Rigid dipeptide mimetics. Stereocontrolled synthesis of all eight stereoisomers of 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic Acid ester

Article abstract of DOI:10.1016/S0040-4020(00)00355-0

Stereopure 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid (AZABIC) methyl and ethyl esters (14a/b and 23a/b, respectively) have been synthesized from readily available (R)- and (S)-pyroglutamic esters 1 and 15. Altogether all eight possible stereoisomers of this type of compound have been prepared in gram quantities. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00355-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4289±4298
Rigid Dipeptide Mimetics. Stereocontrolled Synthesis
of All Eight Stereoisomers of 2-Oxo-3-(N-Cbz-amino)-1-
azabicyclo[4.3.0]nonane-9-carboxylic Acid Ester
b
c
Johann Mulzer,a, Frank Schulzchen and Jan-W. Bats
*
È
a
È
Institut fur Organische Chemie der Universitat Wien, A-1090 Vienna, Wahringer Strasse 38, Austria
Institut fur Organische Chemie der Freien Universitat Berlin, Takustrasse 3, D-14195 Berlin, Germany
È
È
b
È
È
c
È È
Institut fur Organische Chemie der Johann Wolfgang Goethe Universitat, Marie-Curie-Strasse 11, D-60439 Frankfurt, Germany
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 11 April 2000; accepted 2 May 2000
AbstractÐStereopure 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid (AZABIC) methyl and ethyl esters (14a/b and
23a/b, respectively) have been synthesized from readily available (R)- and (S)-pyroglutamic esters 1 and 15. Altogether all eight possible
stereoisomers of this type of compound have been prepared in gram quantities. q 2000 Elsevier Science Ltd. All rights reserved.
In connection with an ongoing program directed towards the
synthesis of conformationally constrained GnRH analogs
we were interested in an easy access to rigid dipeptide
mimetics of the AZABIC type I. For generality our
synthesis was so designed that all eight possible stereo-
isomers of I should be accessible in a stereocontrolled and
facile manner from simple starting materials. We chose
pyroglutamic acid II as our chiral carbon pool precursor
which is inexpensive in the (S)-con®guration and affordable
in the (R)-con®guration. The AZABIC skeleton has been
widely used in form of various heterosubstituted derivatives
III for constructing conformationally rigid surrogates or
biologically active oligopeptides.1 The parent carbon
compound I, however, has only been prepared three times
so far, by the groups of Revesz,2 Lubell3 and Kahn.4 Revesz
5
applied the Schollkopf bislactim ether methodology and
È
got in an stereouncontrolled but short process a mixture of
racemic (3RS,6SR,9SR)-and partially racemic (3S,6S,9S)-
IV. Lubell assembled the AZABIC skeleton by a Claisen
condensation of two identical glutamic acid derivatives. By
this methodology and some additional transformations, all
eight stereoisomers of V were accessible in a stereo-
controlled manner. Kahn followed a similar approach,
however prepared only one stereoisomer, namely
(3S,6S,9S)-IV.4
We used a totally different access which was aimed at the
diastereocontrolled construction of the stereogenic center at
C6, i.e. the ring fusion center with respect to the reference
center C9 (ˆC5 in II). To achieve trans-disubstitution at
C9/C6 the sequence in Scheme 1 was employed.
Readily available6 (S)-pyroglutamate 1 was reduced to
aminal 27 which was converted into proline ester 5 in a
tandem sequence.8
To this effect, 2 which existed in an equilibrium with the
open chain amino aldehyde 3 was subjected to a Horner±
Wadsworth±Emmons reaction. Enoate 4 was generated,
which under the conditions immediately cyclized to a
crystalline 95:5-epimeric mixture of 5. This mixture was
reduced to the alcohols 6 and 7 which were separated by
Keywords: amino acids; peptide mimetics; stereoselection; allylation.
* Corresponding author. Tel.: 143-1-4277-52790; fax: 143-1-4277-
52189; e-mail: mulzer@felix.orc.univie.ac.at
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00355-0

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J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
Scheme 1. Reagents and conditions: (a) LiBEt3H (1 M in THF), THF, 21008C, 30 min, then H2O2 (30% in water), 85%; (b) NaH, THF, (EtO)2POCH2CO2Et,
82%; (c) LiBH4, Et2O, 228C, 80%, 6:7ˆ95.5; (d) Dess±Martin-periodinane (1.3 equiv.), CH2Cl2, 228C, 30 min, 90%; (e) 10 (1.5 equiv.), KotBu (1.1 equiv.),
CH2Cl2, 90 min, 2788C, 82%; (f) 5% Pt/C, ethyl acetate, four days, 3 bar, 228C, 90%, 12:13ˆ2:1 or ligand (R)-11, RuCl2, DMF, 3 bar, 228C, four days, 98%,
12/13ˆ9:1; (g) HCl gas, CH2Cl2, then SOCl2, MeOH, DMF, then MeOH and HuÈnig's base (3 equiv.), re¯ux, 24 h, 90%.
chromatography to give the trans-isomer 6 as colorless
crystals.
Finally the Boc and the t-Bu ester groups in 12 and 13 were
removed with hydrochloric acid and the resulting carboxylic
acids were converted into the methyl esters. The d-lactam
ring was closed by treatment with HuÈnig's base in re¯uxing
methanol to furnish the diastereomerically pure AZABIC
derivatives 14a and 14b in gram quantities. Both
compounds were subjected to single crystal diffraction
analysis13,21 which con®rmed the con®gurational assign-
ments (Figs. 1,2). Repetition of the entire sequence starting
from (R)-1 led to the enantiomers ent-14a and b in identical
yields.
The relative con®guration of 6 was secured by single crystal
diffraction analysis.9,21 Alcohol 6 was oxidized to the
crystalline aldehyde 8 with Dess±Martin periodinane or
the TEMPO reagent,10 and the aldehyde was converted
into dehydroamino acid ester 9 (pure (Z)-isomer) with
phosphoglycinate 10.11 Catalytic hydrogenation of 9 (Pt/C,
H2) furnished a 1.5:1-mixture of the epimers 12 and 13
which were separated chromatographically. Homo-
geneously catalyzed hydrogenation with ruthenium chloride
in the presence of the chiral ligand12 (R)-11 resulted in a 9:1-
mixture of 12 and 13 (matched case), whereas (S)-11
(mismatched case) furnished a 1:1-mixture. Obviously the
stereocontrol exerted by the chiral catalyst is much weaker
than the stereocontrol exerted by the substrate itself.
The C6±C9-cis-arrangement of appendages was addressed
via a different methodology based on an allylsilane addition
to an acyl iminium intermediate14 (Scheme 2). Thus, pyro-
glutamate (S)-1515 was reduced16 to the ethoxy aminal 16
which was subjected to allyltrimethylsilane in the presence
Figure 1. Crystal structure of 14a (two conformers).

J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
4291
The data in Fig. 3 re¯ect the conformational behavior of 23a
and b in solution. From the strong NOE between H-7 and
H-6a and H-7 and H-4 it may be concluded that the lactam
ring in 23a has essentially a boat conformation. In 23b, by
contrast, the strong NOE between H-6a and H-4 indicates a
pseudo chair conformation with these two hydrogens in a
1,3-diaxial arrangement.
Figure 2. Crystal structure of 14b.
The crucial stereodifferentiating processes leading to a
6,9-trans- or cis-di-substitution are illustrated in Fig. 4.
The trans-arrangement (Scheme 1) is achieved with high
selectivity via a base catalyzed intramolecular conjugate
1,4-addition of a NHBoc group to the a,b-enoate.7 Two
diastereomorphous transition states 24A and B may be
envisaged, of whom the extended one, 24A appears clearly
favored for steric reasons, in analogy to the mechanism
postulated for similar exo-trig radical cyclizations.19
of boron tri¯uoride. Smooth allylation17 occurred to
generate a 4:1-cis/trans-mixture of proline esters 17,
which was converted by ozonolysis to aldehyde 18. Ole®na-
tion of 18 led to a 4:1-mixture of 19 and 20. Compound 19
was subjected to a single crystal diffraction analysis which
con®rmed the con®gurational assignments.18,21 After
chromatographic separation the main diastereomer 19 was
hydrogenated as before to furnish a 1.5:1-mixture of
epimers 21 and 22 which were separated and converted
into the AZABIC derivatives 23a and 23b, respectively,
again on a gram scale. The relative con®gurations of 23a
and b were secured by differential NOE spectroscopy (Fig.
3). Repetition of the sequence starting from (R)-15
generated the enantiomers ent-23a and b.
In contrast, the cis-arrangement (Scheme 2) hinges on the
facial preference with which an allylsilane attacks the cyclic
acyliminium species 25 generated by the BF3 catalyzed
OEt-elimination from aminal 16.14 An obvious mechanistic
pathway would involve the formation of a BF3 complex
with the ester in which the ¯uroride would acquire suf®cient
Scheme 2. Reagents and conditions: (a) DIBAL (1.6 M in THF, 2 equiv., THF), 21008C, 30 min, the EtOH, PPTS, 228C, 30 min, 75%; (b) allyltrimehylsilane
(2.5 equiv.), CH2Cl2, 2908C, BF3/Et2O (2 equiv.), 2908C, 79%; (c) O3, MeOH/CH2Cl2, 2788C, then PPh3, 91%; (d) 10 (1.5 equiv.), KotBu (1.1 equiv.),
CH2Cl2, 90 min, 2788C, 87%; HPLC (2-propanol/hexane, 5:95) 69% of 19, 18% of 20; (e) 5% Pt/C, ethyl acetate, four days, 3 bar, 228C, 90%., 21:22ˆ1.5:1;
(f) HCl gas, DME, then HuÈnig's base (3 equiv.) re¯ux, 90%.

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J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
Figure 3. NOE assignments in compounds 23a and b.
Figure 5. Superimposition of X-ray structures of 14a (grey, two confor-
mers) and 14b (black).
nucleophilicity to attack the trimethylsilyl group and, hence,
facilitate the concomitant allyl transfer to the iminium func-
tion. The selective formation of the cis-adduct could thus be
the result of a neighboring group participation of the ester
function.
possible AZABIC stereoisomers in optically pure form and
overall yields of quantities of 3±5 mmol. Two of the stereo-
isomers could be prepared with 90% overall stereo-
selectivity. In the synthesis of the remaining six ones
diastereomeric mixtures had to be separated. Nevertheless,
the overall ef®ciency of the sequences is high, as only
simple, reliable and high yielding reactions are employed.
The AZABIC mimics are now ready in gram quantities for
incorporation in our GnRH analogs.
The conformational behavior of the AZABIC stereoisomers
14a/b can be deduced from the crystal structures. The low
temperature crystal structure of 14a reveals two conformers
(Fig. 1) which slightly differ with respect to the puckering of
the six-membered lactam ring, whereas the proline part
maintains an envelope conformation. This conformational
¯exibility is obviously due to the unfavorable pseudo-axial
a-position of the 3-NHCbz-sidechain which leads to confor-
mational strain with the ring system. In contrast, the
3-NHCbz appendage adopts a pseudo-equatorial position
in 14b, whose solid state conformation is that of a lactam
boat and a proline envelope (Fig. 2). In both structures the
sp2 con®gurated appendages (CO2R and NHCbz) adopt
bisectic conformations with respect to the adjacent ®ve or
six-membered rings. From a superimposition of these
conformations (Fig. 5) it appears that the loop structures
which are induced by the core templates 14a and b differ
signi®cantly, due to the a or b position of the 3-amino-
residue.20
Experimental
General
All reactions were performed in anhydrous and puri®ed
solvents, if necessary, under an argon atmosphere. The reac-
tions were monitored by TLC (Merck 60, alumina). Prepara-
tive column chromatography was performed on silicagel
(Merck 60, 230±400 mesh) with hexane/ethyl acetate
mixtures as eluent. HPLC was performed on 5 mm Nucleo-
sil 50. NMR spectra were recorded on Bruker spectrometers
AC 250, AM 270. MS(EI) on Varian MAT 711. IR spectra
were recorded on Perkin±Elmer 257 or Nicolet (FTIR
system 5SXC) spectrometers.
The optical purity of the compounds prepared was secured
in the following manner. Firstly, HPLC with a chiral column
(Chirobiotic T) revealed an ee of .98% for the starting
materials 1 and 15 and the ®nal products (14a/b and 23a/
b). Secondly, 14a/b and 23a/b were prepared along both
enantiomeric series. The optical rotations (absolute values)
of all key intermediates were identical within 5%, the same
was true for melting points. Thirdly, in all the crystal
structures only homochiral unity cells were detected.
tert-Butyl (2S,5R/S)-1-(tert-butyloxycarbonyl)-5-[(ethoxy-
carbonyl)-methyl]prolinate (5). A solution of pyrogluta-
mate 1 (23.24 g, 81.4 mmol) in THF (150 mL) was treated
dropwise at 21008C with lithium-trietylborhydride (1 M
in THF, 98 mL, 97.7 mmol, 1.2 equiv.) The mixture was
stirred for 30 min. at 21008C and was then quenched with
aqueous NaHCO3 (60 mL). At 2158C hydrogen peroxide
(30% in water, 40 mL) was added dropwise. The mixture
was stirred at ambient temperature for 30 min and decanted
from a white solid residue. The supernatant organic phase
In conclusion, we have achieved practical syntheses of all
Figure 4. Transition state models for the generation of 5 from 4 and 17 from 16.

J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
4293
was concentrated under reduced pressure, diluted with
ether, washed with sodium bicarbonate, water and brine,
dried over MgSO4, ®ltered over silicagel and evaporated
under reduced pressure. Aminal 2 (19.8 g, 85%) was
obtained as a yellow oil which was used for the next step
without further puri®cation.
(100%), 57 (52%), 41 (6%); IR (KBr); nˆ3547 s, 3005 m,
3980 s, 2968 s, 2934 m, 2876 m, 1730 s, 1692 s, 1479 m,
1450 m, 1393 s, 1367 s, 1338 m, 1257 w, 1235 s, 1158 s,
1125 m, 1096 m, 1058 m, 1022 m, 913 m, 816 m, 840 m,
796 w, 759 m, 726 m, 705 m, 573 m cm21 [a]D20ˆ231.28
(cˆ1.12, CHCl3) mp 71±728C. Anal. calcd for C16H29NO5:
C 60.93 H 9.27 N 4.44. Found C 60.70 H 9.22 N 4.69.
A suspension of sodium hydride in mineral oil (2.3 g,
79 mmol, 1.2 equiv.) was diluted with THF (300 mL) and
treated dropwise with ethyl diethylphosphonoacetate
(20.75 g, 79.32 mmol, 18.36 mL, 1.4 equiv.) in THF (50
mL) for 2 h at 228C. Then aminal 2 (19.0 g, 66.1 mmol)
in THF (100 mL) was added dropwise at 2158C and stirred
at 228C for 24 h. The mixture was concentrated under
reduced pressure and then diluted with dichloromethane
and water. The organic layer was separated, dried over
MgSO4 and ®ltered over silicagel. The ®ltrate was evapo-
rated under reduced pressure and puri®ed by chroma-
tography (hexane/ethyl acetate 3:1). The solvent was
removed under reduced pressure and the oily residue
solidi®ed on standing. 4 (19.37 g, 82%) was obtained as a
trans/cis-mixture whose composition was analyzed on the
tert-Butyl (2S)-cis-1-(tert-butyloxycarbonyl)-5-(2-hydroxy-
ethyl)prolinate (7). 1H NMR (270 MHz, CDCl3): dˆ1.49±
1.50 (m, 1H), 1.51±1.79 (m, 3H), 1.85±2.10 (m, 2H), 2.26
(m, 1H), 3.59±3.82 (m, 2H), 4.18 (t, Jˆ17, 8.5 Hz, 1H),
4.24±4.34 (m, 1H), 4.39 (dd, Jˆ11 Hz, 5.5 Hz, 1H); 13C
NMR (67.9 MHz, CDCl3): dˆ27.35, 27.93 28.21, 28.92,
30.38, 37.51, 54.58, 58.83, 60.75, 80.66, 80.98, 155.53,
172.21: MS (EI, 80 eV, 608C): m/eˆ315 [M]1 (12%), 214
(84%), 203 (4%), 186 (22%), 173 (12%), 158 (39%), 114
(100%), 68 (16%), 57 (77%); IR (KBr, ®lm): nˆ3458 s,
2977 s, 2934 m, 2881 m, 1742 s, 1698 s, 1676 s, 1478 m,
1455 m, 1400 s, 1367 s, 1341 w, 1229 m, 1257 m, 1216 m,
1159 s, 1116 m, 1070 m, 988 m, 855 m, 773 m cm21
.
[a]2D0ˆ248.28 (cˆ0.51, CHCl3); HRMS calcd for
1
stage of the alcohols 6/7. H NMR (250 MHz, CDCl3):
(C16H29NO5)1 315.20678. Found 315.204573.
dˆ1.21±1.30 (m, 1H), 1.41±1.50 (m, 18H), 1.73±1.79
(m, 1H), 1.87±1.95 (m, 1H), 2.11±2.22 (m, 2H), 2.26 (dd,
Jˆ14, 1.8 Hz, 0.5H), 2.30 (dd, Jˆ14 Hz, 1.8 Hz, 0.5H),
2.80 (dd, Jˆ14 Hz, 3 Hz, 0.3H), 2.96 (dd, Jˆ14 Hz, 3 Hz,
0.7H), 4.07±4.22 (m, 3H), 4.23±4.43 (m, 1H); 13C NMR
(62.9 MHz, CDCl3): dˆ13.90, 26.96, 27.62, 27.68, 27.75,
27.97, 28.06, 38.15, 39.15, 54.46, 59.94, 60.03, 60.18,
60.33, 79.55, 79.71, 80.64, 153.39, 153.68, 170.99,
171.04, 171.47, 171.62; MS (EI, 80 eV, 1508C): m/eˆ357
[M]1 (3%), 256 (43%), 228 (19%), 200 (27%), 156 (100%),
114 (19%), 111 (31%), 82 (12%), 68 (26%), 57 (98%), 41
(16%), IR (KBr): nˆ2978 s, 2933 m, 1737 s, 1702 s, 1478
m, 1455 m, 1390 s, 1367 s, 1306 m, 1255 m, 1233 m, 1160 s,
tert-Butyl (2S)-trans-1-(tert-butyloxycarbonyl)-5-(formyl-
methyl)prolinate (8). Dess±Martin periodinane (10.5 g,
24.7 mmol, 1.3 equiv.) in CH2Cl2 (100 mL) was treated at
228C with alcohol 6 (6.0 g, 19 mmol) in CH2Cl2 (30 mL).
After 30 min the mixture was diluted with Et2O and poured
into a mixture of aqueous NaHCO3 and an excess of
Na2S2O3. A white precipitate was formed and the mixture
was stirred until a clear solution was obtained. The organic
layer was separated, washed with water and dried over
MgSO4. Evaporation of the solvent furnished aldehyde 8
(5.35 g, 90%) which crystallized from hexane/CH2Cl2
(10:1) in the form of ®ne colorless needles. Similar oxida-
tions were performed with the Swern and TEMPO reagents,
1061 m, 1022 m, 972 w, 944 w, 913 m, 844 m, 774 m cm21
.
mp 65±708C. Anal. calcd for C18H31NO6: C 60.48, H 8.74,
N 3.92. Found C 60.58, H 8.10, N 3.95.
1
however with inferior yields. H NMR (250 MHz, CDCl3):
dˆ1.36±1.56 (m, 18H), 1.65±1.72 (m, 1H), 1.84±1.90 (m,
1H), 2.10±2.36 (m, 2H), 2.40±2.56 (m, 1H), 2.80 (ddd,
Jˆ6.5 Hz, 2 Hz, 1 Hz, 0.3H), 2.92 (ddd, Jˆ6.5 Hz, 2 Hz,
1 Hz, 0.7H), 4.16 (dd, Jˆ7 Hz, 3 Hz, 1H), 4.32±4.60 (m,
1H), 9.72 (t, Jˆ1 Hz, 1H); 13C NMR (62.9 MHz, CDCl3):
dˆ27.35, 27.85, 28.19, 28.27, 28.35, 28.58, 29.79, 48.87,
49.66, 52.66, 52.90, 60.35, 60.46, 80.12, 80.50, 81.09,
153.84, 171.61, 171.73, 200.62; MS (EI, 80 eV, 808C): m/
eˆ313 [M]1(2%), 285 (8%), 256 (5%), 229 (5%), 212
(48%), 210 (5%), 184 (35%), 156 (46%), 128 (5%), 112
(100%), 82 (14%), 68 (42%), 57 (89%); IR (KBr):
nˆ3462 w, 3422 w, 3351 w, 3006 m, 2978 s, 2935 m,
2824 m, 2724 m, 1737 s, 1719 s, 1687 s, 1481 m, 1455 m,
1403 s, 1366 m, 1335 m, 1290 m, 1257 w, 1229 s, 1161 s,
1132 s, 1090 w, 1071 w, 1016 w, 928 m, 854 m, 844 m, 779
w cm21. [a]D20ˆ254.68 (cˆ0.32, CHCl3) mp 100±1018C.
HRMS calcd for [C16H27NO5]1313.188923. Found
313.18921.
tert-Butyl
(2S)-trans-1-(tert-butyloxycarbonyl)-5-(2-
hydroxyethyl)-prolinate (6). LiBH4 (1.38 g (63.78 mmol,
1.2 equiv.) in Et2O (100 mL), was treated dropwise with
ester 4 (19 g, 53.10 mmol) in E2O (80 mL) at 228C. The
clear solution was washed successively with aqueous
K2CO3 and brine and dried over MgSO4. Evaporation
under reduced pressure and ®ltration over silicagel
(hexane/ethyl acetate 1:1) furnished alcohols 6/7 (13.39 g,
80%) as a colorless oil which solidi®ed on standing. A dia-
stereomeric ratio of 95:5 was determined by analytical
HPLC (eluent: 5% 2-propanol/hexane, ¯ow/pressure:
2 mL/min, 120 bar, UV detection at 235 nm, 7 Rtˆ5 min,
6 Rtˆ5.3 min). Separation by HPLC (eluent: 3% 2-propa-
nol/hexane, ¯ow/pressure:420 mL/min, 70 bar, UV-detec-
tion at 235 nm) furnished 11.9 g (71%) of 6 and 0.51 g
(3%) of 7. The main diastereomer 6 was recrystallized
from ether/pentane. 1H NMR (270 MHz, CDCl3):
dˆ1.40±1.60 (m, 19H), 1.63±1.77 (m, 2H), 1.86±1.96
(m, 1H), 2.07±2.32 (m, 2H), 3.50±3.68 (m, 2H), 4.11 (d,
Jˆ8.1 Hz, 1H), 4.16±4.36 (m, 2H); 13C NMR (67.9 MHz,
CDCl3): dˆ27.61, 27.89, 28.60, 30.04, 37.17, 54.38, 58.54,
60.39, 80.19, 80.58, 155.08, 171.88; MS (EI, 80 eV, 608C):
m/eˆ315 [M]1 (1%), 214 (21%), 186 (7%), 158 (11%), 114
tert-Butyl
(2S)-trans-(Z)-1-(tert-butyloxycarbonyl)-5-
[(30-amino-(N-benzyloxycarbonyl)-30-methoxycarbonyl)-
20-propenyl]prolinate (9). KOtBu (2.50 g, 22.8 mmol,
1.1 equiv.) CH2Cl2 (60 mL) was treated at 2788C slowly
with phosphoglycinate 10 (7.88 g, 23.81 mmol, 1.15
equiv.) CH2Cl2 (30 mL). After 1 h aldehyde 8 (6.50 g,

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J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
20.71 mmol) in CH2Cl2 (20 mL) was adapted dropwise. The
mixture was stirred at 2788C for 90 min and then quenched
with aqueous NH4Cl (10 mL). After warming to ambient
temperature the mixture was diluted with water and the
organic layer was separated, washed with brine, dried over
MgSO4 and evaporated under reduced pressure. After chro-
matography (hexane/ethyl acetate 2:1) ole®n 9 (8.80 g,
12:1H NMR (270 MHz, CDCl3): dˆ1.25±1.72 (m, 22H),
1.77±1.92 (m, 2H), 1.95±2.24 (m, 2H), 3.64±3.77 (m,
3H), 3.79±3.88 (m, 0.3H), 3.91±4.01 (m, 0.7H), 4.10 (d,
Jˆ7.5 Hz, 0.7H), 4.61 (d, Jˆ7.5 Hz, 0.3H), 4.31±4.42 (m,
1H), 5.11 (s, 3H), 5.36 (br d, Jˆ7.5 Hz, 0.3H), 5.59 (br d,
Jˆ7.5 Hz, 0.7H), 7.28±7.37 (m, 5H); 13C NMR (67.9 MHz,
CDCl3): dˆ26.82, 27.45, 27.52, 27.85, 27.92, 28.22, 28.29,
28.44, 28.51, 29.20, 29.59, 30.15, 30.48, 52.22, 52.32,
53.77, 53.98, 57.48, 60.41, 60.48, 66.83, 66.94, 79.69,
80.85, 127.96, 127.99, 128.14, 128.40, 136.26, 153.97,
154.25, 155.69, 155.92, 171.93, 172.02, 172.68; MS (EI,
80 eV, 1508C): m/eˆ520 [M]1(05%), 462 (0.7%), 419
(24%), 319 (100%), 114 (15%), 91 (67%), 57 (78%), 14
(41%); IR (KBr, ®lm): nˆ3393 s, 2975 s, 2933 s, 1737
vs, 1700 vs, 1528 vs, 1391 m, 1366 m, 912 s, 843 s,
cm21. [a]D20ˆ233.48 (cˆ1.14, CHCl3); HRMS calcd for
(M12BOC): [C22H31N2O6]1419.21821. Found 419.21890.
1
82%) was obtained as a yellow resin. H NMR (270 MHz,
CDCl3): dˆ1.41 (s, 9H), 1.46 (s, 9H), 1.57±1.73 (m, 1H),
1.81±2.26 (m, 3H), 2.29±2.44 (m, 1H), 2.47±2.66 (m, 1H),
3.72±3.82 (m, 3H), 4.00±4.25 (m, 2H), 5.08±5.21 (m, 2H),
6.20 (br s, 0.4H), 6.48 (t, Jˆ8 Hz, 0.6H), 6.68 (t, Jˆ8 Hz,
0.4H), 6.92 (br s, 0.6H) 7.30±7.42 (m, 5H); 13C NMR
(62.9 MHz, CDCl3): dˆ27.46, 27.84, 27.90, 28.00, 28.17,
28.24, 28.53, 28.77, 32.30, 32.95, 33.97, 52.27, 52.38,
56.75, 57.64, 60.42, 60.64, 66.84, 67.11, 67.38, 79.60,
80.01, 80.09, 80.78, 80.90, 80.97, 126.58, 127.95, 128.03,
128.14, 128.27, 128.38, 128.48, 131.58, 133.94, 135.81,
136.05, 153.94, 154.08, 154.15, 164.75, 164.93, 171.83;
MS (EI, 80 eV, 1508C): m/eˆ518 [M]1(0.3%), 462
(0.3%), 417 (3%), 389 (5%), 362 (3%), 345 (6%), 317
(22%), 270 (46%), 209 (74%), 114 (100%), 91 (57%), 68
(15%), 57 (69%); IR (KBr, ®lm): nˆ3306 s, 2976 s, 1731 s,
1701 s, 1500 s, 1391 s, 1367 s, 1256 s, 1222 s, 1154 s, 1049
1
13: H NMR (270 MHz, CDCl3): dˆ1.25±2.25 (m, 26H),
3.67±3.86 (m, 4H), 3.87±3.97 (m, 1H), 4.09 (d, Jˆ7.5 Hz,
0.7H), 4.15 (d, Jˆ7.5 Hz, 0.3H), 4.30±4.44 (m, 1H), 5.10 (s,
1H), 5.38 (br d, Jˆ7.5 Hz, 0.4H), 5.51 (br d, Jˆ7.5 Hz,
0.6H), 7.28±7.37 (m, 5H; 13C NMR (67.9 MHz, CDCl3):
dˆ27.36, 27.50, 27.83, 27.90, 28.20, 28.28, 28.50, 29.32,
29.74, 29.91, 30.39, 35.05, 52.02, 52.30, 53.63, 53.82,
57.50, 60.32, 66.77, 66.92, 79.63, 80.82, 126.72, 127.91,
127.98, 128.12, 128.38, 136.24, 153.86, 154.18, 155.71,
155.88, 172.01, 172.74; MS (EI, 80 eV, 2008C): m/eˆ520
[M]1(0.4%), 464 (0.6%), 414 (19%), 391 (4%), 363 (8%),
319 (100%), 211 (13%), 114 (15%), 91 (76%), 57 (46%); IR
(KBr, ®lm): nˆ3393 s, 2975 s, 2933 s, 1737 s, 1700 s, 1528
s, 1391 m, 1366 m, 912 s, 843 s, 755 s, 739 s, 698 s, 575 m,
464 m cm21. [a]D20ˆ257.88 (cˆ1.24, CHCl3) HRMS calcd
for [C27H40N2O8]1520.27847. Found 520.27905.
s, 1005 w, 969 w, 915 w, 844 m, 771 s, 754 s, 698 m cm21
.
[a]2D0ˆ257.38 (cˆ0.68, CHCl3) HRMS calcd for
[C27H38N2O8]1518.2628. Found 518.2644.
tert-Butyl (2S,30S)-trans-1-(tert-butyloxycarbonyl)-5-[(30-
amino-(N-benzyloxcarbonyl)-30-methoxycarbonyl)-propyl]-
prolinate (12) and tert-butyl (2S,30R)-trans-1-(tert-butyl-
oxycarbonyl)5-[(30-amino-(N-benzyloxycarbonyl)-30-
methoxycarbonyl)-propyl]prolinate (13). Ole®n 9 (7.0 g,
13.4 mmol) in ethyl acetate (100 mL) was hydrogenated
with 5% Pt/C (4 g) at 3 bar for four days at 228C. The
reaction was monitored by analytical HPLC (eluent: 3%
2-propanol/hexane, UV-detection at 254 nm, ¯ow/pressure:
2 mL/min 120 bar). After the consumption of the starting
material the mixture was ®ltered over Celite and the ®ltrate
was concentrated under reduced pressure and puri®ed by
chromatography (hexane/ethyl acetate 2:1) to furnish a
mixture of 12 and 13 (6.30 g, 90%) as a colorless oil. The
mixture was separated by preparative HPLC (eluent: 3%
2-propanol/hexane, UV-detection at 254 nm, ¯ow/pressure
470 mL/min, 70 bar) to furnish 12 (4.11 g, 58%, Rt:6 min)
and 13 (2.06 g, 29%, Rt:7 min).
(3R, 6R, 9S)-2-Oxo-3-amino-(N-benzyloxycarbonyl)-9-
(methoxycarbonyl)-1-azabicylco[4.3.0]nonane (14a). A
solution of amino acid 12 (4.0 g 7.69 mmol) in CH2Cl2
(70 mL) was stirred under an atmosphere of HCl until all
starting material had been consumed. The solution was
evaporated to dryness under reduced pressure and the resi-
due was dissolved in DMF (0.4 mL) and methanol (80 mL).
Under cooling (ice bath) thionyl chloride (3.3 mL,
46.14 mL, 6 equiv.) was added and the mixture was re¯uxed
for 2 h and concentrated under reduced pressure. The resi-
due was dissolved in methanol (80 mL), HuÈnig's base
(4.5 mL, 23 mmol) was added and the mixture was re¯uxed
for 24 h. The volatiles were removed under reduced
pressure and the residue was chromatographed (hexane/
ethyl acetate/MeOH 2:1:0.5) to furnish a yellow oil which
solidi®ed on standing. Crystallization from ether/pentane
Hydrogenation of 9 in the presence of chiral catalyst
RuCl2(R-11)(DMF)2: a ¯ame-dried 50 mL Schlenk tube
containing a Te¯on coated stirring bar was charged with
[RuCl2(benzene)]2 (2.5 mg, 0.005 mmol), bisphosphine
(R)-11 (10.5 mg, 0.11 mmol, 2.2 equiv.) and DMF (0.5
mL). The resulting brown suspension was heated to 1008C
under argon for 30 min to give a clear reddish±brown
solution. The reaction mixture was cooled and concentrated
at 1 mmHg and then 0.05 mmHg for 1 h to give RuCl2
(R-11)(DMF)2. To the reddish±brown solid of RuCl2
(R-11)(DMF)2 was added a solution of ole®n 9 (1.0 g,
1.92 mmol) in degassed DMF (40 mL) stirred for 5 min.
The solution was transferred in to a 125 mL stainless
steel autoclave and was hydrogenated at 3 bar for four
days at 228C. 12 and 13 were formed in a ratio of 9:1 and
95% yield.
1
furnished 14a (1.59 g, 60%.) as ®ne colorless needles. H
NMR (270 MHz, CDCl3): dˆ1.44±1.69 (m, 3H), 1.85±2.01
(m, 1H), 1.85±2.01 (m, 1H), 2.02±2.14 (m, 1H), 2.17 (m,
2H), 2.44±2.56 (m, 1H), 3.73 (s, 3H), 3.77±3.89 (m, 1H),
4.16±4.26 (m, 1H), 4.60 (t, Jˆ7.5 Hz, 1H), 5.12 (s, 2H),
5.85 (br s, 1H), 7.28±7.37 (m, 5H); H,H-Cosy-90 (250
MHz, CDCl3): cross peaks dx/dy: 1.50/1.65. 1.50/2.10,
1.50/2.50, 1.50/3.85, 1.60/1.95, 1.60/2.25, 1.60/3.85, 1.60/
4.10, 1.60/4.20, 1.95/2.25, 1.95/4.60, 2.10/2.50, 2.10/3.85,
2.20/3.80, 2.30/4.60, 2.50/4.20, 4.20/5.85; 13C NMR
(67.9 MHz, CDCl3): dˆ26.08, 26.32, 27.95, 50.34, 52.36,
56.24, 58.34, 66.73, 127.98, 128.44, 136.39, 168.54, 172.01;

J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
4295
MS (EI, 80 eV, 1608C): m/eˆ346 [M]1(29%), 287 (53%),
255 (6%), 239 (12%), 211 (12%), 179 (31%), 151 (12%),
108 (20%), 91 (100%), 79 (10%), 65 (6%), 28 (6%); IR
(KBr, ®lm): nˆ3295 s, 2977 m, 2947 m, 1749 s, 1717 s,
1644 s, 1557 s, 1523 s, 1435 s, 1368 s, 1314 s, 1258 s, 1203
s, 1177 s, 1127 m, 1068 m, 1026 m, 1015 m, 1003 m, 971 m,
912 m, 884, 857 m, 808 m, 800 m, 775 m, 752 m, 740 m, 699
s cm21. [a]D20ˆ21188 (cˆ0.45, CHCl3) mp 89±908C. HRMS
calcd for [C18H22N2O5]346.15287. Found: 346.15300.
(0.2%), 242 (30%), 214 (61%), 186 (19%), 158 (40%), 142
(98%), 114 (100%), 68 (53%), 57 (71%), 41 (15%), 29
(15%); IR (KBr, ®lm): nˆ2977 s, 2933 m, 2878 m, 1747
s, 1709 s, 1447 m, 1444 m, 1390 s, 1367 s, 1376 s, 1327 m,
1258 m, 1186 s, 1167 s, 1122 m, 1086 s, 1028 m, 996 w, 917
w, 853 m, 795 w, 775 m, 749 w, 585 w cm21. HRMS calcd
for [C14H25NO5]1287.173273. Found 287.17800.
Ethyl (2S,5R/S)-1-(tert-butyloxycarbonyl)-5-allyl-proli-
nate (17). Ethoxy aminal 16 (10.0 g, 34.80 mmol) and allyl-
trimethylsilane (13.8 mL, 87 mmol, 9.94 g, 2.5 equiv.) in
CH2Cl2 (100 mL) at 2908C were treated dropwise with
boron tri¯uoride ethereate (8.7 mL, 69.4 mmol, 9.80 g,
2 equiv.). The mixture was stirred until a clear solution
was formed. Then water (10 mL) was added and the mixture
was warmed to ambient temperature. Saturated aqueous
NaHCO3 (30 mL) was added and the organic layer was
separated, washed with brine, dried over MgSO4 and
concentrated under reduced pressure. Chromatography
(hexane/ethyl acetate 6±3:1 (gradient system)) furnished
(3S, 6R, 9S)-2-Oxo-3-amino(N-benzyloxycarbonyl)-9-
(methoxycarbonyl)-1-azabicyclo[4.3.0]nonane (14b).
Analogously, 13 (3.38 g, 6.49 mmol) was converted into
1
14b (1.61 g, 71%). H NMR (270 MHz, CDCl3): dˆ1.41±
1.61 (m, 2H), 1.70±1.89 (m, 2H), 2.04±2.22 (m, 2H), 2.32±
2.45 (m, 1H), 2.49±2.62 (m, 1H), 3.66±3.80 (m, 4H), 4.07±
4.19 (m, 1H), 4.47 (t, Jˆ8.1 Hz, 1H), 5.12 (s, 2H), 5.53 (br s,
1H), 7.28±7.37 (m, 5H); H,H-Cosy-90 (250 MHz, CDCl3):
cross peaks dx/dy: 1.50/1.81, 1.50/2.15, 1.50/2.40, 1.50/
3.75, 1.81/2.15, 1.81/2.40, 1.81/2.56, 1.81/3.75, 1.81/4.12,
1.81/4.96, 2.37/3.75, 2.37/4.96, 2.56/4.12, 4.12/5.06; 13C
NMR (67.9 MHz, CDCl3): dˆ27.41, 27.84, 28.46, 32.82,
52.22, 57.77, 60.02, 66.67, 127.88, 127.90, 128.38, 136.43,
156.54, 167.41, 172.64; MS (EI, 80 eV, 1508C): m/eˆ346
[M]1(17%), 287 (31%), 255 (6%), 239 (4%), 211 (11%),
183 (17%), 167 (9%), 151 (6%), 108 (16%), 91 (100%), 79
(8%), 65 (7%); IR (KBr, ®lm): nˆ3335 s, 3098 w, 3061 w,
3033 w, 2950 m, 2869 w, 1722 s, 1652 s, 1558 w, 1525 s,
1445 s, 1363 m, 1319 m, 1243 m, 1201 m, 1176 m, 1141 w,
1084 m, 1060 m, 1016 m, 959 w, 916 m, 879 w, 777 m, 734
s, 699 s, 642 w, 584 w cm21, [a]D20ˆ2958 (cˆ1.4, CHCl3)
mp 72±738C HRMS calcd for [C18H22N2O5]1346.15287.
Found 346.15267.
1
an epimeric mixture of 17 (7.79 g, 79%) as a clear oil. H
NMR (270 MHz, CDCl3): dˆ1.22±1.34 (m, 3H), 1.37±1.54
(m, 9H), 1.67±2.05 (m, 3H), 2.11±2.30 (m, 2H), 2.40±2.70
(br m, 1H), 3.80±4.02 (br m, 1H), 4.04±4.35 (m, 3H), 4.99±
5.13 (m, 2H), 5.68±5.90 (m, 1H); 13C NMR (67.9 MHz,
CDCl3): dˆ13.98, 14.06, 26.63, 27.26, 27.65, 27.84,
28.07, 28.17, 28.58, 29.33, 37.91, 37.97, 38.82, 57.33,
57.79, 59.50, 59.78, 60.00, 60.57, 79.51, 79.59, 134.84,
134.92, 135.20, 153.34, 153.46, 153.94, 172.54, 172.92,
173.12; MS (EI, 80 eV, 608C): m/eˆ286[M13]1 (0.98%),
270 (0.78%), 242 (11.39%), 210 (4.36%), 182 (6.67%), 170
(2.48%), 154 (10.04%), 142 (100%), 110 (12.18%), 68
(28.88%), 57 (45.62%); IR (KBr-®lm): nˆ3076 m, 2977
s, 2934 w, 2879 w, 1748 s, 1688 s, 1640 m, 1478 w, 1452
m, 1391 s, 1366 w, 1318 w, 1298 m, 1275 m, 1257 m, 1186
s, 1124 m, 1106 w, 1032 s, 995 w, 967 w, 664 w, 912 m, 860
m, 771 m, 636 m, 564 w, 461 w cm21. HRMS calcd for
[C12H20NO4]1 [M2C3H5]1 242.13923. Found 242.13924.
(2S,5R/S)-1-(tert-Butyloxycarbonyl-5-ethoxy)-proline
ethyl ester (16). Pyroglutamate 15 (25 g, 97.10 mmol) in
THF (200 mL) was treated dropwise at 21008C with diiso-
butyl aluminium hydride (DIBAL) (38 mL, 213 mmol,
30 mmol, 2.2 equiv.) in THF (80 mL). The mixture was
stirred at 2788C for 30 min. Then 2-propanol (15 mL)
was added and the mixture was diluted with aqueous potas-
sium-sodium tartrate (82 g in 500 mL water) and warmed to
ambient temperature. The mixture was ®ltered and the
organic layer was separated from the ®ltrate, washed with
brine, dried over MgSO4 and concentrated under reduced
pressure to give the aminal (22.90 g, 91%) which was used
for the conversion into 16 without puri®cation.
Ethyl
(2S,5R/S)-1-(tert-butyloxycarbonyl)-5-(formyl-
methyl)prolinate (18). Ole®n 17 (7.0 g, 24.70 mmol) in
MeOH (80 mL) and CH2Cl2 (40 mL) was treated with
ozone at 2788C until the solution turned faintly blue.
Then oxygen was bubbled through the solution and tri-
phenylphosphine (7.12 g, 27.17 mmol, 1.1 equiv.) was
added and the mixture was stirred without cooling over-
night. The mixture was concentrated under reduced pressure
and diluted with ether and pentane to crystallize the phos-
phine oxide. The mixture was ®ltered by suction and the
®ltrate was concentrated under reduced pressure and chro-
matographed (hexane/ethyl acetate 2:1) to furnish aldehyde
A solution of the aminal (20.0 g, 96 mmol) in ethanol
(100 mL) was treated at 228C with pyridinium-p-toluene-
sulfonate (500 mg) and stirred for 30 min. The mixture
was concentrated under reduced pressure and puri®ed by
chromatography (hexane/ethyl acetate 3:1) to give 16
1
18 (6.47 g, 91%) as a colorless oil. H NMR (270 MHz,
CDCl3): dˆ1.22±1.34 (m, 3H), 1.37±1.52 (m, 9H), 1.61±
1.80 (m, 1H), 1.87±2.01 (m, 1H), 2.10±2.32 (m, 2H), 2.44±
2.72 (m, 1H), 2.78±3.21 (m, 1H), 4.07±4.55 (m, 4H), 9.76±
9.84 (m, 1H); 13C NMR (67.9 MHz, CDCl3): dˆ13.90,
27.07, 27.90, 27.97, 28.47, 28.52, 29.55, 29.96, 30.96,
48.12, 48.47, 48.94, 49.23, 52.42, 52.73, 53.11, 59.29,
59.44, 59.59, 60.69. 79.97, 80.37, 153.11, 153.41, 172.43,
172.80, 200.19, 200.71.
1
(22.0 g, 80%) as a colorless liquid. H NMR (270 MHz,
CDCl3): dˆ1.16±1.24 (m, 3H), 1.25±1.33 (m, 3H), 1.41±
1.43, 1.49 (3 s, 9H), 1.51±2.54 (m, 4H), 3.45±3.86 (m, 2H),
4.09±4.40 (m, 3H), 5.23 (d, Jˆ4.9 Hz, 0.17H), 5.30 (d,
Jˆ4.9 Hz, 0.13H), 5.38±5.42 (m, 0.7H); 13C NMR
(67.9 MHz, CDCl3): dˆ14.04, 14.17, 15.15, 15.36, 27.01,
28.08, 28.24, 30.52, 31.31, 32.46, 33.04, 58.86, 59.28,
59.56, 60.73, 60.80, 62.25, 62.89, 63.58, 64.08, 80.27,
80.33, 80.47, 86.79, 87.81, 153.77, 153.98, 154.2, 172.44,
172.78; MS (EI, 80 eV, 408C): m/eˆ287 [M]1 (0.4%), 272
Ethyl (2S)-cis-(Z)-1-(tert-butyloxycarbonyl)-5-[(30-amino-
(N-benzyloxycarbonyl)-30-methoxycarbonyl)-20-propenyl]-

4296
J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
prolinate (19) and ethyl (2S)-trans-(Z)-1-(tert-butyloxy-
carbonyl)-5-[(30-amino-(N-benzyloxycarbonyl)-30-meth-
oxycarbonyl)-20-propenyl]prolinate (20). Aldehyde 18
(6.0 g, 21 mmol) in CH2Cl2 (60 mL) was ole®nated with
phosphoglycinate 10 (8.34 g, 2.52 mmol, 1.2 equiv.) in
CH2Cl2 (70 mL) as described previously to furnish a dia-
stereomeric mixture of 19/20 (9.83 g, 87%) which was sepa-
rated by preparative HPLC (eluent: 5% 2-propanol/hexane,
UV-detection at 254 nm, ¯ow/pressure: 470 mL/min,
70 bar) to give 19 (7.20 g (69%) with Rt: 5.5 min and 20
(1.91 g, 18%) with Rt: 4.5 min 19 and 20 solidi®ed on stand-
ing and were recrystallized from ether/pentane to give
colorless prisms (19: 7.05 g, 67%, 20: 1.60 g, 15%).
bonyl)-5-[(30-amino-(N-benzyloxycarbonyl)-30-(methoxy-
carbonyl)-propyl]prolinate (22). Dehydroamino ester 19
(7 g, 14.26 mmol) in ethyl acetate (100 mL) was hydro-
genated as described to furnish a diastereomeric mixture
of 21/22 (6.75 g, 96%) which were separated by preparative
HPLC (eluent: 5% 2-propanol/hexane, UV detection at
254 nm, ¯ow/pressure:470 mL/min, 70 bar) to give 21
(3.95 g, 56%) with Rt: 5 min and 22 (2.61 g, 37%) with
Rt: 6 min.
1
21: H NMR (270 MHz, CDCl3): dˆ1.20±1.30 (m, 3H),
1.37±1.57 (m, 10H), 1.61±2.04 (m, 6H), 2.18±2.27 (m,
1H), 3.74 (s, 1H), 3.82±4.02 (m, 1H), 4.08±4.25 (m, 3H),
4.28±4.42 (m, 1H), 5.02 (d, Jˆ11 Hz, 1H), 5.14 (d,
Jˆ11 Hz, 1H), 5.58 (d, Jˆ8 Hz, 4H), 5.58 (d, Jˆ8 Hz,
0.6H), 7.30±7.42 (m, 5H); 13C NMR (67.9 MHz, CDCl3):
dˆ14.02, 27.76, 28.09, 28.57, 28.70, 29.04, 29.68, 30.13,
30.48, 52.08, 53.78, 57.39, 59.31, 59.66, 60.75, 66.56,
79.80, 127.76, 128.24, 136.30, 153.71, 154.08, 155.92,
172.84, 173.14, 173.29; MS (EI, 80 eV, 1508C): m/eˆ
492[M]1 (2%), 436 (1%), 419 (4%), 405 (1%), 391
(77%), 319 (77%), 211 (11%), 182 (18%), 142 (58%), 108
(10%), 91 (100%), 68 (13%), 57 (39%), 41 (8%); IR (KBr,
®lm): nˆ3427 w, 3342 m, 3090 w, 3030 w, 2976 s, 2936 w,
2956 w, 1741 s, 1702 s, 1608 w, 1586 w, 1527 s, 1477 w,
1454 m, 1392 s, 1348 w, 1301 w, 1257 m, 1202 s, 1188
s, 1171 s, 1126 m, 1095 w, 1083 w, 1048 w, 1028 w,
913 s, 856 m, 755 s, 734 s, 698 s, 666 w, 647 w, 614 w, 574
w, 488 w, 459 w cm21. [a]D20ˆ214.48 (cˆ1.28, CHCl3)
HRMS calcd for [C25H36N2O8]1 492.24717. Found
492.24742.
19:1H NMR (270 MHz, CDCl3): dˆ1.27 (t, Jˆ6 Hz, 3H),
1.37 (s, 9H), 1.67-1.85 (m, 1H), 1.90±2.12 (m, 2H), 2.17±
2.47 (m, 2H), 2.57±2.75 (m, 1H), 3.57 (br s, 3H), 4.05±4.35
(m, 4H), 5.10 (d, Jˆ15 Hz, 1H), 5.20 (d, Jˆ15 Hz, 1H),
6.65 (t, Jˆ9 Hz, 1H), 7.25±7.42 (m, 5H), 7.47 (br s,
0.7H), 7.60 (br s, 0.3H); H,H-Cosy-90 (250 MHz, CDCl3):
cross peaks dx/dy: 1.30/4.20.1.75/1.90, 1.75/2.00, 1.75/2.25,
1.75/4.15, 2.00/2.30, 2.00/4.15, 2.00/4.30, 2.30/2.65, 2.30/
4.15, 2.30/4.30, 2.30/6.75, 2.65/4.10, 2.65/6.75; 13C NMR
(67.9 MHz, CDCl3): dˆ14.03, 27.99, 28.95, 29.87, 31.06,
33.42, 34.14, 51.98, 57.22, 59.91, 60.07, 61.16, 61.32,
66.78, 80.32, 127.72, 127.80, 128.07, 128.25, 132.66,
133.57, 136.34, 153.79, 154.16, 154.70, 165.06, 173.79,
173.91; MS (EI, 80 eV, 1508C): m/eˆ490 [M]1 (0.2%),
434 (0.4%), 417 (0.6%), 390 (3%), 373 (2%), 359 (0.6%),
317 (2.3%), 281 (1.00%), 242 (18%), 142 (100%), 114
(5%), 91 (24%), 68 (8%), 57 (15%); IR (KBr): nˆ3280 s,
2995 m, 2951 m, 2906 w, 1737 s, 1728 s, 1684 s, 1656 w,
1586 w, 1515 s, 1480 w, 1453 w, 1432, 1391 s, 1313 w,
1285 m, 1243 m, 1230 m, 1196 m, 1163 m, 1125 w, 1068 s,
1021 w, 1002 w, 983 w, 963 w, 894 w, 775 m, 745 m, 695 m,
646 w, 618 w, 578 w, 550 w cm21. [a]D20ˆ143.78 (cˆ1.8,
CHCl3). mp 89±908C. Anal. Calcd for C25H24N2O8: C
61.21, H 6.99, N 5.71. Found C 61.01, H 6.96, N 5.53.
1
22: H NMR (270 MHz, CDCl3): dˆ1.20±1.30 (m, 3H),
1.37±1.57 (m, 10H), 1.61±2.04 (m, 6H), 2.18±2.27 (m,
1H), 3.74 (s, 3H), 3.78±3.88 (br s, 0.5H), 3.95±4.02 (br s,
0.5H), 4.08±4.25 (m, 3H), 4.28±4.42 (m, 1H), 5.07 (d,
Jˆ11 Hz, 1H), 5.15 (d, Jˆ11 Hz, 1H), 5.47 (d, Jˆ8 Hz,
0.4H), 5.80 (d, Jˆ8 Hz, 0.6H), 7.30±7.42 (m, 5H); 13C
NMR (67.9 MHz, CDCl3): dˆ14.00, 27.84, 28.08, 28.36,
28.57, 28.96, 29.64, 30.32, 30.68, 52.03, 53.68, 57.58,
59.56, 59.85, 60.74, 66.59, 79.89, 127.79, 128.25, 136.36,
153.86, 155.97, 172.67, 173.20; MS (EI, 80 eV, 1908C): m/
eˆ492[M]1 (0.6%), 436 (1%), 419 (4%), 391 (74%), 319
(69%), 283 (5%), 257 (4%), 211 (11%), 182 (18%), 142
(51%), 108 (10%), 91 (100%), 68 (6%), 57 (42%), 41
(6%); IR (KBr, ®lm): nˆ3427 w, 3342 m, 3090 w, 30 w,
3030 w, 2976 s, 2936 w, 2956 w, 1741 s, 1702 s, 1608 w,
1586 w, 1527 s, 1477 w, 1454 m, 1392 s, 1348 w, 1301 w,
1257 m, 1202 s, 1188 s, 1171 s, 1126 m, 1095 w, 1083 w,
1048 w, 1028 w, 913 s, 856 m, 755 s, 734 s, 698 s, 666 w,
647 w, 614 w, 574 w, 488 w, 459 w cm21. [a]D20ˆ25.38 (cˆ
1.0, CHCl3). HRMS calcd for [C25H36N2O8]1 492.24717.
Found 492.24742.
1
20: H NMR (270 MHz, CDCl3): dˆ1.34±1.31 (m, 3H),
1.3911.45 (2 s, 9H), 1.60±1.70 (m, 1H), 1.81±2.30 (m,
3H), 2.32±2.45 (m, 1H), 2.51±2.68 (m, 1H), 3.7513.77 (2
s, 3H), 4.06±4.33 (m, 4H), 5.41 (t, Jˆ18 Hz, 2H), 6.27 (br s,
0.4H), 6.50 (t, Jˆ7.5 Hz, 0.6H), 6.63 (t, Jˆ7.5 Hz, 0.4H),
6.85 (br s, 0.6H), 7.30±7.42 (m, 5H); 13C NMR (67.9 MHz,
CDCl3): dˆ13.81, 13.96, 27.17, 27.75, 27.88, 27.97, 28.16,
28.46, 32.43, 33.42, 51.98, 52.06, 56.51, 56.96, 59.42,
59.51, 60.58, 60.68, 66.77, 66.98, 79.88, 127.67, 127.76,
127.84, 127.94, 128.11, 128.19, 131.68, 133.71, 135.67,
135.85, 153.59, 153.91, 154.00, 164.51, 164.64, 172.30,
172.55; MS (EI, 80 eV, 1208C): m/eˆ490[M]1 (0.1%),
417 (2%), 390 (10%), 373 (12%), 317 (17%), 281 (5%),
242 (32%), 209 (8%), 142 (100%), 91 (32%), 57 (20%);
IR (KBr): nˆ3314 s, 3112 w, 3090 w, 3065 w, 3032 w,
2977 s, 1782 w, 1738 s, 1701 s, 1500 s, 1393 s, 1125 w,
1044 w, 969 w, 915 m, 854 m, 774 s, 754 w, 698 m, 607 w,
579 w, 490 w, 462 w cm21. [a]D20ˆ255.38 (cˆ1.35, CHCl3)
mp 54±568C. HRMS calcd for [C22H29N2O6]1 (ˆ[M2
C3H5O2]1)417.202562. Found 417.202600.
(3S, 6S, 9S)-2-Oxo-3-amino-(N-benzyloxycarbonyl)-9-
(ethoxycarbonyl)-1-azabicyclo[4.3.0]nonane (23a). Seco
amide 21 (3.0 g, 6.10 mmol) in dichloromethane (60 mL)
was stirred under an atmosphere of HCl for 2 h. The mixture
was evaporated to dryness under reduced pressure, diluted
with DME (60 mL) and re¯uxed with HuÈnig's base
(3 equiv.) for 3 h. Workup as described for 14a furnished
23a (1.85 g, 84%) as a clear viscous oil. 1H NMR
(270 MHz, CDCl3): dˆ1.27 (t, 12 Hz, 3H), 1.61±1.81 (m,
Ethyl (2S,30S)-cis-1-(tert-butyloxycarbonyl)-5-[(30-amino-
(N-benzyloxcarbonyl)-30-(methoxycarbonyl)-propyl]-
prolinate (21) and ethyl (2S,30R)-cis-1-(tert-butyloxycar-

J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
4297
3. Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1996, 61, 943±
9446 and cit. lt.; Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998,
63, 7463±7471.
3H), 2.08±2.72 (m, 4H), 2.44±2.59 (m, 1H), 3.66±3.89 (m,
1H), 4.10±4.24 (m, 1H), 4.19 (t, Jˆ12 Hz, 2H), 4.49 (d,
Jˆ8 Hz, 1H), 5.08 (d, Jˆ20 Hz, 1H), 5.18 (d, Jˆ20 Hz,
1H), 5.85 (d, Jˆ6 Hz, 1H), 7.30±7.42 (m, 5H); H,H-
Cosy-90 (250 MHz, CDCl3): cross peaks dx/dy: 1.30/4.20,
1.70/2.15, 1.70/3.70, 1.70/4.20, 1.70/4.50, 2.15/2.50, 2.15/
3.57, 2.15/4.50, 2.15/4.20, 2.50/4.20, 4.20/5.90; 13C NMR
(67.9 MHz, CDCl3): dˆ13.90, 26.58, 26.83, 28.88, 31.90,
50.14, 56.31, 58.20, 61.14, 66.14, 66.48, 127.73, 127.80,
128.25, 136.31, 155.94, 168.54, 171.41; MS (EI, 80 eV,
808C): m/eˆ360[M]1 (95%), 315 (40%), 287 (65%), 269
(12%), 259 (5%), 225 (9%), 209 (10%), 197 (8%), 179
(100%), 151 (3%), 108 (25%), 91 (37%); IR (KBr, ®lm):
nˆ3395 m, 3319 m, 3069 w, 3032 w, 2975 s, 2954 s, 2875
w, 1726 s, 1667 s, 1528 s, 1498 s, 1464 s, 1444 s, 1373 m,
1334 w, 1292 w, 1187 s, 1085 s, 1072 s, 1027 s, 943 m, 899
4. Kim, H.-O.; Kahn, M. Tetrahedron Lett. 1997, 37, 6483±6484.
È
5. Schollkopf, U. Top. Curr. Chem. 1983, 109, 65. Review:
Hartwig, W. Stereoselective Synthesis. In Houbenweyl, Methods
of Organic Chemistry; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, New York, 1995; Vol.
21a, pp 1041±1055.
6. Kolasa, T.; MuÈller, M. J. J. Org. Chem. 1990, 55, 1711±1721;
August, R. A.; Khan, J. A.; Moody, C. W.; Young, D. W. J. Chem.
Soc., Perkin Trans 1 1996, 507±514.
7. Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.;
Garcia Ruano, J. L. Tetrahedron Lett. 1994, 35, 2053±2056.
8. Collado, I.; Ezquerra, J.; Vaquero, J. J.; Pedregal, C.
Tetrahedron Lett. 1994, 35, 8037±8040; see also Shishido, K.;
Sukagawa, Y.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Perkin
Trans. 1 1987, 993±1004
w, 855 w, 755 m, 743 s, 699 s, 676 w, 582 w, 537 w cm21
.
[a]2D0ˆ215.28 (cˆ0.91, CHCl3) HRMS calcd for
[C19H24N2O5]1 360.168522. Found 360.164210.
9. Crystal dimensions 0.16£0.40£0.75 mm3, temperature
137(2) K, crystal system, orthorhombic, space group P 212121,
Ê
(3R, 6S, 9S)-2-Oxo-3-(amino-N-benzyloxycarbonyl)-9-
(ethoxycarbonyl)-1-azabicyclo[4.3.0]nonane (23b).
Analogously 22 (2.11 g, 4.28 mmol) was converted into
space group number 19, unit cell dimensions aˆ9.117(1) A,
Ê
bˆ10.260(1), cˆ19.110(2), Vˆ1787.6(4) A3, Z 4, rcalcˆ1.172 g/
cm3, linear absorption coeff. 0.81 cm21, radiation Mo-Ka, scan
1
23b (1.42 g, 92% after recrystallization from ether). H
Ê
range sphere, (2 theta)max 638, resolution 0.68 A, number of
NMR (270 MHz, CDCl3): dˆ1.26 (t, Jˆ7 Hz, 3H), 1.60±
1.93 (m, 3H), 1.94±2.20 (m, 4H), 2.44±2.75 (m, 1H), 3.53±
3.69 (m, 1H), 3.95±4.06 (m, 1H), 4.10±4.23 (m, 2H), 4.44
(br d, Jˆ9 Hz, 1H), 5.06 (d, Jˆ12 Hz, 1H), 5.12 (d,
Jˆ12 Hz, 1H), 5.50 (br s, 1H), 7.30±7.42 (m, 5H); H,H-
Cosy-90 (250 MHz, CDCl3): cross peaks dx/dy: 1.25/4.15,
1.70/2.00, 1.65/2.15, 1.80/2.15, 2.15/2.50, 1.85/2.50, 1.70/
3.60, 2.10/3.60, 1.85/4.00, 2.50/4.00, 2.00/4.45, 2.15/4.45,
4.00/5.50 13C NMR (67.9 MHz, CDCl3): dˆ14.06, 27.65,
28.38, 31.51, 52.39, 58.25, 60.48, 61.12, 66.74, 127.99,
128.40, 136.31, 156.37, 167.91, 169.66, 171.56; MS (EI,
80 eV, 1708C): m/eˆ360 [M]1 (47%), 315 (4%), 287
(100%), 253 (9%), 225 (11%), 211 (12%), 179 (13%), 142
(13%), 108 (13%), 91 (71%); IR (KBr, ®lm): nˆ3349 s,
3034 w, 2981 m, 2936 m, 2906 w, 2871 w, 1738 s, 1699
s, 1650 s, 1586 w, 1544 s, 1496 w, 1464 m, 1439 m, 1398 w,
1385 w, 1374 w, 1354 w, 1332 m, 1318 w, 1300 m, 1247 m,
1205 m, 1193 s, 1164 w, 1144 w, 1087 m, 1070 m, 1247 m,
1205 m, 1193 s, 1164 w, 1144 w, 1087 m, 1070 m, 1024 w,
761 w, 736 m, 698 w, 634 w, 613 w, 577 w, 531 w, 468 w
cm21. [a]D20ˆ245.98 (cˆ0.83, CHCl3) mp 111±1128C.
HRMS calcd for [C19H24N2O5]1 360.168522. Found
360.166190.
re¯ections measured 28041, number of independent re¯ections
3187, re¯ections used with I.0 3171, number of variables 316,
R(F) 0.038, wR(F) 0.037, s 0.94.
10. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277±
7287; Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996,
338, 588±590. TEMPO Oxidation: Leanna, M. R.; Sowin, T. J.;
Morton, H. E. Tetrahedron Lett. 1992, 33, 5029±5032.
11. Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53±
60.
12. Enev, V.; Ewers, Ch. L. J.; Harre, M.; Nickisch, K.; Mohr, J. T.
Ewers. J. Org. Chem. 1997, 62, 7092±7093.
13. 14a: Crystal dimensions 0.22£0.60£1.00 mm3, crystal system
monoclinic, space group
Ê
P 21, space group number 4
aˆ19.084(2) A, bˆ9.159(1) cˆ20.312(3), bˆ102.66(1)8, Vˆ
Ê 3
3464.0(9) A , Zˆ8 (four independent molecules), rcalcˆ1.328 g/
cm3, linear absorption coeff. 0.91 cm21, radiation Mo-Ka, scan
Ê
range sphere, (2 theta)max 628, resolution 0.69 A, number of
re¯ections measured 48367, number of independent re¯ections
10526, re¯ections used with I.0 10 254, number of variables
1224, R(F) 0.068, wR(F) 0.057, s 1.12. 14b: Crystal size
0.70£0.60£0.50 mm,
temperature
0.71073 A, crystal system P4(1), space group tetragonal, unit
173(2) K,
wavelength
Ê
Ê
Ê
cell dimensions: aˆ9.8630(10) A, aˆ908, bˆ9.8630(10) A, bˆ
Ê 3
Ê
908, cˆ36.982(4) A, gˆ908. Vˆ3597.6(6) A , Zˆ8, rcalc
ˆ
1.279 g/cm3, absorption coef®cient 0.094 mm21, F(000) 1472,
theta range for data collection 2.06±26.958, re¯ections collected/
unique 24010/7274 [R(int)ˆ0.0223], SADABS (Sheldrick, 1996)
Max. and min. transmission 0.9545 and 0.9372, re®nement method
full-matrix least-squares on F2Data/restraints/parameters 7274/1/
427, goodness-of-®t on F21.022, ®nal R indices [I.2sigma(I)]
R1ˆ0.0451, wR2ˆ0.1017, R indices (all data) R1ˆ0.0563,
wR2ˆ0.1076.
Acknowledgements
We wish to thank Dipl. Chem. Oliver Langer, University of
Vienna, for helpful discussions. Financial support by the
Schering AG, Berlin, is also gratefully acknowledged.
References
14. de Koning, H.; Speckamp, W. N. Stereoselective Synthesis. In
Houben-Weyl, Methods of Organic Chemistry; Helmchen, G.;
Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme: Stutt-
gart, New York, 1995; Vol. E21b, pp 1953±2010.
1. Extensive review: Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789±
12854.
2. Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 34, 4091±
4092.
15. Baldwin, J. E.; Miranda, T.; Moloney, M. Tetrahedron 1989,
45, 7459±7468.

4298
J. Mulzer et al. / Tetrahedron 56 (2000) 4289±4298
16. Reduction and conversion into the 2-methoxy derivative:
Langlois, N.; Rojas, A. Tetrahedron 1993, 49, 77±82.
measured 15134, number of independent re¯ections 3050, re¯ec-
tions used with I.0 3033, number of variables 452, R(F) 0.030,
wR(F) 0.036, S 1.44.
17. Asada, S.; Kato, M.; Ineyama, T.; Nishi, S.; Izawa, K.; Shono,
T. J. Chem. Soc. Chem. Commun. 1989, 486±488; Thaning, M.;
Wistrand, L. G. Helv, Chim. Acta 1986, 69, 1711±1717;
Brocherieux-Lanoy, S.; Dhimane, H.; Poupon, J.-C.; Vanucci,
G.; Lhommet, G. J. Chem. Soc., Perkin Trans. 1 1997, 2163±2165.
18. Crystal dimensions 0.42£0.60£0.75 mm, temperature
183(2) K, crystal system monoclinic, space group P 21, space
group number 4, cell dimensions aˆ7.232(2) A, bˆ15.414(3),
cˆ12.104(2), 106.97(2), Vˆ1290.6(6) A3, Zˆ2, rcalcˆ1.262 g/
cm, linear absorption coeff. 0.9 cm, radiation Mo-K, scan range
sphere, 2theta max 56, resolution 0.75 A, number of re¯ections
19. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985,
26, 373±376; Spellmeyr, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 959±974; Curran, D. P.; Porter, N. A.; Giese, B. Sterochemistry
of Radical Reactions; VCH Weinheim: New York, 1995; p 31.
20. Slomczynsja, U.; Chalmers, D. K.; Cornille, F.; Smythe, M. L.;
Beusen, D. D.; Moeller, K. D.; Marshall, G. R. J. Org. Chem. 1996,
61, 1198±1204.
21. All X-ray crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre.