N,N-Diisopropyl-N-phosphonyl imines lead to efficient asymmetric synthesis of aziridine-2-carboxylic esters

Article abstract of DOI:10.1039/c3ob40251g

Highly diastereoselective asymmetric synthesis of chiral aziridine-2-carboxylic esters is reported for 20 examples with good yields (51-87%) and excellent diastereoselectivities (>99 : 1 dr for most cases). The modified N-phosphonyl imines have proven to be superior to previous imine auxiliaries for the aza Darzens reaction by using a secondary isopropyl group to replace the primary benzyl group for N,N-diamino protection. In the meanwhile, a special operation by slowly adding the pre-cooled imine solution at -78 °C into the preformed β-bromo lithium enolate mixture at this temperature in the presence of 4 A molecular sieves was found to be crucial in terms of yields and diastereoselectivity. The present method can provide an easy and general access to β-hydroxy α-amino acids and other important amino building blocks.

Full text of DOI:10.1039/c3ob40251g

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Organic & Biomolecular
Chemistry
ARTICLE
N,N-Diisopropyl-N-phosphonyl Imines Lead to Efficient Asymmetric
Synthesis of Aziridine-2-Carboxylic Esters
Padmanabha V. Kattamuri,a Yiwen Xiong,b Yi Pan*b and Guigen Li*a,c
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Highly diastereoselective asymmetric synthesis of chiral aziridine-2-carboxylic esters is reported for 20 examples with good yields (51-
87%) and excellent diastereoselectivities (>99:1 dr for most cases). The modified N-phosphonyl imines are proven to be superior to
previous imine auxiliaries for the aza Darzens reaction by using secondary isopropyl to replace primary benzyl group for N,N-diamino
o
protection. In the meanwhile, a special operation by slowly adding the pre-cooled imine solution at -78 C into the preformed -bromo
10 lithium enolate mixture at this temperature in the presence of 4 Å molecular sieves was found to be crucial in terms of yields and
diastereoselectivity. The present method can provide an easy and general access to -hydroxy -amino acids and other important amino
building blocks.
Introduction
15
The asymmetric formation of nitrogen heterocycles from readily
accessible starting materials has become an important topic for
chemical and biomedical research.1 One of the privileged
substructures among the nitrogen-containing heterocycles is
as an irreversible inhibitor of glutamate racemase (Fig. 1).2a,3a,3b
One of the major reasons for aziridines to play an important role
in chemical and biomedical sciences is based on the fact that the
strained three-membered rings can undergo regio- and
20 represented by the aziridine ring which has been found in a 50 stereoselective ring opening reactions.4a,4b For example, the
variety of biologically active natural products including
mitomycin, azicemycin, azinomycin and maduropeptin.2a,2b The
structure-activity relationship (SAR) studies on mitosane
derivatives revealed that the aziridine ring is crucial for their
25 antitumor activity and selectivity.2c-2f This study has led to the
finding that mitomycin C can act as the most potent candidate
possessing antitumor activities against stomach, breast,
oesophagus and bladder tumors.2b Many other aziridine-
containing derivatives have also been found to exhibit various
30 biological properties.2a,3a,3b For example, 2-(4-amino-4-
carboxybutyl)aziridine-2-carboxylic acid 1 can serve as a potent
irreversible inhibitor of the bacterial enzyme diaminopimelic acid
epimerase while 2-(2- carboxyethyl)aziridine-2-carboxylic acid 2
aziridine-2-carboxylic esters can serve as versatile building
blocks for making α- and β-amino acids, β-substituted α-amino
acids, β-hydroxy α-amino acids, α-amino aldehydes and
ketones.5,9a
55
HO2C
CO2H
HO2C
CO2H
NH
HN
NH2
1
2
Fig. 1 Biologically active synthetic aziridine-2-carboxylic acids
The asymmetric synthesis of aziridines has been pursued in
60 several research groups for many years;6 typical known
aziridination methods are represented by organocatalytic
reactions of imines and enals, and transition metal catalyzed
addition of amine or azide onto alkenes.7,8 Although a great
progress has been made on this synthetic topic, it is still remained
65 challenging to develop more efficient and facile approaches to a
broad range of structurally diverse aziridines in enantio- and
diastereoselective manner. In the past several years, we have
designed and synthesized new chiral reagents of N-phosphonyl
and N-phosphinyl amides and imines; we have successfully
70 utilized them in various asymmetric reactions such as asymmetric
aza-Darzen reaction,9a asymmetric aza-Henry reaction,9b
asymmetric addition of allylmagnesium bromides,9c asymmetric
synthesis of N-phosphonyl β-amino Weinreb amides,11a
35 a Department of Chemistry & Biochemistry, Texas Tech University,
Lubbock, Texas 79409-1061, USA. E-mail: Guigen.Li@ttu.edu;
Fax: 001-806-742-1289; Tel: 001-806-742-3015
b School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, P. R. China; E-mail: yipan@nju.edu.cn; cInstitute of
40 Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093,
P. R. China
† Electronic Supplementary Information (ESI) available: Copies of 1H,
13C, 19F, 31P NMR spectra, IR spectra and copies of HRMS analysis for all
45 the new compounds. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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asymmetric synthesis of N-phosphonyl propargyl amines,12a and
asymmetric synthesis of α-amino-1,3-dithianes.12c In our
preliminary work on asymmetric aza-Darzens reaction, we
utilized N,N-dibenzyl N- phosphonyl imines as the electrophiles
to react with pre-generated -bromo lithium enolate to give the
aziridine products in good yields and diastereoselectivities.9a The
important feature of these chiral N-phosphonyl imines is shown
cyclohexane-based
N,N-di-1-naphthylmethylphosphonyl
benzaldimine (5a) and subjected it to the reaction with the pre-
55 generated -bromo lithium enolate. We found the reaction
occurred to completion within a prolonged period of over 8.5
hours, but many impurities were formed with the
diastereoselectivity of dr = 100:42 as revealed by the crude 31P
NMR determination. This observation prove that the N,N-
5
by the fact that the steric and electronic properties can be 60 bisfunctional modifications can result in changes not only on
optimized by making modifications on different positions of the
solubility of products but also on the electrophilicity of N-
phosphonyl imines. We next utilized another chiral imine (5b)
which was available at that time in our labs and found that the
reaction also proceeded at a slower rate with some starting
10 imine auxiliaries. In the continuing project on N-phosphonyl
imines, herein we would like to report a more efficient
asymmetric aza-Darzens reaction by using isopropyl to replace
primary benzyl group for N,N-diamino protection on auxiliary 65 material still remained even after 8.5 h. To make all chiral imine
and by modifying the synthetic operation.
starting materials to be consumed, the reaction was then
performed at room temperature. However, the diastereoselectivity
was not improved much with dr = 100:15 with many impurities
co-existing with the major isomeric product.
15
Results and Discussion
70 In several of our previous systems, the combination of N,N-
diisopropyl and diaminocyclohexyl scaffolds have been proven to
be superior to others in several nucleophilic addition reactions
and syntheses, such as aza-Henry reaction,9b the addition reaction
of allyl magnesium bromide,9c the synthesis of β-amino weinreb
75 amides,11a α,β-diamino esters11d chiral propargyl amines,12a and
umpolung reaction with lithium 1,3-dithianes.12c Therefore, this
combination was considered to enhance the present synthesis of
aziridine-2-carboxylic esters. We now found that (1R, 2R)-
In 1999, one of the great asymmetric methods for synthesizing
aziridine-2-carboxylic esters was reported by Davis and
20 coworkers through N-p-toluenesulfinyl imine-based Darzens
reaction.13 The reaction showed the great success in regard to
chemical yields and diastereoselectivity. Despite the above
approach to these building blocks, we also made efforts on
development of a facile method for the asymmetric synthesis of
25 aziridine-2-carboxylic esters using N-phosphonyl imines as
electrophiles. The advantages of using chiral N-phosphonyl
imines would be showed by the following factors: higher
thermolytic stability, modification and flexibility at their multiple
sites, inertness of phosphonyl group to oxidative conditions, the
30 31P NMR determination of diastereoselectivity and easy recycling
of diamine auxiliary precursors.9-12 Importantly, our N-
phosphonyl and N-phosphinyl imine-based work has resulted in
diaminocyclohexyl
derived
N,N-diisopropyl-N-phosphonyl
80 benzaldimine (5c) can react with -bromo lithium enolate
smoothly to completion within 8 hours. Importantly, we found
that by slowly adding the pre-cooled benzaldimine (5c) solution
in THF at -78 oC into preformed -bromo lithium enolate mixture
at the same temperature in the presence of 4 Å molecular sieves is
85 crucial in terms of yields and diastereoselectivity. With the
optimized conditions in hand, we successfully synthesized
aziridine-2-carboxylic esters with excellent diastereoselectivity
(>99%, almost single diastereomer) as revealed by 31P NMR
determination of crude products. The results were summarized in
90 Table 1.
a
new concept called GAP chemistry (Group-Assisted
Purification chemistry)14 which can enable organic synthesis to
35 be performed without using traditional purification techniques
such as column chromatography and recrystallization, albeit a
few non-GAP exceptions were encountered including the present
aziridine formations in which there is no N-H moiety in the
products.15 In our first aza-Darzens synthesis, we utilized N-
40 benzyl as the protection group on phosphonyl imine auxiliary.
Unfortunately, this auxiliary only showed a limitation on
controlling diastereoselectivities in which only one example gave
an excellent diastereoselectivity of 99% de (Scheme 1).9a
Table 1 Optimizing the stereo effect of chiral N-phosphonyl iminesa
Aux
OLi
N
Br
OCH3
THF, -78 oC
N Aux
O
OCH3
6a-6c
reaction
5a-5c
OLi
Ar
Bn
N
P
N
Bn
80-99% de
H
Aux
Br
drb,c
N
N
Aux
O
entry
1
substrate
auxiliary
OCH3
THF, -78 oC, 6 h
Aux =
time
O
Ar
OCH3
H
3
4
H
H
45
N
O
N
Scheme
1 Synthesis of aziridine-2-carboxylic esters using N,N-
dibenzylphosphonylimines
5a
>8.5 h
100:42
P
In order to achieve more efficient asymmetric synthesis of
aziridine-2-carboxylic esters, we made an effort on the structural
2
5b
>8.5 h
100:15
50 modifications on phosphonyl imine auxiliary by using other
functional groups to replace the original benzyl and by changing
their diamino core structures. We first synthesized the
N
N
P
O

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Br
Cl
Aux
N
N
3
5c
8 h
>99:1
H
H
N
O
N
6
7
69
70
>99:1
>98:2
P
5h
N
Aux
Br
Cl
O
OCH3
6h
Aux
aReaction conditions: 0.57 mmol imine, 1.15 mmol methyl-2-bromo
acetate, 1.20 mmol LiHMDS 14 mL solvent, -78 oC.
bDiastereoselectivities were determined by 31P-NMR analysis of crude
products. c >99:1 means only one isomer was observed by 31P NMR.
5i
N
Aux
O
O
OCH3
6i
Aux
F
N
5
On the basis of the above optimal conditions, the substrate scope
of this reaction was next examined. Besides N,N-
diisopropylphosphonyl imines with both electron donating and
electron withdrawing groups on the aromatic rings (entries 2-15,
Table 2), we also examined substrate scope of two heterocyclic
8
9
79
71
99:1
5j
N
Aux
F
OCH3
6j
OBn
Aux
N
N
10 aldimines to give 85% and 76% yields and excellent
diastereoselectivities (entries 16 and 17, Table 2). For all cases,
isolated yields ranged from 51% to 87% and excellent
diastereoselectivities from 96.2:3.8 to >99:1 were obtained.
Similar to the previous system,9a the major isomeric products
15 were confirmed to be formed in cis-geometry (Table 2).
>99:1
5k
N
Aux
OBn
O
OCH3
6k
Br
Aux
10
11
12
75
61
52
>99:1
>99:1
>99:1
N
Aux
5l
O
Table
2 Asymmetric addition of lithium enolate of methyl 2-
OCH3
Me
6l
Br
bromoacetate onto N,N-diisopropylphosphonyl iminesa
Aux
N
N
Aux
OLi
Ar
Br
Aux
H
H
O
5m
Me
N
OCH3
THF, -78 oC, 8 h
N
N
N
Aux
OCH3
Cl
6m
O
P
Aux =
O
Aux
Ar
4 Å MS
OCH3
6c-6s
N
5c-5s
N
Aux
O
5n
Cl
N
Entry
Substrate
Product
Yield(%)b
78
drc,d
OCH3
F
6n
Aux
N
Aux
1
2
N
Aux
>99:1
13
14
N
Aux
51
73
>99:1
>99:1
5c
O
O
5o
OCH3
6c
F
OCH3
6o
Aux
N
BnO
Aux
N
70
98.8:1.2
98.7:1.7
5d
N
Aux
BnO
5p
O
N
Aux
Aux
6d
OCH3
N
O
MeO
OCH3
6p
5e
Aux
MeO
N
N
Aux
3
4
84
71
15
16
77
85
>99:1
>99:1
O
N
Aux
5q
OCH3
6e
O
Aux
MeS
OCH3
6q
N
O
Aux
N
>99:1
>99:1
5f
N
Aux
MeS
N
Aux
O
5r
OCH3
6f
O
O
S
Aux
Me
OCH3
6r
N
Aux
N
5
S
87
5g
N
Aux
17
76
96.2:3.8
Me
N
Aux
O
5s
O
OCH3 6g
OCH3
6s

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aReaction conditions: 0.57 mmol imine, 1.15 mmol methyl-2-bromo
acetate, 1.20 mmol LiHMDS 14 mL solvent, -78 oC. bIsolated yield of the
pure product. cDiastereoselectivities were determined by 31P-NMR
analysis of crude products. d>99:1 means only diasteroisomer was
5 observed in crude 31P-NMR spectrum.
As anticipated the auxiliary can be successfully cleaved by
treating the aziridine product (6c) with trifluoroacetic acid in
acetone and water co-solvents at room temperature to give the
ring opening product of (2S,3R)-β-hydroxy α-amino acid methyl
40 ester (7a) as major diastereomer (Scheme 2). The cleavage
reaction is used not only for the absolute structure determination,
but also for providing an efficient approach to unnatural amino
acids.16
In addition to N,N-diisopropylphosphonyl imines, we also
examined bromo lithium enolates derived from different bromo
esters. As shown by Table 3, ethyl, isopropyl and tert-butyl
group-derived enolates afforded good chemical yields and
10 excellent diastereoselectivities (>99% dr). The steric effect of
these ester groups did not affect cis-geometry and
diastereoselectivity of the products.
OH
COOCH3
N
Aux
50% Aq. TFA (15.0 equiv)
Acetonitrile
60 °C, 36 h
(90%)
O
NH2
OMe
6c
7a
Table 3 Asymmetric addition of lithium enolates of different 2-
bromoacetates onto N,N-diisopropylphosphonyl benzaldiminea
[]25D = + 10.1 (c = 0.2, MeOH) for (2S,3R);
Lit []20D = - 10.97 (c =1.4 , MeOH)17 for (2R,3S)
45 Scheme 2 Cleavage of the auxiliary and synthesis of (2S,3R)-β-hydroxy
α-amino acid methyl ester
OLi
H
H
Br
Aux
N
N
O
N
OR
N
Aux
P
Aux =
THF, -78 oC, 8 h
O
4 Å MS
Similar to the previous system, a six-membered chair like
transition state was proposed (Figure 3). The lithium metal cation
serves as the Lewis acidic anchor to connect two reaction
50 partners, imine electrophile and enolate nucleophile together,
prior to aza Darzens reaction. This anchored reaction manner
would be responsible for the excellent control of stereochemistry
in which the enolate attacks imine's carbon center on its Re face.
The asymmetric control is indirectly controlled by two nitrogens
55 that are forced to be the original chirality of the nearby (2S,3S)
vicinal centers on cyclohexane ring.
OR
6t-6v
5c
15
Entry
1
R
Product
Yield(%)b
78
drc,d
N
Aux
Ethyl
99.4:0.6
O
O
6t
N
Aux
2
3
Isopropyl
tert-Butyl
77
74
>99:1
>99:1
O
O
6u
N
Aux
O
O
6v
aReaction conditions: 0.57 mmol imine, 1.15 mmol methyl-2-bromo
o
acetate, 1.20mmol LiHMDS 14 mL solvent, -78 C. bIsolated yield of the
pure product. cDiastereoselectivities were determined by 31P-NMR
Fig. 3 Proposed transition state model for the asymmetric aza-Darzens
reaction.
d
analysis of crude products. >99:1 means only one isomer was observed
20 by 31P NMR.
60 Conclusions
As compared to our previous aziridination, the present N,N-
diisopropylphosphonyl imine-based synthesis resulted in much
higher diastereoselectivity. In most cases, only one isomeric
product was observed as proven by the 31P-NMR analysis of
25 resulting crude products. The secondary alkyl group (isopropyl)
is superior to its primary counterpart (benzyl) for cyclohexane
diamino template in controlling asymmetric induction for this
reaction. For many cases, not only diastereoselelectivity but also
chemical yields were increased, particularly, for 4-methyl and 4-
30 fluoro substrates, the yields were increased from 76 % and 64%
to 87% and 79%, respectively (entries 3 and 8, Table 2). The
present synthesis showed the synthesis of twenty (2S,3S)
aziridine-2-carboxylic esters, which may indicate a broader
substrate scope than the previous one.
In conclusion, we have developed an efficient protocol for the
asymmetric synthesis of aziridine-2-carboxylic esters by using
N,N-diisopropyl-N-phosphonyl imines in which the secondary
alkyl is superior to its primary counterpart in providing
65 asymmetric environment. Good yields and excellent
diastereoselectivity have been achieved for a good spectrum of
twenty substrates. A special operation manner by slowly adding
o
the pre-cooled imine solution at -78 C into preformed -bromo
lithium enolate mixture at the same temperature in the presence
70 of 4 Å molecular sieves was found to be crucial for the outcomes.
Experimental Section
35

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column chromatography on silica gel (Rf
=
0.25) using
General experimental methods
55 EtOAc/Hexanes (7:3) as the eluent to afford the aziridine product.
All the reactions were carried out in oven-dried glassware under
an atmosphere of dry argon, unless otherwise stated. All
commercially available reagents were used without further
purification. THF used for the reaction was distilled using
benzophenone-sodium still under nitrogen prior to use. 4 Å
molecular sieves were dried in oven prior to use. Solvents used
for extraction and purification were used directly without further
distillation. Reaction temperatures are reported as bath
o
Compound 6c. White solid: mp 99-101 C; IR (ATR) ν 2965,
2938, 1749, 1455, 1361, 1243, 1198, 1170, 1105, 1058, 1033,
1014, 939, 924, 876, 823, 787, 739, 723 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.44 (d, J = 7 Hz, 2H), 7.36-7.20 (m, 3H), 3.72
60 (dd, J = 15 Hz and 6.5 Hz, 1H), 3.66-3.51 (m, 2H), 3.49 (s, 3H),
3.41 (dd, J = 15 Hz and 6.5 Hz, 1H), 3.09-2.92 (m, 2H), 2.11 (d, J
= 7.5 Hz, 1H), 2.05 (d, J = 10.5 Hz, 1H), 1.91-1.61 (m, 2H), 1.34
(d, J = 7 Hz, 6H), 1.31-1.24 (m, 1H), 1.21 (dd, J = 7.5 Hz and 3.5
Hz, 6H), 1.08 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
65 167.54, 134.09, 127.86, 127.78, 59.99, 58.92, 51.79, 45.53,
44.70, 42.70, 41.98, 31.55, 30.27, 24.23, 23.43, 22.65, 20.28,
20.18; 31P (202 MHz, CDCl3) δ 30.82; HRMS-(ESI) m/z [M+H]+
calcd for C22H35N3O3P, 420.2416; found, 420.2425; [α]D25 = -19.9
(c =1, CHCl3).
5
10 temperatures. NMR data was reported as follows: chemical shifts
in ppm on the δ scale, multiplicity as (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublet, m = multiplet),
coupling constants in (Hz). 1H NMR spectra were recorded at
ambient temperature at 500 MHz. 13C NMR spectra were
15 recorded at ambient temperature at 125 MHz. 31P NMR spectra
were recorded at ambient temperature at 202 MHz. 19F NMR
were recorded at ambient temperature at 376 MHz. 1H NMR
spectra were acquired in CDCl3, chemical shifts were reported as
δ values in ppm and were calibrated according to internal CHCl3
20 (7.26 ppm). For 13C NMR spectra, chemical shifts are reported as
δ values in ppm relative to CDCl3 (77.00 ppm). For 31P NMR
spectra, chemical shifts are reported as δ values in ppm. For 19F
NMR spectra, chemical shifts are reported as δ values in ppm.
Infrared spectra (IR) were obtained on an FTIR
25 spectrophotometer and are reported in wavenumbers (cm-1).
HRMS data was collected at the University of Illinois at Urbana-
Champagne instrumentation facility. Optical rotation values were
taken using AUTOPOL IV automatic polarimeter. Analytical
thin-layer chromatography (TLC) was performed using 0.25mm
30 precoated silica gel plates and the compounds were visualized
with UV light (λ = 254 nm) and/or immersing in iodine stain.
Compounds were purified using flash column chromatography
(forced flow) on silica gel (SiO2) 60 Å (32-63 μm) particle size.
70 Compound 6d. Oily liquid; IR (thin film/NaCl) ν 2935, 2867,
1752, 1728, 1611, 1513, 1455, 1364, 1300, 1243, 1215, 1172,
1107, 1082, 1061, 1024, 929, 826 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.46-7.33 (m, 6H), 7.33-7.27 (m, 1H), 6.90 (d, J = 8.5
Hz, 2H), 5.00 (s, 2H), 3.67 (dd, J = 17.5 Hz and 6 Hz, 1H), 3.63-
75 3.51 (m, 1H), 3.48 (s, 3H), 3.47-3.40 (m, 1H), 3.36 (dd, J = 15 Hz
and 6.5 Hz, 1H), 3.05-2.92 (m, 2H), 2.18-2.07 (m, 1H), 2.06-1.95
(m, 1H), 1.76 (s, 2H), 1.33 (d, J = 7 Hz, 6H), 1.30-1.23 (m, 1H),
1.2 (d, J = 6.5 Hz, 6H), 1.07 (d, J = 7 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 167.52, 158.39, 136.79, 128.86, 128.41, 127.83,
80 127.41, 126.22, 114.10, 69.81, 59.85, 58.81, 51.68, 45.40, 44.57,
42.35, 41.82, 31.43, 30.14, 24.11, 23.33, 22.52, 20.17, 20.05; 31P
(202 MHz, CDCl3) δ 30.80; HRMS-(ESI) m/z [M+H]+ calcd for
25
C29H41N3O4P, 526.2835; found, 526.2842; [α]D = -25.52 (c
=0.76, CHCl3).
85 Compound 6e. White solid: mp 84-86 oC; IR (ATR) ν 2936,
2867, 1748, 1614, 1515, 1456, 1436, 1396, 1367, 1304, 1246,
1217, 1194, 1170, 1107, 1062, 1027, 1010, 995, 921, 879, 829,
General synthetic procedure for the asymmetric aza-Darzens
35 reaction
764, 746, 725 cm-1; H NMR (500 MHz, CDCl3) δ 7.37 (d, J =
1
8.5 Hz, 2H), 6.83 (d, J = 9 Hz, 2H), 3.78 (s, 3H), 3.67 (dd, J = 15
90 Hz and 6.5 Hz, 1H), 3.64-3.53 (m, 1H), 3.51 (s, 3H), 3.49-3.41
(m, 1H), 3.37 (dd, J = 17.5 Hz and 6.5 Hz, 1H), 2.99 (s, 2H), 2.11
(d, J = 6Hz, 1H), 2.04 (d, J = 11 Hz, 1H), 1.78 (s, 2H), 1.34 (d, J
= 7 Hz, 6H), 1.32-1.25 (m, 1H), 1.21 (d, J = 7 Hz, 6H), 1.08 (d, J
= 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.68, 159.21,
95 128.95, 126.07, 113.30, 59.96, 58.93, 55.14, 51.81, 45.52, 44.70,
42.45, 41.94, 31.59, 30.28, 24.27, 23.48, 22.65, 20.27; 31P (202
MHz, CDCl3) δ 30.84; HRMS-(ESI) m/z [M+H]+ calcd for
Into an oven dried and argon flushed reaction vial, 4 Å molecular
sieves were first taken followed by dry THF (7 mL) and methyl
2-bromoacetate (1.15 mmol, 2 equiv) and stirred. Reaction
o
mixture was then cooled to -78 C using dry ice-acetone mixture
40 and lithium bis(trimethylsilylamide) (LiHMDS) (1 M solution in
THF, 1.20 mmol, 2.1 equiv) was added slowly dropwise and the
o
resulting reaction mixture was stirred for 45 min at -78 C. N-
phosphonyl imine (0.57 mmol, 1 equiv, dissolved in 7 mL of dry
THF) properly sealed with a rubber septum in dry argon
25
C23H37N3O4P, 450.2522; found, 450.2511; [α]D = -31.12 (c
=0.75, CHCl3).
o
45 atmosphere, was cooled to -78 C in the same dry ice-acetone
bath for 45 min. After 45 min, the imine was added dropwise via
100
o
a cannula at -78 C and stirring was continued for 8h (reaction
o
Compound 6f. White solid: mp 122-125 C; IR (ATR) ν 2935,
was monitored by TLC and/or crude NMR) at the same
temperature. After confirming the consumption of imine, the
50 reaction mixture was quenched with water (2 mL) and the organic
layer was extracted with ethyl acetate. The organic layers were
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified using flash
2864, 1749, 1494, 1435, 1368, 1245, 1218, 1194, 1163, 1103,
1
1098, 1061, 1028, 997, 925, 883, 823, 746, 727 cm-1; H NMR
(500 MHz, CDCl3) δ 7.34 (d, J = 8 Hz, 2H), 7.13 (d, J = 8 Hz,
105 2H), 3.63 (dd, J = 15 Hz and 6 Hz, 1H), 3.59-3.50 (m, 1H), 3.47
(s, 3H), 3.45-3.39 (m, 1H), 3.35 (dd, J = 15 Hz and 6.5 Hz, 1H),

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2.96 (s, 2H), 2.42 (s, 3H), 2.08 (s, 1H), 2.01 (d, J = 11.5 Hz, 1H),
1.75 (s, 2H), 1.31 (d, J = 7 Hz, 6H), 1.27-1.21 (m, 1H), 1.17 (t, J
3.64 (dd, J = 15 Hz and 6 Hz, 1H), 3.57-3.46 (m, 1H), 3.43 (s,
3H), 3.42-3.37 (m, 1H), 3.33 (dd, J = 15 Hz and 6.5 Hz, 1H),
= 6.5 Hz, 6H), 1.04 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, 60 3.02-2.84 (m, 2H), 2.06 (s, 1H), 1.99 (d, J = 11.5 Hz, 1H), 1.73
CDCl3) δ 167.38, 137.86, 130.73, 128.16, 125.62, 59.87, 58.81,
51.74, 45.40, 44.58, 42.33, 41.89, 31.44, 30.14, 24.12, 23.33,
22.52, 20.13, 15.40; 31P (202 MHz, CDCl3) δ 30.72; HRMS-
(ESI) m/z [M+H]+ calcd for C23H37N3O3PS, 466.2293; found,
466.2305; [α]D25 = -18.13 (c =0.75, CHCl3).
(s, 2H), 1.28 (d, J = 7 Hz, 6H), 1.25-1.18 (m, 1H), 1.15 (t, J = 6.5
Hz, 6H), 1.00 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
167.25, 163.24, 161.28, 129.62, 129.31, 114.66, 59.84, 58.79,
51.66, 45.32, 44.52, 41.81, 31.36, 30.03, 24.06, 23.18, 22.42,
65 20.06; 31P (202 MHz, CDCl3) δ 30.68; 19F NMR (376.17 MHz,
5
CDCl3)
δ
-114.20; HRMS-(ESI) m/z [M+H]+
calcd for
o
25
10 Compound 6g. White solid: mp 120-122 C; IR (ATR) ν 2937,
C22H34FN3O3P, 438.2322; found, 438.2326; [α]D = -30.86 (c
2867, 1749, 1396, 1366, 1249, 1217, 1193, 1164, 1107, 1062,
=0.75, CHCl3).
1
1026, 1010, 923, 881, 821, 759, 746, 726 cm-1; H NMR (500
MHz, CDCl3) δ 7.33 (d, J = 8 Hz, 2H), 7.09 (d, J = 8 Hz, 2H), 70 Compound 6k. Oily liquid: IR (thin film/NaCl) ν 2936, 2868,
3.68 (dd, J = 17.5 Hz and 6 Hz, 1H), 3.63-3.53 (m, 1H), 3.51 (s,
15 3H), 3.48-3.41 (m, 1H), 3.37 (dd, J = 15 Hz and 6.5 Hz, 1H),
2.99 (s, 2H), 2.31 (s, 3H), 2.11 (d, J = 6 Hz, 1H), 2.04 (d, J = 11
Hz, 1H), 1.78 (s, 2H), 1.34 (d, J = 7 Hz, 6H), 1.27 (m, 1H), 1.21
1754, 1730, 1584, 1488, 1449, 1395, 1364, 1246, 1209, 1175,
1106, 1081, 1060, 1026, 955, 928, 903, 878, 815, 791, 734 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 7 Hz, 2H), 7.35 (t, J =
7.5 Hz, 2H), 7.29 (d, J = 7 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.09
(dd, J = 7 Hz, 6H), 1.08 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, 75 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 8 Hz, 1H), 5.03 (s,
CDCl3) δ 167.62, 137.41, 131.023, 128.59, 127.66, 59.96, 58.89,
20 51.79, 45.52, 44.69, 42.72, 41.89, 31.55, 30.29, 24.23, 23.46,
22.65, 21.19, 20.22; 31P (202 MHz, CDCl3) δ 30.87; HRMS-
(ESI) m/z [M+H]+ calcd for C23H37N3O3P, 434.2573; found,
434.2575; [α]D25 = -29.73 (c =0.76, CHCl3).
2H), 3.67 (dd, J = 15 Hz and 6.5 Hz, 1H), 3.61-3.49 (m, 1H),
3.47 (s, 3H), 3.46-3.33 (m, 2H), 2.95 (s, 2H), 2.08 (s, 1H), 2.02
(d, J = 11.5 Hz, 1H), 1.76 (s, 2H), 1.31 (d, J = 7 Hz, 6H), 1.19 (d,
J = 7 Hz, 7H), 1.07 (d, J = 7 Hz, 3H); 13C NMR (125 MHz,
80 CDCl3) δ 167.29, 158.31, 136.86, 135.64, 128.79, 128.30,
127.71, 127.28, 120.37, 114.49, 113.77, 77.25, 77.00, 76.74,
69.70, 59.82, 58.75, 51.67, 45.40, 44.53, 42.59, 41.83, 31.38,
30.12, 24.06, 23.38, 22.47, 20.06; 31P (202 MHz, CDCl3) δ 30.69;
HRMS-(ESI) m/z [M+H]+ calcd for C29H41N3O4P, 526.2835;
o
25 Compound 6h. White solid: mp 139-141 C; IR (ATR) ν 2936,
1752, 1487, 1444, 1389, 1362, 1242, 1216, 1192, 1163, 1103,
1
1063, 1026, 1010, 997, 924, 910, 884, 827, 744, 726 cm-1; H
NMR (500 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 85 found, 526.2829; [α]D25 = -21.01 (c =0.79, CHCl3).
8.5 Hz, 2H), 3.66 (dd, J = 15 Hz and 6.5 Hz, 1H), 3.62-3.52 (m,
o
30 1H), 3.51 (s, 3H), 3.50-3.43 (m, 1H), 3.40 (dd, J = 12.5 Hz and 6
Hz, 1H), 3.06-2.90 (m, 2H), 2.14 (d, J = 6.5 Hz, 1H), 2.03 (d, J =
11.5 Hz, 1H), 1.89-1.67 (m, 2H), 1.37 (d, J = 6.5 Hz, 6H), 1.30-
Compound 6l. White solid: mp 130-132 C; IR (ATR) ν 2981,
2932, 1757, 1400, 1361, 1238, 1219, 1198, 1175, 1140, 1105,
1062, 1042, 1018, 927, 909, 879, 843, 788, 758, 723 cm-1; H
1
1.23 (m, 1H), 1.18 (t, J = 7 Hz, 6H), 1.04 (d, J = 6.5 Hz, 3H); 13
C
90 NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 7.44-7.34 (m, 2H), 7.17
(t, J = 8 Hz, 1H), 3.66 (dd, J = 17.5 Hz and 6.5 Hz, 1H), 3.62-
3.54 (m, 1H), 3.52 (s, 3H), 3.50-3.31 (m, 2H), 3.08-2.93 (m, 2H),
2.12 (s, 1H), 2.05 (d, J = 11.5 Hz, 1H), 1.79 (s, 2H), 1.36 (s, 2H),
1.33 (d, J = 7 Hz, 4H), 1.31-1.24 (m, 1H), 1.21 (dd, J = 6.5 Hz
95 and 3 Hz, 6H), 1.08 (d, J = 7 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 167.30, 136.54, 130.93, 129.465, 126.52, 121.94,
60.06, 58.93, 51.91, 45.54, 44.68, 41.92, 31.48, 30.27, 24.22,
23.36, 22.71, 20.26; 31P (202 MHz, CDCl3) δ 30.50; HRMS-
(ESI) m/z [M+H]+ calcd for C22H34BrN3O3P, 498.1521; found,
NMR (125 MHz, CDCl3) δ 167.35, 133.20, 131.05, 129.55,
35 121.87, 60.01, 58.95, 51.93, 45.50, 44.69, 42.03, 31.51, 30.20,
24.22, 23.38, 22.62, 20.25; 31P (202 MHz, CDCl3) δ 30.59;
HRMS-(ESI) m/z [M+H]+ calcd for C22H34BrN3O3P, 498.1521;
found, 498.1512; [α]D25 = -19.63 (c =0.83, CHCl3).
o
40 Compound 6i. White solid: mp 128-130 C; IR (ATR) ν 2938,
2868, 1752, 1491, 1394, 1362, 1243, 1216, 1192, 1162, 1104,
1086, 1062, 1026, 1011, 998, 923, 909, 886, 825, 745, 727 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 8.5 Hz, 2H), 7.28 (d, J 100 498.1522; [α]D25 = -26.00 (c =0.75, CHCl3).
= 8 Hz, 2H), 3.68 (dd, J = 17.5 Hz and 6.5 Hz, 1H), 3.63-3.53 (m,
45 1H), 3.51 (s, 3H), 3.49-3.37 (m, 2H), 3.08-2.92 (m, 2H), 2.12 (s,
1H), 2.05 (d, J = 12 Hz, 1H), 1.80 (s, 2H), 1.46-1.31 (m, 6H),
1.31-1.24 (m, 1H), 1.21 (t, J = 7 Hz, 6H), 1.06 (d, J = 6.5 Hz,
Compound 6m. Oily liquid: IR (thin film/NaCl) ν 2936, 2867,
1756, 1728, 1460, 1396, 1364, 1201, 1177, 1129, 1106, 1083,
1060, 1028, 930, 830, 780, 742 cm-1; 1H NMR (500 MHz,
3H); 13C NMR (125 MHz, CDCl3) δ 167.36, 133.63, 132.65, 105 CDCl3) δ 7.55 (m, 1H), 7.18-7.07 (m, 2H), 7.04 (m, 1H), 3.71
129.20, 120.10, 60.00, 58.94, 51.90, 45.48, 44.68, 42.02, 31.51,
50 30.20, 24.22, 23.37, 22.61, 20.24; 31P (202 MHz, CDCl3) δ 30.63;
HRMS-(ESI) m/z [M+H]+ calcd for C22H34ClN3O3P, 454.2026;
found, 454.2024; [α]D25 = -35.60 (c =0.86, CHCl3).
(dd, J = 17.5 Hz and 6.5 Hz, 1H), 3.61-3.40 (m, 3H), 3.38 (s, 3H),
3.17-3.05 (m, 1H), 3.03-2.91 (m, 1H), 2.28 (s, 3H), 2.11 (d, J = 8
Hz, 1H), 2.04 (d, J = 8 Hz, 1H), 1.71 (s, 2H), 1.44-1.26 (m, 7H),
1.19 (dd, J = 15 Hz and 7 Hz, 6H), 1.04 (d, J = 6.5 Hz, 3H); 13C
110 NMR (125 MHz, CDCl3) δ 167.57, 136.08, 132.09, 129.14,
128.09, 127.30, 125.14, 59.96, 58.72, 51.53, 45.28, 44.55, 41.25,
40.96, 31.34, 30.12, 24.11, 23.09, 22.58, 20.11, 18.57; 31P (202
MHz, CDCl3) δ 31.60; HRMS-(ESI) m/z [M+H]+ calcd for
Compound 6j. Oily liquid: IR (thin film/NaCl) ν 2937, 2869,
55 1752, 1732, 1605, 1511, 1438, 1396, 1364, 1298, 1212, 1175,
1
1106, 1061, 1026, 929, 881, 831, 770, 726 cm-1; H NMR (500
MHz, CDCl3) δ 7.37 (t, J = 7.5 Hz, 2H), 6.92 (t, J = 9 Hz, 2H),

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C23H37N3O3P, 434.2573; found, 434.2563; [α]D25 = -4.20 (c =0.77,
CHCl3).
2H), 1.36 (d, J = 7 Hz, 7H), 1.22 (dd, J = 15 Hz and 7 Hz, 6H),
1.07 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.43,
60 133.01, 132.84, 131.65, 127.80, 127.58, 127.42, 127.05, 125.89,
125.80, 125.39, 59.95, 58.88, 51.74, 45.48, 44.64, 42.88, 42.04,
31.47, 30.22, 24.15, 23.36, 22.64, 20.18; 31P (202 MHz, CDCl3) δ
30.75; HRMS-(ESI) m/z [M+H]+ calcd for C26H37N3O3P,
470.2573; found, 470.2565; [α]D25 = -20.25 (c =0.77, CHCl3).
65
o
Compound 6n. White solid: mp 122-124 C; IR (ATR) ν 2942,
5
2859, 1751, 1437, 1392, 1360, 1244, 1217, 1199, 1171, 1128,
1105, 1081, 1052, 1030, 1003, 928, 889, 831, 786, 764, 727 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 7.5 Hz, 1H), 7.30 (d, J
= 8 Hz, 1H), 7.25-7.14 (m, 2H), 3.92 (dd, J = 15 Hz and 6.5 Hz,
1H), 3.65-3.38 (m, 6H), 3.08 (t, J = 7.5 Hz, 1H), 3.00 (t, J = 9 Hz,
o
Compound 6r. White solid: mp 98-100 C; IR (ATR) ν 2976,
10 1H), 2.14 (s, 1H), 2.06 (d, J = 10.5 Hz, 1H), 1.80 (s, 2H), 1.37 (s,
3H), 1.33 (d, J = 7 Hz, 4H), 1.21 (d, J = 6.5 Hz, 6H), 1.09 (d, J =
7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.60, 133.77,
2937, 2866, 1745, 1436, 1397, 1365, 1233, 1196, 1168, 1124,
1
1081, 1062, 1019, 981, 925, 873, 819, 801, 767, 750 cm-1; H
NMR (500 MHz, CDCl3) δ 7.48 (s, 1H), 7.31 (s, 1H), 6.44 (s,
132.15, 130.26, 128.86, 128.68, 126.12, 60.10, 58.93, 51.92, 70 1H), 3.62 (s, 3H), 3.60-3.37 (m, 3H), 3.30 (dd, J = 15 Hz and 6.5
45.49, 44.69, 41.29, 40.96, 31.50, 30.22, 24.25, 23.24, 22.67,
Hz, 1H), 3.03-2.83 (m, 2H), 2.14-1.96 (m, 2H), 1.77 (s, 2H), 1.33
(d, J = 7 Hz, 6H), 1.23 (d, J = 6.5 Hz, 4H), 1.18 (d, J = 6.5 Hz,
3H), 1.14 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
167.78, 142.65, 141.73, 119.90, 110.13, 59.91, 58.86, 51.96,
75 45.59, 44.68, 40.78, 36.35, 31.56, 30.23, 24.21, 23.52, 22.46,
20.16; 31P (202 MHz, CDCl3) δ 30.33; HRMS-(ESI) m/z [M+H]+
15 20.29; 31P (202 MHz, CDCl3) δ 31.13; HRMS-(ESI) m/z [M+H]+
25
calcd for C22H34ClN3O3P, 454.2026; found, 454.2018; [α]D
=
+5.60 (c =0.91, CHCl3).
o
Compound 6o. White solid: mp 114-116 C; IR (ATR) ν 2936,
25
20 2867, 1754, 1619, 1492, 1456, 1364, 1234, 1202, 1173, 1094,
calcd for C20H33N3O4P, 410.2209; found, 410.2219; [α]D = -
1
1061, 1028, 930, 822, 779 cm-1; H NMR (500 MHz, CDCl3) δ
51.20 (c =0.80, CHCl3).
Compound 6s. White solid: mp 109-112 C; IR (ATR) ν 2977,
o
7.61 (t, J = 7.5 Hz, 1H), 7.34-7.18 (m, 1H), 7.11 (t, J = 7.5 Hz,
1H), 6.99 (t, J = 7.5 Hz, 1H), 3.90 (dd, J = 15 Hz and 6.5 Hz, 80 2935, 2865, 1755, 1442, 1397, 1366, 1328, 1255, 1218, 1191,
1H), 3.64-3.54 (m, 1H), 3.52 (s, 3H), 3.46 (dd, J = 16 Hz and 6.5
25 Hz, 2H), 3.11-2.92 (m, 2H), 2.12 (d, J = 6.5 Hz, 1H), 2.06 (d, J =
12.5 Hz, 1H), 1.89-1.66 (m, 2H), 1.44-1.29 (m, 7H), 1.22 (d, J =
7 Hz, 6H), 1.09 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
1171, 1144, 1106, 1081, 1057, 1032, 1007, 928, 903, 877, 848,
803, 770, 746, 727 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J
= 5 Hz, 1H), 7.09 (s, 1H), 6.93 (t, J = 4.5 Hz, 1H), 3.85 (dd, J =
15 Hz and 6 Hz, 1H), 3.59 (s, 3H), 3.57-3.26 (m, 3H). 2.98 (s,
167.52, 162.69, 160.73, 129.98, 129.25, 123.44, 121.52, 114.64, 85 2H), 2.11 (s, 1H), 2.07 (d, J = 10 Hz, 1H), 1.77 (s, 2H), 1.33 (d, J
60.04, 58.94, 51.92, 45.52, 44.70, 43.66, 41.26, 37.38, 31.51,
30 30.23, 24.25, 23.32, 22.63, 20.26; 31P (202 MHz, CDCl3) δ 30.89;
19F NMR (376.17 MHz, CDCl3) δ -119.49; HRMS-(ESI) m/z
[M+H]+ calcd for C22H34FN3O3P, 438.2322; found, 438.2317;
[α]D25 = -20.39 (c =0.76, CHCl3).
= 7 Hz, 7H), 1.21 (t, J = 6.5 Hz, 6H), 1.11 (d, J = 7 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 167.38, 137.96, 126.59, 125.16,
59.95, 58.80, 51.97, 45.56, 44.74, 42.41, 39.15, 31.49, 30.19,
24.21, 23.42, 22.46, 20.23; 31P (202 MHz, CDCl3) δ 30.17;
90 HRMS-(ESI) m/z [M+H]+ calcd for C20H33N3O3PS, 426.1980;
found, 426.1974; [α]D25 = -25.46 (c =0.75, CHCl3).
o
Compound 6p. White solid: mp 145-147 C; IR (ATR) ν 2968,
35 2944, 2862, 1729, 1440, 1366, 1333, 1729, 1440, 1366, 1333,
1285, 1246, 1232, 1216, 1198, 1173, 1129, 1060, 1030, 1001,
925, 884, 858, 808, 793, 765, 742 cm-1; 1H NMR (500 MHz,
Compound 6t. Oily liquid: IR (thin film/NaCl) ν 2974, 2935,
2868, 1751, 1725, 1455, 1394, 1370, 1299, 1246, 1196, 1178,
1
CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 7 Hz, 2H), 7.77 (d, 95 1107, 1060, 1026, 955, 925, 809, 740 cm-1; H NMR (500 MHz,
J = 8.5 Hz, 1H), 7.58-7.41 (m, 3H), 4.3 (dd, J = 15 Hz and 6.5
40 Hz, 1H), 3.73 (dd, J = 15 Hz and 6.5 Hz, 1H), 3.66-3.43 (m, 2H),
3.27 (s, 3H), 3.23 (t, J = 9.5 Hz, 1H), 3.04 (t, J = 9.5 Hz, 1H),
2.18 (s, 1H), 2.11 (s, 1H), 1.83 (s, 2H), 1.38 (d, J = 7 Hz, 7H),
CDCl3) δ 7.42 (d, J = 7 Hz, 2H), 7.32-7.16 (m, 3H), 3.98-3.82
(m, 2H), 3.70 (dd, J = 17.5 Hz and 6.5 Hz, 1H), 3.61-3.49 (m,
1H), 3.44 (h, J = 7 Hz, 1H), 3.37 (dd, J = 15 Hz and 6.5 Hz, 1H),
3.08-2.90 (m, 2H), 2.10 (s, 1H), 2.02 (d, J = 13 Hz, 1H), 1.76 (s,
1.26 (d, J = 6.5 Hz, 3H), 1.22 (d, J = 7 Hz, 3H), 1.07 (d, J = 7 Hz, 100 2H), 1.33 (d, J = 6.5 Hz, 6H), 1.19 (dd, J = 10 Hz and 7 Hz, 6H),
3H); 13C NMR (125 MHz, CDCl3) δ 167.67, 133.12, 131.52,
45 129.77, 128.59, 128.01, 126.50, 126.18, 125.59, 125.17, 122.76,
60.18, 58.86, 51.69, 45.50, 44.75, 41.70, 40.76, 31.48, 30.28,
24.28, 23.22, 22.78, 20.31; 31P (202 MHz, CDCl3) δ 31.85;
1.04 (d, J = 7 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 167.01, 134.04, 127.71, 127.60, 77.25, 77.00,
76.74, 60.67, 59.85, 58.83, 45.40, 44.60, 42.43, 42.04, 31.46,
30.14, 24.14, 23.35, 22.50, 20.14, 13.80; 31P (202 MHz, CDCl3) δ
HRMS-(ESI) m/z [M+H]+ calcd for C26H37N3O3P, 470.2573; 105 30.95; HRMS-(ESI) m/z [M+H]+ calcd for C23H37N3O3P,
found, 470.2577; [α]D25 = +83.70 (c =0.75, CHCl3).
434.2573; found, 434.2570; [α]D25 = -34.19 (c =0.75, CHCl3).
50
o
o
Compound 6q. White solid: mp 151-153 C; IR (ATR) ν 2940,
Compound 6u. White solid: mp 114-116 C; IR (ATR) ν 2973,
2860, 1746, 1457, 1392, 1371,1245, 1198, 1166, 1125, 1106,
2933, 2859, 1711, 1455, 1393, 1363, 1287, 1241, 1199, 1171,
1080, 1062, 1018, 960, 927, 883, 866, 842, 822, 752, 723 cm-1; 110 1143, 1107, 1048, 1032, 978, 910, 883, 838, 785, 754, 735 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.88-7.71 (m, 3H),
55 7.59 (d, J = 8 Hz, 1H), 7.44 (p, J = 3.5 Hz, 2H), 3.88 (dd, J = 15
Hz and 6.5 Hz, 1H), 3.72-3.55 (m, 1H), 3.54-3.34 (m, 5H), 3.14-
2.87 (m, 2H), 2.11 (s, 1H), 2.05 (d, J = 10.5 Hz, 1H), 1.78 (s,
1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7 Hz, 2H), 7.34-7.17
(m, 3H), 4.76 (p, J = 6.5 Hz, 1H), 3.72 (dd, J = 15 Hz and 6.5 Hz,
1H), 3.64-3.28 (m, 3H), 3.18-2.87 (m, 2H), 2.31-1.99 (m, 2H),
1.78 (s, 2H), 1.36 (d, J = 7 Hz, 7H), 1.22 (dd, J = 15 Hz and 6.5

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Hz, 6H), 1.06 (d, J = 7 Hz, 3H), 0.92 (t, J = 6.5 Hz, 6H); 13C
NMR (125 MHz, CDCl3) δ 166.66, 134.22, 127.83, 127.67,
127.55, 68.28, 59.89, 58.90, 45.41, 44.66, 42.38, 42.24, 31.54,
30.13, 24.20, 23.41, 22.47, 21.36, 21.25, 20.33, 20.12; 31P (202
MHz, CDCl3) δ 31.09; HRMS-(ESI) m/z [M+H]+ calcd for
Shimizu and T. Takahashi, J. Med. Chem. 1971, 14, 103;
(e) K. R. Kunz, B. S. Iyengar, R. T. Dorr, D. S. Alberts and
W. A. Remers, J. Med. Chem. 1991, 34, 2281; (f) T.
Kuroda, K. Hisamura, I. Matsukuma, Y. Osawa, T. Sugaya,
H. Nishikawa, M. Morimoto, T. Ashizawa, N. Nakamizo
and Y. Otsuji, J. Heterocycl. Chem. 1994, 31, 113;.
5
60
65
70
75
25
C24H39N3O3P, 448.2729; found, 448.2727; [α]D = -35.13 (c
=0.76, CHCl3).
3
4
(a) F. Gerhart, W. Higgins, C. Tardif and J. Ducep, J. Med.
Chem. 1990, 33, 2157; (b) M. E. Tanner and S. Miao,
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o
Compound 6v. White solid: mp 130-133 C; IR (ATR) ν 2971,
10 2934, 2871, 1710, 1455, 1392, 1366, 1348, 1307, 1244, 1214,
1168, 1108, 1084, 1051, 1024, 974, 916, 882, 838, 800, 765, 751
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.5 Hz, 2H),
(a) F. A. Davis, Y. Wu, H. Yan, W. McCoull and K. R.
Prasad, J. Org. Chem. 2003, 68, 2410; (b) S. Stankovic, M.
D’hooghe, S. Catak, H. Eum, M. Waroquier, V. V.
Speybroeck, N. D. Kimpe and H-J. Ha, Chem. Soc. Rev.
2012, 41, 643.
7.34-7.16 (m, 3H), 3.70 (dd, J = 16.5 Hz and 6.5 Hz, 1H), 3.64-
3.51 (m, 1H), 3.51-3.39 (m, 1H), 3.31 (dd, J = 15 Hz and 6.5 Hz,
15 1H), 3.10-2.93 (m, 2H), 2.13 (s, 1H), 2.05 (d, J = 11.5 Hz, 1H),
1.79 (s, 2H), 1.45-1.28 (m, 7H), 1.24 (d, J = 6.5 Hz, 3H), 1.20 (d,
J = 7 Hz, 3H), 1.12 (s, 9H), 1.07 (d, J = 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 166.25, 134.45, 127.92, 127.65, 127.48,
81.29, 59.94, 58.95, 45.43, 44.69, 42.79, 42.09, 31.57, 30.19,
20 27.58, 24.25, 23.42, 22.53, 20.34, 20.19; 31P (202 MHz, CDCl3) δ
31.17; HRMS-(ESI) m/z [M+H]+ calcd for C25H41N3O3P,
462.2886; found, 462.2881; [α]D25 = -33.03 (c =0.77, CHCl3).
5
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Acknowledgements
25
We thank NIH, the National Institute on Drug Abuse and
National Institutes of Health (NIDA, R21DA031860-01, GL). Its
contents are solely the responsibility of the authors and do not
necessarily represent the official views of NIDA, NIH. We also
30 thank the Robert Welch Foundation (D-1361, GL), the
Fundamental Research Funds for the Key Universities (No.
1107020522, YP) and NSF (CHE-1048553) for NMR-instrument
support.
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14
The term “GAP chemistry” is greater to be defined as
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15 Sometimes the GAP aziridination can be achieved by
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