A novel stereoselective tin-free radical protocol for the enantioselective synthesis of pyrrolidinones and its application to the synthesis of?biologically active GABA-derivatives

Article abstract of DOI:10.1016/j.tet.2008.01.063

Optically pure 4-alkyl-pyrrolin-2-ones were synthesized from chiral N-allyl-α-bromoacetamides in high selective and stereo-controlled fashion, via a sequential 5-exo-trig radical cyclization-hydrogen or bromine atom-transfer process, under non-tin conditi

Full text of DOI:10.1016/j.tet.2008.01.063

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2750e2754
www.elsevier.com/locate/tet
A novel stereoselective tin-free radical protocol for the enantioselective
synthesis of pyrrolidinones and its application to the synthesis
of biologically active GABA-derivatives
*
´
Veronica Rodrıguez-Soria, Leticia Quintero, Fernando Sartillo-Piscil
´
Centro de Investigacio´n de la Facultad de Ciencias Qu´ımicas, BUAP, 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, Mexico
Received 25 October 2007; received in revised form 12 January 2008; accepted 14 January 2008
Available online 19 January 2008
Abstract
Optically pure 4-alkyl-pyrrolin-2-ones were synthesized from chiral N-allyl-a-bromoacetamides in high selective and stereo-controlled fash-
ion, via a sequential 5-exo-trig radical cyclization-hydrogen or bromine atom-transfer process, under non-tin conditions. Interestingly, when
N-allyl-a-bromoacetamides were treated with triethylborane/MeOH(excess)/BF3$OEt2 in toluene at ꢀ78 ꢁC, a tandem 5-exo-trig radical cycli-
zation-hydrogen atom-transfer reaction operated, on the other hand, a tandem 5-exo-trig radical cyclization-bromine atom-transfer reaction
proceeded in good yield and high stereoselectivity when the reaction was carried out with equimolar amounts of MeOH in THF at ꢀ78 ꢁC.
Thus, optically pure 4-alkyl-pyrrolin-2-ones were synthesized via this tin-free radical pathway and transformed to their corresponding biolog-
ically active GABA-derivatives, Pregabalin and CAMP.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
as source of hydrogen atom. Apparently, such complex serves
to weaken the OeH bond, so hydrogen atom-transfer process
is highly favored. Deuterium labeling experiments and theoret-
ical calculations suggested that this process operated as a free
radical chain pathway. Based on those results, we thought
that this protocol might work similarly with alkyl halides to
generate their corresponding alkyl radicals, so then if we apply
it to a recently reported stereoselective 5-exo-trig radical cycli-
zation protocol of converting chiral allylic amides 1 to 4-alkyl-
pyrrolidin-2-ones 2 for the enantioselective synthesis of
GABA-derivatives,7 we would have developed an environmen-
tally friendly protocol for the enantioselective synthesis of
GABA-derivatives (Scheme 1).8
Although free radical reactions have emerged as a powerful
tool for the construction of heterocyclic compounds,1 there still
are issues related to the chemo, regio, and stereoselectivities of
those reactions, not to mention that in most of the cases, the free
radical methods usually involve the use of toxic reagents, such
as reagents based on tin, cobalt, manganese, or samarium.2 In
spite of the introduction of non-tin radical reagents such as
silyl3 and thiyl reagents,4 researchers continue to investigate
new reaction systems to generate free radicals capable to carry
out free radical reactions under non-toxic conditions with good
chemo, regio, and stereoselectivities.
In this regard, Wood and co-workers turned the classical tin-
mediated-BartoneMcCombie deoxygenation protocol into a
pretty environmental reaction.5 Their novel protocol consisted
the use of BEt3 as radical initiator6 and BEt3$H2O complex
2. Results
Toward this end, chiral allylic amides (S)-3 and (S)-4 were
prepared according to literature procedure7,9 and exposed un-
der Wood’s conditions at ꢀ78 ꢁC5 using BF3$OEt2 as Lewis
acid.
* Corresponding author. Tel./fax: þ52 2222295500x7391.
E-mail address: fsarpis@siu.buap.mx (F. Sartillo-Piscil).
0040-4020/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.01.063

V. Rodr´ıguez-Soria et al. / Tetrahedron 64 (2008) 2750e2754
2751
R
R
Et
BEt3 + O2
N
Ph
nBu3SnH/BEt3
BF3·OEt2/-78 °C
GABA
derivatives
N
O
O
Ph
Br
N
N
2
Ph
BF3·OEt2
H
+
major
Et
Ph
1
O
H
N
O
pyrrolidin-2-ones
A
R = H or alkyl
Br
(S)-3
R
BEt3·H2O
N
Ph
Ph
Pyrrolidin-2-ones
BF3·OEt2/-78 °C
Tin free and highly
H
O
O
B
BEt3·H2O
3
Br
major
1
stereoselective
Bromine-atom
Hydrogen-atom
transfer
transfer
Scheme 1. Real and hypothetic 5-exo-trig radical cyclization.
Br
H
N
N
Ph
Ph
As we can see from Scheme 2, amide (S)-3 afforded two pairs
of diastereomeric pyrrolidinones (10S,4S)-5 and (10S,4R)-6, and
(10S,4S)-7 and (10S,4R)-8.10 On the other hand amide (S)-4
afforded only one pyrrolidinone (S)-9. Very interestingly, the
first pair of pyrrolidinones (10S,4S)-5 and (10S,4R)-6 retained
the bromine atom at terminal position, which suggests that
an unusual bromine atom-transfer process (compared to iodine
atom transfer11) occurred after the stereoselective 5-exo-trig
radical cyclization process.12 The same stereochemical out-
come was observed for pyrrolidinones (10S,4S)-7 and (10S,4R)-
8, however, a hydrogen atom transfer occurred instead of the
bromine atom transfer. It is important to note that the stereo-
chemical outcome is in accordance with the stereochemical
model previously reported, where the major pyrrolidinones
correspond to those with S absolute stereochemistry at C4.7
H
H
O
O
(1'S,4S)-7
(1'S,4S)-5
Scheme 3. Radical cyclization-bromine or hydrogen atom-transfer sequence.
(S)-9 could be formed by a disproportionation reaction of
tertiary radical D, due to its high stability and steric hindrance,
however, due to the high chemical yield of (S)-9 and the non-
observation of reduction product of (S)-4 (not shown), we be-
lieve that bromine atom process operates, which would result
in possible formation of a tertiary and labile bromine E giving
thus (S)-9 in good yield13 (E to (S)-9). See Scheme 4.
BEt3 + O2
Et
O
Br
+
N
N
H
Ph
BF3·OEt2
Br
Et
Br
Ph
H
N
N
O
C
+
Ph
Ph
Ph
(S)-4
O
O
(1'S,4R)-6
(1'S,4S)-5
30%
BEt3/H2O
BF3·OEt2
4%
O
Ph
Disprotonation
N
Ph
O
O
N
in Toluene
-78 °C
(S)-4
atom-transfer
N
Ph
O
N
+
N
X
N
Ph
Br
Ph
O
Br
(S)-3
O
(S)-9
(1'S,4S)-7
(1'S,4R)-8
28%
5%
E
D
Not isolated
BEt3/H2O
- HBr
N
Ph
BF3·OEt2
N
Ph
in Toluene
-78 °C
81%
Scheme 4. Non-radical chain reaction of (S)-4 to pyrrolidinone (S)-9.
O
O
(S)-9
Br
(S)-4
This novel stereoselective tin-free radical cyclization cou-
Scheme 2. 5-exo-trig Radical cyclization BEt3$H2O complex-mediated in the
presence of BF3$OEt2.
pled with the unusual bromine atom-transfer process prompted
us to seek a more efficient and general method to improve the
stereoselectivity and selective atom-transfer process.
Based on Wood’s proposal for the Barton deoxygenation in
the presence of BEt3$H2O complex, we also proposed a free
radical process for the reaction of (S)-3 which was initiated
by BEt3 and oxygen followed by the propagation step where
BF3OEt2-mediated stereoselective 5-exo-trig cyclization (A
to B) followed by bromine or hydrogen atom transfer (Scheme
3). On the other hand, amide (S)-4 underwent non-chain radi-
cal pathway to give pyrrolidinone (S)-9 as the single product
(Scheme 4). We initially thought that perhaps pyrrolidinone
Taking into account that water crystallizes below 0 ꢁC (so
this may be the reason of the poor incorporation of hydrogen
atom) we decided to use methanol instead of water with the
expectation that it may work similarly to water. As Wood estab-
lished that water (or in our case methanol) was necessary for the
free radical propagation step and the hydrogen atom transfer,
we thought that by reducing the amounts of the source of the
hydrogen atom, the bromine atom-transfer pathway should be

2752
V. Rodr´ıguez-Soria et al. / Tetrahedron 64 (2008) 2750e2754
favored. Thus after many attempts (including different solvents,
excess of BEt3 and BF3$OEt2, and longer reaction times), when
amide (S)-3 was treated with 5 equiv of BEt3, 1.5 equiv of
MeOH in well degassed and dried toluene in the presence of
3 equiv of BF3$OEt2, pyrrolidinones (10S,4S)-5 and (10S,4R)-6
were obtained in good yield and good stereoselectivity (route
B, Scheme 5). On the other hand, when amide (S)-3 was treated
with 5 equiv of BEt3 and the 20 equiv of MeOH in well de-
gassed and dried THF in the presence of 3 equiv of BF3$OEt2,
pyrrolidinones (10S,4S)-7 and (10S,4R)-8 were obtained in good
yield and good sterereoselectivity, and only trace amount of
pyrrolidinone (10S,4S)-5 was observed (Scheme 5).
Ph
N
Br
O
(S)-12
as a mixture of cis/trans olefins
88/12 respectively
Route A
Route B
73%
70%
13/14=89:11
Br
+
N
N
N
O
O
Ph
(1'S,4R)-14
Ph
(1'S,4S)-14
O
Ph
(1'S,4S)-13
Ph
N
Scheme 6. Synthesis of Pregabalin precursor 14. Conditions and reagents.
Route A: 5 equiv of BEt3/MeOH (20 equiv), 3 equiv of BF3$OEt2 in THF at
ꢀ78 ꢁC. Route B: 5 equiv of BEt3/MeOH (2 equiv), 3 equiv of BF3$OEt2 in
toluene at ꢀ78 ꢁC.
O
Br
(S)-3
Route B
88%
Route A
81%
5/6=90:10
7/8=90:10
(CAMP, 10) in good yield and high optical purity (up to 98%
ee,14c Scheme 7).
Br
O
Br
N
N
+
+
N
N
Ph
O
Ph
(1'S,4S)-7
O
OH
Ph
Ph
(1'S,4S)-5
(1'S,4R)-8
O
N
Ph
Ref. 7
(1'S,4R)-6
+ Traces
of (1'S,4S)-5
NH2
O
O
11
(1'S,4S)-13
Pregabalin
Scheme 5. Selective and stereoselective synthesis of pyrrolidinones via free tin
5-exo-trig radical cyclization. Conditions and reagents. Route A: 5 equiv of
BEt3/MeOH (20 equiv), 3 equiv of BF3$OEt2 in THF at ꢀ78 ꢁC. Route B:
5 equiv of BEt3/MeOH (2 equiv), 3 equiv of BF3$OEt2 in toluene at ꢀ78 ꢁC.
Ph
Ph
O
OH
H
NH2
t-BuOK
H3O
N
Birch
96%
O
N
N
O
O
THF, reflux
98%
80%
(1R,2S)-10
(1R,5S)-18
Br
(1'S,4S)-5
CAM
(1'S,3R,4S)-16
Withthisnoveltin-freechemoandstereoselective radicalpro-
tocol for the synthesis of optically pure pyrrolidinones in hand,
we decided to apply it to the enantioselective synthesis of two
pharmacologically important g-amino acids: the (1R,2S)-2-
(aminomethyl)cyclopropanecarboxylic acid (CAMP, 1014) and
(S)-3-aminomethyl-5-methylhexanoic acid (Pregabaline, 1115).
For the synthesis of Pregabalin 11, allylic amide (S)-12 was
prepared according to literature procedure.7 With this compound
in hand, a mixture of cis/trans amide (S)-12 was exposed to the
improved hydrogen atom-transfer reaction conditions to afford
the cyclization-hydrogen atom-transfer products pyrrolidinones
(10S,4S)-13 and (10S,4R)-14 in 73% with a ratio of 93:7 (route A,
Scheme 6). To further explore the generality of this novel proto-
col, the same amide (S)-12 was exposed to the conditions for the
generation of the cyclization-bromine atom-transfer product,
and pyrrolidinone (10S,4S)-1516 was obtained as an inseparable
mixture of CeBr epimers (route B, Scheme 6).
Scheme 7. Synthesis of biologically active g-amino acids.
It is worthy to mention that with this novel protocol of rad-
ical cyclization-bromine atom-transfer reaction, the synthesis
of CAMP was reduced by five steps comparing to the synthetic
route previously reported.14c
In conclusion, we have developed a novel stereoselective
and tin-free protocol for the synthesis of 4-alkyl-pyrrolidin-
2-ones from chiral N-allyl-a-bromoacetamides via a tandem
5-exo-trig radical cyclization-hydrogen or bromine atom-trans-
fer reaction. The enormous potential of this reaction was show-
cased in the synthesis of two important g-amino acids.
3. Experimental
Finally, pyrrolidinone (10S,4S)-13 was converted to optically
pure (S)-3-aminomethyl-5-methylhexanoic acid Pregabalin 11
ingoodyield(70%)andhighopticalpurity(upto98%ee)accord-
ing to literature preocedure.7 On the other hand, pyrrolidinone
(10S,4S)-5 was first transformed to its corresponding cyclopro-
pane derivative (10S,1R,5S)-16 followed by debenzylation afford-
ing (1R,5S)-1814c and finally by acid hydrolysis to give optically
pure (1R,2S)-2-(aminomethyl)cyclopropanecarboxylic acid
3.1. General protocol for cyclization-hydrogen atom transfer
To a solution of (S)-2-bromo-N-(4-methyl-pent-2-enyl)-N-
(1-phenyl-ethyl)-acetamide (S)-127 (0.5 g, 1.7 mmol) in THF
(40 mL) at ꢀ78 ꢁC were added triethylborane (1 g,
10.2 mmol of a 1 M solution in hexane) and BF3$OEt (0.7 g,
5.1 mmol). The resulting solution was stirred for 15 min before
adding methanol (2 mL, 40.8 mmol). Then, an air balloon was

V. Rodr´ıguez-Soria et al. / Tetrahedron 64 (2008) 2750e2754
2753
placed to the flask of reaction and was stirred for 6 h to ensure
completion. Finally, the reaction mixture was concentrated un-
der reduced pressure and the residue was purified by column
chromatography through silica gel (230e400 mesh) with hex-
ane/EtOAc (v/v¼5:1) giving 0.4 g of (10S,4S)-137 as colorless
oil in 73% yield, and traces of (10S,4R)-14.
d: 15.9, 19.5, 20.9, 36.2, 46.3, 48.6, 119.9, 125.8, 127.1,
127.4, 128.5, 139.9, 173.0. IR (CCl4) n 3342, 2977, 1702,
1664, 1495 cmꢀ1. FAB-HRMS m/z calcd for C15H20NO
[MþH]þ: 230.1545. Found: 230.1547.
3.2.4. (10S,4S)-4-(1-Bromo-2-methyl-propyl)-1-(1-phenyl-
ethyl)-pyrrolidin-2-one (15)
3.2. General protocol for cyclization-bromine atom transfer
The title compound was obtained as a diastereomeric mix-
ture at CeBr atom in 70% yield. 1H NMR (300 MHz, CDCl3)
d: 0.93 (d, 3H, J¼6.6 Hz), 0.94 (d, 3H, J¼6.6 Hz), 0.97 (d, 3H,
J¼3.9 Hz), 1.02 (d, 3H, J¼6.9 Hz), 1.53 (d, 3H, J¼7.2 Hz),
1.54 (d, 3H, J¼7.2 Hz), 1.71e1.82 (m, 2H), 2.17 (dd, 1H,
J¼16.1, 10.8 Hz), 2.24 (dd, 1H, J¼16.1, 9.9 Hz), 2.50 (dd,
1H, J¼9.0, 2.4 Hz), 2.56 (dd, 1H, J¼9.0, 2.4 Hz), 2.64 (m,
1H), 2.71e2.84 (m, 2H), 3.15e3.26 (m, 2H), 3.51 (m, 1H),
3.83 (dd, 1H, J¼9.9, 3.3 Hz), 3.94 (dd, 1H, J¼9.3, 3.3 Hz),
5.5 (m, 2H), 7.23e7.42 (m, 10H). 13C NMR (100 MHz,
CDCl3) d: 15.8, 15.9, 24.5, 24.7, 37.0, 37.2, 42.2, 42.5, 43.8,
46.5, 48.6, 48.8, 48.9, 52.4, 52.5, 127.0, 127.4, 127.5, 127.6,
128.4, 128.5, 128.6, 139.5, 139.6, 172.3. IR (CCl4) n 2965,
2853, 1688, 1422, 1249 cmꢀ1. FAB-HRMS m/z calcd for
C16H23BrNO [MþH]þ: 324.0963. Found: 324.0960.
To a solution of (S)-N-allyl-2-bromo-N-(1-phenyl-ethyl)-acet-
amide (S)-37,9 (0.27 g, 0.93 mmol) in dry toluene (50 mL) at
ꢀ78 ꢁC were added triethylborane (0.4 g, 2.81 mmol of a 1 M
solution in hexane) and BF3$OEt (0.5 g, 5.63 mmol). The result-
ing solution was stirred for 15 min before adding methanol
(0.8 mL, 2.81 mmol). Then, an air balloon was placed to the flask
of reaction and was stirred for 6 h to ensure completion. Finally,
the reaction mixture was concentrated under reduced pressure
and the residue was purified by column chromatography through
silica gel (230e400 mesh) with hexane/EtOAc (v/v¼5:1) giving
0.23 g (86% yield) of (10S,4S)-5 as major diastereoisomer and
0.04 g (4%) of (10S,4R)-6 as the minor diastereoisomer, both as
colorless oil.
3.2.1. (10S,4S)-4-Bromomethyl-1-(1-phenyleth-10-yl)-
pyrrolidin-2-one (5)
The title compound was obtained in 86% yield as colorless
3.3. Synthesis of (1R,2S)-CAMP (10)
3.3.1. (10S,1R,5S)-3-(1-Phenyleth-10-yl)-3-aza-bicyclo-
[3.1.0]hexane-2-one (16)14c
1
oil. [a]D ꢀ78.8 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3)
d: 1.53 (d, 3H, J¼6.8 Hz), 2.30 (dd, 1H, J¼15.6, 6.0 Hz),
2.60 (dd, 1H, J¼15.6, 8.8 Hz), 2.65 (m, 1H), 3.14 (br d, 2H,
J¼6.8 Hz), 3.37 (dd, 1H, J¼10.4, 7.6 Hz), 3.43 (dd, 1H,
J¼10.4, 5.6 Hz), 5.49 (q, 1H, 7.2 Hz), 7.26e7.35 (m, 5H).
13C NMR (100 MHz, CDCl3) d: 15.8, 33.2, 35.7, 36.7, 46.6,
48.8, 126.8, 127.4, 128.4, 139.6, 172.2. IR (CCl4) n 3433,
2931,1682, 1422, 1275 cmꢀ1. FAB-HRMS m/z calcd for
C13H16BrNO [MþH]þ: 282.0494. Found: 282.0491.
To a solution of (10S,4S)-57 (0.34 g, 1.2 mmol) in dry THF
(30 mL) at 0 ꢁC was added a solution of potassium tert-butox-
ide (2.4 mmol, 1 M solution in THF). The resulting solution
was stirred for 1 h. The reaction mixture was quenched with
30 mL of water, and extracted with ethyl acetate (30 mL three
times). The organic layer was dried with NaSO4 and evaporate
under reduced pressure and the residue was purified by column
chromatography through silica gel (230e400 mesh) with hex-
ane/EtOAc (v/v¼8:1) to give 0.24 g of (10S,1R,5S,)-16 (98%)
as colorless oil. [a]D ꢀ96.5 (c 1.0, CHCl3) (lit.14c [a]D ꢀ160.8
(c 1.0, CHCl3)). 1H NMR (400 MHz, CDCl3) d: 0.55 (ddd, 1H,
J¼7.6, 4.4, 3.2 Hz), 1.09 (ddd, H, J¼7.6, 4.8, 4.5 Hz), 1.40 (d,
3H, J¼8.0 Hz), 1.74 (m, 1H), 1.93 (m, 1H), 3.05 (dd, 1H,
J¼10.4, 5.6 Hz), 3.19 (dd, 1H, J¼10.4, 1.6 Hz), 5.38 (q, 1H,
J¼7.2 Hz), 7.25e7.36 (m, 5H). 13C NMR (100 MHz,
CDCl3) d: 11.4, 12.4, 16.4, 20.2, 44.2, 48.3, 126.7, 127.2,
128.3, 139.7, 174.4.
3.2.2. (10S,4R)-4-Bromomethyl-1-(1-phenyleth-10-yl)-
pyrrolidin-2-one (6)
The title compound was obtained in 4% yield as colorless oil.
[a]D ꢀ112.4 (c 1.0, CHCl3). 1H NMR(400 MHz, CDCl3) d: 1.44
(d, 3H, J¼7.2 Hz), 2.18 (dd, 1H, J¼16.4, 5.6 Hz), 2.55 (dd, 1H,
J¼16.4, 8.8 Hz), 2.64 (m, 1H), 2.70 (dd, 1H, J¼9.6, 5.6 Hz),
3.12 (dd, 1H, J¼10.0, 7.2 Hz), 3.22 (dd, 1H, J¼10.0, 5.6 Hz),
3.40 (dd, 1H, J¼9.6, 7.6 Hz), 5.41 (q, 1H, J¼7.2 Hz), 7.23e
7.25 (m, 5H). 13C NMR (100 MHz, CDCl3) d: 15.9, 33.6,
35.4, 36.8, 46.6, 48.8, 126.8, 127.4, 128.4, 139.4, 172.2. IR
(CCl4) n 3434, 2933, 1684, 1423, 1276 cmꢀ1. FAB-HRMS m/z
calcd for C13H16BrNO [MþH]þ: 282.0494. Found: 282.0492.
3.3.2. (1R,5S)-3-Aza-bicyclo[3.1.0]hexan-2-one (18)14c
A solution of (10S,1R,5S,)-16 (0.38 g, 1.90 mmol) in 30 mL
of THF was added dropwise to a deep blue solution of Li (0.1 g)
in condensed NH3 (20 mL) at ꢀ78 ꢁC. The reaction mixture
was allowed to stir for 1 h at ꢀ78 ꢁC before the addition of
an aqueous solution of NH4Cl (40 mL), then the reaction mix-
ture was neutralized with a diluted solution of HCl, extracted
with ethyl acetate, dried with Na2SO4, and evaporated under re-
duced pressure. The reaction was purified by column chroma-
tography through silica gel (230e400 mesh) with hexane/
EtOAc (v/v¼1:1) to give 0.2 g of (1R,5S)-18 (96%) as a white
solid. Mp¼108e109 ꢁC (lit.14c 106e109 ꢁC). [a]D þ51.9 (c 1,
3.2.3. (1S)-4-Isopropylidene-1-(phenyleth-10-yl)-pyrrolidin-
2-one (9)
The title compound was obtained in 81% yield as colorless
1
oil. [a]D ꢀ48.9 (c 1.0, CHCl3). H NMR (400 MHZ, CDCl3)
d: 1.52 (br s, 3H), 1.55 (d, 3H, J¼7.2 Hz), 1.62 (apparent t,
3H, J¼1.8 Hz), 3.07 (br s, 2H), 3.52 (d sept, 1H, J¼13.5,
1.5 Hz), 3.89 (d sept, 1H, J¼13.5, 1.5 Hz), 5.62 (q, 1H,
J¼7.2 Hz), 7.20e7.29 (m, 5H). 13C NMR (100 MHz, CDCl3)

2754
V. Rodr´ıguez-Soria et al. / Tetrahedron 64 (2008) 2750e2754
CHCl3) (lit.14c [a]D þ49.2 (c 1, CHCl3)). 1H NMR (400 MHz,
CDCl3) d: 0.68 (dd, 1H, J¼7.6, 4.5 Hz), 1.10 (ddd, 1H, J¼9.0,
8.4, 4.4 Hz), 1.80 (m, 1H), 1.94 (m, 1H), 3.35 (br d, 1H,
J¼10.4 Hz), 3.52 (dd, 1H, J¼10.4, 6.0 Hz), 6.01 (br s, 1H).
13C NMR (100 MHz, CDCl3) d: 12.2, 14.7, 19.3, 44.2, 179.3.
4. (a) Crich, D. Organosulfur Chemistry: Synthetic Aspect; Page, P., Ed.;
Academic: London, 1995; Chapter 2; (b) Bertrand, M. P.; Ferreri, C. Rad-
icals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH: New
York, NY, 2001; Vol. 2, Chapter 5.5.
5. Spiegel, D. A.; Wiberg, K. B.; Schecherer, L. N.; Medeiros, M. R.; Wood,
J. L. J. Am. Chem. Soc. 2005, 127, 12513.
6. Olliver, C.; Renaud, P. Chem. Rev. 2001, 101, 3415.
7. Rodriguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2007, 48,
3.3.3. (1R,2S)-2-(Aminomethyl)cyclopropanecarboxylic
acid (10)
´
4305. See also previous work: Rodrıguez, V.; Sanchez, M.; Quintero, L.;
Sartillo-Piscil, F. Tetrahedron 2004, 60, 10809.
~
8. Ordonez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3.
A solution of (1R,5S)-18 (0.15 g, 2.1 mmol) in 20 mL of
HCl (1 M) was stirred at 70 ꢁC for 8 h. The resulting solution
was evaporated under reduced pressure and the residue was
crystallized with a solution mixture of AcOEt/methanol (v/v¼
1:5) to give 0.12 g of (1R,2S)-10 as a white solid (80% yield).
Mp¼240e250 ꢁC (lit.14c 239e241 ꢁC). [a]D ꢀ32.6 (c 1, H2O)
9. Cardillo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.; Rossetti, M. Heterocy-
cles 1994, 38, 2663.
10. In the case of pyrrolidinones (10S,4S)-7 and (10S,4R)-8 the absolute stereo-
chemistrywas determined bychemicalcorrelation. See Refs. 7 and 9. Theab-
solute configuration of the other pair of pyrrolidinones was also determined
by chemical correlation after removal of the bromine atom with Bu3SnH.
11. See interesting examples of cyclization-iodine atom-transfer sequence: (a)
Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto, K.;
Fujimoto, H. J. Am. Chem. Soc. 2000, 122, 11041; (b) Ikeda, M.; Teranishi,
H.; Nozaki, K.; Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1998, 1691.
12. In a similar way Nicholas reported a cobalt-mediated stereoselective
radical cyclization followed by bromine atom transfer: Salazar, K. L.;
Khan, M. A.; Nicholas, K. M. J. Am. Chem. Soc. 1997, 119, 9053. Other
examples of bromine atom transfer: (a) Baciocchi, E.; Muraglia, E. Tetra-
hedron Lett. 1994, 35, 2763; (b) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka,
M.; Gotanda, K.; Matsugi, M. Tetrahedron Lett. 1997, 38, 3549; (c) Mero,
C. L.; Porter, N. A. J. Am. Chem. Soc. 1999, 121, 5155.
1
(lit.14c [a]D ꢀ38.5 (c 0.99, 1 M HCl)). H NMR (400 MHz,
D2O); d: 0.94 (ddd, 1H, J¼7.2, 5.6, 5.2 Hz), 1.20 (m, 1H),
1.53 (ddd, 1H, J¼8.4, 7.6, 5.1 Hz), 1.80 (m, 1H), 3.14 (t,
2H, J¼8.0 Hz). 13C NMR (100 MHz, D2O) d: 13.0, 17.7,
17.9, 38.2, 176.7. IR (KBr) n 3383, 1575, 1424, 1053 cmꢀ1
.
Acknowledgements
We thank CONACyT and PROMEP-BUAP for financial
support. We also thank Dr. Xianhai Huang from Schering
Plough for helpful discussions. We thank reviewers for their
constructive comments.
13. We thank reviewers for pointing this out.
14. (a) Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya, A.; Taguchi, T. J. Org.
Chem. 1994, 59, 97; (b) Baxandele, I. R.; Ernts, M.; Krahnert, W.-R.; Ley,
S. V. Synlett 2002, 1642; (c) Galeazzi, R.; Mobbili, G.; Orena, M. Tetra-
hedron: Asymmetry 1997, 8, 133 and references cited therein.
15. (a) Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219; (b) Sammis, G. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442; (c) Mita, T.; Sasaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514; (d)
Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote,
T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger,
E. J.; Karrick, G. L. Org. Process Res. Dev. 1997, 1, 26; (e) Chen, Z.;
Chen, Z.; Jiang, Y.; Hu, W. Synlett 2004, 1763; (f) Burk, M. J.; de Koning,
P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.; Jennings, R. A.; Kissel,
W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A.; Ramsden, J. A.; Wade,
R. A. J. Org. Chem. 2003, 68, 5731.
References and notes
1. See representative reviews: (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem. Rev. 1991, 91, 1237; (b) Hartung, J. Eur. J. Org. Chem. 2001, 619;
(c) Cekovic, Z. Tetrahedron 2003, 59, 8073; (d) Zhang, W. Curr. Org.
Chem. 2002, 6, 1015; (e) Bowman, W. R.; Cloonan, M. O.; Krintel,
S. L. J. Chem. Soc., Perkin Trans. 1 2001, 2885.
2. (a) Studer, A.; Amrein, S. Synthesis 2002, 835; (b) Baguley, P. A.; Walton,
J. C. Angew. Chem., Int. Ed. 1998, 37, 3072.
16. The absolute stereochemistry at C4 was determined by chemical correla-
tion after removal of the bromine atom.
3. (a) Chatgilialoglu, C.; Ballestri, M. Organometallics 1995, 14, 5017; (b)
Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem. 1988, 53, 3641.