Tandem chain extension-Mannich reaction: An approach to β-proline derivatives

Article abstract of DOI:10.1016/j.tet.2012.07.039

A zinc carbenoid-initiated chain extension reaction provides access to an organometallic intermediate, which can be used to capture activated imines. Deprotection of the nitrogen and reduction provides access to racemic derivatives of β-proline. The relative stereochemistry of the β-proline can be controlled through use of different activating groups on the imine nitrogen.

Full text of DOI:10.1016/j.tet.2012.07.039

Tetrahedron 68 (2012) 7799e7805
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem chain extensioneMannich reaction: an approach to b-proline derivatives
,
a
b
Alexander M. Jacobine a, Angela L.A. Puchlopek a, Charles K. Zercher a , Jon B. Briggs , Jerry P. Jasinski ,
*
Raymond J. Butcher c
a Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA
b Department of Chemistry, Keene State College, 229 Main Street, Keene, NH 03435, USA
c Department of Chemistry, Howard University, 525 College Street NW, Washington, DC 20059, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 June 2012
Received in revised form 7 July 2012
Accepted 10 July 2012
Available online 17 July 2012
A zinc carbenoid-initiated chain extension reaction provides access to an organometallic intermediate,
which can be used to capture activated imines. Deprotection of the nitrogen and reduction provides
access to racemic derivatives of
b
-proline. The relative stereochemistry of the
b
-proline can be controlled
through use of different activating groups on the imine nitrogen.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chain extension
Zinc carbenoid
b
-Proline
Mannich reaction
1. Introduction
2. Results and discussion
The development of stereoselective synthetic approaches to
b
-
The availability of enantiopure sulfinimines8 encouraged the
exploration of their utility in a tandem chain extensioneimine
capture reaction. Treatment of methyl pivaloylacetate (1) with
3 equiv of the Furukawa reagent (ethyl(iodomethyl)zinc)9 was
followed by the addition of sulfinimine 3. All efforts to trap the
enolate with the sulfinimine resulted initially in the isolation of
chain extended material (4) with no evidence of imine in-
corporation. A lengthening of the reaction time and modification of
the stoichiometry to use a 3-fold excess of the enolate eventually
led to the formation of a product in which the imine had been
trapped with the intermediate zinc enolate (Scheme 1). Surpris-
ingly, the incorporation of an additional methyl group was revealed
through NMR analysis. The N-methylation of amide functionality
with the Furukawa reagent had been reported by Charette,10 and
we had observed O-methylation in an earlier study of tandem chain
extensionealdol reactions.5 In an effort to prevent methylation of
the product, a reduction in the equivalencies of carbenoid was
proposed; however, this resulted in a decreased yield of the
methylated product and no formation of the non-methylated ma-
terial. Based upon the assumed presence of the methylated nitro-
gen, cleavage of the sulfoxamines was expected to provide access to
a methylamine derivative and eventually to a heterocycle. Depro-
tection of the sulfoxamines is reported to proceed under mildly
acidic conditions,2c,11 but the starting material was returned un-
amino acids and their derivatives has been the focus of significant
research effort,1 of which one of the most common strategies has
involved the addition of enolates to imine functionalities. Chiral
enolates and chiral imines have been studied for the purpose of
diastereocontrol,2 and enantioselective methods have also been
investigated.3 Application of this synthetic approach to
b-proline
and its derivatives, however, is complicated by the cyclic nature of
the skeleton. Development of a facile and stereoselective approach
that uses Mannich reactions in the formation of a variety of
proline derivatives would provide an alternative synthetic ap-
proach to these unusual -amino acids.
b-
b
Our research group has developed a zinc carbenoid-mediated
chain extension reaction4 that culminates in the formation of an
intermediate organometallic 2 that is capable of trapping various
electrophiles, including aldehydes,5 electrophilic carbenoids,6 and
halogens.7 We anticipated that activated imines would be suitable
electrophilic partners for this type of tandem reaction process, and
that the presence of a g-keto functionality in the product would
open the possibility for the formation of
through reductive cyclization.
b-proline derivatives
changed after treatment under
a wide variety of reaction
* Corresponding author. E-mail address: ckz@christa.unh.edu (C.K. Zercher).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.039

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A.M. Jacobine et al. / Tetrahedron 68 (2012) 7799e7805
conditions, including excess trifluoroacetic acid in refluxing
methanol for 24 h. Exposure of the -amino ester to concd HCl in
methanol eventually resulted in consumption of starting material,
but no -amino acid derivative was evident. The unanticipated
difficulty in deprotection of the presumed sulfoxamine derivative
led us to reconsider the structural assignment.
b-proline derivatives 8. These diastereomeric b-proline derivatives
b
were formed in a ratio of 1:4:7, as determined by 1H NMR in-
tegration, when using the unpurified Mannich products as starting
materials. The minor diastereomer, which is not illustrated in
Scheme 2, is generated from the anti-Mannich product, while the
two major diastereomers arise from the syn-Mannich product (7).
The cyclic imine derived from the syn-Mannich product would be
expected to undergo reduction with unremarkable facial selection
due the trans relationship of the phenyl and carboxylate ester
functionalities. Modest selectivity observed in the cyclization-
reduction sequence resulting in a 4:7 ratio is consistent with this
analysis. Even though isolation of the major diastereomeric product
of this reaction sequence was possible via chromatography, as-
signment of the relative stereochemistry of the tert-butyl sub-
stituent was not possible.
b
Scheme 1. Tandem chain extensioneMannich reaction with sulfinimine 3.
Crystallization of the product (5) from methanol eventually
provided an X-ray grade crystal that revealed S-methylation of
a syn-Mannich product had taken place. Control studies revealed
that the starting sulfinimine (3) was not affected by the Furukawa
carbenoid, therefore S-methylation took place after nucleophilic
addition to the imine. Literature reports suggest that nitrogen an-
ions of sulfoximines are prone to N-alkylation,12 so S-methylation is
atypical and may be a result of carbenoid use and/or the presence of
Scheme 2. Tandem chain extensioneMannich reaction with diphenylphosphinoyl
imine 6.
the zinc-counter ion. In an effort to generate the targeted
derivatives, imines that lack the capacity for S-nucleophilic be-
havior were investigated.
Diphenylphosphinoyl imine (6) was prepared via a literature
method13 and added to the chain extension reaction mixture using
similar reaction conditions as developed for the tandem chain ex-
b
-proline
The long reaction times required for nucleophilic addition to the
diphenylphosphinoyl imine and the modest stereoselectivity of the
Mannich reaction prompted the exploration of another activated
imine. Utilization of a Boc-activated imine (9) was attractive due to
the reports16 of high reactivity of the imine and the formation of
a Boc-protected b-amino acid as the product. The reaction between
tension aldol reaction. Low yields of a
b
-amino acid (7) were iso-
the zinc organometallic, resulting from chain extension of 1, and
the Boc-activated imine was much more rapid than the phosphi-
noyl imine reaction. Capture of compound 9a provided access to
lated, with the bulk of the material isolated from the reaction
mixture being the chain extended material (4).14 Addition of an
aldehyde to the imine-containing solution prior to the aqueous
quench resulted in formation of an aldol product,5 which confirmed
that reactive enolate was still present and suggested that the
diphenylphosphinoyl imine reacts slowly with the zinc organo-
metallic. Longer reaction times (>48 h) eventually resulted in the
a mixture of the desired
b-amino acid derivative (10a) and the
deprotected cyclic imine (11a). The premature removal of the Boc-
group was not considered a major concern since the next step in the
preparation of the
The crude mixture of products was subjected to trifluoroacetic
acid, which converted the remaining -amino acid to the cyclic
imine (11a). Reduction with NaCNBH3 in acidic methanol gave rise
to -proline derivative (12a) (Scheme 3).
The ratio of diastereomeric -proline derivatives, as determined
b-proline derivative involved Boc-deprotection.
formation of the
a mixture of two stereoisomers (Scheme 2). Chain extension aldol
reactions performed on -keto ester starting materials have typi-
cally favored formation of syn-aldol products, and the vicinal 1H
NMR coupling constants between the - and -protons have proven
b
-amino acid target (7) in modest yields as
b
b
b
b
a
b
by NMR analysis of the crude reaction mixture, was 9:1:2. The
major isomer (12a) was identical to the minor diastereoisomer
generated in the reaction of the diphenylphosphinoyl imine, while
the two minor diastereomers created in the reaction sequence
utilizing Boc-imine (9a) corresponded to the major products (8) of
the phosphinoyl imine reaction. Since the reaction conditions for
the reduction were identical to those used with the phosphinoyl
imine substrate, diastereocontrol in the enolate addition to the Boc-
imine was responsible for the significant differences in
to be good indicators of the diastereocontrol in the tandem chain
extension aldol reactions. This NMR-based predictive tool was not
viewed as reliable for these b-amino acids, so an alternate method
for assessing stereoselectivity was required. Deprotection of the
imine functionality provided access to a mixture of two di-
astereomeric cyclic imines, one derived from the syn-Mannich
product and the other from the anti-Mannich product, and the
imines were immediately reduced with NaCNBH3
15
to yield

A.M. Jacobine et al. / Tetrahedron 68 (2012) 7799e7805
7801
Changes in facial selectivity in the reaction with the two imines
through a closed transition state could account for the divergence in
diastereocontrol. The anti selectivity observed in the reaction of a Z-
enolate with an E-imine has been proposed to proceed through
a chair-like closed transition state, which accounts for the anti se-
lectivity observed in the Boc-imine reactions.17 In order for a closed
chair-like transition state to be operative in the phosphinoyl imine
reaction and result in the formation of the syn product, the imine
must isomerize to a Z-imine. Computational investigation of the EeZ
isomerization at the 321-G* level suggests that the energy difference
between the E and Z isomers is quite small, on the order of 2 kcal/mol.
Furthermore, the barrier (approx. 11 kcal/mol) for imine inversion is
easily accessible at the reaction temperature. The opportunity,
therefore, exists for the Z-phosphinoyl imine to react with the
Z-enolate to provide the syn product. Alternatively, the steric size of
the diphenylphosphinoyl groups18 as presented in an E-imine may
encounter excessive 1,3-diaxial steric interaction when reacting with
a Z-enolate. Alleviation of this steric interaction by reaction through
a twist boat conformationwould also account for formation of the syn
product. The operation of anopen transition statemechanism, similar
to that proposed foraldol reactionwhenperformed in the presence of
excess Lewis base, could also be considered.19
Scheme 3. Formation of racemic b-proline derivatives 12 through use of N-Boc-imines 9.
diastereoselectivity. A syn-Mannich product, as proposed for the
phosphinoyl imine reaction, would produce a cyclic imine with
trans substituents (13). Poor facial selectivity in a NaCNBH3 re-
duction would be expected. In contrast, reduction of the cyclic
imine produced from the anti-Mannich product would be expected
to be more selective due to the presence of both substituents on the
same face of the heterocycle (11a) (Fig.1). This hypothesis proved to
be correct when X-ray analysis of the major product (10a) indicated
that the stereochemical relationship established in the Mannich
reaction was, in fact, anti.
b-Keto imides have been subjected to tandem chain extension
aldol reactions with high anti-aldol selectivity being favored, pre-
sumably through the operation of an open transition state.5,19 The
starting b
-keto imide (16)20 can be synthesized through acetylation
of Meldrum’s acid (14),21 followed by treatment with 2-
oxazolidinone (15).22
The bis-carbenoid provided an enhanced yield in the tandem
chain extension reaction of b-keto imide 16. Analysis by NMR in-
dicated that the open chain form of the b-amino acid derivative was
not present, whereas a 13C NMR resonance at 90 ppm was consis-
The tandem reaction was also studied with other aromatic im-
ines (9b and 9c).3b
b-Proline derivatives derived from p-methox-
tent with the presence of a hemiaminal (17) (Scheme 4). X-ray
ybenzaldehyde (12b) and p-tolualdehyde (12c) were produced
with similar yields and selectivities. An X-ray grade crystal of 10c,
derived from the p-toluene-derived Boc-imine, confirmed the anti
relationship for the Mannich reaction.
crystallographic analysis revealed that the anti-b-amino acid was
generated in the tandem reaction and that the compound crystal-
lized in the N-Boc hemiaminal form. The reduction of N-Boc
hemiaminals through treatment with triethylsilane and BF3$OEt2
The divergent stereoselectivity when using the phosphinoyl
imine and the Boc-imines is a key feature of the method. Tandem
chain extension aldol reactions are syn-selective as a result of
a closed transition state involving a Z-enolate that is selectively
generated through ketone interaction with the organometallic in-
termediate.5 Identical chain extension reaction conditions are uti-
lized for enolate formation in the tandem-aldol and the tandem-
Mannich reactions; therefore, the enolate intermediate generated
in the presence of the imine is expected to be very similar.
provided access to N-Boc protected
b-proline derivative (18) with
outstanding diastereocontrol (Scheme 4).23
O
P
Ph
Ph
N
N
t-Bu
t-Bu
Ph
OMe
N
Ph
Ph
H
Scheme 4. Synthesis of b-proline derivative 18 from b-keto imide 16.
O
13
6
The strategies described above for generating b-proline de-
rivatives, both Boc-protected and unprotected, are direct, versatile,
and practical; however, the method at this time is limited to aryl
imines. Although the diastereocontrol is not exceptional, the N-
Boc
H
Ph
OMe
N
Boc-imines and N-phosphinoyl imines provide access to racemic b-
proline derivatives with complementary diastereocontrol. Fur-
thermore, the sense of the diastereoselection is opposite to that
observed with the catalytic asymmetric Mannich-type reactions
using the same imines.24 Studies targeted at the application of this
method and absolute stereocontrol are underway.
O
11a
9a
Fig. 1. Divergent diastereocontrol based upon imines.

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A.M. Jacobine et al. / Tetrahedron 68 (2012) 7799e7805
3. Experimental section
addition, over 30 s, of diiodomethane (5.00 mmol, 0.38 mL,
5.00 equiv) via syringe. The resulting solution was stirred for ap-
proximately 10 min. Methyl pivaloylacetate (1) (1.00 mmol,
0.14 mL, 1.00 equiv) was added via syringe and the solution was
stirred for 30 min. N-Phosphinoyl imine 6 (0.50 mmol, 0.15 g,
0.50 equiv) was mixed with dichloromethane (5 mL) and dried
3.1. General experimental methods
All reactions were run in oven-dried glassware under nitrogen
atmosphere and stirred with Teflon-coated magnetic stir-bars. The
terms ‘concentrated in vacuo or under reduced pressure’ refer to
the use of a rotary evaporator. All commercially available starting
materials were used as received, unless otherwise described.
Diethylzinc was used as a 1.0 M solution in hexanes. (Neat dieth-
ylzinc can also be used successfully for these reactions, although
extreme caution should be used when using the neat reagent since
diethylzinc is pyrophoric.) Methylene iodide (CH2I2) was purchased
from commercial suppliers and non-oxidized copper wire was
added as a stabilizer. Tetrahydrofuran and dichloromethane were
dried by passing through an alumina column under pressure. Ethyl
acetate and hexanes were distilled prior to use. Column chroma-
ꢀ
with 4 A molecular sieves. The solution was added to the round-
bottomed flask via syringe and the solution was stirred for 48 h.
The solution was quenched with saturated ammonium chloride
(2 mL), extracted with dichloromethane (2ꢂ25 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated on a rotary
evaporator (35 ꢀC, 25 mmHg). The crude reaction mixture was
purified via column chromatography (15:2, hexanes/ethyl acetate,
Rf¼0.22) to afford 0.13 g (0.27 mmol, 27% yield) of the product (7) as
a white solid (mp¼168e172 ꢀC). 1H NMR (400 MHz, CDCl3)
d:
7.80e7.73 (m, 2H), 7.68e7.61 (m, 2H), 7.50e7.36 (m, 5H), 7.31e7.36
(m, 4H), 7.14e7.08 (m, 2H), 4.37 (dt, J¼12.3, 6.2 Hz, 1H), 4.09 (br t,
J¼10.6 Hz, 1H), 3.46e3.35 (m, 4H), 3.05 (dd, J¼6.5, 3.3 Hz, 2H), 1.11
tography was performed on EM Science flash silica gel (35e75 mm),
and the mobile phases were used as noted. 1H and 13C NMR spectra
were referenced to internal tetramethylsilane (TMS). Melting
points are uncorrected. High Resolution Mass Spectroscopy was
performed at the University of Notre Dame Mass Spectrometry
Facility. Crystallographica data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 885735e885738. Computational work was performed using
the SpartanÓ suite of programs.
(s, 9H). 13C NMR (100 MHz, CDCl3)
d: 214.7, 173.4, 141.4 (d,
JCeP¼3.7 Hz), 132.9 (d, JCeP¼9.8 Hz), 132.1 (d, JCeP¼12.0 Hz), 131.8
(d, JCeP¼9.6 Hz), 128.7 (d, JCeP¼15.2 Hz), 128.5 (d, JCeP¼12.8 Hz),
127.8, 126.9, 57.2, 51.9, 48.5 (d, JCeP¼3.7 Hz), 44.2, 36.9, 26.7. IR
(neat)
n 3250, 3059, 2950, 2904, 1771, 1741, 1725, 1698, 1474, 1434,
1366, 1304, 1184, 1106 cmꢃ1. HRMS (ESI) m/z: calcd for C28H33NO4P
[MþH] 478.2142; found [MþH] 478.2134.
3.2.3. (ꢁ)-(2S, 3S)-Methyl 5-tert-butyl-2-phenylpyrrolidine-3-
carboxylate (8). An oven-dried, one-necked, 100 mL round-
bottomed flask was equipped with a magnetic stir bar and a rub-
ber septum. The flask was charged with methanol (50 mL) via sy-
ringe, and flushed with nitrogen through a needle in a rubber
septum. Thionyl chloride (0.5e1.0 mL) was added via syringe and
3.2. Detailed experimental procedures
3.2.1. Product (5) of tandem chain extensioneMannich Reaction with
sulfoximine. Into a 100 mL round-bottomed flask, equipped with
a magnetic stir bar and a nitrogen inlet, was charged with 25 mL of
dichloromethane and 12 mL of a diethylzinc solution (1 M in hex-
anes, 12 mmol). The mixture was cooled to 0 ꢀC in an ice bath and
methylene iodide (0.95 mL, 12 mmol) was added dropwise by sy-
ringe. After stirring for 10 min, 0.48 mL of methyl pivaloylacetate 1
(3 mmol) was added dropwise by syringe to the reaction mixture.
After stirring for another 20 min, (S)-(þ)-benzylidene-p-toluene-
sulfinate 3 (0.365 g, 1 mmol) dissolved in a minimal amount of
dichloromethane was added. The reaction mixture was stirred for
3 h, while monitoring for the disappearance of (S)-(þ)-benzyli-
dene-p-toluenesulfinate by TLC. The reaction mixture was
quenched with 20 mL of saturated ammonium chloride. Ethyl ac-
etate (15 mL) was added and the organic layer removed. A second
portion of ethyl acetate (15 mL) was used to extract the aqueous
layer. The combined organic layers were dried with anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed on silica (hexane/ethyl acetate; 4:1)
to provide 247 mg (59%) of 5 as a yellowish oil. A crystal suitable for
X-ray crystallographic analysis was prepared by crystallization from
the solution became strongly acidic (pH w1e2). a-Substituted g-
keto ester 7 (0.27 mmol, 0.13 g, 1.00 equiv) was added as a solution
in methanol (1e2 mL) and allowed to stir for 12 h. Sodium cyano-
borohydride (0.05 g, 0.81 mmol, 3.0 equiv) was added in one por-
tion and the solution was stirred for 16 h. The reaction mixture was
diluted with water (15 mL) and basified (pH w12e13) with sodium
hydroxide (20%). The basic mixture was extracted with dichloro-
methane (3ꢂ25 mL). The combined organic extracts were dried
over sodium sulfate, filtered and concentrated on a rotary evapo-
rator (35 ꢀC, 25 mmHg). The crude reaction mixture was purified
via column chromatography (5:1, hexanes/ethyl acetate, Rf¼0.17) to
afford 0.04 g (0.15 mmol, 56% yield) of the product (8) as a colorless
oil. 1H NMR (400 MHz, CDCl3)
d: 7.47e7.42 (m, 2H), 7.34e7.28 (m,
2H), 7.24 (m, 1H), 4.38 (d, J¼8.5 Hz, 1H), 3.63 (s, 3H), 3.13 (t,
J¼7.9 Hz, 1H), 2.73 (dd, J¼18.0, 7.9 Hz, 1H), 2.10e1.93 (m, 2H), 0.94
(s, 9H). 13C NMR (100 MHz, CDCl3)
d: 175.4, 143.3, 128.5, 127.6, 127.1,
66.8, 65.8, 52.1, 51.9, 33.7, 31.4, 26.4. IR (neat)
n 2952, 2867, 1733,
1636, 1493, 1453, 1435, 1392, 1361, 1243, 1165, 898 cmꢃ1. HRMS
(ESI) m/z: calcd for C16H24NO2 [MþH] 262.1802; found [MþH]
262.1806.
methanol. 1H NMR (400 MHz, CDCl3)
d
7.77 (d, J¼4.8 Hz, 2H),
7.12e7.51 (m, 7H), 4.61 (d, J¼5.6 Hz, 1H), 3.45 (s, 3H), 3.06e3.28 (m,
2H), 2.93 (s, 3H), 2.70 (dd, J¼17.6, 2.4 Hz, 1H), 2.45 (s, 3H), 1.09 (s,
3.2.4. (ꢁ)-(S)-Methyl
2-((R)-(tert-butoxycarbonylamino)(phenyl)
9H); 13C NMR (400 MHz, CDCl3)
d
215.3, 174.3, 143.9, 137.2, 130.0,
methyl)-5,5-dimethyl-4-oxohex-anoate (10a). An oven-dried, one-
necked, 100 mL round-bottomed flask was equipped with a mag-
netic stir bar and a rubber septum and was then charged with
dichloromethane (20 mL) via syringe, and flushed with nitrogen
through a needle in a septum. The flask was placed in an ice water
bath, cooled to 0 ꢀC, and neat diethylzinc (3.00 mmol, 0.30 mL,
3.00 equiv) was added via syringe in one portion followed by slow
addition, over 30 s, of diiodomethane (3.00 mmol, 0.24 mL,
3.00 equiv) via syringe. The resulting solution was stirred for ap-
proximately 10 min. Methyl pivaloylacetate (1) (1.00 mmol,
0.24 mL, 1.00 equiv) was added via syringe and the solution was
stirred for 30 min. Freshly prepared N-Boc imine 9a (1.00 mmol,
128.4, 127.3, 60.6, 59.7, 51.7, 50.2, 44.9, 44.2, 35.3, 26.7, 21.7, 21.3,
14.4.
3.2.2. (ꢁ)-(S)-Methyl 2-((S)-((diphenylphosphoryl)amino)(phenyl)
methyl)-5,5-dimethyl-4-oxohex-anoate (7). An oven-dried, one-
necked, 100 mL round-bottomed flask was equipped with a mag-
netic stir bar and a rubber septum and was then charged with
dichloromethane (20 mL) via syringe, and flushed with nitrogen
through a needle in a septum. The flask was placed in an ice water
bath, cooled to 0 ꢀC, and neat diethylzinc (5.00 mmol, 0.50 mL,
5.00 equiv) was added via syringe in one portion followed by slow

A.M. Jacobine et al. / Tetrahedron 68 (2012) 7799e7805
7803
0.21 mL, 1.00 equiv) was added as a solution in 3.00 mL of
dichloromethane in one portion via syringe and the solution was
stirred for 15 h, during which the reaction slowly warmed to room
temperature. The solution was quenched with saturated ammo-
nium chloride (2 mL) and extracted with dichloromethane
(3ꢂ25 mL). The organic layers were combined, dried over anhy-
drous sodium sulfate, filtered, and concentrated on a rotary evap-
orator (35 ꢀC, 25 mmHg). The crude reaction mixture was purified
via column chromatography on alumina (5:1, hexanes/ethyl ace-
tate, Rf¼0.27) to afford 0.20 g (0.52 mmol, 52% yield) of the product
10a as a colorless oil. The crude reaction mixture was a mixture of
the desired product (10a) and the deprotected cyclic imine (11a).
The mixture could be used for further chemistry without purifi-
185.8, 172.9, 138.9, 128.1, 127.7. 127.5, 77.8, 51.4, 48.6, 36.8, 36.4 28.5.
IR (neat) 3062, 3029, 2962, 2926, 2868, 1737, 1638, 1493, 1454,
1435, 1363, 1268, 1202, 1174, 1104, 1076, 1033, 1006, 913, 734 cmꢃ1
n
.
HRMS (ESI) m/z: calcd for C16H22NO2 [MþH] 260.1645; found
[MþH] 260.1649.
3.2.8. (ꢁ)-(2R,3S)-Methyl 5-(tert-butyl)-2-(4-methoxyphenyl)-3,4-
dihydro-2H-pyrrole-3-carboxylate (11b). The identical procedure
as used for the formation of 11a was performed on a 1 mmol scale
using 10b (0.41 g) as the starting material to yield 0.27 g (92%) of
11b. 1H NMR (400 MHz, CDCl3)
d: 7.02e6.97 (m, 2H), 6.83e6.76 (m,
2H), 5.47 (d, J¼9.2 Hz, 1H), 3.76 (s, 3H), 3.51 (td, J¼9.4, 6.8 Hz, 1H),
3.23e3.17 (m, 4H), 2.76 (ddd, J¼17.3, 9.4, 0.7 Hz,1H),1.29 (s, 9H). 13C
cation as well. 1H NMR (400 MHz, CDCl3)
d
: 7.36e7.30 (m, 2H),
NMR (100 MHz, CDCl3) d: 185.3,172.9,159.1,130.9,128.6,113.5, 77.3,
7.27e7.23 (m, 3H), 5.76 (d, J¼8.4 Hz, 1H), 4.86 (d, J¼7.1 Hz, 1H), 3.54
55.4, 51.5, 48.5, 36.6, 36.3, 28.5. IR (neat) n 2962, 2869, 2838, 1735,
(s, 3H), 3.33 (s, 1H), 2.93 (dd, J¼18.2, 8.9 Hz, 1H), 2.80 (m, 1H), 1.42
1637, 1612, 1585, 1512, 1461, 1438, 1363, 1248, 1176, 1036, 833,
732 cmꢃ1. HRMS (ESI) m/z: calcd for C17H24NO3 [MþH] 290.1751;
found [MþH] 290.1755.
(s, 9H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3)
d: 213.4, 174.5, 155.4,
140.7, 128.7, 127.7, 126.3, 79.8, 55.1, 52.1, 46.2, 44.2, 37.4, 28.5, 26.5.
IR (neat) 3380, 3062, 3030, 2974, 2907, 2875, 1707, 1498, 1455,
1436, 1391, 1366, 1283, 1168, 737 cmꢃ1
n
.
3.2.9. (ꢁ)-(2R,3S)-Methyl 5-(tert-butyl)-2-(p-tolyl)-3,4-dihydro-2H-
pyrrole-3-carboxylate (11c). The identical procedure as used for the
formation of 11a was performed on a 1 mmol scale using 10c
(0.39 g) as the starting material to yield 0.26 g (95%) of 11c. 1H NMR
3.2.5. (ꢁ)-(S)-Methyl 2-((R)-((tert-butoxycarbonyl)amino)(4-
methoxyphenyl)methyl)-5,5-dimethyl-4-oxohex-anoate (10b). The
identical procedure as used for the formation of 10a was used;
Methyl pivaloylacetate (1) (1.00 mmol, 0.24 mL, 1.00 equiv) and 9b
(1 mmol, 235 mg, 1 equiv) were used. 57% yield, colorless oil. 1H
(400 MHz, CDCl3)
d
: 7.06 (d, J¼7.8 Hz, 2H), 6.95 (d, J¼8.0 Hz, 2H),
5.48 (d, J¼9.2 Hz, 1H), 3.53 (ddt, J¼8.4, 7.0, 1.4 Hz, 1H), 3.18 (s, 4H),
2.76 (ddd, J¼17.3, 9.4, 0.8 Hz, 1H), 2.29 (s, 3H), 1.29 (s, 9H). 13C NMR
NMR (400 MHz, CDCl3)
d
: 7.16 (d, J¼8.6 Hz, 2H), 6.88e6.80 (m, 2H),
(100 MHz, CDCl3) d: 185.4, 172.9, 137.1, 135.7, 128.8, 127.4, 77.6, 51.4,
5.67 (m, 1H), 4.80 (m, 1H), 3.78 (s, 3H), 3.60e3.52 (m, 3H), 2.92 (dd,
J¼18.2, 8.2 Hz,1H), 2.17 (d, J¼2.8 Hz,1H),1.39 (s, 9H),1.11 (s, 9H). 13C
48.5, 36.7, 36.3, 28.5, 21.3. IR (neat) n 3350, 3131, 3094, 3050, 2968,
2874, 2733, 1902, 1698, 1651, 1556, 1455, 1366, 1285, 1079, 1044,
1019 cmꢃ1. HRMS (ESI) m/z: calcd for C17H24NO2 [MþH] 274.1802;
found [MþH] 274.1796.
NMR (100 MHz, CDCl3) d: 213.5, 174.6, 159.1, 155.4, 127.5, 114.1, 55.5,
54.6, 54.0, 46.3, 44.2, 37.4, 29.5, 28.5, 26.5. IR (neat)
n 3386, 2970,
1706, 1610, 1512, 1366, 1292, 1247, 1168, 1030, 888, 835 cmꢃ1. HRMS
(ESI) m/z: calcd for C22H34NO6 [MþH] 408.2381; found [MþH]
408.2383.
3.2.10. (ꢁ)-(2R,3S,5S)-Methyl 5-tert-butyl-2-phenylpyrrolidine-3-
carboxylate (12a). An oven-dried, one-necked, 100 mL round-
bottomed flask was equipped with a magnetic stir bar and rubber
septum. The flask was charged with methanol (50 mL) via syringe,
and flushed with nitrogen through a needle in a rubber septum.
Thionyl chloride (0.5e1 mL) was added via syringe and the solution
3.2.6. (ꢁ)-(S)-Methyl 2-((R)-((tert-butoxycarbonyl)amino)(p-tolyl)
methyl)-5,5-dimethyl-4-oxohex-anoate (10c). The identical pro-
cedure as used for the formation of 10a was used; Methyl piv-
aloylacetate (1) (1.00 mmol, 0.24 mL, 1.00 equiv) and 9c
(1.00 mmol, 0.22 mL, 1.00 equiv) were used. 55% yield, colorless oil.
became strongly acidic (pH w1e2). Cyclic imine
8 (0.08 g,
0.27 mmol, 1.00 equiv) was added as a solution in methanol
(1e2 mL) and allowed to stir for 5 min. Sodium cyanoborohydride
(0.05 g, 0.81 mmol, 3.00 equiv) was added in one portion and the
solution was stirred for 16 h. The reaction mixture was diluted with
water (15 mL) and basified (pH w12e13) with sodium hydroxide
(20%). The basic mixture was extracted with dichloromethane
(3ꢂ25 mL). The combined organic extracts were dried over sodium
sulfate, filtered and concentrated on a rotary evaporator (35 ꢀC, 25
mmHg) to afford 0.05 g (0.21 mmol, 79% yield) of the product as
a colorless oil. The crude reaction mixture required no further pu-
1H NMR (400 MHz, CDCl3)
d: 7.13e7.11 (m, 4H), 5.69 (m, 1H), 4.81
(m, 1H), 3.55 (d, J¼2.2 Hz, 1H), 3.30 (s, 3H), 2.92 (dd, J¼18.2, 8.1 Hz,
1H), 2.75 (d, J¼14.1 Hz, 1H), 2.32, (d, J¼2.7 Hz, 3H), 2.16 (s, 3H), 1.41
(s, 9H), 1.10 (s, 9H). 13C NMR (100 MHz, CDCl3)
d: 213.5, 174.5, 163.1,
155.4, 137.3, 129.4, 126.5, 126.2, 79.7, 54.9, 54.0, 52.0, 46.2, 44.2,
37.4, 36.3, 31.1, 29.9, 28.5, 26.6, 26.5, 21.2. IR (neat) 3330, 3131,
n
3094, 3050, 2968, 2874, 2733, 1902, 1698, 1651, 1556, 1455, 1366,
1285, 1044, 880 cmꢃ1. HRMS (ESI) m/z: calcd for C22H34NO5 [MþH]
392.2431; found [MþH] 392.2424.
rification. 1H NMR (400 MHz, CDCl3)
d: 7.33e7.25 (m, 4H), 7.23e7.17
3.2.7. (ꢁ)-(2R,3S)-Methyl
pyrrole-3-carboxylate (11a). A 20 mL scintillation vial was charged
with -substituted -keto ester 10a (0.38 g, 1.00 mmol, 1.00 equiv),
5-tert-butyl-2-phenyl-3,4-dihydro-2H-
(m, 1H) 4.49 (d, J¼9.0 Hz, 1H), 3.30 (dt, J¼8.7, 7.5 Hz, 1H), 3.12 (s,
3H), 2.99 (dd, J¼10.2, 6.7 Hz, 1H), 2.29 (s, 1H), 2.00 (ddq, J¼12.8, 9.4,
a
g
7.1 Hz, 1H), 1.04 (s, 9H). 13C NMR (100 MHz, CDCl3)
d: 174.4, 140.8,
dichloromethane (10 mL) and a magnetic stir bar. The vial was
place in an ice water bath and trifluoroacetic acid (1.5 mL) was
added dropwise over a 5 min period. The ice water bath was re-
moved and the reaction was stirred for 8 h. The mixture was diluted
with dichloromethane (10 mL), extracted with water (2ꢂ15 mL),
washed with saturated sodium bicarbonate (3ꢂ15 mL), dried over
sodium sulfate, filtered and concentrated on a rotary evaporator
(35 ꢀC, 25 mmHg). The crude reaction mixture was purified via flash
column chromatography (5:1 hexanes/ethyl acetate, Rf¼0.15) to
afford 0.23 g of the product (0.89 mmol, 89%). 1H NMR (400 MHz,
128.1, 127.4, 127.3, 68.7, 65.1, 51.2, 49.9, 33.1, 30.5, 26.9. IR (neat) n
3350, 3062, 3030, 2955, 2927, 2867, 1960, 1899, 1737, 1623, 1577,
1493,1450,1436,1364,1299,1206,1174,1106, 696 cmꢃ1. HRMS (ESI)
m/z: calcd for C16H24NO2 [MþH] 262.1802; found [MþH] 262.1805.
3.2.11. (ꢁ)-(2R,3S,5S)-Methyl
5-(tert-butyl)-2-(4-methoxyphenyl)
pyrrolidine-3-carboxylate (12b). The identical procedure as used for
the formation of 12a was performed on a 0.27 mmol scale using 11b
(0.08 g) as the starting material to yield 0.06 g (82%) of 12b; col-
orless oil. 1H NMR (400 MHz, CDCl3)
d: 7.25e7.22 (m, 2H),
CDCl3)
1H), 3.53 (td, J¼9.3, 6.5 Hz, 1H), 3.20 (ddd, J¼17.3, 6.5, 1.9 Hz, 1H),
3.12 (s, 3H), 2.76 (m, 1H), 1.28 (s, 9H). 13C NMR (100 MHz, CDCl3)
d
: 7.26e7.17 (m, 3H), 7.09e7.04 (m, 2H), 5.51 (d, J¼9.3 Hz,
6.83e6.79 (m, 2H), 4.45 (d, J¼9.1 Hz, 1H), 3.78 (s, 3H), 3.25 (m, 1H),
3.17 (s, 3H), 2.96 (dd, J¼10.2, 6.5 Hz, 1H), 2.04 (ddd, J¼12.7, 10.4,
7.7 Hz, 1H), 1.99e1.87 (m, 2H), 1.03 (s, 9H). 13C NMR (100 MHz,
d:

7804
A.M. Jacobine et al. / Tetrahedron 68 (2012) 7799e7805
CDCl3)
d
: 174.5, 158.9, 133.2, 128.5, 113.4, 68.7, 64.5, 55.4, 51.2, 49.9,
39.1, 28.5, 28.1, 27.2, 21.2, 14.4. IR (neat)
1478, 1455, 1363, 1310, 1272, 1221, 1166, 1105, 1037, 909, 843 cmꢃ1
Representative 1H resonances for the major hemiacetal isomeric form
1H NMR (400 MHz, CDCl3)
1H), 5.19 (s, 1H), 4.45e4.20 (m, 4H), 3.87e3.71 (m, 1H), 3.37e3.28
(m, 1H), 3.01e2.87 (m, 1H), 2.15e1.99 (m, 2H), 1.76 (s, 3H), 1.08 (s,
9H). HRMS (ESI) m/z: calcd for C20H27N2O6 [MþH] 391.1864; found
[MþH] 391.1853.
n 2977, 1779, 1693, 1672,
33.1, 30.4, 26.9. IR (neat)
n
2954, 2929, 2869, 1734, 1637, 1610, 1584,
.
1511, 1462, 1394, 1301, 1244, 1173, 1033, 933, 828 cmꢃ1. HRMS (ESI)
m/z: calcd for C17H26NO3 [MþH] 292.1907; found [MþH] 292.1904.
d
: 7.39e7.19 (m, 5H), 5.33 (d, J¼8.7 Hz,
3.2.12. (ꢁ)-(2R,3S,5S)-Methyl 5-(tert-butyl)-2-(p-tolyl)pyrrolidine-
3-carboxylate (12c). The identical procedure as used for the for-
mation of 12a was performed on a 0.27 mmol scale using 11c
(0.08 g) as the starting material to yield 0.60 g (80%) of 12c. 80%
yield, colorless oil. 1H NMR (400 MHz, CDCl3)
d: 7.19 (d, J¼8.0 Hz,
3.2.15. (ꢁ)-(2R,3S)-tert-Butyl 5-methyl-3-(2-oxo-oxazolidine-3-
carbonyl)-2-phenylpyrrolidine-1-carboxylate (18). An oven-dried,
one-necked, 50-mL round-bottomed flask was equipped with
a magnetic stir bar and a rubber septum and was then charged with
dichloromethane (15 mL) via syringe, N-Boc hemiaminal 17
(0.72 mmol, 0.28 g, 1.00 equiv) and flushed with nitrogen through
a needle in a septum. The flask was placed in dry ice-acetone bath
and was cooled to ꢃ78 ꢀC. Boron trifluoride etherate (0.78 mmol,
0.10 mL, 1.10 equiv) was added via syringe in one portion and
allowed to stir for 10 min. Triethylsilane (0.72 mmol, 0.12 mL,
1.00 equiv) was added via syringe in one portion and allowed to stir
for 2 h. The solution was quenched with saturated sodium bi-
carbonate (5 mL) and was extracted with dichloromethane
(3ꢂ20 mL), dried over anhydrous sodium sulfate, filtered and
concentrated on a rotary evaporator (35 ꢀC, 25 mmHg). The crude
reaction mixture was purified via flash column chromatography
(4:1 hexanes/ethyl acetate, Rf¼0.19) to afford 0.20 g (0.53 mmol,
74% yield) of 18 as a sticky white solid. Mixture of diastereomers
2H), 7.07 (d, J¼7.9 Hz, 2H), 4.45 (d, J¼9.0 Hz, 1H), 3.27 (dt, J¼8.7,
7.6 Hz, 1H), 3.15 (s, 3H), 2.97 (dd, J¼10.2, 6.6 Hz, 1H), 2.30 (s, 3H),
2.10e1.98 (m, 2H), 1.93 (ddd, J¼12.8, 8.5, 6.6 Hz,1H), 1.03 (s, 9H). 13C
NMR (100 MHz, CDCl3) d: 174.5, 137.9, 136.9, 128.7, 127.3, 68.7, 64.9,
51.2, 49.9, 33.1, 30.6, 27.0, 21.3. IR (neat)
n 3346, 2952, 2926, 2859,
1738, 1513, 1435, 1366, 1201, 1165, 1108, 1042, 934, 820, 718 cmꢃ1
.
HRMS (ESI) m/z: calcd for C17H26NO2 [MþH] 276.1958; found
[MþH] 276.1948.
3.2.13. 1-(2-Oxooxazolidin-3-yl)butane-1,3-dione (16). A 250 mL
round-bottomed flask was equipped with a magnetic stir bar and
a reflux condenser. The flask was charged with acetylated Mel-
drum’s acid21 (11.76 g, 62.2 mmol, 1.25 equiv), oxazolidine (4.33 g,
49.8 mmol, 1.00 equiv), and toluene (100 mL) and was flushed with
nitrogen through a needle in a septum. The solution was allowed to
reflux for 8 h and the solution was concentrated under reduced
pressure (30 ꢀC, 25 mmHg). The crude reaction mixture was
recrystallized from ethanol (2ꢂ95%) to afford 6.90 g (40.3 mmol,
81% yield) of the product as a dark brown solid (mp¼54.0e57.0 ꢀC,
(dr¼5:1); 1H NMR (400 MHz, CDCl3)
d: 7.31e7.18 (m, 3H), 7.14 (d,
J¼7.1 Hz, 2H), 5.41 (d, J¼9.3 Hz, 1H) 5.32 (d, J¼9.0 Hz, 1H), 4.40
(ddd, J¼11.9, 9.3, 7.1 Hz, 1H), 4.29 (m, 1H), 4.20 (dt, J¼16.2, 8.2 Hz,
1H), 3.93 (dt, J¼17.2, 6.1, Hz, 1H), 3.78 (ddd, J¼16.5, 9.5, 7.1 Hz, 1H),
3.26 (ddd, J¼10.8, 9.3, 6.6 Hz, 1H), 2.48e2.35 (m, 1H), 2.16 (dt,
J¼13.4, 6.8 Hz, 1H), 1.61 (d, J¼6.0 Hz, 3H), 1.38e1.18 (br s, 9H), 1.06
lit. mp20¼61e63 ꢀC). 1H NMR (400 MHz, CDCl3)
: 4.45 (t, J¼8.2 Hz,
d
2H), 4.09e4.05 (m, 4H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3)
d:
201.1,166.7,153.9, 62.5, 51.2, 42.3, 30.3. IR (neat) n 2985, 2904, 2853,
1768,1724,1701,1526,1477,1420,1396,1362,1334,1256,1188,1047,
1014, 962, 880 cmꢃ1. HRMS (ESI) m/z: calcd for C7H9NNaO4 [MþNa]
194.0424; found [MþNa] 194.0416.
(s, 9H). 13C NMR (100 MHz, CDCl3)
d: 170.2, 154.9, 153.4, 141.1, 128.2,
127.7,126.9, 79.8, 64.2, 62.4, 53.8, 47.3, 42.7, 34.2, 28.4, 21.3 IR (neat)
2972, 2929, 1774, 1686, 1601, 1478, 1455, 1363, 1341, 1299, 1268,
1220, 1125, 1036, 1004, 977, 882 cmꢃ1. Representative 1H resonances
for the major diastereomer 1H NMR (400 MHz, CDCl3)
: 7.30e7.18
n
3.2.14. (ꢁ)-(2R,4S,5S)-tert-Butyl 2-hydroxy-2-methyl-4-(2-oxo-ox-
azolidine-3-carbonyl)-5-phenylpyrrolidine-1-carboxylate
(17). An
d
oven-dried, one-necked, 100 mL round-bottomed flask was
equipped with a magnetic stir bar and a rubber septum and was
then charged with dichloromethane (20 mL) via syringe, and
flushed with nitrogen through a needle in a septum. The flask was
placed in an ice water bath, cooled to 0 ꢀC, and neat diethylzinc
(3.00 mmol, 0.30 mL, 3.00 equiv) was added via syringe in one
portion followed by slow addition, over 30 s, of diiodomethane
(6.00 mmol, 0.48 mL, 6.00 equiv) via syringe. The resulting solution
(m, 3H), 7.16e7.13 (m, 2H), 5.41 (d, J¼9.3 Hz, 1H), 4.40 (ddd, J¼11.9,
9.3, 7.1 Hz, 1H), 4.29 (tt, J¼11.0, 5.5 Hz, 1H), 4.20 (dt, J¼16.2, 8.2 Hz,
1H), 3.94 (tt, J¼12.2, 6.2 Hz, 1H), 3.78 (ddd, J¼16.5, 9.5, 7.1 Hz, 1H),
3.26 (ddd, J¼10.8, 9.3, 6.6 Hz, 1H), 2.48e2.34 (m, 1H), 2.16 (dt,
J¼13.4, 6.8 Hz,1H),1.61 (d, J¼6.0 Hz, 3H),1.27 (s, 9H). HRMS (ESI) m/
z: calcd for C20H27N2O5 [MþH] 375.1914; found [MþH] 375.1909.
Acknowledgements
was stirred for approximately 10 min. Freshly prepared
b-keto
imide 16 (1.00 mmol, 0.17 g, 1.00 equiv) was added as a solution in
3 mL of dichloromethane via syringe and the solution was stirred
for 30 min. Freshly prepared N-Boc imine 9a (1.00 mmol, 0.21 mL,
1.00 equiv) was added as a solution in 3 mL of dichloromethane in
one portion via syringe and the solution was stirred for 15 h, during
which the reaction slowly warmed to room temperature. The so-
lution was quenched with saturated ammonium chloride (2 mL),
extracted with dichloromethane (3ꢂ25 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated on a rotary evaporator
(35 ꢀC, 25 mmHg). The crude reaction mixture was recrystallized
from hexanes to afford 0.23 g (0.59 mmol, 59% yield) of the product
as a crystalline solid, which converted to a mixture of hemiaminal
The support of the NIH (R15 GM-060967) is appreciated. R.J.B.
acknowledges the NSF MRI program (grant No. CHE-0619278) for
funds to purchase the X-ray diffractometer. Professor Franklin Davis
is acknowledged for a generous gift of compound 3.
Supplementary data
1H and 13C NMR spectra for all compounds. Supplementary data
related to this article can be found online at http://dx.doi.org/
10.1016/j.tet.2012.07.039.
isomers in solution. Mixture of isomers: 1H NMR (400 MHz, CDCl3)
d:
References and notes
7.39e7.19 (m, 5H), 5.76 (d, J¼9.5 Hz, 1H), 5.33 (d, J¼8.7 Hz, 1H), 5.19
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4.05e3.93 (m, 2H), 3.89e3.73 (m, 1H), 3.38e3.25 (m, 1H), 3.11 (dd,
J¼18.1, 11.1 Hz, 2H), 3.01e2.89 (m, 1H), 2.15e1.98 (m, 2H), 1.76 (s,
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