Cyclohexyl-Fused, Spirobiindane-Derived, Phosphine-Catalyzed Synthesis of Tricyclic ?3-Lactams and Kinetic Resolution of ?3-Substituted Allenoates

Article abstract of DOI:10.1021/jacs.9b07418

A C₂-symmetric chiral phosphine catalyst, NUSIOC-Phos, which can be easily derived from cyclohexyl-fused spirobiindane, was introduced. A highly enantioselective domino process involving pyrrolidine-2,3-diones and γ-substituted allenoates catalyzed by NUSIOC-Phos has been disclosed. Diastereospecific tricyclic γ-lactams containing five contiguous stereogenic centers were obtained in high yields and with nearly perfect enantioselectivities. A kinetic resolution process of racemic γ-substituted allenoates was developed for the generation of optically enriched chiral allenoates.

Full text of DOI:10.1021/jacs.9b07418

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Article
A Cyclohexyl-Fused Spirobiindane-derived Phosphine-catalyzed Synthesis
of Tricyclic #-Lactams and Kinetic Resolution of #-Substituted Allenoates
Mingyue Wu, Zhaobin Han, Kaizhi Li, Ji'en Wu, Kuiling Ding, and Yixin Lu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07418 • Publication Date (Web): 23 Sep 2019
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Journal of the American Chemical Society
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A Cyclohexyl-Fused Spirobiindane-derived Phosphine-catalyzed
Synthesis of Tricyclic -Lactams and Kinetic Resolution of -
Substituted Allenoates
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†
‡
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,‡
,†,§,○
Mingyue Wu, Zhaobin Han, Kaizhi Li, Ji’en Wu, Kuiling Ding,* Yixin Lu*
†Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 345
Lingling Road, Shanghai, 200032, PR China
§
Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New
City, Fuzhou, Fujian, 359297, PR China
○
National University of Singapore (Suzhou) Research Institute, 377 Lin Quan Street, Suzhou Industrial Park, Suzhou, Jiangsu,
2
15123, PR China
2
ABSTRACT: A C -symmetric chiral phosphine catalyst, NUSIOC-Phos, which can be easily derived from cyclohexyl-fused spi-
robiindane was introduced. A highly enantioselective domino process involving pyrrolidine-2,3-diones and -substituted allenoates
catalyzed by NUSIOC-Phos has been disclosed. Diastereospecific tricyclic -lactams containing five contiguous stereogenic centers
were obtained in high yields and with nearly perfect enantioselectivities. A kinetic resolution process of racemic -substituted al-
lenoates was developed for the generation of optically enriched chiral allenoates.
spirobiindane-7,7’-diol (SPINOL) and its structural analogues
were shown by Zhou and co-workers to be tremendously pow-
INTRODUCTION
The field of asymmetric phosphine catalysis has progressed
remarkably in the past decade, primarily due to the introduc-
tion of novel chiral phosphine catalysts and discovery of new
erful in numerous transition-metal catalyzed asymmetric pro-
cesses. Subsequently, the Zhou group also employed a
6
SPINOL-derived monodentate spiro phosphine ligand (SITCP)
1
7
modes of activations in phosphine-catalyzed reactions. In the
in palladium-catalyzed asymmetric allylation reactions. The
past few years, we introduced a family of amino acid-based
bifunctional phosphines, and applied them to a variety of en-
antioselective transformations, including various cycloaddition
value of SITCP in enantioselective nucleophilic catalysis was
later amply demonstrated by the Fu group in -addition and
8
[4+1] annulation reactions. Currently, SPINOL derivatives
reactions,
-additions,
Michael
additions,
(aza)-
are mainly prepared via optical resolution using chiral resolv-
ing agents, with only one recent report in which Tan et al.
described a catalytic enantioselective synthesis of SPINOL.
Morita−Baylis−Hillman (MBH) reactions, and Rau-
hut−Currier (RC) reactions. As part of our continued interest
2
9
in broader applications of phosphine-catalyzed reactions, we
endeavour to design novel chiral phosphine catalysts to em-
power asymmetric phosphine catalysis to a greater height. We
set our goal to evolve novel chiral phosphines that would be
complementary to our existing amino acid-based phosphine
catalysts, thus offering us more dimensions for the discovery
of phosphine-mediated asymmetric catalytic reactions.
When the design of novel chiral phosphine catalysts is con-
cerned, one practical consideration is whether the chiral pre-
cursors can be readily accessed, which dictates the practicality
of eventual catalysts. We have long-standing interests in de-
veloping chiral spiro ligands, e.g. SpinPHOX and SKP, among
others, and we are particularly interested in practical prepara-
1
0
tion of privileged chiral ligands. Very recently, we disclosed
a scalable enantioselective one-pot synthesis of cyclohexyl-
fused spirobiindanes (>99% ee) in an overall yield of 67%,
The past few decades have seen marvelous development of
transition metal mediated asymmetric catalytic reactions, and
chiral ligands have played indispensable roles in asymmetric
1
1
which requires no chromatographic purification. Making full
use of practical aspects of this protocol, we decided to design a
3
induction. Chiral phosphine ligands are well recognized as
2
novel C -symmetric cyclohexyl-fused SPINOL-derivatized
one of the most important ligand classes, and therefore they
had been utilized directly or served as starting point for cata-
lyst derivatization in asymmetric phosphine catalysis. Binaph-
phosphine catalyst (Figure 1). The excellent performance of
cyclohexyl-fused SPINOL core in transition metal catalysis
suggests efficiency of such a structural motif in controlling
thyl-based C
2
-symmetric monodentate phosphines, first intro-
2
stereochemistry, thus the newly derivatized C -symmetric
duced in 1994 by Gladiali et al. for rhodium-catalyzed asym-
metric hydroformylation of styrene, were later established by
phosphine catalyst is anticipated to be effective in asymmetric
induction. Moreover, this rigid backbone of the monodentate
phosphine has two alkyl groups linked to the phosphorus atom,
4
Fu and co-workers as a class of highly efficient phosphine
5
catalysts. Another class of privileged ligands, 1,1-
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expecting to be highly nucleophilic, which is crucial for appli-
cations in phosphine catalysis.
lyst in excellent yield. This cyclohexyl-fused SPINOL-derived
2
C -symmetric phosphine is structurally novel, and we name it
NUSIOC-Phos.
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5
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7
8
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Scheme 1. Synthesis of NUSIOC-Phosa
Figure 1. A cyclohexyl-fused SPINOL-derived phosphine.
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In modern synthetic organic chemistry, efficient creation of
molecular complexity with good stereochemical control is a
long-standing challenge. For this to be placed in the context of
asymmetric phosphine catalysis, one needs to consider how
unknown reactions and novel modes of reaction can be
achieved by careful selection of substrates and catalysts. In our
on-going research in medicinal chemistry, we became interest-
ed in efficient asymmetric construction of -lactam-bearing
structural scaffolds. Polycyclic -lactams are often present in
bioactive molecules and natural products, and a few illustra-
a
Reaction conditions: (a) Tf
2
O, pyridine, CH
2 2
Cl , r.t., 99% yield; (b)
Pd(OAc)
2
(15 mol%), dppp (15 mol%), Et
3
N, MeOH, DMSO, CO (1 atm),
o
o
o
8
4 2
0 C, 72% yield. (c) LiAlH , THF, 0 C to 50 C, 99% yield. (d) SOCl ,
o o
2 2 2
pyridine, CH Cl , 0 C to RT, 92% yield. (e) PhPH , NaH, THF, -78 C to
reflux, 95% yield.
To construct polycyclic -lactam structural motifs, we chose
pyrrolidine-2,3-diones and -substituted allenes as potential
synthetic precursors. Despite the documentation of the synthe-
12
tive examples are shown in Figure 2. The existence of sever-
14
al stereogenic centers in a crowded -lactam skeleton buried in
multi-ring systems makes their synthesis highly challenging.
To date, catalytic enantioselective construction of fused spi-
sis of pyrrolidine-2,3-diones in 1953, their applications in
asymmetric catalysis were all very recent. Currently, in the
15
existing modes of reaction, the exo-double bond and 3-oxo
1
3
rotricyclic -lactams is unknown. Herein, we introduce a C
2
-
group of pyrrolidine-2,3-diones are involved in the bond form-
ing reactions, leading to the creation of fused or spiro -lactam
structures. Even though allenes are commonly employed sub-
strates in phosphine catalysis, the utilization of -substituted
symmetric cyclohexyl-fused SPINOL-derived phosphine
(NUSIOC-Phos) for the first time, which is shown to be a
powerful catalyst in promoting a domino process between -
substituted allenoates and pyrrolidine-2,3-diones, for highly
enantioselective construction of structurally novel tricyclic -
lactams. Moreover, with the employment of racemic-
substituted allenoates, a kinetic resolution process has been
developed, useful for the construction of optically enriched
chiral allenoates.
1
6
allenes is much less common. We envisioned that combining
pyrrolidine-2,3-diones and -substituted allenoates under
phosphine catalysis may provide a powerful synthetic ap-
proach to access structurally challenging polycyclic -lactam
scaffolds. Our hypothesis is illustrated in Figure 3. The nucle-
ophilic attack of the phosphine catalyst on a -substituted al-
lene creates an intermediate with three potential nucleophilic
sites at the - - and - positions for the subsequent transfor-
mations, highly desirable for generating molecular complexity.
It is noteworthy that the -carbon center of -substituted allen-
17
oates offers an extra site for potential proton transfer, adding
in another dimension for structural manipulation. The other
reaction partner, pyrrolidine-2,3-dione, possessing an existing
amide bond, ideal for subsequent elaboration to -lactam. The
existence of multiple electrophilic centers, i.e. C=O and C=C
moieties, looks to be highly suitable for domino processes
with appropriate nucleophilic reaction counterparts for the
creation of polycyclic ring systems.
Figure 2. Natural products containing polycyclic -lactam
scaffolds.
RESULTS AND DISCUSSION
Enantioselective Synthesis of Tricyclic -Lactams via an
NUSIOC-Phos-catalyzed Domino Process between -
Substituted Allenoates and Pyrrolidine-2,3-diones. We first
established synthetic route to prepare cyclohexyl-fused
SPINOL-derived phosphine catalyst. As outlined in Scheme 1,
optically pure cyclohexyl-fused SPINOL was converted into
the corresponding triflate in quantitative yield, which was then
subjected to esterification via reaction with methanol and car-
bon monoxide in the presence of Pd(OAc)
diester in good yield. Subsequent reduction with LiAlH
2
, affording the
, fol-
4
lowed by chlorination then furnished the advanced dichloride
intermediate. Finally, treatment of the dichloride with phe-
nylphosphine and sodium hydride formed the phosphine cata-
Figure 3. Our hypothesis: creation of polycyclic lactams via a
tandem process.
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Having the above reaction hypothesis and with NUSIOC-
1
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Phos in hand, the stage was set for testing the proposed
domino process, as well as evaluating the efficiency of the
new catalyst scaffold against many known chiral phosphines
in asymmetric induction. We chose the reaction between
pyrrolidine-2,3-dione 1a and -substituted allenoate 2a as a
model reaction to start our investigation, and the catalytic
effects of a broad range of phosphine catalysts were examined
(
Table 1). To our delight, a structurally novel tricyclic -
lactam product 3a was formed. We first examined our amino
acid-based bifunctional phosphines, which were found to be
ineffective, affording 3a in low yields and poor
enantioselectivities (entries 110). Further examination of
non-amino acid based chiral phosphine catalysts was then
followed. Commercially available mono-functional cyclic
phosphine 5k effectively catalyzed the reaction, but with
entry cat.
solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
MTBE
R
additive yield [%]b
ee [%]c
-30
-37
-37
-40
-28
-18
<5
0
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1
2
5a
5b
5c
5d
5e
5f
CHPh
CHPh
CHPh
2
2
2
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
PhOH
23
23
54
39
15
34
65
20
40
20
73
trace
trace
61
55
47
52
50
41
34
23
62
74
51
45
88
89
95
92
83
3
1
8
virtually no asymmetric induction (entry 11). HypPhos 5l
1
9
and bisphosphine Et-BPE 5m were discovered to be totally
ineffective (entries 12 and 13). (S)-BINAP 5n and mono-
phosphine MeO-MOP 5o effectively promoted the reaction,
4
CHPh2
CHPh2
2
0
5
however, the enantioselectivities were poor (entries 14 and 15).
The C -symmetric mono-phosphine catalysts proved to be the
2
final winners. While binaphthyl-based 5p afforded the desired
product with moderate enantioselectivity, SITCP 5q led to the
formation of 3a in high enantiomeric excess (entries 16 and
6
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
2
2
2
2
2
2
2
2
2
7
5g
5h
5i
8
-21
<5
2
17). We were excited to discover our newly designed C -
9
symmetric cyclohexyl-fused SPINOL-based phosphine 5r,
NUSIOC-Phos, was an excellent catalyst, affording tricyclic -
lactam 3a in 96% ee (entry 18). Compared with other allene
esters, allene 2a with a diphenylmethyl ester moiety was
optimal (entry 18 versus entries 1921). To further enhance
the results, we investigated the effects of adding various
Brønsted acid additives. The addition of phenol led to
improvement in both chemical yield and enantioselectivity
10
5j
40
1
1
5k
5l
<5
12
-
1
3
5m
-
14 5n
15 5o
16 5p
-19
<5
(entry 22). Finally, the addition of benzoic acid resulted in
further enhancement (entry 23). A solvent screening was then
carried out, and dioxane was identified as the solvent of choice
CHPh2
CHPh
CHPh
CHPh
Bn
2
2
2
51
(entries 2429). Under the optimized reaction conditions,
NUSIOC-Phos promoted the formation of tricyclic -lactam
3a in 92% yield and with >99% ee (entry 29).
1
7
5q
5r
5r
5r
5r
5r
5r
5r
5r
5r
5r
-91
96
18
19
20
Table 1. A Phosphine-catalyzed Domino Process between
a
94
Pyrrolidine-2,3-diones1aand-Substituted Allenoate 2a.
Me
95
2
1
tBu
94
22
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
2
2
2
2
2
2
2
97
2
3
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
2
2
2
2
2
2
H
H
H
H
H
H
98
24
98
2
5
CHCl
3
>99
>99
>99
>99
>99
>99
26
EtOAc
THF
2
7
28
5r 1,4-Dioxane CHPh
5r 1,4-Dioxane CHPh
30[e] 5r 1,4-Dioxane CHPh
2 [
9
d]
PhCO
PhCO
H
2
2
2
2
H
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a
ortho- or meta- substituent, as well as 1- or 2-naphthyl, were
Reactions were performed with 1a (0.05 mmol), 2a (0.065 mmol), addi-
tive (0.015 mmol) and the catalyst (0.01 mmol) in the solvent specified
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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2
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2
2
2
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3
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
all found to be suitable (4g4l). Interestingly, the reaction
worked for non-benzylic type -substituted allenoates; sub-
strate containing an ester rather than aryl group was found to
be excellent (4m). Surprisingly, when -ethyl- or propyl-
substituted allenoate was used, the corresponding product
could be obtained in moderate chemical yield and with >99%
ee, although 20 mol% catalyst loading, higher temperature and
longer reaction time were required (4n and 4o). Again, in all
the above examples, only one diastereisomer was formed.
b
c
(0.6 mL) at room temperature. Isolated yield. Determined by HPLC
analysis on a chiral stationary phase. 10% mmol 5r was used, reaction
time was 36 h. [e] The reaction was performed with 1a (0.2 mmol), 2a
(
d
0.26 mmol), and 5r (10 mol%) for 36 h.
Substrate Scope. With the established optimal reaction
conditions in hand, we then explored the reaction scope. A
wide range of pyrrolidine-2,3-diones 1 containing different
aromatic subtituents were examined for their reactions with
allenoate 2a, and results are summarized in Figure 4. The aryl
group in 1 was well tolerated, regardless of electronic nature
and substitution pattern of the aryl moieties of the pyrrolidine.
Furthermore, 5-piperonyl, 1-naphthyl-containing substrates
could also be utilized. In almost all the examples examined,
tricyclic -lactams 3 were produced in good chemical yields,
and with nearly perfect enantioselectivities (3a-3n). It is note-
worthy that only one diastereoisomer was obtained for all cas-
es, and the absolute configurations of products 3 were as-
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0
2
1
signed on the basis of X-ray crystallographic analysis of 3j.
Reactions were performed with 1a (0.05 mmol), 2‘ (0.065 mmol),
2
PhCO H (0.015 mmol) and NUSIOC-Phos (0.005 mmol) in 1,4-dioxane
(0.6 mL) at room temperature for 36 h; Yields given are isolated yields;
The ee values were determined by HPLC analysis on a chiral stationary
a
phase. Catalyst loading was 20 mol%, and the reactions were run in
o
PhCl/1,4-dioxane (v/v = 1:1) at 45 C for 72 h.
Figure 5. Utilizing different -substituted allenoates.
Kinetic Resolution of -Substituted Allenoates with
Pyrrolidine-2,3-diones. The axially chiral allenes are im-
portant substructures that often found in natural products and
2
2
bioactive molecules. Despite their importance, highly effi-
cient organocatalytic enantioselective synthesis of this class of
2
3
compounds is under-developed. There are only a handful of
examples in the literature on resolution methods that make use
of racemic allenes as starting materials to access chiral allenes.
While Trost and co-workers documented a palladium-
catalyzed dynamic kinetic asymmetric allylic alkylations of
2
4
Reactions were performed with 1 (0.05 mmol), 2a (0.065 mmol), PhCO
(
at room temperature for 36 hours; Yields given are isolated yields; The ee
values were determined by HPLC analysis on a chiral stationary phase; In
all cases, only one diastereisomer was observed.
2
H
allenes, enzymatic approaches for kinetic resolution and
parallel kinetic resolution of racemic allene alcohols and al-
lenenitriles were reported by Bäckvall and Wang, respective-
0.015 mmol) and NUSIOC-Phos (0.005 mmol) in 1,4-dioxane (0.6 mL)
2
5
ly. Gong and co-workers developed a kinetic resolution of
2
6
2
,3-allenoates via 1,3-dipolar cycloaddition, and Fu et al.
Figure 4. Employment of different pyrrolidine-2,3-diones.
observed kinetic resolution of racemic allenoates during their
5
c,5f,5h
investigations of phosphine-catalyzed -additions.
Hav-
We subsequently examined the reaction scope with regard to
-substituted allenoates 2’, and the results are summarized in
ing developed an efficient synthesis of tricyclic -lactams via
phosphine-triggered domino process, we were interested in
further evolving this tandem process to uncover an effective
method for the kinetic resolution of racemic allenes. As a fea-
sibility study, we reacted excess racemic allene 2a (0.05 mmol)
with pyrrolidine-2,3-dione 1a (0.03 mmol) in the presence of
NUSIOC-Phos. While tricyclic product 3a was obtained in 49%

Figure 5. The phenyl ring at the -benzylic position of alleno-
ates could be replaced by other aryls. The reaction tolerated
well with aryls containing different para-substituents, from
electron-donating to electron-withdrawing groups (4a4f).
Moreover, allenoates bearing an aryl moiety with either an
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yield and with 99% ee, chiral allene (R)-2a was isolated in 16%
The absolute configurations of resolved allenoates were as-
signed by comparison of the optical rotation of 2,3-allenoic
acid with that of authentic sample reported in literature.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
yield and with 55% ee (Table 2, entry 1). Even though the
level of asymmetric induction was less satisfactory, this result
indeed suggested the feasibility of establishing a synthetically
useful kinetic resolution strategy to access chiral allenes. In an
effort to enhance the resolution process, we tested other
Brønsted acid additives (entries 26). Among all the substitut-
ed benzoic acids and triphenylacetic acid examined, o-acetyl
2
8
2
7
benzoic acid was found to be the best (entry 4). Next, the
influence of solvent was evaluated (entries 711), and a mix-
ture of toluene and 1,4-dioxane proved to be a superior solvent
combination (entry 11). To our delight, when the molar ratio
of pyrrolidine-2,3-dione 1a to allene 2a was changed to 0.7,
under the optimal conditions, the chiral allene 2a was obtained
in 84% ee and with a 35% isolated yield (entry 12).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Kinetic Resolution of -Substituted Allenoate 2a
with Pyrrolidine-2,3-dione 1a Catalyzed by NUSIOC-
a
Phos.
b
(R)-2a (yieldb
/ee ) [%]
3
a (yield
c
entry solvent
additive
c
/ee ) [%]
1
2
3
4
5
6
7
8
9
1
1
1,4-Dioxane
PhCO
o-FC
o-ClC
o-AcC
Ph CCO
m-NO
2
H
3a (49/99)
3a (44/>99)
3a (43/>99)
3a (45/>99)
3a (42/>99)
3a (16/>99)
3a (41/99)
3a (28/99)
3a (42/99)
3a (34/99)
3a (43/>99)
(R)-2a (16/55)
(R)-2a (32/65)
(R)-2a (36/61)
(R)-2a (38/66)
(R)-2a (49/50)
(R)-2a (80/15)
(R)-2a (48/40)
(R)-2a (58/18)
(R)-2a (43/64)
(R)-2a (54/22)
(R)-2a (47/65)
Reactions were performed with 1a (0.035 mmol), (±)-2’ (0.05 mmol), o-
AcC CO H (0.01 mmol) and NUSIOC-Phos (0.005 mmol) in a mixture
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
EtOAc
6
H
4
CO
CO
CO
2
H
H
6 4
2
of 1,4-dioxane/toluene (v/v = 3/4, 0.7 mL) at room temperature; Yields
given are isolated yields; The ee values were determined by HPLC analy-
sis on a chiral stationary phase.
6
H
4
2
H
6
H
4
2
H
Figure 6. Kinetic resolution of -substituted allenoates 2’ with
pyrrolidine-2,3-dione 1a catalyzed by NUSIOC-Phos.
3
2
H
2 6 4 2
C H CO H
Proposed Reaction Mechanism and Mechanistic Investi-
gations. A plausible reaction mechanism is proposed in Figure
7. Phosphine attack on the -substituted allenoate creates zwit-
terionic intermediate Int-1, which may potentially react with
electrophiles at either - or - position. With the presence of -
substituent, a proton shift affords -anion Int-2, which adds to
pyrrolidine-2,3-dione in a 1,4-fashion to deliver A. Subsequent
proton shift, followed by an intramolecular addition to the
carbonyl group furnishes intermediate B. Another intramolec-
ular addition to double bond yields the tricyclic scaffold C.
Proton shift, followed by the regeneration of phosphine cata-
lyst then forms the final tricyclic -lactam product.
o-AcC
o-AcC
o-AcC
o-AcC
o-AcC
6
H
4
4
4
4
4
CO
CO
CO
CO
CO
2
2
2
2
2
H
CHCl
3
6
H
6
H
6
H
6
H
H
H
H
H
Toluene
THF
0
1
1,4Dioxane/
Toluene = 3/4
12d 1,4dioxane/
PhMe = 3/4
o-AcC
H
4
CO
H
3a (51/>99)
(R)-2a (35/84)
6
2
a
Reactions were performed with 1a (0.03 mmol), 2a (0.05 mmol), additive
(0.01 mmol) and NUSIOC-Phos (0.005 mmol) in the solvent specified
The phosphorus species involved during the course of the
b
c
31
29
(0.7 mL) at room temperature for 48 h. Isolated yield. The ee values
were determined by HPLC analysis on a chiral stationary phase. 0.035
reaction were investigated by P NMR spectroscopy.
d
NUSIOC-Phos has a resonance at -13.6 ppm, and mixing of
allenoate 2a with NUSIOC-Phos resulted in the formation of a
new resonance of 30.6 ppm corresponding the zwitterionic
intermediate, and the resonance at -13.6 ppm completely dis-
mmol of 1a was used, 61 h; S = 6.5.
This interesting kinetic resolution process was applicable to
various racemic allenoates (Figure 6). Regardless of the elec-
tronic nature and substitution pattern of substituent in the aryl
moiety of the -aryl methyl substituted allenoates, the resolved
allenoates were obtained in decent yields and with good enan-
tioselectivities. Moreover, the allene bearing a 1-naphtyl group
at the -position was also well tolerated for the resolution.
Notably, in all the above reactions, the tricyclic -lactams were
obtained in good yields and with excellent enantioselectivities.
3
1
appeared. P NMR monitoring of the reaction progress
showed that there was only one resonance at 30.6 ppm in the
early stage, and an additional peak at 29.6 was observed when
31
the P NMR measurement of reaction mixture was taken at 18
h. These results suggested that the resting state of NUSIOC-
Phos is the zwitterionic intermediate (Int-1/Int-2 in Figure 7),
and the addition of which to pyrrolidine-2,3-dione 1 appears to
be turnover limiting step.
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fer steps and the anion formation described in the reaction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pathways. Interestingly, when 1a was reacted with equal
amounts of allenoate 2a and deuterated 2a-D, around half of
the deuterium incorporation was observed (eq. 3 vs eq. 2),
indicating that both deuterated and non-deuterated allenoates
have similar reactivities. Moreover, when the reaction employ-
ing 2a was compared with that of utilizing deuterated 2a-D,
virtually same rates were observed (Figure 8). Taken together,
evidences gathered so far support that the rate-determining
step for our domino process is the addition of zwitterionic
intermediate to pyrrolidine-2,3-dione, and the absence of ki-
netic isotope effects suggests that the proton transfer step (a, b,
or c) is not rate-determining.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The proposed mechanism explains the different reactivities
of various -substituted allenoates in this domino process.
Most substrates bearing an aryl substituent at the -position
displayed good reactivity, since the -anion of Int-2 is well
stabilized by the neighbouring aryl moiety through delocaliza-
tion. Along the same line of reasoning, it is not surprising that
Figure 7. Proposed mechanism.

-alkyl substituted allenoates (Scheme 3, 4n & 4o) showed
lower reactivity in the reaction. Moreover, the high reactivity
of -ester substituted allene 4m is anticipated due to the effi-
cient stabilization of -anion by the adjacent ester group.
The above mechanistic proposal also provides the ground for
better understanding of kinetic resolution of allenoates. We
believe that the addition rates of phosphine catalyst to differ-
ent stereoisomers of starting racemic allenoates are different,
resulting in the observed kinetic resolution. The extremely
high enantiomeric purity of the tricyclic -lactam products,
together with the relatively low enantiomeric purity of the
recovered allenoates, suggest that the afore-described resolu-
tion process is an atypical kinetic resolution; the resolution of
allenoates is achieved at the initial phosphine attack on the
racemic allenoates, and the enantiomeric purities of the tricy-
clic products are determined by separate and distinct enantio-
meric differentiating steps in the tandem process. A couple of
additional experiments were performed. When the resolved
optically enriched slow-reacting allene was reacted with pyr-
rolidine-2,3-dione 1a, a much slower reaction was observed,
and the tricyclic -lactam was formed only in moderate yield,
but with the same level of enantioselectivity (eq. 4). These
results are in good agreement with our mechanistic proposal;
the different enantiomers of racemic allenoates are of no con-
sequence to the enantiomeric purity of tricyclic tandem prod-
ucts, since the same zwitterionic intermediate is created and
the enantiomeric determining step for -lactam products lies in
the subsequent tandem reaction. We next reacted excess race-
mic allene 2a with 2-benzylidene-1H-indene-1,3(2H)-dione 5,
3a (%)
25
20
1
5
0
5
0
2
2
a-D
a-H
1
T [min]
0
20
40
60
80
Figure 8. Conversions of 3a with the Employment of Alleno-
ates 2a-D and 2a-H.
We have also carried out deuterium-labeling experiments to
3
0
gain further insights into the reaction mechanism. In the
presence of D O, reaction performed under otherwise identical
2
conditions led to the formation of product with deuterium in-
corporated (eq. 1). When the deuterated allenoate 2a-D was
employed, deuterium incorporation into the product was ob-
served (eq. 2), both experiments are consistent to proton trans-
[
31]
while the [4 + 2] annulation product 6 was obtained with
low enantiomeric excess, the chiral allene 2a was however
obtained with good ee value (eq. 5). It is again proved that the
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Journal of the American Chemical Society
efficiency of the resolution process is determined at the stage
Ye, L.-W.; Zhou, J.; Tang, Y. Phosphine-triggered synthesis of
functionalized cyclic compounds. Chem. Soc. Rev. 2008, 37, 1140-
152. (c) Cowen, B. J.; Miller, S. J. Enantioselective catalysis and
complexity generation from allenoates. Chem. Soc. Rev. 2009, 38,
102-3116. (d) Basavaiah, D. B.; Reddy, S.; Badsara, S. S. Recent
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of initial phosphine addition to the racemic allenoates: chiral
allene could be well resolved (71% ee), even though the sub-
sequent [4 + 2] cycloaddition proceeded with low enantiose-
lectivity.
1
3
Contributions from the Baylis−Hillman Reaction to Organic
Chemistry. Chem. Rev. 2010, 110, 5447-5674. (e) Wang, S.-X.; Han,
X.; Zhong, F.; Wang, Y.; Lu, Y. Novel Amino Acid Based
Bifunctional Chiral Phosphines. Synlett 2011, 2766-2778. (f) Fan, Y.
C.; Kwon, O. Advances in nucleophilic phosphine catalysis of
alkenes, allenes, alkynes, and MBHADs. Chem. Commun. 2013, 49,
11588-11619. (g) Wei, Y.; Shi, M. Applications of Chiral Phosphine-
Based Organocatalysts in Catalytic Asymmetric Reactions. Chem.
Asian J. 2014, 9, 2720-2734. (h) Li, W.; Zhang, J. Recent
developments in the synthesis and utilization of chiral β-
aminophosphine derivatives as catalysts or ligands. Chem. Soc. Rev.
2016, 45, 1657-1677. (i) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu,
Y. Amino Acid-Derived Bifunctional Phosphines for Enantioselective
Transformations. Acc. Chem. Res. 2016, 49, 1369-1378. (j) Ni, H.;
Chan, W.-L.; Lu, Y. Phosphine-Catalyzed Asymmetric Organic
Reactions. Chem. Rev. 2018, 118, 9344-9411. (k) Guo, H.; Fan, Y.;
Sun, Z.; Wu, Y.; Kwon, O. Phosphine Organocatalysis. Chem. Rev.
2018, 118, 10049-10293.
CONCLUSION
In summary, we have introduced NUSIOC-Phos as a novel
C -symmetric chiral phosphine catalyst, which can be readily
2
derived from cyclohexyl-fused spirobiindane. An enantiose-
lective domino reaction between pyrrolidine-2,3-diones and -
substituted allenoates has been developed. In the presence of
NUSIOC-Phos, tricyclic -lactam products containing five
contiguous stereogenic centers were obtained in high chemical
yields and with nearly perfect enantioselectivities, and in a
diastereospecific manner. We also showed that kinetic resolu-
tion of racemic -substituted allenoates led to the formation of
optically enriched allenes. We believe that synthetic method-
ology disclosed herein opens up a new avenue for efficient and
economical access to polycyclic -lactams and similar struc-
tural motifs, important in natural products and bioactive mole-
cules. NUSIOC-Phos possesses excellent nucleophilicity and
has been shown to be superb in stereochemical control. Cur-
rently, we are evaluating NUSIOC-Phos for a broad spectrum
applications in phosphine catalysis and transition metal cataly-
sis. Moreover, based on our current findings on the kinetic
resolution of allenes, we are confident that judicious selection
of chiral phosphine catalysts and careful manipulation of the
racemic allene structures will lead to the discovery of a simple
and efficient resolution method, and this work is ongoing.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2) For our recent examples, see: (a) Jin, Z.; Ni, H.; Zhou, B.; Zheng,
W.; Lu, Y. Phosphine-CatalyzedFormal Oxa-[4+2] Annulation
Employing Nitroethylene and Enones: Enantioselective Synthesis of
Dihydropyrans. Org. Lett. 2018, 20, 5515−5518. (b) Li, K.; Jin, Z.;
Chan, W.-L.; Lu, Y. Enantioselective Construction of Bicyclic Pyran
and Hydrindane Scaffolds via Intramolecular Rauhut–Currier
Reactions Catalyzed by Thiourea-Phosphines. ACS Catal. 2018, 8,
8
810-8815. (c) Ni, H.; Tang, X.; Zheng, W.; Yao, W.; Ullah, N.; Lu,
Y. Enantioselective Phosphine-Catalyzed Formal [4+4] Annulation of
α, β-Unsaturated Imines and Allene Ketones: Construction of Eight-
Membered Rings. Angew. Chem., Int. Ed. 2017, 56, 14222-14226. (d)
Yao, W.; Yu, Z.; Wen, S.; Ni, H.; Ullah, N.; Lan, Y.; Lu, Y. Chiral
phosphine-mediated intramolecular [3+2] annulation: enhanced
enantioselectivity by achiral Brønsted acid. Chem. Sci. 2017, 8, 5196-
ASSOCIATED CONTENT
Supporting Information
5
200. (e) Wang, Z.; Xu, H.; Su, Q.; Hu, P.; Shao, P.-L.; He, Y.; Lu,
Y. Enantioselective Synthesis of Tetrahydropyridines/Piperidines via
Stepwise [4+2]/[2+2] Cyclizations. Org. Lett. 2017, 19, 3111-3114.
Experimental procedure, optimization tables, characterization data
for all the products (PDF).
(
f) Wang, Z.; Wang, T.; Yao, W.; Lu, Y. Phosphine-Catalyzed
Enantioselective [4+2] Annulation of o-Quinone Methides with
Allene Ketones. Org. Lett. 2017, 19, 4126-4129. (g) Ni, H.; Yu, Z.;
Lan, Y.; Ullah, N.; Lu, Y. Catalyst-controlled regioselectivity in
phosphine catalysis: the synthesis of spirocyclic benzofuranones via
regiodivergent [3+2] annulations of aurones and an allenoate. Chem.
Sci. 2017, 8, 5699-5704.
Crystallographic structure of 3j (CIF)
AUTHOR INFORMATION
Corresponding Authors
(
3) (a) Zhu, S.-F.; Zhou, Q.-L. Chiral Spiro Ligands, in Privileged
*E-mail: chmlyx@nus.edu.sg.
Chiral Ligands and Catalysts; Q.-L. Zhou, Ed.; Wiley-VCH: Wein-
heim, 2011; pp 137−170. (b) Carroll, M. P.; Guiry, P. J. P,N ligands
in asymmetric catalysis. Chem. Soc. Rev. 2014, 43, 819-833. (c)
Teichert, J. F.; Feringa, B. L. Phosphoramidites: Privileged Ligands in
Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49, 2486-2528.
*E-mail: kding@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interests.
(
d) Gennari, C.; Piarulli, U. Combinatorial Libraries of Chiral Ligands
ACKNOWLEDGMENTS
for Enantioselective Catalysis. Chem. Rev. 2003, 103, 3071-3100.
(4) Gladiali, S.; Dore, A.; Fabbri, D.; Lucchi, O. D.; Manassero, M.
Novel atropisomeric phosphorus ligands: 4,5-dihydro-3H-
dinaphtho[2,1-c;1’, 2-e]phosphepine derivatives. Tetrahedron
Asymmetry 1994, 5, 511-514.
Y.L. thanks the Singapore National Research Foundation (NRF)
for the NRF Investigatorship Award (R-143-000-A15-281), the
National University of Singapore (R-143-000-695-114 and C-
(
5) (a) Wurz, R. P.; Fu, G. C. Catalytic Asymmetric Synthesis of
1
41-000-092-001), and the National Natural Science Foundation
Piperidine Derivatives through the [4+2] Annulation of Imines with
Allenes. J. Am. Chem. Soc. 2005, 127, 12234-12235. (b) Wilson, J. E.;
Fu, G. C. Synthesis of Functionalized Cyclopentenes through Catalyt-
ic Asymmetric [3+2] Cycloadditions of Allenes with Enones. Angew.
Chem., Int. Ed. 2006, 45, 1426-1429. (c) Sinisi, R.; Sun, J.; Fu, G. C.
Phosphine-catalyzed Asymmetric Additions of Malonate Esters to -
Substituted Allenoates and Allenamides, Proc. Natl. Acad. Sci. USA
2010, 107, 20652-20654. (d) Smith, S. W.; Fu, G. C. Asymmetric
Carbon−Carbon Bond Formation γ to a Carbonyl Group: Phosphine-
Catalyzed Addition of Nitromethane to Allenes. J. Am. Chem. Soc.
of China (21672158) for generous financial support. K.D. thanks
NSFC (21790333) and CAS (QYZDY-SSW-SLH012,
XDB20000000) for generous financial support.
REFERENCES
(
1) For selected reviews on phosphine catalysis, see: (a) Lu, X.;
Zhang, C.; Xu, Z. Reactions of electron-deficient alkynes and allenes
under phosphine catalysis. Acc. Chem. Res. 2001, 34, 535-544. (b)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
2
011, 131, 14231-14233. (e) Fujiwara, Y.; Fu, G. C. Application of a
(10) (a) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Catalytic Asymmetric
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
New Chiral Phosphepine to the Catalytic Asymmetric Synthesis of
Highly Functionalized Cyclopentenes That Bear an Array of Heteroa-
tom-Substituted Quaternary Stereocenters. J. Am. Chem. Soc. 2011,
Synthesis of Aromatic Spiroketals by SpinPhox/Iridium(I)-Catalyzed
Hydrogenation and Spiroketalization of ,’-Bis(2-hydroxyarylidene)
Ketones. Angew. Chem., Int. Ed. 2012, 51, 936-940. (b) Wang, X.;
Meng, F.; Wang, Y.; Han, Z.; Chen, Y. J.; Liu, L.; Wang, Z.; Ding, K.
Aromatic Spiroketal Bisphosphine Ligands: Palladium-Catalyzed
Asymmetric Allylic Amination of Racemic Morita–Baylis-Hillman
Adducts. Angew. Chem., Int. Ed. 2012, 51, 9276-9282. (c) Han, Z.;
Wang, Z.; Zhang, X.; Ding, K. Spiro [4, 4]-1, 6-nonadiene-Based
Phosphine-Oxazoline Ligands for Iridium-Catalyzed Enantioselective
Hydrogenation of Ketimines Angew. Chem., Int. Ed. 2009, 48, 5345-
5349. (d) Wang, X.; Guo, P.; Wang, X.; Wang, Z.; Ding, K. Practical
asymmetric catalytic synthesis of spiroketals and chiral diphosphine
ligands. Adv. Synth. Catal. 2013, 355, 2900-2907.
(11) Zheng, Z.; Cao, Y.; Chong, Q.; Han, Z.; Ding, J.; Luo, C.; Wang,
Z.; Zhu, D.; Zhou, Q.-L. Ding, K. Chiral Cyclohexyl-Fused
Spirobiindanes: Practical Synthesis, Ligand Development, and
Asymmetric Catalysis. J. Am. Chem. Soc. 2018, 140, 10374-10381.
For patent application: Ding, K.; Cao, Y.; Zheng, Z.; Chong, Q.;
Wang, Z. CN 2015-10438450; WO 2016-CN109383.
(12) (a) Deng, J.; Zhu, B.; Lu, Z.; Yu, H.; Li, A. Total Synthesis of
(−)-Fusarisetin A and Reassignment of the Absolute Configuration of
Its Natural Counterpart. J. Am. Chem. Soc. 2012, 134, 920-923. (b)
Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.; Zhang,
X.-M.; Ma, Y.-B. Isatisine A, a Novel Alkaloid with an Unprecedent-
ed Skeleton from Leaves of Isatis indigotica. Org. Lett. 2007, 9, 4127-
4129. (c) Nay, B.; Riache, N.; Evanno, L. Chemistry and biology of
non-tetramic γ-hydroxy-γ-lactams and γ-alkylidene-γ-lactams from
natural sources. Nat. Prod. Rep. 2009, 26, 1044-1062. (d) Caro-Diaz,
E. J. E.; Aung, A.; Xu, J.; Varghese, S.; Theodorakis, E. A. Fusari-
setins: structure–function studies on a novel class of cell migration
inhibitors. Org. Chem. Front. 2014, 1, 135-139.
1
33, 12293-12297. (f) Fujiwara, Y.; Sun, J.; Fu, G. C. Enantioselctive
Carbon-Sulfur Bond Formation:  Additions of Aryl Thiols to Alleno-
ates Catalyzed by a Chiral Phosphepine, Chem. Sci. 2011, 2, 2196-
2198. (g) Lee, S. Y.; Fujiwara, Y. Nishiguchi, A. Kalek, M. Fu, G. C.
Phosphine-Catalyzed
Annulations To Generate Fused Ring Systems. J. Am. Chem. Soc.
015, 137, 4587-4591. (h) Kalek, M.; Fu, G. C. Phosphine-Catalyzed
Enantioselective
Intramolecular
[3+2]
2
Doubly Stereoconvergent γ‑Additions of Racemic Heterocycles to
Racemic Allenoates: The Catalytic Enantioselective Synthesis of
Protected α,α-Disubstituted α‑Amino Acid Derivatives. J. Am. Chem.
Soc. 2015, 137, 9438-9442.
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2
3
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5
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7
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9
0
(
6) (a) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H. Wang, L.-X.; Zhou, Q.-
L. Monodentate Chiral Spiro Phosphoramidites: Efficient Ligands for
Rhodium-Catalyzed Enantioselective Hydrogenation of Enamides.
Angew. Chem., Int. Ed. 2002, 41, 2348-2350. (b) Xie, J.-H.; Wang,
L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan, H.-F.; Zhou, Q.-L.
Synthesis of spiro diphosphines and their application in asymmetric
hydrogenation of ketones. J. Am. Chem. Soc. 2003, 125, 4404-4405.
(
c) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S;. Zhou, Q.-L. Well-
Defined Chiral Spiro Iridium/Phosphine−Oxazoline Cationic Com-
plexes for Highly Enantioselective Hydrogenation of Imines at Ambi-
ent Pressure. J. Am. Chem. Soc. 2006, 128, 12886-12891. (d) Xie, J.-
B.; Xie, J.-H.; Liu, X.-Y.; Kong, W.-L.; Li, S.; Zhou, Q.-L. Highly
enantioselective hydrogenation of α-arylmethylene cycloalkanones
catalyzed by iridium complexes of chiral spiro aminophosphine lig-
ands. J. Am. Chem. Soc. 2010, 132, 4538-4539. (e) Xu, B.; Zhu, S.-F.;
Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L. Asymmetric N-H Insertion Reac-
tion Cooperatively Catalyzed by Rhodium and Chiral Spiro Phosphor-
ic Acids. Angew. Chem., Int. Ed. 2011, 50, 11483-11486. (f) Zhu, S.-
F.; Xu, B.; Wang, G.-P.; Zhou, Q.-L. Well-defined binuclear chiral
spiro copper catalysts for enantioselective N-H insertion. J. Am. Chem.
Soc. 2012, 134, 436-442. (g) Cheng, Q.-Q.; Zhu, S.-F.; Zhang, Y.-Z.;
Xie, X.-L.; Zhou, Q.-L. Copper-Catalyzed B–H Bond Insertion Reac-
tion: A Highly Efficient and Enantioselective C–B Bond-Forming
Reaction with Amine–Borane and Phosphine–Borane Adducts. J. Am.
Chem. Soc. 2013,135, 14094-14097. (h) Xu, B.; Li, M.-L.; Zuo, X.-D.;
Zhu, S.-F.; Zhou, Q.-L. Catalytic asymmetric arylation of α-aryl-α-
diazoacetates with aniline derivatives. J. Am. Chem. Soc. 2015, 137,
8700-8703. (i) Xiao, L.-J.; Fu, X.-N.; Zhou, M.-J.; Xie, J.-H.; Wang,
L.-X.; Xu, X.-F.; Zhou, Q.-L. Nickel-Catalyzed Hydroacylation of
Styrenes with Simple Aldehydes: Reaction Development and Mecha-
nistic Insights. J. Am. Chem. Soc. 2016, 138, 2957-2960.
(13) For the systhesis of spirobicyclic -lactams, see: (a) Xing, J.; Lei,
Y.; Gao, Y.-N.; Shi, M. PPh
1C,3N-Bisnucleophiles Derived from Secondary β-Ketoamides with
δ-Acetoxy Allenoate: Route to Functionalized Spiro N-
3
-Catalyzed [3+2] Spiroannulation of
A
Heterocyclic Derivatives. Org Lett. 2017, 19, 2382-2385. (b) Huang,
L.; Lin, J.-S.; Tan, B.; Liu, X.-Y. Alkene Trifluoromethylation-
Initiated Remote α-Azidation of Carbonyl Compounds toward
Trifluoromethyl γ-Lactam and Spirobenzofuranone-Lactam. ACS
Catal. 2015, 5, 2826-2831. (c) Sivamuthuraman, K.;
Kumarswamyreddy, N.; Kesavan. V. Diastereo-and Enantioselective
Synthesis of 2, 2-Disubstituted Benzofuran-3-one Bearing Adjacent
Quaternary and Tertiary Stereocenters. J. Org. Chem. 2017, 82,
10812-10822. (d) Steinhardt, S. E.; Vanderwal, C. D. Complex
polycyclic lactams from pericyclic cascade reactions of Zincke
aldehydes. J. Am. Chem. Soc. 2009, 131, 7546-7547.
(14) (a) Southwick, P. L.; Crouch, R. T. The Condensation of Oxalic
Esters with Esters of β-Alanine and N-Substituted β-Aminopropionic
Acids. Synthesis of Some Derivatives of 2,3-Dioxopyrrolidine and 2-
Oxo-3-methoxy-3-pyrroline. J. Am. Chem. Soc. 1953, 75, 3413-3417.
(b) Southwick, P. L.; Barnas, E. F. 4-Benzylidine-2,3-
dioxopyrrolidines and 4-Benzyl-2,3-dioxopyrrolidines. Synthesis and
Experiments on Reduction and Alkylation. J. Org. Chem. 1962, 27,
98-106.
(15) (a) Li, J.-L.; Fu, L.; Wu, J.; Yang, K.-C.; Li, Q.-Z.; Gou, X.-J.;
Peng, C.; Han, B.; Shen, X.-D. Highly enantioselective synthesis of
fused bicyclic dihydropyranones via low-loading N-heterocyclic
carbene organocatalysis. Chem. Commun. 2017, 53, 6875-6878. b) Li,
Q.; Zhou, L.; Shen, X.-D. Yang, K.-C.; Zhang, X.; Dai, Q.-S.; Leng,
H.-J.; Li, Q.-Z.; Li, J.-L. Stereoselective Construction of Halogenated
Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2]
Cycloaddition of -Haloaldehydes. Angew. Chem., Int. Ed. 2018, 57,
1913-1917. (c) Li, J.-L.; Yang, K.-C.; Li, Y.; Li, Q.; Zhu, H.-P.; Han,
B.; Peng, C.; Zhi, Y.-G.; Gou, X.-J. Asymmetric synthesis of bicyclic
dihydropyrans via organocatalytic inverse-electron-demand oxo-
Diels–Alder reactions of enolizable aliphatic aldehydes. Chem.
Commun. 2016, 52, 10617-10620. (d) Hu, X.; Zhou, Y.; Lu, Y.; Zou,
S.; Lin, L.; Liu, X.; Feng, X. Catalytic Asymmetric Inverse-Electron-
(
7) (a) Zhu, S.-F.; Yang, Y.; Wang, L.-X.; Liu, B.; Zhou, Q.-L.
Synthesis and application of chiral spiro phospholane ligand in Pd-
catalyzed asymmetric allylation of aldehydes with allylic alcohols.
Org Lett. 2005, 7, 2333-2335. (b) Zhang, W.; Zhu, S.-F.; Qiao, X.-C.;
Zhou, Q.-L. Highly Enantioselective Copper-Catalyzed Ring Opening
of Oxabicyclic Alkenes with Grignard Reagents. Chem. Asian J. 2008,
3
, 2105-2111.
(
8) (a) Chung, Y. K.; Fu, G. C. Phosphine-Catalyzed Enantioselective
Synthesis of Oxygen Heterocycles. Angew. Chem., Int. Ed. 2009, 48,
2225-2227. (b) Lundgren, R. J.; Wilsily, A.; Marion, N.; Ma, C.;
Chung, Y. K.; Fu, G. C. Catalytic Asymmetric C-N Bond Formation:
Phosphine-Catalyzed Intra- and Intermolecular γ-Addition of Nitro-
gen Nucleophiles to Allenoates and Alkynoates. Angew. Chem., Int.
Ed. 2013, 52, 2525-2527. (c) Kramer, S.; Fu, G. C. Use of a new
spirophosphine to achieve catalytic enantioselective [4+1] annulations
of amines with allenes to generate dihydropyrroles, J. Am. Chem.
Soc. 2015, 137, 3803-3806. （d) Ziegler, D. T.； Fu, G. C. Catalytic
Enantioselective Carbon–Oxygen Bond Formation: Phosphine-
Catalyzed Synthesis of Benzylic Ethers via the Oxidation of Benzylic
C–H Bonds. J. Am. Chem. Soc. 2016, 138, 12069-12072.
(9) Li, S.; Zhang, J.-W.; Li, X.-L.; Cheng, D.-J.; Tan, B. Phosphoric
acid-catalyzed asymmetric synthesis of SPINOL derivatives. J. Am.
Chem. Soc. 2016, 138, 16561-16566.
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Demand Hetero-Diels–Alder Reaction of Dioxopyrrolidines with
[2.2.1] Bicyclic Phosphines: Asymmetric Synthesis of (+)- and (-)-
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Hetero-Substituted Alkenes. J. Org. Chem. 2018, 83, 8679-8687. (e)
Lu, Y.; Zhou, Y.; Lin, L.; Zheng, H.; Fu, K.; Liu, X.; Feng, X. N, N’-
Dioxide/nickel (ii)-catalyzed asymmetric Diels-Alder reaction of
cyclopentadiene with 2, 3-dioxopyrrolidines and 2-alkenoyl pyridines.
Chem. Commun. 2016, 52, 8255-8258. (f) Huang, Y.; Li, Y.; Sun, J.;
Li, J.; Zha, Z.; Wang, Z. Enantioselective Hetero-Diels–Alder
Reaction and the Synthesis of Spiropyrrolidone Derivatives. J. Org.
Chem. 2018, 83, 8464-8472. (g) Yang, K.-C.; Li, J.-L.; Shen, X.-D.;
Li, Q.; Leng, H.-J.; Huang, Q.; Zheng, P.-K.; Gou, X.-J.; Zhi, Y.-G.
Facile synthesis of novel spiroheterocycles via diastereoselective
aziridination of cyclic enones. RSC Adv. 2017, 7, 21175-21179. (h)
Zhang, S.; Luo, Y.-C.; Hu, X.-Q.; Wang, Z.-Y.; Liang, Y.-M.; Xu, P.-
F. Enantioselective Amine-Catalyzed [4+2] Annulations of Allene
Ketones and 2,3-Dioxopyrrolidine Derivatives: Synthesis of 4H-Pyran
Derivatives. J. Org. Chem. 2015, 80, 7288-7294. (i) Wang, C.; Jia, H.;
Zhang, C.; Gao, Z.; Zhou, L.; Yuan, C.; Xiao, Y.; Guo, H. Phosphine-
Catalyzed Enantioselective [2+4] Cycloaddition to Synthesize
Pyrrolidin-2-one Fused Dihydropyrans Using α-Substituted
Allenoates as C2 Synthons. J. Org. Chem. 2017, 82, 633-641.
Pyrrolines. J. Am. Chem. Soc. 2014, 136, 11890-11893.
(19) Tan, B.; Candeias, N. R.; Barbas, III, C. F. Core-structure-
motivated design of a phosphine-catalyzed [3+2] cycloaddition
reaction: enantioselective syntheses of spirocyclopenteneoxindoles. J.
Am. Chem. Soc. 2011, 133, 4672-4675.
(20) (a) Uozumi, Y.; Hayashi, T. A highly stereoselective olefination
of aldehydes using new zinc and zirconium 1,1-bimetallic reagents. J.
Am. Chem. Soc. 1991, 113, 9888-9890. (b) Hayashi, T. Chiral
monodentate phosphine ligand MOP for transition-metal-catalyzed
asymmetric reactions. Acc. Chem. Res. 2000, 33, 354-362.
(21) CCDC 1811209 contains the supplementary crystallographic data
for this compound. These data can be obtained free of charge from the
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Crystallographic
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Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
(22) (a) Landor, S. R. Ed. The Chemistry of the Allenes; Academic
Press: London, 1982. (b) Krause, N.; Hashmi, A. S. K. Eds. Modern
Allene Chemistry; Wiley-VCH: Weinheim, 2004. (c) Coppola, G. M.;
Schuster, H. F. Allenes in Organic Synthesis; Wiley: New York, 1984.
(d) Hoffmann-Röder, A.; Krause, N. Synthesis and properties of
allenic natural products and pharmaceuticals. Angew. Chem., Int. Ed.
2004, 43, 1196-1216. (e) Ma, S. Some Typical Advances in the
Synthetic Applications of Allenes. Chem. Rev. 2005, 105, 2829-2872.
(e) Yu, S.; Ma, S. Allenes in catalytic asymmetric synthesis and
natural product syntheses. Angew. Chem., Int. Ed. 2012, 51, 3074-
3112.
(23) (a) Liu, H.; Leow, D.; Huang, K.-W.; Tan, C.-H.
Enantioselective Synthesis of Chiral Allenoates by Guanidine-
Catalyzed Isomerization of 3-Alkynoates. J. Am. Chem. Soc. 2009,
131, 7212-7213. (b) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.;
Guzei, I. A.; Tang, W. Enantioselective Bromolactonization of Con-
jugated (Z)-Enynes. J. Am Chem. Soc. 2010, 132, 3664-3665. (c)
Hashimoto, T.; Sakata, K.; Tamakuni, F.; Dutton, M. J.; Maruoka, K.
Phase-transfer-catalysed asymmetric synthesis of tetrasubstituted
allenes. Nat. Chem. 2013, 5, 240-244. (d) Yao, W.; Dou, X.; Wen, S.;
Wu, J.; Vittal, J. J.; Lu, Y. Enantioselective desymmetrization of
cyclohexadienones via an intramolecular Rauhut–Currier reaction of
allenoates. Nat. Commun. 2016, 7, 13024.
(
16) For selected examples, see: (a) Fujiwara, Y.; Fu, G. C. Applica-
tion of a New Chiral Phosphepine to the Catalytic Asymmetric Syn-
thesis of Highly Functionalized Cyclopentenes That Bear an Array of
Heteroatom-Substituted Quaternary Stereocenters. J. Am. Chem. Soc.
2011, 133, 12293-12297. (b) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin,
T. J.; Belding, L.; Dudding, T.; Kwon, O. Hydroxyproline-Derived
Pseudoenantiomeric [2.2.1] Bicyclic Phosphines: Asymmetric
Synthesis of (+)- and (−)-Pyrrolines. J. Am. Chem. Soc. 2014, 136,
1
(
1890-11893.
17) For related exmples, see: a) Meng, X.; Huang, Y.; Zhao, H.; Xie,
P.; Ma, J.; Chen, R. PPh -Catalyzed Domino Reaction: A Facile
Method for the Synthesis of Chroman Derivatives. Org. Lett. 2009, 11,
91-994. (b) Li, E.; Huang, Y.; Liang, L.; Xie, P. Phosphine-catalyzed
4+2] annulation of γ-substituent allenoates: Facile access to func-
3
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[
tionalized spirocyclic skeletons. Org. Lett. 2013, 15, 3138-3141. (c)
Zheng, J.; Huang, Y.; Li, Z. Phosphine-catalyzed domino benzannula-
tion: An efficient method to construct biaryl skeletons. Org. Lett.
2013, 15, 5064-5067. (d) Zhao, H.; Meng, X.; Huang, Y. One step
synthesis of benzoxazepine derivatives via a PPh
3
catalyzed aza-MBH
(24) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. Dynamic Kinetic
Asymmetric Allylic Alkylations of Allenes. J. Am. Chem. Soc. 2005,
127, 14186-14187.
domino reaction between salicyl N-tosylimines and allenoates. Chem.
Commun. 2013, 49, 10513-10515. (e) Li, E.; Huang, Y. Phosphine-
catalyzed domino reaction: a novel sequential [2+3] and [3+2] annula-
tion reaction of γ-substituent allenoates to construct bicy-
clic[3,3,0]octene derivatives. Chem. Commun. 2014, 50, 948-950. (f)
Li, E.; Jia, P.; Liang, L.; Huang, Y. Phosphine-Catalyzed Sequential
(25) (a) Deska, J., Bäckvall, J. E. Enzymatic kinetic resolution of
primary allenic alcohols. Application to the total synthesis and stereo-
chemical assignment of striatisporolide A. Org. Biomol. Chem. 2009,
7, 3379-3381. (b) Ao, Y.-F.; Wang, D.-X.; Zhao, L.; Wang, M.-X.
Biotransformations of Racemic 2,3-Allenenitriles in Biphasic Systems:
Synthesis and Transformations of Enantioenriched Axially Chiral 2,3-
Allenoic Acids and Their Derivatives. J. Org. Chem. 2014, 79, 3103-
3110.
[
2+3] and [3+2] Annulation Domino Reaction of γ-Benzyl-
Substituted Allenoates with α,β-Unsaturated Ketimines To Construct
aza-Bicyclo[3,3,0]octane Derivatives. ACS Catal. 2014, 4, 600-603.
(g) Li, E.; Huang, Y. Phosphine-Catalyzed Domino Reactions: A
Route to Functionalized Bicyclic Skeletons. Chem. Eur. J. 2014, 20,
(26) Yu, J.; Chen, W.-J.; Gong, L.-Z. Kinetic Resolution of Racemic
2,3-Allenoates by Organocatalytic Asymmetric 1,3-Dipolar Cycload-
dition. Org Lett. 2010, 12, 4050-4053.
3
520-3527. (h) Li, E.; Jin, H.; Jia, P.; Dong, X.; Huang, Y. Bifunc-
tional-Phosphine-Catalyzed Sequential Annulations of Allenoates and
Ketimines: Construction of Functionalized Poly-heterocycle Rings.
Angew. Chem., Int. Ed. 2016, 55, 11591-11594. (h) Gicquel, M.;
Gomez, C.; Retailleau, P.; Voituriez, A.; Marinetti, A. Synthesis of
3,3’-Spirocyclic Oxindoles via Phosphine Catalyzed [4+2] Cycliza-
tions. Org. Lett. 2013, 15, 4002-4005. (i) Wang, D.; Lei, Y.; Wei, Y.;
Shi, M. A Phosphine-Catalyzed Novel Asymmetric [3+2] Cycloaddi-
tion of C, N-Cyclic Azomethine Imines with -Substituted Allenoates
Chem. Eur. J. 2014, 20, 15325-15329. (j) Xu, S.; Zhou, L.; Ma, R.;
Song, H.; He, Z. Phosphane-Catalyzed [3+2] Annulation of Alleno-
ates with Aldehydes: A Simple and Efficient Synthesis of 2-
Alkylidenetetrahydrofurans. Chem. Eur. J. 2009, 15, 8698-8702. (k)
Ma, R.; Xu, S.; Tang, X.; Wu, G.; He, Z. Phosphine-mediated diverse
reactivity of γ-substituted allenoates with aldehydes: syntheses of
highly functionalized chromans and (E,E)-1,3-dienes. Tetrahedron.
2011, 67, 1053-1061.
(27) The beneficial effects of adding Brønsted acid additives in
NUSIOC-Phos-catalyzed domino reaction and kinetic resolution of -
substituted allenoates are not fully understood at this stage. We
hypothesize that added Brønsted acids interact with both allenoates
and pyrrolidine-2,3-diones at distinct steps, initially helping
differentiate the addition of NUSIOC-Phos to different isomers of
racemic allenes, and subsequently facilitating the discrimination of
competing enantiomeric pathways in the domino process. DFT
calculations are currently on-going to gain deeper mechanistic
understanding.
(28) Ao, Y.-F.; Wang, D.-X.; Zhao, L.; Wang, M.-X. Biotransfor-
mations of Racemic 2,3-Allenenitriles in Biphasic Systems: Synthesis
and Transformations of Enantioenriched Axially Chiral 2,3-Allenoic
Acids and Their Derivatives. J. Org. Chem. 2014, 79, 3103-3110.
3
1
(29) See the SI for P NMR studies of the reaction progress.
(30) See the SI for the details of deuterium-labeling experiments.
(18) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin, T. J.; Belding, L.;
Dudding, T.; Kwon, O. Hydroxyproline-Derived Pseudoenantiomeric
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31) For a racemic version of this [4+2] annulation, see: Li, E.; Huang,
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Y.; Liang, L.; Xie, P. Phosphine-catalyzed [4+2] annulation of γ-
substituent allenoates: Facile access to functionalized spirocyclic
skeletons. Org. Lett. 2013, 15, 3138-3141. An enone, i.e. benzyli-
deneacetophenone, was examined as a potential dipolarophile for the
kinetic resolution of -substituted allene 2a. However, no reaction
was observed.
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