Chiral aminophosphines derived from hydroxyproline and their application in allene–imine [4 + 2] annulation

Article abstract of DOI:10.1038/s41429-019-0181-0

A robust synthetic route from l-hydroxyproline (l-Hyp) to phosphines has established an expandable library of six chiral aminophosphines, which were then applied to the phosphine-catalyzed [4 + 2] allene–imine annulation. The enantioinduction in the annulations—induced by a purely steric effect—were moderate (up to 57% ee). A switch of the reaction site from the γ- to the β′-carbon atom of the allenoate was observed during the annulations performed using sterically demanding chiral phosphines.

Full text of DOI:10.1038/s41429-019-0181-0

The Journal of Antibiotics
https://doi.org/10.1038/s41429-019-0181-0
SPECIAL FEATURE: ARTICLE
Chiral aminophosphines derived from hydroxyproline and their
application in allene–imine [4 + 2] annulation
1
San N. Khong1 Changmin Xie1 Xinyi Wang1,2 Hao Tan1,2 Ohyun Kwon
●
●
●
●
Received: 20 February 2019 / Revised: 20 March 2019 / Accepted: 22 March 2019
© The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2019
Abstract
A robust synthetic route from L-hydroxyproline (L-Hyp) to phosphines has established an expandable library of six chiral
aminophosphines, which were then applied to the phosphine-catalyzed [4 + 2] allene–imine annulation. The enantioinduc-
tion in the annulations—induced by a purely steric effect—were moderate (up to 57% ee). A switch of the reaction site from
the γ- to the β′-carbon atom of the allenoate was observed during the annulations performed using sterically demanding
chiral phosphines.
Introduction
efforts have been exerted in the development of chiral
phosphine ligands [13–15]. The chirality of a phosphine
may reside on the phosphorus center, in the carbon back-
bone, or in the phosphine’s molecular framework [16]. As
part of our efforts in phosphine organocatalysis, we have
developed a class of structurally unique P-chiral [2.2.1]
bicyclic phosphines [17, 18]. Recently, we applied one such
bridged bicyclic P-chiral phosphine, exo-(p-anisyl)-Hyp-
Phos, in the asymmetric allene–imine [4 + 2] annulation to
afford valuable chiral piperidines in good yields and with
excellent enantioselectivities [19]. Herein, we report a class
of new chiral phosphines derived from L-hydroxyproline
(L-Hyp) and their application in the allene–imine [4 + 2]
annulation.
The abundance and ready availability of chiral α-amino
acids have made them desirable sources of chirality. Indeed,
many bifunctional chiral aminophosphines have been
derived from α-amino acids [14]. In previous studies, the
presence of a free NH group, responsible for hydrogen
bonding, has been the major focus when designing chiral
aminophosphines for asymmetric phosphine organocata-
lysis (Scheme 1a) [14]. Progress in the field of enamine and
iminium catalysis has revealed that steric interaction is
another useful mode of asymmetric induction [20–23].
Nevertheless, steric interaction has not previously been
considered a promising platform for the design of α-amino
acid-derived aminophosphines. L-Hyp, an abundant non-
proteinogenic amino acid having a proline skeleton and an
additional OH group for further steric tuning, has been
chosen as the platform for our catalyst design (Scheme 1a).
In addition to introducing sterically tunable protecting
Piperidines are among the nitrogen heterocycles most fre-
quently used in pharmaceuticals [1]. Apart from their
appearance in pharmaceutically interesting substances [2],
tetrahydropyridines, and piperidines are present as common
structural motifs in many bioactive natural products [3–5].
Because of the interesting biological effects exerted by
tetrahydropyridine- and piperidine-containing compounds,
many methods have been developed to access these valu-
able structures [2, 6]. In 2003, we disclosed that functio-
nalized tetrahydropyridines could be synthesized through a
PBu3-catalyzed [4 + 2] reaction of allenoates and imines
[7, 8]. Subsequently, Fu [9], Zhao [10], Guo [11], and Sasai
[12] realized asymmetric versions of the [4 + 2] reaction
using various chiral phosphines. In the last 50 years, major
These authors contributed equally: San N. Khong, Changmin Xie
Dedicated to Professor Samuel J. Danishefsky and his great scientific
contributions to total syntheses of highly complex and biologically
important natural products.
Supplementary information The online version of this article (https://
doi.org/10.1038/s41429-019-0181-0) contains supplementary
material, which is available to authorized users.
* Ohyun Kwon
ohyun@chem.ucla.edu
1
Department of Chemistry and Biochemistry, University of
California, Los Angeles, CA, USA
2
College of Chemistry, Nankai University, Tianjin, China

S. N. Khong et al.
Scheme 1 Synthetic design of chiral aminophosphines 2 from L-Hyp
groups at the pyrroline nitrogen atom and the 4-OH group, a
hydrogen-bonding site could also be installed—for exam-
ple, as a urea or thiourea motif—at the pyrroline nitrogen
atom. We envisioned that the aminophosphines 2a–f could
be obtained from L-Hyp by installing a diphenylphosphino
group through the displacement of the mesylate in 1 and
subsequent functional group manipulations (Scheme 1b).
The synthesis of the mesylate 1 also appeared to be
straightforward. Starting from commercially available L-
Hyp, various alcohol and amine protecting groups could be
installed prior to substitution of the mesylate by a diphe-
nylphosphino group.
acyl groups to afford the chiral aminophosphines 2b–f of
varying steric bias (Scheme 3). After Boc-deprotection, an
excess of triethylamine was added to neutralize TFA and
promote the acylation with the acyl chloride. Using this
one-pot procedure, the four aminophosphines 2b–e were
prepared in high yields. When phenyl isocyanate was used
instead of an acyl chloride, the phosphine 2f, presenting a
hydrogen-bonding site, was obtained in 77% yield.
The six chiral phosphines with varied N-substituents
were then applied to our [4 + 2] annulation [7]. We first
examined the [4 + 2] annulation of the activated allenoate
8 and the imine 7 mediated by the phosphine 2a in CH2Cl2
(Table 1, entry 1). An inseparable mixture of the tetra-
hydropyridine 9 and the tetrahydropyridine 10 was obtained
in 68% yield, with the ee of 9 being 30%. When the solvent
was switched to benzene, the ee of 9 increased to 42%, but
10 was now the major product (entry 2). We then tested the
other phosphines for the annulation in CH2Cl2 (entries 3–6).
When using the catalyst 2b for the annulation in CH2Cl2,
the ee of 9 increased to 42% compared with that of 2a in the
same solvent (cf. entries 3 and 1). Under otherwise identical
conditions, the ratio of 10 had also increased. The phos-
phine 2d, featuring a bulkier acyl substituent on the nitro-
gen atom, produced the tetrahydropyridine 9 with a higher
ee of 53% (entry 5). Interestingly, in the reaction catalyzed
by the phosphine 2e presenting an adamantylcarbonyl
group, the selectivity of the product was completely
reversed—now favoring the tetrahydropyridine 10, which
was isolated in 80% yield and contaminated with only a
Results and discussion
The synthesis of compound 2a is illustrated in Scheme 2.
First, the Boc-protection of L-Hyp proceeded to provide N-
Boc-L-Hyp 3. Benzylation of the free OH group followed
by borane-mediated reduction of the carboxyl group resul-
ted in the primary alcohol 5. Only one column chromato-
graphic purification through SiO2 was necessary to prepare
16.3 g of 5 in 70% yield in the three-step process. Mesy-
lation of 5 led to the key intermediate 1 for phosphine
synthesis. The mesylate 1 was converted into the phosphine
2a in high yield after slow addition of an excess of potas-
sium diphenylphosphide at low temperature.
Having prepared the aminophosphine 2a, the acid-liable
N-Boc protecting group was readily replaced with several

Chiral aminophosphines derived from hydroxyproline and their application in allene–imine. . .
Scheme 2 Preparation of the
phosphine 2a
Scheme 3 Preparation of the phosphines 2b–f
trace of 9 (entry 6). The NH group in the phosphine 2f
seemed to have little effect on the enantioselectivity, but the
formation of 10 was largely inhibited (entry 7). From these
preliminary results, it appeared that the enantioselectivity
increased upon increasing the bulk of the N-acyl sub-
stituent, presumably through a mechanism involving steric
control.
It was also interesting that more sterically demanding
phosphines could facilitate the formation of 10 over 9. The
reversed regioselectivity can be explained by two possible
pathways of the imine–allene [4 + 2] reaction (Scheme 4)
[7, 19, 24]. At the onset of the [4 + 2] reaction, addition of
the phosphine 2 to the allene 8 generates intermediate A,
which is in resonance with structure B, which, in turn, is in
equilibrium with intermediate B′. In path I, γ-addition of
intermediate B to the imine 7 affords intermediate C, fol-
lowed by the formation of 9. In path II, β′-addition of
intermediate B′ to the imine 7 generates intermediate C′,
followed by the formation of 10. When a bulkier phosphine
was used in the reaction, the γ-position of intermediate B
was more encumbered, relative to its β′-position. In this
case, path II, which afforded the product 10, became the
favored pathway.
The same catalysts were then employed in the
allene–imine [4 + 2] annulation of the less activated α-
methylallenoate 11 (Table 2). Because the reaction was
slower with this allene 11, the catalyst loading was
increased to 30 mol% and 4-Å MS were added to minimize

S. N. Khong et al.
Table 1 Phosphines 2–catalyzed [4 + 2] annulation of the allenoate 8a
Entry
Catalyst
Solvent
Conv
(%)b
Drc
(cis-9/
trans-
9)
Ratioc
(9/10)
Yield
ee
(%)d (9
+ 10)
(%)e
(9)
1
2
3
4
5
6
7
2a
2a
2b
2c
2d
2e
2f
CH2Cl2
benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
>99
97
5.9:1
9.1:1
5.5:1
6.2:1
7.7:1
–
3.0:1
1:3.1
1:2.3
1:4.4
1:12.5
1:63.0
15:1
68
35
44
66
70
80
39
30
42
42
45
53
57f
27
>99
>99
>99
>99
49
6.7:1
aReaction conditions: 7 (1 equiv, 0.1 mmol), 8 (1.2 equiv), the phosphine 2 (20 mol%), and the solvent (2 mL)
bConversion determined using mesitylene as an internal standard
1
cDetermined from the H NMR spectrum of the crude mixture
dIsolated yield
eThe ee value of 9 was determined through chiral HPLC analysis; its absolute configuration was determined through comparison with the data of
the known compound in ref. [9]
fThe ee of compound 10; the absolute configuration was not determined
Scheme 4 Possible reaction
pathways for the allene–imine
[4 + 2] annulation
hydrolysis of the imine 7. Although the conversion of the
imine 7 and the yield of 12 were not good, we observed a
similar trend in the induction of enantioselectivity as that in
Table 1. Increasing the bulk of the N-acyl substituent in the
phosphine 2 afforded greater enantioselectivity for the for-
mation of the tetrahydropyridine 12. When using the cata-
lyst 2d, an ee of 41% was induced (entry 4). The bulky
phosphines again facilitated the formation of the β′-addition
product, in this case 13 (cf. entries 4 vs. 1 and 2). These
preliminary findings, obtained from nonoptimized reaction
conditions, were consistent with the model of steric control.
Conclusion
Taking advantage of the ready availability of naturally
occurring chiral α-amino acids, we have chosen L-Hyp, a
nonproteinogenic—but abundantly available—amino acid,

Chiral aminophosphines derived from hydroxyproline and their application in allene–imine. . .
Table 2 Phosphines 2–catalyzed [4 + 2] annulation of the α-methylallenoate 11a
Entry
Catalyst
Conv (%)b
Ratioc,d
(12:13)
Yield (%)e
(12)
ee (%)f
(12)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
56
74
77
70
80
47
10:1
23
9
20
29
28
41
23
14
>50:1
7.1:1
1.9:1
14.1:1
>50:1
10
11
26
6
aReaction conditions: 7 (1 equiv, 0.1 mmol), 11 (2 equiv), the phosphine 2 (30 mol%), 4-Å MS (10 mg), and CH2Cl2 (2 mL)
bConversion was determined using mesitylene as an internal standard
1
cDetermined from the H NMR spectrum of the crude mixture
d12 and 13 were obtained as a mixture; no pure 13 was isolated, but its structure was inferred according to our mechanistic proposal in Scheme 4
eNMR yield (internal standard: mesitylene)
fDetermined through chiral HPLC analysis; the absolution configuration was determined through comparison with the data of the known
compound in ref. [19].
for the design of several chiral phosphines. With the goal of
exploiting steric interactions for enantioinduction, we have
developed a synthetic route toward a number of L-
Hyp–derived chiral phosphines. The preliminary applica-
tion of these phosphines in the allene−imine [4 + 2]
annulation has proven moderately successful in terms of
enantioselectivities. When using bulky phosphines, an
interesting switch of the reaction site occurred: from the γ-
to the β′-carbon atom of the allenoate. The clear trend in the
enantioinduction hints at the potential of developing chiral
phosphines that operate with steric tuning as the sole source
of enantioselectivity control in the [4 + 2] annulation.
crude product was used in the next step without further
purification.
The Boc-protected L-Hyp 3 was dissolved in THF (100
mL) and then cannulated into a slurry of NaH (60% in
mineral oil, 11.2 g, 155 mmol) in THF (200 mL) at 0 °C.
Benzyl bromide (15.0 g, 87.7 mmol) was added dropwise to
the reaction mixture. The flask was warmed to room tem-
perature and then the mixture was heated under reflux for 6
h. The reaction mixture was cooled to room temperature and
poured over ice. The organic solvent was evaporated under
reduced pressure and the aqueous solution was washed with
EtOAc. The aqueous phase was acidified with 2N HCl until
the pH was 2, and then it was extracted with EtOAc. The
organic phase was concentrated under reduced pressure to
yield 4 as a brownish yellow oil. This brownish yellow oil
was dissolved in dry THF (300 mL) and cooled to 0 °C.
BH3·DMS (5.7 mL, 58 mmol) was added dropwise to the
reaction mixture, which was then kept stirring at 0 °C for an
additional 1 h. The flask was removed from the ice bath, and
the mixture stirred overnight at room temperature. The
reaction mixture was poured over ice and sequentially
extracted with EtOAc, washed with saturated aqueous
NaHCO3, washed with brine, and dried (Na2SO4). The
solution was concentrated under reduced pressure and
purified through flash column chromatography (FCC; gra-
dient EtOAc/hexanes, from 30 to 50%) to yield 5 [26] as a
slightly yellow oil (16.3 g, 70% over three steps).
Experimental
4-Benzyloxy-2-methanesulfonyloxymethyl-
pyrrolidine-1-carboxylic acid tert-butyl ester (1)
Boc2O (18.3 g, 83.9 mmol) was added slowly to a solution
of L-Hyp (10.0 g, 76.3 mmol) in 1,4-dioxane (80 mL) and 1
N aqueous NaOH (80 mL) at 0 °C. The reaction mixture
was stirred for 8 h at room temperature, then concentrated
under reduced pressure, acidified to pH 1 using 2 N aqueous
HCl, and extracted with EtOAc. The extract was washed
with brine, dried (Na2SO4), and concentrated to provide the
Boc-protected L-Hyp 3 [25] as a clear viscous oil. This

S. N. Khong et al.
The slightly yellow oil from the previous step (16.1 g,
52.3 mmol) was dissolved in dry CH2Cl2 (160 mL) and
cooled to 0 °C. Et3N (7.8 mL, 56.0 mmol) was added and
then MsCl (6.3 g, 54.9 mmol) was added slowly. After the
reaction had reached completion (checked using TLC), the
solvent was evaporated under reduced pressure. The residue
was dissolved in EtOAc and washed sequentially with
water, saturated aqueous NaHCO3, and brine, then dried
(Na2SO4). The product was isolated through FCC (EtOAc/
hexanes, 30%) to provide 1 [26] (20.0 g, 99%) as a slightly
yellow viscous oil.
slowly. The mixture was stirred at room temperature over-
night and then washed with H2O. The organic phase was
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified through FCC.
((2S,4R)-4-(Benzyloxy)-2-((diphenylphosphino)
methyl)pyrrolidin-1-yl)(3,5-bis(trifluoromethyl)
phenyl)methanone (2b)
24
Obtained as a white solid (70%). ½αŠ –58.77 (с 0.65,
D
1
acetone); H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.60
(s, 2H), 7.57–7.53 (m, 4H), 7.38–7.16 (m, 11H), 4.78–4.70
(m, 1H), 4.46 (d, J = 11.9Hz, 1 H), 4.30 (d, J = 11.9 Hz,
1H), 4.14 (br s, 1H), 3.53 (dd, J = 11.3, 3.3 Hz, 1H), 3.32
(d, J = 11.3 Hz, 1H), 2.84–2.76 (m, 2H), 2.48 (dd, J = 13.2,
7.9 Hz, 1H), 2.34 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
167.1, 138.4, 137.6, 137.5, 137.49, 132.8 (d, J = 21.3 Hz),
132.4 (d, J = 18.6 Hz), 131.5 (q, J = 33.7 Hz), 129.1,
128.63, 128.56 (d, J = 7.5 Hz), 128.54 (d, J = 6.8 Hz),
128.4, 127.7, 127.6 (br s), 127.4, 123.6 (sp, J = 3.6 Hz),
122.8 (q, J = 273.7 Hz), 77.1, 70.8, 55.6, 55.0 (d, J = 16.9
Hz), 36.9 (d, J = 10.6 Hz), 32.3 (d, J = 12.9 Hz); 31P NMR
(202 MHz, CDCl3) δ –26.4; IR (film) νmax 3057, 2926,
2867, 1642, 1363, 1280, 1137, 906, 740, 697 cm−1; HRMS-
DART: calcd for C33H29F6NO2P ([M+H]+) m/z 616.1830;
found 616.1830.
(2S,4R)-tert-butyl 4-(benzyloxy)-2-
((diphenylphosphino)methyl)pyrrolidine-1-
carboxylate (2a)
Compound 1 (771 mg, 2 mmol) was placed in a flame-dried
round-bottom flask containing a stirrer bar. Dry THF
(20 mL) was added via syringe under argon. The flask was
cooled to −45 °C (MeCN/dry ice bath) and then 0.5 N
Ph2PK solution in THF (6 mL, 3 mmol) was added over 2 h
via syringe pump. When the addition was complete, the
mixture was stirred at the same temperature for an addi-
tional 7 h. The flask was warmed to room temperature and
then H2O (1–1.5 mL) was added until the reaction color
disappeared. CH2Cl2 (20 mL) was added and then the
organic phase was collected. The aqueous phase was
extracted twice with CH2Cl2. The combined organic phases
were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified through FCC (EtOAc/
hexanes, from 1:10 to 1:5) to afford 2a (846 mg, 89%) as a
1-((2S,4R)-4-(benzyloxy)-2-((diphenylphosphino)
methyl)pyrrolidin-1-yl)-2,2-dimethylpropan-1-one
(2c)
26
D
26
1
clear viscous oil. ½αŠ –47.4 (с 0.35, acetone); H NMR
Obtained as a white solid (78%). ½αŠ –4.0 (с 0.75, acet-
D
1
(500 MHz, CDCl3) δ 7.61 (br s, 1H), 7.54 (br s, 1H), 7.46
(app t, J = 6.6 Hz, 2H), 7.38–7.30 (m, 11H), 4.49 (br s, 2H),
4.27–4.10 (m, 2H), 3.90–3.43 (m, 2H), 3.04–2.88 (m, 1H),
2.33–2.12 (m, 3H), 1.49 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 154.4, 137.8, 132.7 (d, J = 19.2Hz), 132.3
(d, J = 19.5 Hz), 128.6, 128.3 (d, J = 7.1 Hz), 128.2, 127.4,
127.3, 79.4, 70.6, 54.1 (d, J = 18.9 Hz), 53.2, 38.6, 35.0 (d,
J = 10.8 Hz), 33.5 (br s), 28.3; 31P NMR (202 MHz,
CDCl3) δ −22.9; IR (film) νmax 2975, 2930, 2362, 2338,
1690, 1393, 1171, 739, 697 cm−1; HRMS-DART: calcd for
C29H35NO3P ([M+H]+) m/z 476.2349; found 476.2345.
one); H NMR (500 MHz, CDCl3) δ 7.60 (t, J = 7.5 Hz,
2H), 7.44–7.41 (m, 2H), 7.37 (app t, J = 7.0 Hz, 2H),
7.34–7.26 (m, 9H), 4.52–4.43 (m, 3H) (apparent over-
lapping peaks), 4.17 (app s, 1H), 3.90 (d, J = 11.4 Hz, 1H),
3.56 (dd, J = 11.4, 4.4 Hz, 1 H), 2.91 (d, J = 13.9 Hz, 1H),
2.24–2.19 (m, 2 H), 2.16–2.10 (m, 1H), 1.17 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 176.7, 137.8, 132.8 (d, J = 18.8
Hz), 132.7 (d, J = 19.4 Hz), 128.6, 128.5 (d, J = 7.0 Hz),
128.35 (d, J = 7.0 Hz), 128.32, 127.6, 127.3, 77.4, 70.6,
55.7 (d, J = 17.5 Hz), 53.1, 38.8, 35.5 (d, J = 9.3 Hz), 32.8
(d, J = 13.7 Hz), 27.5; 31P NMR (202 MHz, CDCl3)
δ –23.5; IR (film) νmax 2969, 2930, 1620, 1407, 1093, 1074,
738, 697 cm–1; HRMS-DART: calcd for C29H35NO2P
([M+H]+) m/z 460.2400; found 460.2397.
General procedure for preparing 2b–e
The phosphine 2a (0.20 g, 0.42 mmol) was dissolved in
CH2Cl2 (1.5 mL) in a flame-dried round-bottom flask con-
taining a stirrer bar. TFA (0.5 mL) was added dropwise to
the solution at 0 °C and then the mixture was stirred at room
temperature for 1 h. CH2Cl2 (3 mL) was added and then the
mixture was cooled to 0 °C. NEt3 (1.2 mL) was added
dropwise, and then an acyl chloride (1.2 eq) was added
1-((2S,4R)-4-(benzyloxy)-2-((diphenylphosphino)
methyl)pyrrolidin-1-yl)-2,2-diphenylethanone (2d)
27
Obtained as a pale-yellow solid (73%). ½αŠ –50.14
D
1
(с 0.17, acetone); H NMR (500 MHz, CDCl3) δ (in ali-
phatic region, major rotamer) 5.00 (s, 1H), 4.52–4.50 (m,

Chiral aminophosphines derived from hydroxyproline and their application in allene–imine. . .
1H) (overlapping peaks), 4.25 (d, J = 12.2 Hz, 1H), 4.17 (d,
J = 11.9 Hz, 1H), 4.13–4.10 (m, 1H), 3.66 (d, J = 10.2 Hz,
1H), 3.49 (dd, J = 11.0, 4.7 Hz, 1H), 3.26 (dt, J = 13.5, 4.5
Hz, 1H), 2.24–2.14 (m, 2H), 2.05–2.00 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ (major rotamer) 170.3, 139.4, 138.9,
137.7, 133.0 (d, J = 19.3 Hz), 132.7 (d, J = 19.3 Hz), 129.1,
128.9, 128.8, 128.6, 128.59, 128.56, 128.43, 128.41,
128.35, 128.32, 127.6, 127.5, 126.9 (d, J = 8.0 Hz), 76.5 (d,
J = 1.8 Hz), 70.7, 57.0, 54.9 (d, J = 19.2 Hz), 51.9, 36.9
(d, J = 9.8 Hz), 32.7 (d, J = 12.5 Hz); 31P NMR (202 MHz,
CDCl3) δ –22.5 (major rotamer), –23.2 (minor rotamer); IR
(film) νmax 3060, 3028, 1645, 1411, 1192, 738, 697 cm–1;
HRMS-DART: calcd for C38H37NO2P ([M+H]+) m/z
570.2556; found 570.2554.
(hexanes/EtOAc, 5:1) to give 2f as a white semisolid.
28
1
½αŠ –39.8 (с 1.00, acetone); H NMR (500 MHz, d6-acet-
D
one) δ 8.12 (s, 1H), 7.66–6.87 (m, 20H), 4.47 (s, 2H),
4.37–4.21 (m, 2H), 3.68 (d, J = 4.1 Hz, 2H), 3.05 (dt, J =
13.5, 3.4 Hz, 1H), 2.28–2.20 (m, 1H), 2.18–2.06 (m, 2H).
13C NMR (100 MHz, d6-acetone) δ 154.4, 140.5, 139.6 (d,
J = 12.9 Hz), 138.7, 138.2 (d, J = 13.0 Hz), 132.8 (d, J =
19.6 Hz), 132.6 (d, J = 20.0 Hz), 128.7, 128.6 (d, J = 2.5
Hz), 128.5, 128.4 (d, J = 7.0 Hz), 128.3, 128.25 (d, J = 8.1
Hz), 127.4, 121.9 (d, J = 16.7 Hz), 119.5, 118.5, 77.0 (d,
J = 1.7 Hz), 70.4, 54.70 (d, J = 20.4 Hz), 51.9, 37.3 (d, J =
8.4 Hz), 33.7 (d, J = 13.9 Hz). 31P NMR (121 MHz, d6-
acetone) δ –23.12. IR (film) νmax 3324, 3054, 2926, 2426,
1700, 1633, 1443, 1385, 1246, 750, 695 cm−1; HRMS-
DART: calcd for C31H32N2O2P ([M+H]+) m/z 495.2196;
found 485.2219.
(1S,3R)-adamantan-1-yl((2S,4R)-4-(benzyloxy)-2-
((diphenylphosphino)methyl)pyrrolidin-1-yl)
methanone (2e)
General experimental procedure for the
allene–imine [4 + 2] annulation (with the allene 8)
Obtained as a colorless sticky compound (98%). ½αŠ27 + 2.7
D
(с 1.20, acetone); 1H NMR (500 MHz, CDCl3) δ 7.60
(t, J = 7.3 Hz, 2H), 7.44–7.41 (m, 2H), 7.39–7.28 (m, 11H),
4.54–4.50 (m, 2H) (overlapping peaks), 4.44 (d, J = 12 Hz,
1H), 4.19 (br s, 1H), 3.99 (d, J = 11.2 Hz, 1H), 3.62
(dd, J = 11.3, 4.4 Hz, 1H), 2.88 (d, J = 13.3 Hz, 1H), 2.19
(dd, J = 13.4, 9.5 Hz, 2H), 2.12 (br s, 1H), 1.99 (s, 3H),
1.87 (s, 6H), 1.71–1.65 (app q, J = 12.4 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 176.1, 137.9, 132.8 (d, J = 18.8 Hz),
132.7 (d, J = 19.6 Hz), 128.53, 128.48, 128.34, 128.30,
127.6, 127.5, 77.6, 70.8, 55.9 (d, J = 16.3 Hz), 53.1, 41.6,
38.0, 36.5, 35.2 (d, J = 8.2 Hz), 32.9 (d, J = 12.0 Hz), 28.3;
31P NMR (202 MHz, CDCl3) δ –21.8; IR (film) νmax 3053,
2905, 2850, 2235, 1610, 1391, 1073, 909, 734, 697 cm–1;
HRMS-DART: calcd for C35H41F6NO2P ([M + H]+) m/z
538.2869; found 538.2872.
The allenoate (0.12 mmol) was added in one portion to a
solution of N-tosylimine (0.1 mmol) and the aminopho-
sphine catalyst (0.02 mmol) in the solvent (2 mL). The flask
was capped with a Teflon cap under a N2 flow. The mixture
was stirred at room temperature for 2 days. The resulting
solution was concentrated and the residue purified through
FCC on silica gel (eluent: 20–30% EtOAc in hexane) to
give the product.
Diethyl (2S,3S)-2-phenyl-1-tosyl-1,2,3,6-
tetrahydropyridine-3,4-dicarboxylate (10)
Obtained as a white solid (80%). 57% ee—determined
using an SFC instrument, a Daicel ChiralPak IC-3 column,
and 20% MeCN; tR (minor) = 3.74 min; tR (major) = 4.81
25
D
1
min; ½αŠ –38.0 (с 1.10, acetone); H NMR (400 MHz,
(2S,4R)-4-(benzyloxy)-2-((diphenylphosphanyl)
methyl)-N-phenylpyrrolidine-1-carboxamide (2f)
CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.28–7.16 (m, 7H), 6.94
(dd, J = 3.7, 2.7 Hz, 1H), 5.93 (s, 1H), 4.24–4.12 (m, 4H),
4.11–3.97 (m, 2H), 3.69 (dt, J = 19.9, 2.4 Hz, 1H), 2.38 (s,
3H), 1.26 (t, J = 7.4 Hz, 3H), 1.22 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.5, 165.2, 143.5, 137.8,
136.9, 135.2, 129.4, 128.6, 127.8, 127.4, 126.8, 126.4,
61.6, 61.1, 56.1, 44.9, 41.7, 21.4, 14.08, 13.97; IR (film)
νmax 2981, 1717, 1344, 1260, 1160, 1096 cm−1. HRMS-
DART: calcd for C24H28NSO6 ([M + H]+) m/z 458.1632;
found 458.1628.
The phosphine 2a (76.0 mg, 0.158 mmol) was dissolved in
CH2Cl2 (0.5 mL) in a flame-dried round-bottom flask con-
taining with a stirred bar. TFA (0.17 mL) was added
dropwise to the solution at 0 °C and then the mixture was
stirred at room temperature for 1 h. CH2Cl2 (1 mL) was
added and then the mixture was cooled to 0 °C. NEt3 (0.4
mL) was added dropwise and then the reaction was quen-
ched through the addition of H2O (2 mL). The aqueous
phase was exacted with CH2Cl2. The combined organic
phases were washed with brine, dried (Na2SO4), and con-
centrated. The residue was dissolved in CH2Cl2 (1 mL).
Phenyl isocyanate (21.0 mg, 0.176 mmol) was added and
then the mixture was stirred overnight. The solution was
concentrated and the residue purified through FCC
General experimental procedure for the
allene–imine [4+2] annulation (with the allene 11)
The allenoate (0.2 mmol) was added in one portion to a
mixture of N-tosylimine (0.1 mmol), the aminophosphine
catalyst (0.03 mmol), and 4-Å MS (10 mg) in CH2Cl2

S. N. Khong et al.
(2 mL). The flask was capped with a Teflon cap under a N2
flow. The mixture was stirred at room temperature for
3 days. The resulting solution was concentrated and mesi-
tylene was added as an internal standard to determine the
yield and conversion. This mixture was dissolved in THF
and then 1 N HCl was added to hydrolyze the imine. The
aqueous phase was exacted with CH2Cl2. The combine
extracts were washed with brine, dried (Na2SO4), and
concentrated. The residue was purified through PTLC
(hexane/EtOAc, 5:1) to give the product for ee
determination.
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of ethyl 6-phenyl-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate.
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derivatives through the [4+2] annulation of imines with allenes. J
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framework with a chiral tetrasubstituted stereogenic carbon center.
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Acknowledgements Financial support for this study was provided by
the NIH (R01GM071779). We thank Dr. Saeed Khan (UCLA) for the
crystallographic analyses. C.X. thanks Prof. Neil K. Garg and Sarah
Anthony (UCLA) for sharing their SFC instrument.
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talysis. Chem Rev. 2018;118:10049–293.
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reactions. Chem Rev. 2018;118:9344–411.
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catalytic reactions. ACS Catal. 2016;6:4814–58.
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Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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