Formation of Complex α-Imino Esters via Multihetero-Cope Rearrangement of α-Keto Ester Derived Nitrones

Article abstract of DOI:10.1055/s-0037-1610391

A sequential benzoylation and multihetero-Cope rearrangement of α-keto ester derived nitrones has been developed. The reaction furnishes a diverse array of complex α-imino ester derivatives. The products can be transformed into amino alcohols via LiAlH ₄ reduction.

Full text of DOI:10.1055/s-0037-1610391

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
feature
A
en
S. L. Bartlett et al.
Feature
Synthesis
Formation of Complex α-Imino Esters via Multihetero-Cope
Rearrangement of α-Keto Ester Derived Nitrones
Samuel L. Bartlett1
O
Kimberly M. Keiter2
Bn
CO2tBu
Ar
Cl
N
O
Ar
Blane P. Zavesky
R1
R1
O
Bn
DMAP (cat.) Bn
[3,3]
CO2tBu
R2 OCOAr
N
N
Jeffrey S. Johnson*
0
0
0
0-0
0
0
1-
8
8
8
2-9
8
8
1
O
Proton-
R1
sponge®
R2
CO2tBu
Department of Chemistry, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290, USA
jsj@unc.edu
R2
complex a-imino esters
This work was carried out in the Department of Chemistry at UNC
Chapel Hill, which celebrated its bicentennial in 2018.
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Received: 23.10.2018
Accepted: 30.10.2018
Published online: 06.12.2018
DOI: 10.1055/s-0037-1610391; Art ID: ss-2018-z0681-fa
imino esters containing fully substituted β-stereocenters
(Scheme 1, d). Following rearrangement, the C=N π-bond
could, in principle, react with nucleophiles, providing ac-
cess to novel amino acid derivatives possessing contiguous
stereocenters.
License terms:
We initially chose to focus on the β-benzoylation of α-
keto ester derived O-benzoyl-N-oxyenamines. We first test-
ed condensation of α-keto ester 1a with the Tomkinson re-
agent A (Table 1, entry 1). Presumably this reaction was
Abstract A sequential benzoylation and multihetero-Cope rearrange-
ment of α-keto ester derived nitrones has been developed. The reaction
furnishes a diverse array of complex α-imino ester derivatives. The
products can be transformed into amino alcohols via LiAlH4 reduction.
Key words rearrangement, ketones, imines, oxygenations, esters
Table 1 Optimization of the Reaction Conditionsa
Bn
Fragmentation of weak N–O σ-bonds (bond strength
~57 kcal/mol) can be leveraged during the synthesis of
complex organic frameworks, and a comprehensive review
of the rearrangement of N-oxyenamine derivatives has
been penned by Tabolin and Ioffe.3 Within this subclass of
N–O bond-cleaving reactions, sigmatropic rearrangements
of O-acyl- and O-imidoyl-N-oxyenamines can provide α-hy-
droxy or α-amino carbonyl derivatives, which are valuable
intermediates and key structural elements of natural and
unnatural bioactive compounds. An early report by Coates
and Cummins provided a method for the rearrangement of
N-vinyl-O-acylhydroxylamines resulting from acylation of
nitrones with acid chlorides (Scheme 1, a).4 More recently,
Tomkinson and co-workers disclosed the design of N-alkyl-
O-acylhydroxylamine reagents that facilitate the synthesis
of α-hydroxy carbonyl derivatives by way of a tandem con-
densation/rearrangement process (Scheme 1, b).5 Alterna-
tively, the use of a Cbz-protected trifluoromethyl imidoyl
chloride led to α-amination of nitrones analogous to the α-
oxygenation developed by Coates (Scheme 1, c).6 The devel-
opment of methods for the synthesis of β-branched α-keto
esters is a topic of ongoing interest,7–9 and the functional-
ization of such compounds via N-oxyenamine rearrange-
ments appealed to us as a means to generate complex α-
X
N
catalyst
amine base
CO2tBu
CO2tBu
solvent, temp
Me OBz
Me
1a, X = O
2a, X =
3a
O
Bn
N
Entry Reactants Baseb
Catalyst
Temp
(°C)
Solvent
Yield
(%)c
1d
1a/A
2a/B
2a/B
2a/B
none
Et3N
PS
none
55
DMSO (0.375 M)
MTBE (0.06 M)
MTBE (0.06 M)
MTBE (0.06 M)
0
48
86
63
2e,f
3e,g
4e,g
DMAP
DMAP
none
0; 23
0; 23
0; 23
PS
O
OBz
Cl
N
H2
Cl
A
B
a All reactions run using 0.15 mmol of 1a or 2a.
b PS = Proton-sponge®.
c Yield of product isolated via column chromatography.
d 1.0 equiv A used.
e 4 Å molecular sieves (205 mg) were added to the reaction mixture; 0.2
equiv DMAP employed.
f 5.0 equiv Et3N employed with 3.0 equiv B.
g 2.5 equiv Proton-sponge® employed with 2.0 equiv of B.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
S. L. Bartlett et al.
Feature
Synthesis
prevented by the sterically hindered ketone of 1a coupled
with low nucleophilicity of the free base of A. Heating a
mixture of N-benzylhydroxylamine and α-keto ester 1a fur-
nished nitrone 2a, which upon treatment with benzoyl
chloride (B) in the presence of triethylamine and the nucle-
ophilic catalyst 4-(dimethylamino)pyridine (DMAP) deliv-
ered the desired β-benzoylated imino ester 3a in 48% yield
(Table 1, entry 2). In this experiment, the corresponding α-
keto ester resulting from hydrolysis of 3a by adventitious
water was observed in the 1H NMR spectrum of the unpuri-
fied materials. Sequestration of acid is apparently crucial to
the stability of 3a under the reaction conditions as replac-
ing triethylamine with the thermodynamically stronger
base Proton-sponge® suppresses hydrolysis, allowing isola-
tion of 3a in 86% yield (Table 1, entry 3). Despite the sensi-
tivity of 3a under the conditions, it is completely stable to-
ward chromatography on untreated silica gel. The reaction
proceeds in the absence of DMAP, however the yield of 3a is
lower (Table 1, entry 4).
With suitable reaction conditions in hand, we began to
explore the scope of α-imino esters that could be prepared
(Scheme 2). The p-halogen series imines 3b–d were ob-
tained in high yield. In addition, an o-fluoro-substituted ni-
trone underwent the reaction in good yield to afford imino
benzoate 3e. Electron-rich nitrones were also viable sub-
strates, and representative examples include imines 3f–3h.
Biographical Sketches
Samuel L. Bartlett received
his B.S. in chemistry from Ore-
gon State University in 2012
where he conducted research
with Prof. Chris Beaudry. He
completed his Ph.D. in the labo-
ratory of Prof. Jeffrey S. Johnson
at the University of North Caro-
lina at Chapel Hill where he ex-
plored new catalytic
the development of new asym-
metric reactions employing cat-
alytically generated transition-
metal enolates. He is currently a
Medicinal Chemist at Enanta
Pharmaceuticals.
enantioconvergent reactions.
During his doctoral studies, he
was also an NSF EAPSI Fellow
with Prof. Mikiko Sodeoka and
Dr. Yoshihiro Sohtome at RIKEN
in Japan. There he worked on
Kimberly M. Keiter received
her M.S. in analytics from North
Carolina State University and
her B.S. in applied mathematics
and chemistry from the Univer-
sity of North Carolina at Chapel
Hill. During her undergraduate
years, she was a research assis-
tant in the Johnson Group
where she received the Mat-
thew Neely Jackson Undergrad-
uate Research Award. She is
currently a Data Scientist at El-
der Research where she ana-
lyzes clients’ data to find
actionable insights.
Blane P. Zavesky received his
B.S. in chemistry from the Uni-
versity of Michigan in 2014 with
high distinction and honors in
chemistry, where he conducted
research under Prof. John P.
Wolfe. He began his Ph.D. stud-
ies at the University of North
Carolina in 2014, working in the
laboratories of Prof. Jeffrey S.
Johnson. His research focuses
on the total synthesis of biologi-
cally active alkaloid natural
products.
Jeffrey S. Johnson received
his B.S. in chemistry from the
University of Kansas in 1994
with highest distinction and
honors in chemistry. He was a
graduate student at Harvard
University as an NSF Graduate
Fellow in the laboratories of
Prof. David A. Evans, receiving
his Ph.D. in 1999. He conducted
postdoctoral research at the
University of California at Berke-
ley from 1999 to 2001 as an NIH
Postdoctoral Fellow under the
direction of Prof. Robert G.
Bergman. He joined the faculty
of the Department of Chemistry
at the University of North Caro-
lina at Chapel Hill in 2001,
where he is currently the A.
Ronald Gallant Distinguished
Professor and the department
chairperson.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

C
S. L. Bartlett et al.
Feature
Synthesis
In summary, we have developed a sequential benzoyla-
tion–multihetero-Cope rearrangement of α-keto ester de-
rived nitrones. The reaction furnishes complex α-imino es-
ter derivatives in good to excellent yield. The products can
be transformed into complex amino alcohols via LiAlH4 re-
duction. Further exploration of the reactivity of these prod-
ucts, with a particular focus on accessing complex amino
acid derivatives via selective functionalization of the imine
moiety, is currently underway in our laboratory.
a)
O
tBu
H
O
tBu
H
O
tBu
O
tBu
N
N
O
tBu
Cl
i. [3,3]
ii. H2O
70%
O
O
H
Et3N
Et
Et
O
Et
O
b)
c)
Ph
R
Ph
O
O
N
R
O
Ph
O
O
i. [3,3]
ii. H2O
N
H
O
N
N
N
69%
Bz
Bz
Bz
O
Unless noted otherwise, all experiments were carried out in a flame-
dried round-bottomed flask under a stream of nitrogen gas. 1H and
13C NMR spectra were obtained on a Bruker DRX 600 (1H, 600 MHz;
13C, 150 MHz), Bruker 500 (1H, 500 MHz; 13C, 125 MHz), or Bruker
DRX 400 (1H, 400 MHz; 13C, 100 MHz) spectrometer. 1H NMR data are
reported as follows: chemical shift, multiplicity (standard abbrevia-
tions), coupling constant(s) (Hz), and relative integration. For HRMS,
all samples were prepared in MeOH. The HPLC system consisted of an
Agilent 1200 binary pump (G1312A) operating at a flow rate of 0.3
mL·min–1. The solvents were degassed using an on-line membrane
system (Agilent G1379A). The column was maintained in a thermo-
stated compartment at 40 °C (Agilent G1316A). The diode array detec-
tor (Agilent G1315D) was operated at three wavelengths (250, 254,
and 280 nm). Separation was performed on a Waters Acquity UPLC
BEH C18 column (2.1 × 50 mm, 1.7 μm particle size). The injection (5
μL) was performed using an autosampler (Agilent G1329A). LC condi-
tions were set at water with 0.1% formic acid (A) for 1 min, before
ramping linearly over 5 min to 100% acetonitrile with 0.1% formic
acid (B), and then switched back to 100% A and allowed to re-equili-
brate until 10 min. The HPLC system was coupled to the Q-TOF system
via a dual ESI interface operating in positive ion mode using a capil-
lary voltage of +3.5 kV. The other optimum values of the ESI-TOF pa-
rameters were drying gas temperature 325 °C, drying gas flow 5
L·min–1, and nebulizing gas pressure 15 psi. Detection was carried out
considering a mass range of 100–1500 m/z. Prior to acquiring sam-
ples, an external instrument calibration was performed using Agilent
ESI-L Low Concentration Tuning Mix. MassHunter Quantitative Anal-
ysis (Agilent) was used to analyze the data. Solutions were dissolved
in MeOH at 0.1 mg·mL–1 or less, and diluted appropriately based on
responsiveness to the ESI mechanism. Molecular formula assignments
were determined with Molecular Formula Calculator (v 1.2.3). The
success of mass data for molecular ions was considered based on the
widely accepted accuracy threshold for confirmation of elemental
compositions established at 5 ppm. All observed species were singly
charged, as verified by unit m/z separation between mass spectral
peaks corresponding to the 12C and 13C12Cc–1 isotope for each elemen-
tal composition. IR spectra were obtained using a Jasco 460 Plus Fou-
rier transform infrared spectrometer. TLC was performed on Sorbtech
plastic-backed 0.20 mm silica gel 60 plates. Visualization was accom-
plished with UV light and either an aqueous ceric ammonium molyb-
date (CAM) or KMnO4 solution, followed by heating. Flash chromatog-
raphy was performed under positive nitrogen pressure using Sil-
iaFlash-P60 silica gel (40–63 μm) purchased from SiliCycle.
NCbz
CF3
Et3N
PMB
O
PMB
N
PMB
O
CF3
Cbz
N
CF3
N
Cl
NHCbz
N
66%
d)
O
Bn
Bn
O
N
N
CO2tBu
Ar
R1
O
R1
Ar
Cl
O
CO2tBu
R1
R2
OtBu
R2 OCOAr
DMAP (cat.)
BnN
O
Proton-sponge®
MTBE, 0 °C; rt
R2
good to excellent yields
complex α-imino esters
Scheme 1 Functionalization of carbonyl derivatives via O-acyl- and O-
imidoyl-N-oxyenamine rearrangement
Larger alkyl substituents were tolerated at the β-position,
and β-benzyl-substituted tertiary benzoate 3i as well as the
ethyl derivative 3j could be obtained in good and moderate
yield, respectively. The secondary benzoate 3k could be
formed under the reaction conditions; however, this prod-
uct decomposed on silica gel and an NMR yield is provided
in Scheme 2.10 All other products were stable toward chro-
matography on untreated silica gel. The cyclohexyl deriva-
tive 3l was furnished in less than 35% yield (NMR yield) and
could not be separated from impurities, while the desired
pyridyl-substituted derivative 3m was not formed under
the reaction conditions. Other aroyl chlorides could also be
used in the reaction, and p-methylbenzoate 3n, m-chloro-
benzoate 3o, as well as o-bromobenzoate 3p were obtained
in high yield.
Preliminary attempts to selectively functionalize the
azomethine functionality in the rearrangement products
have been unsuccessful, most likely due to the sterically en-
cumbered nature of these electrophiles. At this stage, the
utility of the products has been demonstrated by exhaus-
tive LiAlH4 reduction of 3a and 3f, which delivered the cor-
responding amino alcohols 4a and 4f in intermediate yield
and diastereoselectivity (Scheme 3). The relative stereo-
chemistry of the major diastereomer was established via
synthesis of the cyclic carbamate 5f, which exhibited the il-
lustrated NOESY interactions between the methyl protons
and the methine proton.
Et3N was purified and dried by passing through a column of activated
t
alumina. DMAP and BuOH were purchased from Sigma-Aldrich and
used without further purification. Benzoyl chloride was purchased
from Acros and used without further purification. Methyl tert-butyl
ether (MTBE) was purified via distillation from calcium hydride and
stored over activated 13X-type molecular sieves (bead form). The pro-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
S. L. Bartlett et al.
Feature
Synthesis
Ph
Ph
DMAP (20 mol%)
ArCOCl (2.0 equiv)
O
R1
N
N
Proton-sponge® (2.5 equiv)
R1
CO2tBu
CO2tBu
R2 OCOAr
4 Å MS, MTBE (0.06 M)
0 °C; rta
R2
2
3
Ph
Ph
Ph
N
Ph
N
Ph
F
Cl
Br
MeO
N
N
N
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
Me OBz
Me OBz
Me OBz
Me OBz
Me OBz
F
3b
3c
3d
3e
3f
85%
72%
91%
87%
73%
Ph
Me
Ph
N
Ph
N
Ph
Ph
N
Me
F3C
N
N
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
Me OBz
Me OBz
Bn OBz
Et OBz
H
OBz
3g
95%
3h
83%
3i
77%
3j
68%
3k
57%b
Ph
N
Ph
Ph
Ph
N
Ph
N
N
CO2tBu
CO2tBu
CO2tBu
Br
N
BzO
CO2tBu
Me
O
O
N
Me
O
O
Me
O
CO2tBu
Cl
Me OBz
O
3m
0%
Me
3l
<35%c
3n
93%
3o
3p
96%
87%
Scheme 2 Scope of the rearrangement reaction. a All reactions were conducted on 0.15 mmol scale. The reactions were monitored by silica gel TLC
and were generally complete within 4 h. b Product is unstable to silica gel; yield was obtained via 1H NMR analysis using mesitylene as an internal
standard. c Product could not be separated from impurities; yield was obtained via 1H NMR analysis using mesitylene as an internal standard.
cedures for the preparation of tert-butyl 2-oxo-4-phenylbutanoate
(1k)11 and tert-butyl 2-oxo-4-phenyl-3-(4-(trifluoromethyl)phenyl)-
butanoate (1i)12 are reported in the literature.
(3 M, 4 mL) was added and the reaction mixture was stirred for 24 h
at rt. The mixture was then acidified (pH ~5) with aqueous HCl (3 M),
and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were dried over MgSO4. Filtration through a
plug of cotton and concentration delivered the corresponding α-keto
acid which was carried on without purification. Step 2: The crude α-
keto acid from step 1 was dissolved in CH2Cl2 (4.5 mL), and several
small drops of DMF were added. The reaction mixture was cooled to
0 °C using an ice–water bath, and oxalyl chloride (0.57 mL, 6.69
mmol, 1.5 equiv) was slowly added. The reaction mixture was stirred
for 20 h and concentrated. Residual oxalyl chloride was removed un-
der reduced pressure. The acid chloride was immediately used in the
Bn
N
H
NHBn
OH
LiAlH4 (8 equiv)
THF, 0 °C
Ar
Ar
CO2tBu
Me OH
Me OBz
4a
3a Ar = C6H5
Ar = C6H5
58%, 3:1 dr
56%, 4:1 dr
3f Ar = 4-MeOC6H4
4f Ar = 4-MeOC6H4
O
Bn
t
O
N
next step without purification. Step 3: BuOH (1.27 mL, 13.4 mmol,
MeO
3.0 equiv) and pyridine (719 μL, 8.92 mmol, 2.0 equiv) were dissolved
in CH2Cl2 (4.5 mL, 1 M), and the mixture was cooled to 0 °C using an
ice–water bath. The acid chloride from step 2 was slowly added in
CH2Cl2 (1.96 mL, 2.3 M). The reaction mixture was stirred for 24 h,
then diluted with water. The aqueous phase was extracted three
times with CH2Cl2 (20 mL), and the combined organic layers were
dried over MgSO4. The product was purified by silica gel column chro-
matography.
OTBS
H
CH3
5f
nOe
Scheme 3 LiAlH4 reduction of products 3a and 3f and determination
of diastereoselectivity via NOESY experiments with the derived cyclic
carbamate 5f
tert-Butyl α-Keto Esters 1; General Procedure
tert-Butyl 2-Oxo-3-phenylbutanoate (1a)
Step 1: The ethyl 2-oxo-3-arylbutanoate (4.46 mmol), prepared in
two steps via a literature method,11 was added neat to a 25-mL
round-bottomed flask equipped with a stir bar. Next, aqueous NaOH
Prepared from ethyl 2-oxo-3-phenylbutanoate. Purified by silica gel
column chromatography using 5% EtOAc/hexanes (636 mg, 61% yield).
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

E
S. L. Bartlett et al.
Feature
Synthesis
IR (thin film): 3446, 3030, 2980, 2035, 2875, 2319, 1744, 1725, 1494,
1455, 1371, 1259, 1164, 1120, 1023, 839 cm–1
HRMS (ESI): m/z calcd for C14H17FO3 [M + Na]: 275.1059; found:
275.1055.
.
1H NMR (600 MHz, CDCl3): δ = 7.31–7.35 (m, 2 H), 7.24–7.28 (m, 1 H),
7.19–7.21 (m, 2 H), 4.34 (q, J = 6.92 Hz, 1 H), 1.44 (d, J = 7.0 Hz, 3 H),
1.33 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 195.2, 161.0, 138.1, 128.9, 122.5,
127.5, 83.9, 48.8, 27.6, 16.6.
tert-Butyl 3-(4-Methoxyphenyl)-2-oxobutanoate (1f)
Prepared from ethyl 3-(4-methoxyphenyl)-2-oxobutanoate. Purified
by silica gel column chromatography using 2.5% EtOAc/hexanes (1.12
g, 59% yield).
IR (thin film): 2979, 2936, 2838, 1742, 1721, 1610, 1513, 1457, 1395,
HRMS (ESI): m/z calcd for
257.1148.
C14H18O3[M + Na]: 257.1154; found:
1371, 1303, 1254, 1179, 1122, 1026, 837 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7
Hz, 2 H), 4.30 (q, J = 7.0 Hz, 1 H), 3.78 (s, 3 H), 1.41 (d, J = 7.0 Hz, 3 H),
1.36 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 195.2, 161.2, 159.0, 129.8, 129.7,
114.3, 83.8, 55.3, 47.7, 27.6, 16.6.
tert-Butyl 3-(4-Fluorophenyl)-2-oxobutanoate (1b)
Prepared from ethyl 3-(4-fluorophenyl)-2-oxobutanoate. Purified by
silica gel column chromatography using 2.5% EtOAc/hexanes (819 mg,
46% yield).
IR (thin film): 2981, 2937, 1732, 1603, 1509, 1457, 1395, 1371, 1259,
HRMS (ESI): m/z calcd for C15H20O4 [M + Na]: 287.1259; found:
287.1248.
1225, 1161, 1135, 1026, 841, 759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.14–7.18 (m, 2 H), 6.97–7.03 (m, 2 H),
4.34 (q, J = 7.0 Hz, 1 H), 1.41 (d, J = 7.0 Hz, 3 H), 1.34 (s, 9 H).
tert-Butyl 2-Oxo-3-(p-tolyl)butanoate (1g)
13C NMR (150 MHz, CDCl3): δ = 194.7, 162.1 (d, J19F–13C = 244.7 Hz),
160.8, 133.8 (d, J19F–13C = 3.0 Hz), 130.1 (d, J19F–13C = 8.2 Hz), 115.7 (d,
J19F–13C = 21.7 Hz), 84.0, 47.7, 27.5, 16.5.
Prepared from ethyl 2-oxo-3-(p-tolyl)butanoate. Purified by silica gel
column chromatography using 2.5% EtOAc/hexane and subsequently
CH2Cl2 (2.20 g, 60% yield).
1H NMR (400 MHz, CDCl3): δ = 7.08–7.14 (m, 4 H), 4.31 (q, J = 7.3 Hz,
1 H), 2.32 (s, 3 H), 1.42 (d, J = 7.3 Hz, 3 H), 1.35 (s, 9 H).
HRMS (ESI): m/z calcd for C14H17FO3 [M + Na] : 275.1059; found:
275.1057.
HRMS (ESI): m/z calcd for C15H20O3 [M + Na]: 271.1310; found:
271.1304.
tert-Butyl 3-(4-Chlorophenyl)-2-oxobutanoate (1c)
Prepared from ethyl 3-(4-chlorophenyl)-2-oxobutanoate. Purified by
silica gel column chromatography using 2.5% EtOAc/hexanes (519 mg,
47% yield).
tert-Butyl 2-Oxo-3-(m-tolyl)butanoate (1h)
Prepared from ethyl 2-oxo-3-(m-tolyl)butanoate. Purified by silica gel
column chromatography using 2.5% EtOAc/hexane (252 mg, 23%
yield).
IR (thin film): 3446, 2981, 2936, 2875, 2294, 1724, 1594, 1493, 1457,
1410, 1395, 1371, 1259, 1163, 1093, 1026, 836 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 8.5 Hz, 2 H), 7.15 (d, J = 8.5
Hz, 2 H), 4.35 (q, J = 7.0 Hz, 1 H), 1.42 (d, J = 7.0 Hz, 3 H), 1.38 (s, 9 H).
IR (thin film): 2979, 2934, 1770, 1744, 1724, 1607, 1457, 1370, 1282,
1258, 1166, 1119, 1025, 851, 784, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.23 (m, 1 H), 7.06–7.08 (m, 1 H),
6.99–7.01 (m, 2 H), 4.31 (q, J = 7.0 Hz, 1 H), 2.32 (s, 3 H), 1.43 (d, J = 7.0
Hz, 3 H), 1.34 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 195.1, 161.0, 138.4, 137.8, 129.1,
128.7, 128.1, 125.5, 83.7, 48.6, 27.5, 21.2, 16.5.
13C NMR (150 MHz, CDCl3): δ = 194.6, 160.7, 136.6, 133.5, 129.8,
129.0, 84.2, 47.9, 27.6, 16.7.
HRMS (ESI): m/z calcd for C14H17ClO3 [M + Na]: 291.0764; found:
291.0756.
HRMS (ESI): m/z calcd for C15H20O3 [M + Na]: 271.1310; found:
tert-Butyl 3-(4-Bromophenyl)-2-oxobutanoate (1d)
271.1303.
Prepared from ethyl 3-(4-bromophenyl)-2-oxobutanoate using Proce-
dure A. Purified by silica gel column chromatography using 2.5% ethyl
acetate/hexanes (531 mg, 48% yield).
ethyl-Butyl 2-Oxo-3-phenylpentanoate (1j)
1H NMR (CDCl3, 400 MHz):  7.46 (d, J = 8.4 Hz, 2 H), 7.09 (d, J = 8.4
Hz, 2 H), 4.34 (q, J = 7.0 Hz, 1 H), 1.42 (d, J = 7.0 Hz, 3 H), 1.38 (s, 9 H)
Prepared from ethyl 2-oxo-3-(m-tolyl)butanoate. Purified by silica gel
column chromatography using 2.5% EtOAc/hexane (773 mg, 69%
yield).
1H NMR (400 MHz, CDCl3): δ = 7.31–7.33 (m, 2 H), 7.25–7.27 (m, 1 H),
7.18–7.19 (m, 2 H), 4.14 (dd, J = 6.6, 8.2 Hz, 1 H), 2.06–2.14 (m, 1 H),
1.71–1.79 (m, 1 H), 1.34 (s, 9 H), 0.87 (t, J = 7.4 Hz, 3 H).
tert-Butyl 3-(2-Fluorophenyl)-2-oxobutanoate (1e)
Prepared from ethyl 3-(2-fluorophenyl)-2-oxobutanoate. Purified by
silica gel column chromatography using 2.5% EtOAc/hexanes (681 mg,
61% yield).
tert-Butyl 2-Cyclohexyl-2-oxoacetate (1l)
IR (thin film): 2981, 2937, 2877, 2357, 2321, 1746, 1732, 1507, 1492,
1456, 1395, 1371, 1258, 1163, 1123, 1023, 830, 758 cm–1
.
Compound 1l was prepared via the procedure employed for com-
pound 1k with slight modification. Magnesium turnings (0.31 g, 12.7
mmol) were added to a flame-dried 25 mL round-bottomed flask
equipped with a reflux condenser and a stir bar. The flask containing
the magnesium turnings was held under direct flame using a Bunsen
burner for 1 min while being flushed with nitrogen gas. Once the
flask had returned to room temperature, THF (12.7 mL) was added.
Bromocyclohexane (2.00 g, 12.7 mmol, 1.53 mL) was slowly added via
1H NMR (400 MHz, CDCl3): δ = 7.23–7.28 (m, 1 H), 7.04–7.11 (m, 3 H),
4.57 (q, J = 7.0 Hz, 1 H), 1.43 (d, J = 7.0 Hz, 3 H), 1.33 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 194.6, 160.5, 160.4 (d, J19F–13C = 245
Hz), 129.3 (d, J19F–13C = 6.8 Hz), 129.3 (d, J19F–13C = 11.0 Hz), 125.9 (d,
J19F–13C = 15.6 Hz), 124.5 (d, J19F–13C = 4.2 Hz), 115.7 (d, J19F–13C = 21.8
Hz), 84.1, 42.0 (d, J19F–13C = 2.5 Hz), 27.5, 15.7.
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syringe. The mixture was stirred for approximately 15 min at room
temperature and initiation of Grignard formation was not observed.
The flask was heated using a heat gun to initiate Grignard formation.
Once the magnesium turnings had been visibly consumed, the solu-
tion of the Grignard reagent was added dropwise to a separate solu-
tion of tert-butyl 2-(1H-imidazol-1-yl)-2-oxoacetate in THF (25.4 mL)
that had been pre-cooled to -78 °C using a dry ice/acetone bath. The
resulting mixture was allowed to stir at -78 °C for 1 h prior to being
quenched at -78 °C with 10 mL of 1M HCl. Upon warming to room
temperature, the reaction mixture was quenched with 40 mL of wa-
ter, and the aqueous phase was extracted several times with diethyl
ether. Purification by silica gel column chromatography delivered
tert-butyl 2-cyclohexyl-2-oxoacetate 1l (869 mg, 32% yield).
1H NMR (400 MHz, CDCl3): δ = 7.40–7.43 (m, 2 H), 7.34–7.36 (m, 3 H),
7.23–7.26 (m, 2 H), 6.96–7.00 (m, 2 H), 5.42 (d, J = 13.0 Hz, 1 H), 5.25
(d, J = 13.0 Hz, 1 H), 4.76 (q, J = 7.0 Hz, 1 H), 1.52 (d, J = 7.0 Hz, 3 H),
1.24 (s, 9 H).
13C NMR (150 MHz, CDCl3): complex spectrum due to 19F–13C cou-
pling (see the Supporting Information).
HRMS (ESI): m/z calcd for C21H24FNO3 [M + H]: 358.1813; found:
358.1823.
(E)-N-Benzyl-1-(tert-butoxy)-3-(4-chlorophenyl)-1-oxobutan-2-
imine Oxide (2c)
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (89.0 mg, 48% yield).
1H NMR (CDCl3, 400 MHz):  2.90–2.98 (m, 1 H), 1.31–1.91 (m, 19 H).
IR (thin film): 3032, 2978, 2934, 1733, 1716, 1698, 1684, 1647, 1558,
1541, 1507, 1457, 1316, 1137, 845, 705 cm–1
.
tert-Butyl 2-Oxo-3-(pyridin-3-yl)butanoate (1m)
1H NMR (400 MHz, CDCl3): δ = 7.33–7.43 (m, 5 H), 7.20–7.27 (m, 4 H),
5.42 (d, J = 13.2 Hz, 1 H), 5.27 (d, J = 13.2 Hz, 1 H), 4.75 (q, J = 7.1 Hz, 1
H), 1.52 (d, J = 7.1 Hz, 3 H), 1.25 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 161.8, 146.0, 139.4, 133.6, 132.4,
129.0, 128.6, 128.6, 128.5, 128.3, 84.0, 66.9, 37.1, 27.5, 14.4.
The procedure for the preparation of this compound is reported in the
literature.8
IR (thin film): 2981, 2936, 1723, 1576, 1479, 1455 cm– 1
.
1H NMR (400 MHz, CDCl3):  8.55−8.51 (m, 2 H), 7.55−7.50 (m, 1 H),
7.30−7.25 (m, 1 H), 4.42 (q, J = 7.0 Hz, 1 H), 1.48 (d, J = 7.1 Hz, 3 H),
1.39 (s, 9 H).
HRMS (ESI): m/z calcd for C21H24ClNO3 [M + H] : 374.1517; found:
374.1520.
13C NMR (151 MHz, CDCl3):  194.3, 160.3, 150.1, 148.8, 135.5, 134.0,
123.7, 84.5, 46.0, 27.6, 16.7.
(E)-N-Benzyl-1-(tert-butoxy)-3-(4-bromophenyl)-1-oxobutan-2-
imine Oxide (2d)
HRMS: (ESI): calcd for
236.1282.
C
13H17NO3: ([M+H+]): 236.1287; found:
Prepared using procedure B. Purified via silica gel column chromato-
graphy using 80:20 hexanes/ethyl acetate as eluent (137 mg, 66% yield)
1H NMR (CDCl3, 500 MHz):  7.40–7.42 (m, 4 H), 7.34–7.35 (m, 3H),
7.15 (d, J = 7.7 Hz, 2 H), 5.42 (d, J = 13.0 Hz, 1 H), 5.26 (d, J = 13.0 Hz, 1
H), 4.72 (q, J = 7.1 Hz, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 1.24 (s, 9 H).
Nitrones 2; General Procedure12
The α-keto ester (0.500 mmol) and N-benzylhydroxylamine (1.50
mmol) were combined neat in a flame-dried reaction tube equipped
with a stir bar. tBuOH (1.52 mL) was added and the reaction mixture
was sealed and heated at 85 °C for 48 h. Upon complete consumption
of the starting α-keto ester, as indicated by TLC (staining with CAM),
the reaction mixture was concentrated and purified by silica gel col-
umn chromatography.
(E)-N-Benzyl-1-(tert-butoxy)-3-(2-fluorophenyl)-1-oxobutan-2-
imine Oxide (2e)
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (89.0 mg, 50% yield).
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-3-phenylbutan-2-imineOxide
(2a)
IR (thin film): 3033, 2978, 2935, 2385, 1733, 1716, 1706, 1684, 1653,
1558, 1541, 1457, 1312, 1134, 1113, 844, 758 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 6.97–7.42 (m, 9 H), 5.38 (d, J = 13.1 Hz,
1 H), 5.32 (d, J = 13.1 Hz, 1 H), 4.91 (q, J = 7.1 Hz, 1 H), 1.56 (d, J = 7.1
Hz, 3 H), 1.21 (s, 9 H).
13C NMR (150 MHz, CDCl3): complex spectrum due to 19F–13C cou-
pling (see the Supporting Information).
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (94.4 mg, 56% yield).
IR (thin film): 2977, 1709, 1540, 1497, 1456, 1369, 1299, 1254, 1136,
1092, 843, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.46 (m, 2 H), 7.33–7.39 (m, 3 H),
7.20–7.31 (m, 5 H), 5.46 (d, J = 13.0 Hz, 1 H), 5.25 (d, J = 13.0 Hz, 1 H),
4.82 (q, J = 7.1 Hz, 1 H), 1.55 (d, J = 7.1 Hz, 3 H), 1.17 (s, 9 H).
HRMS (ESI): m/z calcd for C21H24FNO3 [M + H] : 358.1813; found:
358.1817.
13C NMR (150 MHz, CDCl3): δ = 162.0, 146.7, 140.8, 133.8, 128.7,
128.6, 128.4, 128.2, 127.6, 126.6, 83.7, 66.8, 37.5, 27.4, 14.0.
(E)-N-Benzyl-1-(tert-butoxy)-3-(4-methoxyphenyl)-1-oxobutan-
2-imine Oxide (2f)
HRMS (ESI): m/z calcd for C21H25NO3 [M + H] : 340.1907; found:
340.1916.
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (144.0 mg, 78% yield).
(E)-N-Benzyl-1-(tert-butoxy)-3-(4-fluorophenyl)-1-oxobutan-2-
imine Oxide (2b)
IR (thin film): 2978, 1733, 1716, 1698, 1684, 1653, 1558, 1541, 1507,
1457, 1249, 1137, 1032, 846 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.44 (m, 2 H), 7.32–7.38 (m, 3 H),
7.20 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 5.41 (d, J = 13.1 Hz, 1
H), 5.21 (d, J = 13.1 Hz, 1 H), 4.74 (q, J = 7.1 Hz, 1 H), 3.80 (s, 3 H), 1.52
(d, J = 7.1 Hz, 3 H), 1.22 (s, 9 H).
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (78.9 mg, 44% yield).
IR (thin film): 2926, 1748, 1733, 1715, 1684, 1558, 1541, 1508, 1497,
1457, 1395, 1371, 1314, 1225, 1136, 846 cm–1
.
13C NMR (150 MHz, CDCl3): δ = 162.1, 158.4, 146.9, 133.7, 132.7,
128.7, 128.6, 128.6, 128.4, 113.6, 83.7, 66.7, 55.3, 36.9, 27.5, 14.4.
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HRMS (ESI): m/z calcd for C22H27NO4 [M + H] : 370.2013; found:
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-4-phenylbutan-2-imineOxide
370.2018.
(2k)
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (146 mg, 86% yield).
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-3-(p-tolyl)butan-2-imine Ox-
ide (2g)
1H NMR (500 MHz, CDCl3): δ = 7.48–7.49 (m, 2 H), 7.32–7.40 (m, 3 H),
7.21–7.24 (m, 2 H), 7.15–7.18 (m, 1 H), 7.10–7.12 (m, 2 H), 5.63 (s, 2
H), 2.96–2.99 (m, 2 H), 2.83–2.86 (m, 2 H), 1.40 (s, 9 H).
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (128 mg, 72% yield).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.44 (m, 2 H), 7.34–7.37 (m, 3 H),
7.08–7.16 (m, 4 H), 5.42 (d, J = 13.0 Hz, 1 H), 5.22 (d, J = 13.0 Hz, 1 H),
4.75 (q, J = 7.0 Hz, 1 H), 2.30 (s, 3 H), 1.52 (d, J = 7.0 Hz, 3 H), 1.19 (s, 9
H).
13C NMR (150 MHz, CDCl3): δ = 161.6, 141.9, 141.1, 134.2, 128.9,
128.5, 128.5, 128.4, 128.3, 126.0, 83.0, 66.9, 31.2, 30.3, 27.8.
HRMS (ESI): m/z calcd for C21H25NO3 [M + Na]: 362.1732; found:
362.1722.
13C NMR (150 MHz, CDCl3): δ = 162.1, 146.8, 137.7, 136.2, 133.8,
128.8, 128.6, 128.6, 128.4, 127.5, 83.6, 66.7, 37.2, 27.4, 20.9, 14.2.
(E)-N-Benzyl-2-(tert-butoxy)-1-cyclohexyl-2-oxoethan-1-imine
HRMS (ESI): m/z calcd for C22H27NO3 [M + H]: 354.2064; found:
Oxide (2l)
354.2070.
Prepared using procedure B. Purified via silica gel column chromatog-
raphy using 80:20 hexanes/ethyl acetate as eluent (103 mg, 65%
yield).
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-3-(m-tolyl)butan-2-imine Ox-
ide (2h)
1H NMR (CDCl3, 400 MHz):  7.37–7.39 (m, 2 H), 7.29–7.33 (m, 3 H),
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (116 mg, 66% yield).
3.18–3.26 (m, 1 H), 1.29–1.82 (m, 19 H).
IR (thin film): 3032, 2977, 2934, 1749, 1733, 1716, 1699, 1653, 1558,
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-3-(pyridin-3-yl)butan-2-
imine Oxide (2m)
1541, 1522, 1507, 1457, 1315, 1135, 841, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.48 (m, 2 H), 7.35–7.40 (m, 3 H),
7.18–7.22 (m, 1 H), 7.04–7.09 (m, 3 H), 5.48 (d, J = 13.0 Hz, 1 H), 5.27
(d, J = 13.0 Hz, 1 H), 4.81 (q, J = 7.3 Hz, 1 H), 2.33 (s, 3 H), 1.55 (d, J =
7.3 Hz, 3 H), 1.20 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 162.0, 150.0, 146.9, 140.7, 137.7,
133.8, 128.7, 128.6, 128.4, 128.4, 128.1, 127.3, 124.7, 83.6, 66.7, 37.5,
27.4, 21.4, 14.1.
Prepared using procedure B. Purified via silica gel column chromatog-
raphy using gradient elution from 40% to 60% ethyl acetate in hexanes
as eluent (129 mg, 76% yield).
1H NMR (CDCl3, 400 MHz):  8.50 (s, 1 H), 8.41–8.42 (m, 1 H), 7.54–
7.56 (m, 1 H), 7.29–7.35 (m, 5 H), 5.37 (d, J = 13.0 Hz, 1 H), 5.27 (m, J =
13.0 Hz, 1 H), 4.74 (q, J = 6.8 Hz, 1 H), 1.52 (d, J = 6.8 Hz, 1 H), 1.23 (s, 9
H).
HRMS (ESI): m/z calcd for C22H27NO3 [M + H]: 354.2064; found:
354.2071.
α-Imino Esters 3 via Multihetero-Cope Rearrangement; General
Procedure
Activated 4 Å molecular sieves were added to a 15-mL flame-dried
round-bottomed flask. DMAP (0.2 equiv) and Proton-sponge® (2.5
equiv) were added to the flask. The nitrone 2 (0.15 mmol) was then
added in MTBE (1.50 mL) and the resulting suspension was cooled in
an ice bath. The aroyl chloride (2.0 equiv) was added slowly in MTBE
(1.0 mL), and the mixture was gradually allowed to warm to rt. The
reaction mixture was stirred for 4 h. Upon complete consumption of
the nitrone, as indicated by TLC (staining with CAM), the crude mix-
ture was passed through a pad of Celite using diethyl ether to rinse.
The crude residue was purified by silica gel column chromatography,
unless otherwise noted.
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-4-phenyl-3-(4-(trifluoro-
methyl)phenyl)butan-2-imine Oxide (2i)
Purified by silica gel column chromatography using 80:20 hex-
anes/EtOAc (260 mg, 50% yield).
1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 8.3 Hz, 2 H), 7.46 (d, J = 8.3
Hz, 2 H), 7.29–7.34 (m, 3 H), 7.25–7.26 (m, 2 H), 7.16–7.20 (m, 3 H),
7.10–7.12 (m, 2 H), 5.39 (d, J = 12.8 Hz, 1 H), 5.28 (d, J = 12.8 Hz, 1 H),
5.01–5.04 (app t, J = 8.1 Hz, 1 H), 3.51 (dd, J = 8.8, 13.6 Hz, 1 H), 3.22
(dd, J = 7.4, 13.7 Hz, 1 H), 1.32 (s, 9 H).
13C NMR (150 MHz, CDCl3): complex spectrum due to 19F–13C cou-
pling (see the Supporting Information).
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-2-phenylbutan-2-yl
HRMS (ESI): m/z calcd for C28H28F3NO3 [M + H] : 484.2094; found:
Benzoate (3a)
484.2105.
Purified by silica gel column chromatography using 5% and then 10%
EtOAc/hexane (57.6 mg, 86% yield).
(E)-N-Benzyl-1-(tert-butoxy)-1-oxo-3-phenylpentan-2-imine
Oxide (2j)
IR (thin film): 2977, 1709, 1540, 1497, 1456, 1369, 1299, 1254, 1136,
Prepared using procedure B. Purified via silica gel column chromatog-
raphy using 80:20 hexanes/ethyl acetate as eluent (106 mg, 60%
yield).
1H NMR (CDCl3, 500 MHz):  7.20–7.40 (m, 10 H), 5.35 (d, J = 13.0 Hz,
1 H), 5.20 (d, J = 13.0 Hz, 1 H), 4.56–4.59 (dd or app t, J = 7.6 Hz, 7.6
Hz, 1 H), 1.98–2.08 (m, 2 H), 1.31 (s, 9 H), 0.95 (t, J = 7.3 Hz, 3 H).
1092, 843, 700 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.19–8.20 (m, 2 H), 7.60–7.61 (m, 3 H),
7.50–7.52 (m, 2 H), 7.36–7.42 (m, 6 H), 7.28–7.34 (m, 2 H), 4.84 (d, J =
15.0 Hz, 1 H), 4.71 (d, J = 15.0 Hz, 1 H), 2.23 (s, 3 H), 1.24 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 164.7, 164.4, 162.7, 141.7, 138.7,
133.1, 130.8, 129.7, 128.4, 128.3, 128.1, 127.8, 127.5, 126.9, 125.2,
85.5, 83.5, 57.4, 27.8, 25.5.
HRMS (ESI): m/z calcd for C28H29NO4 [M + H] : 444.2169; found:
444.2161.
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(Z)-3-(Benzylimino)-4-(tert-butoxy)-2-(4-fluorophenyl)-4-oxobu-
(Z)-3-(Benzylimino)-4-(tert-butoxy)-2-(4-methoxyphenyl)-4-
tan-2-yl Benzoate (3b)
oxobutan-2-yl Benzoate (3f)
Purified by silica gel column chromatography using 5% and then 10%
EtOAc/hexane (59.1 mg, 85% yield).
Purified by silica gel column chromatography using 80:20 hex-
ane/EtOAc (52.0 mg, 73% yield).
IR (thin film): 2926, 1748, 1733, 1715, 1684, 1558, 1541, 1508, 1497,
IR (thin film): 2978, 1733, 1716, 1698, 1684, 1653, 1558, 1541, 1507,
1457, 1395, 1371, 1314, 1225, 1136, 846 cm–1
.
1457, 1249, 1137, 1032, 846 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.15–8.16 (m, 2 H), 7.60–7.63 (m, 1 H),
7.54–7.57 (m, 2 H), 7.49–7.51 (m, 2 H), 7.35–7.38 (m, 4 H), 7.27–7.31
(m, 1 H), 7.06–7.09 (m, 2 H), 4.81 (d, J = 14.9 Hz, 1 H), 4.68 (d, J = 14.9
Hz, 1 H), 2.20 (s, 3 H), 1.26 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 8.15–8.17 (m, 2 H), 7.58–7.61 (m, 1 H),
7.46–7.51 (m, 4 H), 7.35–7.36 (m, 4 H), 7.26–7.30 (m, 1 H), 6.92 (d, J =
8.9 Hz, 2 H), 4.80 (d, J = 14.8 Hz, 1 H), 4.68 (d, J = 14.8 Hz, 1 H), 3.82 (s,
3 H), 2.21 (s, 3 H), 1.26 (s, 9 H).
13C NMR (150 MHz, CDCl3): complex spectrum due to 19F–13C cou-
pling (see the Supporting Information).
HRMS (ESI): m/z calcd for C29H31NO5 [M + H]: 474.2275; found:
474.2264.
HRMS (ESI): m/z calcd for C28H28FNO4 [M + H]: 462.2075; found:
462.2070.
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-2-(p-tolyl)butan-2-yl
Benzoate (3g)
Purified by silica gel column chromatography using 2.55% and then
5% EtOAc/hexane (65.2 mg, 95% yield).
(Z)-3-(Benzylimino)-4-(tert-butoxy)-2-(4-chlorophenyl)-4-oxobu-
tan-2-yl Benzoate (3c)
Purified by silica gel column chromatography using 5% and then 10%
EtOAc/hexane (51.9 mg, 72% yield).
IR (thin film): 3062, 3030, 2979, 2935, 2870, 1731, 1453 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.16–8.17 (m, 2 H), 7.59–7.61 (m, 1 H),
7.46–7.50 (m, 4 H), 7.35–7.38 (m, 4 H), 7.27–7.29 (m, 1 H), 7.19–7.20
(m, 2 H), 4.80 (d, J = 14.9 Hz, 1 H), 4.68 (d, J = 14.9 Hz, 1 H), 2.36 (s, 3
H), 2.20 (s, 3 H), 1.24 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 164.7, 164.6, 162.9, 138.8, 137.2,
133.1, 130.9, 129.7, 128.9, 128.4, 128.3, 127.8, 126.8, 125.1, 85.5, 83.5,
57.4, 27.8, 25.4, 21.1.
IR (thin film): 3032, 2978, 2934, 1733, 1716, 1698, 1684, 1647, 1558,
1541, 1507, 1457, 1316, 1137, 845, 705 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.14–8.16 (m, 2 H), 7.61–7.63 (m, 1 H),
7.50–7.53 (m, 4 H), 7.35–7.39 (m, 6 H), 7.28–7.30 (m, 1 H), 4.82 (d, J =
14.9 Hz, 1 H), 4.68 (d, J = 14.9 Hz, 1 H), 2.19 (s, 3 H), 1.27 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 164.5, 164.1, 162.6, 140.4, 138.5,
133.4, 133.3, 130.5, 129.7, 128.5, 128.4, 128.3, 127.8, 127.0, 126.7,
85.1, 83.8, 77.2, 57.4, 27.8, 25.4.
HRMS (ESI): m/z calcd for C29H31NO4 [M + H]: 458.2326; found:
458.2323.
HRMS (ESI): m/z calcd for C28H28ClNO4 [M + H]: 478.1780; found:
478.1777.
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-2-(m-tolyl)butan-2-yl
Benzoate (3h)
Purified by silica gel column chromatography using 5% and then 10%
EtOAc/hexane (57.2 mg, 83% yield).
(Z)-3-(benzylimino)-4-(tert-butoxy)-2-(4-bromophenyl)-4-oxobu-
tan-2-yl benzoate (3d)
Prepared using procedure C. Purified via silica gel column chromatog-
raphy using 5% and then 10% ethyl acetate/hexane as eluent (71.1 mg,
91% yield).
1H NMR (CDCl3, 600 MHz):  8.15 (d, J = 8.2 Hz, 2H), 7.61–7.63 (m,
1H), 7.49–7.52 (m, 4H), 7.45–7.47 (m, 2 H), 7.35–7.39 (m, 4 H), 7.28–
7.30 (m, 1 H), 4.82 (d, J = 14.9 Hz, 1 H), 4.68 (d, J = 14.9 Hz, 1 H), 2.19
(s, 3 H), 1.27 (9 H).
13C NMR (CDCl3, 150 MHz): 164.5, 164.0, 162.6, 141.0, 138.5, 133.3,
131.3, 130.5, 129.7, 128.5, 128.4, 127.8, 127.0, 127.0, 121.7, 85.1, 83.8,
57.4, 27.8, 25.4.
IR (thin film): 3032, 2977, 2934, 1749, 1733, 1716, 1699, 1653, 1558,
1541, 1522, 1507, 1457, 1315, 1135, 841, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.17–8.19 (m, 2 H), 7.59–7.62 (m, 1 H),
7.48–7.52 (m, 2 H), 7.41–7.44 (m, 1 H), 7.34–7.37 (m, 5 H), 7.26–7.30
(m, 2 H), 7.12–7.14 (m, 1 H), 4.82 (d, J = 14.8 Hz, 1 H), 4.70 (d, J = 14.8
Hz, 1 H), 2.36 (s, 3 H), 2.21 (s, 3 H), 1.24 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 164.7, 164.5, 162.8, 141.6, 138.7,
137.6, 133.1, 130.9, 129.7, 128.4, 128.3, 128.3, 128.0, 127.9, 126.9,
126.0, 122.2, 85.5, 83.4, 57.5, 27.8, 25.4, 21.7.
HRMS (ESI): m/z calcd for C29H31NO4 [M + H]: 458.2326; found:
458.2316.
(Z)-3-(Benzylimino)-4-(tert-butoxy)-2-(2-fluorophenyl)-4-oxobu-
tan-2-yl Benzoate (3e)
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-1-phenyl-2-(4-(triflu-
Purified by silica gel column chromatography using 5% and then 10%
EtOAc/hexane (60.5 mg, 87% yield).
oromethyl)phenyl)butan-2-yl Benzoate (3i)
Purified by silica gel column chromatography using 5% and then 10%
EtOAc/hexane (67.9 mg, 77% yield).
IR (thin film): 3064, 3032, 2979, 2933, 1733, 1327 cm–1
IR (thin film): 3033, 2978, 2935, 2385, 1733, 1716, 1706, 1684, 1653,
1558, 1541, 1457, 1312, 1134, 1113, 844, 758 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.5 Hz, 2 H), 7.65–7.69 (m, 1
H), 7.55–7.59 (m, 1 H), 7.43–7.47 (m, 2 H), 7.26–7.35 (m, 6 H), 7.17–
7.20 (m, 1 H), 7.00–7.06 (m, 1 H), 4.70–4.79 (m, 2 H), 2.36 (s, 3 H),
1.37 (s, 9 H).
13C NMR (150 MHz, CDCl3): complex spectrum due to 19F–13C cou-
pling (see the Supporting Information).
1H NMR (600 MHz, CDCl3): δ = 8.00–8.01 (m, 2 H), 7.54–7.62 (m, 5 H),
7.45–7.48 (m, 4 H), 7.41–7.43 (m, 2 H), 7.32–7.35 (m, 1 H), 7.04–7.07
(m, 1 H), 6.95–6.98 (m, 2 H), 6.60–6.61 (m, 2 H), 4.94 (d, J = 14.8 Hz, 1
H), 4.76 (d, J = 14.8 Hz, 1 H), 4.42 (d, J = 14.6 Hz, 1 H), 3.73 (d, J = 14.6
Hz, 1 H), 1.15 (s, 9 H).
13C NMR (150 MHz, CDCl3): complex spectrum due to 19F–13C cou-
pling (see the Supporting Information).
HRMS (ESI): m/z calcd for C28H28FNO4 [M + H]: 462.2075; found:
462.2075.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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S. L. Bartlett et al.
Feature
Synthesis
HRMS (ESI): m/z calcd for C35H32F3NO4 [M + H]: 588.2356; found:
588.2352.
product was purified by silica gel column chromatography using 30%
and then 50% EtOAc/hexanes to give the major diastereomer of 4f
(87.5 mg isolated, 56% yield).
1H NMR (500 MHz, CDCl3): δ = 7.26–7.35 (m, 7 H), 6.86–6.88 (m, 2 H),
3.95 (d, J = 13.0 Hz, 1 H), 3.88 (d, J = 13.0 Hz, 1 H), 3.80 (s, 3 H), 3.50
(dd, J = 4.4, 11.5 Hz, 1 H), 3.42 (dd, J = 3.4, 11.5 Hz, 1 H), 2.75–2.77 (m,
1 H), 1.59 (s, 3 H).
(Z)-2-(Benzylimino)-1-(tert-butoxy)-1-oxo-3-phenylpentan-3-yl
Benzoate (3j)
Purified by silica gel column chromatography using 5% EtOAc/hexane
(46.7 mg, 68% yield).
1H NMR (600 MHz, CDCl3): δ = 8.21 (d, J = 7.5 Hz, 2 H), 7.59–7.64 (m, 3
H), 7.51 (t, J = 7.5 Hz, 2 H), 7.36–7.42 (m, 6 H), 7.28–7.34 (m, 2 H), 4.83
(d, J = 14.9 Hz, 1 H), 4.68 (d, J = 14.9 Hz, 1 H), 3.14 (dq, J = 7.4, 14.8 Hz,
1 H), 2.54 (dq, J = 7.4, 14.8 Hz, 1 H), 1.21 (s, 9 H), 0.73 (app t, 3 H).
HRMS (ESI): m/z calcd for C18H23NO3 [M + H]: 302.1756; found:
302.1743.
syn-2-(Benzylamino)-3-phenylbutane-1,3-diol (4a)
13C NMR (150 MHz, CDCl3): δ = 164.6, 164.4, 162.7, 139.9, 138.7,
133.2, 130.6, 129.7, 128.5, 128.3, 128.0, 127.9, 127.4, 126.9, 125.5,
88.1, 83.3, 57.4, 29.1, 27.7, 6.96.
α-Imino ester 3a (146 mg, 0.329 mmol) was used as starting material,
to give the major diastereomer of 4a (51.8 mg isolated, 58% yield).
1H NMR (600 MHz, CDCl3): δ = 7.39–7.40 (m, 2 H), 7.33–7.36 (m, 6 H),
7.25–7.30 (m, 2 H), 3.96 (d, J = 13.0 Hz, 1 H), 3.88 (d, J = 13.0 Hz, 1 H),
3.48 (dd, J = 4.1, 11.5 Hz, 1 H), 3.37 (dd, J = 3.3, 11.5 Hz, 1 H), 2.78–
2.80 (m, 1 H), 1.61 (s, 3 H).
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-2-phenylbutan-2-yl 4-
Methylbenzoate (3n)
13C NMR (150 MHz, CDCl3): δ = 145.8, 140.0, 128.5, 128.3, 128.2,
127.2, 126.8, 124.7, 77.1, 64.9, 61.1, 53.4, 27.9.
Purified by silica gel column chromatography using 20% EtOAc/hex-
ane (63.8 mg, 93% yield).
1H NMR (600 MHz, CDCl3): δ = 8.08 (d, J = 8.2 Hz, 2 H), 7.60–7.61 (m, 2
H), 7.28–7.41 (m, 10 H), 4.84 (d, J = 15 Hz, 1 H), 4.70 (d, J = 15.0 Hz, 1
H), 2.45 (s, 3 H), 2.22 (s, 3 H), 1.24 (s, 9 H).
(±)-(2R,3S)-3-(Benzylamino)-4-((tert-butyldimethylsilyl)oxy)-2-
(4-methoxyphenyl)butan-2-ol ((±)-S1)
13C NMR (150 MHz, CDCl3): 164.7, 164.5, 162.7, 143.8, 141.8, 138.7,
129.7, 129.1, 128.3, 128.1, 128.0, 127.8, 127.4, 126.8, 125.2, 85.3, 83.4,
57.3, 27.8, 25.5, 21.7.
A flame-dried vial was cooled under N2, and charged with alcohol (±)-
4f (34.0 mg, 0.113 mmol, 1 equiv), imidazole (23.0 mg, 0.338 mmol, 3
equiv), and CH2Cl2 (1 mL). The solution was cooled to 0 °C, and TBSCl
(37.4 mg, 0.248 mmol, 2.2 equiv) was added. The reaction mixture
was allowed to warm to rt slowly overnight, and stirred for a total of
16 h. The reaction mixture was passed through a plug of silica gel, and
the plug was washed with EtOAc (3 × 2 mL), then concentrated. The
crude product was purified by silica gel column chromatography
(EtOAc/hexanes, 10:90), which afforded (±)-S1 (39.0 mg, 83% yield) as
a clear and colorless liquid.
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-2-phenylbutan-2-yl 3-
Chlorobenzoate (3o)
Purified by silica gel column chromatography using 20% EtOAc/hex-
ane (68.8 mg, 96% yield).
1H NMR (600 MHz, CDCl3): δ = 8.15 (m, 1 H), 8.05–8.06 (m, 1 H), 7.57–
7.59 (m, 3 H), 7.28–7.46 (m, 9 H), 4.82 (d, J = 14.9 Hz, 1 H), 4.70 (d, J =
14.9 Hz, 1 H), 2.23 (s, 3 H), 1.27 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 164.1, 163.5, 162.7, 141.3, 138.6,
134.6, 133.1, 132.5, 129.8, 129.7, 128.3, 128.2, 127.8, 127.8, 127.7,
126.9, 125.2, 86.0, 83.7, 57.4, 27.8, 25.2.
Rf = 0.2 (EtOAc/hexane, 10:90).
1H NMR (600 MHz, CDCl3): δ = 7.24–7.37 (m, 7 H), 6.84 (d, J = 7.3 Hz, 2
H), 3.95 (d, J = 13.0 Hz, 1 H), 3.75–3.82 (m, 4 H), 3.57 (dd, J = 10.4, 3.9
Hz, 1 H), 3.34 (app d, J = 8.1 Hz, 1 H), 2.76 (br s, 1 H), 1.59 (s, 3 H), 0.86
(s, 9 H), –0.01 (s, 3 H), –0.05 (s, 3 H).
(Z)-3-(Benzylimino)-4-(tert-butoxy)-4-oxo-2-phenylbutan-2-yl 2-
Bromobenzoate (3p)
(±)-(4S,5R)-3-Benzyl-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-
(4-methoxyphenyl)-5-methyloxazolidin-2-one ((±)-5f)
Purified by silica gel column chromatography using 20% EtOAc/hex-
ane (68.2 mg, 87% yield).
1H NMR (500 MHz, CDCl3): δ = 7.89–7.92 (m, 1 H), 7.68–7.69 (m, 1 H),
7.57–7.59 (m, 2 H), 7.27–7.42 (m, 10 H), 4.83 (d, J = 15.0 Hz, 1 H), 4.70
(d, J = 15.0 Hz, 1 H), 2.26 (s, 3 H), 1.26 (s, 9 H).
13C NMR (150 MHz, CDCl3): 164.3, 164.1, 162.6, 141.3, 138.7, 134.2,
132.9, 132.4, 131.3, 128.3, 128.1, 127.8, 127.5, 127.1, 126.9, 125.4,
121.4, 86.3, 83.5, 57.4, 27.8, 25.1.
A flame-dried vial was cooled under N2, and charged with amino al-
cohol (±)-S1 (34.0 mg, 0.0828 mmol, 1 equiv), THF (0.5 mL), and Et3N
(34 μL, 0.245 mmol, 3 equiv). The solution was cooled to 0 °C, and a
solution of triphosgene (29.1 mg, 0.0982 mmol, 1.2 equiv) in THF (1
mL) was added dropwise. The reaction mixture was allowed to warm
to rt slowly overnight, and stirred for a total of 16 h. The reaction
mixture was diluted with saturated aqueous ammonium chloride (1
mL), and stirred for 30 min. The reaction mixture was added to a sep-
aratory funnel, and diluted with CH2Cl2 (30 mL) and saturated aque-
ous ammonium chloride (30 mL). The layers were separated, and the
organic layer was collected. The aqueous layer was extracted with
CH2Cl2 (2 × 30 mL), and the combined organic extracts were dried
over Na2SO4, filtered, and concentrated. The crude product was puri-
fied by silica gel column chromatography (EtOAc/hexanes, 10:90 to
15:85), which afforded (±)-5f (32.9 mg, 91% yield) as a clear and color-
less liquid.
syn-2-(Benzylamino)-3-(4-methoxyphenyl)butane-1,3-diol (4f)
via LiAlH4 Reduction; Typical Procedure
α-Imino ester 3f (248 mg, 0.52 mmol) was dissolved in THF (3.50 mL).
The resulting solution was cooled in an ice bath, and LiAlH4 (2 M in
THF, 2.10 mL, 8.0 equiv) was slowly added. The reaction mixture was
stirred for 12 h, and then quenched with saturated aqueous sodium
sulfate until gas evolution had ceased. The resulting mixture was
passed through a plug of Celite using EtOAc to rinse. The resulting
Rf = 0.15 (EtOAc/hexane, 10:90).
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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S. L. Bartlett et al.
Feature
Synthesis
1H NMR (600 MHz, CDCl3): δ = 7.34–7.39 (m, 2 H), 7.30–7.35 (m, 3 H),
7.23–7.28 (m, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 4.98 (d, J = 15.0 Hz, 1 H),
4.09 (d, J = 15.0 Hz, 1 H), 3.80 (s, 3 H), 3.39 (app t, J = 4.1 Hz, 1 H), 3.25
(app qd, J = 11.0, 4.2 Hz, 2 H), 1.63 (s, 3 H), 0.80 (s, 9 H), –0.15 (s, 3 H),
–0.26 (s, 3 H).
(4) Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070.
(5) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.; Jones, T. C.;
Killeen, N. M.; Taylor, P. H.; Thomas, S. P.; Tomkinson, N. C. O.
Org. Lett. 2005, 7, 5729.
(6) Malinowski, J. T.; Malow, E. J.; Johnson, J. S. Chem. Commun.
2012, 48, 7568.
(7) Steward, K. M.; Johnson, J. S. Org. Lett. 2011, 13, 2426.
(8) Zavesky, B. P.; Bartlett, S. L. Org. Lett. 2017, 19, 2126.
(9) Esteves, C. H. A.; Koyioni, M.; Christensen, K. E.; Smith, P. D.;
Donohoe, T. J. Org. Lett. 2018, 20, 4048.
(10) For the decomposition of 3k (Scheme 4) via a mechanism remi-
niscent of serine and threonine dehydratases, see: Grabowski,
R.; Hofmeister, A. E. M.; Buckel, W. Trends Biochem. Sci. 1993, 18,
297.
Funding Information
The project described was supported by Award R35 GM118055 from
the National Institute of General Medical Sciences. K.M.K. was sup-
ported in part through the Matthew Neely Jackson Undergraduate Re-
search Fellowship (UNC).()
Supporting Information
Ph
Ph
O
N
Supporting information for this article is available online at
H2O/silica gel
CO2tBu
N
Bn
CO2tBu
Bn
https://doi.org/10.1055/s-0037-1610391.
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3k
References
Scheme 4
(1) Current address: Enanta Pharmaceuticals, 500 Arsenal Street,
Watertown, MA 02472, USA.
(2) Current address: Elder Research, 14 E Peace St., Suite 302,
Raleigh, NC 27604, USA.
(11) Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4036.
(12) Pfeiffer, J. Y.; Beauchemin, A. M. J. Org. Chem. 2009, 74, 8381.
(3) Tabolin, A. A.; Ioffe, S. L. Chem. Rev. 2014, 114, 5426.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J