem. Soc. 130, 8118–8119 (2008).
Competing financial interests
The authors declare no competing financial interests.
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