Amino analogs of actic acids - Synthesis and lactamization

Article abstract of DOI:10.1016/S0040-4020(02)00393-9

Novel THF-amino acids were efficiently synthesized from actic acid methyl esters. The conformational restriction imposed by the 2,5-cis disubstituted tetrahydrofuran moiety is apparent from their facile cyclization to give medium-sized lactams.

Full text of DOI:10.1016/S0040-4020(02)00393-9

TETRAHEDRON
Pergamon
Tetrahedron 58 92002) 4451±4457
Amino analogs of actic acidsÐsynthesis and lactamization
a
Heiko Bernsmann, Yuzhou Wang, Roland Frohlich and Peter Metz
a
b
a,p
È
a
È È
Institut fur Organische Chemie, Technische Universitat Dresden, Bergstraûe 66, D-01069 Dresden, Germany
b
È
È
È
Organisch-Chemisches Institut, Universitat Munster, Corrensstraûe 40, D-48149 Munster, Germany
Dedicated to Professor Roland Mayer on the occasion of his 75th birthday
Received 8 March 2002; accepted 10 April 2002
AbstractÐNovel THF-amino acids were ef®ciently synthesized from actic acid methyl esters. The conformational restriction imposed by
the 2,5-cis disubstituted tetrahydrofuran moiety is apparent from their facile cyclization to give medium-sized lactams. q 2002 Published by
Elsevier Science Ltd.
1. Introduction
2. Results and discussion
Tetrahydrofuran containing amino acids combine the cation
complexing ability of ethers with the synthetic potential
offered by amino acids.1 These designed structures have
proven to be interesting building blocks for peptidomi-
metics and have recently been used successfully for the
construction of arti®cial ion channels.2 Moreover, replace-
ment of the hydroxyl function in naturally occurring
hydroxy acids by an amino group and incorporation of the
resultant unnatural amino acids into b- or g-peptides has led
to highly bioactive peptide mimics.3 Inspired by this work,
we studied the conversion of actic acids such as nonactic
acid 1a,4 the monomeric subunit of the macrotetrolide anti-
biotic nonactin,5 as well as of the propyl substituted
compound 1b,6 a precursor for both hydroxy acid fragments
of the macrodiolide antibiotic pamamycin-607,7 into their
amino analogs with overall retention of relative con®gura-
tion 9Fig. 1). Here we describe a convenient protocol for this
transformation, as well as the smooth lactamization of the
resultant novel THF-amino acids.
2.1. Synthesis of THF-amino acids 6
The methyl esters 2 of acids 1 are readily available in only
six steps from furan by our highly diastereoselective and
general sultone route.4,6a,8 While these esters can be easily
prepared in enantiomerically pure form either by departing
from an enantiopure epoxide6a or by application of a facile
resolution technique,9 we ®rst used racemic 2a,b for our
purposes 9Scheme 1).
Attempted tosylation of 2b with inversion of con®guration
using zinc tosylate10 under Mitsunobu conditions failed.
However, treatment of 2a,b with triphenylphosphine
dibromide11 cleanly effected the desired SN2 substitution
to give the bromides 3.
A second inversion of
con®guration during azide displacement12 then provided
the azido esters 4 as single diastereomers in high
yields. In order to aid product isolation, esters 4 were ®rst
hydrolyzed without epimerization at C92) to give the
relatively unpolar azido acids 5, puri®cation of which by
¯ash chromatography was facile. In case of azido acid
5b, suitable crystals were obtained that allowed an
unambiguous determination of its relative con®guration by
X-ray diffraction analysis 9Fig. 2).13 Finally, reductive
release14 of the amino group provided the target compounds
6.
Having established suitable conditions for the conversion of
racemic actic acid methyl esters 2 into racemic amino acids
6, we applied this double inversion procedure to the prepara-
tion of enantiomerically pure building blocks ready for
peptide coupling. As exempli®ed in Scheme 2 for
92R,3R,6S,8S) methyl nonactate 992)-2a),9 hydrogenation14
of azido ester 91)-4a afforded amino ester 92)-7a in
excellent yield. Likewise, the N-protected amino acid
Figure 1. Actic acids 1a 9nonactic acid) and 1b.
Keywords: amino acids; hydroxy acids; lactams; medium-ring heterocycles.
Corresponding author. Tel.: 149-351-463-37006; fax: 149-351-463-
33162; e-mail: peter.metz@chemie.tu-dresden.de
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020902)00393-9

4452
H. Bernsmann et al. / Tetrahedron 58 /2002) 4451±4457
Scheme 1. Preparation of amino acids 6a and 6b: 9a) Ph3P´Br2, CH2Cl2, toluene, 08C to rt, 83% 3a, 7 5%3b; 9b) NaN3, DMF, 608C, 98% 4a, 97 %4b; 9c) 2N
NaOH, MeOH, rt, 92% 5a, 90% 5b; 9d) H2, 10% Pd/C, MeOH, rt, 83% 6a, 7 9%6b.
the resultant sodium carboxylates, treatment with DPPA
induced a smooth ring closure to give the lactams 10.16b
Application of high dilution conditions6d was not required
in this case, which clearly underlines the conformational
restriction caused by the cyclic ether. In contrast to the
corresponding lactonization of acids 1a,b, no epimerization
was observed during the formation of 10a,b, the relative
Figure 2. Crystal structure of azido acid 5b.13
con®guration of which was unequivocally established by
single crystal X-ray analyses 9Figs. 3 and 4).
3. Conclusion
In summary, the novel THF-amino acids 6 and partially
protected derivatives suitable for peptide coupling were
ef®ciently synthesized from actic acid methyl esters 2.
Utilization of these conformationally constrained building
blocks for peptidomimetics and ion transport systems is
currently under investigation in our laboratories and will
be reported in due course.
Scheme 2. Preparation of partially protected, enantiomerically pure build-
ing blocks 92)-7a and 92)-9a: 9a,b) see Scheme 1; 9c) H2, 10% Pd/C,
MeOH, rt, 98%; 9d) Ph3CCl, Et3N, CH2Cl2, rt, 96%; 9e) KOH, THF,
MeOH, rt, 84%.
Scheme 3. Preparation of lactams 10a and 10b: 9a) H2, 10% Pd/C, MeOH, rt, 98% 7a, 96% 7b; 9b) 9i) 2N NaOH, MeOH, rt, 9ii) N3PO9OPh)2, Et3N, DMF, 08C
to rt, 53% 10a, 61% 10b.
92)-9a was ef®ciently secured by N-tritylation of 92)-7a
followed by mild ester hydrolysis.
2.2. Lactamization of THF-amino acids 6
We recently reported the lactonization of hydroxy acids
1a,b under Yamaguchi conditions.6d Formation of the corre-
sponding medium-sized lactones was accompanied by
Figure 3. Crystal structure of lactam 10a.13
extensive epimerization at C92). With amino acids 6a,b at
hand, it was tempting to see as to whether the conforma-
tional constraint imposed by the 2,5-cis disubstituted tetra-
hydrofuran moiety would also facilitate lactamization.
Among the various methods used for the synthesis of
medium-ring lactams by amide bond formation,15 we
chose carboxyl activation by diphenylphosphoryl azide
9DPPA) 9Scheme 3).16
To this end, the racemic azides 4a,b were hydrogenated to
give the amino esters 7. After saponi®cation and drying of
Figure 4. Crystal structure of lactam 10b.13

H. Bernsmann et al. / Tetrahedron 58 /2002) 4451±4457
4453
4. Experimental
4.2.2. Bromide 3b. Colorless oil; Rf 0.479dichloromethane/
ether 40:1); IR 9neat): 2960 9s), 2912 9m), 2876 9m), 1740 9s,
CvO), 1461 9m), 1434 9m), 1378 9w), 1353 9w), 1340 9w),
1260 9m), 1199 9s), 1164 9m), 10879m), 1065 9s) cm 21; 1H
NMR 9CDCl3, 500 MHz): d 0.90 9t, Jˆ7.4 Hz, 3H), 1.10 9d,
Jˆ7.0 Hz, 3H), 1.38±1.65 9m, 4H), 1.73±1.85 9m, 2H),
1.87±1.93 9ddd, Jˆ6.2, 6.2, 14.3 Hz, 1H), 1.94±2.06 9m,
2H), 2.18±2.40 9ddd, Jˆ7.3, 7.3, 14.2 Hz, 1H), 2.50 9dq,
Jdˆ7.1 Hz, Jqˆ7.1 Hz, 1H), 3.68 9s, 3H), 3.98±4.03 9m,
1H), 4.04±4.14 9m, 2H); 13C NMR 9CDCl3, 125.8 MHz):
d 13.38 9q), 13.44 9q), 20.679t), 28.39 9t), 30.66 9t), 40.58
9t), 45.22 9t), 45.37 9d), 51.64 9q), 54.17 9d), 77.33 9d), 80.54
9d), 175.26 9s); MS 9GC/MS, 70 eV) m/z 9relative intensity):
277 92) [M12OCH3], 275 92) [M12OCH3], 22796)
[M12Br], 221 931) [M12CH3CHCO2CH3], 219 932)
[M12CH3CHCO2CH3], 1579100) [M 12C5H10Br], 125
980) [M12C5H10Br2CH3OH], 43 939) [C3H71]; Anal.
calcd for C13H23BrO3: C, 50.82; H, 7.55; Br 26.01. Found
C, 51.08; H, 7.67; Br, 26.16.
4.1. General experimental information
All reactions requiring exclusion of moisture were run under
argon using ¯ame-dried glassware. Solvents were dried by
distillation from potassium 9THF) or else CaH2. Flash
chromatography was performed on Merck silica gel 60
940±63 mm). Capillary GC analyses were performed with
a Shimadzu GC-14A or GC-14B, a Shimadzu C-R6A
integrator, and a HP 5 column 925 m length, 0.25 mm i.d.,
0.25 mm ®lm). Melting points were determined on a Ko¯er
microscope desk. Optical rotations were measured with a
Perkin±Elmer 241 and a Perkin±Elmer 341 polarimeter.
FT-IR spectra were obtained on a Nicolet 205; wˆweak,
1
sˆstrong, mˆmedium, brˆbroad. H NMR and 13C NMR
spectra were obtained on a Bruker ASP-300 91H: 300 MHz,
13C: 75.5 MHz) and a Bruker DRX-500 91H: 500 MHz, 13C:
126 MHz); brˆbroad. 13C multiplicities were determined
using DEPT pulse sequences. Mass spectra 9GC/MS,
70 eV) were recorded with a Hewlett Packard 5972 detector
coupled with a Hewlett Packard 5890 GC. Mass spectra
9ESI) were obtained with a Bruker Esquire-LC. Mass
spectra 9EI, 70 eV) and high resolution mass spectra
9HR-EI, 70 eV and HR-CI) were obtained with a Finnigan
MAT 95. Microanalyses were performed by the analytical
laboratory of the Institut fuÈr Organische Chemie,
4.3. Preparation of azido esters 4
Sodium azide 9820 mg, 12.6 mmol) was added at 608C to a
solution of bromide 3a 92.35 g, 8.42 mmol) in dry DMF
9100 mL), and stirring was continued at this temperature
for 2 h. The mixture was allowed to cool to room tempera-
ture, and the solvent was removed in vacuo. Puri®cation of
the crude product by ¯ash chromatography 9dichloro-
methane/ether 40:1 for 3a, pentane/ethyl acetate 10:1 for
3b) gave azido ester 4a 91.99 g, 98%). Similarly, 4b
92.00 g, 97%) was obtained from 3b 92.36 g, 7.68 mmol).
È
Technische Universitat Dresden.
4.2. Preparation of bromides 3
A solution of methyl nonactate 92a) 92.20 g, 10.2 mmol) in
anhydrous dichloromethane 915 mL) was added dropwise
by syringe to a suspension of triphenylphosphine dibromide
94.77 g, 11.3 mmol) in dry toluene 925 mL) cooled to 08C.
After stirring for 3.5 h at room temperature, the reaction
mixture was ®ltered through a plug of silica and eluted
with ether. The solvent was removed in vacuo, and the
residue was puri®ed by ¯ash chromatography 9dichloro-
methane/ether 40:1) to give the bromide 3a 92.35 g, 83%).
Similarly, 3b 9944 mg, 75%) was obtained from 2b 91.00 g,
4.09 mmol).
4.3.1. Azido ester 4a. Colorless oil; Rf 0.44 9dichloro-
methane/ether 40:1); IR 9neat): 2973 9s), 2950 9s), 2880
9m), 2101 9s, N3), 1741 9s, CvO), 1461 9m), 1436 9m),
1378 9m), 1256 9s), 1199 9s), 1164 9m), 1093 9m), 1059
1
9s); H NMR 9CDCl3, 300 MHz): d 1.08 9d, Jˆ7.0 Hz,
3H), 1.24 9d, Jˆ6.5 Hz, 3H), 1.43±1.49 9m, 1H), 1.53±
1.69 9m, 3H), 1.91±2.02 9m, 2H), 2.479dq, Jdˆ7.1 Hz,
Jqˆ7.1 Hz, 1H), 3.58±3.64 9m, 1H), 3.68 9s, 3H), 3.97±
4.05 9m, 2H); 13C NMR 9CDCl3, 75.5 MHz): d 13.40 9q),
20.15 9q), 28.53 9t), 31.26 9t), 42.93 9t), 45.53 9d), 51.62 9q),
55.73 9d), 76.31 9d), 80.58 9d), 175.20 9s); MS 9GC/MS,
70 eV) m/z 9relative intensity): 198 90.4) [M12HN3], 182
98) [M12CO2CH3], 157926) [M 12C3H6N3], 154 913)
[M12CH3CHCO2CH3], 88 985) [C4H8O21], 55 9100);
Anal. calcd for C11H19N3O3: C, 54.76; H, 7.94; N, 17.42.
Found C, 54.87; H, 8.00; N, 17.71.
4.2.1. Bromide 3a. Colorless oil; Rf 0.46 9dichloromethane/
ether 40:1); IR 9neat): 2976 9s), 2949 9s), 1740 9s, CvO),
1460 9m), 1435 9m), 1378 9m), 1262 9m), 1200 9s), 1161
9m), 1081 9s), 1061 9m) cm21; 1H NMR 9CDCl3, 500 MHz):
d 1.09 9d, Jˆ7.2 Hz, 3H), 1.45±1.50 9m, 1H), 1.57±1.63
9m, 1H), 1.70 9d, Jˆ6.7Hz, 3H), 1.83±1.88 9m, 1H), 1.93±
2.04 9m, 2H), 2.17±2.22 9m, 1H), 2.49 9dq, Jdˆ7.1 Hz,
Jqˆ7.1 Hz, 1H), 3.68 9s, 3H), 3.98±4.02 9m, 2H), 4.18 9m,
1H); 13C NMR 9CDCl3, 126 MHz): d 13.43 9q), 25.95 9q),
28.35 9t), 30.71 9t), 45.33 9d), 47.19 9t), 47.44 9d), 51.62 9q),
77.23 9d), 80.58 9d), 175.22 9s); MS 9GC/MS, 70 eV) m/z
9relative intensity): 249 90.1) [M12OCH3], 24790.1)
25
Azido ester 91)-4a obtained from 92)-3a: [a]D ˆ152.3 9c
1.44, CHCl3).
4.3.2. Azido ester 4b. Colorless oil; Rf 0.24 9pentane/ethyl
acetate 10:1); IR 9neat): 2960 9s), 2941 9s), 2876 9s), 2102 9s,
N3), 1741 9s, CvO), 1462 9m), 1436 9m), 1378 9m), 1360
9m), 1341 9m), 1261 9s), 1198 9s), 1163 9m), 1119 9m), 1089
[M12OCH3],
199
90.9)
[M12Br],
193
920)
[M12CH3CHCO2CH3], 191 922) [M12CH3CHCO2CH3],
157931) [M 12C3H6Br], 125 933) [M12C3H6Br2CH3OH],
41 9100); Anal. calcd for C11H19BrO3: C, 47.33; H, 6.86.
Found C, 47.23; H, 6.84.
9m), 1066 9s); H NMR 9CDCl3, 500 MHz): d 0.92 9t,
1
Jˆ7.1 Hz, 3H), 1.10 9d, Jˆ7.0 Hz, 3H), 1.34±1.64 9m,
8H), 1.94±2.06 9m, 2H), 2.40 9dq, Jdˆ7.1 Hz, Jqˆ7.1 Hz,
1H), 3.44±3.50 9m, 1H), 3.68 9s, 3H), 3.97±4.05 9m, 2H);
13C NMR 9CDCl3, 126 MHz): d 13.379q), 13.81 9q), 19.23
9t), 28.579t), 31.31 9t), 37.31 9t), 41.16 9t), 45.59 9d), 51.61
9q), 60.35 9d), 76.34 9d), 80.54 9d), 175.20 9s); MS 9GC/MS,
25
Bromide 92)-3a obtained from 92)-2a: [a]D ˆ255.79 c
1.29, CHCl3).

4454
H. Bernsmann et al. / Tetrahedron 58 /2002) 4451±4457
70 eV) m/z 9relative intensity): 241 90.5) [M12N2], 226 94)
[M12C3H7 or M12HN3], 210 910) [M12CO2CH3], 198
923) [M12C3H72N2], 182 95) [M12CH3CHCO2CH3],
171 96) [M12C4H8N3], 157939) [M 12C5H10N3], 112
934) [C5H10N31], 88 977) [C4H8O21], 43 965) [C3H71], 41
9100); Anal. calcd for C13H23N3O3: C, 57.97; H, 8.61; N,
15.60. Found C, 58.00; H, 8.68; N, 15.48.
®lter funnel G5, and the ®ltrate was evaporated in vacuo to
give the amino acid 6a 9156 mg, 83%). Similarly, 6b
9253 mg, 79%) was obtained from 5b 9356 mg,
1.39 mmol) after puri®cation by ¯ash chromatography
9methanol).
4.5.1. Amino acid 6a. Colorless solid; mp 185±1888C
9decomposition); IR 9KBr): 3200±2500 9br, s, OH), 2970
9s), 2918 9s), 2877 9s), 2568 9m), 2224 9m), 1629 9s, CvO),
1552 9s), 15479s), 1460 9m), 1406 9s), 1362 9m), 1103 9m),
1074 9m), 1060 9m) cm21; 1H NMR 9CD3OD, 300 MHz): d
1.10 9d, Jˆ7.0 Hz, 3H), 1.32 9d, Jˆ6.8 Hz, 3H), 1.56±2.07
9m, 6H), 2.23 9dq, Jdˆ7.0 Hz, Jqˆ7.0 Hz, 1H), 3.48±3.58
9m, 1H), 3.86±3.93 9m, 1H), 4.06±4.11 9m, 1H); 13C NMR
9CD3OD, 75.5 MHz): d 16.50 9q), 19.58 9q), 30.82 9t), 32.06
9t), 39.76 9t), 47.20 9d), 50.65 9d), 77.50 9d), 84.78 9d),
184.28 9s); MS 9ESI) m/z: 224.1 [M1Na1], 202.1
[M1H1], 184 [M1H12H2O]; Anal. calcd for
C10H19NO3: C, 59.68; H, 9.52; N, 6.96. Found C, 59.56;
H, 9.87; N, 6.95.
4.4. Preparation of azido acids 5
To a solution of azido ester 4a 91.21 g, 5.0 mmol) in MeOH
920 mL) was added 2N NaOH 920 mL, 40.0 mmol) at room
temperature, and the mixture was stirred vigorously for
10 h. The mixture was acidi®ed to pH 1 with 2N HCl,
extracted with ethyl acetate 94£15 mL), and the combined
organic layers were dried over MgSO4. Concentration in
vacuo and puri®cation of the residue by ¯ash chromato-
graphy 9dichloromethane/ether 4:1) gave azido acid 5a
91.04 g, 92%). Similarly, 5b 9861 mg, 90%) was obtained
from 4b 91.01 g, 3.75 mmol).
4.5.2. Amino acid 6b. White needles; Rf 0.44 9methanol);
mp 2498C 9decomposition); IR 9KBr): 3419 9m), 2963 9s),
2936 9s), 2874 9s), 2364 9m), 2146 9w), 1567 9s, CvO),
1461 9m), 1402 9s), 1365 9m), 12879w), 1090 9w), 1062
4.4.1. Azido acid 5a. Colorless oil; Rf 0.27±0.54 9dichloro-
methane/ether 1:1); IR 9neat): 3500±2500 9br, m, OH), 2966
9s), 2945 9s), 2109 9s, N3), 1715 9s, CvO), 1455 9s), 1419
1
9s), 1377 9s), 1251 9s), 1089 9s), 1061 9s) cm21; H NMR
9m) cm21
;
1H NMR 9CD3OD, 500 MHz): d 1.05 9t,
9CDCl3, 300 MHz): d 1.179d, Jˆ7.1 Hz, 3H), 1.29 9d,
Jˆ6.5 Hz, 3H), 1.42±1.72 9m, 4H), 1.97±2.11 9m, 2H),
2.51 9dq, Jdˆ7.1 Hz, Jqˆ7.1 Hz, 1H), 3.61±3.72 9m, 1H),
4.01±4.09 9m, 2H); 13C NMR 9CDCl3, 75.5 MHz): d 13.30
9q), 20.04 9q), 28.71 9t), 31.16 9t), 42.85 9t), 45.26 9d), 55.54
9d), 76.62 9d), 80.35 9d), 179.63 9s); MS 9GC/MS, 70 eV)
m/z 9relative intensity): 184 93) [M12HN3], 154 913)
[M12CH3CHCO2H], 143 917) [M12C3H6N3], 125 940)
[M12C3H6N32H2O], 84 923) [C3H6N31], 70 924)
[C2H4N31], 42 9100); Anal. calcd for C10H17N3O3: C,
52.85; H, 7.54; N, 18.49. Found C, 53.11; H, 7.66; N, 18.55.
Jˆ7.3 Hz, 3H), 1.17 9d, Jˆ7.1 Hz, 3H), 1.45±1.53 9m,
2H), 1.64±1.80 9m, 4H), 1.90 9ddd, Jˆ3.4, 7.2, 15.3 Hz,
1H), 1.98 9ddd, Jˆ2.9, 7.9, 15.3 Hz, 1H), 2.02±2.12 9m,
2H), 2.36 9dq, Jdˆ7.1 Hz, Jqˆ7.1 Hz, 1H), 3.43 9ddd,
Jˆ2.9, 7.1, 7.1 Hz, 1H), 3.96 9ddd, Jˆ7.2, 7.2, 7.2 Hz,
1H), 4.12±4.179m, 1H); 13C NMR 9CD3OD, 126 MHz): d
14.879q), 16.56 9q), 20.60 9t), 30.82 9t), 32.179t), 36.379t),
37.49 9t), 50.88 9d), 51.14 9d), 77.46 9d), 84.89 9d), 184.48
9s); MS 9EI, 70 eV) m/z 9relative intensity): 186 931)
[M12C3H7], 15791) [M 12C4H8NH2], 143 942)
[M12C5H10NH2], 86 94) [C5H10NH21], 72 9100)
[C4H8NH21]; HRMS 9EI, 70 eV) Calcd for C12H23NO3
[M1]: 229.168. Found: 229.164.
4.4.2. Azido acid 5b. White needles; Rf 0.30±0.48
9dichloromethane/ether 4:1); mp 34±398C; IR 9KBr): 3029
9br, m, OH), 2962 9s), 2939 9s), 2876 9s), 2102 9s, N3), 1737
9s, CvO), 1712 9s, CvO), 1465 9m), 1276 9s), 1259 9s),
4.6. Preparation of amino esters 7
1
1228 9s), 1066 9s) cm21; H NMR 9CDCl3, 500 MHz): d
0.93 9t, Jˆ7.1 Hz, 3H), 1.15 9d, Jˆ7.0 Hz, 3H), 1.37±1.68
9m, 8H), 2.00±2.08 9m, 2H), 2.51 9dq, Jdˆ7.5 Hz,
Jqˆ7.5 Hz, 1H), 3.47±3.50 9m, 1H), 4.01±4.08 9m, 2H);
13C NMR 9CDCl3, 126 MHz): d 13.92 9q), 13.82 9q),
19.19 9t), 28.81 9t), 31.21 9t), 37.13 9t), 41.04 9t), 45.22
9d), 60.18 9d), 76.75 9d), 80.30 9d), 179.32 9s); MS
9GC/MS, 70 eV) m/z 9relative intensity): 212 91)
[M12C3H7 or M12HN3], 184 911) [M12C3H72N2], 143
928) [M12C5H10N3], 125 957) [M12C5H10N32H2O], 112
922) [C5H10N31], 98 913) [C4H8N31], 69 972) [C5H91], 43
997) [C3H71], 41 9100); Anal. calcd for C12H21N3O3: C,
56.45; H, 8.29; N, 16.46. Found C, 56.57; H, 8.57; N, 16.80.
To a solution of azido ester 4a 91.61 g, 6.67mmol) in
MeOH 940 mL) was added 10% Pd/C 9160 mg) at ambient
temperature. After purging the suspension with hydrogen
95 min), stirring was continued for 12 h 94a) or 24 h 94b)
under a hydrogen atmosphere of 10 bar 94a) or 1.5 bar 94b).
The catalyst was removed by ®ltration through a glass ®lter
funnel G5, and the ®ltrate was evaporated in vacuo to give
the amino ester 7a 91.40 g, 98%). Similarly, 7b 9447mg,
96%) was obtained from 4b 9515 mg, 1.91 mmol).
4.6.1. Amino ester 7a. Colorless oil; IR 9neat): 3311 9w,
NH), 3302 9w, NH), 2955 9s), 2877 9s), 1740 9s, CvO),
1596 9w), 1460 9m), 1436 9m), 1377 9m), 1263 9m), 1199
1
4.5. Preparation of amino acids 6
9s), 1164 9s), 1085 9s), 1063 9s) cm21; H NMR 9CDCl3,
300 MHz): d 1.079d, Jˆ6.4 Hz, 3H), 1.10 9d, Jˆ7.0 Hz,
3H), 1.39±1.63 9m, 6H), 1.89±2.03 9m, 2H), 2.51 9dq,
Jdˆ7.0 Hz, Jqˆ7.0 Hz, 1H), 3.01±3.12 9m, 1H), 3.67 9s,
3H), 3.92±4.02 9m, 3H); 13C NMR 9CDCl3, 75.5 MHz): d
13.40 9q), 24.31 9q), 28.52 9t), 31.32 9t), 44.34 9d), 45.42 9d),
45.61 9t), 51.59 9q), 76.91 9d), 80.53 9d), 175.38 9s); MS
9ESI) m/z: 238 [M1Na1], 216 [M11H1]; Anal. calcd for
To a solution of azido acid 5a 9210 mg, 0.93 mmol) in dry
MeOH 930 mL) was added 10% Pd/C 930 mg) at ambient
temperature. After purging the suspension with hydrogen
95 min), stirring was continued for 10 h 95a) or 1 h 95b)
under a hydrogen atmosphere of 10 bar 95a) or 1.5 bar
95b). The catalyst was removed by ®ltration through a glass-

H. Bernsmann et al. / Tetrahedron 58 /2002) 4451±4457
4455
C11H21NO3: C, 61.37; H, 9.83; N, 6.51. Found C, 61.77; H,
9.50; N, 6.38.
with brine, dried over MgSO4 and concentrated in vacuo.
Puri®cation of the residue by ¯ash chromatography
9dichloromethane/ether 5:1) yielded N-trityl acid 92)-9a
9900 mg, 84%) as a colorless foamy solid. Rf 0.15 9dichloro-
methane/ether 5:1); mp 53±558C; [a]D ˆ23.16 9c 1.05,
25
Amino ester 92)-7a obtained from 91)-4a: [a]D ˆ214.5
25
9c 1.25, CHCl3).
CHCl3); IR 9KBr): 3600±2500 9br, m, OH), 33379w,
NH), 3057 9m), 2971 9s), 2876 9m), 1710 9s, CvO), 1490
9m), 1448 9m), 1208 9m), 1095 9m), 1056 9m), 771 9m), 747
9m), 707 9s) cm21; 1H NMR 9CDCl3, 500 MHz): d 0.84 9d,
Jˆ6.4 Hz, 3H), 1.10 9d, Jˆ7.1 Hz, 3H), 1.12±1.25 9m, 3H),
1.41±1.48 9m, 1H), 1.70±1.76 9m, 1H), 1.84±1.91 9m, 1H),
2.40 9dq, Jdˆ7.1 Hz, Jqˆ7.1 Hz, 1H), 2.57±2.61 9m, 1H),
3.81 9m, 1H), 3.89 9m, 1H), 7.15±7.18 9m, 3H), 7.23±7.27
9m, 6H), 7.54±7.56 9m, 6H); 13C NMR 9CDCl3, 126 MHz):
d 13.38 9q), 22.61 9q), 28.75 9t), 30.71 9t), 43.77 9t), 44.63
9d), 46.92 9d), 71.44 9s), 78.01 9d), 80.08 9d), 126.15 9d),
127.69 9d), 128.86 9d), 147.09 9s), 177.60 9s); MS 9ESI) m/z:
466.2 [M1Na1], 444.0 [M1H1], 243.1 [Tr1]; Anal. calcd
for C29H33NO3: C, 78.52; H, 7.50; N, 3.16. Found C, 78.69;
H, 7.75; N, 3.19.
4.6.2. Amino ester 7b. Colorless oil; Rf 0.50 9methanol); IR
9neat): 2956 9s), 2935 9s), 2874 9m), 1740 9s, CvO), 1575
9w), 1573 9w), 1462 9m), 1436 9m), 1378 9m), 1340 9w),
1265 9w), 1199 9m), 1164 9m), 10879w), 1062 9m) cm 21; 1H
NMR 9CDCl3, 500 MHz): d 0.89 9t, Jˆ6.7Hz, 3H), 1.09 9d,
Jˆ7.0 Hz, 3H), 1.20±1.42 9m, 5H), 1.43±1.65 9m, 5H),
1.90±2.00 9m, 2H), 2.50 9dq, Jdˆ7.1 Hz, Jqˆ7.1 Hz, 1H),
2.86±2.91 9m, 1H), 3.66 9s, 3H), 3.96±4.03 9m, 2H); 13C
NMR 9CDCl3, 125.8 MHz): d 13.34 9q), 14.11 9q), 19.21 9t),
28.52 9t), 31.43 9t), 40.61 9t), 43.73 9t), 45.42 9d), 48.14 9d),
51.57 9q), 76.82 9d), 80.49 9d), 175.39 9s); MS 9GC/MS,
70 eV) m/z 9relative intensity): 212 96) [M12OCH3], 200
927) [M12C3H7], 157954) [M 12C5H10NH2)], 86 95)
[C5H10NH21], 72 9100) [C4H8NH21], 43 919) [C3H71];
HRMS 9CI) Calcd for C13H26NO3 [M1H1]: 244.1913.
Found: 244.1903.
4.9. Preparation of lactams 10
4.7. Preparation of N-trityl ester /2)-8a
To a solution of amino ester 7a 9302 mg, 1.40 mmol) in
MeOH 95 mL) was added 2N NaOH 90.70 mL,
1.40 mmol) at ambient temperature, and stirring was con-
tinued for further 3 d. The solvent was evaporated at
reduced pressure, and the residue was dried in vacuo over
phosphorous pentoxide for 3 d. The resultant amino acid
sodium salt was dissolved in dry DMF 9300 mL), and
diphenylphosphoryl azide 9389 mL, 1.80 mmol) and
anhydrous triethylamine 9297 mL, 2.00 mmol) were subse-
quently added at 08C. While stirring was continued, the
reaction mixture was allowed to warm to room temperature
overnight. The solvents were evaporated in vacuo, and the
residue was puri®ed by ¯ash chromatography 9dichloro-
methane/methanol 20:1) to give the lactam 10a 9136 mg,
53%). Similarly, 10b 9184 mg, 61%) was obtained from
7b 9346 mg, 1.42 mmol).
To a solution of amino ester 92)-7a 91.18 g, 5.48 mmol) and
triethylamine 91.21 g, 12.0 mmol) in anhydrous dichloro-
methane 930 mL) cooled to 08C was added a solution of
trityl chloride 91.65 g, 5.92 mmol) in dichloromethane
915 mL). The mixture was stirred for 6 h at room tempera-
ture and diluted with ether 9100 mL). The organic layer was
washed with 5% aqueous citric acid 950 mL) and saturated
aqueous NaHCO3 950 mL), dried over MgSO4 and con-
centrated in vacuo. Puri®cation of the residue by ¯ash
chromatography 9dichloromethane/pentane/ether 10:10:1
containing 0.5% triethylamine) afforded N-trityl ester
92)-8a 92.40 g, 96%) as a colorless oil. Rf 0.28 9dichloro-
25
methane/pentane/ether 5:5:1); [a]D ˆ26.51 9c 2.09,
CHCl3); IR 9neat): 3330 9w, NH), 3085 9w), 3031 9m),
2972 9s), 2873 9s), 1740 9s, CvO), 1696 9m), 1489 9s),
14579s), 1448 9s), 1376 9m), 1259 9m), 1201 9s), 1164 9s),
1067 9s), 901 9m), 775 9m), 746 9m), 708 9s) cm21; 1H NMR
9CDCl3, 300 MHz): d 0.82 9d, Jˆ6.4 Hz, 3H), 1.05 9d,
Jˆ7.0 Hz, 3H), 1.09±1.15 9m, 3H), 1.36±1.47 9m, 1H),
1.63±1.86 9m, 2H), 1.90 9br s, 1H), 2.43 9dq, Jdˆ7.1 Hz,
Jqˆ7.1 Hz, 1H), 2.55±2.62 9m, 1H), 3.54 9s, 3H), 3.69±3.78
9m, 1H), 3.92 9m, 1H), 7.13±7.18 9m, 3H), 7.22±7.27 9m,
6H), 7.53±7.57 9m, 6H); 13C NMR 9CDCl3, 75.5 MHz): d
13.38 9q), 22.62 9q), 28.079t), 31.10 9t), 43.71 9t), 45.13 9d),
47.04 9d), 51.51 9q), 71.46 9s), 77.21 9d), 80.30 9d), 126.05
9d), 127.65 9d), 128.91 9d), 147.27 9s), 175.37 9s); MS 9ESI)
m/z: 480.2 [M1Na1], 458.1 [M1H1], 243.1 [Tr1]; Anal.
calcd for C30H35NO3: C, 78.74; H, 7.71; N, 3.06. Found C,
78.51; H, 7.97; N, 3.18.
4.9.1. Lactam 10a. Colorless solid; Rf 0.25 9dichloro-
methane/methanol 20:1); mp 177±1808C; IR 9KBr): 3214
9s, NH), 30879m, NH), 2969 9s), 2932 9s), 2916 9s), 2891
9m), 1660 9s, CvO), 1464 9m), 1451 9m), 1423 9s), 1384
9w), 1371 9m), 1338 9m), 1301 9s), 1178 9m), 1100 9m), 1029
9s), 8179m), 738 9m) cm 21; 1H NMR 9CDCl3, 300 MHz): d
1.09 9d, Jˆ6.5 Hz, 3H), 1.20 9d, Jˆ6.5 Hz, 3H), 1.479d,
Jˆ14.5 Hz, 1H), 1.85±1.96 9m, 3H), 1.98±2.14 9m, 2H),
2.52 9dq, Jdˆ9.1 Hz, Jqˆ6.5 Hz, 1H), 3.86 9dd, Jˆ6.0,
9.2 Hz, 1H), 3.90±3.95 9m, 1H), 4.44±4.48 9m, 1H), 5.21
9d, Jˆ7.2 Hz, 1H); 13C NMR 9CDCl3, 75.5 MHz): d 13.40
9q), 22.81 9q), 26.95 9t), 32.80 9t), 41.52 9d), 42.18 9t), 43.87
9d), 76.67 9d), 82.59 9d), 175.16 9s); MS 9GC/MS, 70 eV)
m/z 9relative intensity): 183 947) [M1], 168 95) [M12CH3],
44 9100); Anal. calcd for C10H17NO2: C, 65.54; H, 9.35; N,
7.64. Found C, 65.94; H, 9.77; N, 7.70.
4.8. Preparation of N-trityl acid /2)-9a
To a solution of N-trityl ester 92)-8a 91.11 g, 2.43 mmol) in
THF 910.5 mL)/MeOH 93.5 mL) was added 5N KOH
93.5 mL, 17.5 mmol) at room temperature. After stirring
the mixture for 15 h at ambient temperature, it was acidi®ed
to pH 5 with 5% citric acid and extracted with ether
93£50 mL). The combined organic layers were washed
4.9.2. Lactam 10b. White needles; Rf 0.22 9dichloro-
methane/methanol 20:1); mp 110±1128C; IR 9KBr): 3299
9m, NH), 32079s, NH), 3086 9s), 2962 9s), 29279s), 2905
9s), 2872 9s), 1662 9s, CvO), 1465 9m), 14579m), 1442 9m),
1423 9s), 1376 9m), 1340 9m), 1309 9m), 1294 9s), 1160 9m),
1
1109 9m), 1090 9s), 1040 9m), 980 9m), 8179m) cm 21; H

4456
H. Bernsmann et al. / Tetrahedron 58 /2002) 4451±4457
12. 9a) Bif®n, M. E. C.; Miller, J.; Paul, D. B. In The Chemistryof
the Azide Group, Patai, S., Ed.; Interscience: London, 1971;
pp 57±190. 9b) Scriven, E.; Turnbull, K. Chem. Rev. 1988, 88,
297±368. 9c) Ward, R. S.; Pelter, A.; Goubet, D.; Pritchard,
M. C. Tetrahedron: Asymmetry 1995, 6, 469±498.
NMR 9CDCl3, 500 MHz): d 0.91 9t, Jˆ6.9 Hz, 3H), 1.10 9d,
Jˆ6.4 Hz, 3H), 1.33±1.50 9m, 5H), 1.83±1.95 9m, 3H),
1.99±2.14 9m, 2H), 2.51 9dq, Jdˆ8.7Hz, Jqˆ6.5 Hz, 1H),
3.70±3.76 9m, 1H), 3.87 9dd, Jˆ6.0, 9.0 Hz, 1H), 4.46±4.51
9m, 1H), 5.179d, Jˆ7.5 Hz, 1H); 13C NMR 9CDCl3,
126 MHz): d 13.45 9q), 13.74 9q), 19.17 9t), 26.95 9t),
32.83 9t), 38.70 9t), 40.56 9t), 41.52 9d), 48.02 9d), 76.75
9d), 82.62 9d), 175.25 9s); MS 9GC/MS, 70 eV) m/z 9relative
intensity): 211 932) [M1], 196 91) [M12CH3], 168 924)
[M12C3H7], 72 9100), 43 926) [C3H71]; Anal. calcd for
C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found C, 67.99;
H, 10.36; N, 6.53.
13. Crystal data for 5b: C12H21N3O3, Mˆ255.32, monoclinic,
space group P21/c 9No. 14), aˆ5.37191), bˆ20.65493),
Ê
Ê 3
cˆ12.68892) A, bˆ100.8191)8, Vˆ1382.594) A , Zˆ4,
Dcˆ1.227g cm 23
,
mˆ7.30 cm21
,
empirical absorption
correction via C-scan data 90.839#T#0.931), F9000)ˆ552,
colorless crystal with dimensions 0.25£0.10£0.10 mm3,
Ê
lˆ1.54178 A, Tˆ22392) K, u-range 4.14±74.268, index
ranges, 0#h#6, 225#k#0, 215#l#15, 3122 re¯ections
collected, 2819 independent [Rintˆ0.035], 1651 observed
[I.2s9I)], full matrix least-squares re®nement on F2, 166
parameters, GOF on F2 1.000, ®nal R indices [I.2s9I)]
Rˆ0.052 and wR2ˆ0.132, largest difference peak and hole
Acknowledgements
Financial support of this work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and
elbion AG, Radebeul, is gratefully acknowledged. The
authors thank B. Wibbeling for X-ray data collection and
Professor Dr G. Erker for solving one of the X-ray
structures.
Ê 23
0.34 and 20.36 eA , hydrogen atoms calculated and re®ned
as riding atoms. Crystal data for 10a: C10H17NO2, Mˆ183.25,
monoclinic, space group P21/c 9No. 14), aˆ8.65094),
Ê
Ê 3
bˆ12.73894), cˆ9.77492) A, bˆ114.0493)8, Vˆ983.596) A ,
Zˆ4, Dcˆ1.238 g cm23, mˆ6.88 cm21, empirical absorption
correction via C-scan data 90.875#T#0.966), F9000)ˆ400,
colorless crystal with dimensions 0.20£0.20£0.05 mm3,
Ê
lˆ1.54178 A, Tˆ22392) K, u-range 5.60±74.358, index
References
ranges 29#h#10, 215#k#0, 212#l#0, 2117re¯ections
collected, 1998 independent [Rintˆ0.031], 1269 observed
[I.2s9I)], full matrix least-squares re®nement on F2, 124
parameters, GOF on F2 1.014, ®nal R indices [I.2s9I)]
Rˆ0.052 and wR2ˆ0.128, largest difference peak and hole
1. For a recent review, see: Koert, U. J. Prakt. Chem. 2000, 342,
325±333.
2. Schrey, A.; Vescovi, A.; Knoll, A.; Rickert, C.; Koert, U.
Angew. Chem. 2000, 112, 928±931; Angew. Chem., Int. Ed.
Engl. 2000, 39, 900±902.
Ê 23
0.28 and 20.23 eA , hydrogen atoms calculated and re®ned
as riding atoms. Crystal data for 10b: C12H21NO2, Mˆ211.30,
orthorhombic, space group Pbca 9No. 61), aˆ9.73793),
3. Seebach, D.; Albert, M.; Arvidsson, P. I.; RuÈping, M.;
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È
4. 9a) Metz, P.; Meiners, U.; Cramer, E.; Frohlich, R.; Wibbeling,
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Ê
Ê 3
bˆ21.20491), cˆ23.91791) A, Vˆ4939.0916) A , Zˆ16,
Dcˆ1.137g cm 23
,
mˆ6.07cm 21
,
data
empirical absorption
90.751#T#0.915),
correction
via
C-scan
È
E.; Frohlich, R.; Wibbeling, B.; Metz, P. Eur. J. Org. Chem.
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F9000)ˆ1856,
colorless
crystal
Ê
with
dimensions
3
0.50£0.25£0.15 mm , lˆ1.54178 A, Tˆ22392) K, u-range
3.70±74.228, index ranges 0#h#12, 0#k#26, 229#l#0,
5021 re¯ections collected, 5021 independent [Rintˆ0.000],
3781 observed [I.2s9I)], full matrix least-squares re®nement
on F2, 282 parameters, GOF on F2 1.025, ®nal R indices
[I.2s9I)] Rˆ0.046 and wR2ˆ0.128, largest difference peak
5. For reviews, see: 9a) Keller-Schierlein, W.; Gerlach, H.
Fortschr. Chem. Org. Naturst. 1968, 26, 161±189.
9b) Nawata, Y.; Ando, K.; Iitaka, Y. Met. Ions Biol. Syst.
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7±14.
È
6. 9a) Bernsmann, H.; Hungerhoff, B.; Fechner, R.; Frohlich, R.;
Metz, P. Tetrahedron Lett. 2000, 41, 1721±1724.
Ê 23
and hole 0.22 and 20.22 eA , hydrogen atoms calculated and
re®ned as riding atoms, two independent molecules in the
asymmetric unit, bridged by hydrogen bonds. Data sets were
collected with an Enraf-Nonius CAD4 diffractometer.
Programs used: data collection EXPRESS 9Nonius B.V.,
1994), data reduction MolEN 9Fair, K. Enraf-Nonius B.V.,
1990), structure solution SHELXS-979Sheldrick, G. M.
Acta Crystallogr. A, 1990, A46, 467±473), structure re®ne-
È
9b) Bernsmann, H.; Frohlich, R.; Metz, P. Tetrahedron Lett.
2000, 41, 4347±4351. 9c) Bernsmann, H.; Gruner, M.; Metz,
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È
Gruner, M.; Frohlich, R.; Metz, P. Tetrahedron Lett. 2001, 42,
5377±5380. 9e) Wang, Y.; Bernsmann, H.; Gruner, M.; Metz,
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È
ment SHELXL-979Sheldrick, G. M., Universita t Gottingen,
1997), graphics SCHAKAL 99 9Keller, E. Universitat
È
È
Freiburg, 1999). Crystallographic data 9excluding structure
factors) for the structures in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publications numbers CCDC 176898 95b), CCDC
176899 910a), CCDC 176900 910b). Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: 144-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
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