A general approach to dehydro-Freidinger lactams: Ex-chiral pool synthesis and spectroscopic evaluation as potential reverse turn inducers

Article abstract of DOI:10.1021/jo0261653

Starting from natural α-amino acids, a practical synthesis of the dehydro-Freidinger lactams 9a-h based on the ring-closing olefin metathesis reaction was investigated. The presented examples comprise 6-, 7-, 8-, 9-, and 10-membered cyclic dipeptide mimics. Structural variations were demonstrated. We approached the metathesis precursors 8a-h employing an N-alkylation/peptide-coupling strategy. Subsequent ring closure was promoted by the ruthenium-based catalyst 10a or 10b. The resulting tetraresidue 11d was shown to undergo intramolecular hydrogen bonding based on NMR and FT-IR studies. Thus, the development of dehydro-Freidinger lactams as potential reverse turn inducers stabilizing an intramolecular NHⁱ⁺³...COⁱ hydrogen-bond was demonstrated.

Full text of DOI:10.1021/jo0261653

A Gen er a l Ap p r oa ch to Deh yd r o-F r eid in ger La cta m s: Ex-Ch ir a l
P ool Syn th esis a n d Sp ectr oscop ic Eva lu a tion a s P oten tia l Rever se
Tu r n In d u cer s†
Tobias Hoffmann, Reiner Waibel, and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander-University,
Schuhstr. 19, D-91052 Erlangen, Germany
gmeiner@pharmazie.uni-erlangen.de
Received J uly 9, 2002
Starting from natural R-amino acids, a practical synthesis of the dehydro-Freidinger lactams 9a -h
based on the ring-closing olefin metathesis reaction was investigated. The presented examples
comprise 6-, 7-, 8-, 9-, and 10-membered cyclic dipeptide mimics. Structural variations were
demonstrated. We approached the metathesis precursors 8a -h employing an N-alkylation/peptide-
coupling strategy. Subsequent ring closure was promoted by the ruthenium-based catalyst 10a or
10b. The resulting tetraresidue 11d was shown to undergo intramolecular hydrogen bonding based
on NMR and FT-IR studies. Thus, the development of dehydro-Freidinger lactams as potential
reverse turn inducers stabilizing an intramolecular NHi+3‚‚‚COi hydrogen-bond was demonstrated.
SCHEME 1
In tr od u ction
The regulation of biological signal transduction in-
volves interactions of peptide ligands with their receptors
when the binding process of a highly flexible peptide
ligand leads to an unfavorable loss of entropy due to the
reduction of conformational freedom. Hence, the confor-
mational restriction of the backbone of endogenic pep-
tides offers a great challenge to increase the affinity and
selectivity to a given receptor and provides indirect
information about the bio-active conformation of the
natural ligand. Extensive efforts have been made on the
preparation of peptide mimics for the development of
enzyme inhibitors and receptor modulators.1 Reverse-
turn templates have attracted particular attention since
â- or γ-turn conformations are commonly found among
bioactive peptides.2 Freidinger developed γ-, δ-, and
ꢀ-lactams of type 13 (Scheme 1) as molecular scaffolds
that were assigned to stabilize type-âII turns.4
employing an olefin linker to constrain the peptide
backbone.6 Recently, these findings were extended by
Piscopio and co-workers describing lactam-bridged â-turn
mimics based on a metathesis strategy.7 The examples
were limited to seven-membered heterocycles obtained
as mixtures of diastereomers. On the other hand, the
ability of cyclic templates to stabilize an intramolecular
hydrogen bond strongly depends on both ring size and
substitution pattern.8 Complementary to our ongoing
research concerning the design and conformational char-
acterization of lactam-bridged â-amino acid analogues,9
During the past decade, the ring-closing olefin meta-
thesis reaction (RCM) emerged as an elegant manner of
carbon-carbon-bond formation.5 Initial results on the
synthesis of rigidified peptides by RCM published by
Grubbs and co-workers involved the R-amino ꢀ-lactam 2
† This paper is dedicated to the memory of Professor Henry Rapo-
port.
(1) (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993,
32, 1244; Angew. Chem. 1993, 105, 1303. (b) Gante, J . Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1699; Angew. Chem. 1994, 106, 1780. (c)
Liskamp, R. M. J . Recl. Trav. Chim. Pays-Bas 1994, 113, 1.
(2) (a) Vacca, J . P.; Condra, J . H. Drug Discovery Today 1997, 2,
261. (b) Hruby, V. J . Drug Discovery Today 1997, 2, 165.
(3) Freidinger, R. M. J . Org. Chem. 1985, 50, 3631.
(6) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606.
(4) Valle, G.; Crisma, M.; Toniolo, C.; Yu, K.-L.; J ohnson, R. L. J .
Chem. Soc., Perkin Trans. 2 1998, 83.
(5) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036; Angew. Chem 1997, 109, 2124. (b) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012; Angew. Chem. 2000, 112, 3140. (c) Armstrong,
S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371.
(7) Piscopio, A. D.; Miller, J . F.; Koch, K. Tetrahedron 1999, 55, 8189.
(8) (a) Kim, K.; Germanas, J . P. J . Org. Chem. 1997, 62, 2847. (b)
Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew. Chem., Int.
Ed. 2001, 40, 3361; Angew. Chem. 2001, 113, 3465.
(9) Weber, K.; Ohnmacht, U.; Gmeiner, P. J . Org. Chem. 2000, 65,
7406.
10.1021/jo0261653 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/21/2002
62
J . Org. Chem. 2003, 68, 62-69

General Approach to Dehydro-Freidinger Lactams
SCHEME 2a
a
Reagents: (a) 4-nitrobenzenesulfonyl chloride, NEt3, CH2Cl2, 0 °C (62-69%); (b) allyl bromide, K2CO3, DMF for 5a (92%) and for 5f
(95%) 3-bromo-2-methyl-1-propane, K2CO3, DMF for 5e (94%); DEAD, PPh3, CH2Cl2, 3-buten-1-ol for 5b (76%), 4-penten-1-ol for 5c (66%),
5-hexen-1-ol for 5d (55%); (c) PhSH, K2CO3, DMF (28-71%); (d) HCl, ether, 0 °C (99%).
SCHEME 3a
we herein report a widely applicable and general protocol
for the preparation of differently sized unsaturated
lactams of type 3 (which we call dehydro-Freidinger
lactams). The strategy is based on an ex-chiral pool
approach involving N-alkylation, peptide-coupling, and
ring-closing olefin metathesis as the key reaction step.
Furthermore, the ability of the tetraresidue sequences
to stabilize â-turn conformations is described.
Resu lts a n d Discu ssion
Meta th esis P r ecu r sor s. Based upon work published
by Fukuyama10 and Reichwein and Liskamp,11 the pro-
tected building blocks 6a -g (Scheme 2) were obtained
from the glycine and alanine esters 4a and 4b by
transformation into the corresponding sulfonamides and
subsequent N-alkylation. Thiol-induced N-deprotection
afforded the respective secondary amines that were
isolated as their hydrochloride salts 6a -g.12
The metathesis precursors 8b-h were readily avail-
Reagents: (a) NMM/ClCO2 iBu, THF, -15 °C for 8a (28%);
DCC/HOBt, DIEA, CH2Cl2 for 8b-h (19-83%); (b) 10a (10 mol
%) or 10b (5 mol %), see Table 1.
a
able employing DCC/HOBt-promoted peptide coupling of
the secondary amines 6a -g with the N-terminal-pro-
tected allyl glycine 7b13 (Scheme 3). The preparation of
the diene 8a starting from the vinyl glycine derivative
7a 14 was achieved using the mixed anhydride method.
smoothly to furnish the corresponding seven-membered
lactams 9b-d (entry 2).
Meta th esis Rea ction a n d Syn th esis of â-Tu r n
Mod el System s. Starting from the cyclization precursor
8a , the ring-closing olefin metathesis reaction was elabo-
rated. RCM-based transformations of vinyl glycine de-
rivatives are described as problematic and strongly
dependent on substitution patterns.6,15 Employing 1,2-
dichloroethane (DCE) at reflux temperature and a diene
concentration of 5 mM, we obtained the aminopiperidi-
none 9a in 53% yield after 48 h employing the ruthenium
complex 10a 16 (Table 1, entry 1). The metathesis of the
N-allylglycine derived dienes 8b -d also proceeded
Exchange of glycine by alanine in position i + 2 slightly
lowered the yield. The highly active catalyst 10b16 was
employed to promote the ring closure of the methyl-
substituted diene 8d , resulting in the formation of
azepinone 9d in 89% yield. For the synthesis of medium-
sized rings being known as a remarkable challenge, the
diene concentration for the RCM of 8e-g was lowered
to 2 mM, since previous results8b indicated this concen-
tration to be sufficient to prevent possible oligomerization
processes. As a consequence, the azocanone 9e could be
isolated in 70% yield (entry 3). No byproducts were
detected. The alanine-derived diene 8f led to the cycloole-
fin 9f (60% yield). The synthetic potential of the strategy
was demonstrated by the synthesis of the nine-membered
azacycle 9g which was isolated in 86% yield (entry 4).
No side reactions were observed. According to the NMR
spectra, only the cis isomer was formed. We attempted
to enlarge the ring size of the lactam templates by the
synthesis of a 10-membered ring compound. There are
only a few examples in the literature that describe the
(10) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373.
(11) (a) Reichwein, J . F.; Liskamp, R. M. J . Eur. J . Org. Chem. 2000,
2335. (b) Reichwein, J . F.; Versluis, C.; Liskamp, R. M. J . J . Org. Chem.
2000, 65, 6187. (c) Reichwein, J . F.; Liskamp, R. M. J . Tetrahedron
Lett. 1998, 39, 1243.
(12) Hoffmann, T.; Gmeiner, P. Synlett 2002, 6, 1014.
(13) Prepared from commercially available (S)-allylglycine.
(14) (a) Afzali-Ardakani, A.; Rapoport, H. J . Org. Chem. 1980, 45,
4817. (b) Meffre, P.; Vo-Quang, L.; Vo-Quang, F. Le Goffic Synth.
Commun. 1989, 19, 3457.
(15) Campagne, J .-M.; Ghosez, L. Tetrahedron Lett. 1998, 39, 6175.
(16) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
J . Org. Chem, Vol. 68, No. 1, 2003 63

Hoffmann et al.
SCHEME 4a
TABLE 1. Resu lts of th e Meta th esis Rea ction of th e
Dien es 8b-h (1,2-Dich lor oeth a n e, 81 °C)
a
Reagents: (a) MeNH2, EtOH, rt (55-95%).
TABLE 2. 1H NMR Da ta for P ep tid e Con ju ga tes 8b -h (2
m M, CDCl3)
∆δNH2 b (ppm)
CDCl3 f DMSO-d6
compd
δNH1 a (ppm)
δNH2 a (ppm)
11b
11c
11d
5.66
5.54
5.51
6.02
6.41
6.67
-1.69
-1.18
-0.86
a
b
Designation as indicated in Scheme 4. Difference of NH
chemical shift.
NMR data are visualized in Table 2. The chemical shift
value, the behavior upon addition of a competitive
solvent, the temperature and concentration dependence
of their chemical shift, and particularly NOE experiments
are discussed as parameters reflecting the hydrogen-
bonding states of amide protons.19 To distinguish a
hydrogen-bonded from a non-hydrogen-bonded popula-
tion, all these parameters have to be considered.20 The
resonances for the amide protons NH2 of all peptide
analogues 11b-d were observed at lower field when
compared to the protons NH1. Interestingly, the protons
NH2 resonate increasingly downfield when the ring size
is enlarged (6.02 ppm for 11b, 6.41 ppm for 11c, 6.67
ppm for 11d ). Furthermore, when the hydrogen bond
acceptor DMSO-d6 was employed for NMR experiments,
the signals for the protons NH2 appeared at lower field.
More important, the differences between the chemical
shifts in CDCl3 and the chemical shifts in DMSO-d6 were
decreased when the ring size is enlarged from 11b to 11d
consistent with an increasing amount of intramolecular
hydrogen bonding.21 VT-NMR experiments displayed a
strong chemical shift change of the NH2 signal of the
azonine-based peptide mimetic 11d (δ/∆T -5.8 ppb/K)
indicating a temperature-dependent equilibrium of hy-
drogen-bonded and nonbonded populations.
synthesis of 10-membered rings by olefin metathesis.17
When a high-dilution/slow addition strategy for the
metathesis reaction of 8h at a concentration of 0.5 mM
was employed, the azacycle 9h was isolated with 8% yield
besides unreacted material and some polar byproducts.
The NMR spectra of the chromatographic clean product
9h displayed a minor impurity (likely the E-isomer,
unambiguous assignment was impossible). Subsequent
treatment of the representative lactams 9a ,b,e,g with
methylamine furnished the model peptide mimics 11a -d
(Scheme 4). Due to an obvious deprotonation of the acidic
R-proton of the vinyl glycine substructure, a migration
of the double bond of the lactam 9a occurred under the
reaction conditions investigated when the R,â-unsatur-
ated lactam 11a was isolated. Nevertheless, the amides
11b-d were obtained in 55-95 yield.
This deduction is independently reinforced by confor-
mational analysis of the nine-membered azacycle 11d
based on NOE experiments (Figure 1).
NMR Sp ectr oscop y. To investigate the conforma-
tional preferences of the â-turn model systems, NMR
studies were performed at 2 mM concentrations thus
excluding intermolecular interactions.18 Characteristic
(18) Boussard, G.; Marraud, M. J . Am. Chem. Soc. 1985, 107, 1825-
1828.
(19) (a) Estiarte, M. A.; Rubiralta, M.; Diez, A. J . Org. Chem. 2000,
65, 6992. (b) Derrer, S.; Davies, J . E.; Holmes, A. B. J . Chem. Soc.,
Perkin Trans. 1 2000, 2943. (c) Kessler, H. Angew. Chem., Int. Ed.
Engl. 1982, 21, 512; Angew. Chem. 1982, 94, 509.
(20) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C.
Eur. J . Org. Chem. 1999, 389.
(17) For examples, see: (a) Heinrich, M. R.; Steglich, W. Tetrahedron
Lett. 2001, 42, 3287. (b) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J .
A. J . Am. Chem. Soc. 1998, 120, 4334. (c) Nevalainen, M.; Koskinen,
A. M. P. J . Org. Chem. 2002, 67, 1554. (d) Fu¨rstner, A.; Langemann,
K. Synlett 1997, 8, 1010.
(21) Liang, G. B.; Rito, C. J .; Gellman, S. H. J . Am. Chem. Soc. 1992,
114, 4440.
64 J . Org. Chem., Vol. 68, No. 1, 2003

General Approach to Dehydro-Freidinger Lactams
Exp er im en ta l Section
Gen er a l Meth od s. All manipulations were carried out in
dry solvents under an atmosphere of dry N2. Commercially
available reagents were used without further purification.
DMF and 1,2-dichloroethane were purchased (0.005% water).
Et2O was freshly distilled from Na/benzophenone prior to use.
Evaporations of solutions were done with a rotary evaporator.
Flash chromatography was conducted on silica gel (230-400
mesh) using freshly distilled solvents. All 1H NMR experiments
were performed at 360 MHz and all 13C NMR at 62.9 MHz
with internal standard TMS (1H NMR) and the solvent signal
(13C NMR), respectively; NOEs were obtained using difference
spectroscopy with a pre-irradiation period of 4 s. Coupling
constants are reported in hertz. Multiple irradiation points per
resonance were used to suppress SPT. NOE samples were
degassed by 5 freeze-pump-thaw cycles. MS were run by EI
ionization (70 eV).
F IGURE 1. Diagnostic NOEs for the equilibrium between the
conformations A and B for compound 11d .
Nos-Gly-OEt (I). Obtained from 4a (1.0 g, 7.16 mmol), Nos-
Cl (1.75 g, 7.88 mmol), and NEt3 (2.99 mL, 21.5 mmol) in CH2-
Cl2 (25 mL) as described for Nos-Gly-OMe in ref 11a. Purifi-
cation by flash chromatography (ligroin-EtOAc, 1:1) yielded I
(1.27 g, 62%) as a pale yellow solid: mp 114-115 °C; Rf 0.32
(ligroin-EtOAc, 1:1); IR (film) 3289, 1739, 1530 cm-1; 1H NMR
(CDCl3) δ 1.22 (t, J ) 7.1, 3H), 3.87 (d, J ) 5.3, 2H), 4.12 (q,
J ) 7.1, 2H), 5.41 (m, 1H), 8.01-8.15 (m, 2H), 8.32-8.42 (m,
2H); 13C NMR δ 13.9, 44.1, 62.2, 124.4, 128.5, 145.3, 150.2,
168.4; EIMS 288 (M+). Anal. Calcd for C10H12N2O6S: C, 41.66;
H, 4.20; N, 9.72; S, 11.12. Found: C, 41.55; H, 4.30; N, 9.58;
S, 11.00.
Nos-(S)-Ala -OMe (II). Obtained from 4b (1.0 g, 7.16 mmol),
Nos-Cl (1.75 g, 7.88 mmol), and NEt3 (2.99 mL, 21.5 mmol) in
CH2Cl2 (25 mL) as described for Nos-Gly-OMe in ref 11a.
Purification by flash chromatography (ligroin-EtOAc, 6:4)
yielded II (1.42 g, 69%) as a pale yellow solid: mp 108-109
°C; Rf 0.33 (ligroin-EtOAc, 6:4); [R]20D +16.6 (c ) 1.0, CHCl3);
IR (film) 3275, 1741, 1530 cm-1; 1H NMR (CDCl3) δ 1.44 (d, J
) 7.1, 3H), 3.60 (s, 3H), 4.12 (m, 1H), 5.49 (d, J ) 8.2, 1H),
8.00-8.10 (m, 2H), 8.35-8.41 (m, 2H); 13C NMR (CDCl3) δ
19.9, 51.6, 52.9, 124.3, 128.4, 145.9, 150.2, 172.1; EIMS 288
(M+). Anal. Calcd for C10H12N2O6S: C, 41.66; H, 4.20; N, 9.72;
S, 11.12. Found: C, 41.34; H, 4.24; N, 9.55; S, 10.38.
F IGURE 2. NH-stretch FT-IR data of 11d (2 mM sample in
CHCl3) after subtraction of the spectrum of 9g.
At room temperature, strong NOEs between H-6/H-5,
H-5/H-4a, H-4a/H-3, and H-11/H-3 are indicative for the
boatlike conformation A of the nine-membered lactam
which enables the formation of an intramolecular hydro-
gen bond NHi+3‚‚‚COi. The coexistence of conforma-
tion B was confirmed by diagnostic NOEs between
H-3/H-9 and H-6/H-12 which are diminished by lowering
the temperature (+5 °C) indicating an increase of A. This
is consistent with the observed temperature coeffi-
cient (see above) indicating a substantially higher amount
of intramolecular hydrogen bonding at low tempera-
ture.
Nos-N-(a llyl)-Gly-OEt (5a ). Obtained from I (250 mg, 0.87
mmol), K2CO3 (360 mg, 2.61 mmol), and allyl bromide (151
µL, 1.74 mmol) in DMF (15 mL) as described for Nos-N-allyl-
Phe-OMe in ref 11a. Purification by flash chromatography
(ligroin-EtOAc, 8:2) furnished 5a (263 mg, 92%) as a pale
yellow solid: mp 69-71 °C; Rf 0.19 (ligroin-EtOAc, 8:2); IR
1
(film) 1743, 1645, 1535 cm-1; H NMR (CDCl3) δ 1.21 (t, J )
F T-IR Sp ectr oscop y. IR spectroscopy is believed as
a more valuable tool for attributing hydrogen bonding
to amide protons. Due to a much shorter time scale, a
differentiation between N-H-stretching absorptions for
hydrogen-bonded and non-hydrogen-bonded states is
possible.
After subtraction of the spectrum of 9g from the
spectrum of 11d and subsequent baseline correction, the
NH region of the IR spectrum of 11d at a 2 mM
concentration in CHCl3 displays only NH-stretch absorp-
tions for NH2 (Figure 2). The absorption band at 3446
cm-1 clearly results from a non-hydrogen-bonded amide
NH2.22 The broad absorption at 3370 cm-1 represents the
intramolecularly bonded portion of NH2, which is in
accordance to the results of the NMR-measurements. In
summary, both NMR and FT-IR experiments strongly
indicate the ability of the azoninone 11d to stabilize
intramolecularly hydrogen-bonded conformations.
7.3, 3H), 3.94 (d, J ) 6.3, 2H), 4.09 (q, J ) 7.2, 2H), 4.10 (s,
2H), 5.20-5.30 (m, 2H), 5.72 (dddd, J ) 6.5, 16.8, 10.2, 6.5,
1H); 13C NMR (CDCl3) δ 14.1, 46.9, 50.8, 61.5, 120.5, 124.1,
128.7, 131.5, 145.8, 150.0, 168.5; EIMS 255 (M - CO2Et+), M+
not observed. Anal. Calcd for C13H16N2O6S: C, 47.56; H, 4.91;
N, 8.53; S, 9.77. Found: C, 47.54; H, 4.93; N, 8.49; S, 9.60.
Nos-N-(3-bu ten yl)-Gly-OEt (5b). Obtained from I (100
mg, 0.35 mmol), PPh3 (104 mg, 0.46 mmol), 3-buten-1-ol (39
µL, 0.46 mmol), and DEAD (209 µL, 40% in toluene, 0.46
mmol) in CH2Cl2 (20 mL) as described for Nos-N-(3-butenyl)-
Gly-OMe in ref 11a. Purification by flash chromatography
(ligroin-EtOAc, 8:2) yielded 5b (104 mg, 87%) as a colorless
solid: mp 51-53 °C; Rf 0.23 (ligroin-EtOAc, 8:2); IR (film)
1747, 1642, 1531 cm-1 1H NMR (CDCl3) δ 1.22 (t, J ) 7.1,
;
3H), 2.30-2.41 (m, 2H), 3.37 (t, J ) 7.1, 2H), 4.09 (q, J ) 7.1,
2H), 4.16 (s, 2H), 5.01-5.18 (m, 2H), 5.71 (m, 1H), 7.95-8.10
(m, 2H), 8.30-8.40 (m, 2H); 13C NMR (CDCl3) δ 14.0, 32.4,
47.6, 47.9, 61.6, 117.8, 124.1, 128.7, 133.9, 145.7, 150.0, 168.5;
EIMS 342 (M+). Anal. Calcd for C14H18N2O6S: C, 49.11; H,
5.30; N, 8.18; S, 9.37. Found: C, 49.22; H, 5.37; N, 8.10; S,
8.97.
Nos-N-(4-p en ten yl)-Gly-OEt (5c). Obtained from I (98 mg,
0.34 mmol), PPh3 (100 mg, 0.44 mmol), 4-penten-1-ol (45 µL,
0.44 mmol), and DEAD (200 µL, 40% in toluene, 0.44 mmol)
(22) (a) Gellman, S. H.; Dado, G. P.; Liang, G. B.; Adams, R. B. J .
Am. Chem. Soc. 1991, 113, 1164. (b) Gellman, S. H.; Desper, J . M.;
Liang, G. B. J . Am. Chem. Soc. 1993, 115, 925.
J . Org. Chem, Vol. 68, No. 1, 2003 65

Hoffmann et al.
in CH2Cl2 (20 mL) as described for 5b. Purification by flash
chromatography (ligroin-EtOAc, 8:2) yielded 5c (80 mg, 66%)
as a colorless solid: mp 73-75 °C; Rf 0.25 (ligroin-EtOAc, 8:2);
IR (film) 1748, 1641, 1530 cm-1; 1H NMR (CDCl3) δ 1.22 (t, J
) 7.1, 3H), 1.65-1.78 (m, 2H), 2.05-2.17 (m, 2H), 3.29 (t, J )
7.5, 2H), 4.09 (q, J ) 7.1, 2H), 4.14, (s, 2H), 4.95-5.10 (m,
2H), 5.76 (dddd, J ) 6.7, 17.0, 10.3, 6.7, 1H), 8.00-8.10 (m,
2H), 8.30-8.41 (m, 2H); 13C NMR (CDCl3) δ 14.1, 26.9, 30.5,
47.6, 47.8, 61.6, 115.7, 124.1, 128.7, 136.9, 145.7, 150.0, 168.5;
EIMS 356 (M+). Anal. Calcd for C15H20N2O6S: C, 50.55; H,
5.66; N, 7.86; S, 8.99. Found: C, 50.54; H, 5.71; N, 7.81; S,
8.77.
Nos-N-(5-h exen yl)-Gly-OE t (5d ). Obtained from I (150
mg, 0.52 mmol), PPh3 (154 mg, 0.68 mmol), 5-hexen-1-ol (78
µL, 0.68 mmol), and DEAD (124 µL, 0.68 mmol) in CH2Cl2 (10
mL) at 0 °C as described for 5b. Purification by flash chro-
matography (ligroin-EtOAc, 8:2) yielded 5d (106 mg, 55%)
as a pale yellow solid: mp 47-49 °C; Rf 0.30 (ligroin-EtOAc,
8:2); IR (film) 1749, 1639, 1531 cm-1; 1H NMR (CDCl3) δ 1.14
(t, J ) 7.1, 3H), 1.25-1.40 (m, 2H,), 1.45-1.55 (m, 2H), 1.90-
2.05 (m, 2H), 3.21 (t, J ) 7.5, 2H), 4.01 (q, J ) 7.1, 2H), 4.10
(s, 2H), 4.85-5.00 (m, 2H), 5.68 (dddd, J ) 10.5, 13.2, 10.5,
6.5, 1H), 7.90-8.00 (m, 2H), 8.28-8.35 (m, 2H); 13C NMR
(CDCl3) δ 14.0, 25.6, 27.0, 33.1, 47.5, 48.0, 61.6, 115.1, 124.1,
128.6, 137.9, 145.7, 149.9, 168.5; EIMS 370 (M+). Anal. Calcd
for C16H22N2O6S: C, 51.88; H, 5.99; N, 7.56; S, 8.66. Found:
C, 51.71; H, 6.10; N, 7.50; S, 8.47.
yielded 6a (98 mg, 67%) as a colorless oil. Analytical data are
in agreement with data previously published.11a
N-(3-Bu ten yl)-Gly-OEt‚HCl (6b). Obtained from 5b (463
mg, 1.35 mmol), K2CO3 (560 mg, 4.05 mmol), and PhSH (166
µL, 1.62 mmol) in DMF (7 mL) as described for 6a . Purification
by flash chromatography (ligroin-EtOAc, 3:7) yielded a yellow
oil. To a solution of this crude product in ether (3 mL) was
added a saturated solution of HCl in ether (2 mL) at 0 °C.
The resulting precipitate was filtered and dried (P4O10) to
furnish 6b (164 mg, 63%). 6b: colorless needles; mp 176-179
1
°C; IR (KBr) 3487, 1753, 1643 cm-1; H NMR (CH3OH-d4) δ
1.31 (t, J ) 7.2, 3H), 2.45-2.55 (m, 2H), 3.15 (t, J ) 7.6, 2H,),
3.98 (s, 2H), 4.31 (q, J ) 7.2, 2H), 5.20 (ddd, J ) 10.4, 2.4, 1.2,
1H), 5.25 (ddd, J ) 17.2, 3.1, 1.6, 1H), 5.82 (dddd, J ) 6.8,
17.2, 10.4, 6.8, 1H); 13C NMR (CH3OH-d4) δ 14.3, 31.3, 47.9,
48.3, 63.6, 119.3, 133.8, 167.7. Anal. Calcd for C8H16NO2Cl:
C, 49.61; H, 8.33; N, 7.23. Found: C, 49.74; H, 8.51; N, 7.10.
N-(4-P en ten yl)-Gly-OEt‚HCl (6c). Obtained from 5c (1.13
g, 3.17 mmol), K2CO3 (1.10 g, 7.93 mmol), and PhSH (419 µL,
3.80 mmol) in DMF (7 mL) as described for 6b. Yield: 184 mg
(28%). 6c: colorless solid; mp 186-188 °C; IR (KBr) 3448,
1747, 1641 cm-1; 1H NMR (CH3OH-d4) δ 1.31 (t, J ) 7.2, 3H),
1.78-1.85 (m, 2H), 2.12-2.22 (m, 2H), 3.05-3.10 (m 2H), 3.97
(s, 2H), 4.31 (q, J ) 7.1, 2H), 5.05 (ddd, J ) 10.3, 2.9, 1.2, 1H),
5.11 (ddd, J ) 17.1, 3.4, 1.7, 1H), 5.83 (dddd, J ) 6.7, 17.1,
10.3, 6.7, 1H); 13C NMR (CH3OH-d4) δ 14.3, 26.2, 31.5, 63.6,
74.3, 83.7, 116.7, 137.7, 167.8. Anal. Calcd for C9H18NO2Cl:
C, 52.05; H, 8.74; N, 6.74. Found: C, 51.62; H, 8.78; N, 6.64.
Nos-N-(2-m eth yl-2-pr open yl)-Gly-OEt (5e). Obtained from
I (2.0 g, 6.94 mmol), K2CO3 (1.92 g, 13.9 mmol), and 3-bromo-
2-methyl-2-propene (1.40 mL, 13.9 mmol) in DMF (20 mL) as
described for 6a . Purification by flash chromatography (li-
groin-EtOAc, 8:2) yielded 5e (2.20 g, 94%) as a light yellow
solid: mp 44-46 °C; Rf 0.29 (ligroin-EtOAc, 8:2); IR (film)
N-(5-Hexen yl)-Gly-OEt‚HCl (6d ). Obtained from 5d (930
mg, 2.51 mmol), K2CO3 (1.04 g, 7.53 mmol), and PhSH (309
µL, 3.01 mmol) in DMF (10 mL) as described for 6b. Yield:
206 mg (37%). 6d : colorless needles; mp 181-183 °C; IR (KBr)
3440, 1752, 1641 cm-1 1H NMR (CH3OH-d4) δ 1.32 (t, J )
;
1743, 1662, 1535 cm-1 1H NMR (CDCl3) δ 1.19 (t, J ) 7.1,
;
7.1, 3H), 1.45-1.55 (m, 2H), 1.69-1.79 (m, 2H), 2.07-2.20 (m,
2H), 3.00-3.10 (m, 2H), 4.30 (q, J ) 7.1, 2H), 4.99 (dddd, J )
10.2, 1.1, 2.2, 1.1, 1H), 5.05 (ddd, J ) 17.2, 3.6, 1.5, 1H), 5.82
(dddd, J ) 6.7, 17.2, 10.2, 6.7, 1H); 13C NMR (CH3OH-d4) δ
14.3, 24.2, 26.5, 26.8, 34.1, 63.6, 83.6, 115.8, 138.9, 167.7. Anal.
Calcd for C10H20NO2Cl: C, 54.17; H, 9.09; N, 6.32. Found: C,
53.88; H, 8.99; N, 6.27.
3H), 1.73 (s, 3H), 3.89 (s, 2H), 4.00-4.15 (m 2H), 4.05 (q, J )
7.1, 2H), 4.81-5.05 (m, 2H), 8.00-8.10 (m, 2H), 8.30-8.40 (m,
2H); 13C NMR (CDCl3) δ 14.0, 19.6, 46.5, 53.9, 61.4, 116.3,
124.1, 128.6, 138.8, 145.7, 149.9, 168.3; EIMS 342 (M+). Anal.
Calcd for C14H18N2O6S: C, 49.11; H, 5.30; N, 8.18; S, 9.37.
Found: C, 49.31; H, 5.30; N, 8.21; S, 9.34.
Nos-N-(a llyl)-(S)-Ala -OMe (5f). Obtained from II (300 mg,
1.04 mmol), K2CO3 (287 mg, 2.08 mmol), and allyl bromide
(180 µL, 2.08 mmol) in DMF (25 mL) as described for 5a .
Purification by flash chromatography (ligroin-EtOAc, 8:2)
yielded 5f (323 mg, 95%) as a pale yellow solid: mp 62-64
°C; Rf 0.20 (ligroin-EtOAc, 8:2); [R]22D -50.0 (c ) 0.50, CHCl3);
IR (film) 1743, 1641, 1531 cm-1; 1H NMR (CDCl3) δ 1.49 (d, J
) 7.2, 3H), 3.58 (s, 3H), 3.75-4.01 (m, 2H), 4.71 (q, J ) 7.2,
1H), 5.15-5.29 (m, 2H), 5.78 (m, 1H).; 13C NMR (CDCl3) δ 16.9,
48.7, 52.3, 55.6, 118.5, 124.1, 128.7, 134.2, 145.9, 149.9, 171.3;
EIMS 328 (M+). Anal. Calcd for C13H16N2O6S: C, 47.55; H,
4.91; N, 8.53; S, 9.77. Found: C, 47.87; H, 4.94; N, 8.49; S,
9.38.
N-(2-Meth yl-2-p r op en yl)-Gly-OEt ‚HCl (6e). Obtained
from 5e (2.38 g, 6.94 mmol), K2CO3 (2.87 g, 20.8 mmol), and
PhSH (852 µL, 8.30 mmol) in DMF (15 mL) as described for
6b. Yield: 578 mg (43%). 6e: pale yellow needles; mp 64-66
1
°C; IR (KBr) 3484, 1746, 1650 cm-1; H NMR (CH3OH-d4) δ
1.32 (t, J ) 7.1, 3H), 1.45-1.55 (m, 2H), 1.69-1.79 (m, 2H),
2.07-2.20 (m, 2H), 3.00-3.10 (m, 2H), 4.30 (q, J ) 7.1, 2H),
4.99 (dddd, J ) 10.2, 1.1, 2.2, 1.1, 1H), 5.05 (ddd, J ) 17.2,
3.6, 1.5, 1H), 5.82 (dddd, J ) 6.7, 17.2, 10.2, 6.7, 1H); 13C NMR
(CH3OH-d4) δ 14.3, 24.2, 26.5, 26.8, 34.1, 63.6, 83.6, 115.8,
138.9, 167.7. Anal. Calcd for C8H16NO2Cl: C, 49.61; H, 8.33;
N, 7.23. Found: C, 49.56; H, 8.24; N, 7.02.
N-(Allyl)-(S)-Ala -OMe‚HCl (6f). Obtained from 5f (3.60 g,
10.9 mmol), K2CO3 (4.54 g, 3.63 mmol), and PhSH (1.35 mL,
13.1 mmol) in DMF (20 mL) as described for 6b. Yield: 935
Nos-N-(3-bu ten yl)-(S)-Ala -OMe (5g). Obtained from II
(400 mg, 1.39 mmol), PPh3 (410 mg, 1.81 mmol), 3-buten-1-ol
(156 µL, 1.81 mmol), and DEAD (823 µL, 40% in toluene, 1.81
mmol) in CH2Cl2 (20 mL) as described for 5b. Purification by
flash chromatography (ligroin-EtOAc, 8:2) yielded 5g (362 mg,
mg (60%). 6f: colorless needles; mp 144-146 °C; [R]23 -1.3
D
(c ) 0.45, CH3OH); IR (KBr) 3489, 1752, 1648 cm-1; 1H NMR
(CH3OH-d4) δ 1.58 (d, J ) 7.1, 3H), 3.68-3.75 (m, 2H), 3.86
(s, 3H), 4.13 (q, J ) 7.1, 1H), 5.52 (ddd, J ) 10.3, 1.8, 0.9, 1H),
5.57 (ddd, J ) 17.2, 2.5, 1.3, 1H), 5.95 (dddd, J ) 6.9, 17.2,
10.3, 6.9, 1H); 13C NMR (CH3OH-d4) δ 14.9, 49.2, 53.9, 55.8,
124.6, 128.9, 170.9. Anal. Calcd for C7H14NO2Cl: C, 46.80; H,
7.86; N, 7.80. Found: C, 46.54; H, 7.99; N, 7.79.
76%) as a colorless oil: Rf 0.21 (ligroin-EtOAc, 8:2); [R]23
D
-56.0 (c ) 0.98, CHCl3); IR (film) 1743, 1643, 1531 cm-1; H
1
NMR (CDCl3) δ 1.51 (d, J ) 7.5, 3H), 2.25-2.40 (m, 1H), 2.36-
2.60 (m, 1H), 3.15 (ddd, J ) 15.3, 10.4, 5.4, 1H), 3.36 (ddd, J
) 15.4, 10.5, 5.1, 1H), 3.55 (s, 3H), 4.69 (q, J ) 7.5, 1H), 5.00-
5.19 (m, 2H), 5.65-5.80 (m, 1H); 13C NMR (CDCl3) δ 17.1, 35.4,
45.8, 52.3, 55.8, 117.4, 124.1, 128.6, 134.1, 145.6, 149.9, 171.3;
EIMS 342 (M+). Anal. Calcd for C14H18N2O6S: C, 49.11; H,
5.30; N, 8.18; S, 9.37. Found: C, 49.06; H, 5.42; N, 8.01; S,
9.15.
N-(Allyl)-Gly-OEt (6a ). Obtained from 5a (150 mg, 0.46
mmol), K2CO3 (191 mg, 1.38 mmol), and PhSH (56 µL, 0.55
mmol) in DMF (6 mL) as described for N-allyl-Ph-OMe in ref
11a. Purification by flash chromatography (ligroin-EtOAc, 1:1)
N-(3-Bu ten yl)-(S)-Ala -OMe.HCl (6g). Obtained from 5g
(1.74 g, 5.08 mmol), K2CO3 (2.11 g, 15.2 mmol), and PhSH (626
µL, 6.09 mmol) in DMF (10 mL) as described for 6b. Yield:
696 mg (71%). 6g: colorless needles; mp 139-141 °C; [R]21
D
+4.8° (c ) 0.17, CH3OH); IR (KBr) 3477, 1747, 1644 cm-1; 1H
NMR (CH3OH-d4) δ 1.58 (d, J ) 7.2, 3H), 2.45-2.56 (m, 2H),
3.10-3.20 (m, 2H), 3.86 (s, 3H), 4.15 (q, J ) 7.2, 1H), 5.19
(ddd, J ) 17.1, 3.11, 1.5, 1H), 5.25 (ddd, J ) 10.2, 2.8, 1.3,
1H), 5.83 (dddd, J ) 6.8, 17.1, 10.2, 6.8, 1H); 13C NMR (CH3-
66 J . Org. Chem., Vol. 68, No. 1, 2003

General Approach to Dehydro-Freidinger Lactams
OH-d4) δ 14.9, 31.5, 46.4, 53.9, 56.6, 119.2, 133.8, 170.9. Anal.
Calcd for C8H15NO2Cl: C, 49.61; H, 8.33; N, 7.23. Found: C,
49.59; H, 7.99; N, 7.38.
NMR (CDCl3) δ 14.1, 19.9, 28.3, 37.8, 48.2, 49.9, 61.2, 61.6,
79.6, 113.3, 118.6, 132.8, 139.5, 155.1, 168.9, 172.6; EIMS 354
(M+). Anal. Calcd for C18H30N2O5: C, 60.99; H, 8.53; N, 7.90.
Found: C, 60.92; H, 8.68; N, 7.98.
N-(Allyl)-N-[(2S)-ter t-bu toxycar bon ylam in o-3-bu ten oyl]-
glycin e Eth yl Ester (8a ). A solution of 7a (50 mg, 0.25
N-(3-Bu ten yl)-N-[(2S)-ter t-bu toxycar bon ylam in o-4-pen -
ten oyl]glycin e Eth yl Ester (8e). Obtained from a solution
of DCC (124 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), and
7b (129 mg, 0.60 mmol) in CH2Cl2 (20 mL) and a solution of
6b (116 mg, 0.60 mmol) and DIEA (115 µL, 0.66 mmol) in CH2-
Cl2 (2 mL) as described for 8c. 8e (168 mg, 79%): colorless
oil; Rf 0.16 (ligroin-EtOAc, 8:2); [R]20D -6.3 (c ) 0.48, CHCl3);
IR (film) 3324, 1747, 1708, 1654 cm-1; 1H NMR (CDCl3) δ 1.27
(t, J ) 7.3, 3H), 1.43 (s, 9H), 2.25-2.40 (m, 3H), 2.44-2.59
(m, 1H), 3.35 3.42 (m 1H), 3.50-3.62 (m, 1H), 3.77 (d, J )
17.4, 1H), 4.19 (q, J ) 7.3, 2H), 4.34 (d, J ) 17.0, 1H), 4.65-
4.75 (m, 1H), 5.02-5.20 (m, 5H), 5.70-5.85 (m, 2H); 13C NMR
(CDCl3) δ 14.1, 28.3, 33.1, 37.9, 47.9, 48.4, 49.7, 61.2, 61.8,
118.1, 118.4, 132.9, 133.8, 155.1, 168.9, 172.3; EIMS 354 (M+).
Anal. Calcd for C18H30N2O5: C, 60.99; H, 8.53; N, 7.90.
Found: C, 61.00; H, 8.20; N, 8.11.
i
mmol), N-methylmorpholine (27 µL, 0.25 mmol), and ClCO2 Bu
(32 µL, 0.25 mmol) in THF at -15 °C was stirred for 10 min,
and then a solution of 6a (36 mg, 0.25 mmol) in THF (2 mL)
was added. After slow warming to room temperature, the
mixture was stirred overnight. Evaporation and flash chro-
matography (ligroin-EtOAc, 8:2) of the resulting residue
yielded 8a (23 mg, 28%) as a colorless oil. 8a : Rf 0.11 (ligroin-
EtOAc, 8:2); [R]23D +2.1 (c ) 1.01, CHCl3); IR (film) 3339, 1789,
1682, 1619 cm-1; 1H NMR (CDCl3) δ 1.27 (t, J ) 7.1, 3H), 1.44
(s, 9H), 3.80 (d, J ) 17.0, 1H), 4.05-4.15 (m, 2H), 4.19 (q, J )
7.1, 2H), 4.33 (d, J ) 17.0, 1H), 5.05-5.15 (m, 1H), 5.20-5.45
(m, 4H), 5.58 (br d, J ) 7.8, 1H), 5.70-5.90 (m, 2H); 13C NMR
(CDCl3) δ 14.1, 19.0, 27.8, 47.0, 51.0, 61.3, 79.8, 118.5, 118.6,
131.9, 133.3, 154.9, 168.9, 170.5; EIMS 326 (M+). Anal. Calcd
for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58. Found: C, 58.68;
H, 7.94; N, 8.50.
(S)-N-(3-Bu t en yl)-N-[(2S)-ter t-b u t oxyca r b on yla m in o-
4-p en ten oyl]a la n in e Meth yl Ester (8f). Obtained from a
solution of DCC (142 mg, 0.69 mmol), HOBt (93 mg, 0.69
mmol), and 7b (150 mg, 0.69 mmol) in CH2Cl2 (40 mL) and a
solution of 6g (134 mg, 0.69 mmol) and DIEA (120 µL, 0.69
mmol) in CH2Cl2 (2 mL) as described for 8c. Yield: (46 mg,
N -(Allyl)-N -[(2S )-t er t -b u t oxyca r b on yla m in o-4-p e n -
ten oyl]glycin e Eth yl Ester (8b). At 0 °C, DCC (47 mg, 0.23
mmol) and HOBt (31 mg, 0.23 mmol) were added to a solution
of 7b (50 mg, 0.23 mmol) in CH2Cl2 (20 mL). After 1 h of
stirring, a solution of 6a (33 mg, 0.23 mmol) in CH2Cl2 (2 mL)
was added. Warming to room temperature and stirring
overnight was followed by evaporation and subsequent flash
chromatography (ligroin-EtOAc, 8:2) of the resulting residue
yielding 8b (66 mg, 84%) as a colorless solid. 8b: mp 74-76
°C; Rf 0.13 (ligroin-EtOAc, 8:2); [R]23D +4.2 (c ) 0.21, CHCl3);
IR (film) 3325, 1747, 1704, 1650 cm-1; 1H NMR (CDCl3) δ 1.27
(t, J ) 7.1, 3H), 1.43 (s, 9H), 2.32-2.45 (m, 1H), 2.49-2.60
(m, 1H), 3.83 (d, J ) 17.4, 1H), 3.99-4.10 (m, 2H), 4.18 (q, J
) 7.1, 2H), 4.26 (d, J ) 17.0, 1H), 4.65-4.75 (m, 1H), 5.09-
5.20 (m, 3H), 5.25-5.32 (m, 2H), 5.60-5.90 (m, 2H); 13C NMR
(CDCl3) δ 14.1, 28.3, 37.7, 47.1, 49.8, 51.3, 61.2, 83.3, 118.2,
118.7, 132.3, 132.7, 155.1, 168.9, 172.3; EIMS 340 (M+). Anal.
Calcd for C17H28N2O5: C, 59.98; H, 8.29; N, 8.23. Found: C,
60.29; H, 8.43; N, 8.37.
19%). 8f: colorless oil; Rf 0.19 (ligroin-EtOAc, 8:2); [R]20
D
-37.7 (c ) 0.13, CHCl3); IR (film) 3324, 1743, 1710, 1645 cm-1
;
1H NMR (CDCl3) δ 1.43 (s, 9H), 1.46 (d, J ) 7.1, 3H), 2.30-
2.41 (m, 2H), 2.43-2.56 (m, 2H), 3.30 (ddd, J ) 15.3, 10.0,
5.4, 1H), 3.50 (ddd, J ) 15.3, 10.1, 6.0, 1H), 3.70 (s, 3H), 4.48
(q, J ) 7.1, 1H), 4.64 (ddd, J ) 13.9, 8.0, 6.8, 1H), 5.08-5.19
(m, 4H), 5.24 (br d, J ) 8.5, 1H), 5.66-5.83 (m, 2H); 13C NMR
(CDCl3) δ 14.8, 19.1, 28.4, 38.4, 47.7, 49.2, 52.2, 53.6, 79.0,
116.2, 117.3, 134.2, 136.2, 155.5, 171.7, 176.1; EIMS 354 (M+).
Anal. Calcd for C18H30N2O5: C, 60.99; H, 8.53; N, 7.90.
Found: C, 61.13; H, 8.65; N, 7.72.
N-(4-P en t en yl)-N-[(2S)-ter t-b u t oxyca r b on yla m in o-4-
p en ten oyl]glycin e Eth yl Ester (8g). Obtained from a solu-
tion of DCC (47 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol),
and 7b (50 mg, 0.23 mmol) in CH2Cl2 (10 mL) and a solution
of 6c (48 mg, 0.23 mmol) and DIEA (44 µL, 0.25 mmol) in CH2-
Cl2 (2 mL) as described for 8c. Yield: (56 mg, 66%). 8g:
colorless oil; Rf 0.22 (ligroin-EtOAc, 8:2); [R]20D +5.5 (c ) 0.15,
(S)-N-(Allyl)-N-[(2S)-ter t-bu toxyca r bon yla m in o-4-p en -
ten oyl]a la n in e Meth yl Ester (8c). Obtained from DCC (95
mg, 0.46 mmol), HOBt (62 mg, 0.46 mmol), and 7b (100 mg,
0.46 mmol) in CH2Cl2 (15 mL) as described for 8b. A solution
of 6f (83 mg, 0.46 mmol) and DIEA (88 µL, 0.51 mmol) in CH2-
Cl2 (2 mL) was added. Stirring overnight at room temperature
and workup as mentioned for 8b yielded 8c (67 mg, 43%) as a
CHCl3); IR (film) 3421, 1747, 1708, 1650 cm-1 1H NMR
;
(CDCl3) δ 1.27 (t, J ) 7.1, 3H), 1.43 (s, 9H), 1.59-1.80 (m,
2H), 2.05-2.17 (m, 2H), 2.31-2.40 (m, 1H), 2.45-2.58 (m, 2H),
3.26-3.50 (m, 2H), 3.77 (d, J ) 17.0, 1H), 4.19 (q, J ) 7.1,
2H), 4.32 (d, J ) 17.0, 1H), 4.65-4.75 (m, 1H), 4.96-5.20 (m,
4H), 5.26 (d, J ) 8.5, 1H), 5.79 (dddd, J ) 13.5, 17.1, 7.0, 3.5,
1H), 5.80 (dddd, J ) 10.3, 17.1, 10.3, 3.8, 1H); 13C NMR (CDCl3)
δ 14.1, 27.7, 28.3, 30.6, 37.9, 47.8, 48.4, 49.7, 61.2, 79.6, 115.9,
118.6, 132.8, 136.9, 155.1, 168.9, 172.3; EIMS 368 (M+). Anal.
Calcd for C19H32N2O5: C, 61.93; H, 8.75; N, 7.60. Found: C,
62.06; H, 8.87; N, 7.61.
N-(4-Hexen yl)-N-[(2S)-ter t-bu toxycar bon ylam in o-4-pen -
ten oyl]glycin e Eth yl Ester (8h ). Obtained from a solution
of DCC (47 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol), and
7b (50 mg, 0.23 mmol) in CH2Cl2 (10 mL) and a solution of 6d
(51 mg, 0.23 mmol) and DIEA (44 µL, 0.25 mmol) in CH2Cl2
(2 mL) as described for 8c. Yield: (73 mg, 83%). 8h : colorless
oil; Rf 0.20 (ligroin-EtOAc, 8:2); [R]22D -12.2 (c ) 0.09, CHCl3);
IR (film) 3318, 1749, 1708, 1648 cm-1; 1H NMR (CDCl3) δ 1.27
(t, J ) 7.1, 3H), 1.43 (s, 9H), 1.37-1.70 (m, 4H), 2.01-2.12
(m, 2H), 2.30-2.42 (m, 1H), 2.45-2.60 (m, 1H), 3.28-3.50 (m,
2H), 3.77 (d, J ) 17.0, 1H), 4.18 (q, J ) 7.1, 2H), 4.32 (d, J )
17.0, 1H), 4.65-4.72 (m, 1H), 4.90-5.20 (m, 4H), 5.26 (d, J )
8.5, 1H), 5.70-5.85 (m, 2H); 13C NMR (CDCl3) δ 14.1, 25.8,
26.5, 28.2, 37.5, 37.9, 47.7, 49.7, 61.1, 79.5, 115.1, 118.5, 132.8,
137.9, 155.1, 168.9, 172.1; EIMS 382 (M+). Anal. Calcd for
colorless oil. 8c: Rf 0.14 (ligroin-EtOAc, 8:2); [R]23 -46.3 (c
D
) 0.43, CHCl3); IR (film) 3429, 1747, 1712, 1650 cm-1; 1H NMR
(CDCl3) δ 1.41 (d, J ) 7.4, 3H), 1.42 (s, 9H), 2.30-2.39 (m,
1H), 2.45-2.56 (m, 1H), 3.70 (s, 3H), 3.90-4.15 (m, 2H), 4.55-
4.61 (m, 1H), 4.74 (q, J ) 7.4, 1H), 5.08-5.19 (m, 2H), 5.22-
5.30 (m, 3H), 5.76 (dddd, J ) 7.1, 17.1, 9.9, 7.1, 1H), 5.90 (dddd,
J ) 5.4, 17.0, 10.6, 5.3, 1H); 13C NMR (CDCl3) δ 14.7, 28.3,
37.9, 48.9, 50.3, 52.2, 53.7, 54.9, 117.9, 118.7, 132.7, 133.7,
155.1, 172.0, 172.3; EIMS 340 (M+). Anal. Calcd for
C
17H28N2O5: C, 59.98; H, 8.29; N, 8.23. Found: C, 60.17; H,
8.28; N, 8.26.
N-(2-Meth yl-2-p r op en yl)-N-[(2S)-ter t-bu toxyca r bon yl-
a m in o-4-p en ten oyl]glycin e Eth yl Ester (8d ). Obtained
from a solution of DCC (47 mg, 0.23 mmol), HOBt (31 mg, 0.23
mmol) and 7b (50 mg, 0.23 mmol) in CH2Cl2 (10 mL) and a
solution of 6e (45 mg, 0.23 mmol) and DIEA (44 µL, 0.25 mmol)
in CH2Cl2 (2 mL) as described for 8c. 8d (66 mg, 81%):
colorless oil; Rf 0.15 (ligroin-EtOAc, 8:2); [R]21 -20.0 (c )
D
0.14, CHCl3); IR (film) 3318, 1747, 1708, 1651, 1643 cm-1; 1H
NMR (CDCl3) δ 1.27 (t, J ) 7.1, 3H), 1.42 (s, 9H), 1.73 (s, 3H),
2.37 (ddd, J ) 6.9, 14.0, 6.9, 1H), 2.52 (ddd, J ) 6.5, 14.0, 6.5,
1H), 3.82 (d, J ) 17.0, 1H), 3.97 (d, J ) 10.7, 1H), 4.06 (d, J )
10.7, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 4.60-4.75 (m, 1H), 4.75-
5.00 (m, 2H), 5.05-5.20 (m, 2H), 5.13 (d, J ) 17.0, 1H), 5.27
(d, J ) 8.2, 1H), 5.78 (dddd, J ) 7.2, 17.1, 10.0, 7.2, 1H); 13C
C
20H34N2O5: C, 62.80; H, 8.96; N, 7.32. Found: C, 62.61; H,
8.85; N, 7.31.
J . Org. Chem, Vol. 68, No. 1, 2003 67

Hoffmann et al.
(S)-(3-ter t-Bu t oxyca r b on yla m in o-2-oxo-3,6-d ih yd r o-
2H-p yr id in -1-yl)a cetic Acid Eth yl Ester (9a ). The catalyst
10a (6 mg, 0.007 mmol) was added to a solution of 8a (23 mg,
0.07 mmol) in DCE (35 mL) employing flame-dried glassware.
The mixture was heated to reflux until TLC indicated comple-
tion of the reaction. After cooling, the solution was evaporated
and the resulting residue purified by flash chromatography
(ligroin-ETOAc, 1:1) to yield 9a (11 mg, 53%). 9a : colorless
oil; Rf 0.15 (ligroin-EtOAc, 1:1); [R]24D -12.4 (c ) 0.21, CHCl3);
IR (film) 3336, 1743, 1712, 1658 cm-1; 1H NMR (CDCl3) δ 1.28
(t, J ) 7.1, 3H), 1.46 (s, 9H), 3.85-3.95 (m, 1H), 4.05-4.15
(m, 2H), 4.20 q, J ) 7.1, 2H), 4.19-4.25 (m, 1H), 4.65-4.72
(m, 1H), 5.20-5.30 (br s, 1H), 5.81-5.90 (m, 1H), 5.95-6.10
(m, 1H); 13C NMR (CDCl3) δ 14.1, 28.3, 48.4, 49.6, 61.4, 77.2,
79.9, 127.2, 121.5, 155.9, 167.5, 168.5; EIMS 298 (M+). Anal.
Calcd for C14H22N2O5: C, 56.36; H, 7.43; N, 9.39. Found: C,
56.13; H, 7.44; N, 9.37.
(q, J ) 7.1, 2H), 4.39 (d, J ) 17.0, 1H), 4.81-4.95 (m, 1H),
5.56 (ddd, J ) 11.8, 6.1, 5.8, 1H), 5.70 (ddd, J ) 11.5, 6.0, 6.0,
1H), 5.84 (d, J ) 6.0, 1H); 13C NMR (CDCl3) δ 14.1, 27.6, 27.9,
28.4, 35.9, 47.4, 49.1, 51.3, 61.3, 126.7, 127.8, 159.8, 168.9,
172.7; EIMS 326 (M+). Anal. Calcd for C16H26N2O5‚1/3H2O: C,
57.30; H, 8.11; N, 8.35. Found: C, 57.32; H, 7.81; N, 8.30.
(2S)-[(3S)-ter t-Bu toxyca r bon yla m in o-2-oxo-3,4,7,8-tet-
r a h yd r o-2H -a zocin -1-yl]p r op ion ic Acid Met h yl E st er
(9f). Obtained from 8f (20 mg, 0.056 mmol) and 10a (5 mg,
0.006 mmol) in DCE (28 mL) as described for 9a . Purification
by flash chromatography (ligroin-EtOAc, 6:4) yielded 9f (11
mg, 60%). 9f: colorless oil; Rf 0.21 (ligroin-EtOAc, 6:4); [R]23
D
-34.7 (c ) 1.0, CHCl3); IR (film) 3413, 1747, 1700, 1650 cm-1
;
1H NMR (CDCl3) δ 1.41 (d, J ) 7.1, 3H), 1.44 (s, 9H), 2.27
(ddd, J ) 8.1, 16.0, 8.1, 1H), 2.42 (ddd, J ) 15.5, 7.5, 7.5, 1H),
2.56-2.65 (m, 1H), 2.78-2.85 (m, 1H), 3.34 (ddd, J ) 14.9,
7.4, 7.0, 1H), 3.69 (s, 3H), 3.86 (ddd, J ) 14.8, 7.1, 7.0, 1H),
4.80 (q, J ) 7.1 Hz, 1H), 4.80-4.90 (m, 1H), 5.50-5.60 (m,
1H), 5.64-5.77 (m, 2H); 13C NMR (CDCl3) δ 14.9, 28.2, 28.4,
35.5, 44.1, 51.2, 52.0, 54.4, 79.6, 126.8, 127.6, 155.2, 171.8,
172.4; EIMS 326 (M+). Anal. Calcd for C16H26N2O5: C, 58.88;
H, 8.03; N, 8.58. Found: C, 58.62; H, 7.67; N, 8.51.
(S)-(3-ter t-Bu toxyca r bon yla m in o-2-oxo-2,3,4,7-tetr a h y-
d r oa zep in -1-yl)a cetic Acid Eth yl Ester (9b). Obtained
from 8b (123 mg, 0.36 mmol) and 10a (30 mg, 0.036 mmol) in
DCE (72 mL) as described for 9a . Purification by flash
chromatography (ligroin-EtOAc, 6:4) yielded 9b (76 mg, 68%).
9b: colorless oil; Rf 0.25 (ligroin-EtOAc, 6:4); [R]20 +20.6 (c
D
(S )-(3-t er t -Bu t oxyca r b on yla m in o-2-oxo-2,3,4,7,8,9-
h exa h yd r oa zon in -1-yl)a cetic Acid Eth yl Ester (9g). Ob-
tained from 8g (100 mg, 0.27 mmol) and 10a (22 mg, 0.027
mmol) in DCE (135 mL) as described for 9a . Purification by
flash chromatography (ligroin-EtOAc, 6:4) yielded 9g (82 mg,
) 1.27, CHCl3); IR (film) 3413, 1751, 1712, 1658 cm-1; 1H NMR
(CDCl3) δ 1.27 (t, J ) 7.3, 3H), 1.45 (s, 9H), 2.20-2.30 (m,
1H), 2.63-2.75 (m, 1H), 3.36 (dd, J ) 17.7, 6.7, 1H), 4.09 (d J
) 17.4, 1H), 4.19 (q, J ) 7.1, 2H), 4.35 (d, J ) 17.4, 1H), 4.50-
4.60 (m, 1H), 4.96 (ddd, J ) 12.1, 6.7, 4.5, 1H), 5.70-5.82 (m,
3H); 13C NMR (CDCl3) δ 14.1, 28.4, 33.3, 47.4, 50.1, 50.3, 55.8,
61.4, 123.6, 129.9, 154.9, 168.9, 172.9; EIMS 239 ((M - CO2-
Et)+), M+ not observed. Anal. Calcd for C15H24N2O5: C, 57.68;
H, 7.74; N, 8.97. Found: C, 57.10; H, 7.88; N, 9.02.
86%). 9g: colorless oil; Rf 0.29 (ligroin-EtOAc, 6:4); [R]26
D
-15.2 (c ) 0.65, CHCl3); IR (film) 3419, 1751, 1710, 1643 cm-1
;
1H NMR (CDCl3) δ 1.21 (t, J ) 7.1, 3H), 1.38 (s, 9H), 1.40-
1.50 (m, 1H), 1.80 (dddd, J ) 14.1, 13.7, 6.9, 3.7, 1H), 1.92
(dddd, J ) 13.4, 13.0, 10.8, 2.8, 1H), 2.57 (ddd, J 8.3, 14.2,
8.3, 1H), 3.00 (ddd, J ) 14.5, 2.5, 2.4, 1H), 3.63-3.75 (m, 1H),
3.93 (s, 2H), 4.14 (q, J ) 7.1, 2H), 4.30-4.39 (m, 1H), 5.51
(ddd, J ) 10.6, 10.0, 6.2, 1H), 5.91 (br d, J ) 6.7, 1H), 6.01
(ddd, J ) 9.2, 8.8, 10.0, 1H); 13C NMR (CDCl3) δ 14.1, 21.0,
22.4, 28.4, 34.4, 45.6, 47.6, 51.2, 61.2, 79.4, 129.1, 130.4, 154.9,
172.9, 180.9; EIMS 340 (M+). Anal. Calcd for C17H28N2O5: C,
59.98; H, 8.29; N, 8.22. Found: C, 59.50; H, 8.31; N, 8.17.
(2S)-[(3S)-ter t-Bu toxyca r bon yla m in o-2-oxo-2,3,4,7-tet-
r a h yd r oa zep in -1-yl)p r op ion ic Acid Meth yl Ester (9c).
Obtained from 8c (34 mg, 0.10 mmol) and 10a (8 mg, 0.01
mmol) in DCE (21 mL) as described for 9a . Purification by
flash chromatography (ligroin-EtOAc, 6:4) yielded 9c (13 mg,
42%). 9c: colorless oil; Rf 0.28 (ligroin-EtOAc, 6:4); [R]23
D
-33.6 (c ) 0.62, CHCl3); IR (film) 3413, 1743, 1712, 1654 cm-1
;
1H NMR (CDCl3) δ 1.39 (d, J ) 7.5, 3H), 1.45 (s, 9H), 2.21-
2.32 (m, 1H), 2.65 (ddd, J ) 18.0, 7.4, 3.6, 1H), 3.42-3.58 (m,
1H, 3.68 (s, 3H), 4.19-4.31 (m, 1H), 4.92 (ddd, J ) 12.1, 7.3,
4.4, 1H), 5.27 (q, J ) 7.2, 1H), 5.69-5.82 (m, 3H); 13C NMR
(CDCl3) δ 14.8, 28.3, 30.9, 33.3, 41.9, 50.1, 52.1, 52.7, 124.1,
129.5, 155.0, 171.9, 172.3; EIMS 312 (M+). Anal. Calcd for
C15H24N2O5‚1/3H2O: C, 56.06; H, 7.84; N, 8.72. Found: C, 55.95;
H, 7.87; N, 8.51.
(S)-(9-ter t-Bu t oxyca r b on yla m in o-10-oxo-3,4,5,8,9,10-
h exa h yd r o-2H-a zecin -1-yl)a cetic Acid Eth yl Ester (9h ).
A solution of 8h (30 mg, 0.078 mmol) in DCE (16 mL) was
added dropwise to a solution of 10b (3 mg, 0.004 mmol) in DCE
(140 mL) at 60 °C. Subsequent heating to reflux and workup
was done as described for 9a . Purification by flash chroma-
tography (ligroin-EtOAc, 6:4) yielded 9h (2 mg, 8%). 9h :
colorless oil; Rf 0.32 (ligroin-EtOAc, 6:4); [R]22 -21.2 (c )
D
(S)-(3-ter t-Bu toxycar bon ylam in o-6-m eth yl-2-oxo-2,3,4,7-
tetr a h yd r oa zep in -1-yl)a cetic Acid Eth yl Ester (9d ). Ob-
tained from 8d (45 mg, 0.12 mmol) and 10b (5 mg, 0.006 mmol)
in DCE (24 mL) as described for 9a . Purification by flash
chromatography (ligroin-EtOAc, 6:4) yielded 9d (35 mg, 89%).
0.34, CHCl3); IR (film) 3431, 1749, 1711, 1639 cm-1; 1H NMR
(CDCl3) δ 1.28 (t, J ) 7.2, 3H), 1.45 (m, 1H), 1.44 (s, 9H), 1.60-
2.10 (m, 4H), 2.23 (dd, J ) 14.0, 9.0, 1H), 2.34 (dddd, J ) 13.2,
13.2, 10.5, 2.7, 1H), 2.64 (ddd, J ) 14.0, 8.3, 7.5 1H), 3.07 (dd,
J ) 13.0, 1.5, 1.5, 1H), 3.77 (dd, 13.0, 13.0, 1H), 4.00 (s, 2H),
4.21 (q, J ) 7.2, 2H), 4.40 (dd, J ) 7.5, 7.1, 1H), 5.58 (ddd, J
) 10.5, 10.5, 6.2, 1H), 5.99 (brd, J ) 7.1, 1H), 6.08 (ddd, J )
10.5, 9.0, 8.3, 1H); 13C NMR (CDCl3) δ 14.1, 22.4, 27.2, 28.4,
27.0, 34.5, 45.6, 47.6, 51.6, 61.1, 79.4, 129.3, 130.4, 155.0, 168.8,
172.9; EIMS 354 (M+); HRMS m/z calcd for C18H30N2O5
354.2155, found 354.2157.
9d : colorless oil; Rf 0.29 (ligroin-EtOAc, 6:4); [R]21 +58.5 (c
D
) 0.13, CHCl3); IR (film) 3417, 1749, 1714, 1662 cm-1; 1H NMR
(CDCl3) δ 1.27 (t, J ) 7.1, 3H), 1.44 (s, 9H), 1.74 (s, 3H), 2.16-
2.28 (m, 1H), 2.55.2.65 (m, 1H), 3.15 (d, J ) 17.7, 1H), 4.08-
4.14 (m, 1H), 4.19 (q, J ) 7.1, 2H), 4.32 (d, J ) 17.1, 1H), 4.58-
4.65 (m, 1H), 4.91 (ddd, J ) 12.3, 6.6, 4.2, 1H), 5.45-5.52 (m,
1H), 5.76 (d, J ) 6.6, 1H); 13C NMR (CDCl3) δ 14.1, 24.6, 28.3,
33.1, 50.2, 50.4, 52.1, 61.3, 79.5, 123.3, 132.3, 155.0, 168.9,
172.9; EIMS 326 (M+). Anal.Calcd for C16H26N2O5: C, 58.88;
H, 8.03; N, 8.58. Found: C, 58.49; H, 8.04; N, 8.26.
(5-ter t-Bu t oxyca r b on yla m in o-6-oxo-3,6-d ih yd r o-2H -
p yr id in -1-yl)a cetic Acid Meth yl Am id e (11a ). Compound
9a (41 mg, 0.41 mmol) was added to a solution of methylamine
in EtOH (5 mL, 8.03 M). The mixture was stirred overnight
when evaporation followed by flash chromatography (CH2Cl2-
MeOH, 95:5) of the resulting residue yielded 11a (25 mg, 63%).
11a : colorless oil; Rf 0.33 (CH2Cl2-MeOH, 95:5); IR (film)
(S)-3-ter t-Bu toxyca r bon yla m in o-2-oxo-3,4,7,8-tetr a h y-
d r o-2H-a zocin -1-yl)a cetic Acid Eth yl Ester (9e). Obtained
from 8e (50 mg, 0.14 mmol) and 10a (12 mg, 0.014 mmol) in
DCE (70 mL) as described for 9a . Purification by flash
chromatography (ligroin-EtOAc, 6:4) yielded 9e (32 mg, 70%).
1
3398, 1718, 1697, 1666, 1639 cm-1; H NMR (CDCl3) δ 1.47
9e: colorless oil; Rf 0.20 (ligroin-EtOAc, 6:4); [R]23 +33.1 (c
(s, 9H), 2.51 (td, J ) 7.3, 4.8, 2H), 2.81 (d, J ) 4.5, 3H), 3.52
(t, J ) 7.3, 2H), 4.03 (s, 2H), 6.09 (br s, 1H), 6.88 (t, J ) 4.8,
1H), 7.38 (s, 1H); 13C NMR (CDCl3) δ 22.4, 26.3, 28.2, 47.1,
52.1, 80.4, 115.3, 127.3, 152.9, 162.8, 168.9; EIMS 283 (M+);
HRMS m/z calcd for C13H21N3O4 283.1532, found 283.1542.
D
) 0.16, CHCl3); IR (film) 3405, 1747, 1712, 1650 cm-1; 1H NMR
(CDCl3) δ 1.27 (t, J ) 7.1, 3H), 1.44 (s, 9H), 2.27 2.35 (m, 2H),
2.49-2.60 (m, 1H), 2.80-2.91 (m, 1H), 3.22 (ddd, J ) 15.6,
5.7, 5.7, 1H), 3.75 (d, J ) 17.0, 1H), 3.99-4.10 (m, 1H), 4.19
68 J . Org. Chem., Vol. 68, No. 1, 2003

General Approach to Dehydro-Freidinger Lactams
(S)-(3-ter t-Bu toxyca r bon yla m in o-2-oxo-2,3,4,7-tetr a h y-
d r oa zep in -1-yl)a cetic Acid Meth yl Am id e (11b). Obtained
from 9b (20 mg, 0.064 mmol) and a solution of methylamine
in EtOH (6 mL, 8.03 M) as described for 11a . Purification by
flash chromatography (CH2Cl2-MeOH, 95:5) yielded 11b (18
mg, 95%). 11b: colorless solid; mp 63-65 °C; Rf 0.33 (CH2-
11.3, 6.7, 1H), 6.81 (d, J ) 7.1, 1H), 7.59 (br s, 1H); 13C NMR
(CDCl3) δ 18.1, 25.5, 26.8, 28.2, 33.9, 47.1, 51.6, 80.1, 126.6,
127.4, 155.6, 169.0, 174.8; EIMS 311 (M+). Anal. Calcd for
C15H25N3O4‚1/4H2O: C, 56.76; H, 8.15; N, 13.24. Found: C,
56.07; H, 8.04; N, 13.04.
(S )-(3-t er t -Bu t oxyca r b on yla m in o-2-oxo-2,3,4,7,8,9-
h exa h yd r oa zon in -1-yl)a cetic Acid Meth yl Am id e (11d ).
Obtained from 9g (82 mg, 0.23 mmol) and a solution of
methylamine in EtOH (6 mL, 8.03M) as described for 11a .
Purification by flash chromatography (CH2Cl2-MeOH, 95:5)
yielded 11d (83 mg, 84%). 11d : colorless solid; mp 54-56 °C;
Cl2-MeOH, 95:5); [R]22 +23.0 (c ) 0.34, CHCl3); IR (film)
D
3417, 3324, 1706, 1654 cm-1; H NMR (2 mM, CDCl3) δ 1.45
1
(s, 9H), 2.24 (ddd, J ) 17.1, 12.8, 3.9, 1H), 2.70 (ddd, J ) 18.4,
6.7, 2.9, 1H), 2.79 (d, J ) 4.9, 3H), 3.55-3.60 (m, 1H), 4.05 (d,
J ) 15.6, 1H), 4.14 (d, J ) 15.6, 1H), 4.51 (ddd, J ) 17.7, 3.7,
3.7, 1H), 4.98 (ddd, J ) 12.1, 7.0, 4.6, 1H) 5.66 (d, J ) 6.9,
1H), 5.75-5.88 (m, 2H), 6.02 (br s, 1H); 1H NMR (2 mM,
DMSO-d6) δ 1.39 (s, 9H), 2.10-2.22 (m, 1H), 2.30-2.44 (m,
1H), 2.58 (d, J ) 4.6, 3H), 3.47 (dd, J ) 17.9, 7.3, 1H), 3.71 (d,
J ) 16.3, 1H), 4.19 (d, J ) 16.3, 1H), 4.38-4.51 (m, 1H), 4.79
(ddd, J ) 12.1, 7.1, 4.4, 1H), 5.60-5.80 (m, 2H), 6.49 (d, J )
7.1, 1H), 7.71 (br q, J ) 4.4, 1H); 13C NMR (CDCl3) δ 26.2,
28.3, 33.1, 47.2, 50.1, 53.0, 79.9, 124.1, 130.3, 155.1, 168.9,
173.3; EIMS 297 (M+); HRMS m/z calcd for C14H23N3O4
297.1689, found 297.1670.
Rf 0.25 (CH2Cl2-MeOH, 95:5); [R]16 +6.0 (c ) 0.05, CHCl3);
D
IR (film) 3332, 1700, 1670, 1637 cm-1; IR (2 mM, CHCl3,
background: 9g) 3430, 3370, 1708, 1670, 1648 cm-1; 1H NMR
(2 mM, CDCl3) δ 1.39 (s, 9H), 1.85-2.00 (m, 3H), 2.17 (ddd, J
) 14.4, 7.8, 1.6, 1H), 2.38-2.50 (m, 1H), 2.71 (d, J ) 4.9, 3H),
3.08 (d, J ) 15.3, 1H), 3.65-3.80 (m, 2H), 4.18 (d, J ) 15.3,
1H), 4.34-4.43 (m, 1H), 5.43 (d, J ) 6.4, 1H), 5.50 (ddd, J )
8.5, 9.8, 8.9, 1H), 5.82 (ddd, J ) 9.8, 8.9, 8.9, 1H), 6.59 (br s,
1H); 1H NMR (2 mM, DMSO-d6) δ 1.38 (s, 9H), 1.79-2.00 (m,
2H), 2.05-2.20 (m, H), 2.31-2.40 (m, 1H), 2.57 (d, J ) 4.5,
3H), 3.00-3.12 (m, 1H), 3.62 (d, J ) 16.3, 1H), 3.60-3.70 (m,
1H), 3.99 (d, J ) 16.3, 1H), 4.30-4.40 (m, 1H), 5.49-5.61 (m,
1H), 5.72-5.85 (m, 1H), 6.91 (d, J ) 6.4, 1H), 7.53 (br q, J )
4.5, 1H); 13C NMR (CDCl3) δ 23.3, 26.4, 26.8, 28.5, 31.8, 46.3,
49.6, 51.2, 79.9, 127.2, 131.6, 155.8, 169.1, 173.9; EIMS 325
(M+). Anal. Calcd for C16H27N3O4: C, 59.06; H, 8.36; N, 12.91.
Found: C, 59.02; H, 8.52; N, 12.76.
(S)-(3-ter t-Bu toxyca r bon yla m in o-2-oxo-3,4,7,8-tetr a h y-
d r o-2H-a zocin -1-yl)a cetic Acid Meth yl Am id e (11c). Ob-
tained from 9e (139 mg, 0.43 mmol) and a solution of
methylamine in EtOH (8 mL, 8.03 M) as described for 11a .
Purification by flash chromatography (CH2Cl2-MeOH, 95:5)
yielded 11c (74 mg, 55%). 11c: colorless solid; mp 46-48 °C;
Rf 0.33 (CH2Cl2-MeOH, 95:5); [R]16 +86.7 (c ) 0.03, CHCl3);
D
IR (film) 3328, 1700, 1650 cm-1
;
1H NMR (2 mM, CDCl3) δ
1.45 (s, 9H), 2.30 (ddd, J ) 7.9, 16.1, 7.9, 1H), 2.40-2.62 (m,
2H), 2.78 (d, J ) 4.9, 3H), 2.80-2.82 (m, 1H), 3.31 (ddd, J )
6.5, 14.9, 6.5, 1H), 3.86 (d, J ) 15.3, 1H), 4.03 (ddd, J ) 7.5,
14.9, 7.5, 1H), 4.13 (d, J ) 15.3, 1H), 4.87 (dd, J ) 14.7, 7.3,
1H), 5.50-5.61 (m, 2H), 5.66-5.75 (m, 1H), 6.41 (br s, 1H);
1H NMR (2 mM, DMSO-d6) δ 1.39 (s, 9H), 2.10-2.20 (m, 1H),
2.32-2.45 (m, 2H), 2.57 (d, J ) 4.3, 3H), 2.61-2.75 (m, 1H),
3.40-3.50 (m, 1H), 3.49 (d, J ) 16.3, 1H), 3.86 (ddd, J ) 15.9,
14.1, 6.7, 1H,), 4.09 (d, J ) 16.3, 1H), 4.68 (ddd, J ) 9.3, 7.1,
4.9, 1H), 5.48 (ddd, J ) 5.8, 11.3, 5.6, 1H), 5.61 (ddd, J ) 6.7,
Ack n ow led gm en t. Generous support by the BMBF
and the Fonds der Chemischen Industrie is acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
8a -h , 9a -h , and 11a -d and 13C NMR, 1H/1H COSY, HMQC,
and NOE spectra for 11d . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0261653
J . Org. Chem, Vol. 68, No. 1, 2003 69