Diastereoselective synthesis of (2S,5S)- and (2S,5R)-N-benzyloxycarbonyl-5-hydroxypipecolic acids from trans-4-hydroxy-l-proline

Article abstract of DOI:10.1016/j.tetasy.2006.07.035

An efficient diastereoselective synthesis of cis- and trans-5-hydroxy-(2S)-N-benzyloxycarbonyl pipecolic acids, starting from trans-4-hydroxy-l-proline is described. The key synthetic strategies involve the regioisomeric ring expansion of keto ester 8 and diastereoselective reduction of ketone 11 in high selectivity and yield.

Full text of DOI:10.1016/j.tetasy.2006.07.035

Tetrahedron: Asymmetry 17 (2006) 2479–2486
Diastereoselective synthesis of (2S,5S)- and
(2S,5R)-N-benzyloxycarbonyl-5-hydroxypipecolic acids
from trans-4-hydroxy-L-proline
Jae-Chul Junga and Mitchell A. Averya,b,c,
*
aDepartment of Medicinal Chemistry, School of Pharmacy, University of Mississippi, PO Box 1848, University of Mississippi,
MS 38677, USA
bDepartment of Chemisty, School of Pharmacy, University of Mississippi, PO Box 1848, University of Mississippi, MS 38677, USA
cNational Center for Natural Products Research, School of Pharmacy, University of Mississippi, PO Box 1848,
University of Mississippi, MS 38677, USA
Received 24 July 2006; accepted 28 July 2006
Abstract—An efficient diastereoselective synthesis of cis- and trans-5-hydroxy-(2S)-N-benzyloxycarbonyl pipecolic acids, starting from
trans-4-hydroxy-L-proline is described. The key synthetic strategies involve the regioisomeric ring expansion of keto ester 8 and diaste-
reoselective reduction of ketone 11 in high selectivity and yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
method. The Valela group6 developed a route to (2S,4S)-
and (2S,4R)-4-hydroxy pipecolic acids from D-glucohep-
tono-1,4-lactone as a chiral template using b-elimination
and diastereoselective hydrogenation.
Diastereoselective syntheses of pipecolic acid and its deriv-
atives have attracted considerable attention in organic,
pharmaceutical, and medical chemistry due to their key
biological roles as components of peptides, proteins, and
other natural products.1 Furthermore, functionalized pipe-
colic acids also represent key intermediates in the synthesis
of conformationally constrained molecular scaffolds as
elements in the design of small molecule combinational
libraries.2 A variety of routes for the synthesis of 5-substi-
tuted pipecolic acid and its derivatives were described in the
literature.3 Most of these methods are based on the intra-
molecular ring cyclization of N-protected diazoketone or
alkyl halides derived from glutamic acid or glycinate chiral
Schiff bases. Recently, Dhimane et al.4 reported on the
preparation of 5-substituted pipecolic acid derivatives from
racemic N-Boc methylpipecolate in a diastereodivergent
manner in high yield. Machetti et al.5 introduced the prep-
aration of cis- and trans-4-aminopipecolic acid, a conform-
ationally constrained basic amino acid bearing orthogonal
N-protection suitable for solid-phase peptide synthesis
through a reductive amination and protection/deprotection
In the context of our medicinal chemistry program dealing
with the development of a new type of antimalarial deriva-
tives, we require cis- and trans-5-hydroxypipecolic acid and
its derivatives, as important fragments to generate novel
cysteine protease inhibitors.7 Herein, we report an efficient
diastereoselective synthesis of cis- and trans-5-hydroxy-
(2S)-N-benzyloxycarbonyl pipecolic acid, starting from
trans-4-hydroxy-L-proline via regioisomeric ring expansion
and diastereoselective reduction.
2. Results and discussion
To generate the Cbz-protected pipecolic acids, Cbz-trans-
4-OTBS proline 2 was prepared from trans-4-hydroxy-L-
proline 1, which was protected with benzyloxycarbonyl
chloride (Cbz–Cl) in the presence of sodium bicarbonate
(NaHCO3) to give the Cbz-protected acid,8 which was
subsequently treated with tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf) and 2,6-lutidine to give acid
2 in 91% (three steps) yield. Acid 2 was protected with
*
Corresponding author. Tel.: +1 662 915 5879; fax: +1 662 915 5638;
e-mail: mavery@olemiss.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.035

2480
J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
2-(trimethylsilyl)ethoxymethyl chloride (SEM–Cl) in the
presence of diisopropylethylamine (DIPEA) to yield the
fully protected compound, followed by hydrolysis with
AcOH in THF/H2O (8:2, v/v) to give the SEM ester, which
was treated with tetrabutylammonium fluoride (TBAF) to
give the secondary alcohol in 93% yield (two steps).
due to inseparable regioisomeric mixtures by flash column
chromatography. N-Cbz protection of 1 could also be
achieved by treatment of Cbz–Cl in the presence of chloro-
trimethylsilane (TMS–Cl) to give acid 6 in 95% yield (two
steps). Acid 6 was oxidized by Jones reagent at 0 ꢁC in ace-
tone to generate keto acid 7 in 92% yield, which was treated
with isobutylene in acidic media to afford keto ester 8 in
80% yield.11 Keto ester 8 was treated with BF3ÆEt2O and
EDA in ether to yield ring expansion regioisomeric keto–
enol tautomers 9a and 9b and 10a and 10b. In this stage,
we found that the keto–enol ratio of these mixtures is 9:1
based on 1H NMR analysis. Decarboxylation of keto esters
9a and 9b and 10a and 10b was performed with NaCl in
DMSO at 140 ꢁC to give regioisomeric 4-ketone 11 and
5-ketone 12 (isolated ratio, 1.5:1, 11:12) in 75% combined
yield.12 Regioisomers 11 and 12 were hydrolyzed using
TFA in dichloromethane to give the corresponding acids
13 and 14 in 95% and 97% yields, respectively (Scheme 1).
Oxidation of the alcohol was accomplished by using freshly
prepared pyridinium chlorochromate (PCC) to afford
ketone 3 in 89% yield.9 Oxidation of the secondary alcohol
was also attempted by using Dess–Martin periodinane
(DMP), manganese dioxide (MnO2), tetrapropylammo-
nium perruthenate (TPAP), and Swern conditions.
Although these latter conditions were more convenient
due to the ease of handling and shorter reaction time,
PCC conditions afforded a superior yield. Ketone 3 was
subjected to ring expansion with boron trifluoride–diethyl
etherate (BF3ÆEt2O) and ethyl diazoacetate (EDA) to gen-
erate pipecolic acids 4 and 5 as a regioisomeric mixture
(ratio, 1.3:1, 4:5) in 72% combined yield,10 which could not
be used efficiently for the preparation of pipecolic acids,
With the 4- and 5-ketones 11 and 12 in hand, we turned our
attention to formation of the desired cis- and trans-pipeco-
O
CO2Et
N
TBSO
O
EtO2C
O
OH
OSEM
b,c
d
+
OH
OH
N
N
N
O
O
Cbz
Cbz
Cbz O
Cbz
O
2
3
4
5
a
HO
O
HO
O
OH
OH
OH
Ot-Bu
g
e
f
N
H
N
N
N
O
O
O
O
Cbz
Cbz
Cbz
1
6
7
8
O
OEt
O
O
O
O
O
EtO
i
+
Ot-Bu
+
Ot-Bu
Ot-Bu
Ot-Bu
N
N
N
N
Cbz
O
Cbz
O
Cbz
O
Cbz
O
9a
11
10a
12
h
K/E: 9:1
Ot-Bu
j
j
O
OEt
O
O
OH
HO
O
EtO
+
OH
OH
Ot-Bu
N
N
N
N
Cbz
O
Cbz
O
Cbz
O
Cbz
O
9b
10b
13
14
Scheme 1. Reagents and conditions: (a) Cbz–Cl, NaHCO3, H2O, toluene, rt, 16 h; then TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 1 h; then AcOH, THF/H2O
(8:2, v/v), 0 ꢁC, 1 h, 91%; (b) SEM–Cl, DIPEA, CH2Cl2, 0 ꢁC to rt, 1 h; then TBAF, THF, 0 ꢁC, 1 h, 93%; (c) PCC, Florisil, CH2Cl2, rt, 16 h, 89%; (d)
EDA, BF3ÆEt2O, Et2O, rt, 2 h, 72%; (e) TMS–Cl, DIPEA, CH2Cl2, reflux, 2 h; then, Cbz–Cl, 0 ꢁC to rt, 16 h, 95%; (f) Jones Ox. acetone, 0 ꢁC, 10 min,
92%; (g) isobutylene, H2SO4 (cat), CH2Cl2, rt, 16 h, 80%; (h) EDA, BF3ÆEt2O, Et2O, rt, 1 h, 90%; (i) NaCl, DMSO, H2O (cat), 140 ꢁC, 4 h, 75%; (j) TFA,
CH2Cl2, rt, 2 h, 95% for 13, 97% for 14.

J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
2481
lic acid. Reduction of 11 was achieved with sodium boro-
hydride in methanol to give cis-alcohol 15a and trans-alco-
hol 15b (97:3 ratio, 15a:15b, 82% combined yield). The
resulting diastereomeric mixture of the reduction products
was successfully separated by column chromatography.
Furthermore, cis-diastereomer 15a could be identified via
intramolecular lactonization, accomplished by refluxing
for 1 h in benzene with a catalytic amount of p-toluenesulf-
onic acid monohydrate (p-TsOHÆH2O) to afford N-benzyl-
oxycarbonyl lactone 17 in 90% yield,3a,b while no similar
lactone could be obtained with trans-diastereomer 15b as
expected (Scheme 2).
generated, respectively, with 60:40 and 75:25 ratios in high
yields (Table 1, entries 1–3). Among the sodium boro-
hydride reagents considered, we have found that the bulk-
ier reducing agents showed low diastereoselectivity and
reduced yields, presumably due to steric coordinating effect
(Table 1, entries 5–7).13 Unfortunately, upon treatment of
11 with polymer bound-zinc borohydride (PB-ZnBH4) or
diisobutylaluminum hydride (DIBAL) in dichloromethane,
the reaction led to the formation of undesired diol due to
over reduction (Table 1, entries 8–9).
Likewise, treatment of 4-ketone 12 with sodium boro-
hydride in methanol gave a diastereomeric mixture of the
reduction product (2S,4S) 4-hydroxypipecolate 18a and
its (2S,4R)-diastereomer 18b (95:5 ratio 18a:18b, 86%
combined yield), which was also cleanly separated by flash
column chromatography. Stereoselective reduction of 4-
ketone 12 with L-Selectride and Super-H in THF failed to
enhance the diastereoselectivity (80:20 ratio, cis-18a:trans-
18b, 96% combined yield for L-Selectride; 70:30 ratio, cis-
18a:trans-18b, 88% combined yield for Super-H). Pure cis-
18a and trans-18b were hydrolyzed by treatment with TFA-
in dichloromethane to afford (2S,4S) 4-hydroxypipecolic
In an attempt to improve further the selectivity of the
reduction of 5-ketone 11 to cis-alcohol 15a and trans-alco-
hol 15b with a view to synthesize 5-hydroxypipecolates,
other reducing agents were examined (Table 1). The best
result was obtained with 5-ketone 11 in the presence of
sodium borohydride in methanol at 0 ꢁC to room temper-
ature for 30 min (Table 1, entry 4). When the carbonyl
group of ketone 11 was reduced using L-Selectride,
K-Selectride, and Super-H in THF, the diastereomeric
mixture of equatorial and axial alcohols 15a and 15b was
HO
HO
O
a
c
b
Ot-Bu
OH
Ot-Bu
N
N
N
Cbz
O
Cbz O
Cbz
O
11
15a
16a
+
O
HO
HO
Cbz
O
b
Ot-Bu
OH
N
N
N
Cbz
O
Cbz O
15b
16b
17
Scheme 2. Reagents and conditions: (a) NaBH4, MeOH, 0 ꢁC to rt, 30 min, 82%; (b) TFA, CH2Cl2, rt, 2 h, 90% for 16a, 88% for 16b; (c) p-TsOH, benzene,
reflux, 1 h, 86%.
Table 1. Diastereoselective reduction of 11 with various reducing agents to generate 15a and 15b
Entry
Reducing agenta
Solvent
Temperature (ꢁC)
Time (h)
Selectivity (S/R)b
Yieldc (%)
1
2
3
4
5
6
7
8
9
Li–BH[CH(CH3)CH2CH3]3
K–BH[CH(CH3)CH2CH3]3
Li–BH(C2H5)3
NaBH4
NaBH3CN
NaBH(OAc)3
Me4NBH(OAc)3
ZnBH4
THF
THF
THF
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CH2Cl2
ꢀ45
0.5
0.5
1
0.5
0.5
0.5
5
60:40
60:40
75:25
97:3
92
88
90
82
60
25
—
75
71
ꢀ45
ꢀ78 to 0
0 to rt
ꢀ45 to rt
ꢀ45 to rt
0 to rt
95:5
90:10
—
Diole
Diole
d
ꢀ45 to 10
1
1
AlH[(CH3)2CHCH2]2
ꢀ45 to 10
a L-Selectride: lithium tri-sec-butylborohydride; K-Selectride: potassium tri-sec-butylborohydride; Super-hydride: lithium triethylborohydride; NaBH4:
sodium borohydride; NaBH3CN: sodium cyanoborohydride; NaBH(OAc)3: sodium triacetoxyborohydride; Me4NB(OAc)3: tetramethylammonium
triacetoxyborohydride; ZnBH4: polymer bound-zinc borohydride (PB); DIBAL: diisobutylaluminum hydride.
b Diastereoselectivity.
c Isolated pure yield.
d No reaction.
e Over-reduction product.

2482
J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
O
OH
OH
a
b
Ot-Bu
Ot-Bu
OH
N
N
N
Cbz
O
Cbz
O
Cbz
O
12
19a
18a
+
OH
OH
Ot-Bu
OH
b
N
N
Cbz
O
Cbz
O
19b
18b
Scheme 3. Reagents and conditions: (a) NaBH4, MeOH, 0 ꢁC to rt, 30 min, 86%; (b) TFA, CH2Cl2, rt, 2 h, 90% for 19a, 88% for 19b.
acid 19a and (2S,4R) 4-hydroxypipecolic acid 19b in 90%
and 88% yields, respectively (Scheme 3).
tion of benzyl chloroformate (3.0 g, 17.5 mmol) in
toluene (10 mL). The mixture was stirred at room tempera-
ture for 16 h. The two phases were separated and the aque-
ous phase extracted with ether (3 · 8 mL) and acidified to
pH 2 with 3 M HCl solution. The oily residue was
extracted with ethyl acetate (3 · 15 mL), and the combined
organic layer was dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue
was used in the next reaction without purification. The res-
idue was dissolved in dichloromethane (70 mL), and 2,6-
lutidine (5.4 g, 50.5 mmol) was added, followed by
TBSOTf (12.1 g, 45.9 mmol) at 0 ꢁC. The mixture was
warmed to room temperature for 30 min and stirred for
1 h. The reaction mixture was diluted with dichlorometh-
ane (35 mL) and washed with saturated aqueous NH4Cl
solution (35 mL). The organic layer was separated, dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The mixture was treated with AcOH
(9.1 mL) in THF/H2O (90 mL, 8:2, v/v) at 0 ꢁC and the
mixture was stirred at 0 ꢁC for 1 h. The resulting mixture
was evaporated under reduced pressure and the residue
was diluted with dichloromethane (70 mL) and washed
with saturated aqueous NH4Cl solution (40 mL). The
organic layer was separated, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (silica
gel, 5% methanol in dichloromethane) to give 2 (5.3 g,
3. Conclusion
In conclusion, we have developed a diastereoselective
synthesis of (2S,4S)- and (2S,4R)-5-hydroxypipecolic acid
through a regioisomeric ring expansion reaction and
stereoselective reduction. This method is versatile and
allows for the preparation of key fragments for enzyme
inhibitor studies.
4. Experimental
Reactions requiring anhydrous conditions were performed
with the usual precautions for rigorous exclusion of air
and moisture. Tetrahydrofuran was distilled from sodium
benzophenone ketyl prior to use. Thin layer chromatogra-
phy (TLC) was performed on precoated silica gel G and
GP uniplates from Analtech and visualized with a
254 nm UV light. Flash chromatography was carried out
on silica gel 60 [Scientific Adsorbents Incorporated (SAI),
particle size 32–63 lm, pore size 60 A]. 1H NMR, 13C
˚
NMR, and 2D NMR spectra were recorded on a Bruker
DPX 400, 500 at 400, 500 MHz, and 100, 125 MHz, respec-
tively. Chemical shifts are reported in parts per million
(ppm) downfield from tetramethylsilane, and J-values are
in hertz. Infrared (IR) spectra were obtained on an ATI
Mattson FT/IR spectrometer. Mass spectra were recorded
with a Waters Micromass ZQ LC-Mass system and Q-TOP
micro mass spectrometer with electrospray interface and
lockspray source. When necessary, chemicals were purified
according to the reported procedures.14
91%) as a colorless oil. Rf = 0.5 (5% methanol/dichloro-
22
methane); ½aꢁD ¼ ꢀ36:5 (c 0.8, CHCl3); IR (neat, NaCl)
3417, 3034, 2955, 2867, 1713, 1423, 1359, 1255, 1120,
1
1022, 837 cmꢀ1; H NMR (CDCl3, 500 MHz) mixture of
two rotamers d 7.41–7.27 (m, 5H, Ar–H), 7.14 (br s, 1H,
CO2H), 5.26–5.13 (m, 2H, PhCH2O), 4.57–4.42 (m, 2H,
NCHCO2H, CH2CHOSi), 3.71–3.61 (m, 1H, NCH2CHO),
3.57–3.42 (m, 1H, NCH2CHO), 2.31–2.19 (m, 1H,
NCHCH2), 2.18–2.07 (m, 1H, NCHCH2), 0.89 (s, 1/
2 · 9H, SiCMe3), 0.88 (s, 1/2 · 9H, SiCMe3), 0.12 (s, 3H,
Si–Me), 0.08 (s, 3H, Si–Me); 13C NMR (CDCl3,
125 MHz) mixture of two rotamers d 177.4, 176.5, 175.9,
155.9, 154.4, 136.3, 136.1, 128.4, 128.3, 128.0, 127.8,
127.7, 127.5, 70.4, 69.9, 67.8, 67.4, 58.5, 57.9, 55.4, 55.0,
40.2, 38.7, 18.4, 18.3, ꢀ3.2, ꢀ4.3, ꢀ4.4, ꢀ4.5; HRMS
4.1. (2S,4R)-4-(tert-Butyldimethylsilyloxy)-1-(benzyloxy-
carbonyl)pyrrolidine-2-carboxylic acid 2
To a stirred solution of trans-4-hydroxy-L-proline 1 (2.0 g,
15.3 mmol) in water (30 mL) was added sodium bicarbon-
ate (3.2 g, 38.0 mmol), followed by the addition of a solu-

J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
2483
calcd for C19H30NO5SiNa: 380.1893 [M+Na]+, found:
380.1888.
diluted with dichloromethane (10 mL) and washed with
saturated aqueous NH4Cl solution (10 mL) and brine
(10 mL). The organic layer was separated, dried over anhy-
drous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography (silica gel, 60:30:10; n-hexane–ethyl acetate–
methanol, v/v) to give 4 and 5 (0.51 g, 72%) as a viscous
4.2. (2S)-4-Oxopyrrolidine-1,2-dicarboxylic acid 1-benzyl
ester 2-(2-trimethylsilylethoxymethoxy) ester 3
To a stirred solution of acid 2 (7.6 g, 20.0 mmol) in dichlo-
romethane (150 mL) was added DIPEA (2.8 g, 22.0 mmol),
followed by the addition of a solution of SEM–Cl (3.7 g,
22.0 mmol) at 0 ꢁC. The mixture was warmed to room tem-
perature for 1 h. The reaction mixture was diluted with
dichloromethane (50 mL) and washed with saturated aque-
ous NH4Cl solution (120 mL) and brine (120 mL). The
organic phase was separated and dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
The residue was used in the next reaction without purifica-
tion. The residue was dissolved in THF (180 mL) and trea-
ted with TBAF (38.8 g, 40.0 mmol, 1.0 M soln, in THF) at
0 ꢁC. The mixture was stirred for 1 h, diluted with dichloro-
methane (150 mL), and washed with saturated aqueous
NH4Cl solution (150 mL) and brine (150 mL). The organic
layer was separated, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue
was purified by flash column chromatography (silica gel,
75:20:5; n-hexane–ethyl acetate–methanol, v/v) to give
alcohol (7.3 g, 93%) as a pale yellow oil. To a stirred solu-
tion of alcohol (1.7 g, 4.3 mmol) in dry dichloromethane
(50 mL) was added pyridinium chlorochromate (2.4 g,
10.8 mmol), followed by addition of Florisil (1.7 g) and
the mixture was stirred at room temperature for 16 h.
The reaction mixture was diluted with dichloromethane
(10 mL) and filtered through Celite. The residue was trea-
ted with active carbon (2.2 g) and filtered again through
a pad of Celite. The filtrate was concentrated under re-
duced pressure. The residue was purified by flash column
chromatography (silica gel, 20% ethyl acetate in n-hexanes)
oil. Rf = 0.1 (60:30:10; n-hexane–ethyl acetate–methanol,
27
v/v); ½aꢁD ¼ þ4:0 (c 0.2, CHCl3); IR (neat, NaCl) 3445,
2983, 1714, 1669, 1498, 1309, 1230, 1113, 1029, 769 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 12.01 (br s, 2/3 · 1H),
7.49–7.46 (m, 5H), 5.24 (dd, J = 11.5, 12.0 Hz, 2H), 4.48–
3.90 (m, 4H), 3.51 (dd, J = 7.0, 7.0 Hz, 1H), 3.01 (t,
J = 17.0 Hz, 1/2 · 1H), 2.89 (t, J = 17.0 Hz, 1/2 · 1H),
2.79 (br s, 1/3 · 1H), 1.36–1.26 (m, 2H), 1.23 (t,
J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 170.9,
155.6, 135.8, 128.5, 128.2, 127.9, 127.8, 68.1, 66.0, 61.9,
61.8, 52.2, 43.6, 39.2, 30.2, 24.3, 15.6, 14.6; HRMS calcd
for C17H20NO7: 350.1240 [M+H]+, found: 350.1264.
4.4. (2S)-4-Oxopyrrolidine-1,2-dicarboxylic acid 1-benzyl
ester 2-tert-butyl ester 8
A stirred solution of keto acid 7 (9.3 g, 35.4 mmol) in dry
dichloromethane (71 mL) was cooled to 0 ꢁC, and concen-
trated sulfuric acid (0.35 mL) was added dropwise. Iso-
butylene was bubbled into the solution until the volume
of the mixture had increased by approximately 50%. The
reaction mixture was stirred at room temperature for
16 h. The reaction mixture was diluted with dichlorometh-
ane (140 mL) and washed with saturated aqueous Na2CO3
solution (120 mL) and water (120 mL). The organic layer
was separated, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue
was purified by flash column chromatography (silica gel,
30% ethyl acetate in n-hexanes) to give 8 (9.0 g, 80%) as
to give 3 (1.5 g, 89%) as a colorless oil. Rf = 0.4 (20% ethyl
a viscous bright yellow oil. Rf = 0.4 (30% ethyl acetate/
27
25
acetate/n-hexanes); ½aꢁD ¼ ꢀ10:0 (c 0.3, CHCl3); IR (neat,
n-hexanes); ½aꢁD ¼ þ5:4 (c 1.0, CHCl3); IR (neat, NaCl)
NaCl) 3066, 3034, 2954, 2899, 1768, 1715, 1499, 1356,
3034, 2979, 1768, 1738, 1714, 1415, 1151, 1027, 833 cmꢀ1
;
1
1250, 1111, 1055, 837 cmꢀ1; H NMR (CDCl3, 500 MHz)
1H NMR (CDCl3, 500 MHz) mixture of two rotamers d
7.39–7.30 (m, 5H), 5.25–2.15 (m, 2H), 4.72 (dd, J = 18.0,
10.5 Hz, 1H), 4.03–3.89 (m, 2H), 2.99–2.84 (m, 1H), 2.55
(d, J = 18.0 Hz, 1H), 1.45 (s, 1/2 · 9H), 1.37 (s, 1/2 ·
9H); 13C NMR (CDCl3, 125 MHz) mixture of two rota-
mers d 207.7, 207.0, 170.3, 170.2, 154.7, 154.1, 136.0,
135.8, 128.4, 128.2, 128.0, 82.8, 67.7, 57.1, 53.0, 52.8,
41.6, 41.0, 28.2, 28.0; HRMS calcd for C17H22NO5:
320.1498 [M+H]+, found: 320.1495.
mixture of two rotamers d 7.41–7.32 (m, 5H, Ar–H), 5.42
(d, J = 6.0 Hz, 1/2 · 1H, OCH2O), 5.34 (d, J = 6.0 Hz,
1/2 · 1H, OCH2O), 5.29–5.14 (m, 3H, OCH2O, PhCH2O),
4.89 (dd, J = 11.0, 10.0 Hz, 1H), 4.01–3.93 (m, 2H), 3.79–
3.59 (m, 2H), 3.06–2.94 (m, 1H), 2.66 (d, J = 2.5 Hz,
1/2 · 1H), 2.62 (d, J = 2.5 Hz, 1/2 · 1H), 0.98 (t, J =
8.0 Hz, 1H), 0.92 (t, J = 8.5 Hz, 1H), 0.04 (s, 6H), 0.03
(s, 3H, SiMe3); 13C NMR (CDCl3, 125 MHz) mixture of
two rotamers d 207.0, 206.4, 170.8, 170.6, 154.7, 153.9,
135.8, 128.5, 128.2, 128.0, 90.3, 68.4, 67.9, 56.4, 56.3,
52.9, 52.7, 41.8, 40.8, 26.0, 18.4, ꢀ1.0; HRMS calcd. for
C19H27NO6SiNa: 416.1505 [M + Na]+, found: 416.1441.
4.5. N-Benzyloxycarbonyl-4-ethoxycarbonyl-5-oxo-(S)-pipe-
colic acid tert-butyl ester 9a and 9b/N-benzyloxycarbonyl-
4-oxo-5-ethoxycarbonyl-(S)-pipecolic acid tert-butyl ester
10a and 10b
4.3. N-Benzyloxycarbonyl-4-ethoxycarbonyl-5-oxo-(S)-pipe-
colic acid 4/N-benzyloxycarbonyl-4-oxo-5-ethoxycarbonyl-
(S)-pipecolic acid 5
To a stirred solution of keto ester 8 (6.0 g, 18.8 mmol) in
ether (70 mL) was added dropwise boron trifluoride–
diethyl etherate (2.8 g, 19.7 mmol), followed by addition
of ethyl diazoacetate (3.2 g, 28.2 mmol) at 5 ꢁC and the
mixture was stirred at room temperature for 1 h. The reac-
tion mixture was diluted with ether (70 mL) and washed
with saturated aqueous NH4Cl solution (100 mL) and
brine (80 mL). The organic layer was separated, dried over
To a stirred solution of ketone 3 (0.79 g, 2.0 mmol) in ether
(7 mL) was added boron trifluoride–diethyl etherate
(0.31 g, 2.2 mmol), followed by addition of ethyl diazoace-
tate (0.34 g, 3.0 mmol) at 5 ꢁC and the mixture was stirred
at room temperature for 2 h. The reaction mixture was

2484
J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
anhydrous MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash column
chromatography (silica gel, 25% ethyl acetate in n-hexanes)
to give 9a and 9b and 10a and 10b as regioisomeric mix-
1H), 3.71 (dd, J = 7.5, 7.5 Hz, 1H), 2.85–2.62 (m, 2H),
2.60–2.43 (m, 2H), 1.43 (s, 1/2 · 9H), 1.36 (s, 1/2 · 9H);
13C NMR (CDCl3, 100 MHz): d 205.4, 169.8, 155.6,
136.2, 128.5, 128.2, 128.0, 82.7, 67.8, 55.2, 41.2, 40.3,
39.5, 27.8; HRMS calcd for C18H24NO5: 334.1654
[M+H]+, found: 334.1647.
tures (6.9 g, 90%) of bright yellow oil. Rf = 0.5 (25% ethyl
25
acetate/n-hexanes); ½aꢁD ¼ þ22:4 (c 1.0, CHCl3); IR (neat,
NaCl) 3034, 2979, 1733, 1714, 1668, 1630, 1407, 1310,
1155, 1066, 845 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d
4.8. N-Benzyloxycarbonyl-4-oxo-(S)-pipecolic acid 13
12.1 (s, 1H), 7.42–7.30 (m, 5H), 5.24 (dd, J = 13.0,
16.5 Hz, 2H), 5.16–5.06 (m, 1/2 · 1H), 5.02–4.94 (m,
1/2 · 1H), 4.24 (dd, J = 7.5, 7.5 Hz, 2H), 4.10–3.85 (m,
3/2 · 1H), 3.61 (dd, J = 7.0, 7.0 Hz, 1/2 · H), 2.98 (t,
J = 15.5 Hz, 2/3 · 1H), 2.80 (t, J = 17.5 Hz, 1/3 · 1H),
2.70 (dd, J = 6.0, 6.0 Hz, 1/3 · 1H), 2.52 (dd, J = 5.0,
5.0 Hz, 2/3 · 1H), 1.43 (s, 1/4 · 9H), 1.42 (s, 1/4 · 9H),
1.40 (s, 1/4 · 9H), 1.38 (s, 1/4 · 9H), 1.32 (d, J = 6.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz): d 171.0, 170.9, 169.5,
168.8, 167.4, 166.7, 166.5, 166.1, 155.5, 155.0, 136.1,
136.0, 128.4, 128.1, 127.9, 127.7, 94.9, 94.5, 94.1, 82.5,
82.4, 82.2, 68.3, 67.9, 67.7, 67.3, 61.0, 60.6, 53.6, 53.1,
52.9, 52.6, 44.0, 43.8, 39.4, 39.0, 30.6, 28.3, 28.2, 24.4,
24.1, 15.4, 14.6; HRMS calcd for C21H28NO7: 406.1866
[M+H]+, found: 406.1859.
To a stirred solution of 5-ketone 11 (0.25 g, 0.75 mmol) in
dichloromethane (4 mL) was added trifluoroacetic acid
(0.5 mL) at 5 ꢁC and the mixture was stirred at room tem-
perature for 2 h. The reaction mixture was evaporated in
vacuo, and the residue was diluted with dichloromethane
(35 mL) and washed with 2.5% aqueous NaHCO3 solution
(20 mL) and brine (20 mL). The organic layer was sepa-
rated, dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 50% ethyl ace-
tate in n-hexanes) to give 5-keto acid 13 (0.16 g, 95%) as
a colorless oil. Rf = 0.2 (50% ethyl acetate/n-hexanes);
25
½aꢁD ¼ þ0:4 (c 1.0, CHCl3); IR (neat, NaCl) 3600–3410,
3035, 2964, 1714, 1542, 1418, 1324, 1218, 1118, 1043,
879 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 8.67 (br s,
;
4.6. N-Benzyloxycarbonyl-5-oxo-(S)-pipecolic acid tert-
butyl ester 11
1H), 7.40–7.25 (m, 5H), 5.23–5.10 (m, 2H), 4.89 (t,
J = 6.4 Hz, 2/3 · 1H), 4.78 (t, J = 6.4 Hz, 1/3 · 1H), 4.42
(dd, J = 24.0, 18.8 Hz, 1H), 4.00 (d, J = 19.2 Hz, 1H),
2.58–2.34 (m, 3H), 2.32–2.15 (m, 1H); 13C NMR (CDCl3,
100 MHz): d 204.7, 176.1, 155.9, 135.5, 128.8, 128.6,
128.0, 68.4, 53.5, 51.9, 35.6, 23.3; HRMS calcd for
C14H16NO5: 278.1028 [M+H]+, found: 278.1049.
To a stirred solution of keto-enol tautomers 9a and 9b and
10a and 10b (4.1 g, 10.1 mmol) in dimethylsulfoxide
(10 mL) were added water (0.2 mL) and sodium chloride
(0.6 g, 10.1 mmol) at room temperature. The mixture was
heated at 140 ꢁC for 4 h, and cooled to room temperature.
The resulting reaction mixture was diluted with dichloro-
methane (150 mL) and washed with 50% aqueous NaCl
solution (3 · 50 mL). The organic layer was separated,
dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 20% ethyl acetate in
n-hexanes) to give 5-ketone 11 (1.5 g, 45%) and 4-ketone
4.9. N-Benzyloxycarbonyl-4-oxo-(S)-pipecolic acid 14
Bright yellow oil; yield (0.17 g, 97%). Rf = 0.2 (50% ethyl
25
acetate/n-hexanes); ½aꢁD ¼ ꢀ19:6 (c 1.0, CHCl3); IR (neat,
NaCl) 3433, 3034, 2961, 1727, 1704, 1542, 1423, 1317,
1251, 1186, 1057, 865 cmꢀ1
;
1H NMR (CDCl3, 400
MHz): d 9.30 (br s, 1H), 7.42–7.24 (m, 5H), 5.23–4.98
(m, 3H), 4.10 (t, J = 6.0 Hz, 1H), 4.68 (t, J = 6.0 Hz, 1H),
2.92–2.71 (m, 2H), 2.55–2.43 (m, 2H); 13C NMR (CDCl3,
100 MHz): d 206.0, 174.1, 156.0, 155.4, 135.8, 128.6,
128.4, 128.0, 68.3, 54.3, 53.5, 40.8, 40.3, 39.4; HRMS calcd
for C14H16NO5: 278.1028 [M+H]+, found: 278.1032.
12 (1.0 g, 30%) as a colorless oil. Rf = 0.27 (20% ethyl ace-
25
tate/n-hexanes); ½aꢁD ¼ ꢀ4:8 (c 1.0, CHCl3); IR (neat,
NaCl) 3034, 2977, 2857, 1733, 1711, 1414, 1251, 1153,
1046, 845 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 7.36–
;
7.27 (m, 5H), 5.14 (dq, J = 19.4, 12.4 Hz, 2H), 4.74 (t,
J = 6.5 Hz, 1/2 · 1H), 4.60 (t, J = 6.5 Hz, 1/2 · 1H), 4.38
(dd, J = 39.2, 19.0 Hz, 1H), 3.94 (dd, J = 26.4, 19.0 Hz,
1H), 2.50–2.03 (m, 4H), 1.44 (s, 1/2 · 9H), 1.36 (s, 1/2 ·
9H); 13C NMR (CDCl3, 100 MHz): d 204.9, 204.8, 170.5,
170.4, 155.5, 155.3, 136.0, 128.5, 128.2, 128.0, 127.9, 82.3,
67.7, 54.5, 54.1, 52.2, 51.8, 35.7, 35.5, 28.0, 27.9, 23.8,
23.7; HRMS calcd for C18H24NO5: 334.1654 [M+H]+,
found: 334.1645.
4.10. General procedure for the preparation of N-benzyloxy-
carbonyl-(2S,5S)-5-hydroxypipecolic acid tert-butyl ester
15a and N-benzyloxycarbonyl-(2S,5R)-5-hydroxypipecolic
acid tert-butyl ester 15b
To a stirred solution of 5-ketone 11 (0.33 g, 1.0 mmol) in
the appropriate solvent (10 mL) was slowly added a reduc-
ing agent (1.2 mmol) at ꢀ78 to 0 ꢁC. After the reaction was
completed, the mixture was quenched with saturated aque-
ous NH4Cl solution (5 mL) and diluted with ethyl acetate
(15 mL). The organic layer was separated, dried over anhy-
drous MgSO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(silica gel, 45% ethyl acetate in n-hexanes) to give cis-5-
hydroxypipecolate 15a and trans-5-hydroxypipecolate
4.7. N-Benzyloxycarbonyl-4-oxo-(S)-pipecolic acid tert-
butyl ester 12
Bright yellow oil. Rf = 0.24 (20% ethyl acetate/n-hex-
25
anes); ½aꢁD ¼ ꢀ15:4 (c 1.0, CHCl3); IR (neat, NaCl) 3033,
2978, 2875, 1732, 1707, 1414, 1247, 1155, 1058, 845 cmꢀ1
;
1H NMR (CDCl3, 400 MHz): d 7.38–7.28 (m, 5H), 5.16
(dd, J = 12.4, 12.8 Hz, 2H), 5.03 (d, J = 6.5 Hz, 1/2 · 1H),
4.86 (t, J = 5.5 Hz, 1/2 · 1H), 4.11 (dd, J = 8.0, 7.5 Hz,
15b. Compound 15a: viscous oil. Rf = 0.41 (45% ethyl acet-
26
ate/n-hexanes); ½aꢁD ¼ ꢀ27:9 (c 2.0, CHCl3); IR (neat,

J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
2485
NaCl) 3343, 3033, 2976, 2941, 2871, 1728, 1707, 1499,
1420, 1330, 1236, 1147, 1073, 847 cmꢀ1; 1H NMR (CDCl3,
400 MHz): d 7.40–7.26 (m, 5H, Ar–H), 5.13 (dd, J = 12.8,
12.4 Hz, 2H, Bn), 4.78 (d, J = 3.4 Hz, 1/2 · 1H, H–2), 4.65
(d, J = 3.4 Hz, 1/2 · 1H, H–2), 4.20 (dd, J = 12.0, 14.4 Hz,
1H, H–5), 3.70–3.55 (m, 1H, H–6), 2.88 (t, J = 11.6 Hz,
1/2 · 1H, H–6), 2.78 (t, J = 11.2 Hz, 1/2 · 1H, H–6), 2.39
(br s, OH), 2.27 (t, J = 11.5 Hz, 1H, H–3), 1.97 (d, J =
12.0 Hz, 1H, H–4), 1.47 (s, 1/2 · 9H, t-Bu), 1.43 (s,
1/2 · 9H, t-Bu), 1.27 (dt, J = 6.0, 6.8 Hz, 1H, H-4); 13C
NMR (CDCl3, 100 MHz): d 170.1, 155.9, 136.5, 128.6,
128.0, 127.9, 81.9, 67.4, 66.6, 60.4, 54.2, 53.9, 48.1, 30.3,
29.9, 25.1, 24.9, 21.0; HRMS calcd for C18H25NO5Na:
358.1630 [M+Na]+, found: 358.1642. Compound 15b:
J = 13.5 Hz, 1H), 1.56 (t, J = 13.5 Hz, 1H); 13C NMR
(acetone-d6, 125 MHz): d 172.0, 156.4, 156.8, 137.1,
128.2, 127.6, 127.4, 66.7, 62.9, 54.2, 53.9, 47.8, 47.6, 27.4,
27.3, 20.5; HRMS calcd for C14H17NO5Na: 302.1004
[M+Na]+, found: 302.1019.
4.13. Benzyl 3-oxo-2-oxa-5-azabicyclo[2.2.2]octane-5-carb-
oxylate 17
To a stirred solution of cis-alcohol 15a (0.1 g, 0.3 mmol) in
benzene (4 mL) was added p-toluenesulfonic acid mono-
hydrate (0.01 g) and the mixture was refluxed for 1 h. The
reaction mixture was diluted with ethyl acetate (20 mL)
and washed with 5% aqueous sodium bicarbonate solution
(2 · 10 mL). The organic layer was separated, dried over
anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica gel, 45% ethyl acetate in n-hexanes)
viscous oil. Rf = 0.35 (45% ethyl acetate/n-hexanes);
26
½aꢁD ¼ ꢀ19:6 (c 2.0, CHCl3); IR (neat, NaCl) 3346, 3034,
2976, 2939, 1732, 1702, 1499, 1424, 1325, 1249, 1146,
1084, 849 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 7.40–
;
7.28 (m, 5H, Ar–H), 5.13 (dd, J = 12.4, 12.0 Hz, 2H, Bn),
4.89 (d, J = 3.0 Hz, 1/2 · H, H-2), 4.76 (d, J = 3.0 Hz,
1/2 · H, H–2), 4.1 (dd, J = 13.6, 13.6 Hz, 1H, H-5), 3.98
(d, J = 36.8 Hz, 1H, H-6), 3.33 (d, J = 14.0 Hz, 1/2 · H,
H-6), 2.21 (d, J = 14.0 Hz, 1/2 · H, H-6), 2.16 (br s, OH),
2.27–1.88 (m, 2H, H-3), 1.80 (d, J = 14.4 Hz, 1H, H-4),
1.54 (d, J = 14.0 Hz, 1H, H-4) 1.47 (s, 1/2 · 9H, t-Bu),
1.43 (s, 1/2 · 9H, t-Bu); 13C NMR (CDCl3, 100 MHz):
d 170.4, 156.8, 136.5, 128.5, 128.0, 127.8, 81.8, 67.4, 63.7,
54.9, 53.5, 47.8, 30.0, 27.1, 26.7, 20.3; HRMS calcd for
C18H25NO5Na: 358.1630 [M+Na]+, found: 358.1645.
to give N-Cbz lactone 17 (68 mg, 86%) as a colorless oil.
26
Rf = 0.35 (45% ethyl acetate/n-hexanes); ½aꢁ ¼ ꢀ10:0
(c 2.0, CHCl3); IR (neat, NaCl) 3034, 2947, 2D889, 1771,
1
1707, 1418, 1348, 1292, 1136, 1080, 852 cmꢀ1; H NMR
(CDCl3, 400 MHz): d 7.40–7.30 (m, 5H), 5.17 (s, 2H),
4.89–4.68 (m, 2H), 3.71 (d, J = 11.6 Hz, 1H), 3.53 (d,
J = 11.6 Hz, 1H), 2.30–2.18 (m, 1H), 2.17–1.97 (m, 2H),
1.81 (t, J = 12.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d 169.7, 154.3, 136.0, 128.6, 128.4, 128.3, 128.1, 73.6,
67.7, 50.5, 49.7, 47.5, 24.5, 23.6; HRMS calcd for
C14H15NO4Na: 284.0899 [M+Na]+, found: 284.0913.
4.11. N-Benzyloxycarbonyl-(2S,5S)-5-hydroxypipecolic acid
16a
4.14. N-Benzyloxycarbonyl-(2S,4R)-4-hydroxypipecolic acid
tert-butyl ester (18a)
Acids 16a and 16b were prepared from cis-alcohol 15a and
trans-alcohol 15b by the procedure described previously for
preparing the acids 13 and 14, respectively. Compound
Viscous oil; yield 86%. Rf = 0.35 (50% ethyl acetate/n-hex-
26
anes); ½aꢁD ¼ ꢀ39:2 (c 2.0, CHCl3); IR (neat, NaCl) 3469,
3034, 2976, 2893, 1735, 1702, 1420, 1349, 1279, 1159,
1
16a: yield; 88%. Rf = 0.1 (50% ethyl acetate/n-hexanes);
1086, 850 cmꢀ1; H NMR (CDCl3, 400 MHz): d 7.40–7.25
24
mp 131–132 ꢁC; ½aꢁD ¼ 76:5 (c 0.17, MeOH); IR (neat,
(m, 5H), 5.26–5.02 (m, 2H), 4.75 (d, J = 4.5 Hz, 1/2 ·
1H), 4.63 (d, J = 4.5 Hz, 1/2 · 1H), 5.13 (s, 1H), 3.92 (t,
J = 18.0 Hz, 1H), 3.48 (t, J = 12.8 Hz, 1/2 · 1H), 3.39 (t,
J = 12.8 Hz, 1/2 · 1H), 2.50–2.25 (m, 2H), 1.88 (br s, 1H),
1.87–1.85 (m, 2H), 1.45 (s, 1/2 · 9H), 1.43 (s, 1/2 · 9H);
13C NMR (CDCl3, 100 MHz): d 170.5, 156.2, 136.7,
128.4, 128.1, 128.0, 127.9, 81.6, 67.2, 63.2, 54.9, 52.1, 51.8,
40.6, 35.8, 33.2, 31.2, 27.9; HRMS calcd for C18H26NO5:
336.1811 [M+H]+, found: 336.1824.
NaCl) 3270, 3035, 2922, 1737, 1592, 1420, 1246, 1122,
1
1081, 854 cmꢀ1; H NMR (DMSO-d6, 500 MHz): d 10.52
(br s, 1H), 7.42–7.25 (m, 5H), 5.17 (s, 2H), 4.92 (d,
J = 5.5 Hz, 1H), 4.75 (br s, 1H), 4.10 (d, J = 14.0 Hz,
1H), 3.98 (d, J = 18.0 Hz, 1H), 3.32–3.13 (m, 1H), 2.35–
2.22 (m, 1H), 1.95 (t, J = 13.0 Hz, 1H), 1.72 (d,
J = 13.5 Hz, 1H), 1.58 (t, J = 13.5 Hz, 1H); 13C NMR
(DMSO-d6, 125 MHz): d 171.9, 156.1, 155.9, 137.3, 128.4,
128.0, 127.6, 66.8, 61.5, 54.1, 53.7, 47.9, 47.5, 27.5, 27.3,
20.8; HRMS calcd for C14H17NO5Na: 302.1004
[M+Na]+, found: 302.1012.
4.15. N-Benzyloxycarbonyl-(2S,4R)-4-hydroxypipecolic acid
19a
4.12. N-Benzyloxycarbonyl-(2S,5R)-5-hydroxypipecolic acid
16b
Acid 19a was prepared from 18a through hydrolysis similar
to procedure for acid 16a. White foam; yield 90%. Rf = 0.1
26
(50% ethyl acetate/n-hexanes); ½aꢁD ¼ ꢀ17:1 (c 2.0,
Semisolid; yield; 88%. Rf = 0.1 (50% ethyl acetate/n-hex-
MeOH); IR (neat, NaCl) 3423, 2925, 2856, 1682, 1431,
28
anes); ½aꢁD ¼ ꢀ7:2 (c 1.0, MeOH); IR (neat, NaCl) 3400,
1357, 1282, 1142, 1084, 850 cmꢀ1 1H NMR (CDCl3,
;
3201, 3033, 2946, 1737, 1681, 1498, 1324, 1238, 1132,
400 MHz): d 7.40–7.31 (m, 5H), 5.14 (d, J = 12.0 Hz,
2H), 4.90 (br s, 1H), 4.12 (s, 1H), 3.86 (d, J = 7.0 Hz,
1H), 3.69–4.42 (m, 1H), 2.49 (t, J = 7.5 Hz, 1H), 1.88 (d,
J = 6.0 Hz, 1H), 1.79–1.58 (m, 3H); 13C NMR (CDCl3,
100 MHz): d 171.9, 155.4, 141.9, 128.5, 128.1, 127.6, 66.8,
62.5, 54.3, 51.4, 36.0, 33.0, 31.2; HRMS calcd for
C14H17NO5Na: 302.1004 [M+Na]+, found: 302.1015.
1067, 856 cmꢀ1
;
1H NMR (acetone-d6, 500 MHz): d
10.45 (br s, 1H), 7.44–7.29 (m, 5H), 5.15 (s, 2H), 4.90
(dd, J = 4.5, 4.5 Hz, 1H), 4.87 (br s, 1H), 4.07 (d,
J = 13.5 Hz, 1H), 3.96 (d, J = 27.0 Hz, 1H), 3.31 (d,
J = 13.5 Hz, 2/3 · 1H), 3.17 (d, J = 14.0 Hz, 1/3 · 1H),
2.32–2.23 (m, 1H), 1.99 (t, J = 14.0 Hz, 1H), 1.75 (d,

2486
J.-C. Jung, M. A. Avery / Tetrahedron: Asymmetry 17 (2006) 2479–2486
lardo, L.; Roumestant, M. L.; Viallefont, P. Tetrahedron:
Acknowledgements
Asymmetry. 1996, 7, 2585–2593; (c) Shirude, P.; Kumar,
V. A.; Ganesh, K. N. Tetrahedron 2004, 60, 9485–
9491.
This work has been supported by the University of Missis-
sippi and CDC Grant.
4. Corre, L. L.; Dhimane, H. Tetrahedron Lett. 2005, 46, 7495–
7497.
5. Machetti, F.; Cordero, F. M.; De Sarlo, F.; Papini, A. M.;
Alcaro, M. C.; Brandi, A. Eur. J. Org. Chem. 2004, 2928–
2935.
References
6. Nardo, C. D.; Varela, O. J. Org. Chem. 2004, 64, 6119–
6125.
7. Huang, L.; Brinen, L. S.; Ellman, J. A. Bioorg. Med. Chem.
2003, 11, 21–29.
8. Bridges, R. J.; Stanley, M. S.; Anderson, M. W.; Cotman,
C. W.; Chamberlin, A. R. J. Med. Chem. 1991, 34, 717–
725.
9. Tamaki, M.; Han, G.; Hruby, V. J. J. Org. Chem. 2001, 66,
3593–3596.
10. Pellicciari, R.; Natalini, B.; Luneia, R.; Marinozzi, M.;
Roberti, M.; Rosato, G. C.; Sadeghpour, B. M.; Synyder, J.
P.; Monahan, J. B.; Moroni, F. Med. Chem. Res. 1992, 2,
491–496.
11. Levins, C. G.; Schafmeister, C. E. J. Am. Chem. Soc. 2003,
125, 4702–4703.
1. (a) Despontin, J.; Marlier, M.; Dardenne, G. Phytochemistry
1977, 16, 387–388; (b) Mester, L.; Szabados, L.; Mester, M.;
Yadav, N. Planta Med. 1979, 35, 339–341; (c) Fujii, T.;
Murai, M.; Morimoto, H.; Maeda, Y.; Yamaoka, M.;
Hagiwara, D.; Miyake, H.; Ikari, N.; Matsuo, M. Br. J.
Pharmacol. 1992, 107, 785–789; (d) Koehn, F. E.; McConnell,
O. J.; Longley, R. E.; Sennett, S. H.; Reed, J. K. J. Med.
Chem. 1994, 37, 3181–3816; (e) Hays, S. J.; Malone, T. C.;
Johnson, G. J. Org. Chem. 1991, 56, 4084–4086; (f) Beaulieu,
P. L.; Lavallee, P.; Abraham, A.; Anderson, P. C.; Boucher,
C.; Bousquet, Y.; Duceppe, J. S.; Gillard, J.; Gorys, V.;
Grand-Maitre, C.; Grenier, L.; Guse, I.; Plamondon, L.;
Soucy, F.; Valois, S.; Wernic, D.; Yoakim, C. J. Org. Chem.
1997, 62, 3440–3448; (g) Barluenga, J.; Aznar, F.; Valdes, C.;
Ribas, C. J. Org. Chem. 1998, 63, 3918–3924.
12. (a) Liu, H. J.; Ogino, T. Tetrahedron Lett. 1973, 4937–4940;
(b) Krapcho, A. P.; Jahngen, E. G. E., Jr.; Lovey, A. J.;
Short, F. W. Tetrahedron Lett. 1974, 1091–1094.
13. Vuljanic, T.; Kihlberg, J.; Somfai, P. J. Org. Chem. 1998, 63,
279–286.
14. Perrin, D. D.; Armarego, L. F.; Perrin, D. R. Purification of
Laboratory Chemicals, 2nd ed.; Pergamon Press: New York,
1980.
2. (a) Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A.
Curr. Opin. Chem. Biol. 1997, 1, 47–53; (b) Marx, M. A.;
Grillot, A. L.; Louer, C. T.; Beaver, K. A.; Bartlett, P. A.
J. Am. Chem. Soc. 1997, 119, 6153–6167; (c) Booth, S.;
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1998, 54, 15385–15443.
3. (a) Bailey, P. D.; Bryans, J. S. Tetrahedron Lett. 1988,
29, 2231–2234; (b) Hoarau, S.; Fauchere, J. L.; Pappa-