Synthesis of a 3-aminopiperidin-2,5-dione as a conformationally constrained surrogate of the Ala-Gly dipeptide

Article abstract of DOI:10.1016/S0040-4020(00)00990-X

The preparation of the Boc-{Ala-Gly}-OBn pseudopeptide 4 is reported. The key intermediate, aminoester 5b, was obtained by a cross-coupling reaction of alaninezinc iodide 6 and the thioester of glycine 9.

Full text of DOI:10.1016/S0040-4020(00)00990-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 157±161
Synthesis of a 3-aminopiperidin-2,5-dione as a conformationally
constrained surrogate of the Ala-Gly dipeptide
a
a
b
M. Angels Estiarte,a,b, Anna Diez, Mario Rubiralta and Richard F. W. Jackson
*
a
Â
Á
Á
Laboratori of Quõmica Organica, Facultat de Farmacia, Universitat de Barcelona, 08028 - Barcelona, Spain
bDepartment of Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
Received 10 July 2000; revised 28 September 2000; accepted 17 October 2000
AbstractÐThe preparation of the Boc-{Ala-Gly}-OBn pseudopeptide 4 is reported. The key intermediate, aminoester 5b, was obtained by a
cross-coupling reaction of alaninezinc iodide 6 and the thioester of glycine 9. q 2000 Elsevier Science Ltd. All rights reserved.
Compounds that possess a 3-amino-2-piperidone nucleus
often show important biological activities. For instance,
compound 1 (Fig. 1) has been reported as a serine pro-
tease inhibitor,1 and compound 2 is an angiotensin
converting enzyme (ACE) inhibitor.2 Compound 1 con-
sists of the thiazolopiperidone bicyclic system known to
be a b-turn mimetic,3 and cyclo-arginine. Compound 3,
a thrombin inhibitor,4 is a combination of compound 2
and cyclo-arginine. We present here the preparation of
3-aminopiperidin-2,5-dione 4. Compound 4 is a new
conformationally constrained Ala-Gly surrogate, func-
tionalised at C5, in which the conformational restriction
is caused by the cyclisation between the Ca of alanine
and the nitrogen atom of glycine. We also intend to
use diketopiperidine 4 for the preparation of other
pseudodipeptides by using the reactivity of the C5 carbonyl
group.
We considered that 2,5-dioxopiperidine 4 could be prepared
by lactamisation of an appropriate aminoester, such as 5
(Fig. 2). In turn, compound 5 could be obtained from simple
aminoacid precursors, by acylation of an alanine b-anion
equivalent.
Such acylations are usually best achieved by palladium-
catalysed coupling of the organozinc derivative 6a with
acid chlorides in benzene/dimethylacetamide as solvent.5
Although we have successfully coupled the Fmoc-protected
glycine acid chloride with the iodoalanine-derived zinc
reagent 6a, to give ketone 5a (Scheme 1), the yield was
very poor (26%).6
Therefore, we decided to apply the recently reported
palladium-catalysed acylation of simple organozinc
iodides with thioesters,7 which proceeds well in THF, in
contrast with acylation using acid chlorides which is gener-
ally inef®cient in this solvent. In order to assess the reactiv-
ity towards thioesters of zinc reagent 6b, obtained from
protected iodoalanine 7 by zinc insertion,8 we ®rst treated
compound 6b with ethyl acetylthiolate.9 The coupling,
Figure 1.
Figure 2.
Keywords: aminolactam; diketopiperidine; dioxopiperidine; peptide mimetic; b-turn mimetic.
* Corresponding author. Tel.: 134-93-402-58-49; fax: 134-93-402-45-40; e-mail: adiez@farmacia.far.ub.es
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00990-X

158
M. A. Estiarte et al. / Tetrahedron 57 (2001) 157±161
Scheme 1.
Scheme 2.
using PdCl2(PPh3)2 as the catalyst, gave the expected
ketoester 8 in 39% yield. The modest yield partly re¯ects
the use of the less reactive ethyl thioester.
As an alternative to promote lactamisation over dimerisa-
tion, we activated the methyl ester 5b by transforming it into
a penta¯uorophenyl ester, via acid 15 (Scheme 5). To our
satisfaction, hydrogenolysis of the Cbz group of the penta-
¯uorophenyl derivative 16 gave 3-amino-2,5-dioxopiperi-
dine 11 in 79% yield. The most relevant 13C NMR data of
lactam 11 were the C3 methine carbon at d 47.8, and two
methylene signals at d 42.3 and 51.5, corresponding to C4
and C6, in addition to the new lactam carbonyl signal at d
170.9. Finally, alkylation of lactam 11 with benzyl bromo-
acetate using LHMDS as the base yielded the target
Once the reactivity of 6b towards thioesters had been
established, we studied its coupling to the thioester derived
from Cbz-glycine 9.9 The reaction gave the expected
ketoester 5b in 39% yield, together with the protonated
by-product Boc-Ala-OMe (51%). In order to improve this
result, we explored various reaction conditions, and
identi®ed a catalyst prepared in situ from Pd2(dba)3 and
P(o-tolyl)3, as optimal (Scheme 2).10
1
piperidin-2,5-dione 4, albeit in poor yield. In the H NMR
spectrum, compound 4 showed a characteristic AB system
at d 3.78 and 4.25 (Jˆ17 Hz), corresponding to the exo-
cyclic NCH2 protons (a-H), and two singlets at d 4.25
and 5.12 corresponding to the 6-H and benzyl protons,
respectively. In the 13C NMR spectrum C6 and Ca were
coincident at d 48.4.
Once the preparation of compound 5b had been optimised,
its lactamisation to obtain compound 11 was ®rst attempted
by hydrogenolysis of the Cbz group. The only compound
isolated from the reaction was identi®ed as pyrazine 10, and
resulted from the dimerisation and aromatisation of the
deprotected aminoketone (Scheme 3).
With the synthesis of compound 4, we have demonstrated
the usefulness of organozinc chemistry for the preparation
of 3-amino-2,5-dioxopiperidines. In future work, we intend
to study some applications of compound 4, both as a
constrained surrogate of the Ala-Gly dipeptide and as a
precursor of other pseudopeptides.
Since all attempts to prepare ethylene acetal 12 were
unsuccessful11 (Scheme 4), we treated compound 5 with
l-Selectride, which yielded lactone trans-13.6,12 The most
1
characteristic H NMR signals of lactone trans-13 were a
broad doublet at d 4.22 and a broad singlet at d 4.73, corre-
sponding to H-3 and H-5, respectively. The trans stereo-
chemistry was assigned on the basis of the small chemical
shift difference between the protons at C-4 (Dd<0.16).6
Hydrogenolysis of the Cbz group of lactone 13 gave the
desired 5-hydroxylactam 14 in 15% yield, which was
identi®ed by comparison of its spectral data to that
reported.13
1. Experimental
1.1. General
Melting points were determined in a capillary tube on a
Scheme 3.

M. A. Estiarte et al. / Tetrahedron 57 (2001) 157±161
159
Scheme 4.
Scheme 5.
BuÈchi apparatus. Optical rotations were measured with a
Perkin±Elmer 241 polarimeter, at 238C. IR spectra were
recorded on a Nicolet FT-IR spectrophotometer. H and
sulfanylacetic acid (470 ml, 4.5 mmol) and PdCl2(PPh3)2
(111 mg, 0.15 mmol) were sequentially added to the
organozinc derivative thus obtained. After stirring at 458C
for 4.5 h, the reaction was quenched by addition of AcOEt
and 1 M NH4Cl. The mixture was ®ltered through Celitew to
remove the excess of Zn, the solution was diluted with
AcOEt, and washed with brine. The organic extracts were
dried and evaporated to give a yellow oil which was chro-
matographed (hexane: AcOEt, 7:3) to obtain the desired
ketoester 8 (lower Rf, 279 mg, 39%) and a small proportion
of Boc-Ala-OMe (higher Rf, 43 mg, 7%). Ketoester 8:
1
13C NMR spectra were recorded in CDCl3 unless otherwise
indicated, on a Varian Gemini-300 instrument. Chemical
shifts are expressed in parts per million (d) relative to
Me4Si. Mass spectra were determined on a Hewlett±Pack-
ard 5988A mass spectrometer by electronic impact (EIMS).
TLC was performed on SiO2 (silica gel 60 F254, Macherey±
Nagel) and developed with the eluent described for column
chromatography. The spots were located with ninhydrin,
potassium hexachloroplatinate, anisaldehyde, or KMnO4.
Puri®cation of reagents and solvents was performed accord-
ing to standard methods. Microanalyses were performed on
[a]D22ˆ132.7 (c 1, CHCl3). IR (NaCl) 1718 (CO) cm21
;
1H NMR (CDCl3) 1.48 (s, 9H, C(CH3)3), 2.17 (s, 3H, H-
5), 2.96 (dd, Jˆ18, 4 Hz, 1H, HA-3), 3.18 (dd, Jˆ18, 4 Hz,
1H, HB-3), 3.73 (s, 3H, CO2CH3), 4.49 (t, Jˆ4 Hz, 1H, H-2),
5.51 (d, Jˆ8 Hz, 1H, NH). 13C NMR (CDCl3) 28.3
(C(CH3)3), 29.9 (C-5), 45.4 (C-3), 49.4 (C-2), 52.6
(CO2CH3), 80.0 (C(CH3)3), 155.5 (NH±CO-Boc), 171.8
(CO2CH3), 206.6 (C-4). EIMS m/z (%) 245 (M1, 0.1), 130
(12), 86 (28), 57 (100). Anal. Calcd for C11H19NO5: C,
53.87; H, 7.81; N, 5.71. Found: C, 53.40; H, 7.93; N, 5.76.
Â
Á
a Carlo Erba 1106 analyzer at the Serveis Cientõ®co-Tecnics
(Universitat de Barcelona). Protected iodoalanine 7 was
prepared by the literature method.8
1.1.1. Methyl (S)-2-(tert-butoxycarbonylamino)-4-oxo-
pentanoate (8). To a suspension of Zn (1.17 g, 18 mmol)
in dry THF (2 ml) 1,2-dibromoethane (77 ml, 0,9 mmol)
was added and the mixture was stirred at 458C under N2
atmosphere for 20 min. The mixture was cooled, TMSCl
(22 ml, 0.18 mmol) was added, and the suspension was
stirred for 20 min at rt. A solution of protected iodoalanine
7 (987 mg, 3 mmol) in dry THF (2 ml) was added via
syringe. The mixture was stirred at 458C until complete
consumption of the substrate (tlc control, 1.45 h). S-Ethyl-
1.1.2. S-Phenyl N-benzyloxycarbonylaminoethanothioate
(9). To a solution of Z-Gly (20 g, 95.6 mmol) in dry THF
(500 ml) cooled at 2108C and under N2 atmosphere, DMAP
(2.92 g, 23.9 mmol) was added. After 10 min, DCC (49.2 g,
239 mmol) was added, and the formation of a white preci-
pitate was observed. After 30 min at 2108C, recently

160
M. A. Estiarte et al. / Tetrahedron 57 (2001) 157±161
distilled C6H5SH (54 ml, 382 mmol) was added, and the
mixture was stirred for 2 h at 2108C and 1 h at rt. The
reaction mixture was ®ltered, the solvent was evaporated,
and the residue was dissolved in AcOEt and was washed
with 1 M HCl. The organic extracts were dried and evapor-
ated to give a yellow oil which was ¯ash chromatographed
(hexane:AcOEt, 7:3) to yield thioester 9 as a white solid
(21 g, 73%). Mp 72±748C (hexane±AcOEt). IR (KBr)
solution of ketoester 5 (125 mg, 0.31 mmol) in dry THF
(1.6 ml) cooled at 2788C and under N2 atmosphere, l-
Selectride (0.37 ml, 0.37 mmol) was slowly added. After
stirring for 2 h at 2788C, the reaction was quenched by
addition of 1 M NH4Cl. The THF was evaporated, the resi-
due was dissolved in AcOEt and was washed with 1 M
NH4Cl and with brine. The organic extracts dried and
evaporated yielded an oil which was chromatographed
(hexane:AcOEt, 2:1) to obtain lactone trans-13 (40 mg,
45%). [a]2D2ˆ222.4 (c 0.5, CHCl3). Mp 143±1458C
(AcOEt). IR (NaCl) 3400 (NH), 1706 and 1802 (CO)
1
1687 and 1656 (CO) cm21; H NMR (CDCl3) 4.30 (d,
Jˆ6 Hz, 2H, H-a), 5.16 (s, 2H, CH2C6H5), 5.40±5.55 (m,
1H, NH), 7.35 (s, 5H, CH2C6H5), 7.40 (s, 5H, SC6H5); 13C
NMR (CDCl3) 50.6 (C-a), 67.4 (CH2C6H5), 126.4
(CH2C6H5-ipso), 128.2, 128.3, 128.6, 129.4, 129.7, 134.7
(C6H5), 136.1 (SC6H5-ipso), 156.2 (NH±CO-Cbz), 196.0
(COSC6H5). EIMS m/z (%) 301 (M1, 0.1), 200 (30), 109
(39), 91 (100).
1
cm21; H NMR (CDCl3) 1.43 (s, 9H, C(CH3)3), 2.27±2.37
(m, 1H, H-4a), 2.48 (br t, Jˆ9 Hz, 1H, H-4b), 3.34 (dt,
Jˆ15, 6 Hz, 1H, H-10a), 3.53 (ddd, Jˆ15, 6 and 4 Hz, 1H,
H-10b), 4.22 (br d, Jˆ7.5 Hz, 1H, H-3), 4.73 (br s, 1H, H-5),
5.10 (s, 3H, NH-Boc, CH2C6H5), 5.20 (t, Jˆ6 Hz, 1H, NH-
Cbz), 7.35 (s, 5H, C6H5); 13C NMR (CDCl3) 28.2 (C(CH3)3),
31.5 (C-4), 44.7 (C-10), 49.5 (C-3), 67.1 (CH2C6H5), 77.1
(C-5), 80.8 (CO2(CH3)3), 128.1 (C6H5-o), 128.2 (C6H5-p),
128.5 (C6H5-m), 136.0 (C6H5-ipso), 155.1 (NH±CO-Boc),
156.5 (NH±CO-Cbz), 174.8 (C-2). EIMS m/z(%) 308
(M12CO2(CH3)3, 2), 201 (3), 91 (72), 57 (100). Anal.
Calcd for a C18H24N2O6: C, 59.33; H, 6.64; N, 7.69.
Found: C, 59.28; H, 6.76; N, 7.48.
1.1.3. Methyl (S)-5-(benzyloxycarbonylamino)-2-(tert-
butoxycarbonylamino)-4-oxopentanoate (5b). Operating
as for the preparation of 8, from Zn (588.5 mg, 9 mmol)
activated with 1,2-dibromoethane (38 ml, 0.45 mmol) and
TMSCl (11 ml, 0.09 mmol), iodoalanine
1.5 mmol), dry THF (2 ml), thioester
7
9
(493 mg,
(677 mg,
2.25 mmol), Pd2(dba)3 (34 mg, 0.03 mmol), and P(o-tol)3
(45.65 mg, 0.15 mmol), a yellow oil was obtained, which
was chromatographed (hexane:AcOEt, 8:2 and 2:8) to
obtain the desired aminoester 5b (288 mg, 49%), Boc-Ala-
OMe (92 mg, 30%), and the unaltered excess thioester 9
(305 mg). Aminoester 5b: [a]2D2ˆ122.4 (c 1, CHCl3). Mp
80±818C (AcOEt). IR (NaCl) 1760, 1750 and 1725 (CO)
1.1.6. (3S,5R)-3-tert-Butoxycarbonylamino-5-hydroxy-2-
piperidone (14). To a solution of lactone 13 (80 mg,
0.21 mmol) in CH3OH (1 ml) a catalytic amount 10% of
Pd/C was added, and the dispersion was hydrogenated at
Patm and room temperature for 2 h. The mixture was ®ltered
through Celitew, the solvent was evaporated, and the result-
ing oil was chromatographed (AcOEt:CH3OH, 94:6) to
obtain 5-hydroxylactam 1413 (10 mg, 19%). 1H NMR
(CDCl3) 1.46 (s, 9H, C(CH3)3), 1.65±1.85 (m, 1H, H-4a),
2.85 (br s, 1H, H-4b), 3.24±3.52 (m, 2H, H-6), 4.05 (br s,
1H, H-3), 4.20 (br s, 1H, H-5), 5.59 (d, Jˆ4 Hz, NH±Boc),
6.62 (br s, NH-lactam); 13C NMR (CDCl3) 28.4 (C(CH3)3),
37.0 (C-4), 49.8 (C-6), 51.6 (C-3), 63.6 (C-5), 80.4
(C(CH3)3), 155.2 (NH-Boc), 170.9 (C-2). EIMS m/z (%)
175 (M12C(CH3)3, 11), 157 (12), 57 (100).
1
cm21; H NMR (CDCl3) 1.43 (s, 9H, C(CH3)3), 2.95 (dd,
Jˆ17, 4 Hz, 1H, HA-3), 3.09 (br d, Jˆ17 Hz, 1H, HB-3),
3.72 (s, 3H, CO2CH3), 4.11 (d, Jˆ5 Hz, 2H, H-5), 4.56
(br s, 1H, H-2), 5.24 (s, 2H, CH2C6H5), 5.48 (d, Jˆ6 Hz,
2H, NH), 7.27 (s, 5H, C6H5); 13C NMR (CDCl3) 28.3
(C(CH3)3), 41.9 (C-3), 49.4 (C-2), 50.6 (C-5), 52.8
(CO2CH3), 67.1 (CH2C6H5), 80.3 (C(CH3)3), 128.1 (C6H5-
o and -p), 128.4 (C6H5-m), 136.2 (C6H5-ipso), 155.4 (NH±
CO-Boc), 156.1 (NH±CO-Cbz), 171.5 (CO2CH3), 203.6 (C-
4). EIMS m/z (%) 395 (M111, 0.1), 294 (3), 174 (14), 146
(14), 91 (100), 57 (63). Anal. Calcd for C19H26N2O7: C,
57.86; H, 6.64; N, 7.10. Found: C, 57.70; H, 6.60; N, 6.76.
1.1.7. (S)-5-(Benzyloxycarbonylamino)-2-(tert-butoxy-
carbonylamino)-4-oxopentanoic acid (15). To a solution
of ketoester 5 (150 mg, 0.38 mmol) in CH3OH (0.95 ml)
cooled at 08C, 1 M NaOH (0.38 ml) was slowly added.
After 1 h the reaction mixture was acidi®ed by addition of
AcOH at 08C, and the solvent was removed under reduced
pressure. The residue was dissolved in AcOEt and was
washed with H2O and brine to give acid 15 as a red foam
1.1.4. (S,S)-2,5-Bis(2-tert-butoxycarbonylamino-2-meth-
oxycarbonylethyl)pyrazine (10). To a solution of ketoester
5b (100 mg, 0.25 mmol) in CH3OH (1.3 ml) a catalytic
amount of 10% Pd/C was added and the dispersion was
hydrogenated in a shaker at rt for 24 h. The reaction mixture
was ®ltered through Celitew, the solvent was evaporated,
and the residue was chromatographed (hexane:AcOEt,
3:7) to obtain pyrazine 10 (75 mg, 25%) as a yellow oil.
[a]2D2ˆ127.3 (c 1, CHCl3). IR (NaCl) 1748, 1716 and 1680
(144 mg, 98%). IR (NaCl) 3600 (CO2H), 1790 (CO) cm21
;
1H NMR (CDCl3) 1.44 (s, 9H, C(CH3)3), 2.96 (dd, Jˆ18,
6 Hz, 1H, HA-3), 3.12 (br d, Jˆ18 Hz, 1H, HB-3), 4.07±4.17
(m, 2H, H-5), 4.58 (br s, 1H, H-2), 5.11 (s, 2H, CH2C6H5),
5.48 (br s, 1H, NH), 5.56 (d, Jˆ4 Hz, 1H, NH), 7.35 (s, 5H,
C6H5); 13C NMR (CDCl3) 28.3 (C(CH3)3), 41.6 (C-3), 49.3
(C-2), 50.4 (C-5), 67.2 (CH2C6H5), 80.5 (C(CH3)3), 128.1
(C6H5-o and m), 128.4 (C6H5-p), 136.0 (C6H5-ipso), 155.6
(NH±CO-Boc), 156.4 (NH±CO-Cbz), 174.4 (CO2H), 204.5
(C-4). EIMS m/z (%) 381 (M111, 0.1), 91 (100), 57 (47).
1
(CO) cm21; H NMR (CDCl3) 1.42 (s, 9H, C(CH3)3), 3.29
(d, Jˆ5 Hz, 2H, H-30), 3.71 (s, 3H, CO2CH3), 4.68±4.74 (m,
1H, H-20), 5.55 (d, Jˆ8 Hz, 1H, NH), 8.32 (s, 1H, H-3, and
13
H-6 Ar); C NMR (CDCl3) 28.2 (C(CH3)3), 36.5 (C-10),
52.4 (CO2CH3), 52.6 (C-20), 80.0 (C(CH3)3), 143.9 (C-3
and C-6), 150.8 (C-2 and C-5), 155.2 (NH±CO-Cbz),
171.9 (CO2CH3). EIMS m/z (%) 482 (M1, 0.1), 426 (3),
353 (7), 57 (100).
1.1.8. Penta¯uorophenyl (S)-5-benzyloxycarbonylamino-
2-tert-butoxycarbonylamino-4-oxopentan-oate (16). To
a solution of acid 15 (650 mg, 1.71 mmol) in dry THF
1.1.5. (3S,5R)-5(N-Benzyloxycarbonylaminomethyl)-3-
(tert-butoxycarbonylamino)-d-butyrolactone (13). To a

M. A. Estiarte et al. / Tetrahedron 57 (2001) 157±161
161
(8.55 ml) cooled at 08C and under N2 atmosphere, DCC
(352 mg, 1.71 mmol) was added. After 10 min penta¯uoro-
phenol (346 g, 1.88 mmol) was added, and the temperature
was left to rise to rt. After stirring for 5 h, the reaction mixture
was ®ltered and the solvent was evaporated under reduced
pressure. The resulting yellow oil was chromatographed
(hexane:AcOEt, 7:3) to yield the activated ester 16
67.6 (CH2Ph), 81.3 (C(CH3)3), 128.4 (Ph-mand Ph-p), 156.1
(NH-Boc), 170.1 (C-2), 201.3 (C-5). EIMS m/z (%) 375
(M121, 0.1), 303 (1), 259 (28), 91 (95), 57 (100). Anal.
Calcd for C19H24N2O6: C, 60.63; H, 6.43; N, 7.44. Found: C,
60.52; H, 6.57; N, 7.21.
(766 mg, 85%). IR (NaCl) 1713 (CO), 1520 (CF) cm21
;
Acknowledgements
1H NMR (CDCl3) 1.45 (s, 9H, C(CH3)3), 3.14 (dd, Jˆ18,
4 Hz, 1H, HA-3), 3.31 (dd, Jˆ18, 4 Hz, 1H, HB-3), 4.13 (t,
Jˆ5 Hz, 2H, H-5), 4.94 (t, Jˆ5 Hz, 1H, H-2), 5.12 (s, 2H,
CH2C6H5), 5.41 (br s, 1H, NH), 5.55 (d, Jˆ8 Hz, 1H, NH),
7.35 (s, 5H, C6H5); 13C NMR (CDCl3) 28.2 (C(CH3)3), 41.9
(C-3), 49.0 (C-2), 50.4 (C-5), 67.3 (CH2C6H5), 81.0
(C(CH3)3), 128.2 (C6H5-o and -m), 128.5 (C6H5-p), 135.9
(C6H5-ipso), 139±143 (C6F5), 155.1 (NH±CO-Boc), 156.2
(NH±CO-Cbz), 167.5 (CO2C6F5), 203.2 (C-4). MS m/z (%)
527 (M12F, 0.1), 184 (13), 136 (16), 91 (96), 57 (100).
Â
This work has been funded by the Ministerio of Educacion y
Cultura (MEC, Spain) through grants PB97-0976 and
2FD97-0293, and by the CIRIT (Generalitat of Catalunya)
through grants 1997SGR-0075 and 1999SGR-0077. We
also thank the MEC for the grant given to M. A. E, and
Dr C. A. G. N. Montalbetti (University of Newcastle) for
preliminary work.
References
1.1.9. (S)-3-tert-Butoxycarbonylaminopiperidin-2,5-dione
(11). To a solution of penta¯uorophenyl ester 16 (650 mg,
1.19 mmol) in CH3OH (119 ml) a catalytic amount of 10%
Pd/C was added, and the mixture was hydrogenated for
1.5 h under atmospheric pressure. The reaction mixture
was ®ltered through Celitew, the solvent was evaporated,
and the oily residue was chromatographed (hexane:AcOEt,
1:9) to obtain 5-oxolactam 11 (215 mg, 79%). IR (NaCl)
1. Tamura, S. Y.; Goldman, E. A.; Brunck, T. K.; Ripka, W. C.;
Semple, J. E. Bioorg. Med. Chem. Lett. 1997, 7, 331±336.
2. Thorsett, E. D.; Harris, E. E.; Aster, S. D.; Peterson, E. R.;
Snyder, J. P. J. Med. Chem. 1986, 29, 251±260.
3. For reviews, see: (a) Nagai, U.; Sato, K.; Nakamura, R.; Kato,
R. Tetrahedron 1993, 49, 3577±3592. (b) Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789±12854.
1
3300 (NH), 1682 (CO) cm21; H NMR (CDCl3) 1.46 (s,
9H, C(CH3)3), 2.53 (dd, Jˆ17, 13 Hz, 1H, H-6a), 3.25
(dd, Jˆ17, 4.5 Hz, 1H, H-6b), 3.85 (dd, Jˆ19, 5 Hz, 1H,
H-4a), 4.00 (d, Jˆ19 Hz, 1H, H-4b), 4.50 (br t, Jˆ6 Hz, 1H,
H-3), 5.59 (d, Jˆ4.5 Hz, NH±Boc), 6.62 (br s, NH-lactam);
13C NMR (CDCl3) 28.3 (C(CH3)3), 42.3 (C-4), 47.8 (C-3),
51.5 (C-6), 80.4 (C(CH3)3), 155.2 (NH±CO-Boc), 170.9
(CO lactam), 202.3 (C-5). EIMS m/z (%) 155 (M12
OC(CH3)3, 13), 111 (38), 57 (100). Anal. Calcd for
C10H16N2O4: C, 52.63; H, 7.01; N, 12.28. Found: C,
53.03; H, 6.98; N, 12.30.
4. Semple, J. E.; Rowley, D. C.; Brunck, T. K.; Ha-Uong, T.;
Minami, N. K.; Owens, T. D.; Tamura, S. Y.; Goldman, E. A.;
Siev, D. V.; Ardecky, R. J.; Carpenter, S. H.; Ge, Y.; Richard,
B. M.; Nolan, T. G.; Hakanson, K.; Tulinsky, A.; Nutt, R.;
Ripka, W. C. J. Med. Chem. 1996, 39, 4531±4536.
5. Jackson, R. F. W. Preparation and Use of Organozinc Halides.
In Organozinc Reagents: A Practical Approach; Knochel, P.,
Jones, P., Eds.; Oxford University Press: Oxford, 1999; pp 37±
56.
6. Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J.
J. Chem. Soc., Perkin Trans. 1 1994, 1719±1726.
7. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189±3192.
1.1.10. (S)-N-Benzyloxycarbonylethyl-3-(N-tert-butoxy-
carbonylamino)piperidin-2,5-dione (4). To a solution of
lactam 11 (60 mg, 0.26 mmol) in dry THF (1 ml) cooled at
2788C and under N2 atmosphere, LHMDS (0.26 ml,
0.26 mmol) was added. After stirring for 30 min, benzyl
bromoacetate (0.06 ml, 0.39 mmol) was added, and the
temperature was left to raise to rt. After 5 h, the reaction
was quenched by addition of saturated aqueous NH4Cl and
was partitioned with AcOEt/H2O. The organic extracts,
dried and evaporated gave a yellow oil which was chroma-
tographed (hexane: AcOEt, 7:3) to obtain the target lactam 4
(13 mg, 13%). IR (NaCl) 3500 (NH), 1741, 1728 and 1676
8. Bajgrowicz, J. A.; El Hallaoui, A.; Jacquier, R.; Pigiere, C.;
Viallefont, P. Tetrahedron 1985, 41, 1833±1843.
9. The thioester from alanine was prepared according to: Neises,
B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522±
523.
10. For the Pd2(dba)3 use of higher reaction temperatures or more
catalyst gave poorer results.
11. The starting material was recovered, or when the reaction
conditions were forced, the hydrolysis of carbamates led to
polymeric mixtures.
1
(CO) cm21; H NMR (CDCl3) 1.46 (s, 9H, C(CH3)3), 2.58
È
12. Schmidt, U.; Meyer, R.; Leitenberger, V.; Stabler, F.;
Lieberknecht, A. Synthesis 1991, 409±413.
13. Gordon, S.; Costa, L.; Incerti, M.; Manta, E.; SaldanÄa, J.;
(dd, Jˆ16, 13 Hz, 1H, H-4a), 3.25 (dd, Jˆ16, 4.5 Hz, 1H,
H-4b), 3.78(d, Jˆ17 Hz, 1H, NCHA), 4.25 (d, Jˆ17 Hz, 1H,
NCHB), 4.25 (s, 2H, H-6), 4.45-4.56 (m, 1H, H-3), 5.12 (s,
2H, CH2Ph), 5.59 (d, Jˆ4 Hz, NH-Boc); 13C NMR (CDCl3)
28.3 (C(CH3)3), 42.3 (C-4), 48.4 (C-3 and C-a), 58.0 (C-6),
Â
Domõnguez, L.; Mariezcurrena, R.; Suescun, L. Il Farmaco
1997, 52, 603±608.