A new synthetic route to protected α-hydrazinoesters in high optical purity using the mitsunobu protocol

Full text of DOI:10.1021/jo005696t

J . Org. Chem. 2001, 66, 2869-2873
2869
In this paper, we aim to extend our current method to
include the preparation of chiral hydrazinoacid deriva-
tives. We demonstrate that these compounds can be
efficiently obtained starting from the corresponding
R-hydroxyesters.
A New Syn th etic Rou te to P r otected
r-Hyd r a zin oester s in High Op tica l P u r ity
Usin g th e Mitsu n obu P r otocol
Nicolas Brosse, Maria-Fatima Pinto,
J acques Bodiguel, and Brigitte J amart-Gre´goire*
Resu lts a n d Discu ssion
MAEM UMR mixte CNRS-UHP nï. 7567,
Faculte´ des Sciences, Universite´ H. Poincare´ Nancy I,
Bld. des Aiguillettes, BP 239 F-54506
Mitsu n obu Rea ction : F or m a tion of 2. The (R)- and
(S)-R-hydroxyesters used in this study are commercially
available or prepared from their acid form (see Experi-
mental Section).
As a first step, the reactivity of N-tert-butyloxycarbo-
nylaminophthalimide (1, P ) BOC) toward (S)-R-hydrox-
yesters in the Mitsunobu protocol was studied. Shown
in the following Scheme 1 (step a) and Table 1 are the
results obtained.
Vandoeuvre-le`s-Nancy, France
Brigitte.J amart@maem.uhp-nancy.fr
Received October 24, 2000
In tr od u ction
Among the variety of amino acid analogues currently
investigated in organic chemistry, there is a growing
interest in the synthesis of R-hydrazinoacids (2-hydrazi-
nyl acids) which present interesting biological activities1
and can be used for the preparation of (N-aminoamide)
peptides2 or (hydrazide) peptides.2a,3 A few reaction
pathways have been described for the preparation of
optically pure R-hydrazinoacids,1,4 although these involve
laborious methods. In addition, the presence of the
additional NR sometimes presents difficulties in prepara-
tion of these compounds and their incorporation in
pseudopeptides design where coupling of R-hydrazinoac-
ids with amino acids is not always regioselective. In that
context, the availability of a general method for the
production of NR- or Nâ-protected (R)- or (S)-R-hydrazi-
noacids is of great interest.
As part of our research aimed at developing synthetic
protocols for the preparation of protected hydrazines,5 we
have demonstrated that N-tert-butyloxycarbonyl- and
N-benzyloxycarbonyl-aminophthalimides, efficiently ob-
tained using phthalic anhydride and carbazates as start-
ing materials, are very good acid partners in a Mitsunobu
protocol.5b,c We demonstrated that primary, secondary
alkyl, benzyl groups as well as functionalized groups can
be introduced with good overall yields. Furthermore, we
showed that a final dephthaloylation step results in an
efficient method for the preparation of 1,1-substituted
hydrazines.
The corresponding N,N-triprotected R-hydrazinoesters
2a -d were obtained with very good yields for R ) H and
Me. However, for R ) CH2-CH(CH3)2, the yield of 2e
decreased to 50%. For R ) CH2Ph and CH(CH3)2 no
reaction was observed (unreported results). In compari-
son, when the less hindered N-benzyloxycarbonylami-
nophthalimide (1, P ) Z) was used as the acid partner,
compounds 2f-p were obtained with good to very good
yields regardless of the nature of the side chain group R
or of the ester group R′(methyl or benzyl group) used.
The observation of two sets of resonances for some
groups in 1H and 13C NMR spectra (see Experimental
Section) suggested that compounds 2 were present as two
isomers in a ratio 45/55. We and others have observed
this phenomenon before in the preparation of hydrazides
derivatives5c or amide containing compounds.6 The dif-
ferent resonances of the isomers arise from a hindered
rotation about the nitrogen to carbonyl bond thus allow-
ing one to distinguish between Z and E forms. Comple-
mentary studies are under active investigation to fully
assign resonance signals.
P r ep a r a tion of Nâ-P r otected r-Hyd r a zin oester s.
Selective removal of the benzyloxycarbonyl or the tert-
butyloxycarbonyl group can be readily achieved using
HBr/CH3COOH7 or HCl/EtOAc,8 respectively (Scheme 1
(step b), Table 1). These deprotection steps permit the
general preparation of Nâ-protected R-hydrazinoesters.
However, during the Z deprotection of compounds 2f, 2h ,
and 2n (R′ ) CH2Ph), partial proteolysis of the benzylic
ester function occurred contributing to a decrease in the
yield of compounds 3. We circumvented this problem by
using the corresponding methyl esters as starting ma-
terials thus enabling compounds 3 (R′ ) Me) to be
obtained in good yields.
* To whom correspondence should be addressed. Tel/fax: 33 (0) 383
91 27 48.
(1) Trimble, L. A.; Vederas, J . C. J . Am. Chem. Soc. 1986, 108, 6397-
6399 and references therein.
(2) (a) Niedrich, H. Chem. Ber. 1965, 3451-3461. Niedrich, H. Chem.
Ber. 1967, 100, 3273-3282. Marraud, M.; Dupont, V.; Grand, V.;
Zerkout, S.; Lecoq, A.; Boussard, G.; Vidal, J .; Collet, A.; Aubry, A.
Biopolymers 1993, 33, 1135-1148. (b) Dupont, V.; Lecoq, A.; Mangeot,
J .-P.; Aubry, A.; Boussard, G.; Marraud, M. J . Am. Chem. Soc. 1993,
115, 8898-8906. Cheguillaume, A.; Lehardy, F.; Bouget, K.; Baudy-
Floc’h, M.; Le Grel, P. J . Org. Chem. 1999, 64, 2924-2927. Bonnet,
D.; Rommens, C.; Gras-Masse, H.; Melnyk, O. Tetrahedron Lett. 2000,
41, 45-48.
(3) Guy, L.; Vidal, J .; Collet, A. J . Med. Chem. 1998, 41, 4833-4843.
(4) Hoffman, R. V.; Kim, H.-O. Tetrahedron Lett. 1990, 31, 2953-
2956. Vidal, J .; Guy, L.; Ste´rin, S.; Collet, A. J . Org. Chem. 1993, 58,
4791-4793. Burk, M. J .; Martinez, J . P.; Feaster, J . E.; Cosford, N.
Tetrahedron 1994, 50, 4399-4428. Cheguillaume, A.; Doubli-Bounoua,
I.; Baudy-Floc’h, M.; Le Grel, P. Synlett 2000, 331-334.
(5) (a) Brosse, N.; Pinto, M.-F.; J amart-Gre´goire, B. J . Chem. Soc.,
Perkin Trans. 1 1998, 3685-3688. (b) Brosse, N.; Pinto, M.-F.; J amart-
Gre´goire, B. Tetrahedron Lett. 2000, 41, 205-207. (c) Brosse, N.; Pinto,
M.-F.; J amart-Gre´goire, B. J . Org. Chem. 2000, 65, 4370-4374.
P r ep a r a tion of Nr-P r otected r-Hyd r a zin oester s.
We previously demonstrated that dephthaloylation of
N-subtituted aminophthalimides could be improved by
using methylhydrazine in THF.5b Using these conditions,
NR-protected hydrazinoesters 4 were obtained, starting
from compounds 2, with very good yields in most cases
(Scheme 1 (step c), Table 1). However, dephthaloylation
(6) Lewin, A. H.; Frucht, M. Org. Magn. Res. 1975, 7, 202-225.
(7) Ben-Ishai, D.; Berger, A. J . Org. Chem. 1952, 17, 1564-1570.
(8) Stahl, G. L.; Walter, R.; Smith, C. W. J . Org. Chem. 1978, 43,
2285-2286.
10.1021/jo005696t CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/15/2001

2870 J . Org. Chem., Vol. 66, No. 8, 2001
Notes
mm particle size. R-Hydroxyacids ((S)-(+)-2-hydroxy-3-methyl-
butyric acid (ee: 98%) and (S)-(-)-2-hydroxyisocaproic acid (ee:
99%)) or R-hydroxyesters (benzyl-(S)-(-)-2-hydroxy-3-phenyl-
propionate (ee: 97%), (benzyl-(R)-(+)-2-hydroxy-3-phenylpropi-
onate (ee: 97%), benzylglycolate, (S)-benzyllactate (ee: 98%), and
(S)-methyllactate (ee: 97%)) were purchased from Aldrich.
Benzylation of R-hydroxyacids was accomplished using benzyl
bromide in accordance with previously described procedure11 and
methylation by reaction with diazomethane.12
Sch em e 1. F or m a tion of 2, 3, a n d 4
Gen er a l P r oced u r e for th e Alk yla tion of N-Acyl or
N-Alk oxyca r bon yla m in op h th a lim id es via Mitsu n obu P r o-
tocol. To a solution of 1 (5 mmol), PPh3 (7.5 mmol), and
R-hydroxyester RCH(OH)COOR′, 5 mmol) in dry THF (50 mL)
and under Nitrogen was added in one portion DEAD (diethyla-
zodicarboxylate, 7.5 mmol) with stirring at -20 °C or 0-5 °C
(see Table 1). The resulting solution was stirred at room
temperature (monitored by TLC until completion) and concen-
trated in vacuo. The residue was triturated in EtOAc and most
of the triphenylphosphine oxide and diethylhydrazinedicarboxy-
late was removed by filtration. The filtrate was evaporated and
the residue was chromatographed on silica gel.
N-ter t-Bu tyloxyca r bon yl-N-p h th a lim id oglycin e Ben zyl
Ester . 2a P ) Boc, R ) H, R′ ) CH2P h . Mp 94-98 °C; Rf )
0.55 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 1798, 1745; 1H
NMR (250 MHz, CDCl3) 7.96-7.70 (m, 4 H), 7.47-7.23 (m, 5
H), 5.21 and 5.18 (2 s, 2 H), 4.50 and 4.41 (2 s, 2 H), 1.44 and
1.35 (2 s, 9 H); 13C NMR (CDCl3) 168.2, 165.3, 165.0, 153.2, 135.7,
135.1, 130.3, 130.2, 129.0, 128.9, 128.7, 124.3, 84.3, 83.6, 67.5,
52.6, 50.5, 28.3; HRMS Calcd for C22H26N3O6 [M+NH4+] m/z
428.1821, found 428.1815.
For description of P, R, and R′ and configuration of compounds
see Table 1. a(R)- or (S)-RCHOHCOOR′, 1 equiv, DEAD, 1.5 equiv,
PPh3, 1.5 equiv, THF; bP ) BOC: HCl/EtOAc. P ) Z: HBr/AcOH.
cNH2NHCH3, 1.5 equiv, THF.
of compound 2j was less successful resulting in a yield
of only 35%. Starting material was recovered, and the
yield of 4j was constant whatever the amount of reactant
used.
Deter m in a tion of th e Op tica l P u r ity. Starting from
4h , 4j, 4l, 4n , or 4p , the corresponding amino acids can
be obtained by hydrogenolysis with an excess of Raney
nickel9 (50 bar of H2, 24 h, 25 °C). These conditions
allowed simultaneous cleavage of the N-N bond, depro-
tection of the Z group, and conversion of the benzylester
group into the corresponding acid form. For compounds
4c and 4e, a preliminary deprotection of the BOC group
with CF3COOH was necessary. The enantiomeric purities
of amino acids were determined by HPLC after deriva-
tization of the free amine with o-phthalaldehyde and the
chiral thiol N-isobutyryl-D-cysteine.10 The very high chiral
purities obtained (ee > 97%, see Table 1) established that
the conversion of the R-hydrazinoesters to the corre-
sponding amino acids via the illustrated steps sequence
proceed with complete inversion of configuration and
were accompanied by a negligible loss of enantiomeric
purity (<1% compared to enantiomeric purities of com-
mercial hydroxyesters or hydroxyacids, see Experimental
Section).
N-ter t-Bu tyloxyca r bon yl-N-p h th a lim id oglycin e Meth yl
Ester . 2b P ) Boc, R ) H, R′ ) CH3. Mp 117-118 °C; Rf )
0.60 (EtOAc/Hexane 4/6); IR (KBr) νmax/cm-1 1797, 1758, 1722;
1H NMR (250 MHz, CDCl3) 7.95-7.73 (m, 4 H), 4.47 and 4.41
(2 s, 2 H), 3.78 and 3.75 (2 s, 3 H), 1.53 and 1.35 (2 s, 9 H); 13C
NMR (CDCl3) 168.7, 165.9, 153.1, 130.2, 130.1, 124.3, 84.2, 83.5,
52.6, 52.3, 50.2, 28.3, 28.1; HRMS Calcd for
C16H22N3O6
[M+NH4+] m/z 352.1509, found 352.1519.
(R)-N-ter t-Bu tyloxycar bon yl-N-ph th alim idoalan in e Ben -
zyl Ester . 2c P ) Boc, R ) CH3, R′ ) CH2P h . Mp 110-112
°C; [R]D ) -1.5 (c 1.12, CHCl3); Rf ) 0.55 (EtOAc/Hexane 4/6);
IR (NaCl) νmax/cm-1 1799, 1742; 1H NMR (400 MHz, CDCl3)
7.90-7.69 (m, 4 H), 7.49-7.19 (m, 5 H), 5.20 and 5.19 (2 s, 2
H), 5.09 and 4.85 (2 q, J ) 7 Hz, 1 H), 1.47-1.16 (m with 2 s at
1.35 and 1.26, 12 H); 13C NMR (CDCl3) 170.6, 166.4, 166.2, 166.0,
165.7, 152.5, 136.1, 135.2, 130.2, 130.0, 128.9, 128.7, 128.5, 124.3,
84.0, 83.1, 67.7, 67.4, 57.2, 55.4, 28.1, 15.0, 14.6; HRMS Calcd
for C23H28N3O6 [M+NH4+] m/z 442.1974, found 442.1978.
(R)-N-ter t-Bu tyloxycar bon yl-N-ph th alim idoalan in e Meth -
yl Ester . 2d P ) Boc, R ) CH3, R′ ) CH3. Mp 91-92 °C; [R]D
) +20.10 (c 0.78, CHCl3); Rf ) 0.50 (EtOAc/Hexane 4/6); IR
(NaCl) νmax/cm-1 1799, 1741; 1H NMR (400 MHz, CDCl3) 7.76-
7.64 (m, 4 H), 4.94 and 4.70 (2 q, 1 H, J ) 7 Hz), 3.68 and 3.64
(2 s, 3 H), 1.42-1.07 (m with 2 s at 1.37 and 1.17 and with 2 d
at 1.29 and 1.25, J ) 8 Hz, 12 H); 13C NMR (CDCl3) 171.1, 166.3
166.1, 165.5, 152.5, 135.3, 130.2, 124.2, 83.9, 83.1, 57.2, 55.0,
52.6, 28.2, 28.0, 15.0, 14.6; HRMS Calcd for C17H21N2O6 [M+H+]
m/z 349.1400, found 349.1426.
(R)-N-ter t-Bu tyloxycar bon yl-N-ph th alim idoleu cin e Ben -
zyl Ester . 2e P ) Boc, R ) CH2-CH(CH3)2, R′ ) CH2P h .
Oil; [R]D ) +14.3 (c 0.91, CHCl3); Rf ) 0.70 (EtOAc/Hexane 4/6);
IR (NaCl) νmax/cm-1 1799, 1737; 1H NMR (400 MHz, CDCl3)
7.91-7.83 (m, 4 H), 7.46-7.20 (m, 5 H), 5.26-5.10 and 4.9 (m
with s at 5.17 and t at 4.94, J ) 9 Hz, 3 H), 1.94-1.54 (m, 3 H),
1.40 and 1.26 (2 s, 9 H), 1.00-0.80 (m, 6 H); 13C NMR (CDCl3)
170.1, 166.3, 165.0, 165.3, 152.7, 135.9, 135.1, 130.2, 130.1, 128.9,
128.7, 128.5, 124.2, 84.0, 83.1, 67.7, 67.5, 59.5, 57.5, 38.3, 28.2,
28.1, 24.9, 24.7, 22.8, 22.6; HRMS Calcd for C26H31N2O6 [M+H+]
m/z 467.2182, found 467.2174.
Con clu sion
We have demonstrated that N-tert-butyloxycarbonyl-
and N-benzyloxycarbonyl-aminophthalimides can be re-
acted with commercially available (S)- and (R)-R-hydrox-
yesters for an efficient preparation of either NR-protected,
Nâ-bisprotected or orthogonal NR, Nâ-triprotected, respec-
tively, (R)- and (S)-R-hydrazinoesters with high optical
purity. It follows that these procedures represent an
attractive alternative to the methods currently used for
the preparation of R-hydrazinoacid derivatives. Applica-
tion of this protocol to the synthesis of more complex
varieties of hydrazinoacids is under active investigation.
Exp er im en ta l Section
Gen er a l. Melting points were obtained on a hot-stage ap-
paratus and were uncorrected. NMR spectra were recorded on
spectrometers operating at 400 or 250 MHz. Optical rotations
were measured in a 1 dm cell at 20 °C. Electron Impact Mass
Spectra were performed by the ULIRS Mass Spectrometry
Facility (the School of Pharmacy, London). Tetrahydrofuran was
dried by distillation over sodium-benzophenone. Column chro-
matography was performed using silica gel 60 of 0.063-0.200
N-Ben zyloxyca r bon yl-N-p h th a lim id oglycin e Ben zyl Es-
t er . 2f P ) Z, R ) H, R ′ ) CH2P h . Oil; Rf ) 0.35 (EtOAc/
Hexane 4/6); IR (NaCl) νmax/cm-1 1805, 1742; 1H NMR (400 MHz,
CDCl3) 7.85-7.64 (m, 4 H), 7.45-7.06 (m, 10 H), 5.23-5.05 (m,
(9) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J . F. J . Am.
Chem. Soc. 1986, 108, 6395-6397.
(10) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993, 115,
5021-5030. Bru¨ckner, H.; Westhauser, T.; Godel, H. J . Chromatogr.,
A 1995, 711, 201-215.
(11) Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U. J . Chem.
Soc., Perkin Trans. 1 1993, 11-14.
(12) Bitan, G.; Gilon, C. Tetrahedron 1995, 54, 10513-10522.

Notes
J . Org. Chem., Vol. 66, No. 8, 2001 2871
Ta ble 1. P r ep a r a tion of Or th ogon a l Nr,Nâ-Tr ip r otected 2, Nâ-Bisp r otected 3, or Nr-Mon op r otected r-Hyd r a zin oester s 4
Configuration Time
R
R′
CH2-Ph BOC
CH3 BOC
CH2-Ph BOC
CH3 BOC
P
of 2, 3, 4
(h)
Yields, 2 (%) Time (h) Yields, 3 (%) Time (h) Yields, 4 (%) ee (%)
H
H
CH3
CH3
1
0.5
4
4
18
2a 85
2b 70
2c 94
2d 82
2e 50
2f 93
2g 81
2h 87
2i 90
15
15
3a 84
3c 72
2.5a
4a 90
4c 87
R
R
R
1.5a
>99
CH2-CH(CH3)2 CH2-Ph BOC
72
2
3e 63
3a 61
3g 93
3c 60
3i 81
24a
4e 55
4f 92
98
H
H
CH3
CH3
CH2-Ph
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
0.5
2.5
0.25
1
1b
CH3
CH2-Ph
CH3
R
R
R
R
R
R
R
R
S
1
1
1b
4h 86
4j 35
4l 73
4n 68
4p 73
>99
>99
98
CH(CH3)2
CH(CH3)2
CH2-CH(CH3)2 CH2-Ph
CH2-CH(CH3)2 CH3
CH2-Ph
CH2-Ph
CH2-Ph
CH2-Ph
5a
2j 74
24a
60a
5a
CH3
0.75
0.2
0.25
1.5a
0.25
2
2k 54
2l 80
4
3k 65
2m 77
2n 92
2o 64
2p 77
1
4
2
3m 80
3n 57
3o 60
CH2-Ph
CH3
97
CH2-Ph
5a
99
a
b
The reaction mixture was stirred at -20 °C for 30 min before raising to room temperature. The reaction mixture was stirred at 0
°C for 30 min before raising to room temperature.
4 H), 4.56 and 4.47 (2 s, 2 H); 13C NMR (CDCl3) 167.7, 164.9,
164.6, 135.6, 135.3, 130.1, 130.0, 128.9, 128.8, 128.7, 128.5, 127.7,
124.4, 69.7, 69.1, 67.6, 52.4, 51.2; HRMS Calcd for C25H24N3O6
[M+NH4+] m/z 462.1665, found 462.1660.
N-Ben zyloxyca r bon yl-N-p h th a lim id oglycin e Meth yl Es-
ter . 2g P ) Z, R ) H, R′ ) CH3. Mp 100 °C; Rf ) 0.25 (EtOAc/
Hexane 4/6); IR (NaCl) νmax/cm-1 1799, 1742; 1H NMR (400 MHz,
CDCl3) 7.81-7.60 (m, 4 H), 7.32-7.02 (m, 5 H), 5.15 and 5.05
(2 s, 2 H), 4.42 and 4.38 (2 s, 2 H), 3.62 and 3.59 (2 s, 3 H); 13C
NMR (CDCl3) 168.3, 164.9, 164.6, 154.5, 154.0, 135.6, 135.3,
130.0, 129.9, 129.0, 128.8, 128.4, 127.6, 124.3, 69.6, 69.1, 52.6,
52.1, 51.0; HRMS Calcd for C19H16N2O6 m/z 368.1008, found
368.1007.
(R)-N-Ben zyloxyca r bon yl-N-p h th a lim id oa la n in e Ben zyl
Ester . 2h P ) Z, R ) CH3, R′ ) CH2P h . Oil; [R]D ) +3.47 (c
1.9, CHCl3); Rf ) 0.25 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1
1798, 1745; 1H NMR (400 MHz, CDCl3) 7.92-7.70 (m, 4 H),
7.49-7.19 (m, 10 H), 5.35-4.96 (m, 5 H), 1.53-1.38 (m, 3 H);
13C NMR (CDCl3) 170.3, 166.2, 165.9, 165.8, 165.3, 154.0, 136.0,
ν
max/cm-1 1799, 1751; 1H NMR (400 MHz, CDCl3) 7.89-7.68 (m,
4 H), 7.46-7.0.06 (m, 10 H), 5.33-4.97 (m, 5 H), 1.92-1.53 (m,
3 H), 1.04-0.77 (m, 6 H); 13C NMR (CDCl3) 169.8, 166.2, 165.9,
165.5, 154.1, 135.9, 135.7, 130.1, 128.9, 128.7, 128.5, 127.5, 124.3,
69.7, 69.0, 67.9, 67.7, 59.6, 58.6, 38.4, 24.9, 24.7, 22.8, 22.7;
HRMS Calcd for C29H32N3O6 [M + NH4+] m/z 518.2291, found
518.2281.
(R)-N-Ben zyloxyca r bon yl-N-p h th a lim id oleu cin e Meth yl
Ester . 2m P ) Z, R ) CH2-CH(CH3)2, R′ ) CH3. Oil; [R]D
+45.96 (c 0.57, CHCl3); Rf ) 0.55 (EtOAc/Hexane 4/6); IR (NaCl)
max/cm-1 1800, 1746; 1H NMR (400 MHz, CDCl3) 7.91-7.70 (m,
)
ν
4 H), 7.44-7.06 (m, 5 H), 5.27, 5.23, 5.12, 5.01 (2 s, 2 t, J ) 6
Hz, 3 H), 3.75 and 3.72 (2 s, 3 H), 1.87-1.59 (m, 3 H), 1.02-
0.81 (m, 6 H); 13C NMR (CDCl3) 170.4, 165.9, 135.9, 135.3, 130.1,
129.0, 128.7, 128.4, 127.5, 124.4, 69.7, 69.1, 59.4, 58.2, 52.8, 38.4,
38.2, 24.8, 24.7, 23.0, 22.7; HRMS Calcd for C23H24N2O6 m/z
424.1634, found 424.1644.
(R )-N -Be n zyloxyca r b on yl-N -p h t h a lim id op h e n yla la -
n in e Ben zyl Ester . 2n P ) Z, R ) CH2C6H5, R′ ) CH2P h .
Oil; [R]D ) +28.9 (c 0.56, CHCl3); Rf ) 0.50 (EtOAc/Hexane 4/6);
IR (NaCl) νmax/cm-1 1799, 1745; 1H NMR (400 MHz, CDCl3)
7.96-7.70 (m, 4 H), 7.48-7.00 (m, 15 H), 5.51 and 5.27 (2 dd, J
135.7, 135.3, 130.2, 130.0, 128.9, 128.7, 128.5, 127.5, 124.3, 69.7,
+
67.7, 57.2, 56.4, 14.7; HRMS Calcd for C26H26N3O6 [M+NH4
m/z 476.1821, found 476.1814.
]
(R)-N-Ben zyloxyca r bon yl-N-p h th a lim id oa la n in e Meth yl
Ester . 2i P ) Z, R ) CH3, R′ ) CH3. Oil; [R]D ) +22.1 (c 1.45,
CHCl3); Rf ) 0.40 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 1799,
1747; 1H NMR (250 MHz, CDCl3) 8.00-7.82 (m, 4 H), 7.36-
7.12 (m, 5 H), 5.39-4.97 (m, 3 H), 3.85 and 3.73 (2 s, 3 H), 1.45
(d, J ) 8 Hz, 3 H); 13C NMR (CDCl3) 170.8, 165.8, 154.2, 135.7,
135.3, 129.0, 128.7, 128.4, 127.6, 124.4, 69.7, 67.0, 57.1, 56.0,
52.6, 15.6.
(R)-N-Ben zyloxyca r bon yl-N-p h th a lim id ova lin e Ben zyl
Ester . 2j P ) Z, R ) CH(CH3)2, R′ ) CH2P h . Mp 80 °C; [R]D
) +31.8 (c 1.29, CHCl3); Rf ) 0.60 (EtOAc/Hexane 4/6); IR
(NaCl) νmax/cm-1 1799, 1746; 1H NMR (400 MHz, CDCl3) 7.94-
7.73 (m, 4 H), 7.45-7.06 (m, 10 H), 5.30-5.06 (m, 4 H), 4.88
and 4.64 (2 d, J ) 11 Hz, 1 H), 2.18-2.03 (m, 1 H), 1.36-1.20
and 0.97-0.82 (2 m, 6 H); 13C NMR (CDCl3) 168.9, 168.7, 166.0,
165.6, 154.5, 154.3, 135.2, 135.3, 130.3, 130.2, 128.9, 128.7, 128.5,
127.4, 124.3, 69.7, 67.8, 67.6, 66.6, 67.6, 29.35, 29.1, 19.8, 19.3;
HRMS Calcd for C28H27N2O6 [M+H+] m/z 487.1869, found
487.1867.
) 10 Hz, 5 Hz, 1H), 5.25-5.06 (m, 4 H), 3.40-3.22 (m, 2 H); 13
C
NMR (CDCl3) 168.9, 166.3, 166.0, 165.4, 154.0, 153.8, 136.4,
136.2, 135.6, 135.4, 130.3, 130.1, 129.0, 128.9, 128.7, 128.5, 127.7,
127.4, 124.5, 69.9, 69.2, 67.9, 67.7, 62.9, 61.8, 36.4; HRMS Calcd
for C32H30N3O6 [M+NH4+] m/z 552.2135, found 552.2120.
(R )-N -Be n zyloxyca r b on yl-N -p h t h a lim id op h e n yla la -
n in e Meth yl Ester . 2o P ) Z, R ) CH2C6H5, R′ ) CH3. Oil;
Rf ) 0.50 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 1799, 1744;
1H NMR (400 MHz, CDCl3) 7.94-7.66 (m, 4 H), 7.44-7.10 (m,
10 H), 5.45 and 5.31-5.10 (dd and m, J ) 12 Hz, 6 Hz, 3 H),
3.66 and 3.62 (2 s, 3 H), 3.34-3.19 (m, 2 H); 13C NMR (CDCl3)
169.5, 169.4, 166.2, 165.9, 165.7, 165.3, 154.0, 153.7, 136.6, 136.4,
135.6, 135.4, 130.2, 130.1, 129.7, 129.0, 128.8, 128.5, 127.7, 127.3,
124.5, 69.8, 69.2, 62.8, 61.5, 52.8, 36.5, 36.1; HRMS Calcd for
C
26H22N2O4 m/z 458.1478, found 458.1482.
(S )-N -Be n zyloxyca r b on yl-N -p h t h a lim id op h e n yla la -
n in e Ben zyl Ester . 2p P ) Z, R ) CH2C6H5, R′ ) CH2P h .
Oil; [R]D ) -28.2 (c 0.56, CHCl3); Rf ) 0.50 (EtOAc/Hexane 4/6).
Gen er a l P r oced u r e for th e Rem ova l of th e Ca r ba m a te
Gr ou p (BOC or Z). A solution of dry hydrobromic acid in glacial
acetic acid (33%, 5 mL) (for P ) Z) or of dry hydrochloric acid in
EtOAc (3 N, 5 mL) (for P ) BOC) was added to the carbamate
2 (5 mmol). The mixture was stirred at room temperature for
the time indicated in Table 1 (monitored by TLC). The mixture
was poured into a saturated solution of NaHCO3 (50 mL)
(CAUTION required) and extracted 3 times with EtOAc. The
combined organic layers were dried over MgSO4 and evaporated
in vacuo. The residue was chromatographed on silica gel.
N-P h th a lim id oglycin e Ben zyl Ester . 3a P ) H, R ) H,
R′ ) CH2P h . Mp 92 °C; Rf ) 0.30 (EtOAc/Hexane 4/6); IR (KBr)
(R)-N-Ben zyloxyca r bon yl-N-p h th a lim id ova lin e Meth yl
Ester . 2k P ) Z, R ) CH(CH3)2, R′ ) CH3. Oil; Rf ) 0.45
1
(EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 1799, 1741; H NMR
(400 MHz, CDCl3) 7.91-7.69 (m, 4 H), 7.41-7.06 (m, 5 H), 5.30-
5.06 (m, 2 H) 4.88 and 4.64 (2 d, J ) 12 Hz, 1 H), 3.71 (s, 3 H),
2.18-2.03 (m, 1 H), 1.28 and 1.22, 0.90 and 0.87 (4 d, J ) 8 Hz,
6 H); 13C NMR (CDCl3) 169.5, 166.4, 165.9, 165.5, 154.5, 135.7,
135.2, 130.3, 130.0,129.0, 128.7, 128.4, 127.4, 124.3, 69.7, 69.1,
67.6, 66.2, 52.9, 29.1, 19.7, 19.3; HRMS Calcd for C22H22N2O6
m/z 410.1478, found 410.1475.
(R)-N-Ben zyloxyca r bon yl-N-p h th a lim id oleu cin e Ben zyl
Ester . 2l P ) Z, R ) CH2-CH(CH3)2, R′ ) CH2P h . Oil; [R]D
)
ν
max/cm-1 3302, 1780, 1768, 1727; 1H NMR (250 MHz, CDCl3)
7.86-7.66 (m, 4 H), 7.40-7.24 (m, 5 H), 5.30-5.07 (m, 3 H), 3.91
+19.2 (c 1.13, CHCl3); Rf ) 0.60 (EtOAc/Hexane 4/6); IR (NaCl)

2872 J . Org. Chem., Vol. 66, No. 8, 2001
Notes
(s, 2 H); 13C NMR (CDCl3) 169.5, 166.5, 135.5, 134.7, 130.5, 128.9,
67.5, 52.0; HRMS Calcd for C17H14N2O4 m/z 310.0953, found
310.095.
N-Am in o-N-ter t-bu tyloxyca r bon ylglycin e Ben zyl Ester .
4a P ) Boc, R ) H, R′ ) CH2P h . Oil; Rf ) 0.45 (EtOAc/Hexane
4/6); IR (NaCl) νmax/cm-1 3337, 1747, 1712; 1H NMR (400 MHz,
CDCl3) 7.37-7.20 (m, 5 H), 5.12 (s, 2 H), 4.40-4.02 (m, 4 H),
1.54-1.26 (m, 9 H); 13C NMR (CDCl3) 170.1, 157.7, 135.8, 128.9,
128.7, 128.6, 81.5, 67.1, 53.8, 28.5; HRMS Calcd for C14H21N2O4
[M+H+] m/z 281.1501, found 281.1507.
(R)-N-P h th a lim id oa la n in e Ben zyl Ester . 3c P ) H, R )
CH3, R′ ) CH2P h . Mp 77-78 °C; [R]D ) +24.0 (c 0.96, CHCl3);
Rf ) 0.38 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 3298, 1786,
1729; 1H NMR (250 MHz, CDCl3) 7.86-7.64 (m, 4 H), 7.37-
7.21 (m, 5 H), 5.25 (d, J ) 6 Hz, 1 H), 5.15 (d, J ) 6 Hz, 2 H),
4.11-3.98 (m, 1 H), 1.40 (d, J ) 8 Hz, 3 H); 13C NMR (CDCl3)
171.9, 166.5, 135.4, 134.4, 130.1, 128.6, 128.4, 67.2, 57.5, 16.2;
HRMS Calcd for C18H16N2O4 m/z 324.1109, found 324.1110.
(R)-N-P h th a lim id oleu cin e Ben zyl Ester . 3e P ) H, R )
CH2-CH(CH3)2, R′ ) CH2P h . Oil; Rf ) 0.45 (EtOAc/Hexane
4/6); IR (NaCl) νmax/cm-1 3298, 1788, 1727; 1H NMR (400 MHz,
CDCl3) 7.83-7.58 (m, 4 H), 7.53-7.14 (m, 5 H), 5.22-5.00 (m, 3
H), 4.11 and 3.89 (2 m, 1 H), 1.97-1.78 (m, 1 H), 1.67 (t, J ) 9
Hz, 2 H), 1.04-0.77 (m, 6 H); 13C NMR (CDCl3) 172.9, 166.3,
135.7, 135.6, 130.5, 128.8, 128.6, 123.7, 67.5, 61.8, 40.4, 25.2,
22.9, 22.6.
(R)-N-Am in o-N-ter t-bu tyloxycar bon ylalan in e Ben zyl Es-
ter . 4c P ) Boc, R ) CH3, R′ ) CH2P h . Oil; [R]D ) +21.5 (c
2.03, CHCl3); Rf ) 0.65 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1
1
3351, 1743, 1702; H NMR (400 MHz, CDCl3) 7.36-7.18 (m, 5
H), 5.09 (s, 2 H), 4.92-4.74 and 4.74-4.54 (2 m, 1 H), 3.98-
3.73 (2 m, 2 H), 1.43 (d, J ) 10 Hz, 3 H), 1.36 (s, 9 H); 13C NMR
(CDCl3) 172.3, 157.7, 136.1, 128.9, 128.5, 128.4, 81.3, 67.2, 57.5,
28.8, 15.2; HRMS Calcd for C15H23N2O4 [M+H+] m/z 295.1657,
found 295.1652.
(R)-N-Am in o-N-ter t-bu tyloxyca r bon ylleu cin e Ben zyl Es-
ter . 4e P ) Boc, R ) CH2-CH(CH3)2, R′ ) CH2P h . Mp 50 °C;
Rf ) 0.75 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 3351, 1737,
1702; 1H NMR (400 MHz, CDCl3) 7.48-7.21 (m, 5 H), 5.18 (s, 2
H), 5.00-4.85 and 4.82-4.60 (2 m, 1 H), 3.97-3.70 (m, 2 H),
2.12-1.97 (m, 1 H), 1.70-1.35 (m with s at 1.45, 11 H), 0.97
and 0.91 (2 d, J ) 13 Hz, 6 H); 13C NMR (CDCl3) 172.4, 159.0,
136.1, 128.9, 128.6, 128.3, 81.4, 67.0, 59.2, 37.6, 28.6, 25.2, 23.7,
21.3; HRMS Calcd for C18H29N2O4 [M+H+] m/z 337.2127 found
337.2128.
N-P h th a lim id oglycin e Meth yl Ester . 3g P ) H, R ) H,
R′ ) CH3. Mp 147-148 °C; Rf ) 0.20 (EtOAc/Hexane 4/6); IR
(KBr) νmax/cm-1 3307, 1778, 1746, 1712; 1H NMR (400 MHz,
CDCl3) 7.86-7.62 (m, 4 H), 5.22-5.07 (m, 1 H), 3.81 (d, J ) 6
Hz, 2 H), 3.70 (s, 3H); 13C NMR (CDCl3) 170.1, 166.5, 134.7,
130.5, 123.9, 52.6, 51.8; HRMS Calcd for
234.0640, found 234.0643.
C11H10N2O4 m/z
N-Am in o-N-ben zyloxyca r bon ylglycin e Ben zyl Ester . 4f
P ) Z, R ) H, R′ ) CH2P h . Mp 66 °C; Rf ) 0.35 (EtOAc/Hexane
4/6); IR (NaCl) νmax/cm-1 3355, 1723, 1700; 1H NMR (400 MHz,
CDCl3) 7.60-7.14 (m, 10 H), 5.34 and 5.06 (m, 4 H), 5.51-4.14
(m, 4 H); 13C NMR (CDCl3) 169.8, 158.5, 136.4, 135.7, 129.0,
128.8, 128.4, 68.6, 67.4, 53.5; HRMS Calcd for C17H19N2O4
[M+H+] m/z 315.1345, found 315.1339.
(R)-N-Am in o-N-ben zyloxyca r bon yla la n in e Ben zyl Es-
ter . 4h P ) Z, R ) CH3, R′ ) CH2P h . Oil; [R]D ) +3.3 (c 1.5,
CHCl3); Rf ) 0.53 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 3355,
1723, 1700; 1H NMR (400 MHz, CDCl3) 7.46-7.20 (m, 10 H),
5.14 and 5.09 (2 s, 4 H), 5.05-4.90 and 4.90-4.60 (2 m, 1 H),
4.14-3.8 (m, 2 H), 1.4 (d, 3 H, J ) 11 Hz); 13C NMR (CDCl3)
172.0, 158.7, 136.6, 136.2, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4,
68.3, 67.2, 57.3, 15.3; HRMS Calcd for C18H20N2O4 m/z 328.1423,
found 328.1420.
(R)-N-Am in o-N-ben zyloxyca r bon ylva lin e Ben zyl Ester .
4j P ) Z, R ) CH(CH3)2, R′ ) CH2P h . Oil; [R]D ) +33.0 (c
1.14, CHCl3); Rf ) 0.55 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1
3353, 1741, 1707; 1H NMR (400 MHz, CDCl3) 7.34-7.11 (m, 10
H), 5.17-4.97 (m, 4 H), 4.57-4.20 (2 m, 1 H), 4.06-3.80 (m, 2
H), 2.49-2.31 (m, 1 H), 1.00 and 0.91 (2 d, J ) 6 Hz, 6 H); 13C
NMR (CDCl3) 171.2, 158.7, 136.5, 136.0, 129.0, 128.9, 128.7,
128.6, 128.4, 128.3, 68.4, 67.0, 28.5, 20.2; HRMS Calcd for
C20H24N2O4 m/z 356.1736, found 356.1737.
(R)-N-P h th a lim id oa la n in e Meth yl Ester . 3i P ) H, R )
CH3, R′ ) CH3. Mp 82 °C; [R]D ) +32.8 (c 0.73, CHCl3); Rf )
0.35 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 3302, 1783, 1710;
1H NMR (400 MHz, CDCl3) 7.71-7.55 (m, 4 H), 5.13 (d, J ) 7
Hz, 1 H), 3.90-3.77 (m, 1 H), 3.58 (s, 3 H), 1.26 (d, J ) 8 Hz, 3
H); 13C NMR (CDCl3) 170.7, 166.8, 136.6, 130.3, 123.7, 57.6, 52.6,
16.4; HRMS Calcd for C12H13N2O4 [M+H+] m/z 249.0868, found
249.0875.
(R)-N-P h th a lim id ova lin e Meth yl Ester . 3k P ) H, R )
CH(CH3)2, R′ ) CH3. Oil; Rf ) 0.50 (EtOAc/Hexane 4/6); IR
1
(NaCl) νmax/cm-1 3297, 1787, 1728; H NMR (400 MHz, CDCl3)
7.81-7.64 (m, 4 H), 5.10 (d, J ) 7 Hz, 1 H) 3.71 (s, 3 H), 3.43 (t,
J ) 7 Hz, 1 H), 2.09-1.96 (m, 1 H), 1.10 and 0.98 (2 d, J ) 7
Hz, 6 H); 13C NMR (CDCl3) 173.2, 166.5, 134.6, 130.5, 123.7,
69.5, 52.3, 30.9, 19.2; HRMS Calcd for C14H16N2O4 m/z 276.1110,
found 276.1107.
(R)-N-P h th a lim id oleu cin e Meth yl Ester . 3m P ) H, R )
CH2-CH(CH3)2, R′ ) CH3. Oil; [R]D ) +45.96 (c 0.57, CHCl3);
Rf ) 0.50 (EtOAc/Hexane 4/6); IR (NaCl) νmax/cm-1 3300, 1787,
1727; 1H NMR (400 MHz, CDCl3) 7.76-7.59 (m, 4 H), 5.04 (d, J
) 10 Hz, 1 H), 3.73 (q, J ) 9 Hz, 1 H), 3.62 (s, 3 H), 1.85-1.70
(m, 1 H), 1.56 (t, J ) 9 Hz, 2 H), 0.88 and 0.85 (2 d, J ) 9 Hz,
6 H); 13C NMR (CDCl3) 173.4, 166.4, 134.6, 130.4, 123.7, 61.8,
52.5, 40.3, 25.6, 22.8 and 22.6; HRMS Calcd for C15H18N2O4 m/z
290.1267, found 290.1269.
(R)-N-P h th a lim id op h en yla la n in e Ben zyl Ester . 3n P )
H, R ) CH2C6H5, R′ ) CH2C6H5. Oil; Rf ) 0.45 (EtOAc/Hexane
4/6); IR (NaCl) νmax/cm-1 3298, 1787, 1725; 1H NMR (400 MHz,
CDCl3) 7.83-7.63 (m, 4 H), 7.40-7.04 (m, 10 H), 5.20-5.03 (m,
3 H), 4.37-4.25 (m, 1 H), 3.20 and 3.13 (2 dd, J ) 8 Hz, 14 Hz,
2 H); 13C NMR (CDCl3) 171.5, 166.6, 136.4, 135.5, 134.6, 130.4,
129.6, 128.9, 128.7, 127.3, 123.8, 67.6, 63.5, 36.5; HRMS Calcd
for C24H20N2O4 m/z 400.1423, found 400.1424.
(R)-N-P h th a lim id op h en yla la n in e Meth yl Ester . 3o P )
H, R ) CH2C6H5, R′ ) CH3. Mp 80-82 °C; Rf ) 0.40 (EtOAc/
Hexane 4/6); IR (NaCl) νmax/cm-1 3294, 1787, 1726; 1H NMR (400
MHz, CDCl3) 7.77-7.59 (m, 4 H), 7.31-6.88 (m, 5 H), 4.99 (d, J
) 5 Hz, 1 H), 4.19 (m, 1 H), 3.63 (s, 3 H), 3.15 and 3.05 (2 dd, J
) 14 Hz, 8 Hz, 2 H); 13C NMR (CDCl3) 172.0, 166.5, 136.5, 134.5,
130.4, 129.5, 128.8, 127.2, 123.7, 63.4, 52.6, 37.5; HRMS Calcd
for C18H16N2O4 m/z 324.1110, found 324.1098.
Gen er a l P r oced u r e for th e Dep h th a loyla tion Rea ction .
To a solution of compound 2 (3 mmol) in THF (20 mL) was added
MeNHNH2 (4.5 mmol) at -20 °C or 0 °C (see Table 1) and the
mixture was stirred at this temperature for 30 mn. The solution
was then allowed to warm to room temperature, stirred for the
time indicated in the table, and then concentrated in vacuo.
EtOAc was added and the white precipitate was filtered off. The
filtrate was evaporated and the residue was chromatographed
on neutral alumina gel.
(R)-N-Am in o-N-ben zyloxyca r bon ylleu cin e Ben zyl Ester .
4l P ) Z, R ) CH2-CH(CH3)2, R′)CH2P h . Mp 59-62 °C; [R]D
) +12.9 (c 1.08, CHCl3); Rf ) 0.65 (EtOAc/Hexane 4/6); IR
1
(NaCl) νmax/cm-1 3353, 1739, 1702; H NMR (250 MHz, CDCl3)
7.42-7.16 (m, 10 H), 5.16 and 5.13 (2 s, 4 H), 5.00-4.84 and
4.84-4.64 (m, 1 H), 4.03-3.77 (m, 2 H), 2.16-1.93 (m, 1 H),
1.81-1.45 (m, 2 H), 0.93 (d, J ) 6 Hz, 6 H); 13C NMR (CDCl3)
172.2, 159.0, 136.5, 136.1, 129.0, 128.9, 128.7, 128.5, 68.5, 67.2,
59.7, 59.2, 37.5, 37.2, 25.1, 23.7, 21.4; HRMS Calcd for C21H26N2O4
m/z 370.1893, found 370.1893.
(R)-N-Am in o-N-ben zyloxyca r bon ylp h en ya la n in e Ben zyl
Ester . 4n P ) Z, R ) CH2C6H5, R′ ) CH2P h . Mp 44 °C; [R]D
) +20.8 (c 1.63, CHCl3); Rf ) 0.60 (EtOAc/Hexane 4/6); IR
1
(NaCl) νmax/cm-1 3345, 1741, 1702; H NMR (400 MHz, CDCl3)
7.31-6.89 (m, 15 H), 5.22-4.77 (m, 5 H), 3.97-3.70 (m, 2 H),
3.28 (d, J ) 7 Hz, 2 H); 13C NMR (CDCl3) 171.0, 158.5, 138.2,
136.5, 136.0, 129.4, 129.1, 129.0, 128.9, 128.6, 128.4, 128.1, 127.1,
68.3, 67.5, 63.0, 35.1; HRMS Calcd for C24H24N2O4 m/z 404.1736,
found 404.1733.
(S)-N-Am in o-N-ben zyloxyca r bon ylp h en ya la n in e Ben zyl
Ester . 4p P ) Z, R ) CH2C6H5, R′ ) CH2P h . Mp 44 °C; [R]D
) -20.4 (c 1.84, CHCl3); Rf ) 0.60 (EtOAc/Hexane 4/6).
Deter m in a tion of En a n tiom er ic P u r ity: Dep r otection of
Hyd r a zin oa cid s 4. A solution of hydrazinoacid 4 (4h , 4j, 4l,
4n , or 4p , 1 mmol) in ethanol was hydrogenated with Raney
nickel (50 bar of H2, 18 h, 25 °C, 6 mmol). In the cases of

Notes
J . Org. Chem., Vol. 66, No. 8, 2001 2873
compounds 4c and 4e, a preliminary removal of the BOC group
with CF3COOH in CH2Cl2 was necessary. The amino acid was
obtained after filtration over Celite and evaporation of the
solvent. Der iva tiza tion a n d HP LC An a lysis. A solution of
amino acid (40 µL of approximatively 1 mg/mL) was mixed with
borate buffer (80 µL of a 0.133 M solution in borate buffer pH
10.4), o-phthalaldehyde (40 µL of a 5 mg/mL solution in a borate
buffer), and N-isobutyryl-D-cysteine (40 µL of a 20 mg/mL
solution in a borate buffer). After 5 min, 25 µL of this solution
was injected onto a Merck LichroCart 250-4 Purospher RP-18e
(5 µm). The mobile phase was acetonitrile/ammonium acetate
(50 mM, pH 7.0) at 1 mL/min under isocratic conditions (27/73
for leucine, retention time for DD isomer 4.34 and 4.91 min for
LD); (20/80 for alanine, retention time for DD and LD isomers
is respectively 3.64 min and 4.00 min); (25/75 for valine,
retention time for DD and LD isomers is respectively 3.80 and
4.80 min); (25/75 for phenylalanine, retention time for DD and
LD isomers is respectively 10.42 min and 11.72 min). The
derivatives were identified by comparison with authentic samples.
Chiral purity was determined by integration of HPLC profile
monitored at 338 nm and comparison to the peaks of authentic
samples.
Ack n ow led gm en t. We are grateful to the European
Communities Commission for financial support (con-
tract BMH4-CT96-1492).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of 2a , 2c, 2e, 2g, 2k , and 2n . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O005696T