Synthesis of polysubstituted pyrroles from sulfinimines (N-sulfinyl imines)

Article abstract of DOI:10.1016/j.tet.2008.02.102

Polysubstituted 2-carboxylate and 2-phosphonate pyrroles are prepared by aromatization of the corresponding 3-oxo 2-carboxylate and 2-phosphonate NH-pyrrolidines using air. Reaction of electrophiles with 3-oxo pyrrolidine dianions readily introduces subst

Full text of DOI:10.1016/j.tet.2008.02.102

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4174e4182
www.elsevier.com/locate/tet
Synthesis of polysubstituted pyrroles from
sulfinimines (N-sulfinyl imines)
*
Franklin A. Davis , Kerisha A. Bowen, He Xu, Venkata Velvadapu
Department of Chemistry, Temple University, Philadelphia, PA 19122, United States
Received 24 January 2008; received in revised form 21 February 2008; accepted 28 February 2008
Available online 5 March 2008
Abstract
Polysubstituted 2-carboxylate and 2-phosphonate pyrroles are prepared by aromatization of the corresponding 3-oxo 2-carboxylate and
2-phosphonate NH-pyrrolidines using air. Reaction of electrophiles with 3-oxo pyrrolidine dianions readily introduces substituents, regioselec-
tively at C-4 in these pyrrolidines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyrroles; Aromatization; Dianions; N-Sulfinyl imines
1. Introduction
biological properties including antibacterial, antiviral, antitu-
mor, anti-inflammatory, and antioxidant activities.8 They are
also important intermediates in the synthesis of natural prod-
ucts.9 For these reasons many methods have been devised for
their preparation, which include the classical Hantzsch, Knorr,
and PaaleKnorr procedures.10 While newer methods provide
access to ring substituted examples, their synthesis continues
to be a challenge.11,12 Some of these newer procedures involve
aromatization of stable preformed pyrrolidines.13 Although
The current focus of our research efforts is the design and
synthesis of sulfinimine-derived building blocks, templates,
and scaffolds for the asymmetric synthesis of nitrogen hete-
rocycles.1,2 In this context, we reported the synthesis of
N-sulfinyl d-amino b-ketoesters 13 and N-sulfinyl d-amino b-
ketophosphonates 24 for the asymmetric synthesis of 3-oxo
pyrrolidine 2-carboxylates 35 and 3-oxo pyrrolidine 2-phos-
phonates 4,6 respectively (Scheme 1).1 The oxo pyrrolidines
3 were elaborated to cis-5-substituted prolines5a,b and the
anti-fungal alkaloid (þ)-preussin.5c Pyrrolidine 2-phospho-
nates 4 were transformed into cis-5-substitute pyrrolidine
2-phosphonates (proline surrogates)6 and into polyfunctional-
ized pyrrolidines, including the pharoh’s ant pheromone pyrro-
lidine 225C.7 We describe here, the details of a new method
for preparing polysubstituted pyrroles 5 from 3 and 4. The
advantage of this methodology is that electrophiles can be
regioselectively introduced at C-4 of 3 and 4 via the corre-
sponding dianions and that aromatization is accomplished at
room temperature under non-aqueous conditions. Pyrroles
are heterocyclic compounds that exhibit a broad range of
O
S
O
3
4
p-Tolyl
NH
O
O
2
5
CO2Me
R
N
1
R
OMe
H
1
3
O
S
O
p-Tolyl
NH
O
O
P(OMe)2
P(OMe)2
O
R
N
H
R
2
4
R'
R
OH
Z
Z = CO2Me
Z = P(O)(OMe)2
N
H
5
* Corresponding author. Tel.: þ1 215 204 0477; fax: þ1 215 204 0478.
E-mail address: fdavis@temple.edu (F.A. Davis).
Scheme 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.102

F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
4175
phosphonopyrrolidines have been examined as HIV protease in-
hibitors,14 only a few procedures have been reported for their
preparation.11,15 Furthermore, much less is known concerning
the properties of phosphonopyrroles, undoubtedly due to the
fact that there is no general method for their preparation.11,16
corresponding 2,4-carbonyl dianions.19 Regioselective re-
action of electrophiles at the C-4 carbanions of 13/14 is ex-
pected because of the lower nucleophilicity and steric
hindrance of the C-2 b-dicarbonyl anion. Optimized yields
of products were obtained when the dianions were generated
by treatment of 13/14 with 3 equiv of LDA at ꢀ78 ꢁC. At
this temperature 1.5 equiv of the appropriate electrophiles
(Eþ) were added (Scheme 3). In each case only a single re-
gioisomer was detected resulting in exclusive reaction at
C-4 affording 15 and 16 in moderate to good yields (Table
1).20 However, attempts to introduce a hydroxy group at C-4
in 13a (R¼Ph) using 8.8-(dichlorocamphorsulfonyl)oxaziri-
dine (Oxaz)21 and a benzyl group at C-4 in 13c (R¼t-Bu)
were unsuccessful and likely due to increased steric demands
of oxaziridine and the pyrrolidine. These results are summa-
rized in Table 1.
2. Results and discussion
2.1. Synthesis of 3-oxo pyrrolidines
cis-3-Oxo pyrrolidine 2-carboxylates 13 and cis-3-oxo
pyrrolidine 2-phosphonates 14 were prepared as previously
described using the highly diastereoselective intramolecular
metal carbenoide NH insertion reaction of N-Boc d-amino
a-diazo b-ketoesters and phosphonates 11 and 12, respectively
(Scheme 2).5,6,7 While a number of these compounds were
originally prepared as pure diastereoisomers from the corre-
sponding enantiopure sulfinimines (p-tolyleS(O)N]CHR),
this is not necessary.17 Racemic sulfinimines are readily avail-
able from the corresponding racemic sulfinamide (p-tolyle
S(O)NH2) prepared using the procedure described by Garcia
Ruano and co-workers.18
E
O
1) LDA, -78 °C
2) E+
O
CO2Me
R
N
CO2Me
R
N
Boc
Boc
13
15a: R = Ph, E = Me
15b: R = Ph, E = Bn
15c: R = 2-furan, E = Me
15d: R = Me3C, E = Me
O
S
O
S
MeCO2Me or
E
O
1) LDA, -78 °C
2) E+
MeP(O)(OMe)2
p-Tolyl
NH
O
p-Tolyl
NH
O
O
base
Z
R
OMe
P(OMe)2
N
R
R
(80-85%)
Boc
O
P(OMe)2
O
R
N
Boc
7: Z = CO2Me
8: Z = P(O)(OMe)2
6
16a: R = Ph, E = Bn
14
16b: R = 2-furan, E = Me
16c: R = 2-furan, E = Bn
1) TFA/MeOH
Boc
4-HO2CPhSO2N3 or
Scheme 3.
2) (Boc)2O/Et3N
DMAP
NH
O
4-CH3CONHPhSO2N3
Z
R
base
(80-90%)
In another study, it was found possible to introduce a chlo-
rine atom at C-4 in 19 by treatment of the 2,4-dicarbonyl di-
anion with 0.75 equiv of 1,3-dichloro-5,5-dimethylhydantoin
(DMDCH) affording 4-chloropyrrolidine 20 in 53% yield as
a single isomer (Scheme 4). The reason that chlorination
was carried out with the N-Cbz 3-oxo pyrroline 19 was to
demonstrate that the intramolecular metal carbenoide NH in-
sertion reaction, 18 to 19, is also compatible with this protect-
ing group (Scheme 4).
(71-95%)
9: Z = CO2Me
10: Z = P(O)(OMe)2
Boc
Boc
R
NH
O
O
NH
O
4 mol% Rh2(OAc)4
or
P(OMe)2
CO2Me
DCM 35 °C
R
N2
N2
12
11
O
O
a: R = Ph
or
R
Table 1
Reaction of electrophiles with the dianions of 13 and 14 at ꢀ78 ꢁC in THF
b: R = 2-Furan
c: R = Me3C-
P(OMe)2
O
N
R
CO2Me
N
Boc
Boc
Entry
Pyrrolidine 13/14, R
Eþ
15/16, E
(% isolated yield)
d: R = CH2=CH-
13a (86%)
13b (74%)
13c (63%)
13d (87%)
14a (80%)
14b (67%)
14c (61%)
1
2
3
4
5
6
7
8
9
a
13a, R¼Ph
MeI
15a, E¼Me (83)
15b, E¼Bn (79)
NRb
BnBr
Oxaza
MeI
Scheme 2.
13b, R¼2-furan
13c, R¼t-Bu
15c, E¼Me (88)
15d, E¼Me (50)
NRb
MeI
BnBr
BnBr
MeI
2.2. Synthesis of 4-substituted 3-oxo 2,5-disubstituted
pyrrolidines
14a, R¼Ph
16a, E¼Bn (41)
16b, E¼Me (40)
16c, E¼Bn (70)
14b, R¼2-furyl
BnBr
The presence of the 3-oxo group in 13 and 14 provides an
avenue for functionalization of these building blocks via the
8,8-(Dichlorocamphorsulfonyl)oxaziridine (3 equiv) was used.
Starting material was recovered.
b

4176
F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
Table 2
Aromatization of pyrrolidine salt 22 to pyrrole 23 for 5 h in EtOAc at rt
1) TFA/MeOH
2) Cbz-Cl/Et3N
DMAP
O
S
Cbz
NH
O
p-Tolyl
NH
O
CO2Me
Entry
Additives
% Isolated yield of pyrrole 23
CO2Me
Cbz
Ph
(77%)
Ph
1
2
3
4
5
6
7
8
SiO2, air
SiO2, argon
Air
88
17
7a
No reaction
No reaction
80
TFA, air
TFA, argon
Et3N, air
Pyridine, air
Cs2CO3
NH
O
4-CBSA
Et3N
(83%)
No reaction
33
4 mol% Rh2(OAc)4
(93%)
CO2Me
Ph
No reaction
20
N2
18
33% (Table 2, entry 6). Optimum yields of 23 were obtained
using the combination of SiO2 and air in EtOAc.
Cl
Ph
O
O
a) LDA
b) DMDCH
Most mechanisms proposed for the aromatization of stable
and unstable hydroxy and oxo pyrrolidines invoke a base pro-
moted elimination of a nitrogen (9-phenylfluorene, TsOH) or
ring substituent.12g,13b,d The results summarized in Table 2
suggest a different mechanism, an acid catalyzed radical mech-
anism. We suggest that SiO2 promotes formation of the enol 22,
required for aromatization, and that molecular oxygen abstracts
hydrogen atoms with concomitant formation of the pyrrole 23
and hydrogen peroxide.22 In support of this hypothesis is the
fact that N-Boc pyrrolidine 13a in the presence of SiO2eair
does not form the pyrrole. Perhaps interaction between the large
N-Boc and the CO2Me may sterically inhibit enol formation.
The radical mechanism is further supported by the fact that per-
oxide was detected in the reaction mixture using a KI peroxide
test.23 In the absence of pyrrolidine 21, the SiO2eair system did
not produce detectable amounts of peroxide.
CO2Me
N
Ph
CO2Me
(53%)
N
Cbz
20
Cbz
19
Scheme 4.
2.3. Aromatization of 3-oxo pyrrolidines to pyrroles
Treatment of 13a (R¼Ph) with 10 equiv of TFA, neutraliza-
tion with NaHCO3, and concentration removed the N-Boc
group to give the intermediate 3-oxo pyrrolidine 21 (Scheme
5). The 1H NMR of this material has the NH protons at
O
O
OH
CO2Me
1) TFA
2) NaHCO
3
Ph
CO2Me
Ph
CO2Me
N
Ph
N
H
N
H
Boc
This aromatization procedure is remarkable, generally
working with various substituted pyrrolidine 2-carboxylates
13 and 15 and pyrrolidine 2-phosphonates 14 and 16 to afford
the corresponding pyrroles 25 and 26 in good yields (Scheme
6). Only in the case of 15d (R¼t-butyl, E¼Me) was the
isolated yield modest, i.e., 50%.
13a
21
22
O
H
O
SiO2
air
Ph
N
H
OMe
1) TFA
23
E
E
O
OH
CO2Me
2) NaHCO3
3) SiO2
Scheme 5.
R
CO2Me
R
N
N
H
air
Boc
d 9.41 ppm (D2O exchangeable), and the C-2 proton appears
at d 5.42 ppm suggesting that the enol 22 was not formed in
detectable amounts. Under these conditions, in an NMR tube
in CDCl3, 21 was stable for more than 48 h. However, at-
tempts to purify this material resulted in decomposition.
When pyrrolidine 21 was stirred for 4 h in EtOAc in the pres-
ence of SiO2 in an open flask exposed to the atmosphere, 5-
phenyl-3-hydroxy-1H-pyrrole-2-carboxylate (23) was isolated
in 88% yield (Table 2, entry 1). The structure of 23 is sup-
ported by the downfield shift of the C-4 protons from d 2.59
and 3.70 ppm to one proton at d 6.13 ppm.
The influence of the reaction parameters on the aromatiza-
tion of 21 to 23 was next explored to optimize yields and de-
termine the mechanism of the reaction. In the absence of air,
formation of pyrrole 23 was not detected (Table 2, entries 2
and 5). In the absence of SiO2 or TFA, even in the presence
of air, the pyrrole was not formed (Table 2, entries 3 and 7).
The only exception was with Et3N, but the yield was low,
25a (75%)
25b (81%)
25c (81%)
25d (78%)
25e (67%)
25f (67%)
25g (50%)
13b: R = 2-Furyl, E =H
13c: R = Me3C, E = H
13d: R = CH2=CH, E = H
15a: R = Ph, E = Me
15b: R = Ph, E = Bn
15c: R = 2-Furyl, E = Me
15d: R = Me3C, E = Me
1) TFA
E
E
O
OH
P(OMe)2
2) NaHCO3
3) SiO2
R
P(OMe)2
O
R
N
N
H
air
Boc
O
26a (75%)
26b (80%)
26c (61%)
26d (51%)
26e (60%)
26f (75%)
14a: R = Ph, E = H
14b: R = 2-Furyl, E = H
14c: R = Me3C, E = H
16a: R = Ph, E = Bn
16b: R = 2-Furyl, E = Me
16c: R = 2-Furyl, E = Bn
Scheme 6.

F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
4177
When N-Cbz chloropyrrolidine 20 was treated with SiO2e
air for 5 h, the N-CBz pyrrole 27 was obtained in 82% yield.
Heating 20 with Et3N at 45 ꢁC for 6 h in the absence of air also
gave the pyrrolidine 27 in 68% yield (Scheme 7). In these
examples aromatization is induced by elimination of the C-3
chlorine atom.
dimethyl-3-oxohep-tanoate
(9c),5b
dimethyl-(þ)-2-oxo-
N-(tert-butoxycarbonyl)-4-amino-4-phenylbutylphosphonate
(10a),6 dimethyl-(ꢀ)-2-oxo-N-(tert-butoxycarbonyl)-4-amino-
5,5-dimethylhexylphosphonoate (10c),6 methyl-(þ)-2-diazo-
3-oxo-5-(tert-butyloxycarbonylamino)-5-phenylpentanoate
(11a),5a methyl-(þ)-2-diazo-6,6-dimethyl-3-oxo-N-(tert-bu-
toxycarbonyl)-5-aminoheptanoate (11c),5b dimethyl-(þ)-1-
diazo-2-oxo-N-(tert-butoxycarbonyl)-4-amino-4-phenylbutyl-
phosphonate (12a),6 (þ)-diazo-2-oxo-N-(tert-butoxycarbonyl)-
4-amino-5,5-dimethylhexylphosphonate (12c),6 methyl-(þ)-
N-(tert-butyloxycarbonyl)-3-oxo-5-phenylpyrrolidine-2-carbo-
xylate (13a),5a methyl-(þ)-5-tert-butyl-3-hydroxypyrroli-
dine-1-dicarboxylate (13c),5b dimethyl-(þ)-N-(tert-butoxy-
carbonyl)-3-oxo-5-phenylpyrrolidine-2-phosphonate (14a),6
dimethyl-(ꢀ)-N-(tert-butoxycarbonyl)-3-oxo-5-tert-butylpyr-
rolidine-2-phosphonate (14c),6 5-tert-butyl-3-hydroxy-1H-pyr-
role-2-carboxylic acid methyl ester (25f),5b dimethyl 5-tert-
butyl-3-hydroxy-1H-pyrrole-2-phosphonate (26c)6 were previ-
ously synthesized as enantiomerically and diastereomerically
pure compounds. The racemic forms of these materials ex-
hibited identical physical and spectral properties when com-
pared to their optically active counterparts.
Cl
Ph
O
OH
Et3N or SiO2-air
(68-82%)
CO2Me
Ph
CO2Me
N
N
Cbz
Cbz
20
27
Scheme 7.
3. Summary
In summary, the dianions of 2,5-disubstituted 3-oxo pyrro-
lidines regioselectively undergo electrophilic substitution at
the C-4 position affording tetrasubstituted pyrrolidines. Air
oxidation of these pyrrolidines affords the corresponding tetra-
substituted pyrroles at room temperature without the need for
a pyrrolidine leaving group. Importantly, this methodology
provides convenient access to the relatively unexplored
2-phosphopyrroles 26 for further biological and chemical
evaluation.
4.1.1. Methyl-(ꢂ)-5-(2-furyl)-5-(p-toluenesulfinylamino)-3-
oxopentanoate (7b). Typical procedure
In an oven-dried, 250-mL, single-necked round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
and argon balloon was placed NaHMDS (14.70 mL,
14.70 mmol) in anhydrous THF (15 mL). The reaction mixture
was cooled to ꢀ78 ꢁC and methyl acetate (1.20 mL,
15.13 mmol) was added. After stirring at this temperature
for 1 h, 6b (1.129 g, 3.67 mmol) in THF (35 mL) was added.
The solution was stirred at ꢀ78 ꢁC for 4 h, quenched with sat-
urated NH4Cl (5 mL), and warmed to rt. Water (10 mL) was
added and the solution was extracted with EtOAc
(3ꢃ10 mL). The combined organic phases were washed with
brine (10 mL), dried (Na2SO4), and concentrated. Flash chro-
matography (50% EtOAc/hexanes) afforded 1.077 g (84%) as
4. Experimental
4.1. General
Column chromatography was performed on silica gel,
Merck grade 60 (230e400 mesh). TLC plates were visualized
with UV, in an iodine chamber, or with phosphomolybdic acid,
unless otherwise noted. Melting points were recorded on
a Mel-Temp apparatus and are uncorrected. IR spectra were
recorded, using NaCl plates or as KBr disks on a Mattson
1
4020 FTIR. H NMR and 13C NMR spectra were recorded
on a Bruker Avance-400, operating at 400 and 125 MHz, re-
spectively. HRMS were performed in the Department of
Chemistry, Drexel University, Philadelphia, PA, using a Fis-
sions ZAB HF double-focusing mass spectrometer. Solvents,
DCM, THF, and diethyl ether were purified by filtration on
a Glass Contour Seca solvent purification system. Unless
stated otherwise, all reagents were purchased from commer-
cial sources and used without additional purification.
1
an orange oil; IR (neat) 3423, 3224, 1748, 1716 cmꢀ1; H
NMR (CDCl3) d 2.27 (s, 3H), 3.08 (qd, 2H), 3.29 (s, 2H),
3.57 (s, 3H), 4.78e4.82 (m, 2H), 6.13 (d, J¼8.1, 1H), 6.26
(d, J¼8.0 Hz, 1H), 7.15 (d, J¼8.4 Hz, 2H), 7.22 (s, 1H),
7.45 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3) d 21.7, 47.7,
49.5, 52.7, 108.2, 110.9, 126.0, 129.9, 141.8, 142.6, 153.4,
167.5, 200.5. HRMS calcd for C17H20NO5S (MþH)
350.1062. Found 350.1059.
Methyl-(ꢂ)-N-(p-toluenesulfinyl)-3-amino-3-phenylpropa-
noate (6a),5a methyl-(þ)-3-(furan-2-yl)-3-(p-toluenesulfinyl-
amino)propanoate (6b),5a methyl-(þ)-4,4-dimethyl-N-(p-tol-
uenesulfinyl)-3-aminopentanoate (6c),5b methyl-(þ)-3-(p-tol-
uenesulfinyl)-pent-4-enoate (6d),6 methyl-(þ)-3-oxo-5-(p-
toluenesulfinylamino)-5-phenylpentanoate (7a),5a methyl-
(þ)-6,6-dimethyl-3-oxo-5-(p-toluenesulfinylamino)heptanoate
4.1.2. Methyl-(ꢂ)-5-(p-toluenesulfinylamino)-3-oxo-hept-6-
enoate (7d)
Yield 85% of a yellow liquid; IR (neat) 1735, 1718, cmꢀ1
;
1H NMR (CDCl3) d 2.28 (s, 3H), 2.78e2.75 (m, 2H), 3.29 (s,
2H), 3.58 (s, 3H), 4.16e4.13 (m, 1H), 4.67 (d, J¼9 Hz, 1H),
5.07 (m, 1H), 5.16 (m, 1H), 5.77 (m, 1H), 7.15 (d, J¼10 Hz,
2H), 7.43 (d, J¼10 Hz, 2H); 13C NMR (CDCl3) d 21.8,
48.8, 49.7, 52.6, 53.2, 117.3, 125.9, 129.8, 138.1, 141.7,
142.3, 168.9, 200.9. HRMS calcd for C15H19NO4S (MþH)
310.1113. Found 310.1115.
(7c),5b
dimethyl-(ꢀ)-2-oxo-4-(p-toluenesulfinylamino)-4-
phenylbutylphosphonate (8a),6 dimethyl-(ꢀ)-N-(tert-butoxy-
carbonyl)-3-oxo-5-tert-butylpyrrolidine-2-phosphonate (8c),6
methyl-(þ)-3-oxo-5-(tert-butyloxycarbonylamino)-5-phenyl-
pentanoate (9a),5a methyl-(þ)-5-(tert-butoxycarbonyl)-6,6-

4178
F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
4.1.3. Dimethyl-(ꢂ)-2-oxo-4-(p-toluenesulfinylamino)-
4.1.6. Dimethyl-(ꢂ)-2-oxo-N-(tert-butoxycarbonyl)-
4-amino-4-(2-furyl)-butylphosphonate (10b)
Yield 97% of a yellow oil; IR (neat) 3306, 1716, 1255,
4-(2-furyl)-butylphosphonate (8b)
In a 50-mL, single-necked, round-bottom flask equipped
with a magnetic stirring bar, rubber septum, and argon balloon
was placed n-BuLi (2 M in cyclohexane, 2.70 mL, 5.40 mmol)
in anhydrous THF (5 mL). The mixture was cooled to ꢀ78 ꢁC
and dimethyl methylphosphonate (0.60 mL, 5.61 mmol) was
added. After stirring at this temperature for 1 h, 6b (0.207 g,
0.67 mmol) in THF (15 mL) was added via cannula. The reac-
tion mixture was stirred at this temperature for 4 h, quenched
with saturated NH4Cl (0.5 mL), and warmed to rt. Water
(5 mL) was added and the solution was extracted with EtOAc
(3ꢃ10 mL). The combined organic phases were washed with
brine (5 mL), dried (Na2SO4), and concentrated. Flash chro-
matography (EtOAc) afforded a colorless oil that was sub-
jected to Kugelrohr vacuum distillation (60 ꢁC under
2.5 mmHg) to remove dimethyl menthylphosphonate, afford-
ing 0.219 g (82%) as an orange oil; IR (neat) 3379, 3192,
1
1031 cmꢀ1; H NMR (CDCl3) d 1.37 (s, 9H), 3.01 (m, 2H),
3.38 (s, 2H), 3.61 (m, 6H), 5.14 (m, 2H), 6.16 (m, 1H), 6.22
(m, 1H), 7.25 (s, 1H); 13C NMR (CDCl3) d 28.7, 41.9, 50.2,
51.1, 53.3, 53.6, 126.6, 127.7, 129.0, 141.6, 155.5, 200.2;
31P NMR (CDCl3) d 23.82. HRMS calcd for C17H27NO6P
(MþH) 372.1576. Found 372.1575.
4.1.7. Methyl-(ꢂ)-5-(tert-butoxycarbonyl)-2-diazo-5-
(2-furyl)-3-oxopentanoate (11b). Typical procedure
In an oven-dried, 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and ar-
gon balloon was placed 9b (0.020 g, 0.06 mmol) in anhydrous
CH3CN (3 mL). The reaction mixture was cooled to 0 ꢁC, and
4-carboxybenzenesulfonazide (4-CBSA) (0.019 g, 0.09 mmol)
and Et3N (0.05 mL, 0.36 mmol) were added. The reaction
mixture was warmed to rt, and after 4 h H2O (0.5 mL) was
added and the solution was extracted with EtOAc (3ꢃ5 mL).
The combined organic phases were washed with brine
(5 mL), dried (Na2SO4), and concentrated. Flash chromatogra-
phy (20% EtOAc/hexanes) afforded 0.015 g (76%) of a yellow
1
1753, 1717, 1246, 1089 cmꢀ1; H NMR (CDCl3) d 2.32 (s,
3H), 2.85 (s, 1H), 2.89 (s, 1H), 3.65 (m, 6H), 5.15 (m, 2H),
6.11 (m, 1H), 6.23 (m, 1H), 7.24 (s, 1H), 7.29 (m, 2H), 7.37
(m, 2H); 13C NMR (CDCl3) d 20.3, 38.5, 48.1, 50.9, 106.6,
109.5, 124.6, 125.0, 128.6, 140.5, 141.4, 201.3; 31P NMR
(CDCl3) d 22.06. HRMS calcd for C17H23NO6P (MþH)
400.0984. Found 400.0987.
1
oil; IR (neat) 3421, 3226, 1745, 1716, 1316, 1201 cmꢀ1; H
NMR (CDCl3) d 1.36 (s, 9H), 3.11 (qd, 2H), 3.68 (s, 3H),
4.70 (m, 2H), 6.23 (s, 1H), 7.18 (m, 2H); 13C NMR (CDCl3)
d 21.7, 48.5, 53.1, 106.0, 111.3, 146.1, 166.7, 201.8. HRMS
calcd for C15H20N3O6 (MþH) 338.1352. Found 338. 1355.
4.1.4. Methyl-(ꢂ)-5-(tert-butoxycarbonyl)-5-(2-furyl)-
3-oxopentanoate (9b). Typical procedure
In an oven-dried, 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon was placed 7b (0.097 g, 0.28 mmol) in anhydrous meth-
anol (2 mL). Thesolutionwas cooled to 0 ꢁC and TFA (0.06 mL,
0.78 mmol) was added. The reaction mixture was stirred for 1 h,
concentrated, and anhydrous THF (2 mL) was added. The solu-
tion was cooled to 0 ꢁC, Et3N (0.20 mL, 1.43 mmol) and Boc2O
(0.60 mL, 0.60 mmol) were added, and the solution was warmed
to rt. After 8 h, H2O (0.5 mL) was added and the solution was
extracted with EtOAc (3ꢃ2 mL). The combined organic phases
were washed with brine (2 mL), dried (Na2SO4), and concen-
trated. Flash chromatography (20% EtOAc/hexanes) afforded
0.071 g (82%) of a yellow oil; IR (neat) 3421, 3226, 1745,
4.1.8. Methyl-(ꢂ)-5-(tert-butoxycarbonylamino)-2-diazo-3-
oxohept-6-enoate (11d)
Yield 95% of a yellow oil; IR (neat): 3278, 2132, 1730, 1715,
1653 cmꢀ1; 1H NMR (CDCl3) d 1.49 (s, 9H), 3.06 (m, 2H), 3.80
(s, 3H), 4.65 (br s, 1H), 5.05 (m, 1H), 5.13 (m, 1H), 5.15 (m, 1H),
5.45 (m, 1H); 13C NMR d 28.6, 44.8, 49.7, 50.0, 52.6, 115.2,
138.1, 155.5, 162.0, 190.8 (C]N2 was not observed). HRMS
calcd for C13H19N3O5 (MþH) 298.1403. Found 298.1409.
4.1.9. Dimethyl-(ꢂ)-1-diazo-2-oxo-N-(tert-butoxycarbon-
yl)-4-amino-4-(2-furyl)-butylphosphonate (12b). Typical
procedure
1
1716 cmꢀ1; H NMR (CDCl3) d 1.36 (s, 9H), 3.07 (m, 2H),
In a 50-mL, single-necked, round-bottom flask equipped
with a magnetic stirring bar, rubber septum, and argon balloon
was placed NaH (60% in mineral oil, 0.020 g, 0.50 mmol),
which was washed by petroleum ether (2 mL). After removal
of the petroleum ether by syringe, the flask was placed under
vacuum for 2 min, and THF (5 mL) was added by syringe.
In another 50-mL round-bottom flask were placed 8b
(0.075 g, 0.24 mmol) and 4-acetamidobenzenesulfonyl azide
(4-ABSA, 0.058 g, 0.24 mmol) in THF (10 mL). The solution
was transferred to the 50-mL, round-bottom flask containing
NaH and THF via cannula quickly at rt. After stirring for
1 h, the reaction mixture was quenched by addition of satu-
rated aqueous NH4Cl (0.5 mL) and extracted with Et2O
(20 mL) and EtOAc (2ꢃ20 mL). The combined organic
phases were washed with brine (10 mL), dried (Na2SO4),
and concentrated. To the residue was added CHCl3 (5 mL),
3.37 (s, 2H), 3.64 (s, 3H), 5.18 (m, 2H), 6.18 (d, J¼8.1 Hz,
1H), 6.21 (d, J¼8.0 Hz, 1H), 7.19 (s, 1H); 13C NMR (CDCl3)
d 28.5, 40.3, 47.8, 48.4, 52.6, 80.1, 106.9, 109.8, 140.5, 141.8,
156.3. HRMS calcd for C15H22NO6 (MþH) 312.1447. Found
312.1441.
4.1.5. Methyl-(ꢂ)-(tert-butoxycarbonyl)-3-oxohept-6-
enoate (9d)
Yield 92% of a slight yellow oil; IR (neat) 3123, 1720,
1
1707, 1649 cmꢀ1; H NMR (CDCl3) d 1.49 (s, 9H), 2.90 (m,
2H), 3.52 (s, 2H), 3.79 (s, 3H), 4.55 (br s, 1H), 5.15 (m,
1H), 5.19 (m, 1H), 5.26 (m, 1H), 5.90e5.70 (m, 1H); 13C
NMR (CDCl3) d 28.4, 47.5, 49.6, 52.7, 80.3, 115.7, 137.5,
155.4, 167.6, 201.2. HRMS calcd for C13H21NO5 (MþH)
272.1498. Found 272.1491.

F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
4179
and the solution was filtered and concentrated. Flash chroma-
tography (EtOAc) afforded 0.065 g (71%) of a yellow oil; IR
(neat) 3317, 1710, 1314, 1256 cmꢀ1; 1H NMR (CDCl3) d 1.33
(s, 9H), 3.02 (m, 2H), 3.64 (d, J¼12.1 Hz, 3H), 3.70 (d,
J¼12.1 Hz, 3H), 4.74 (m, 2H), 6.24 (s, 1H), 7.17 (m, 2H);
13C NMR (CDCl3) d 21.6, 48.6, 53.5, 106.2, 111.5, 146.7,
166.9, 202.0; 31P NMR (CDCl3) d 14.32. HRMS calcd for
C15H22N3O7PNa (MþNa) 410.1093. Found 410.1089.
argon balloon was placed 13a (0.021 g, 0.06 mmol) in THF
(1 mL). The reaction flask was cooled to ꢀ78 ꢁC, and LDA
(0.20 mL, 0.20 mmol, in THF) was added. The solution was
stirred for 1 h at which time methyl iodide (0.01 mL,
0.16 mmol) was added. After stirring at ꢀ78 ꢁC for 2 h, the
solution was quenched with saturated NH4Cl (0.5 mL) and
warmed to rt. Water (0.5 mL) was added, and the solution
was extracted with EtOAc (3ꢃ1 mL). The combined organic
phases were washed with brine (1 mL), dried (Na2SO4), and
concentrated. Preparative TLC (20% EtOAc/hexanes) afforded
0.017 g (83%) of a slight yellow oil; IR (neat) 1774, 1746,
4.1.10. 1-tert-Butyl-2-methyl-5-(2-furyl)-3-oxopyrrolidine-
1,2-dicarboxylate (13b). Typical procedure
1
In an oven-dried, 100-mL, single-necked round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
and argon balloon were placed 11b (0.813 g, 2.41 mmol) and
Rh2(OAc)4 (0.107 g, 0.24 mmol) in CH2Cl2 (30 mL), and the
reaction mixture was warmed to 35 ꢁC. After stirring for 8 h
at this temperature the solution was concentrated. Flash chro-
matography (20% EtOAc/hexanes) afforded 0.552 g (74%) of
a yellow oil; IR (neat) cmꢀ1 3094, 1737, 1667, 1314; 1H NMR
(CDCl3) d 1.17 (s, 9H), 2.67 (m, 1H), 3.15 (m, 1H), 3.73 (s,
3H), 4.72 (m, 1H), 5.30 (m, 1H), 6.14 (s, 1H), 7.08 (m, 2H);
13C NMR (CDCl3) d 28.5, 43.1, 46.8, 51.6, 79.8, 106.1,
142.8, 155.3, 170.9, 202.1. HRMS calcd for C15H19NO6Na
(MþNa) 332.1111. Found 332.1114.
1699, 1391, 1157 cmꢀ1; H NMR (CDCl3) d 1.09 (2s, 9H),
2.09 (m, 3H), 3.12 (m, 1H), 3.84 (2s, 3H), 4.72 (m, 2H),
5.51 (m, 1H), 7.04 (m, 2H), 7.24 (m, 2H), 7.41 (m, 1H); 13C
NMR (CDCl3) d 10.3, 27.8, 52.6, 64.6, 67.9, 79.5, 126.7,
128.1, 128.2, 129.4,129.5, 141.9, 154.3, 166.8, 203.8; 31P
NMR (CDCl3) d 17.21. HRMS calcd for C18H24NO5 (MþH)
334.1654. Found 334.1658.
4.1.14. 1-tert-Butyl-2-methyl-5-(2-furyl)-4-methyl-3-
oxopyrrolidine-1,2-dicarboxylate (15c)
Yield 88% of a yellow oil; IR (neat) 1763, 1703, 1667,
1315, 1032 cmꢀ1
;
1H NMR (CDCl3) d 1.16 (d, J¼5.0 Hz,
3H), 1.41 (s, 9H), 3.40 (m, 1H), 3.77 (s, 3H), 3.99 (m, 1H),
5.34 (m, 1H), 6.11 (s, 1H), 7.09 (m, 2H); 13C NMR (CDCl3)
d 10.2, 28.3, 46.9, 52.1, 56.6, 72.5, 79.3, 106.8, 109.4,
145.1, 156.2, 172.0, 200.9. HRMS calcd for C16H22NO6
(MþH) 324.1447. Found 324.1441.
4.1.11. 1-tert-Butyl 2-methyl 3-oxo-5-vinylpyrrolidine-1,2-
dicarboxylate (13d)
Yield 87% of a yellow oil; IR (neat) 2956, 1735, 1710,
1
815 cmꢀ1; rotamers were observed. H NMR (CDCl3) d 1.45
(d, J¼10 Hz, 9H), 2.56e2.46 (m, 1H), 3.02 (dd, J¼3.15 Hz,
1H), 3.83 (d, J¼3.0 Hz, 3H), 4.71 (m, 2H), 5.26 (m, 2H),
5.98 (m, 1H); 13C NMR (CDCl3) d 28.5, 43.2, 53.3, 55.6,
66.4, 66.6, 81.6, 81.7, 116.0, 116.8, 137.1, 137.6, 153.4,
167.1, 167.9, 203.4, 203.9. HRMS calcd for C13H20NO5
(MþH) 271.1341. Found 271.1340.
4.1.15. Methyl-(ꢂ)-N-(tert-butoxycarbonyl)-3-oxo-
4-methyl-5-(tert-butyl)pyrrolidine-2-carboxylate (15d)
Yield 50% of a colorless oil; IR (neat) 1755, 1716 cmꢀ1; 1H
NMR (CDCl3) d 0.95 (s, 9H), 1.21 (d, J¼5.1 Hz, 3H), 1.41 (s,
9H), 3.25 (m, 1H), 3.89 (s, 3H), 4.19 (m, 1H), 4.71 (m, 1H);
13C NMR (CDCl3) d 11.1, 26.9, 29.0, 37.5, 41.6, 53.2, 62.9,
67.4, 82.1, 156.3, 167.4, 203.9. HRMS calcd for C16H28NO5
(MþH) 314.1967. Found 314.1958.
4.1.12. Dimethyl-(ꢂ)-N-(tert-butoxycarbonyl)-3-oxo-5-
(2-furyl)-pyrrolidine-2-phosphonate (14b)
In an oven-dried, 25-mL, single-necked round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon were placed 12b (0.070 g, 0.18 mmol) and Rh2(OAc)4
(0.008 g, 0.02 mmol)inCH2Cl2 (5 mL), andthereactionmixture
waswarmedto35 ꢁC. Afterstirringfor8 h atthistemperaturethe
solution was concentrated, and flash chromatography (50%
EtOAc/hexanes) afforded 0.043 g (67%) of a yellow oil; IR
4.1.16. Methyl-(ꢂ)-N-(tert-butoxycarbonyl)-3-oxo-4-benzyl-
5-phenylpyrrolidine-2-carboxylate (15b)
Yield 79% of a slight yellow oil; IR (neat) 1743, 1711,
1401 cmꢀ1 1H NMR (CDCl3) d 1.10 (2s, 9H), 3.40 (m,
;
1H), 3.85 (2s, 3H), 4.30 (m, 2H), 5.02 (m, 1H), 5.61 (m,
1H), 7.33 (m, 8H), 7.53 (m, 2H); 13C NMR (CDCl3) d 29.5,
32.7, 57.6, 65.3, 80.7, 128.3, 128.4, 128.5, 128.8, 129.0,
129.1, 129.2, 129.3, 141.1, 141.8, 157.4, 171.9, 202.1.
HRMS calcd for C24H28NO5 (MþH) 410.1967. Found
410.1964.
1
(neat) 1762, 1701, 1668, 1315, 1032 cmꢀ1; H NMR (CDCl3)
d 1.41 (s, 9H), 2.70 (m, 1H), 3.19 (m, 1H), 3.72 (m, 6H), 4.79
(m, 1H), 5.31 (m, 1H), 6.15 (s, 1H), 7.09 (m, 2H); 13C NMR
(CDCl3) d 28.5, 43.1, 47.6, 53.1, 62.8, 80.1, 105.8, 112.6,
142.6, 151.2, 154.9, 201.8; 31P NMR (CDCl3) d 17.52. HRMS
calcd for C15H22NO7PNa (MþNa) 382.1032. Found 382.1027.
4.1.17. (ꢂ)-tert-Butyl-4-benzyl-2-(dimethoxyphosphoryl)-3-
oxo-5-phenylpyrrolidine-1-carboxylate (16a)
Yield 41% of an oil; IR (neat) 3252, 1568, 1180,
;
1024 cmꢀ1 1H NMR (CDCl3) d 1.24 (s, 9H), 3.01 (d,
J¼10.8 Hz, 3H), 3.03 (s, 1H), 3.30 (q, J¼6.4 Hz, 1H), 3.79
(d, J¼10.8 Hz, 3H), 3.80 (d, J¼10.8 Hz, 3H), 4.57 (d,
J¼18.0 Hz, 1H), 4.72 (m, 1H), 7.21 (m, 8H), 7.36 (m, 2H);
13C NMR (CDCl3) d 28.3, 30.0, 33.7, 54.0, 58.0, 64.4, 81.8,
4.1.13. Methyl-(ꢂ)-N-(tert-butoxycarbonyl)-3-oxo-4-
methyl-5-phenylpyrrolidine-2-carboxylate (15a). Typical
procedure
In an oven-dried, 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and

4180
F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
127.1, 127.1, 127.6, 128.6, 128.9, 129.8, 137.6, 142.5, 155.0,
205.2; 31P NMR (CDCl3) d 17.21. HRMS calcd for
C24H31NO6P (MþH) 460.1889. Found 460.1890.
anhydrous CH3CN (80 mL). The reaction mixture was cooled
to 0 ꢁC, 4-carboxybenzenesulfonazide (4-CBSA) (0.665 g,
2.92 mmol) and Et3N (1.1 mL, 7.89 mmol) were added, and
the solution was warmed to rt. After stirring for 4 h, H2O
(10 mL) was added and the solution was extracted with EtOAc
(3ꢃ20 mL). The combined organic phases were washed with
brine (10 mL), dried (Na2SO4), and concentrated. Flash chro-
matography (20% EtOAc/hexanes) afforded 0.770 g (83%) of
4.1.18. (ꢂ)-tert-Butyl-3-methyl-5-(dimethoxyphosphoryl)-
4-oxo-2-(2-furyl)-pyrrolidine-1-carboxylate (16b)
Yield 40% of a yellow oil; IR (neat) cmꢀ1 1736, 1668,
1
1315; H NMR (CDCl3) d 1.18 (d, J¼5.1 Hz, 3H), 1.40 (s,
1
9H), 3.56 (m, 1H), 3.81 (d, J¼10.8 Hz, 3H), 3.84 (d,
J¼10.8 Hz, 3H), 4.02 (s, 1H), 5.36 (m, 1H), 6.12 (s, 1H),
7.08 (m, 2H); 13C NMR (CDCl3) d 10.5, 28.3, 46.9, 52.3,
56.7, 72.5, 79.3, 106.8, 109.4, 145.1, 156.2, 172.0, 201.1;
31P NMR (CDCl3) d 17.19. HRMS calcd for C16H25NO7P
(MþH) 374.1369. Found 374.1360.
a colorless oil; IR (neat) 3312, 2138, 1720, 1654 cmꢀ1; H
NMR (CDCl3) d 3.34 (m, 1H), 3.44 (dd, J¼15.0, 15.5 Hz,
1H), 3.83 (s, 3H), 5.08 (dd, J¼21.5, 21.0 Hz, 2H), 5.25
(m, 1H), 5.74 (m, 1H), 7.29 (m, 2H), 7.34 (m, 6H), 7.42 (m,
2H); 13C NMR (CDCl3) d 30.1, 46.1, 52.3, 52.7, 67.2,
126.5, 127.9, 128.4, 128.7, 128.8, 129.0, 136.8, 141.7,
155.9, 162.1, 190.4. HRMS calcd for C20H20N3O5 (MþH)
382.1403. Found 382.1398.
4.1.19. (ꢂ)-tert-Butyl-4-benzyl-2-(dimethoxyphosphoryl)-
3-oxo-5-(2-furyl)-pyrrolidine-1-phosphonate (16c)
Yield 40% of a yellow oil; IR (neat) 3256, 1736, 1668; H
1
4.1.22. Methyl-(ꢂ)-(N-benzyloxycarbonyl)-3-oxo 5-
NMR (CDCl3) 1.40 (s, 9H), 2.82 (d, J¼10.6 Hz, 1H), 3.10 (s,
1H), 3.16 (d, J¼17.8 Hz, 1H), 3.71 (m, 6H), 3.96 (m, 1H),
6.17 (s, 1H), 6.27 (s, 1H), 7.16 (m, 6H); 13C NMR (CDCl3)
d 28.5, 29.9, 33.7, 54.1, 60.1, 62.6, 80.4, 105.9, 112.4,
127.1, 127.1, 127.6, 128.6, 128.9, 129.8, 142.6, 151.2,
154.8, 202.0; 31P NMR (CDCl3) d 17.36. HRMS calcd for
C22H29NO7PNa (MþNa) 450.1682. Found 450.1674.
phenylpyrrolidine-2-carboxylate (19)
In an oven-dried, 100-mL, single-necked, round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
and argon balloon were placed 18 (0.018 g, 0.05 mmol) and
Rh2(OAc)4 (0.004 g, 0.01 mmol) in CH2Cl2 (2 mL). After stir-
ring for 8 h at 35 ꢁC, the solution was concentrated, and flash
chromatography (20% EtOAc/Hexanes) afforded 0.016 g
(93%) of a clear oil; IR (neat) 3256, 1772, 1747, 1700,
1
4.1.20. Methoxy-(ꢂ)-3-oxo-5-(N-benzyloxycarbonyl-
1391, 1159 cmꢀ1; H NMR (CDCl3) d 2.56 (m, 1H), 3.17
amino)-5-phenylpentanoate (17)
(m, 1H), 3.86 (s, 3H), 4.60 (m, 2H), 4.95(m, 1H), 5.36 (m,
1H), 7.14 (m, 8H), 7.22 (m, 2H); 13C NMR (CDCl3) d 45.8,
46.8, 52.5, 67.9, 68.0, 83.6, 125.8, 126.0, 126.5, 126.8,
127.3, 127.9, 128.2, 128.4, 129.3, 130.0, 142.4, 143.1,
154.9, 165.1, 203.6, 204.0. HRMS calcd for C20H19NO5Na
(MþNa) 376.1161. Found 376.1156.
In an oven-dried, 300-mL, single-necked, round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
and argon balloon was placed 7a (1.170 g, 3.26 mmol) in an-
hydrous methanol (100 mL). The solution was cooled to 0 ꢁC,
and TFA (1.3 mL, 16.87 mmol) was added. After stirring for
1 h, the mixture was concentrated. The residue was dissolved
in THF (100 mL), cooled to 0 ꢁC, and Et3N (2.8 mL,
20.09 mmol), DMAP (0.415 g, 3.40 mmol), and benzyl chloro-
formate (0.6 mL, 3.40 mmol) were added. After warming to rt,
the solution was stirred for 5 h and quenched by addition of
satd NH4Cl (5 mL). Water (30 mL) was added, the solution
was extracted with EtOAc (3ꢃ30 mL), and the combined
organic phases were washed with brine (30 mL), dried
(Na2SO4), and concentrated. Flash chromatography (30%
EtOAc/hexanes) afforded 0.892 g (77%) of a white solid, mp
4.1.23. Methyl-(ꢂ)-(N-benzyloxycarbonyl)-3-oxo-4-chloro-
5-phenylpyrrolidine-2-carboxylate (20)
In an oven-dried, 50-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and ar-
gon balloon was placed 19 (0.242 g, 0.68 mmol) in anhydrous
THF (5 mL), and the solution was cooled to ꢀ78 ꢁC. At this
time LDA (2.00 mL, 2.00 mmol, in THF) was added, and
the solution was stirred for 1 h. 1,3-Dichloro-5,5-dimethylhy-
dantoin (0.201 g, 1.02 mmol) was added, and the reaction mix-
ture was stirred at ꢀ78 ꢁC for 2 h.20 At this time satd NH4Cl
(0.5 mL) was added, and the solution was warmed to rt. Water
(2 mL) was added, the solution was extracted with EtOAc
(3ꢃ2 mL), and the combined organic phases were washed
with brine (2 mL), dried (Na2SO4), and concentrated. Flash
chromatography (20% EtOAc/hexanes) afforded 0.140 g
(53%) of a slight yellow oil; IR (neat) 3256, 1772, 1747,
1
82e84 ꢁC; IR (neat) 3314, 1747, 1716, 1688 cmꢀ1, H NMR
(CDCl3) d 3.07 (d, J¼5.4 Hz, 1H), 3.13 (d, J¼6.5 Hz, 1H),
3.40 (s, 2H), 3.69 (s, 3H), 5.09 (m, 1H), 5.20 (m, 1H), 5.67
(m, 2H), 7.24 (m, 2H), 7.32 (m, 6H), 7.41 (m, 2H); 13C
NMR (CDCl3) d 48.6, 49.8, 51.7, 52.8, 67.3, 126.5, 128.1,
128.7, 129.1, 129.2, 136.7, 141.1, 155.9, 167.6, 200.9.
HRMS calcd for C20H21NO5Na (MþH) 378.1317. Found
378.1314.
1
1700, 1391, 1159 cmꢀ1; H NMR (CDCl3) d 3.89 (s, 3H),
4.60 (m, 2H), 5.36 (m, 1H), 5.38 (d, J¼16.1 Hz, 1H), 5.48
(d, J¼8.0 Hz, 1H), 7.16 (m, 8H), 7.22 (m, 2H); 13C NMR
(CDCl3) d 45.8, 52.5, 67.9, 68.0, 75.8, 75.9, 83.6, 125.8,
126.0, 126.5, 126.8, 127.3, 127.9, 128.2, 128.4, 129.3,
130.0, 142.4, 143.1, 154.9, 165.1, 203.6, 204.0. HRMS calcd
for C20H19NO5Cl (MþH) 388.0952. Found 388.0944.
4.1.21. Methyl-(ꢂ)-2-diazo-3-oxo-5-(N-benzyloxycarbonyl-
amino)-5-phenylpentanoate (18)
In an oven-dried, 250-mL, single-necked, round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
and argon balloon was placed 17 (0.866 g, 2.44 mmol) in

F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
4181
4.1.24. 5-Phenyl-3-hydroxy-1H-pyrrole-2-carboxylic acid
methyl ester (23). Typical procedure
128.7, 128.8, 136.4. HRMS calcd for C19H18NO3 (MþH)
308.1287. Found 308.1281.
In an oven-dried, 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon was placed 13a (0.050 g, 0.16 mmol) in CH2Cl2 (5 mL),
and TFA (0.06 mL, 0.79 mmol) was added. The reaction mix-
turewas stirred at rt for 3 h, at which time aqueous satd NaHCO3
(3 mL) and H2O (1 mL) were added. The phases were separated,
the aqueous phase was extracted with CH2Cl2 (2ꢃ3 mL), and
the combined organic phases were dried (Na2SO4) and concen-
trated in a 25 mL round-bottom flask. To the residue was added
ca. 1 g of silica gel (0.035e0.07 mm for column chromatogra-
phy pore diameter ca. 6 nm) and EtOAc (6 mL). The suspension
in the reaction flask, open to the atmosphere, was stirred for 5 h,
filtered, and concentrated. Flash chromatography (20% EtOAc/
hexanes) afforded 0.030 g (88%) of a white solid, mp 77e79 ꢁC;
IR (neat) 3496, 1672, 2934 cmꢀ1; 1H NMR (CDCl3) d 2.56 (br,
2H), 3.81 (s, 3H), 6.17 (s, 1H), 7.30 (m, 3H), 7.44 (d, J¼6.1 Hz,
2H); 13C NMR (CDCl3) d 96.5, 103.1, 148.9, 158.2, 164.9.
HRMS calcd for C12H11NO3Na (MþNa) 240.0637. Found
240.0634.
4.1.29. 4-Methyl-5-(2-furyl)-3-hydroxy-1H-pyrrole-2-
carboxylic acid methyl ester (25f)
Yield 67% of a yellow solid, mp 132e134 ꢁC; IR (neat)
1
3493, 1672, 1254 cmꢀ1; H NMR (CDCl3) d 3.03 (br, 1H),
3.71 (s, 3H), 3.81 (s, 3H), 6.47 (s, 1H), 6.24 (s, 1H), 7.23 (s,
1H), 7.92 (br, 1H); 13C NMR (CDCl3) d 10.1, 51.4, 96.4,
105.2, 110.0, 120.3, 131.5, 149.4, 154.9, 157.6, 164.9.
HRMS calcd for C11H11NO4Na (MþNa) 244.0586. Found
244.0578.
4.1.30. 4-Methyl-5-tert-butyl-3-hydroxy-1H-pyrrole-2-
carboxylate acid methyl ester (25g)
Yield 50% of a white solid, mp 114e116 ꢁC; IR (neat)
1
3480, 3326, 1679 cmꢀ1; H NMR (CDCl3) d 1.27 (s, 9H),
3.69 (s, 3H), 3.86 (s, 3H), 6.49 (br, 2H); 13C NMR (CDCl3)
d 10.0, 30.4, 33.6, 51.5, 95.3, 120.6, 149.2, 154.6, 164.4.
HRMS calcd for C11H18NO3 (MþH) 212.1287. Found
212.1284.
4.1.31. Dimethyl 5-phenyl-3-hydroxy-1H-pyrrole-2-
phosphonate (26a)
4.1.25. 5-(2-Furyl)-3-hydroxy-1H-pyrrole-2-carboxylic acid
methyl ester (25a)
Yield 75% of a clear oil; IR (neat) 3256, 3026, 1716 cmꢀ1
;
Yield 75% of a yellow solid, mp 128e129 ꢁC; IR (neat)
1H NMR (CDCl3) d 3.73 (s, 3H), 3.75 (s, 3H), 5.59 (s, 1H),
6.53 (br, 2H), 7.24 (m, 3H), 7.45 (m, 2H); 13C NMR
(CDCl3) d 53.0, 93.4, 93.5, 95.2, 112.5, 112.9, 120.6, 125.9,
126.1, 126.7, 127.2, 133.1; 31P NMR (CDCl3) d 16.38.
HRMS calcd for C12H15NO4P (MþH) 268.0739. Found
268.0735.
1
3492, 1669, 1254 cmꢀ1; H NMR (CDCl3) d 3.01 (br, 1H),
3.82 (s, 3H), 6.12 (s, 1H), 6.48 (s, 1H), 6.24 (s, 1H), 7.25 (s,
1H), 7.89 (br, 1H); 13C NMR (CDCl3) d 51.5, 96.3, 105.2,
105.8, 110.0, 131.6, 149.4, 154.8, 157.7, 165.1 cmꢀ1. HRMS
calcd for C10H9NO4Na (MþNa) 230.0429. Found 230.0422.
4.1.26. 5-Vinyl-3-hydroxy-1H-pyrrole-2-carboxylate acid
methyl ester (25c)
4.1.32. Dimethyl 5-(2-furyl)-3-hydroxy-1H-pyrrole-2-
phsophonate (26b)
Yield 81% of a white solid, mp 121e123 ꢁC; IR (neat)
Yield 80% of a yellow oil, IR (neat) 3356, 1718, 1246 cmꢀ1
;
1
3483, 3354, 3034, 1678 cmꢀ1; H NMR (CDCl3) d 3.27 (m,
1H NMR (CDCl3) d 3.72 (s, 3H), 3.75 (s, 3H), 5.63 (s, 1H), 6.12
(s, 1H), 6.42 (br, 1H), 7.20 (m, 2H), 7.87 (br, 1H); 13C NMR
(CDCl3) d 53.0, 93.4, 93.5, 105.2, 105.8, 108.9, 109.0, 136.9,
156.3; 31P NMR (CDCl3) d 16.42. HRMS calcd for
C10H13NO5P (MþH) 258.0531. Found 258.0533.
1H), 3.88 (s, 3H), 4.21 (m, 1H), 4.71 (m, 1H), 5.70 (s, 1H),
6.33 (br, 2H); 13C NMR (CDCl3) d 51.4, 105.9, 116.7,
121.0, 129.8, 130.1, 134.7, 154.9. HRMS calcd for
C8H9NO3Na (MþNa) 190.0480. Found 190.0471.
4.1.27. 4-Methyl-5-phenyl-3-hydroxy-1H-pyrrole-2-
carboxylic acid methyl ester (25d)
4.1.33. Dimethyl 4-benzyl-5-phenyl-3-hydroxy-1H-pyrrole-
2-phosphonate (26d)
Yield 78% of a white solid, mp112e114 ꢁC; IR (neat)
Yield 51% of a clear oil; IR (neat) 3257, 3025, 1716 cmꢀ1
;
1
3492, 1674 cmꢀ1; H NMR (CDCl3) d 2.59 (br, 2H), 3.69
1H NMR (CDCl3) d 3.72 (s, 3H), 3.74 (s, 3H), 4.54 (s, 2H),
6.59 (br, 2H), 7.29 (m, 8H), 7.49 (m, 2H); 13C NMR
(CDCl3) d 29.9, 53.0, 93.4, 93.5, 95.2, 95.3, 112.6, 118.9,
120.6, 125.8, 125.9, 126.2, 126.7, 127.1, 128.7, 128.8,
129.0, 129.1, 133.1, 136.4; 31P NMR (CDCl3) d 17.26.
HRMS calcd for C19H21NO4P (MþH) 358.1208. Found
358.1202.
(s, 3H), 3.84 (s, 3H), 7.27 (m, 3H), 7.42 (d, J¼6.0 Hz, 2H);
13C NMR (CDCl3) d 9.9, 51.5, 96.5, 103.4, 120.6, 124.8,
125.3, 137.6, 148.9, 158.2, 164.9. HRMS calcd for
C13H13NO3Na (MþNa) 254.0793. Found 254.0782.
4.1.28. 4-Benzyl-5-phenyl-3-hydroxy-1H-pyrrole-2-
carboxylic acid methyl ester (25e)
Yield 67% of a white solid, mp 115e117 ꢁC; IR (neat)
4.1.34. Dimethyl 4-methyl-5-(2-furyl)-3-hydroxy-1H-
pyrrole-2-phosphonate (26e)
Yield 60% of a yellow oil; IR (neat) 3358, 1716,
1
3487, 1678 cmꢀ1; H NMR (CDCl3) d 2.59 (br, 2H), 3.79
(s, 3H), 4.03 (s, 2H), 7.27 (m, 2H), 7.34 (m, 6H), 7.52 (m,
2H); 13C NMR (CDCl3) d 29.3, 51.4, 120.3, 121.4, 125.6,
126.5, 126.8, 127.3, 127.9, 128.0, 128.2, 128.4, 128.5,
1
1252 cmꢀ1; H NMR (CDCl3) d 2.01 (s, 3H), 3.72 (s, 3H),
3.74 (s, 3H), 6.11 (s, 1H), 6.47 (br, 1H), 7.19 (m, 2H), 7.84

4182
F.A. Davis et al. / Tetrahedron 64 (2008) 4174e4182
(br, 1H); 13C NMR (CDCl3) d 10.4, 53.0, 93.4, 93.5, 105.2,
108.9, 109.0, 120.4, 136.9, 156.3; 31P NMR (CDCl3)
d 17.26. HRMS calcd for C11H15NO5P (MþH) 272.0688.
Found 272.0689.
2003, 68, 8061; (g) Davis, F. A.; Zhang, J.; Li, Y.; Xu, H.; DeBrosse,
C. J. Org. Chem. 2005, 70, 5413.
4. Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
5. (a) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599; (b)
Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147; (c) Davis,
F. A.; Deng, J. Tetrahedron 2004, 60, 5111.
4.1.35. Dimethyl 4-benzyl-5-(2-furyl)-3-hydroxy-1H-
pyrrole-2-phosphonate (26f)
Yield 75% of a yellow oil; IR (neat) 3355, 1717,
6. Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523.
7. Davis, F. A.; Xu, H.; Wu, Y.; Zhang, J. Org. Lett. 2006, 8, 2273.
8. For reviews, see: (a) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238; (b)
Pyrroles; Jones, R. A., Ed.; The Chemistry of Heterocyclic Compounds;
Wiley: New York, NY, 1996; Vol. 48, Part 1.
1247 cmꢀ1 1H NMR (CDCl3) 3.71 (s, 3H), 3.74 (s, 3H),
;
4.60 (s, 2H), 6.12 (s, 1H), 7.19 (m, 2H), 7.28 (m, 5H); 13C
NMR (CDCl3) d 29.8, 53.0, 93.4, 93.5, 105.3, 109.0, 109.1,
120.6, 125.8, 128.6, 128.7, 128.9, 129.0, 136.9, 142.7,
156.3; 31P NMR (CDCl3) d 17.28. HRMS calcd for
C17H19NO5P (MþH) 348.1001. Found 348.1003.
9. For leading references, see: Rivero, M. R.; Buchwald, S. L. Org. Lett.
2007, 9, 973.
10. For recent reviews on these procedures, see: (a) Schmuck, C.; Rupprecht,
D. Synthesis 2007, 3095; (b) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha,
A. C.; Pereira, L. O. R.; Ferreira, M. L. C. Org. Prep. Proced. Int. 2001,
33, 413.
11. Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177.
12. Pyrroles: (a) Peng, L.; Zhang, X.; Ma, J.; Zhong, Z.; Wang, J. Org. Lett.
2007, 9, 1445; (b) Dong, H.; Shen, M.; Redford, J. E.; Stokes, B. J.;
Pumphrey, A. L.; Driver, T. G. Org. Lett. 2007, 9, 5191; (c) See Ref. 9;
(d) Dong, C.; Deng, G.; Wang, J. J. Org. Chem. 2006, 71, 5560; (e) Binder,
J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151; (f) Crawley, M. L.; Goljer, I.;
Jenkins, D. J.; Mehlmann, J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org.
Lett. 2006, 8, 5837; (g) Wang, Y.; Zhu, S. Org. Lett. 2003, 5, 745.
13. Pyrrolidines: (a) Freifeld, I.; Shojaei, H.; Langer, P. J. Org. Chem. 2006,
71, 4965; (b) Jolicoeur, B.; Lubell, W. D. Org. Lett. 2006, 8, 6107; (c)
Verniest, G.; Claessens, S.; De Kimpe, N. Tetrahedron 2005, 61, 4631;
(d) Marcotte, F.-A.; Lubell, W. D. Org. Lett. 2002, 4, 2601; (e) Xu, Z.;
Lu, X. Tetrahedron Lett. 1997, 38, 3461.
14. (a) Haebich, D.; Hansen, J.; Paessens, A. Eur. Pat. Appl., EP 472077,
1992; Chem. Abstr. 1992, 117, 217161; (b) Haebich, D.; Hansen, J.; Paes-
sens, A. Eur. Pat. Appl., EP 472078, 1992; Chem. Abstr. 1992, 117,
2506059; (c) Haebich, D.; Henning, R.; Hansen, J.; Paessens, A. Ger.
Offen. DE 4016994, 1991; Chem. Abstr. 1992, 116, 152414.
15. 2-Phosphonopyrrolidines: (a) Dieltiens, N.; Moonen, K.; Stevens, C. V.
Chem.dEur. J. 2007, 13, 203; (b) Moonen, K.; Dieltiens, N.; Stevens,
C. V. J. Org. Chem. 2006, 71, 4006.
4.1.36. 5-Phenyl-3-hydroxy-1-benzyloxycarbonyl-pyrrole-
2-carboxylate (27)
In an oven-dried, 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and ar-
gon balloon was placed 20 (0.100 g, 0.29 mmol) in anhydrous
THF (10 mL), and Et3N (0.15 mL, 1.08 mmol) was added. The
reaction mixture was refluxed for 6 h, H2O (0.5 mL) was
added, and the solution was extracted with EtOAc
(3ꢃ5 mL). The combined organic phases were washed with
brine (5 mL), dried, and concentrated. Flash chromatography
(40% EtOAc/Hexanes) afforded 0.041 g (68%) of a clear oil;
1
IR (neat) 3354, 1716, 1668 cmꢀ1; H NMR (CDCl3) d 3.88
(s, 3H), 4.96 (br, 1H), 5.51 (br, 2H), 6.13 (s, 1H), 7.17 (m,
8H), 7.23 (m, 2H); 13C NMR (CDCl3) d 52.5, 68.0, 110.2,
118.5, 120.6, 123.6, 125.7, 126.1, 126.6, 126.8, 127.4, 127.9,
128.2, 128.3, 129.3, 130.1, 142.3, 143.1, 154.9. HRMS calcd
for C20H18NO5 (MþH) 352.1185. Found 352.1179.
16. 2-Phosphonopyrroles: (a) Mu, X.-J.; Zou, J.-P.; Qian, Q.-F.; Zhang, W.
Org. Lett. 2006, 8, 5291; (b) Palacios, F.; Ochoa de Retana, A. M.;
Acknowledgements
´
´
Martınez de Marigorta, E.; Rodrıguez, M.; Pagalday, J. Tetrahedron 2003,
59, 2617; (c) Quin, L. D.; Marsi, B. G. J. Am. Chem. Soc. 1985, 107,
3389; (d) Griffin, C. E.; Peller, R. P.; Peters, J. A. J. Org. Chem. 1965, 30, 91.
17. For recent reviews on the chemistry of sulfinimines, see: (a) Morton, D.;
Stockman, R. A. Tetrahedron 2006, 62, 8869; (b) Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichimica Acta
2005, 38, 93; (c) See Ref. 9; (d) Ellman, J. A.; Owens, T. D.; Tang,
T. P. Acc. Chem. Res. 2002, 35, 984.
We thank Clinton Ballard for preliminary studies. This
work was supported by grants from the National Institutes of
General Medical Sciences (GM 57870) and Boehringer Ingel-
heim Pharmaceuticals, Inc.
References and notes
18. Garcia Ruano, J. L.; Aleman, J.; Cid, M. B.; Parra, A. Org. Lett. 2005, 7,
179.
19. For reviews on carbonyl dianions, see: (a) Langer, P.; Freiberg, W. Chem.
Rev. 2004, 104, 4125; (b) Thompson, C. M.; Green, D. L. C. Tetrahedron
1991, 47, 4225.
1. Davis, F. A. J. Org. Chem. 2006, 71, 8993.
2. For reviews on sulfinimine-derived chiral building blocks, see: (a) Davis,
F. A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang, T.; Burns,
D. M.; Rao, A.; Szewczyk, J. M. Heteroat. Chem. 2002, 13, 486; (b)
Davis, F. A.; Yang, B.; Deng, J.; Zhang, J. ARKIVOC 2006, 120.
3. For references to the application of N-sulfinyl d-amino b-keto esters for
the asymmetric synthesis of piperidine derivatives, see: (a) Davis, F. A.;
Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2, 1041; (b) Davis,
F. A.; Chao, B. Org. Lett. 2000, 2, 2623; (c) Davis, F. A.; Fang, T.; Chao,
B.; Burns, D. M. Synthesis 2000, 2106; (d) Davis, F. A.; Chao, B.; Rao, A.
Org. Lett. 2001, 3, 3169; (e) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett.
2003, 5, 3855; (f) Davis, F. A.; Zhang, Y.; Anilkumar, G. J. Org. Chem.
20. The electrophile (Eþ) adds from the sterically least hindered direction to
give the trans-2,4-disubstituted pyrrolidine. Full details of the addition
stereochemistry will be published elsewhere using enantiopure examples.
21. (a) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919; (b) Chen, B.-C.;
Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003, 62, 1.
22. Campaigne, E.; Shutske, G. M. J. Heterocycl. Chem. 1974, 11, 929.
23. Commercially available LR (low range) tablets from Orbeco Analytical
Systems, Inc. were used. The peroxide reacts with KI to produce I2, which
reacts with diethyl-p-phenylenediamine to produce a pink-red color.