Enantioselective synthesis of Nα-Fmoc protected (2S,3R)-3-phenylpipecolic acid. A constrained phenylalanine analogue suitably protected for solid-phase peptide synthesis

Article abstract of DOI:10.1021/jo010124+

Reported herein is the first enantioselective preparation of (2S,3R)-3-phenylpipecolic acid as a conformationally constrained phenylalanine analogue bearing N^α-protection suitable for solid-phase peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-1,3-oxazolidin-2-one. By constraining φ and χ¹ torsion angles, this novel amino acid analogue can serve as a useful tool for the induction of defined geometry in phenylalanine-containing peptides.

Full text of DOI:10.1021/jo010124+

1448
J . Org. Chem. 2002, 67, 1448-1452
En a n tioselective Syn th esis of Nr-F m oc P r otected
(2S,3R)-3-P h en ylp ip ecolic Acid . A Con str a in ed P h en yla la n in e
An a logu e Su ita bly P r otected for Solid -P h a se P ep tid e Syn th esis
Ding-Guo Liu, Yang Gao, Xiangzhu Wang, J ames A. Kelley, and Terrence R. Burke, J r.*
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bldg. 376, Boyles Street, NCI-Frederick, P.O. Box B,
Frederick, Maryland 21702-1201
tburke@helix.nih.gov
Received J anuary 30, 2001
Reported herein is the first enantioselective preparation of (2S,3R)-3-phenylpipecolic acid as a
conformationally constrained phenylalanine analogue bearing NR-protection suitable for solid-phase
peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a
single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-
1,3-oxazolidin-2-one. By constraining φ and ø1 torsion angles, this novel amino acid analogue can
serve as a useful tool for the induction of defined geometry in phenylalanine-containing peptides.
Biological activities of peptides are highly dependent
on backbone conformation and on the three-dimensional
orientation of amino acid side chains. Accordingly, induc-
tion of “biologically active conformations” in peptides and
peptide mimetics is an important area of investigation
that frequently entails utilization of constrained amino
acid analogues.1-3 In the case of phenylalanine (1),
important design considerations may include restriction
of side chain ø1 and ø2 torsion angles as well as the φ
torsion angle between CR and NR positions. A number of
cyclic conformationally constrained phenylalanine de-
rivatives have been reported.4 These include exocyclic NR
analogues 2,5 3,6 and 4,7 which constrain ø1, ø2, and both
ø1and ø2 angles, respectively, as well as endocyclic NR
analogue 5,8 which simultaneously constrains ø1, ø2, and
φ torsion angles (Figure 1). Pipecolic acid substituted with
a phenyl group at the 3-position (6, Figure 1) represents
an endocyclic NR phenylalanine analogue having its ø1
and φ angles constrained. Recent use of a C-3-substituted
pipecolic acid as an amino acid analogue in solid-phase
synthesis9 highlights the potential utility of the pipecolic
acid nucleus in the design of constrained amino acid
analogues. Despite its potential versatility as a confor-
mationally constrained phenylalanine analogue, to date
3-phenylpipecolic acid has been described only as a
F igu r e 1. Structures of selected ring-utilizing conformation-
ally constrained phenylalanine analogues.
racemic mixture of diastereomers.10 We report herein the
first enantioselective synthesis of NR-Fmoc protected
(2S,3R)-3-phenylpipecolic acid (7) as a constrained phen-
ylalanine analogue suitably protected for use in solid-
phase peptide synthesis.
* To whom correspondence should be addressed. Tel: (301) 846-
5906; Fax: (301) 846-6033.
Syn th esis
(1) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359-1472.
(2) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 441-
452.
(3) Hruby, V. J .; Balse, P. M. Curr. Med. Chem. 2000, 7, 945-970.
(4) Gibson, S. E.; Guillo, N.; Tozer, M. J . Tetrahedron 1999, 55, 585-
615.
Introduction of chirality at both the 2- and 3-positions
was achieved through sequential stereochemical induc-
tion originating from commercially available Evans
auxiliary 911 (Scheme 1). The first stereocenter to be
introduced was at the 3-position. Beginning with known
1012 allowed 1,4-addition of the allylic functionality to
be achieved diastereoselectively via a copper bromide-
(5) Cativiela, C.; Avenoza, A.; Pars, M.; Peregrina, J . M. J . Org.
Chem. 1994, 59, 7774-7778.
(6) J osien, H.; Chassaing, G. Tetrahedron: Asymmetry 1992, 3,
1341-1354.
(7) Schiller, P. W.; Weltrowska, G.; Nguyen, T. M. D.; Lemieux, C.;
Chung, N. N.; Marsden, B. J .; Wilkes, B. C. J . Med. Chem. 1991, 34,
3125-3132.
(10) Pillai, K. M. R.; Kapil, R. S.; Nand, N. Ind. J . Chem. 1990, 29B,
892-894.
(8) J ulian, P. L.; Karpel, W. J .; Magnani, A.; Meyer, E. W. J . Am.
Chem. Soc. 1948, 70, 180-183.
(11) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011-4030.
(9) Souers, A. J .; Ellman, J . A. J . Org. Chem. 2000, 65, 1222-1224.
(12) Ru¨ck, K.; Kunz, H. Synthesis 1993, 10, 1018-1028.
10.1021/jo010124+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/08/2002

NR-Fmoc Protected (2S,3R)-3-Phenylpipecolic Acid
J . Org. Chem., Vol. 67, No. 5, 2002 1449
Sch em e 1a
Sch em e 2a
a
(a) TBSCl, imidazole, DMF, 95%; (b) [(CH3)3Si]2NK, trisyl
azide, THF, -78 °C, then HOAc, KOAc, 30-35 °C, 92%; (c)
HF‚pyridine, THF, 0 °C, 95%; (d) TsCl, pyridine, 0 °C, 39%; (e) (i)
Ph3P, H2O, THF; (ii) NaOAc, EtOH, reflux.
hexamethyldisilazide followed by treatment first with
2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) and
then with acetic acid. Azide 14 resulted upon exposure
to potassium acetate at 30-35 °C. Hydrogenation of 14
(30 psi H2 over 10% Pd‚C) gave amino alcohol 15 along
with benzyl-containing 16, which was converted to 15 by
further hydrogenation in the presence of acetic acid. In
an effort to effect a direct ring closure of 15 to 18,
Kilonda’s cyclization protocol was employed.18 Here,
amino alcohol 15 was initially protected in situ as its
methanesulfonate salt. Bromination of the primary al-
cohol was then attempted using Ph3P and CBr4. Unex-
pectedly, bromination failed. As an alternative, chemose-
lective tosylation of the hydroxyl group was achieved by
treatment of 15 with TsCl/pyridine at 0 °C to afford 17
in 48% yield. The failed bromination, together with a low
yield of tosylation, suggested unusual steric crowding.
This was substantiated when refluxing 17 with NaHCO3
in acetonitrile provided the desired piperidine derivative
18 in very low yield (16%).
The low yield of cyclized product combined with a
cumbersome multistep benzylation/debenzylation proce-
dure led us to examine alternative approaches toward
18. As shown in Scheme 2, protection of alcohol 12 as its
tert-butyldimethylsilyl (TBS) ether 19, followed by asym-
metric azidation, provided 20 in 92% yield. When sub-
sequently attempted removal of the TBS group using
tetrabutylammonium fluoride (TBAF) gave a complex
mixture resulting from partial removal of the Evans
auxiliary, a milder reagent (HF‚pyridine) was employed.19
This effected smooth removal of the TBS group to provide
alcohol 21 in 95% yield. Tosylation of 21 to 22 (39% yield),
followed by reduction with Ph3P and treatment with base,
disappointingly failed to give the desired 18.
a
(a) 9, n-BuLi, 8, THF, -78 °C, 90%; (b) allylmagnesium
bromide, CuBr‚Me2S, THF, -78 °C, 98%; (c) (i) BH3, THF, 0 °C;
(ii) NaBO3‚H2O, H2O, 65%; (d) Ag2O, BnBr, CH2Cl2, 100%; (e)
[(CH3)3Si]2NK, trisyl azide, -78 °C, then HOAc, KOAc, 30-35 °C,
73%; (f) 10% Pd‚C, EtOH, H2 (30 psi); (g) 10% Pd‚C, EtOH, HOAc,
H2 (30 psi), 60%; (h) TsCl, pyridine, 0 °C, 48%; (i) NaHCO3,
CH3CN, reflux, 16%.
dimethyl sulfide complex, providing known 11 in 98%
yield.13,14 It was envisioned that stereoselective creation
of a 2-amino group could be readily accomplished by
known procedures. This would then allow piperidine ring
formation via nucleophilic attack onto the three carbon
chain originating from the 3-position following suitable
derivatization. Therefore, a multistep approach was used
to introduce this latter functionality. Hydroboration of
alkene 11 at 0 °C, followed by sodium perborate oxida-
tion,15 gave alcohol 12 in 65% yield over two steps. To
minimize potential base-catalyzed lactonization during
subsequent benzylation, mild conditions were employed
(Ag2O and BnBr)16 to afford 13 in 100% yield based on a
quantitative recovery of unreacted 12. Introduction of a
2-amino functionality was initiated by asymmetric azi-
dation at the C-R position according to the method of
Evans.17 This involved enolization of 13 with potassium
(13) Wu, M. J .; Wu, C. C.; Lee, P. C. Tetrahedron Lett. 1992, 33,
2547-2548.
(14) Chang, C. J .; Fang, J . M.; Liao, L. F. J . Org. Chem. 1993, 58,
1754-1761.
Since satisfactory ring closure by nucleophilic displace-
ment had proven to be unsuccessful in two attempts
(15) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J . Org. Chem.
1989, 54, 5930-5933.
(16) Bouzide, A.; Sauve´, G. Tetrahedron Lett. 1997, 38, 5945-5948.
(17) Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Fru¨h, T.;
Whittingham, W. G.; DeVries, K. M. Tetrahedron Lett. 1992, 33, 1189-
1192.
(18) Kilonda, A.; Compernolle, F.; Hoornaert, G. J . J . Org. Chem.
1995, 60, 5820-5824.
(19) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 3, 453-461.

1450 J . Org. Chem., Vol. 67, No. 5, 2002
Liu et al.
Sch em e 3a
drying. Analytical HPLC was conducted using a Vydac C18
Peptide & Protein column (10 mm ID × 250 mm; solvent A )
0.1% aqueous TFA; solvent B ) 0.1% TFA in acetonitrile; flow
rate ) 2 mL/min.). Unless otherwise indicated, 1H NMR were
run at 250 MHz. Positive ion FAB mass spectra (FABMS) were
obtained on a VG-7070-EHF mass spectrometer using either
glycerol or 3-nitrobenzyl alcohol as the matrix. For compounds
so indicated, accurate mass measurement of the protonated
molecule (MH+) and other structurally diagnostic ions was
carried out at a resolution of 3500 employing a limited range
voltage scan under data system control. The appropriate FAB
matrix ions were used for internal mass reference. The
measured accurate mass, in conjunction with the structural
constraints imposed by other chemical information, allowed
calculation of a unique elemental composition for each com-
pound.
(4S)-3-((3S)-3-P h en ylh ex-5-en oyl)-4-b en zyl-1,3-oxa zo-
lid in -2-on e (11). To a slurry of CuBr‚SMe2 (1.0 g, 4.88 mmol)
in THF (20 mL) was added a solution of allylmagnesium
bromide (8.4 mL, 8.4 mmol) at -78 °C under argon, and the
resulting mixture was stirred at -78 °C (1.5 h). A solution of
1012 (1.0 g, 3.25 mmol) in THF (30 mL) was added to the above
mixture at -78 °C, and stirring was continued (2.5 h). The
reaction was quenched by addition of saturated NH4Cl; the
mixture was extracted with ethyl acetate, and this extract was
evaporated to a residue, which was purified by silica gel flash
chromatography (ethyl acetate:hexane, 1:8) to afford 1113 as
a
(a) oxalyl chloride, DMSO, CH2Cl2, -78 °C, then NEt3, 100%;
(b) 10% Pd‚C, HCO2NH4, MeOH, 17%; (c) 10% Pd‚C, H2 (40 psi),
MeOH, 52%; (d) (i) 1 N NaOH, 1,4-dioxane, H2O, 0 °C; (ii) CO2(s),
Fmoc-OSu, 40%.
(Schemes 1 and 2), an alternative cyclization strategy was
explored that relied on imine formation (Scheme 3). Azido
alcohol 21 was subjected to Swern oxidation,20 with
resulting aldehyde 23 then being ring closed by reductive
amination using 10% Pd‚C and ammonium formate. This
provided piperidine compound 18 in 17% yield ac-
companied by free Evans reagent (9). Use of more
vigorous conditions (hydrogenating aldehyde 23 at 40 psi
H2 over 10% Pd‚C), gave methyl ester 24 as the main
product in 52% yield (no 18 was detected). Ester 24 was
readily converted by known procedures21,22 to a mixture
of Fmoc protected products, with purification by HPLC
providing 7 as a white solid.
a white solid (1.1 g, 98% yield), mp ) 90.6-91.8 °C, [R]22
)
D
1
+64.7 (c 2.22, CHCl3). H NMR (CDCl3) δ: d 7.17-7.37 (10H,
m), 5.73 (1H, ddt, J ) 16.9, 10.0, 7.1 Hz), 4.99-5.10 (2H, m),
4.09 (1H, dd, J ) 9.0, 2.7 Hz), 4.01 (1H, m), 3.23-3.48 (3H,
m), 3.22 (1H, dd, J ) 13.4, 3.4 Hz), 2.67 (1H, dd, J ) 13.4,
10.0 Hz), 2.48 (2H, t, J ) 7.1 Hz).
(4S)-3-((3S)-6-H yd r oxy-3-p h en ylh exa n oyl)-4-b en zyl-
1,3-oxa zolid in -2-on e (12). To a solution of 11 (1.0 g, 2.9
mmol) in THF (8 mL) was added under argon BH3, 1.0 M in
THF, (2.9 mL, 2.9 mmol) at 0 °C, and the mixture was stirred
at 0 °C (1 h). To the mixture was then added H2O (8 mL) and
NaBO3‚H2O (290 mg, 2.9 mmol), and the mixture was warmed
to room temperature and stirred (3 h). The mixture was diluted
with ethyl acetate, subjected to an extractive workup (ethyl
acetate), and evaporated to a residue, which was purified by
silica gel flash chromatography (ethyl acetate:hexane, from 1:4
Con clu sion s
Reported herein is the first enantioselective prepara-
tion of (2S,3R)-3-phenylpipecolic acid bearing NR-protec-
tion suitable for solid-phase peptide synthesis. Because
the stereochemistries at both the 3- and 2-positions are
derived inductively from a single chiral center provided
by a commercially available Evans chiral auxiliary, (4S)-
4-benzyl-1,3-oxazolidin-2-one, the optical antipode of the
product reported herein ((2R,3S)-3-phenylpipecolic acid),
would theoretically be readily obtainable starting from
commercially available (4R)-4-benzyl-1,3-oxazolidin-2-
one. With synthetic access to the pipecolic nucleus
bearing (2S)-configuration at the NR-center provided, a
new conformationally constrained phenylalanine ana-
logue results with the same absolute configuration as
naturally occurring phenylalanine. This novel amino acid
analogue provides a useful platform for the induction of
defined geometry in phenylalanine-containing peptides.
to 3:4) to afford 12 as a white solid (687 mg, 65% yield), mp )
1
106-108 °C, [R]20 ) +58.6 (c 1.26, CHCl3). H NMR (CDCl3)
D
δ: d 7.15-7.35 (10H, m), 4.50 (1H, m), 4.09 (1H, dd, J ) 9.0,
2.7 Hz), 4.01 (1H, m), 3.62 (2H, t, J ) 6.6 Hz), 3.16-3.43 (4H,
m), 2.67 (1H, dd, J ) 13.4, 10.0 Hz), 1.78 (2H, m), 1.49 (2H,
m). FABMS, m/z: 368 (MH+). Anal. Calcd for C22H25NO4: C,
71.91; H, 6.86; N, 3.81. Found: C, 71.74; H, 6.76; N, 3.81.
(4S)-3-[(3S)-3-P h en yl-6-(p h en ylm eth oxy)h exa n oyl]-4-
ben zyl-1,3-oxa zolid in -2-on e (13). To a solution of 12 (485
mg, 1.32 mmol) in CH2Cl2 (3 mL) were added Ag2O (460 mg,
1.98 mmol) and BnBr (0.24 mL, 1.98 mmol). The mixture was
stirred (2 days), filtered, and evaporated to a residue, which
was purified by silica gel flash chromatography (ethyl acetate:
hexane, from 1:10 to 1:1) to afford 13 as a viscous oil (224 mg,
100% yield based on recovered starting 12 (306 mg)), [R]21
)
D
1
+41.7 (c 0.69, CHCl3). H NMR (CDCl3) δ: d 7.15-7.40 (15H,
m), 4.48 (1H, m), 4.47 (2H, s), 4.07 (1H, dd, J ) 9.0, 2.7 Hz),
3.98 (1H, m), 3.44 (2H, t, J ) 6.6 Hz), 3.40 (1H, m), 3.17-3.32
(3H, m), 2.66 (1H, dd, J ) 13.4, 10.0 Hz), 1.80 (2H, m), 1.55
Exp er im en ta l Section
(2H, m). FABMS, m/z: 458 (MH+). Anal. Calcd for C29H31
-
Gen er a l P r oced u r es. Elemental analyses were obtained
from Atlantic Microlab, Inc., Norcross, GA. Solvent was
removed by rotary evaporation under reduced pressure, and
silica gel chromatography was performed using high perfor-
mance silica gel (60 Å pore, 10 µ particle size). Anhydrous
solvents were obtained commercially and used without further
NO4: C, 76.12; H, 6.83; N, 3.06. Found: C, 76.22; H, 6.96; N,
2.86.
1-[(4S)-2-Oxo-4-b en zyl(1,3-oxa zolid in -3-yl)](2S,3R)-2-
a zid o-3-p h en yl-6-(p h en ylm eth oxy)h exa n -1-on e (14). To a
solution of [(CH3)3Si]2NK (0.5 M in toluene, 2.4 mL, 1.20 mmol)
in THF (4 mL) was added under argon a solution of 13 (474
mg, 1.04 mmol) in THF (3 mL) at -78 °C, and the mixture
was stirred at -78 °C (40 min). To the mixture was added a
cooled solution (-78 °C) of trisyl azide (386 mg, 1.25 mmol) in
THF (3 mL), and the mixture was stirred at -78 °C (2 min).
The reaction was quenched by addition of AcOH (0.3 mL, 5.2
mmol) and KOAc (1.02 g, 10.4 mmol), and the mixture was
(20) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(21) Carpino, L. A.; Han, G. Y. J . Am. Chem. Soc. 1970, 92, 5748-
5749.
(22) Burke, T. R., J r.; Knight, M.; Chandrasekhar, B. Tetrahedron
Lett. 1989, 30, 519-522.

NR-Fmoc Protected (2S,3R)-3-Phenylpipecolic Acid
J . Org. Chem., Vol. 67, No. 5, 2002 1451
stirred at 30-35 °C (1.5 h). Ethyl acetate was added, and the
mixture was washed with saturated NaHCO3, H2O, and brine;
then, the organic phase was dried (Na2SO4) and evaporated
to a residue. Purification by silica gel flash chromatography
(ethyl acetate:hexane, from 1:20 to 1:5) afforded 14 as a
and the mixture was stirred at room temperature (5 h). DMF
was evaporated, and the resulting residue was dissolved in
ethyl acetate (100 mL). This solution was washed with
saturated NaHCO3, H2O, and brine, and then the organic
phase was dried (Na2SO4) and evaporated to a provide a
residue. Purification by silica gel flash chromatography (ethyl
acetate:hexane, from 1:20 to 1:4) afforded 19 as a white solid
colorless oil (377 mg, 73% yield), [R]20 ) +137.4 (c 0.94,
D
1
CHCl3). H NMR (CDCl3) δ: d 7.13-7.36 (15H, m), 5.30 (1H,
d, J ) 10.0 Hz), 4.47 (2H, s), 4.03 (1H, m), 3.91 (1H, dd, J )
9.0, 1.8 Hz), 3.45 (2H, t, J ) 6.6 Hz), 3.41 (1H, m), 3.10-3.23
(2H, m), 2.68 (1H, dd, J ) 13.4, 9.8 Hz), 2.20 (1H, m), 1.92
(1H, m), 1.47-1.56 (2H, m). FABMS, m/z: 499 (MH+), 471 (6.8,
MH+-N2). Accurate mass calcd for C29H31N4O4 (MH+), 499.2345;
found, 499.2339. Calcd for C29H31N2O4 (MH+ - N2), 471.2284;
found, 471.2270. The accurate mass difference between m/z
499 and m/z 471 corresponds to a neutral loss of N2. Calcd for
N2, 28.0062; found, 28.0069.
(3.72 g, 95% yield), mp ) 102.7-103.4 °C, [R]23 ) + 43.7 (c
D
1
2.02, CHCl3). H NMR (CDCl3) δ: d 7.17-7.34 (10H, m), 4.49
(1H, m), 4.07 (1H, dd, J ) 9.2, 2.6 Hz), 3.98 (1H, t, J ) 8.3
Hz), 3.57 (2H, t, J ) 6.6 Hz), 3.43 (1H, dd, J ) 15.4, 8.3 Hz),
3.17-3.27 (3H, m), 2.66 (1H, dd, J ) 13.6, 9.9 Hz), 1.81 (1H,
m), 1.71 (1H, m), 1.46 (1H, m), 1.38 (1H, m), 0.88 (9H, s), 0.03
(3H, s), 0.02 (3H, s). FABMS, m/z: 482 (MH+). Anal. Calcd
for C28H39NO4Si: C, 69.82; H, 8.16; N, 2.91. Found: C, 69.73;
H, 8.18; N, 2.92.
1-[(4S)-2-Oxo-4-b en zyl(1,3-oxa zolid in -3-yl)](2S,3R)-2-
a m in o-6-h yd r oxy-3-p h en ylh exa n -1-on e (15). A mixture of
14 (377 mg, 0.76 mmol) and 10% Pd‚C (80 mg) in ethanol (30
mL) was hydrogenated under 30 psi H2 (10 h). The mixture
was filtered through Celite, and the filtrate was evaporated
to give a residue, which was purified by silica gel flash
chromatography (MeOH:CHCl3, from 1:100 to 1:10) to afford
product 15 as a white solid (72 mg, 25% yield) along with
incompletely deprotected 16 (140 mg, 39% yield), mp ) 129-
130 °C, [R]21D ) -130.8 (c 0.65, CHCl3). 1H NMR (CDCl3) δ: d
7.18-7.37 (10H, m), 5.64 (1H, s), 4.42 (1H, m), 4.09 (1H, m),
3.97 (1H, m), 3.76 (1H, dd, J ) 12.0, 3.2 Hz), 3.52 (2H, t, J )
6.1 Hz), 3.00-3.19 (3H, m), 1.76 (1H, m), 1.26-1.43 (3H, m).
FABMS, m/z: 383 (MH+). Anal. Calcd for C22H26N2O4: C,
69.09; H, 6.85; N, 7.32. Found: C, 68.78; H, 6.88; N, 7.14.
Con ver sion of In ter m ed ia te 16 to 15. A mixture of 16
(140 mg, 0.30 mmol) in ethanol (10 mL) with four drops of
acetic acid was hydrogenated over 10% Pd‚C (50 mg) under
30 psi H2 (5 h). The mixture was filtered through Celite, and
the filtrate was evaporated to provide a residue, which was
purified by silica gel flash chromatography (MeOH:CHCl3,
from 1:100 to 1:10) to afford 15 (68 mg, 60% yield).
1-[(4S)-2-Oxo-4-b en zyl(1,3-oxa zolid in -3-yl)](2S,3R)-2-
azido-3-ph en yl-6-(1,1,2,2-tetr am eth yl-1-silapr opoxy)h exan -
1-on e (20). To a solution of [(CH3)3Si]2NK, 0.5 M in toluene
(18.5 mL, 9.25 mmol), in THF (20 mL) was added a solution
of 19 (3.72 g, 7.72 mmol) in THF (20 mL) at -78 °C under
argon, and the mixture was stirred at -78 °C (40 min). To
the mixture was added a cooled solution (-78 °C) of trisyl azide
(3.58 g, 11.6 mmol) in THF (5 mL), and the mixture was stirred
at -78 °C (2 min); then, the reaction was quenched by addition
of AcOH (2.2 mL, 38.6 mmol) and KOAc (7.58 g, 77.2 mmol),
and the mixture was stirred at 30-35 °C (1.5 h). The mixture
was diluted with ethyl acetate, washed with saturated NaH-
CO3, H2O, and brine, dried over anhydrous Na2SO4, and
evaporated to provide a residue, which was purified by silica
gel flash chromatography (ethyl acetate:hexane, from 1:20 to
1:5) to afford 20 as a colorless oil (3.73 g, 92% yield), [R]20
)
D
+112.0 (c 1.65, CHCl3). 1H NMR (CDCl3) δ: d 7.14-7.33 (10H,
m), 5.28 (1H, d, J ) 10.3 Hz), 4.03 (1H, m), 3.90 (1H, dd, J )
8.8, 1.5 Hz), 3.57 (2H, t, J ) 6.6 Hz), 3.42 (1H, t, J ) 8.1 Hz),
3.19 (1H, dd, J ) 13.2, 2.9 Hz), 3.12 (1H, m), 2.67 (1H, dd, J
) 13.2, 10.3 Hz), 2.18 (1H, m), 1.86 (1H, m), 1.35-1.42 (2H,
m), 0.88 (9H, s), 0.03 (3H, s), 0.02 (3H, s). FABMS, m/z: 523
(MH+). Anal. Calcd for C28H38N4O4Si: C, 64.34; H, 7.33; N,
10.72. Found: C, 64.53; H, 7.39; N, 10.42.
6-[(4S)-2-Oxo-4-b en zyl(1,3-oxa zolid in -3-yl)](5S,4R)-5-
a m in o-6-oxo-4-p h en ylh exyl 4-Met h ylb en zen esu lfon a t e
(17). To a solution of 15 (68 mg, 0.18 mmol) in pyridine (2
mL) was added TsCl (68 mg, 0.36 mmol) at 0 °C, and the
mixture was stirred at 0 °C (overnight). Pyridine was evapo-
rated to provide a residue, which was purified by silica gel
flash chromatography (MeOH:CHCl3, from 1:100 to 1:20) to
1-[(4S)-2-Oxo-4-b en zyl(1,3-oxa zolid in -3-yl)](2S,3R)-2-
a zid o-6-h yd r oxy-3-p h en ylh exa n -1-on e (21). To a solution
of 20 (680 mg, 1.30 mmol) in THF (15 mL) in a plastic vial
was added HF‚pyridine (1.35 mL) at 0 °C, and the mixture
was stirred at 0 °C (30 min) and then at room temperature (3
h). The mixture was cooled to 0 °C, diluted with ethyl acetate,
and neutralized by addition of saturated NaHCO3 until
evolution of CO2 ceased. The mixture was subjected to an
extractive workup (ethyl acetate) and evaporated to a residue,
which was purified by silica gel flash chromatography (ethyl
acetate:hexane, from 1:2 to 7:10) to afford 21 as a colorless oil
afford 17 as a colorless oil (46 mg, 48% yield), [R]24 ) -92.8
D
(c 0.83, CHCl3). 1H NMR (CDCl3) δ: d 7.71 (2H, d, J ) 8.4
Hz), 7.06-7.30 (13H, m), 5.44 (1H, s), 4.37 (1H, m), 4.00 (1H,
dd, J ) 3.3, 1.8 Hz), 3.89 (1H, m), 3.83 (1H, t, J ) 6.2 Hz),
3.82 (1H, t, J ) 6.2 Hz), 3.71 (1H, dt, J ) 11.7, 3.3 Hz), 3.06
(1H, dd, J ) 13.9, 9.5 Hz), 2.98-3.03 (2H, m), 2.84 (1H, dd, J
) 8.4, 3.3 Hz), 2.41 (3H, s), 1.71 (1H, m), 1.31-1.42 (2H, m),
1.12 (1H, m). FABMS, m/z: 537 (MH+). Accurate mass calcd
for C29H33N2O6S (MH+), 537.2059; found, 537.2035.
(504 mg, 95%), [R]20 ) + 161.4 (c 0.83, CHCl3). 1H NMR
D
(CDCl3) δ: d 7.11-7.30 (10H, m), 5.28 (1H, d, J ) 10.3 Hz),
4.02 (1H, m), 3.89 (1H, dd, J ) 8.8, 1.5 Hz), 3.59 (2H, t, J )
6.6 Hz), 3.42 (1H, t, J ) 8.8 Hz), 3.16 (1H, dd, J ) 14.0, 3.7
Hz), 3.11 (1H, m), 2.65 (1H, dd, J ) 14.0, 10.3 Hz), 2.16 (1H,
m), 1.87 (1H, m), 1.38-1.46 (2H, m). FABMS, m/z: 409 (MH+).
Anal. Calcd for C22H24N4O4: C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.70; H, 6.08; N, 13.45.
(4S)-3-[((2S,3R)-3-P h en yl(2-p ip er id yl))ca r bon yl]-4-ben -
zyl-1,3-oxa zolid in -2-on e (18). A mixture of 17 (46 mg, 0.086
mmol) and NaHCO3 (36 mg, 0.43 mmol) in acetonitrile (3 mL)
was refluxed (2 days), and then solvent was evaporated to
provide a residue, which was purified by silica gel flash
chromatography (MeOH:CHCl3, from 1:100 to 1:20) to afford
6-[(4S)-2-Oxo-4-b en zyl(1,3-oxa zolid in -3-yl)](5S,4R)-5-
azido-6-oxo-4-ph en ylh exyl 4-m eth ylben zen esu lfon ate (22).
To a solution of 21 (100 mg, 0.24 mmol) in pyridine (2.5 mL)
was added TsCl (93 mg, 0.49 mmol) at 0 °C, and the mixture
was stirred at 0 °C (overnight). Pyridine was evaporated to
provide a residue, which was purified by silica gel flash
chromatography (ethyl acetate:hexane, from 1:10 to 1:2) to
18 as a white solid (5 mg, 16% yield), mp ) 156-159 °C, [R]21
D
) -7.0 (c 0.63, CHCl3). 1H NMR (400 MHz, CDCl3) δ: d 7.20-
7.31 (8H, m), 6.91-6.93 (2H, m), 4.40 (1H, m), 4.18 (1H, dd, J
) 13.3, 5.1 Hz), 3.91 (1H, dd, J ) 12.0, 6.0 Hz), 3.83 (1H, dd,
J ) 12.0, 2.9 Hz), 3.78 (1H, d, J ) 10.5 Hz), 3.37 (1H, m), 3.28
(1H, dd, J ) 13.6, 10.5 Hz), 3.00 (1H, dd, J ) 13.3, 6.0 Hz),
2.81 (1H, td, J ) 13.3, 3.5 Hz), 1.87 (1H, ddd, J ) 26.2, 11.3,
3.1 Hz), 1.75 (1H, ddd, J ) 13.3, 3.1, 2.6 Hz), 1.64 (1H, ddd, J
) 26.2, 13.0, 3.1 Hz), 1.42 (1H, dddd, J ) 26.2, 12.9, 5.1, 3.5
Hz). FABMS, m/z: 365 (MH+). Accurate mass calcd for
afford 22 as a colorless oil (54 mg, 39% yield), [R]24 ) +103.6
D
1
(c 0.92, CHCl3). H NMR (400 MHz, CDCl3) δ: d 7.72 (2H, d,
J ) 8.4 Hz), 7.18-7.32 (8H, m), 7.10-7.14 (4H, m), 5.25 (1H,
d, J ) 9.2 Hz), 4.09 (1H, m), 3.88-3.99 (3H, m), 3.54 (1H, t, J
) 8.1 Hz), 3.16 (1H, dd, J ) 13.6, 3.3 Hz), 3.05 (1H, ddd, J )
11.7, 9.2, 3.7 Hz), 2.67 (1H, dd, J ) 13.6, 9.5 Hz), 2.42 (3H, s),
2.02 (1H, m), 1.79 (1H, m), 1.43-1.54 (2H, m). FABMS, m/z:
563 (MH+). Anal. Calcd for C29H30N4O6S: C, 61.91; H, 5.37;
N, 9.96. Found: C, 62.11; H, 5.51; N, 9.81.
C
22H25N2O3 (MH+), 365.1865; found, 365.1857.
(4S)-3-[(3S)-3-P h en yl-6-(1,1,2,2-tetr a m eth yl-1-sila p r o-
p oxy)h exa n oyl]-4-ben zyl-1,3-oxa zolid in -2-on e (19). To a
solution of 12 (3.0 g, 8.16 mmol) in DMF (30 mL) were added
TBSCl (1.48 g, 9.80 mmol) and imidazole (1.39 g, 20.4 mmol),

1452 J . Org. Chem., Vol. 67, No. 5, 2002
Liu et al.
Meth yl (2S,3R)-3-P h en ylp ip er id in e-2-ca r boxyla te (24).
To a solution of oxalyl chloride, 2 M in CH2Cl2 (0.61 mL, 1.22
mmol), in CH2Cl2 (1 mL) was added a solution of DMSO (174
µL, 2.45 mmol) in CH2Cl2 (1 mL) at -78 °C, and the mixture
was stirred at -78 °C (20 min). To the mixture was added a
solution of 21 (100 mg, 0.24 mmol) in CH2Cl2 (3 mL) at -78
°C, and the mixture was stirred at -78 °C (20 min); then,
triethylamine (341 µL) was added and stirring continued at
-78 °C (20 min). The mixture was allowed to come to ambient
temperature, diluted with ethyl acetate, and washed sequen-
tially with 1 N HCl, saturated NaHCO3, and brine. Drying
over anhydrous Na2SO4 and evaporation provided a residue,
which was filtered through a short silica gel column to give
crude aldehyde 23. This was dissolved in MeOH (10 mL) and
hydrogenated over 10% Pd‚C (20 mg) under 40 psi H2
(overnight). Filtration through Celite and evaporation provided
a residue, which was purified by silica gel flash chromatog-
raphy (MeOH:CHCl3, from 1:100 to 1:20) to afford 24 as a
of a small quantity of dry ice; then, Fmoc-OSu (78 mg, 0.23
mmol) was added, and the mixture was stirred at ambient
temperature (overnight). Following adjustment of the pH to
6.5 at 0 °C using a 2 M solution of KHSO4, dioxane was
removed by evaporation and the solution was diluted with
H2O. The mixture was acidified to pH 5 using a 2 M solution
of KHSO4, subjected to an extractive workup (ethyl acetate),
and evaporated to a residue, which was purified by silica gel
flash chromatography (ethyl acetate:hexane, from 1:1 to 1:50
MeOH:CHCl3) to afford semipure 7 as a white solid (81 mg).
Analysis by HPLC indicated approximately 25% contamina-
tion. Therefore, further purification by preparative HPLC
(retention time ) 21.1 min) provided 18 mg from 37 mg of
semipure material, resulting in a 40% effective overall yield
1
of title compound 7. H NMR (400 MHz, DMSO-d6, 50 °C) δ:
d 7.82 (2H, m), 7.57 (2H, m), 7.35 (2H, m), 7.30-7.17 (8H, m),
4.83 (1H, brs), 4.38 (2H, brs), 4.23 (1H, m), 3.80 (1H, m), 3.50
(1H, brs), 3.08 (1H, brs), 1.84-1.75 (1H, m), 1.72-1.62 (1H,
m), 1.41-1.22 (2H, m). FABMS, m/z: 428 (MH+). Accurate
mass calcd for C27H26NO4 (MH+), 428.1862; found, 428.1847.
white solid (28 mg, 52% yield), mp ) 176.5 °C dec, [R]20
)
D
1
+35.0 (c 0.36, CHCl3). H NMR (400 MHz, CDCl3) δ: d 7.13-
7.26 (5H, m), 3.45 (1H, d, J ) 10.2 Hz), 3.36 (3H, s), 3.17 (1H,
m), 2.67-2.74 (2H, m), 1.99 (1H, m), 1.68-1.79 (2H, m), 1.56
(1H, m). FABMS, m/z: 220 (MH+). Accurate mass calcd for
Calcd for
C
26H24NO2 (MH+ - HCO2H), 382.1807; found,
382.1784. The accurate mass difference between m/z 428 and
m/z 382 corresponds to a neutral loss of HCO2H. Calcd for
HCO2H, 46.0055; found, 46.0063.
C
13H18NO2 (MH+), 220.1338; found, 220.1354.
(2S,3R)-1-[(F lu or en -9-ylm eth yl)oxyca r bon yl]-3-p h en -
ylp ip er id in e-2-ca r boxylic Acid (7). To a solution of 24 (50
mg, 0.23 mmol) in a mixture of 1,4-dioxane (3 mL) and H2O
(2 mL) was added a 1:1 mixture of 1 N NaOH (10 mL) and
1,4-dioxane portionwise at 0 °C. Following complete hydrolysis
of the methyl ester (2 h), the mixture was buffered by addition
Ack n ow led gm en t. Appreciation is expressed to Ms.
Lynne Anderson of this laboratory for assistance with
the mass spectral analyses.
J O010124+