Isothiourea-catalyzed asymmetric synthesis of β-lactams and β-amino esters from arylacetic acid derivatives and N -sulfonylaldimines

Article abstract of DOI:10.1021/jo402590m

The isothiourea HBTM-2.1 (5 mol %) catalyzes the asymmetric formal [2 + 2] cycloaddition of both arylacetic acids (following activation with tosyl chloride) and preformed 2-arylacetic anhydrides with N-sulfonylaldimines, generating stereodefined 2,3-diary

Full text of DOI:10.1021/jo402590m

Article
pubs.acs.org/joc
Isothiourea-Catalyzed Asymmetric Synthesis of β‑Lactams and
β‑Amino Esters from Arylacetic Acid Derivatives and
N‑Sulfonylaldimines
Siobhan R. Smith,† James Douglas,† Hugues Prevet,† Peter Shapland,‡ Alexandra M. Z. Slawin,†
and Andrew D. Smith†,*
†EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.
‡GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: The isothiourea HBTM-2.1 (5 mol %) catalyzes
the asymmetric formal [2 + 2] cycloaddition of both arylacetic
acids (following activation with tosyl chloride) and preformed
2-arylacetic anhydrides with N-sulfonylaldimines, generating stereo-
defined 2,3-diaryl-β-amino esters (after ring-opening) and 3,4-
diaryl-anti-β-lactams, respectively, with high diastereocontrol (up
to >95:5 dr) and good to excellent enantiocontrol. Deprotection
of the N-tosyl substituent within the β-lactam framework was
possible without racemization by treatment with SmI2.
Scheme 1. Lectka’s Route to β-Lactams and β-Amino Esters
INTRODUCTION
■
The β-lactam motif continues to find great importance in the
pharmaceutical and biochemical sciences as well as generate
significant interest from the broader synthetic community.1
Their historically widespread role as antibacterial agents has
come under increased pressure due to recent discoveries of
bacterial strains resistant to current drugs.2 This challenge,
coupled with their emerging use in nonantibacterial therapeutic
areas such as serine protease inhibitors and cholesterol
absorption inhibitors,3 makes the development of synthetic
methods to prepare novel β-lactam based scaffolds a valuable
endeavor.1−3
The most enduring synthetic route to access β-lactams re-
mains the formal [2 + 2] cycloaddition of ketenes and imines4
that was first reported by Staudinger in 1907.5 Chiral auxiliary
methods were used historically to control the relative and ab-
solute product configuration within this process.6 More recent
approaches have detailed, among others,7 the use of chiral
Lewis base catalysis,8 with pioneering work within this area
initially reported by Lectka and co-workers.9 Using cinchona
alkaloid derivative 2, a range of syn-3,4-disubstituted-β-lactams
4 was accessed in typically 45−65% yield and with superb
diastereo- and enantioselectivity (typically >90:10 dr and 99% ee),
derived from the use of in situ generated monosubstituted ketenes
and activated aldimine 1. An alternative two-step β-lactam
formation and ring-opening sequence provided both β-amino
amides and esters in moderate yield (typically 40−60%) and
with excellent diastereo- and enantioselectivity (dr up to 14:1
and up to 96% ee) (Scheme 1). A variety of related synthetic
methods have been investigated, predominantly through Lewis
base catalyzed processes involving isolable disubstituted ketenes
and imines. For example, Fu has used a planar chiral PPY deriv-
ative to selectively generate either syn- or anti-β-lactams using
N-tosyl- and N-triflylaldimines, respectively.10 Alternatively,
NHCs11 have been used by Ye12 and ourselves,13 while Kerrigan14
has used a chiral phosphine to prepare α,α-disubstituted β-lactams
with good to excellent levels of stereocontrol. Despite these
precedents, there remains a clear rationale for the development
Received: November 22, 2013
Published: January 16, 2014
© 2014 American Chemical Society
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of synthetic methods directed toward the synthesis of alternative
substitution patterns within the β-lactam core, especially if such a
process could be rendered both catalytic and asymmetric.
ammonium enolate derived from phenylacetic acid and imine 8.
Using achiral isothiourea DHPB 10 and chiral isothioureas 7, 11,
and 12, the diastereoselectivity of this process was uniformly
excellent (>95:5 dr anti:syn, enty 1−4), generating preferentially
anti-β-lactam 9; however, the yields were variable and the ee
moderate at best (66% ee, Table 1, entry 4). A consistent
Following their induction as acyl-transfer agents by Birman15
and Okamoto,16 the use of isothioureas as Lewis base catalysts
has seen appreciable recent growth, with a range of processes
that utilize these catalysts having been developed.17 Recent
work has showcased their use for the generation of ammonium
enolates from bench stable carboxylic acids via in situ mixed-
anhydride formation as a convenient alternative to using ketenes.
Within this arena, research by Romo and co-workers has
demonstrated the versatility of these catalysts in asymmetric
intramolecular β-lactone formation,18,19 while our own research
has demonstrated this methodology in both intra- and
intermolecular formal [4 + 2] cycloadditions.20 Building upon
this work and that of Connon and co-workers who performed
the functionalization of enolizable anhydrides with a bifunc-
tional squaramide,21 alternative Lewis base mediated ester
enolate equivalents have recently been reported. For example,
Chi and co-workers have utilized activated p-nitrophenyl esters
as azolium enolate precursors,22 while we have used preformed
2-arylacetic anhydrides in ammonium enolate catalyzed cyclo-
additions.23,24 Mindful of these precedents, this paper
demonstrates the ability of isothioureas to provide facile access
to the β-lactam and β-amino ester motifs via an intermolecular
formal [2 + 2] cycloaddition between N-sulfonylaldimines
and ammonium enolates generated using isothiourea catalysis
from a carboxylic acid or isolable anhydride (Scheme 2).25
Table 1. Optimization of Reaction Conditions
a
b
c
activating
agent
T
(°C)
time
dr
yield
% ee
(anti)
entry catalyst
(h) (anti:syn)
(%)
d
1
2
3
4
5
6
7
8
9
10
7
tBuCOCl
tBuCOCl
tBuCOCl
tBuCOCl
tBuCOCl
TsCl
rt
rt
2
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
67
N/A
d
2
37
57
d
11
12
-
rt
2
89
57 (ent)
66
d
rt
2
67
d
rt
2
39
ND
72
7
rt
4.5
2
32
77
58
17
12
12
12
TsCl
rt
88
TsCl
0
5
93
TsCl
−78
18
80
Scheme 2. This Work: Preparation of β-Lactams and
β-Amino Esters
a
Calculated by inspection of the 1H NMR of the crude reaction
mixture. Isolated yield of single diastereoisomer. ee determined by
HLPC analysis on a chiral stationary phase. Yield including pivalic
b
c
d
anhydride contaminent.
problem encountered with the use of pivaloyl chloride was the
isolation of the β-lactam, with products contaminated with
pivalic anhydride that was generated in situ (entries 1−5).
Furthermore, an iPr2NEt base-catalyzed background reaction in
the absence of catalyst was operative under these conditions,
leading to a competitive racemic reaction process that leads to
erosion of product ee (entry 5). To circumvent these issues
associated with the use of pivaloyl chloride, tosyl chloride was
screened as an alternative activating agent for the carboxylic acid.
Pleasingly, a marked increase in ee was observed, and in the case
of benzotetramisole 12 a concurrent increase in isolated yield,
while maintaining the excellent levels of diastereoselectivity
(entry 7). Further optimization via lowering of reaction
temperature to 0 °C was successful in increasing product ee at
the expense of yield, whereas further reduction to −78 °C was
detrimental to both yield and ee (entries 8 and 9).
Applying these conditions to a small selection of arylacetic
acids provided the corresponding 3,4-diaryl β-lactams in mod-
erate to good yield (42−77% yield), excellent diastereoselec-
tivity (exclusively >95:5 dr) and in high levels of enantio-
selectivity (79−88% ee) (Table 2). The relative configuration
within β-lactam 9 was assigned via a combination of NOE and
coupling constant analysis (typically, J = 3.4 Hz),29 with the
absolute configuration assigned by analogy to β-amino ester 17
as anti-(3S,4R).30 Pleasingly, previous efforts directed toward
the catalytic asymmetric synthesis of β-lactams have not pro-
vided efficient access to this anti-3,4-diaryl structural motif.
Additionally, (thiophenyl)acetic acid could also be used in
Although referred to as formal [2 + 2] cycloadditions in this
and the following paper (10.1021/jo402591v), these reactions
could also be described as intermolecular enolate−imine
cyclizations or Gilman−Speeter-type reactions.26 Notably, this
methodology provides access to β-lactams with the distinct
3,4-diaryl anti-stereochemical motif,27,28 in contrast with the
organocatalytic methods previously reported that often give the
syn-diastereoisomer.9−14
RESULTS AND DISCUSSION
■
Reaction Optimization. Following our previous method-
ology, initial studies utilized pivaloyl chloride as an in situ carbox-
ylic acid activating agent, in tandem with a range of isothiourea
catalysts, to promote the formal [2 + 2] cycloaddition of an
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Table 2. Variation of Acid Component
a
b
c
Isolated yield of single anti-diastereoisomer (>95:5 dr). Calculated by inspection of the 1H NMR of the crude reaction mixture. ee determined by
HLPC analysis on a chiral stationary phase.
Table 3. Optimization of Methanolysis Conditions and Catalyst Loading
a
b
c
entry
methanolysis conditions
T (°C)
rt
time (h)
n mol % (7)
% ee
dr (anti:syn)
yield (%)
1
2
3
4
5
6
7
8
9
excess NaN3/MeOH
NaN3 (10 mol %)/MeOH
NaOMe/MeOH
NaOMe/MeOH
BuLi/MeOH
1
20
20
20
20
20
20
10
5
83
85
96
96
95
93
95
99
85
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
24
66
40
53
62
65
53
50
rt
4
rt
2
0
4
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
1
BuLi/MeOH
2.5
2.5
2.5
2.5
BuLi/MeOH
BuLi/MeOH
BuLi/MeOH
1
44
a
b
c
1
ee determined by HLPC analysis on a chiral stationary phase. Calculated by inspection of the H NMR of the crude reaction mixture. Isolated
yield of single anti-diastereoisomer (>95:5 dr).
this protocol, generating 16 with moderate diastereo- and
enantiocontrol.
promoted methanolysis31 provided a reproducible yield of
β-amino ester 17 over multiple runs.32,33 Re-evaluating a range
of chiral isothiourea catalysts in this newly developed protocol
revealed HBTM-2.1 7 to provide marginally better levels of
enantioselectivity (24% yield, 83% ee) over 12 (30% yield, 74%
ee) over the two steps.34 To improve the yield, a further range
of methanolysis conditions were screened (Table 3, entries
1−6). Reducing the quantity of sodium azide to 10 mol %
had a positive effect on yield with comparable diastereo- and
enantioselectivity. Switching to NaOMe/methanol at rt had a
detrimental effect on yield but provided product in high ee,
while lowering the reaction temperature maintained product ee
Although proceeding in excellent diastereo- and good
enantioselectivity, this procedure suffers from typically
moderate and often variable product yields that were not
representative of reaction conversion. This was rationalized as
being due to the instability of the β-lactam products toward
chromatographic purification, and therefore, a range of in situ
derivatization methods was investigated. In our hands, attempted
ring-opening with benzylamine following formation of the
β-lactam, or reduction into the corresponding amino alcohol,
both proved unsuccessful. However, in situ sodium azide
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and led to increased isolated yield (53%) of β-amino ester
17.27 Finally, optimum conditions utilized the generation
of methoxide in situ via the addition of nBuLi to methanol
at −78 °C, which was then added to a solution of the β-lactam,
followed by warming to rt over 1 h to effect ring-opening.
This procedure led to the formation of β-amino ester 17 in
acceptable yield over two steps (62%) and with excellent
diastereo- and enantioselectivity (>95:5 dr and 93% ee).
Furthermore, under these conditions the catalyst loading could
be lowered to 5 mol % without significant erosion of either
yield or enantioselectivity (Table 3, Entry 8). The yields ob-
tained over this two-step procedure are acceptable, reprodu-
cible and are consistent with the findings of Lectka.9
Table 4. Variation of the Acid and Imine Components
β-Amino Ester Series: Scope and Limitations. A range
of arylacetic acids was next tested within this protocol to probe
the reaction scope. Tolylacetic acids proceeded with com-
parable yield (40−61%) to that obtained for the parent
phenylacetic acids, albeit in lower ee (74−87% ee) (Table 4).
2-Tolylacetic acid displayed slightly reduced diastereoselectivity
(90:10 dr, anti:syn) as did 1-naphthyl (90:10 dr, anti:syn),
which is thought to be due to steric effects. Arylacetic acids with
electron donor (−OMe) and halogen substituents also proved
compatible in this process, proceeding with excellent
diastereoselectivity (>95:5 dr) in all cases, with good to ex-
cellent ee (76−98% ee) and in moderate yield (42−56%). In
certain cases, the product ee could be increased to near
enantiopurity via recrystallization of the β-amino ester products
(18, 22) at the expense of isolated yield. Crystallization effects
during purification of both 17 (>99% ee) and 26 (98% ee) are
postulated to account for the higher than average ee obtained in
these cases.
Alternative aryl-substituted N-sulfonylaldimines were next
evaluated in this methodology (Table 4). Phenyl and 2-naphthyl
substitution were well tolerated giving 29 and 30 in good dr
and ee. However, 1-naphthyl and heteroaromatic 2-furyl-
substituted imine (31 and 32) both proceeded with reduced
diastereoselectivity, while the incorporation of a strongly
electron-withdrawing trifluoromethyl unit performed poorly
leading to 33 in greatly reduced enantioselectivity. Variation of
the N-substituent was briefly investigated with an N-nosylimine
providing 34 with comparable results to N-tosyl substitution,
although N-Boc- or N-PMP-aldimines failed to provide any
β-lactam.
2-Arylacetic Anhydrides for β-Lactam Synthesis. While
this two-step procedure is effective at providing a range of anti-
2,3-diaryl-β-amino esters with excellent diastereocontrol and
good to excellent enantiocontrol, reproducible access to the
corresponding β-lactam motif as the direct reaction product
was still desired. Attention therefore turned to simplification of
the reaction components with the aim of aiding purification,
leading to the consideration of 2-arylacetic anhydrides (35)
as alternative ammonium enolate precursors. Treatment of
benzoic anhydride (Ar1 = Ph) and aldimine 8 with HBTM 2.1
7 (5 mol %) and iPr2NEt (1.5 equiv) led to formation of the
β-lactam 9 that could be consistently isolated as the major
reaction product, albeit in low yield (30%). It was postulated
that this low yield was a result of competitive Claisen-type
condensation through addition of the ammonium enolate to
the phenylacetic anhydride, resulting in incomplete imine con-
sumption and so moderate conversion to β-lactam. Further
optimization through dropwise addition of an increased
quantity of anhydride (1.5 equiv), combined with a lower
reaction temperature (−78 °C), improved the yield to 74%
a
b
Isolated yield of single anti-diastereoisomer (>95:5 dr). Calculated
c
by inspection of the 1H NMR of the crude reaction mixture. ee
determined by HLPC analysis on a chiral stationary phase. Isolated
yield of inseparable diastereoisomers. Isolated yield of single anti-
diastereoisomer (>95:5 dr) following recrystallization. Combined
d
e
f
isolated yield of separable diastereoisomers.
with continued excellent diastereoselectivity and reasonable
enantioselectivity (>95:5 dr and 79% ee), that following re-
crystallization could be isolated in 90% ee. Under these
conditions, a range of both 2-arylacetic anhydrides and imines
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Table 5. Variation of the Acid and Imine Components in Reaction from a Preformed Homoanhydride
a
d
f
b
c
1
Dropwise addition. Isolated yield of anti-diastereoisomer (>95:5 dr). Calculated by inspection of the H NMR of the crude reaction mixture.
e
Determined by HLPC analysis on a chiral stationary phase. Isolated yield of single anti-diastereoisomer (>95:5 dr) following recrystallization.
Combined isolated yield of separable diastereoisomers.
were tested, all leading to the isolation of the parent β-lactam
in moderate to good yield (44−74% yield) (Table 5).
Modification of the anhydride portion allowed the incorpo-
ration of a range of aryl and heteroaryl substitution, providing
β-lactams 9, 15, 36, and 37 with good to excellent diastereo-
and enantiocontrol (up to >95:5 dr; ee up to 83%). A selec-
tion of other aryl-substituted N-sulfonylaldimines were also
tolerated, giving β-lactams in similar yield (47−60% yield) and
enantioselectivity (68−92% ee), but with slightly reduced
diastereoselectivity (up to 93:7 dr). Importantly, as opposed to
the original procedure from the arylacetic acid, the use of a
2-arylacetic anhydride allowed consistent isolation of the
β-lactam heterocycle. Additionally, removal of the N-tosyl
substituent of the parent β-lactam without racemization was
possible by treatment with SmI2.35
Control Studies. When using the premade isolable
arylacetic anhydrides as ammonium enolate precursors, slightly
reduced diastereocontrol was observed in formation of the
β-lactam products when compared with the analogous example
in the β-amino ester series accessed directly from the parent
acid. This observation prompted us to investigate the possibility
of in situ product epimerization leading to enhanced
diastereocontrol. To test this hypothesis, the diastereoselectiv-
ity of this process was monitored with time using phenylacetic
acid and imine 42 (Scheme 3, control experiment 1). After
short reaction times and modest conversion, a dr of ca. 85:15
was observed, but after prolonged exposure to the reaction
conditions enhanced diastereocontrol was observed (dr >95:5),
consistent with in situ epimerization. Also, an isolated example
of β-lactam 39 (dr anti:syn 21:79; anti 90% ee; syn 52% ee)
was treated at rt with iPr2NEt (1.5 equiv) and HBTM-2.1 7
(5 mol %) in CH2Cl2, generating (ent)-anti-39 (>95:5 dr,
32% ee) in quantitative yield (Scheme 3, control experiment
2).36 This is consistent with the syn-diastereoisomer having
preferentially the (3S,4S)-configuration and with in situ epimeri-
zation generating ent-39 preferentially. Under identical exper-
imental conditions, a sample of anti-39 (>95:5 dr, 90% ee)
showed no change in dr or ee, consistent with no epimerization
of the anti-β-lactam under the reaction conditions. Finally, given
that the isothiourea catalyzed ring-opening kinetic resolution of
( )-syn-β-lactams has been recently reported by Birman et al.,37
we were mindful of such an effect operating within our own
system. Control investigations indicated the potential for a
moderate, but not significant, resolution effect during the ring-
opening methanolysis step, as treatment of ( )-9 with HBTM-
2.1 7 and NaOMe in MeOH gave β-amino ester 17 (dr >95:5) in
16% ee (Scheme 3, control experiment 3).38
Consistent with our previous reports, we propose a catalytic
cycle that proceeds via generation of an acylammonium species
from either mixed- or homo-anhydride 43 (Scheme 4).
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Scheme 3. Control Experiments
Scheme 4. Proposed Catalytic Cycle and Pre-Transition-
State Assembly
0 and −78 °C obtained using ice/water and CO2(s)/acetone baths,
respectively. 1H NMR spectra were acquired at either 300, 400, or 500
MHz, 13C{1H} NMR spectra were acquired at either 75, 100, or 125 MHz,
and 19F{1H} NMR spectra were acquired at either 282, 376, or
471 MHz. Chemical shifts are quoted in parts per million (ppm)
relative to the residual solvent peak, coupling constants, J, are quoted
1
in hertz (Hz). NMR peak assignments were confirmed using 2D H
COSY, 2D H NOESY, 2D H−13C HMBC, and 2D H−13C HSQC
where necessary. Infrared spectra were recorded as thin films using an
ATR accessory. Mass spectrometry (m/z) data were acquired using
either electrospray ionization (ESI), electron impact (EI), chemical
ionization (CI), atmospheric solids analysis probe (ASAP), atmos-
pheric pressure chemical ionization (APCI), or nanospray ionization
(NSI) using a TOF mass analyzer. Optical rotations were recorded
with a path length of 1 dm and concentrations, c, are quoted in g/100 mL.
All chiral HPLC traces were compared with an authentic racemic trace
prepared using racemic 7 or DHPB 10.
1.2. General Experimental Procedures. General Procedure A.
Asymmetric Formal [2 + 2] Cycloaddition of Arylacetic Acids and
Imines. To a stirred solution of the appropriate carboxylic acid
(1 equiv) in dichloromethane (0.2 M) at 0 °C were added tosyl
chloride (1.5 equiv) and iPr2NEt (1.5 equiv). The solution was stirred
at 0 °C for 20 min. The isothiourea catalyst 12 (20 mol %) and the
imine (1 equiv) were added followed by iPr2NEt (1.5 equiv). The
solution was then stirred at rt for 5 h, quenched using 1 M HCl
(0.2 M), and extracted (3 × EtOAc), and the combined organic layers
were dried (MgSO4) and concentrated in vacuo to give the crude
product which was purified by column chromatography under the
stated conditions to give the β-lactam product.
General Procedure B. Asymmetric Formal [2 + 2] Cycloaddition
of Arylacetic Acids and Imines with in Situ Ring-Opening. To a
stirred solution of the carboxylic acid (1 equiv) in dichloromethane
(0.2 M) at 0 °C were added tosyl chloride (1.5 equiv) and iPr2NEt
(1.5 equiv). The solution was stirred at 0 °C for 20 min. The
isothiourea catalyst, 7 (5 mol %), and the imine (1 equiv) were added
followed by iPr2NEt (1.5 equiv). The solution was then stirred at rt for
5 h. nBuLi (2.5 M) solution in hexanes (55 equiv) was added to
methanol (0.2 M) at −78 °C, and this solution was added by canula to
1
1
1
Deprotonation to generate the (Z)-enolate 45, followed by
addition to the imine furnishes intermediate 46. Intramolecular
cyclization to provide the β-lactam with concurrent catalyst
regeneration completes the cycle. The selective formation
of the anti-β-lactam is postulated by the pre-transition state
assembly 47 depicted below. High facial selectivity toward the
Re face of enolate 45 is controlled by the axial orientation of the
phenyl group, with a potential no→σ*C−S stabilizing interaction
or electrostatic stabilization rigidifying this arrangement.39
Addition of this enolate to the Re face of the imine, occupying
a staggered arrangement about the forming C−C bond, would
account for the observed anti selectivity.
In conclusion, isothioureas catalyze the highly diastereo- and
enantioselective formation of β-lactams and β-amino esters from
arylacetic anhydrides or arylacetic acids and N-sulfonylimines
(typically >90:10 dr). Good to excellent enantioselectivity (up to
>99% ee) is typically observed in the formation of the β-amino
esters, with reduced enantioselectivity but higher isolated pro-
duct yields observed in formation of β-lactams from arylacetic
anhydrides.
EXPERIMENTAL SECTION
■
1.1. General Information. All reactions were performed in open-
flask conditions with bench-grade solvents. All reagents were obtained
from commercial sources and were used without further purification.
Room temperature (rt) refers to 20−25 °C, with temperatures of
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the reaction mixture. After 1 h, the reaction was quenched using water
(0.2 M) and extracted (3 × EtOAc), and the combined organic layers
were dried (MgSO4) and concentrated in vacuo followed by purification
by column chromatography under the stated conditions to give the
β-amino ester product.
General Procedure C. Asymmetric Formal [2 + 2] Cycloaddition
of Homoanhydrides and Imines. To a stirred solution of the imine
(1 equiv) in dichloromethane (0.2 M) at −78 °C were added the
isothiourea catalyst 7 (5 mol %) and iPr2NEt (1.25 equiv) followed by
the anhydride (1.5 equiv) as a solution in dichloromethane (0.25 M)
dropwise (2.3 mL h−1) via syringe pump. The solution was then
warmed to rt and stirred for a further 30 min, quenched using 1 M
HCl (0.2 M), and extracted (3 × EtOAc), and the combined organic
layers were dried (MgSO4) and concentrated in vacuo followed by
purification by column chromatography under the stated conditions to
give the β-lactam product.
132.6 (ArC), 135.4 (Cipso), 135.8 (Cipso), 139.3 (Cipso), 145.7
(NSO2ArC(4)CH3), 165.5 (C(2)); m/z (NSI+) 489 ([M + NH4]+,
100); HRMS (NSI+) m/z [M + NH4]+ calcd for C23H24BrN2O3S+
487.0683, found 487.0686 (−0.5 ppm).
(3S,4R)-4-(4-Bromophenyl)-3-(p-tolyl)-1-tosylazetidin-2-one 14.
The title compound was prepared according to general procedure A
from p-tolylacetic acid (30.0 mg, 0.20 mmol), tosyl chloride (57.3 mg,
0.30 mmol), two portions of iPr2NEt (52 μL, 0.30 mmol), 12 (10 mg,
20 mol %, 0.04 mmol), and imine 8 (70.8 mg, 0.20 mmol) and purified
by chromatography (5:95 EtOAc/petroleum ether) to afford the
β-lactam 14 as a white solid (39.3 mg, 42%): mp 40−44 °C; [α]D22
−2.5 (c 1.0 in CH2Cl2); chiral HPLC analysis, Chiralcel OD-H (20%
iPrOH/hexane, flow rate 1.0 mL min−1, 211 nm, rt), tR major: 13.6
min, tR minor: 16.1 min, 86% ee; νmax (KBr)/cm−1 1795 (CO),
1368 (C−N), 1158 (R-SO2N); δH (400 MHz, CDCl3) 2.31 (3H, s,
C(3)ArCH3), 2.47 (3H, s, NSO2ArCH3), 4.17 (1H, d, J 3.4, C(3)H),
4.87 (1H, d, J 3.4, C(4)H), 6.90 (2H, d, J 8.2, C(3)ArC(2)H), 7.10
(2H, d, J 8.2, C(3)ArC(3)H), 7.15 (2H, d, J 8.3, SO2ArC(2)H), 7.31
(2H, d, J 8.6, C(4)ArC(2)H), 7.46 (2H, d, J 8.5, C(4)ArC(3)H), 7.73
(2H, d, J 8.3, SO2ArC(2)H); δC (100 MHz, CDCl3) 21.3
(C(3)ArCH3), 21.9 (NSO2ArCH3), 64.3 (C(3)), 65.4 (C(4)), 123.1
(C(4)ArC(4)), 127.3 (ArC), 127.7 (C(3)ArC(2)), 128.2
(NSO2ArC(2)), 129.6 (Cipso), 130.0 (ArC), 130.1 (ArC), 132.3
(C(4)ArC(3)), 135.3 (C(3)ArC(1)), 135.7 (SO2ArC(1)), 138.8
(C(3)ArC(4)), 145.7 (SO2ArC(4)), 165.4 (C(2)); m/z (NSI+) 489
([M + NH4]+, 100); HRMS (NSI+) C23H24BrN2O3S+ ([M + NH4]+),
requires 487.0682, found 487.0686 (−0.7 ppm).
1.3. Starting Materials. Isothiourea Catalysts. DHPB, ( )-HBTM-
2.1 ( )-7, (2S,3R)-HBTM-2.1 7, and (+)-benzotetramisole 12 were
synthesized according to literature procedures.15,20d
N-Sulfonylaldimines. (E)-N-(4-Bromobenzylidene)-4-methylben-
zenesulfonamide 8, (E)-4-methyl-N-(naphthalen-2-ylmethylene)-
benzenesulfonamide 42, (E)-N-benzylidene-4-methylbenzenesulfonamide
S1, (E)-N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide S2,
(E)-4-methyl-N-(4-(trifluoromethyl)benzylidene)benzenesulfonamide
S3, (E)-N-(furan-2-ylmethylene)-4-methylbenzenesulfonamide S4, (E)-4-
methyl-N-(naphthalen-1-ylmethylene)benzenesulfonamide S5, and (E)-
N-benzylidene-4-nitrobenzenesulfonamide S6 were synthesized following
literature procedures.13,40
(3S,4R)-4-(4-Bromophenyl)-3-(4-methoxyphenyl)-1-tosylazetidin-
2-one 15. The title compound was prepared according to general
procedure A from p-methoxyphenylacetic acid (33.0 mg, 0.20 mmol),
tosyl chloride (57.3 mg, 0.30 mmol), two portions of iPr2NEt (52 μL,
0.30 mmol), 12 (10 mg, 20 mol %, 0.04 mmol), and imine 8 (70.8 mg,
0.20 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to afford the β-lactam 15 as a white solid (62.0
mg, 67%): mp 32−36 °C; [α]D22 −30.0 (c 1.0 in CH2Cl2); chiral HPLC
analysis, Chiralcel OD-H (10% iPrOH/hexane, flow rate 1.0 mL
min−1, 211 nm, rt), tR minor: 33.4 min, tR major: 42.0 min, 86% ee;
νmax (film)/cm−1 1792 (CO), 1514, 1167 (R-SO2N); δH (400 MHz,
CDCl3) 2.47 (3H, s, NSO2ArCH3), 3.77 (3H, s, OCH3), 4.19 (1H, d,
J 3.4, C(3)H), 4.85 (1H, d, J 3.4, C(4)H), 6.01 (2H, d J 8.8, ArH),
6.93 (2H, d J 8.5, ArH), 7.15 (2H, d, J 8.3, ArH), 7.31 (2H, m, ArH),
7.45 (2H, d, J 8.5, ArH), 7.73 (2H, d, J 8.3, ArH); δC (100 MHz,
CDCl3) 21.9 (NSO2ArCH3), 55.5 (OCH3), 64.1 (C(3)), 65.6 (C(4)),
114.8 (ArC), 123.2, (Cipso), 124.6 (Cipso), 127.7 (ArC), 128.2 (ArC),
128.6 (ArC), 130.1 (ArC), 132.3 (ArC), 135.4 (Cipso), 135.7 (Cipso),
145.7 (NSO2ArC(4)CH3), 159.8 (C(3)ArC(4)OMe), 165.7 (C(2));
m/z (NSI+) 505 ([M + NH4]+, 100); HRMS (NSI+) m/z [M + H]+
calcd for C23H21BrNO4S+ 486.0368, found 486.0369 (−0.2 ppm).
(3S,4S)-4-(4-Bromophenyl)-3-(phenylthio)-1-tosylazetidin-2-one
16. The title compound was prepared according to general procedure
A from (phenylthio)acetic acid (33.6 mg, 0.20 mmol), tosyl chloride
(57.3 mg, 0.30 mmol), two portions of iPr2NEt (52 μL, 0.30 mmol),
12 (10 mg, 20 mol %, 0.04 mmol), and imine 8 (70.8 mg, 0.20 mmol)
and purified by chromatography (10:90 EtOAc/petroleum ether) to
afford the β-lactam 16 as a white solid (40.7 mg, 42% as a mixture of
syn:anti 85:15). Anti: isolated white solid (8.3 mg, 14%); mp 78−84 °C;
[α]2D2 +7.0 (c 0.1 in CHCl3); chiral HPLC analysis, Chiralcel OD-H (10%
iPrOH/hexane, flow rate 1.0 mL min−1, 211 nm, 30 °C), tR major: 16.1
min, tR minor: 20.8 min, 61% ee; νmax (film)/cm−1 1790 (CO),
1366 (C−N), 1170 (R-SO2N); δH (400 MHz, CDCl3) 2.46 (3H, s,
NSO2ArCH3), 4.11 (1H, d, J 3.2, C(3)H), 4.70 (1H, d, J 3.2, C(4)H),
7.12−7.24 (2H, m, ArH), 7.21−7.30 (5H, m, ArH), 7.42−7.47 (4H,
m, ArH), 7.57−7.59 (2H, m, ArH); δC (100 MHz, CDCl3) 21.9
(NSO2ArCH3), 61.5 (C(3)), 63.6 (C(4)), 123.5 (CBr), 127.9 (Ph),
128.1 (Ph), 128.6 (ArC), 129.3 (ArC), 129.6 (ArC), 130.1 (ArC),
132.3 (ArC), 134.5 (ArC), 134.5 (Cipso), 135.3 (Cipso), 145.6 (CMe),
163.2 (C(2)); m/z (ESI+) 512 ([M + Na]+, 100); HRMS (NSI+) m/z
[M + Na]+ calcd for C22H18BrNO3S2Na+ 509.9798, found 509.9804
(−1.1 ppm). Syn: from mixture of diastereoisomers, selected data δH
(400 MHz, CDCl3) 2.49 (3H, s, NSO2ArCH3), 4.79 (2H, d, J 6.4,
Anhydrides. 2-Phenylacetic anhydride 35, 2-(4-methoxyphenyl)-
acetic anhydride S7, 2-(naphthalen-2-yl)acetic anhydride S8, and 2-
(thiophene-2-yl)acetic anhydride S9 were synthesized following
literature procedures.23
1.4. Experimental Procedures. (3S,4R)-4-(4-Bromophenyl)-3-
phenyl-1-tosylazetidin-2-one 9. The title compound was prepared
according to general procedure A from phenyl acetic acid (27.2 mg,
0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two portions of
iPr2NEt (52 μL, 0.30 mmol), 12 (10 mg, 20 mol %, 0.04 mmol), and
imine 8 (70.8 mg, 0.20 mmol) and purified by chromatography
(5:95−10:90 EtOAc/petroleum ether) to afford the β-lactam 9 as a
white solid (52.7 mg, 58%): mp 60−64 °C; [α]2D2 −2.3 (c 1.0 in
CH2Cl2); chiral HPLC analysis, Chiralcel OD-H (10% iPrOH/hexane,
flow rate 1.0 mL min−1, 211 nm, rt), tR minor: 19.4 min, tR major:
21.0 min, 93% ee; νmax (KBr)/cm−1 1797 (CO), 1369 (C−N), 1172
(R-SO2N); δH (400 MHz, CDCl3) 2.48 (3H, s, SO2ArCH3), 4.22 (1H,
d, J 3.4, C(3)H), 4.92 (1H, d, J 3.4, C(4)H), 7.04 (2H, m, ArH), 7.18
(2H, m, ArH), 7.32 (5H, m, ArH), 7.47 (2H, m, ArH), 7.75 (2H, m,
ArH); δC (100 MHz, CDCl3) 21.8 (SO2ArCCH3), 64.4. (C(3)), 65.1
(C(4)), 123.4 (CBr), 127.3 (Ph), 127.6 (Ph), 128.1 (Ph), 128.6 (ArC),
129.3 (ArC), 130.0 (ArC), 132.2 (Ph), 132.5 (Cipso), 135.2 (Cipso),
135.6 (Cipso), 145.6 (CMe), 165.2 (C(2)); m/z (NSI+) 475 ([M +
NH4]+, 100); HRMS (NSI+) m/z [M + NH4]+ calcd for C22H22BrN2O3S+
473.0528, found 473.0539 (−0.2 ppm).
(3S,4R)-4-(4-Bromophenyl)-3-(m-tolyl)-1-tosylazetidin-2-one 13.
The title compound was prepared according to general procedure A
from m-tolylacetic acid (30.0 mg, 0.20 mmol), tosyl chloride (57.3 mg,
0.30 mmol), two portions of iPr2NEt (52 μL, 0.30 mmol), 12 (10 mg,
20 mol %, 0.04 mmol), and imine 8 (70.8 mg, 0.20 mmol) and purified
by chromatography (10:90 EtOAc/petroleum ether) to afford the β-
lactam 13 as a white solid (50.2 mg, 53%): mp 130−134 °C; [α]D22
−2.6 (c 1.0 in CH2Cl2); chiral HPLC analysis, Chiralcel OD-H (20%
iPrOH/hexane, flow rate 0.25 mL min−1, 211 nm, rt), tR minor:
45.0 min, tR major: 51.5 min, 79% ee; νmax (KBr)/cm−1 1806 (CO),
1370 (C−N), 1172 (R-SO2N); δH (400 MHz, CDCl3) 2.25 (3H, s,
NSO2ArCH3), 2.47 (3H, s, C(3)ArCH3) 4.15 (1H, d, J 3.4, C(3)H)
4.87 (1H, d, J 3.4, C(4)H), 6.72 (1H, s, ArH), 6.80 (1H, d, J 7.7, ArH),
6.71 (1H, d, J 7.7, ArH), 7.18 (3H, m, ArH), 7.33 (2H, d, J 8.3, ArH),
7.46 (2H, d, J 8.4, ArH), 7.76 (2H, d, J 8.3, ArH); δC (100 MHz,
CDCl3) 21.4 (NSO2ArCH3), 21.9 (C(3)ArCH3), 64.8 (C(3)), 65.3
(C(4)), 123.3 (ArC(4)Br), 124.7 (ArC), 127.7 (ArC), 127.8 (ArC),
128.3 (ArC), 129.2 (ArC), 129.5 (ArC), 130.2 (Cipso), 132.3 (ArC),
1632
dx.doi.org/10.1021/jo402590m | J. Org. Chem. 2014, 79, 1626−1639

The Journal of Organic Chemistry
Article
CH), 5.35 (2H, d, J 6.1, CH), 6.99−7.02 (2H, m, ArH), 7.71−7.76
(2H, m, ArH); chiral HPLC analysis, Chiralcel OD-H (10% iPrOH/hexane,
flow rate 1.0 mL min−1, 211 nm, 24 °C), tR major: 25.9 min, tR major:
33.6 min, 62% ee.
minor: 39.9 min, tR major: 42.8 min, 74% ee; νmax (film)/cm−1 3248.1
(NH), 1736 (CO), 1159 (R-SO2N); δH (400 MHz, CDCl3)
2.23 (3H, s, C(2)ArC(3)CH3), 2.34 (3H, s, C(3)NHSO2ArCH3), 3.60
(3H, s, OCH3), 3.90 (1H, d, J 6.6, C(2)H), 4.79 (1H, dd, J 8.9, 6.7,
C(3)H), 6.14 (1H, d, J 8.9, NH), 6.91−6.93 (4H, m, ArH), 7.00 (3H,
d, J 7.9, ArH), 7.07 (1H, t, J 7.9, C(2)ArC(3)H), 7.22 (2H, d, J 8.5,
ArH), 7.32 (2H, d, J 8.3, ArH); δC (100 MHz, CDCl3) 21.5
(C(2)ArC(3)CH3), 21.6 (C(3)NHSO2ArCH3), 52.6 (OCH3), 57.4
(C(2)), 60.6 (C(3)), 121.6 (CBr), 125.6 (C(3)ArC(2)), 126.9 (ArC),
128.7 (2 × ArC), 128.8 (ArC), 129.2 (ArC), 129.3 (ArC), 131.4
(ArC), 134.4 (C(2)ArC(1)), 137.6 (C(3)NHSO2ArC(1)), 138.0
(C(3)ArC(1)), 138.5 (C(2)ArC(3)), 143.0 (C(3)NHSO2ArC(4)),
172.3 (C(1)); m/z (NSI+) 214 (100), 519 ([M + NH4]+, 40); HRMS
(NSI+) m/z [M + H]+ calcd for C24H25BrNO4S+ 502.0681, found
502.0682 (−0.2 ppm).
(2S,3R)-Methyl 3-(4-bromophenyl)-3-(4-methylphenylsulfonami-
do)-2-(p-tolyl)propanoate 20. The title compound was prepared
according to general procedure B from p-tolylacetic acid (30 mg,
0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two portions of
iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi
(2.5 M) solution in hexanes (0.1 mL, 11 mmol), and imine 8
(70.8 mg, 0.20 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 20 as a white solid (45.8 mg,
46%): mp 163−168 °C; [α]2D2 −26.0 (c 0.25 in CHCl3); chiral HPLC
analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 0.5 mL
min−1, 211 nm, 30 °C), tR major: 33.9 min, tR minor: 38.3 min, 87%
ee; νmax (film)/cm−1 3252 (NH), 1736 (CO), 1352.1 (R-SO2N),
1159.2 (R-SO2N); δH (400 MHz, CDCl3) 2.28 (3H, s, C(2)ArCH3),
2.35 (3H, s, C(3)NHSO2ArCH3), 3.59 (3H, s, OCH3), 3.89 (1H, d,
J 6.5, C(2)H), 4.77 (1H, dd, J 8.8, 6.5, C(3)H), 6.03 (1H, d, J 8.8,
NH), 6.91 (2H, d, J 8.4, C(3)ArC(2)H), 6.99−7.02 (6H, m, ArH),
7.22 (2H, d, J 8.5, C(3)ArC(3)H), 7.33 (2H, d, J 8.3, C(3)-
NHSO2ArC(2)H); δC (100 MHz, CDCl3) 21.3 (C(2)ArCH3), 21.6
(C(3)NHSO2ArCH3), 52.5 (OCH3), 57.1 (C(2)), 60.6 (C(3)), 121.6
(ArCBr), 127.0 (C(3)NHSO2ArC(2)), 128.8 (C(3)ArC(2)), 128.4
(ArC), 129.3 (C(3)NHSO2ArC(3)), 129.6 (ArC), 131.4 (C(2)-
ArC(1)), 131.5 (C(3)ArC(3)), 137.6 (C(3)NHSO2ArC(1)), 137.9
(C(2)ArC(4)), 138.0 (C(3)ArC(1)), 143.0 (C(3)NHSO2ArC(4)),
172.4 (C(1)); m/z (NSI+) 519 ([M + NH4]+, 45), 526 (100); HRMS
(NSI+) m/z [M + H]+ calcd for C24H25BrNO4S+ 502.0681, found
502.0682 (−0.2 ppm).
(2S,3R)-Methyl-3-(4-bromophenyl)-3-(4-methylphenylsulfonami-
do)-2-phenylpropanoate 17. The title compound was prepared
according to general procedure B from phenylacetic acid (27 mg,
0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two portions of
iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi
(2.5 M) solution in hexanes (0.1 mL, 55 eq, 11 mmol), and imine 8
(70.8 mg, 0.20 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 17 as a white solid (49.0 mg,
50%): mp 156−159 °C; [α]2D2 −24.3 (c 1 in CHCl3); chiral HPLC anal-
ysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL min−1,
211 nm, 30 °C), tR minor: 29.0 min, tR major: 42.7 min, 99% ee; νmax
(film)/cm−1 3237 (NH), 1740 (CO), 1331 (R-SO2N), 1153
(R-SO2N); δH (400 MHz, CDCl3) 2.35 (3H, s, ArCH3), 3.61 (3H,
s, OCH3), 3.92 (1H, d, J 6.45, C(2)H), 4.80 (1H, dd, J 8.82, 6.53,
C(3)H), 5.98 (1H, d, J 8.64, NH), 6.89−6.91 (2H, m, C(3)ArC(2)H),
7.01 (2H, d, J 7.95, C(3)NHSO2ArC(3)H), 7.13−7.16 (2H, m, ArH),
7.20−7.23 (5H, m, ArH), 7.33 (2H, d, J 8.29, C(3)NHSO2Ar(2)H);
δC (100 MHz, CDCl3) 21.6 (ArCH3), 52.6 (OCH3), 57.5 (C(2)), 60.6
(C(3)), 121.7 (ArCBr), 127.0 (C(3)NHSO2ArC(2)), 128.1 (ArC),
128.6 (ArC), 128.7 (ArC), 128.9 (C(3)ArC(2)), 129.3 (C(3)-
NHSO2ArC(3)), 131.5 (ArC), 134.5 (C(2)ArC(1)), 137.5 (C(3)-
NHSO2ArC(1)), 137.8 (C(3)ArC(1)), 143.1 (C(3)NHSO2ArC(4)),
172.2 (C(1)); m/z (NSI+) 507 ([M + NH4]+, 100); HRMS (NSI+)
m/z [M + H]+ calcd for C23H23BrNO4S+ 488.0523, found 488.0526
(−0.5 ppm).
(2S,3R)-Methyl-3-(4-bromophenyl)-3-(4-methylphenylsulfonami-
do)-2-(o-tolyl)propanoate 18. The title compound was prepared
according to general procedure B from o-tolylacetic acid (150 mg,
1.0 mmol), tosyl chloride (286.5 mg, 1.50 mmol), two portions of
iPr2NEt (260 μL, 1.50 mmol), 7 (15.5 mg, 5 mol %, 0.05 mmol),
nBuLi (2.5 M) solution in hexanes (0.5 mL, 55 mmol), and imine 8
(354.0 mg, 1.0 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 18 as a white solid (304.5 mg,
61%): mp 124−128 °C; [α]2D2 −17.2 (c 0.25 in CHCl3); chiral HPLC
analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL
min−1, 211 nm, 30 °C), tR minor: 16.7 min, tR major: 24.2 min, 76%
ee; νmax (film)/cm−1 3246.2 (NH), 1746 (CO), 1163 (R-SO2N); δH
(400 MHz, CDCl3) 2.20 (3H, s, C(2)ArCH3), 2.34 (3H, s,
C(3)NHSO2ArCH3), 3.59 (3H, s, OCH3), 4.20 (1H, d, J 6.8 Hz,
C(2)H), 4.76 (1H, dd, J 8.7, 6.8, C(3)H), 6.30 (1H, d, J 8.8, NH),
6.93−6.96 (2H, m, C(3)ArC(2)H), 6.99−7.02 (3H, m, ArH), 7.07−
7.09 (2H, m, C(2)ArC(4)H and C(2)ArC(5)H), 7.19−7.21 (2H, m,
C(3)ArC(3)H), 7.26−7.28 (1H, m, C(2)ArC(6)H), 7.33 (2H, d, J 8.3,
C(3)NHSO2ArC(2)H); δC (100 MHz, CDCl3) 19.7 (C(2)ArC(2)
CH3), 21.6 (C(3)NHSO2ArCH3), 52.5 (CH3O), 52.9 (C(2)), 59.5
(C(3)), 121.6 (CBr), 126.5 (C(3)NHSO2ArC(2)), 126.9 (C(2)ArC(4)),
127.8 (C(2)ArC(6)), 128.0 (C(2)ArC(5)), 128.7 (C(3)ArC(2)), 129.3
(ArC), 130.9 (ArC), 132.9 (C(3)ArC(3)), 133.0 (C(2)ArC(1)), 135.9
(C(2)ArC(2)), 137.4 (C(3)ArC(1)), 138.0 (C(3)NHSO2ArC(1)), 143.0
(C(3)NHSO2ArC(4)), 172.6 (C(1)); m/z (NSI+) 521 ([M + NH4]+,
100); HRMS (NSI+) m/z [M + H]+ calcd for C24H25BrNO4S+ 502.0682,
found 502.0682 (−0.0 ppm). This was recrystallized from CH2Cl2/
petroleum ether to give the β-lactam as a white solid (209.7 mg, 42%):
mp 116−120 °C; [α]2D2 −12.0 (c 0.5 in CHCl3); chiral HPLC analysis,
ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL min−1,
211 nm, 30 °C), tR minor: 16.7 min, tR major: 24.2 min, 97% ee.
(2S,3R)-Methyl 3-(4-Methylphenylsulfonamido)-3-phenyl-2-(m-
tolyl)propanoate 19. The title compound was prepared according
to general procedure B from m-tolylacetic acid (30 mg, 0.20 mmol),
tosyl chloride (57.3 mg, 0.30 mmol), two portions of iPr2NEt (52 μL,
0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi (2.5 M) solution
in hexanes (0.1 mL, 11 mmol), and imine 8 (70.8 mg, 0.20 mmol) and
purified by chromatography (20:80 EtOAc/petroleum ether) to give
β-amino ester 19 as a white solid (40.7 mg, 40%): mp 124−130 °C;
[α]2D2 −25.0 (c 0.1 in CHCl3); chiral HPLC analysis, ChiralPak AD-H
(20% iPrOH/hexane, flow rate 1.0 mL min−1, 211 nm, 30 °C), tR
(2S,3R)-Methyl 3-(4-Bromophenyl)-3-(4−2-(naphthalene-1-yl)-
propanoate 21. The title compound was prepared according to
general procedure B from 1-naphthylacetic acid (37.2 mg, 0.20 mmol),
tosyl chloride (57.3 mg, 0.30 mmol), two portions of iPr2NEt (52 μL,
0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi (2.5 M) solution
in hexanes (0.1 mL, 11 mmol), and imine 8 (70.8 mg, 0.20 mmol) and
purified by chromatography (20:80 EtOAc/petroleum ether) to give
β-amino ester 21 as a white solid (49.8 mg, 46%): mp 122−128 °C;
[α]2D2 −12.2 (c 0.5 in CHCl3); chiral HPLC analysis, ChiralPak AD-H
(20% iPrOH/hexane, flow rate 1.0 mL min−1, 270 nm, 30 °C), tR
major: 24.9 min, tR minor: 30.6 min, 82% ee; νmax (film)/cm−1 3244.3
(NH), 1736 (CO), 1331 (R-SO2N), 1157 (R-SO2N); δH (400
MHz, CDCl3) 2.24 (3H, s, ArCH3), 3.57 (3H, s, OCH3), 4.82 (1H, d,
J 4.7, C(2)H), 4.86−4.89 (1H, m, C(3)H), 6.47 (1H, d, J 8.7,
NH), 6.74 (2H, d, J 8.0, C(3)NHSO2ArC(3)H), 7.07−7.10 (2H, m,
C(3)NHSO2ArC(2)H), 7.21−7.25 (2H, m, C(3)ArC(2)H), 7.27−
7.37 (4H, m, ArH), 7.46−7.58 (2H, m, ArH), 7.69 (1H, d, J 7.9, ArH),
7.79−7.82 (1H, m, ArH), 7.90 (1H, d, J 8.4, ArH); δC (100 MHz,
CDCl3) 21.5 (ArCH3), 52.2 (C(2)), 52.6 (OCH3), 58.7 (C(3)), 121.8
(CBr), 121.82 (ArC), 125.4 (ArC), 125.9 (ArC), 126.1 (ArC), 126.4
(C(3)NHSO2ArC(2)), 127.1 (ArC)), 128.5 (C(3)ArC(2)), 128.9
(ArC), 129.0 (C(3)NHSO2ArC(3)), 129.5 (ArC), 130. Two (Cipso),
130.7 (Cipso), 131.75 (ArC), 134.2 (Cipso), 136.9 (C(3)-
NHSO2ArC(1)), 139.0 (C(3)ArC(1)), 142.6 (ArC(4)CH3), 172.8
(C(1)); m/z (NSI+) 555 ([M + NH4]+, 45), 562 (100); HRMS
(NSI+) m/z [M + H]+ calcd for C27H25BrNO4S+ 538.0680, found
538.0682 (−0.4 ppm).
(2S,3R)-Methyl 3-(4-bromophenyl)-3-(4-methylphenylsulfonamido)-
2-(naphthalen-2-yl)propanoate 22. The title compound was prepared
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according to general procedure B from 2-naphthylacetic acid (186.0 mg,
1.0 mmol), tosyl chloride (286.5 mg, 1.50 mmol), two portions of
iPr2NEt (260 μL, 1.50 mmol), 7 (15.5 mg, 5 mol %, 0.05 mmol),
nBuLi (2.5 M) solution in hexanes (0.5 mL, 55 mmol), and imine 8
(354.0 mg, 1.0 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 22 as a white solid (368.5 mg,
68%): mp 164−170 °C; [α]2D2 −35.8 (c 0.25 in CHCl3); chiral HPLC
analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL
min−1, 220 nm, 30 °C), tR major: 24.0 min, tR minor: 27.7 min, 85%
ee; νmax (film)/cm−1 3210 (NH), 1711 (CO), 1337 (R-SO2N),
1163 (R-SO2N); δH (400 MHz, CDCl3) 2.17 (3H, s, ArCH3), 3.61
(3H, s, OCH3), 4.13 (1H, d, J 6.0, C(2)H), 4.87 (1H, dd, J 9.0, 5.9,
C(3)H), 6.23 (1H, d, J 9.0, NH), 6.72 (2H, d, J 7.9, C(3)-
NHSO2ARC(3)H), 7.04−7.07 (2H, m, C(3)ArC(2)H), 7.20−7.23
(3H, m, ArH), 7.26−7.29 (2H, m, C(3)ArC(3)H), 7.46−7.49 (2H, m,
ArH), 7.56 (1H, d, J 1.2, C(2)ArC(3)H), 7.60−7.63 (1H, m, ArH),
7.67−7.70 (1H, m, ArH), 7.74−7.77 (1H, m, ArH); δC (100 MHz,
CDCl3) 21.5 (ArCH3), 52.6 (OCH3), 57.3 (C(2)), 60.6 (C(3)), 121.8
(CBr), 126.0 (ArC), 126.5 (2 × ArC), 126.6 (C(3)NHSO2ArC(2)),
127.6 (C(2)ArC(3)), 127.7 (ArC), 128.1 (ArC), 128.6 (C(3)ArC(2)),
128.7 (C(3)ArC(2)), 129.1 (C(3)NHSO2ArC(3)), 131.6 (C(3)-
ArC(3)), 131.9 (C(2)ArC(2)), 132.9 (Cipso), 133.2 (Cipso), 137.2
(C(3)NHSO2ArC(1)), 138.3 (C(3)ArC(1)), 142.9 (ArC(4)CH3), 172.2
(C(1)); HRMS (NSI+) m/z [M + NH4]+ calcd for C27H28BrN2O4S+
555.0945, found 555.0948 (−0.5 ppm). This was recrystallized from
CH2Cl2/petroleum ether to give the β-lactam as a white solid (222.2 mg,
41%); mp 106−112 °C; [α]D22 −39.0 (c 0.5 in CHCl3); chiral HPLC
analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL min−1,
220 nm, 30 °C), tR major: 24.0 min, tR minor: 27.7 min, 91% ee.
(2S,3R)-Methyl 3-(4-Bromophenyl)-2-(4-methoxyphenyl)-3-(4-
methylphenylsulfonamido)propanoate 23. The title compound
was prepared according to general procedure B from p-methox-
yphenylacetic acid (33.0 mg, 0.20 mmol), tosyl chloride (57.3 mg,
0.30 mmol), two portions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg,
5 mol %, 0.01 mmol), nBuLi (2.5 M) solution in hexanes (0.1 mL, 11
mmol), and imine 8 (70.8 mg, 0.20 mmol) and purified by
chromatography (20:80 EtOAc/petroleum ether) to give β-amino
ester 23 as a white solid (43.2 mg, 42%): mp 168−172 °C; [α]D22
−27.6 (c 0.5 in CHCl3); chiral HPLC analysis, ChiralPak AD-H (20%
iPrOH/hexane, flow rate 1.0 mL min−1, 220 nm, 30 °C), tR major:
24.1 min, tR minor: 27.1 min, 76% ee; νmax (film)/cm−1 3254 (NH),
1734 (CO), 1157 (R-SO2N); δH (400 MHz, CDCl3) 2.35 (3H, s,
ArCH3), 3.60 (3H, s, C(1)(O)OCH3), 3.76 (3H, s, ArOCH3), 3.86
(1H, d, J 6.66, C(2)H), 4.73−4.77 (1H, dd, J 8.79, 6.49, C(3)H),
5.97−5.99 (1H, d, J 8.89, NH), 6.69 (2H, d, J 8.79, C(2)ArC(2)H),
6.89 (2H, d, J 8.62, C(3)ArC(2)H), 6.99−7.01 (2H, m, C(3)-
NHSO2ArC(3)H), 7.04 (2H, d, J 8.81, C(2)ArC(3)H), 7.21 (2H, d, J
8.52, C(3)ArC(3)H), 7.32−7.34 (2H, m, C(3)NHSO2ArC(2)H); δC
(100 MHz, CDCl3) 21.6 (ArCH3), 52.5 (C(1)(O)OCH3), 55.3
(ArOCH3), 56.6 (C(2)), 60.7 (C(3)), 114.2 (C(2)ArC(2)), 121.6
(CBr), 126.5 (C(2)ArC(1)), 127.0 (C(3)NHSO2ArC(2)), 128.7
(C(3)ArC(2)), 129.3 (ArC), 129.6 (ArC), 131.5 (C(3)ArC(3)),
137.6 (C(3)NHSO2ArC(1)), 137.9 (C(3)ArC(1)), 143.0 (ArC(4)-
CH3), 159.4 (ArC(4)OCH3), 172.5 (C(1)); m/z (NSI+) 535 ([M +
NH4]+, 90), 542 (100); HRMS (NSI+) m/z [M + H]+ calcd for
C24H25BrNO5S+ 518.0630, found 518.0631 (−0.3 ppm).
J 9.0, NH), 6.85 (2H, t, J 8.6, C(2)ArC(3)H), 6.90 (2H, d, J 8.4,
C(3)ArC(2)H), 7.02 (2H, d, J 8.0, C(3)NHSO2ArC(3)H), 7.10 (2H,
dd, J 8.6, 5.3, C(2)ARC(2)H), 7.23 (2H, d, J 8.4, C(3)ArC(3)H), 7.34
(2H, d, J 8.2, NHSO2ARC(2)H); δC (100 MHz, CDCl3) 21.5
(ArCH3), 52.7 (OCH3), 56.6 (C(2)), 60.7 (C(3)), 115.8 (d, J 21.3,
C(2)ArC(3)), 121.8 (CBr), 126.9 (C(3)NHSO2ArC(2)), 128.6
(C(3)ArC(2)), 129.4 (C(3)NHSO2ArC(3)), 130.2 (d, J 7.5, C(2)-
ArC(2)), 130.3 (d, J 3.8, C(2)ArC(1)), 131.6 (C(3)ArC(3)), 137.5
(C(3)ArC1)), 137.7 (C(3)NHSO2C(1)), 143.3 (ArC(4)CH3), 162.5
(d, J 246.3, ArCF), 172.1 (C(1)); δF (470 MHz, CDCl3) −114.3
(ArF); m/z (NSI+) 524 ([M + NH4]+, 100); HRMS (NSI+) m/z [M +
H]+ calcd for C23H22BrFNO4S+ 506.0430, found 506.0431 (−0.3 ppm).
(2S,3R)-Methyl 3-(4-Bromophenyl)-2-(4-chlorophenyl)-3-(4-
methylphenylsulfonamido)propanoate 25. The title compound
was prepared according to general procedure B from 4-chlorophenyl-
acetic acid (34.1 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol),
two portions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01
mmol), nBuLi (2.5 M) solution in hexanes (0.1 mL, 11 mmol), and
imine 8 (70.8 mg, 0.20 mmol) and purified by chromatography (20:80
EtOAc/petroleum ether) to give β-amino ester 25 as a white solid
(71.3 mg, 68%): mp 120−124 °C; [α]2D2 −27.2 (c 0.5 in CHCl3);
chiral HPLC analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate
1.0 mL min−1, 211 nm, 30 °C), tR major: 15.6 min, tR minor: 17.7 min,
78% ee; νmax (film)/cm−1 3304 (NH), 3258 (NH), 1736 (CO),
1719 (CO), 1153 (R-SO2N), 1090 (C−Cl); δH (400 MHz, CDCl3)
2.37 (3H, s, CH3), 3.60 (3H, s, CH3OC(1)), 3.91 (1H, d, J 6.4, C(2)
H), 4.74 (1H, dd, J 9.2, 6.4, C(3)H), 6.13 (1H, d, J 9.1, NH), 6.90−
6.96 (2H, m, C(3)CCH), 6.99−7.08 (4H, m, ArH), 7.09−7.15 (2H,
m, C(2)CCH), 7.23−7.29 (2H, m, CHCBr), 7.30−7.36 (2H, m,
SO2CCH); δC (100 MHz, CDCl3) 21.3 (CH3), 52.4 (CH3C(1)),
56.3 (C(2)), 60.2 (C(3)), 121.5 (CBr), 126.7 (SO2CArC), 128.4
(C(3)CArCH), 128.8 (ArC), 129.2 (C(2)CCH), 129.6 (ArC), 131.5
(ArCCBr), 132.7 (C(2)ArC), 133.9 (ArCCl), 137.1 (SO2C), 137.4
(C(3)ArC), 143.0 (ArCCH3), 171.6 (C(1)(O)); m/z (NSI+) 522
([M + NH4]+, 50), 546 (100); HRMS (NSI+) m/z [M + H]+ calcd for
C23H22BrClNO4S+ 522.0134, found 522.0136 (−0.4 ppm).
(2S,3R)-Methyl 2,3-Bis(4-bromophenyl)-3-(4-methylphenyl-
sulfonamido)propanoate 26. The title compound was prepared
according to general procedure B from 4-bromophenylacetic acid
(43.0 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two
portions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01
mmol), nBuLi (2.5 M) solution in hexanes (0.1 mL, 11 mmol), and
imine 8 (70.8 mg, 0.20 mmol) and purified by chromatography (20:80
EtOAc/petroleum ether) to give β-amino ester 26 as a white solid
(49.6 mg, 43%): mp 168−172 °C; [α]2D2 −28.0 (c 1.0 in CHCl3);
chiral HPLC analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate
1.0 mL min−1, 220 nm, 30 °C), tR major: 15.7 min, tR minor: 18.5 min,
98% ee; νmax (film)/cm−1 3368 (NH), 3298 (NH), 1719 (CO),
1709 (CO), 1339 (R-SO2N), 1155 (R-SO2N); δH (400 MHz,
CDCl3) 2.38 (3H, s, ArCH3), 3.59 (3H, s, OCH3), 3.90 (1H, d, J 6.3,
C(2)H), 4.73 (1H, dd, J 9.1, 6.3, C(3)H), 6.09 (1H, d, J 9.1, NH),
6.94−6.96 (2H, m, C(3)ArC(2)H), 6.99−7.01 (2H, m, C(2)ArC(2)H),
7.02−7.05 (2H, m, ArH), 7.24−7.26 (1H, m, ArH), 7.27−7.29 (3H, m,
ArH), 7.31−7.33 (2H, m, C(3)NHSO2ArC(2)H); δC (100 MHz,
CDCl3) 21.7 (ArCH3), 52.7 (OCH3), 56.7 (C(2)), 60.5 (C(3)), 121.9
(C(3)ArC(4)Br), 122.4 (C(2)ArC(4)Br), 126.8 (C(3)-
NHSO2ArC(2)), 128.6 (C(3)ArC(2)), 129.4 (C(2)ArC(2)), 130.1
(C(3)NHSO2ArC(3)), 131.7 (C(3)ArC(3)), 131.9 (C(2)ArC(3)),
133.6 (C(2)ArC(1)), 137.4 (C(3)NHSO2ArC(1)), 137.7 (C(3)-
ArC(1)), 143.4 (ArC(4)CH3), 171.9 (C(1)); m/z (NSI+) 582
([M + NH4]+, 35), 589 (100); HRMS (NSI+) m/z [M + H]+ calcd
for C23H22Br2NO4S+ 565.9630, found 565.9631 (−0.1 ppm).
(2S,3R)-Methyl 3-(4-Bromophenyl)-2-(4-fluorophenyl)-3-(4-
methylphenylsulfonamido)propanoate 24. The title compound
was prepared according to general procedure B from 4-fluorophenyl-
acetic acid (30.8 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol),
two portions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01
mmol), nBuLi (2.5 M) solution in hexanes (0.1 mL, 11 mmol), and
imine 8 (70.8 mg, 0.20 mmol) and purified by chromatography (20:80
EtOAc/petroleum ether) to give β-amino ester 24 as a white solid
(56.5 mg, 56%): mp 138−144 °C; [α]2D2 −22.2 (c 0.5 in CHCl3);
chiral HPLC analysis, Chiralcel OD-H (20% iPrOH/hexane, flow rate
0.5 mL min−1, 211 nm, 30 °C), tR minor: 17.8 min, tR major: 22.4 min,
76% ee; νmax (film)/cm−1 3273 (NH), 1719 (CO), 1153 (R-SO2N);
δH (400 MHz, CDCl3) 2.35 (3H, s, ArCH3), 3.61 (3H, s, OCH3), 3.91
(1H, d, J 6.6, C(2)H), 4.75 (1H, dd, J 8.8, 6.8, C(3)H), 6.05 (1H, d,
(2S,3R)-Methyl 2-([1,1′-Biphenyl]-4-yl)-3-(4-bromophenyl)-3-(4-
methylphenylsulfonamido)propanoate 27. The title compound
was prepared according to general procedure B from biphenylacetic
acid (42.4 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two
portions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01
mmol), nBuLi (2.5 M) solution in hexanes (0.1 mL, 11 mmol), and
imine 8 (70.8 mg, 0.20 mmol) and purified by chromatography (20:80
EtOAc/petroleum ether) to give β-amino ester 27 as a white solid
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(49.7 mg, 44%): mp 148−154 °C; [α]2D2 −45.5 (c 0.5 in CHCl3);
chiral HPLC analysis, ChiralPak AD-H (10% iPrOH/hexane, flow rate
1.0 mL min−1, 220 nm, 30 °C), tR major: 39.4 min, tR minor: 50.3 min,
73% ee; νmax (film)/cm−1 3306 (NH), 1719 (CO), 1153 (R-SO2N);
δH (400 MHz, CDCl3) 2.20 (3H, s, ArCH3), 3.63 (3H, s, OCH3), 4.00
(1H, d, J 6.5, C(2)H), 4.84 (1H, dd, J 9.1, 6.5, C(3)H), 6.23 (1H, d,
J 9.1, NH), 6.93−7.01 (4H, m, ArH), 7.16−7.22 (2H, m,
C(3)NHSO2ArC(3)H), 7.22−7.26 (2H, m, C(3)ArC(3)H), 7.31−
7.36 (3H, m, ArH), 7.36−7.48 (4H, m, ArH), 7.50−7.57 (2H, m,
ArH); δC (100 MHz, CDCl3) 21.4 (ArCH3), 52.6 (OCH3), 57.1
(C(2)), 60.7 (C(3)), 121.2 (CBr), 127.0 (NHSO2ArC(2)), 127.2
(ArC), 127.4 (ArC), 127.7 (ArC), 128.7 (ArC), 128.9 (ArC), 129.0
(ArC), 129.2 (NHSO2ArC(3)), 131.5 (C(3)ArC(3)), 133.5 (Cipso),
137.6 (C(3)NHSO2ArC(1)), 138.0 (C(3)ArC(1)), 140.2 (C(2)-
ArC(1)), 140.8 (Cipso), 143.1 (ArC(4)CH3), 172.3 (C(1)); m/z
(NSI+) 581 ([M + NH4]+, 70), 588 (100); HRMS (NSI+) m/z [M + H]+
calcd for C29H27BrNO4S+ 564.0838, found 564.0839 (−0.1 ppm).
(2S,3S)-Methyl 3-(4-Bromophenyl)-3-(4-methylphenylsulfonamido)-
2-(phenylthio)propanoate 28. The title compound was prepared
according to general procedure B from (phenylthio)acetic acid
(33.6 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two por-
tions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol),
nBuLi (2.5 M) solution in hexanes (0.1 mL, 11 mmol), and imine 8
(70.8 mg, 0.20 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 28 as a white solid and a
mixture of diastereoisomers (73.8 mg, 71%). Anti: isolated white solid
(8.3 mg, 14%); mp 120−124 °C; [α]2D2 +6.0 (c 0.2 in CHCl3); chiral
HPLC analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate
1.0 mL min−1, 220 nm, 30 °C), tR major: 20.4 min, tR minor: 24.7 min,
61% ee; νmax (film)/cm−1 3289 (NH), 1711 (CO), 1339 (R-SO2N),
1159 (R-SO2N); δH (400 MHz, CDCl3) 2.37 (3H, s, ArCH3), 3.52
(3H, s, OCH3), 3.85 (1H, d, J 5.3, C(2)H), 4.82 (1H, dd, J 8.8, 5.3,
C(3)H), 6.18 (1H, d, J 8.8, NH), 6.90 (2H, d, J 8.4, C(3)ArC(2)H),
7.10−7.15 (2H, m, C(3)NHSO2ArC(3)H), 7.25−7.31 (7H, m, ArH),
7.53−7.55 (2H, m, C(3)NHSO2ArC(2)H); δC (100 MHz, CDCl3)
21.6 (ArCH3), 52.7 (OCH3), 56.8 (C(2)), 58.7 (C(3)), 122.2 (CBr),
127.3 (C(3)NHSO2ArC(3)), 128.6 (C(3)ArC(2)), 128.8 (ArC),
129.4 (C(3)NHSO2ArC(2)), 129.5 (ArC), 131.7 (C(3)ArC(3)),
132.8, SArC(1)), 133.3 (ArC), 136.8 (C(3)ArC(1), 137.6
(SO2ArC(1)), 143.5 (ArC(4)CH3), 170.9 (C(1)); m/z (NSI+) 537
([M + NH4]+, 75), 544 (100); HRMS (NSI+) m/z [M + Na]+ calcd
for C23H22BrNO4S2Na+ 542.0060, found 542.0066 (−1.1 ppm). Syn:
isolated as a colorless oil (6.2 mg, 8%); selected data: δH (400 MHz,
CDCl3) 2.41 (3H, s, ArCH3), 3.50 (3H, s, OCH3), 3.80 (1H, d, J 9.1,
C(2)H), 4.55−4.58 (1H, m, C(3)H), 5.70−5.75 (1H, m, NH), 6.97−
7.00 (2H, m, C(3)ArC(2)H), 7.13−7.16 (2H, m, C(3)NHSO2ArC(3)
H), 7.22−7.24 (2H, m, C(3)ArC(3)H), 7.32−7.43 (5H, m, ArH),
7.43−7.46 (2H, m, C(3)NHSO2ArC(2)H); δC (100 MHz, CDCl3)
21.7 (ArCH3), 52.6 (OCH3), 56.9 (C(2)), 57.3 (C(3)), 122.5 (CBr),
127.4 (C(3)NHSO2ArC(2)), 129.2 (ArC), 129.5 (C(3)-
NHSO2ArC(3)), 129.5 (ArC), 129.9 (C(3)ArC(2)), 130.8
(SArC(1)), 131.4 (C(3)ArC(3)), 134.0 (ArC), 135.7 (C(3)ArC(1)),
136.9 (SO2ArC(1)), 143.7 (ArC(4)CH3),169.1 (C(1)); [α]2D2 −7.0
(c 0.1 in CHCl3); chiral HPLC analysis, ChiralPak AD-H (20%
iPrOH/hexane, flow rate 1.0 mL min−1, 220 nm, 30 °C), tR major:
30.6 min, tR minor: 38.4 min, 57% ee.
C(3)NHSO2ArC(3)H), 7.00−7.03 (2H, m, ArH), 7.10 (3H, m, ArH),
7.16−7.20 (5H, m, ArH), 7.34−7.36 (2H, m, C(3)NHSO2ArC(2)H);
δC (100 MHz, CDCl3) 21.5 (ArCH3), 52.5 (OCH3), 57.8 (C(2)),
61.2 (C(3)), 126.8 (ArC), 127.0 (C(3)NHSO2ArC(2)), 127.6 (ArC),
127.9 (ArC), 128.4 (ArC), 128.6 (ArC), 128.8 (ArC), 129.2
(C(3)NHSO2ArC(3)), 134.9 (C(2)ArC(1)), 138.8 (C(3)-
NHSO2C(1)), 142.8 (ArC(4)CH3), 151.1 (C(3)ArC(1)), 172.4
(C(1)); m/z (NSI+) 427 ([M + NH4]+, 100); HRMS (NSI+) m/z
[M + H]+ calcd for C23H24NO4S+ 410.1422, found 410.1421 (+0.4
ppm). This was recrystallized from CH2Cl2/petroleum ether to give
the β-lactam as a white solid (105.6 mg, 26%): mp 168−172 °C; [α]D22
−30.8 (c 0.5 in CHCl3); chiral HPLC analysis, ChiralPak AD-H (10%
iPrOH/hexane, flow rate 0.5 mL min−1, 211 nm, 30 °C), tR minor:
61.7 min, tR major: 82.0 min, 93% ee.
(2S,3R)-Methyl 3-(4-Methylphenylsulfonamido)-3-(naphthalen-
2-yl)-2-phenylpropanoate 30. The title compound was prepared
according to general procedure B from phenylacetic acid (27.2 mg,
0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two portions of
iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi
(2.5 M) solution in hexanes (0.1 mL, 11 mmol), and imine 42
(61.9 mg, 0.20 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 30 as a white solid (50.3 mg,
55%) as a white solid: mp 164−170 °C; [α]2D2 −24.4 (c 0.5 in CHCl3);
chiral HPLC analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate
1.0 mL min−1, 211 nm, 30 °C), tR minor: 18.5 min, tR major: 21.2 min,
95% ee; νmax (film)/cm−1 3258 (NH), 1722 (CO), 1165 (R-SO2N);
δH (400 MHz, CDCl3) 2.08 (3H, s, ArCH3), 3.61 (3H, s, OCH3), 4.09
(1H, d, J 6.7, C(2)H), 5.03 (1H, dd, J 9.2, 6.7, C(3)H), 6.18 (1H, d,
J 9.2, NH), 6.77−6.80 (2H, m, ArH), 7.04−7.26 (5H, m, ArH), 7.27−
7.37 (4H, m, ArH), 7.39−7.43 (2H, m, ArH), 7.52−7.64 (2H, m,
ArH), 7.69−7.72 (1H, m, ArH); δC (100 MHz, CDCl3) 21.3 (ArCH3),
52.5 (OCH3), 57.7 (C(2)), 61.3 (C(3)), 124.3 (ArC), 126.1 (ArC),
126.2 (ArC), 126.6 (ArC), 126.9 (ArC), 127.5 (ArC), 127.9 (ArC),
128.0 (ArC), 128.3 (ArC), 128.7 (ArC), 128.8 (ArC), 129.1 (ArC),
132.7 (Cipso), 132.9 (Cipso), 134.8 (Cipso), 135.6 (Cipso), 137.6 (Cipso),
142.8 (ArC(4)CH3), 172.5 (C(1)); m/z (NSI+) 477 ([M + NH4]+,
80), 482 (100); HRMS (NSI+) m/z [M + Na]+ calcd for
C27H25NO4SNa+ 482.1387, found 482.1397 (−2.0 ppm).
(2S,3R)-Methyl 3-(4-Methylphenylsulfonamido)-3-(naphthalen-
1-yl)-2-phenylpropanoate 31. The title compound was prepared
according to general procedure B from phenylacetic acid (27.2 mg,
0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two portions of
iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi
(2.5 M) solution in hexanes (0.1 mL, 11 mmol), and imine S5 (61.9
mg, 0.20 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-amino ester 31 as a white solid (57.6 mg,
63%): mp 122−128 °C; [α]D22 −30.4 (c 0.5 in CHCl3); chiral HPLC
analysis, Chiralcel OD-H (5% iPrOH/hexane, flow rate 0.4 mL min−1,
211 nm, 30 °C), tR minor: 80.1 min, tR major: 101.2 min, 56% ee; νmax
(film)/cm−1 3287 (NH), 1721 (CO), 1161 (R-SO2N); δH (400
MHz, CDCl3) 2.21 (3H, s, ArCH3), 3.53 (3H, s, OCH3), 4.23 (1H,
d, J 5.0, C(2)H), 5.62 (1H, dd, J 9.2, 5.0, C(3)H), 6.63 (1H, d,
J 9.0, NH), 6.72−6.86 (2H, m, ArH), 7.15−7.25 (6H, m, ArH), 7.30−
7.38 (3H, m, ArH), 7.48 (1H, ddd, J 8.0, 6.8, 1.2, ArH), 7.56 (1H, ddd,
J 8.5, 6.8, 1.5, ArH), 7.64 (1H, d, J 8.1, ArH), 7.75−7.83 (1H, m, ArH),
8.00 (1H, d, J 8.5, ArH); δC (100 MHz, CDCl3) 21.3 (ArCH3), 52.5
(OCH3), 57.6 (C(2)), 61.3 (C(3)), 124.3 (ArC), 126.2 (ArC), 126.3
(ArC), 126.6 (ArC), 126.9 (ArC), 127.6 (ArC), 127.9 (ArC), 128.0
(ArC), 128.3 (ArC), 128.7 (ArC), 128.8 (ArC), 129.1 (ArC), 132.7
(Cipso), 133.0 (Cipso), 134.8 (Cipso), 135.7 (Cipso), 137.6 (Cipso), 142.8
(ArC(4)CH3), 172.5 (C(1)); m/z (NSI+) 477 ([M + NH4]+, 80), 482
(100); HRMS (NSI+) m/z [M + Na]+ calcd for C27H25NO4SNa+
482.1387, found 482.1397 (−2.0 ppm).
(2R,3S)-Methyl 3-(4-Methylphenylsulfonamido)-2,3-diphenylpro-
panoate 29. The title compound was prepared according to general
procedure B from phenylacetic acid (136.0 mg, 1.0 mmol), tosyl
chloride (286.5 mg, 1.50 mmol), two portions of iPr2NEt (260 μL,
1.50 mmol), 7 (15.5 mg, 5 mol %, 0.05 mmol), nBuLi (2.5 M) solu-
tion in hexanes (0.5 mL, 55 mmol), and imine S1 (259.5 mg, 1.0 mmol)
and purified by chromatography (20:80 EtOAc/petroleum ether) to give
β-amino ester 29 as a white solid (219.3 mg, 54%): mp 162−165 °C;
[α]2D2 −25.6 (c 0.5 in CHCl3); chiral HPLC analysis, ChiralPak AD-H
(10% iPrOH/hexane, flow rate 0.5 mL min−1, 211 nm, 30 °C), tR minor:
61.7 min, tR major: 82.0 min, 77% ee; νmax (film)/cm−1 3283 (NH),
1715 (CO), 1159 (R-SO2N); δH (400 MHz, CDCl3) 2.30 (3H, s,
ArCH3), 3.59 (3H, s, OCH3), 3.97 (1H, d, J 6.5, C(2)H), 4.85 (1H,
dd, J 9.1, 6.5, C(3)H), 6.01 (1H, d, J 9.1, NH), 6.98 (2H, d, J 8.0,
(2S,3R)-Methyl 3-(Furan-2-yl)-3-(4-methylphenylsulfonamido)-2-
phenylpropanoate 32. The title compound was prepared according
to general procedure B from phenylacetic acid (27.2 mg, 0.20 mmol),
tosyl chloride (57.3 mg, 0.30 mmol), two portions of iPr2NEt (52 μL,
0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi (2.5 M) solution
in hexanes (0.1 mL, 11 mmol), and imine S4 (53.6 mg, 0.20 mmol)
and purified by chromatography (20:80 EtOAc/petroleum ether) to
1635
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The Journal of Organic Chemistry
Article
give β-amino ester 32 as a white solid (43.7 mg, 55%); mp 154−160 °C;
[α]2D2 −4.6 (c 0.5 in CHCl3); chiral HPLC analysis, Chiralcel OJ-H
(10% iPrOH/hexane, flow rate 0.5 mL min−1, 211 nm, 30 °C), tR major:
45.3 min, tR minor: 53.9 min, 69% ee; νmax (film)/cm−1 3264 (NH),
1726 (CO), 1163 (R-SO2N); δH (400 MHz, CDCl3) 2.43 (3H, s,
ArCH3), 3.65 (3H, s, OCH3), 4.12 (1H, d, J 7.1, C(2)H), 4.97 (1H, dd,
J 9.7, 7.1, C(3)H), 5.66 (1H, d, J 9.8, NH), 5.84 (1H, d, J 3.3,
C(3)ArC(3)H), 6.04 (1H, dd, J 3.2, 1.8, C(3)ArC(4)H), 7.09 (2H, d,
J 8.0, NHSO2ArC(3)H), 7.13 (3H, dd, J 9.3, 1.2, ArH), 7.20 (3H dd,
J 4.8,2.4, ArH), 7.46 (2H, d, J 8.2, SO2ArC(2)H); δC (100 MHz,
CDCl3) 21.6 (ArCH3), 52.5 (OCH3), 55.0 (C(2)), 55.4 (C(3)), 108.4
(ArC), 110.4 (ArC), 127.0 (ArC), 128.0 (ArC), 128.6 (C(3)-
NHSO2ArC(3)), 128.7 (C(2)ArC(1)), 129.4 (C(3)NHSO2ArC(1)),
134.4 (ArC), 137.7 (C(3)NHSO2ArC(1)), 142.0 (C(3)NHSO2ArC(4)),
143.0 (ArC(4)CH3), 151.1 (C(3)ArC(1)), 172.0 (C(1)); m/z (NSI+)
229 (100), 417 ([M + NH4]+, 55); HRMS (NSI+) m/z [M + H]+ calcd
for C21H22NO5S+ 400.1209, found 400.1213 (−1.0 ppm).
(2S,3R)-Methyl 3-(4-Methylphenylsulfonamido)-2-phenyl-3-(4-
(trifluoromethyl)phenyl)propanoate 33. The title compound was
prepared according to general procedure B from phenylacetic acid
(27.2 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two
portions of iPr2NEt (52 μL, 0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01
mmol), nBuLi (2.5 M) solution in hexanes (0.1 mL, 11 mmol), and
imine S3 (65.5 mg, 0.20 mmol) and purified by chromatography
(20:80 EtOAc/petroleum ether) to give β-amino ester 33 as a white
solid (46.4 mg, 49%): mp 118−124 °C; [α]2D2 −17.6 (c 0.5 in CHCl3);
chiral HPLC analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate
1.0 mL min−1, 211 nm, 30 °C), tR minor: 15.9 min, tR major: 20.9 min,
47% ee; νmax (film)/cm−1 3237 (NH), 1742 (CO), 1323 (R-SO2N),
1161 (R-SO2N), 1117 (CF3); δH (400 MHz, CDCl3) 2.28 (3H, s,
ArCH3), 3.64 (3H,s, OCH3), 3.96 (1H, d, J 7.3, C(2)H), 4.94 (1H, dd,
J 9.1, 7.3, (C(3)H), 6.34 (1H, d, J 9.1, NH), 6.95 (2H, d J 8.3,
C(3)NHSO2ArC(3)H), 7.07−7.10 (2H, m, ArH), 7.16−7.19 (5H, m,
ArH), 7.29−7.34 (4H, m, ArH); δC (100 MHz, CDCl3) 21.4 (ArCH3),
52.7 (OCH3), 57.6 (C(2)), 60.8 (C(3)), 124.0 (q, J 271.3, CF3), 125.2
(q, J 5, C(3)ArC(3)), 126.9 (ArC), 127.6 (ArC), 128.2 (ArC), 128.6
(ArC), 128.9 (ArC), 129.3 (ArC), 129.7 (q, J 36.6, C(3)ArC(4)CF3),
134.3 (C(2)ArC(1)), 137.4 (C(3)NHSO2ArC(1)), 142.4 (C(3)-
ArC(1)), 143.2 (C(3)NHSO2ArC(4)CH3), 172.2 (C(1)); δF (470
MHz, CDCl3) −63.2 (CF3); m/z (NSI+) 495 ([M + NH4]+, 100);
HRMS (NSI+) m/z [M + H]+ calcd C24H23F3NO4S+ 478.1289, found
478.1294 (−1.1 ppm).
(2S,3R)-Methyl 3-(4-Nitrophenylsulfonamido)-2,3-diphenylpro-
panoate 34. The title compound was prepared according to general
procedure B from phenylacetic acid (27.2 mg, 0.20 mmol), tosyl
chloride (57.3 mg, 0.30 mmol), two portions of iPr2NEt (52 μL,
0.30 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol), nBuLi (2.5 M) solution
in hexanes (0.1 mL, 11 mmol), and imine S6 (58.1 mg, 0.20 mmol)
and purified by chromatography (20:80 EtOAc/petroleum ether) to
give β-amino ester 34 as a white solid (47.4 mg, 54%): mp 158−
162 °C; [α]2D2 −20.8 (c 0.5 in CHCl3); chiral HPLC analysis, Chiralcel
OD-H (10% iPrOH/hexane, flow rate 0.5 mL min−1, 211 nm, 30 °C),
tR minor: 63.7 min, tR major: 106.7 min, 75% ee; νmax (film)/cm−1
3240 (NH), 1740 (CO), 1390 (NO2), 1323 (RSO2N), 1161
(RSO2N); δH (400 MHz, CDCl3) 3.60 (s, 3H, OCH3), 4.02 (1H, d,
J 5.4, C(2)H), 4.86 (1H, dd, J 9.2, 5.4, C(3)H), 6.59 (1H, d, J 9.2,
NH), 7.09−7.12 (3H, m, ArH), 7.14−7.23 (7H, m, ArH), 7.58 (2H, d,
J 8.8, NHSO2ArC(2)H), 7.98 (2H, d, J 8.8, NHSO2ArC(3)H); δC
(125 MHz, CDCl3) 52.6 (OCH3), 57.1 (C(2)), 61.7 (C(3)), 123.8
(NHSO2ArC(3)), 126.7 (ArC), 128.0 (ArC), 128.1 (ArC), 128.2
(ArC), 128.3 (ArC), 128.7 (ArC), 129.0 (NHSOArC(2)), 134.8
(NHSO2ArC(1)), 138.5 (Cipso), 146.5 (Cipso), 149.4 (CNO2), 172.6
(C(1)); m/z (NSI+) 458 ([M + NH4]+, 100); HRMS (NSI+) m/z [M +
NH4]+ calcd for C22H24N3O6S+ 458.1382, found 458.1380 (+0.4 ppm).
(3S,4R)-4-(4-Bromophenyl)-3-(2-naphthylene)-1-tosylazetidin-2-
one 36. The title compound was prepared according to general
procedure C from imine 8 (70.8 mg, 0.20 mmol), 7 (3.1 mg, 5 mol %,
0.01 mmol), iPr2NEt (43.0 μL, 0.25 mmol), and 2-naphthoic
anhydride (106.4 mg, 0.30 mmol) and purified by chromatography
(10:90 EtOAc/petroleum ether) to give β-lactam 36 as a white solid
(44.4 mg, 44%): mp 120−126 °C; [α]2D2 −63.0 (c 0.5 in CHCl3);
chiral HPLC analysis, Chiralcel OD-H (10% iPrOH/hexane, flow rate
1.0 mL min−1, 221 nm, 30 °C), tR minor: 22.2 min, tR major: 28.4 min,
83% ee; νmax (KBr)/cm−1 1774 (CO), 1374 (C−N), 1173 (R-
SO2N); δH (400 MHz, CDCl3) 2.50 (3H, s, NSO2ArCH3), 4.39 (1H,
d, J 3.4, C(3)H), 4.98 (1H, d, J 3.3, C(4)H), 7.07 (1H, dd, J 8.5, 1.9,
ArH), 7.21 (2H, d, J 8.3, ArH), 7.35 (2H, m, ArH), 7.47−7.53 (5H, m,
ArH), 7.69−7.72 (1H, m, ArH), 7.77−7.83 (4H, m, ArH); δC (100
MHz, CDCl3) 21.8 (NSO2ArCH3), 64.5 (C(3)), 66.8 (C(4)), 123.3
(ArC, CBr), 126.7 (2 × ArC), 126.9 (ArC), 127.5 (ArC), 127.8 (ArC),
127.9 (ArC), 128.2 (ArC), 128.6 (ArC), 129.2 (ArC), 129.4
(C(3)NHSO2ArC(2)), 130.0 (ArC), 133.0 (Cipso), 133.2 (Cipso),
133.3 (Cipso), 135.9 (Cipso), 145.5 (NSO2ArC(4)CH3), 165.4 (C(2));
m/z (NSI+) 524 ([M + NH4]+, 100); HRMS (NSI+) m/z [M + NH4]+
calcd for C26H24BrN2O3S+ 523.0674, found 523.0686 (−2.2 ppm).
(3S,4R)-4-(4-Bromophenyl)-3-(thiophene-3-yl)-1-tosylazetidin-2-
one 37. The title compound was prepared according to general
procedure C from imine 8 (70.8 mg, 0.20 mmol), 7 (3.1 mg, 5 mol %,
0.01 mmol), iPr2Net (43.0 μL, 0.25 mmol), and anhydride S9 (79.9
mg, 0.30 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-lactam 37 as a white solid (43.5 mg, 47%):
mp 104−106 °C; [α]2D2 +20.0 (c 0.5 in CHCl3); chiral HPLC analysis,
Chiralcel OD-H (10% iPrOH/hexane, flow rate 1.0 mL min−1,
220 nm, 30 °C), tR minor: 26.6 min, tR major: 34.1 min, 82% ee; νmax
(film)/cm−1 3109 (thiophene CH), 1792 (CO), 1487 (C−N), 1373
(R-SO2N), 1173 (R-SO2N); δH (400 MHz, CDCl3) 2.47 (3H, s,
NSO2ArCH3), 4.29 (1H, d, J 3.3, C(3)H), 4.87 (1H, d, J 3.3, C(4)H),
6.76 (1H, dd, J 5.0, 1.3, C(3)ArH), 7.08 (1H, dt, J 1.8, 0.9, C(3)ArH),
7.16−7.18 (2H, m, ArH), 7.31−7.34 (3H, m, ArH), 7.46−7.48
(2H, m, ArH), 7.72−7.74 (2H, m, ArH); δC (100 MHz, CDCl3) 21.9
(NSO2ArCH3), 60.1 (C(3)), 64.9 (C(4)), 123.4 (C(3)ArC), 125.8
(C(3)ArC), 127.6 (ArC), 127.7 (ArC), 128.2 (ArC), 130.1 (ArC),
132.1 (Cipso), 135.2 (Cipso), 135.5 (Cipso), 145.8 (NSO2ArC(4)CH3),
164.9 (C(2)), 185.4 (Cipso); m/z (NSI+) 579 ([M + NH4]+, 85), 481
+
(100); HRMS (NSI+) m/z [M + NH4]+ calcd for C20H17BrNO3S2
461.9830, found 461.9828 (+0.5 ppm).
(3S,4R)-4,3-Diphenyl-1-tosylazetidin-2-one 38. The title com-
pound was prepared according to general procedure C from imine
S1 (338.0 mg, 1.0 mmol), 7 (15.5 mg, 5 mol %, 0.05 mmol), iPr2NEt
(215 μL, 1.25 mmol), and benzoic anhydride 35 (381.0 mg,
1.5 mmol) and purified by chromatography (10:90 EtOAc/petroleum
ether) to give β-lactam 38 as a white solid (228.7 mg, 60%): chiral
HPLC analysis, Chiralcel OD-H (10% iPrOH/hexane, flow rate
1.0 mL min−1, 254 nm, 30 °C), tR major: 14.8 min, tR minor: 19.6 min,
89% ee; δH (400 MHz, CDCl3) 2.45 (3H, s, CH3), 4.27 (1H, d, J 3.4,
C(3)H), 4.98 (1H, d, J 3.4, C(4)H), 7.06 (2H, m, PhH), 7.26−7.34
(10H, m, PhH), 7.71 (2H, m, PhH). All NMR data was in accordance
to the literature.27a This was recrystallized from CH2Cl2/petroleum
ether to give the β-lactam as a white solid (129.5 mg, 34%): mp
91−98 °C (lit.27a mp 123−124 °C); [α]D22 +35.6 (c 0.5 in CHCl3);
chiral HPLC analysis, Chiralcel OD-H (10% iPrOH/hexane, flow rate
1.0 mL min−1, 254 nm, 30 °C), tR major: 14.8 min, tR minor: 19.6 min,
>99% ee.
(3S,4R)-4-(Naphthalene-2-yl)-3-phenyl-1-tosylazetidin-2-one 39.
The title compound was prepared according to general procedure C
from imine 42 (61.9 mg, 0.20 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol),
iPr2NEt (43.0 μL, 0.25 mmol), and benzoic anhydride 35 (76.2 mg,
0.30 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-lactam 39 as a white solid (47.8 mg,
56%): mp 38−44 °C; [α]2D2 −8.8 (c 0.25 in CHCl3); chiral HPLC
analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL
min−1, 211 nm, 30 °C), tR major: 19.3 min, tR minor: 41.5 min, 92%
ee; νmax (film)/cm−1 2920, 1792 (CO), 1456 (C−N), 1364
(R-SO2N), 1166 (R-SO2N); δH (400 MHz, CDCl3) 2.41 (3H, s,
NSO2ArCH3), 4.36 (1H, d, J 3.0, C(3)H), 5.16 (1H, d, J 3.0, C(4)H),
7.11−7.14 (2H, m, ArH), 7.16−7.24 (2H, m, ArH), 7.31−7.35 (3H,
m, ArH), 7.48−7.57 (2H, m, ArH), 7.69- 7.72 (3H, m, ArH), 7.72−
7.76 (2H, m, ArH), 7.80 (1H, d, J 8.5, ArH), 7.82−7.89 (1H, m, ArH);
δC (100 MHz, CDCl3) 21.8 (NSO2ArCH3), 64.5 (C(3)), 66.2 (C(4)),
123.3 (ArC), 126.7 (ArC), 126.9 (ArC), 127.0 (ArC), 127.4 (ArC),
1636
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127.8 (ArC), 127.9 (ArC), 128.2 (ArC), 128.6 (ArC), 129.2 (ArC),
129.4 (ArC), 130.0 (ArC), 133.0 (Cipso), 133.1 (Cipso), 133.3 (Cipso),
133.6 (Cipso), 135.8 (C(3)ArC(1)), 145.5 (NSO2ArC(4)CH3), 165.5
(C(2)); m/z (NSI+) 445 ([M + NH4]+, 100); HRMS (NSI+) m/z
[M + NH4]+ calcd for C26H25N2O3S+ 445.1578, found 445.1580
(−0.5 ppm). Syn: from mixture of diastereoisomers, selected data δH
(400 MHz, CDCl3) 2.43 (3H, s, NSO2ArCH3), 5.04 (1H, J 6.8, CH),
5.65 (1H, J 6.9, CH); chiral HPLC analysis, ChiralPak AD-H (20%
iPrOH/hexane, flow rate 1.0 mL min−1, 211 nm, 30 °C), tR major:
18.1 min, tR minor: 25.6 min, 54% ee.
(3S,4R)-3-Phenyl-1-tosyl-4-(4-(trifluoromethyl)phenyl)azetidin-2-
one 40. The title compound was prepared according to general procedure
C from imine S3 (65.5 mg, 0.20 mmol), 7 (3.1 mg, 5 mol %, 0.01 mmol),
iPr2NEt (43.0 μL, 0.25 mmol), and benzoic anhydride 35 (76.2 mg,
0.30 mmol) and purified by chromatography (20:80 EtOAc/
petroleum ether) to give β-lactam 40 as a white gum (41.9 mg,
47%): [α]2D2 +17.2 (c 0.5 in CHCl3); chiral HPLC analysis, Chiralcel
OD-H (5% iPrOH/hexane, flow rate 0.25 mL min−1, 211 nm, 30 °C),
tR minor: 82.7 min, tR major: 90.2 min, 68% ee; νmax (film)/cm−1 1796
(CO), 1323 (R-SO2N), 1167 (R-SO2N); δH (400 MHz, CDCl3)
2.47 (3H, s, NSO2ArCH3), 4.25 (1H, d, J 3.4, C(3)H), 5.00 (1H, d,
J 3.4, C(4)H), 6.98−7.08 (2H, m, ArH), 7.29−7.37 (5H, m, ArH),
7.40−7.43 (2H, m, ArH), 7.55−7.63 (2H, m, ArH), 7.73−7.76 (2H,
m, ArH); δF (282 MHz, CDCl3) 62.7 (CF3); δC (100 MHz, CDCl3)
21.9 (NSO2ArCH3), 64.6 (C(3)), 65.0 (C(4)), 123.9 (q, J 217, CF3),
126.2 (q, J 3, C(4)ArC(3)), 126.9 (ArC), 127.4 (ArC), 127.7 (ArC),
128.8 (ArC), 129.5 (ArC), 130.2 (ArC), 131.5 (q, J 26, C(4)ArC(4)-
CF3), 132.5 (Cipso), 135.5 (Cipso), 140.3 (C(4)ArC(1)), 145.9
(NSO2ArC(4)CH3), 165.1 (C(1)); m/z (NSI+) 463 ([M + NH4]+,
100); HRMS (NSI+) m/z [M + NH4]+ calcd for C23H19BF3NO3S+
446.1031, found 446.1032 (−0.3 ppm).
(3S,4R)-1-((4-Nitrophenyl)sulfonyl)-3,4-diphenylazetidin-2-one
41. The title compound was prepared according to general procedure
C from imine S6 (58.1 mg, 0.20 mmol), 7 (3.1 mg, 5 mol %, 0.01
mmol), iPr2NEt (43.0 μL, 0.25 mmol), and benzoic anhydride 35
(72.6 mg, 0.30 mmol) and purified by chromatography (10:90 EtOAc/
petroleum ether) to give β-lactam 41 as a white solid (41.6 mg, 51%):
mp 108−114 °C; [α]2D2 −2.1 (c 0.9 in CHCl3); chiral HPLC analysis,
ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL min−1,
211 nm, 30 °C), tR minor: 28.3 min, tR major: 32.6 min, 85% ee; νmax
(KBr)/cm−1 1797 (CO), 1529 (NO2), 1379 (C−N), 1176 (R-
SO2N); δH (400 MHz, CDCl3) 4.42 (1H, d, J 3.45, C(3)H), 5.12 (1H,
d, J 3.43, C(4)H), 7.17−7.20 (2H, m, ArH), 7.24−7.25 (1H, m, ArH),
7.32−7.40 (7H, m, ArH), 7.92−7.97 (2H, m, NSO2ArC(2)H), 8.27−
8.29 (2H, m, NSO2ArC(3)H); δC (100 MHz, CDCl3) 64.2 (C(3)),
66.3 (C(4)), 124.3 (NSO2ArC(3)), 126.8 (ArC), 127.0 (ArC), 128.6
(ArC), 128.8 (NSO2ArC(2)), 129.1 (ArC), 129.3 (ArC), 129.6 (ArC),
132.2 (C(4)ArC(1)), 135.0 (C(3)ArC(1)), 144.1 (NSO2ArC(1)),
150.7 (NSO2ArC(4)), 164.8 (C(2)); m/z (APCI+) 409 ([M + H]+,100);
HRMS (APCI+) m/z [M + H]+ calcd for C21H17N2O5S+ 409.0851,
found 409.0853(−0.4 ppm).
Detosylation Reaction. (3S,4R)-4-(4-Bromophenyl)-3-phenyla-
zetidin-2-one S10. Using a modified version of the procedure by
Lectka et al.41 N-tosylazetidinone 9 (54.1 mg, 0.12 mmol, 1 equiv) was
stirred in THF (1 mL) at rt, and ∼0.1 M SmI2 in THF (7.80 mL,
0.72 mmol, 6 equiv) was added dropwise until the color remained
consistent. The reaction mixture was stirred for 5 min, quenched with
NaHCO3 (5 mL), extracted (3 × EtOAc), dried (MgSO4), and
concentrated in vacuo to give the crude product as a yellow oil.
Following purification by column chromatography (40:60 EtOAc/
petroleum ether), β-lactam S10 was isolated as a colorless oil (14.6 mg,
48%): [α]2D2 −55.6 (c 0.5 in CHCl3); chiral HPLC analysis, Chiralcel
OD-H (20% iPrOH/hexane, flow rate 1.0 mL min−1, 211 nm, 25 °C),
tR major: 29.2 min, tR minor: 38.9 min, 90% ee; νmax (film)/cm−1 3263
(NH), 1751 (CO); δH (400 MHz, CDCl3) 4.17 (1H, d, J 2.40, C(3)
H), 4.65 (1H, d, J 2.40, C(4)H), 6.34 (1H, br s, NH), 7.28−7.32 (4H,
m, ArH), 7.34−7.39 (2H, m, ArH), 7.53−7.55 (2H, m, ArH); δC (100
MHz, CDCl3) 59.8 (C(3)), 66.4 (C(4)), 122.5 (CBr), 127.4 (ArC),
127.5 (ArC), 128.1 (ArC), 129.2 (ArC), 132.3 (ArC), 134.5 (Cipso),
138.7 (Cipso), 168.8 (C(2)); m/z (NSI+) 324 (100), 319 ([M + NH4]+,
85); HRMS (NSI+) m/z [M + H]+ calcd for C15H13BrNO+ 302.0178,
found 302.0175 (+1.0 ppm).
Control Experiments. Control Experiment 1. β-Lactam 39 was
prepared according to general procedure C from phenylacetic acid
(27.2 mg, 0.20 mmol), tosyl chloride (57.3 mg, 0.30 mmol), two
portions of iPr2NEt (52 μL, 0.30 mmol), 12 (10 mg, 20 mol %,
0.04 mmol), and imine 42 (70.8 mg, 0.20 mmol). The reaction was
monitored over time using 1H NMR for changes in the diastereomeric
ratio. The results are shown in Scheme 3.
Control Experiment 2. A sample of β-lactam 39 (3.3 mg, 0.007
mmol) with of a known dr (anti:syn 21:79) and ees (anti 90%, syn 52%)
was dissolved in CH2Cl2 (1 mL) and treated with iPr2NEt
(100 μL, 0.6 mmol) and 7 (3.1 mg, 0.01 mmol). The reaction was
stirred at rt for 3 h, quenched with 1 M HCl, extracted (3 × CH2Cl2),
dried (MgSO4), and concentrated in vacuo to give the crude product (dr
>95:5) with identical spectroscopic data as previously reported; chiral
HPLC analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL
min−1, 211 nm, 30 °C), tR minor: 19.3 min, tR major: 41.5 min, 32% ee.
Control Experiment 3. To a stirred solution of phenylacetic acid
(27.2 mg, 1 equiv, 0.20 mmol) in CH2Cl2 (1 mL) at 0 °C were added
tosyl chloride (57.3 mg, 1.5 equiv, 0.30 mmol) and iPr2NEt (52 μL,
1.5 equiv, 0.30 mmol). The solution was stirred at 0 °C for 20 min.
The achiral isothiourea catalyst, 10 (7.6 mg, 20 mol %, 0.04 mmol),
and imine 8 (70.8 mg, 1 equiv, 0.20 mmol) were added followed by
iPr2NEt (52 μL, 1.5 equiv, 0.30 mmol). The solution was then stirred
at rt for 1 h before quenching with 1 M HCl and extracted (3 ×
EtOAc), and the combined organic layers (MgSO4) were dried and
concentrated in vacuo. The resulting residue was redissolved in
CH2Cl2 (1 mL) and treated with 7 (12.3 mg, 20 mol %), NaOMe
(23.0 mg, 2 eq, 0.40 mmol), and methanol (1 mL). The reaction
mixture was stirred for 1 h at rt before being quenched with water
(1 mL) and extracted (3 × EtOAc), and the combined organic layers
were dried (MgSO4) and concentrated in vacuo to give the crude
product. Following purification by column chromatography (20:80
EtOAc/petroleum ether), 17 was obtained as a white solid (38.5 mg, 39%)
with identical spectroscopic data as reported previously; chiral HPLC
analysis, ChiralPak AD-H (20% iPrOH/hexane, flow rate 1.0 mL min−1,
211 nm, 30 °C), tR minor: 29.0 min, tR major: 42.7 min, 16% ee.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C{1H} NMR spectra and HPLC traces of all products.
X-ray crystallographic data for anti-17 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ads10@st-andrews.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Royal Society for a University Research
Fellowship (A.D.S.) and the EPSRC and GSK (Case Award
to S.R.S.), for funding. We also thank the European Research
Council under the European Unionʼs Seventh Framework
Programme (FP7/2007-2013) (ERC Grant Agreement No.
279850) and thank the EPSRC National Mass Spectrometry
Service Centre (Swansea).
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