Regio- and stereoselective synthesis of constrained enantiomeric β-amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.09.026

Chlorosulfonyl isocyanate addition to (-)- and (+)-apopinene furnished monoterpene-fused β-lactams in highly regio- and stereospecific reactions. β-Lactams 5 and 13 exhibited reactivities similar to those of the cycloalkane-fused analogs and were easily c

Full text of DOI:10.1016/j.tetasy.2008.09.026

Tetrahedron: Asymmetry 19 (2008) 2296–2303
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Regio- and stereoselective synthesis of constrained enantiomeric
b-amino acid derivatives
Zsolt Szakonyi a, Tamás A. Martinek a, Reijo Sillanpää b, Ferenc Fülöp a,
*
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged Eötvös utca 6, Hungary
b Department of Chemistry, University of Jyväskylä, PO Box 35, 40351 Jyväskylä, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Chlorosulfonyl isocyanate addition to (ꢀ)- and (+)-apopinene furnished monoterpene-fused b-lactams in
highly regio- and stereospecific reactions. b-Lactams 5 and 13 exhibited reactivities similar to those of the
cycloalkane-fused analogs and were easily converted to the b-amino acid and its protected derivatives.
The base-catalyzed isomerization of the cis-amino ester afforded the corresponding trans-amino acid
enantiomers in excellent yields. The complete isomerization is explained by the stability difference,
which was estimated by ab initio calculations between the cis- and trans-diastereomers.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 August 2008
Accepted 26 September 2008
Available online 22 October 2008
1. Introduction
restricts the wide application of these compounds in organic
syntheses.4,5 These disadvantages may be reduced by removal of
There is an increasing demand for the production of new chiral
building blocks and catalysts that can be widely used for asymmet-
ric syntheses. These valuable chiral building blocks must be avail-
able in both enantiomeric forms, on at least a gram scale, and with
high enantiomeric purity. Many natural monoterpenes, such as (+)-
the 2-methyl substituent, resulting in apo derivatives.
In addition to the chemical importance of b-amino acids, some
of them exert significant pharmacological effects, for example, the
antifungal antibiotic (1R,2S)-2-aminocyclopentanecarboxylic acid
(cispentacin).6 Icofungipen (PLD-118; (1R,2S)-2-amino-4-methyl-
enecyclopentanecarboxylic acid), a b-amino acid, upsets the bio-
synthesis of protein in Candida albicans.7 b-Amino acids can also
be used as building blocks for the preparation of modified analogs
of pharmacologically active peptides. b-Amino acids and their
foldameric oligomers are currently the focus of research interest.8
Herein, we report the preparation and some transformations of
a new family of monoterpene-based chiral b-lactams and b-amino
acid derivatives derived from (ꢀ)- and (+)-apopinene 2 and 13, in
order to eliminate the disadvantageous steric effect of the 2-
methyl substituent on the pinane ring system.2,3
pulegone, myrtenal, fenchone-camphor, and
a-pinene, have been
prepared on a large scale with excellent enantiomeric excess. Var-
ious powerful catalysts derived from these monoterpenes have
been reported as chiral ligands in enantioselective syntheses.1
We recently described the transformations of enantiomerically
pure
a-pinene and 3-carene to b-amino acid derivatives, which
proved to be excellent building blocks for the syntheses of mono-
terpene-fused saturated 1,3-heterocycles, and were also applied
as chiral auxiliaries in the enantioselective reactions of Et2Zn with
aromatic aldehydes.2 These results revealed that a methyl substi-
tuent (present in the natural monoterpenes) next to the amino
group dramatically decreases the reactivities of the synthons rela-
tive to those containing a secondary carbon next to the adjacent
functional groups.2 We previously reported the synthesis of cis-d-
pinene-based derivatives;3 the amino acid derivatives described
2. Results and discussion
(ꢀ)-Apopinene 1 was synthesized from commercially available
(ꢀ)-myrtenal via a literature method.9 Chlorosulfonyl isocyanate
(CSI) addition to 1 was successfully accomplished by stirring the
mixture in dry Et2O for 48 h.10 The NMR and GC studies on the
crude product proved that the cycloaddition took place highly
regio- and stereospecifically (ee >98%), resulting in only b-lactam
2 (Scheme 1). Full crystallographic data for this structure have
been deposited with the Cambridge Crystallographic Data Centre
(CCDC no. 705012).
proved to be more reactive than the
a-pinene-based compounds,
but the strong steric hindrance of the ring system restricted their
synthetic applications. In addition to the disadvantageous steric
effect, it is well known that constrained pinane terpenoids in an
acidic medium generally undergo numerous transformations, lead-
ing to complex mixtures of products; their facile rearrangement
The structure of azetidinone 2 was determined by X-ray crystal-
lography (Fig. 1), and the relative stereochemistry established by
NOESY.
* Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.026

Z. Szakonyi et al. / Tetrahedron: Asymmetry 19 (2008) 2296–2303
2297
(S)
NH2. HCl
COOR
ii
NH
i
(S)
O
1
2
3
R = Me:
R = Et: 4
iv
vi
iii
NH2
Boc
NH2.HCl
COOH
v
N
COOH
O
6
5
7
vii
ix
viii
NHBoc
COOH
NHFmoc
COOH
NMe2.HCl
COOH
10
8
9
Scheme 1. Reaction conditions: (i) 1.01 equiv CSI, Et2O, rt, 48 h, then Na2SO3/10% KOH soln, 2 h, 82%; (ii) 3: 10% HCl/MeOH, 4: 10% HCl/EtOH, rt, 1.5 h, 71–89%; (iii) 15% HCl/
H2O, rt, 1 h, 94%; (iv) 1.1 equiv SOCl2, 3: dry MeOH, 4: dry EtOH, ꢀ12 °C, then 30 min, 0 °C, 3 h, rt, 80%; (v) 10% NaHCO3/H2O to pH 7.4, 0 °C, 1 h, 58%; (vi) 1.3 equiv Boc2O, THF,
cat. DMAP, 2.6 equiv Et3N, rt, 6 h, 89%; (vii) 3% NaOH/H2O to pH 8.0, 1.1 equiv Boc2O, 0 °C, rt, 6 h, then 5% HCl/H2O, 61%; (viii) 10% NaHCO3/H2O to pH 8.0, MeCN, 0 °C,
1.0 equiv Fmoc-OSu, then 12 h at rt, 63%; (ix) 2.2 equiv HCHO, H2O, 10% Pd/C, 10 atm. H2, rt, 12 h, 89%.
These results differ significantly from those observed for the
a-
pinene-based lactam, where acidic hydrolysis was unsuccessful.2
When the aqueous solution of amino acid hydrochloride 5 was
adjusted to pH 7.4, the poorly water-soluble free amino acid 6 was
isolated readily. Treatment of b-lactam 2 with di-tert-butyl dicar-
bonate resulted in the N-Boc b-lactam 7. The N-Boc b-amino acid
8 was prepared in good yield (94%) directly from amino acid 5.
Similarly, Fmoc-protected amino acid 9 was prepared, resulting
in promising building blocks for peptide chemistry. N,N-Disubsti-
tuted amino acid 10 was synthesized via the reductive methylation
of amino acid 5 (Scheme 1).12
Under alkaline conditions, the cis-amino ester 4 underwent fast
and complete isomerization at the carboxylic function, resulting in
the trans-amino ester in excellent yield (Scheme 2).
Complete cis–trans isomerization is not common among b-ami-
no esters.6,13 To explain this phenomenon, ab initio modelling was
carried out on 3 and the methyl ester derivatives of 11 at the
B3LYP/6-31G(d) level implemented in the GAUSSIAN program pack-
age.14 Simplification of the ester group was not expected to affect
the relative stabilities. After geometrical optimization, the final
energies were ꢀ635.784040543 a.u. and ꢀ635.787701000 a.u. for
4 and 11, respectively. This means that, under thermodynamic
control, the estimated stability difference of 2.30 kcal/mol in favor
of the methyl analog of 11 can lead to a 40-fold higher concentra-
Figure 1. The Ortep plot of azetidinone 2 with thermal ellipsoids drawn at the 30%
probability level.
Treatment of azetidinone 2 with aqueous HCl resulted in amino
acid 5 in excellent yield. Amino esters 3 and 4 were prepared by
acid-catalyzed alcoholysis of 2 (Scheme 1). Our results suggest that
the absence of the methyl group at the 2-position of
a-pinene
(practically apopinene) yields compounds with normal reactivity,
similar to those with a cyclopentane or cyclohexane skeleton.6,11
i
O
NH2.HCl
NH2
NH2. HCl
COOEt
ii
COOEt
COOH
4
11
12
iii
NHFmoc
COOH
NH2.HCl
COOH
NHBoc
COOH
v
vi
15
13
14
Scheme 2. Reaction conditions: (i) 2.0 equiv NaOEt, dry EtOH, rt, 4 h, then 15% dry HCl/EtOH, 69%; (ii) 10% NaOH/H2O, then dioxane/H2O, 80 °C, 6 h, 65%; (iii) 10% HCl/H2O, rt,
48 h, 85%; (iv) 3% NaOH/H2O to pH 8.0, 1.1 equiv Boc2O, rt, 6 h, then 5% HCl/H2O, 65%; (v) 10% NaHCO3/H2O to pH 8.0, MeCN, 0 °C, 1.0 equiv Fmoc-OSu, then 12 h at rt, 63%.

2298
Z. Szakonyi et al. / Tetrahedron: Asymmetry 19 (2008) 2296–2303
(R)
NH2.HCl
COOH
NH
ii
i
(R)
O
16
18
19
17
iii
NH2.HCl
COOH
NH2.HCl
COOEt
NH2.HCl
COOEt
v
O
iv
21
20
Scheme 3. Reaction conditions: (i) 1.01 equiv CSI, Et2O, rt, 48 h, then Na2SO3/10% KOH soln, 2 h, 82%; (ii) 15% HCl/H2O, rt, 1 h, 94%; (iii) 10% HCl/EtOH, 25 °C, 1.5 h, 89%; (iv)
2.0 equiv NaOEt, dry EtOH, then 15% dry HCl/EtOH, rt, 4 h, 69%; (v) 10% HCl/H2O, rt, 48 h, 85%.
NHBoc
NHBoc
H
H
N
COOEt
N
COOEt
O
O
26
28
NHBoc
COOH
NHBoc
NHBoc
H
H
N
COOEt
N
COOEt
O
O
27
Scheme 4. Reaction conditions: 1.0 equiv (S)-phenylalanine ethyl ester, 1.0 equiv ClCO2iBu, 1.0 equiv Et3N, dry THF, ꢀ10 °C, then rt, 5 h, 67%.
29
tion for the trans-isomer under the conditions applied. This finding
fully explains the unusual and complete transformation of 4 to 11.
Since the (+)-enantiomer of myrtenal is not commercially avail-
4. Experimental
4.1. General experimental procedures
able, it was prepared from available (+)-a-pinene according to a lit-
erature method.15 (+)-Myrtenal was then transformed successfully
via (+)-apopinene 16 to enantiomeric b-lactam 17, amino acid 18
and to all the other amino acid derivatives 22–25 (Section 4) by
the methods presented in Schemes 1–3.
1H NMR spectra were recorded on a Bruker Avance DRX 400
spectrometer at 400.13 MHz (1H) and 100.61 MHz (13C) [d = 0
(TMS)] in CDCl3 or in D2O in a 5-mm tube. Chemical shifts are ex-
pressed in ppm (d) relative to TMS as the internal reference. J val-
ues are given in hertz. Microanalyses were performed on a Perkin–
Elmer 2400 elemental analyzer. Optical rotations were obtained
with a Perkin–Elmer 341 polarimeter. Melting points were deter-
mined on a Kofler apparatus and are uncorrected. Chromato-
graphic separations were carried out on Merck Kieselgel 60
(230–400 mesh ASTM). Reactions were monitored with Merck Kie-
selgel 60 F254-precoated TLC plates (0.25 mm thickness).
The enantiomeric purities of 2, 17, 4, and 19 were determined
by GC on a chiral column. Since there was no sign of the presence
of any other diastereomer in the NMR spectra of the crude prod-
ucts after the transformations, the high enantiomeric purities of
the compounds prepared can be regarded as proven.
To prove the applicability of the resulting b-amino acid deriva-
tives, starting from the N-Boc amino acid epimers, all four repre-
sentative dipeptide derivatives 26–29 were prepared by coupling
with phenylalanine methyl ester (Scheme 4).
The enantiomeric purities of the prepared compounds were
determined by means of GC measurements involving direct sepa-
ration of the enantiomers on
a CHIRASIL-DEX CB column
(2500 ꢁ 0.25 mm I.D.) at 160 °C and 80 kPa for azetidinones 2
and 17. IR spectra were measured with a FT-IR spectrometer.
Et2O and THF were dried over Na wire; all other chemicals and
solvents were used as supplied. (ꢀ)-(1S,5S)- and (+)-(1R,5R)-
apopinene (1 and 16) were prepared by a literature method, and
were identical with those reported therein.9
3. Conclusion
The disadvantageous steric effect of the 2-methyl substituent
on the pinane ring system was eliminated by the synthesis of
apopinane enantiomers. The highly regio- and stereospecific addi-
tion of CSI to apopinene resulted in the successful large-scale prep-
aration of b-lactam enantiomers. b-Lactams 2 and 17 and the
corresponding constrained b-amino acids 5, 13, 18, and 21 and
their derivatives exhibited reactivities similar to those of cyclopen-
tane and cyclohexane, apart from the facile isomerization of the
cis-amino esters toward the trans-amino esters under alkaline con-
ditions. The lactams and b-amino acids prepared are highly valu-
able building blocks for the synthesis of bioactive compounds
and combinatorial libraries.
4.2. (1R,2R,5S,7R)-8,8-Dimethyl-3-azatricyclo[5.1.1.02,5]nonan-
4-one 2
A mixture of 12.21 g (100.0 mmol) of (ꢀ)-(1S,5S)-apopinene 1
and 14.30 g (101.2 mmol) of chlorosulfonyl isocyanate was stirred
in 300 mL of dry Et2O for 48 h at room temperature. 20.4 g
(162 mmol) of dry Na2SO3 in 140 mL of water was then cautiously

Z. Szakonyi et al. / Tetrahedron: Asymmetry 19 (2008) 2296–2303
2299
added dropwise to the solution. The pH was held at 7–8 by the
addition of 20% aqueous KOH. After stirring for 2 h at the appropri-
ate pH, the organic phase was separated off and the aqueous layer
was extracted with Et2O (2 ꢁ 100 mL). The combined organic layer
was dried (Na2SO4) and evaporated, and the white crystalline prod-
uct obtained was recrystallized from iPr2O. Isolated compound:
NMR (CDCl3) d (ppm): 13.7 (Me), 19.7 (Me), 24.4 (CH2), 25.8
(CH), 29.4 (CH2), 34.7 (CH) 39.4 (Cq), 39.6 (Me), 44.2 (CH), 50.4
(CH), 63.0 (CH2), 176.7 (C@O). IR = 2918, 1729, 1373, 1189 cmꢀ1
.
Anal. Calcd for C12H22ClNO2 (247.76): C, 58.17; H, 8.95; N, 5.65.
Found: C, 58.43; H, 9.26; N, 5.51.
Method B: 0.22 mL (3.05 mmol) of SOCl2 was added dropwise to
dry EtOH (4 mL) the internal temperature being kept below ꢀ12 °C
during the addition. Next, 0.61 g (2.78 mmol) of (1R,2R,3S,5R)-2-
13.54 g (82%); mp: 68–72 °C; ½a D20
¼ ꢀ80:0 (c 0.5, MeOH) ee 98%;
ꢂ
1H NMR (CDCl3) d (ppm): 0.88 (3H, s), 1.30 (3H, s), 1.50 (1H, d,
J = 11.1 Hz), 1.82–1.98 (2H, m), 2.07–2.29 (3H, m), 3.28 (1H, dd,
J = 4.8, 10.7 Hz), 3.95–4.00 (1H, m), 5.87 (1H, s); 13C NMR (CDCl3)
d (ppm): 19.7 (Me), 23.3 (CH2), 24.7 (CH2), 26.8 (Me), 40.0 (Cq),
41.9 (CH), 43.7 (CH), 44.9 (CHC@O), 51.8 (CHN), 173.9 (C@O).
IR = 3247, 2914, 1710, 1380, 1256, 1189 cmꢀ1. Anal. Calcd for
C10H15NO (165.23): C, 72.69; H, 9.15; N, 8.48. Found: C, 72.52; H,
9.27; N, 8.31.
amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic
acid
hydrochloride 5 was added to the solution in one portion and the
mixture was stirred for 30 min at 0 °C, for 3 h at room temperature,
and then for 30 min at the boiling point. The solution was finally
evaporated to dryness and the resulting crude yellow product
was recrystallized from an iPr2O/EtOAc mixture. The isolated prod-
uct 4 weighed 0.56 g (81%).
4.3. (1S,2S,5R,7S)-8,8-Dimethyl-3-azatricyclo[5.1.1.02,5]nonan-
4.6. Ethyl (1S,2S,3R,5S)-2-amino-6,6-dimethyl-
4-one 17
bicyclo[3.1.1]heptane-3-carboxylate hydrochloride 19
The (1S,2S,5R,7S)-enantiomer 17 was synthesized analogously
The (1S,2S,3R,5S)-enantiomer 19 was synthesized analogously
to 2, from (+)-(1R,5R)-apopinene 16; ½a D20
ꢂ
¼ þ61:5 (c 0.5, MeOH)
to 4, from the (1S,2S,5R,7S)-enantiomer 17; ½a D20
¼ ꢀ19:6 (c 0.5,
ꢂ
ee = 90%; all the spectroscopic data and mp were similar to those
for the (ꢀ)-enantiomer 2. Anal. Calcd for C10H15NO (165.23): C,
72.69; H, 9.15; N, 8.48. Found: C, 72.57; H, 9.31; N, 8.25.
MeOH); all the spectroscopic data and the mp were similar to those
for the (1R,2R,3S,5R)-enantiomer 4. Anal. Calcd for C12H22ClNO2
(247.76): C, 58.17; H, 8.95; N, 5.65. Found: C, 58.35; H, 9.07; N,
5.73.
4.4. Methyl (1R,2R,3S,5R)-2-amino-6,6-dimethyl-
bicyclo[3.1.1]heptane-3-carboxylate hydrochloride 3
4.7. (1R,2R,3S,5R)-2-Amino-6,6-dimethylbicyclo[3.1.1]heptane-
3-carboxylic acid hydrochloride 5
Method A: A solution of 2.0 g (12.1 mmol) of (1R,2R,5S,7R)-8,8-
dimethyl-3-azatricyclo[5.1.1.02,5]nonan-4-one 2 in dry MeOH con-
taining 10% anhydrous HCl (20 mL) was stirred at room tempera-
ture. After 1.5 h, the solution was evaporated to dryness and the
resulting crystalline product was recrystallized from an iPr2O/
EtOAc mixture. Isolated compound: 1.98 g (71%); mp: 157–
A solution of 0.50 g (3.0 mmol) of (1R,2R,5S,7R)-8,8-dimethyl-3-
azatricyclo[5.1.1.02,5]nonan-4-one 2 in 5 mL of 15% aqueous HCl
was stirred at room temperature. When the mixture became clear
(approx. 1 h), the solution was evaporated to dryness and the
resulting white crystalline product was washed with acetone and
filtered off. Isolated compound: 0.61 g (94%); mp: 248–249 °C;
160 °C; ½a 2D0
ꢂ
¼ þ4:8 (c 0.5, MeOH); 1H NMR (CDCl3) d (ppm): 0.97
(3H, s), 1.35 (3H, s), 1.54 (1H, d, J = 11.1 Hz), 2.08–2.22 (3H, m),
2.36–2.45 (1H, m), 3.54 (1H, dt, J = 3.5, 10.1 Hz), 3.84 (3H, s), 4.09
(1H, d, J = 10.1 Hz). 13C NMR (CDCl3) d (ppm): 19.2, 25.3, 28.5,
38.7, 39.0, 43.6, 44.1, 47.8, 49.9, 53.1, 176.7. IR = 2926, 1724,
1498, 1205 cmꢀ1. Anal. Calcd for C11H20ClNO2 (233.74): C, 56.52;
H, 8.62; N, 5.99. Found: C, 56.73; H, 9.01; N, 6.17.
½
a 2D0
ꢂ
¼ þ22:5 (c 0.5, MeOH); 1H NMR (D2O) d (ppm): 0.89 (3H, s),
1.27 (3H, s), 1.48 (1H, d, J = 11.1 Hz), 2.04–2.16 (2H, m), 2.31–
2.39 (2H, m) 3.39 (1H, dt, J = 3.6, 10.7 Hz), 3.98 (1H, d, J = 9.6 Hz).
13C NMR (CDCl3) d (ppm): 19.7 (Me), 24.3 (CH2), 25.8 (Me), 29.4
(CH2), 34.4 (CH), 39.3 (Cq), 39.6 (CH), 44.2 (CH), 50.2 (CH), 178.5
(C@O). IR = 2904, 1724, 1584, 1489, 1175 cmꢀ1. Anal. Calcd for
C10H18ClNO2 (219.71): C, 54.67; H, 8.26; N, 6.38. Found: C, 54.87;
H, 8.02; N, 6.71.
Method B: At first 0.31 mL (4.57 mmol) of SOCl2 was added
dropwise with stirring to 4 mL of dry MeOH, the internal temper-
ature being kept below ꢀ12 °C during the addition. Next, 0.91 g
(4.17 mmol) of (1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]-
heptane-3-carboxylic acid hydrochloride 5 was added to the solu-
tion in one portion and the mixture was stirred for 30 min at 0 °C,
for 3 h at room temperature, and then for 30 min at the boiling
point. The solution was finally evaporated to dryness and the
resulting crude yellow product was recrystallized from an iPr2O/
EtOAc mixture. The isolated product 3 weighed 0.78 g (80%).
4.8. (1S,2S,3R,5S)-2-Amino-6,6-dimethylbicyclo[3.1.1]heptane-
3-carboxylic acid hydrochloride 18
(1S,2S,3R,5S)-2-Amino-6,6-dimethylbicyclo[3.1.1]heptane-3-car-
boxylic acid hydrochloride 18 was synthesized analogously to 5,
from the (1S,2S,5R,7S)-azetidinone enantiomer 17; ½a D20
¼ ꢀ21:6
ꢂ
(c 0.5, MeOH); all the spectroscopic data and the mp were similar
to those for the (1R,2R,3S,5R)-enantiomer 5. Anal. Calcd for
C10H18ClNO2 (219.71): C, 54.67; H, 8.26; N, 6.38. Found: C, 54.75;
H, 8.09; N, 6.35.
4.5. Ethyl (1R,2R,3S,5R)-2-amino-6,6-dimethyl-
bicyclo[3.1.1]heptane-3-carboxylate hydrochloride 4
Compound 4 was prepared by two methods.
4.9. (1R,2R,3S,5R)-2-Amino-6,6-dimethylbicyclo[3.1.1]heptane-
Method A: A solution of 1.16 g (7.0 mmol) of (1R,2R,5S,7R)-8,8-
dimethyl-3-azatricyclo[5.1.1.02,5]nonan-4-one 2 in dry EtOH con-
taining 10% anhydrous HCl (20 mL) was stirred at room tempera-
ture. After 1.5 h, the solution was evaporated to dryness and the
resulting crystalline product was recrystallized from an iPr2O/
EtOAc mixture. Isolated compound: 1.54 g (89%); mp: 138–
3-carboxylic acid 6
At first, 0.61 g (2.8 mmol) of (1R,2R,3S,5R)-2-amino-6,6-dim-
ethylbicyclo[3.1.1]heptane-3-carboxylic acid hydrochloride 5 was
dissolved in 5 mL of water and the solution was adjusted to pH
7.4 with a 10% solution of NaHCO3 under ice cooling in the pres-
ence of methylthymol blue as indicator. After stirring for 1 h at
0 °C, the precipitated product 6 was filtered off and washed with
a small amount of ice-cold distilled water. Isolated compound:
139 °C; ½a 2D0
ꢂ
¼ þ23:0 (c 0.5, MeOH); 1H NMR (CDCl3) d (ppm):
0.97 (3H, s), 1.36 (3H, s), 1.35 (3H, t, J = 7.3 Hz), 1.56 (1H, d,
J = 11.1 Hz), 2.08–2.23 (3H, m), 2.35–2.46 (2H, m), 3.51 (1H, dt,
J = 3.0, 10.1 Hz), 4.08 (1H, d, J = 9.6 Hz), 4.24–4.35 (2H, m). 13C
0.29 g (58%); mp: 270 °C; ½a D20
ꢂ
¼ ꢀ1:6 (c 0.50, MeOH); 1H NMR

2300
Z. Szakonyi et al. / Tetrahedron: Asymmetry 19 (2008) 2296–2303
(CD3OD) d (ppm): 0.99 (3H, s), 1.36 (3H, s), 1.73 (1H, d, J = 10.6 Hz),
2.00–2.06 (1H, m), 2.12 (1H, dt, J = 2.0, 5.5 Hz), 2.26–2.39 (3H, m),
3.02 (1H, dt, J = 4.5, 9.6 Hz), 3.82 (1H, dt, J = 2.0, 9.6 Hz). 13C NMR
(CDCl3) d (ppm): 22.9 (Me), 26.1 (CH2), 27.6 (Me), 32.5 (CH2),
37.8 (CH), 39.3 (Cq), 42.3 (CH), 47.2 (CH), 52.0 (CH), 183.1 (C@O).
IR = 3243, 2972, 1625, 1576, 1474, 1382 cmꢀ1. Anal. Calcd for
C10H17NO2 (183.25): C, 65.54; H, 9.35; N, 7.64. Found: C, 65.48;
H, 9.57; N, 7.42.
Calcd for C15H25NO4 (283.36): C, 63.58; H, 8.89; N, 4.94. Found: C,
63.69; H, 8.57; N, 5.05.
4.13. (1R,2R,3S,5R)-2-(9H-Fluoren-9-yl-methoxy-
carbonylamino)-6,6-dimethylbicyclo[3.1.1]heptane-3-
carboxylic acid 9
At first, 0.34 g (1.56 mmol) of (1R,2R,3S,5R)-2-amino-6,6-di-
methylbicyclo[3.1.1]heptane-3-carboxylic acid hydrochloride
5
4.10. (1R,2R,5S,7R)-N-tert-Butoxycarbonyl-8,8-dimethyl-3-
was dissolved in 6 mL of distilled water at 0 °C. 0.50 g (6 mmol)
of NaHCO3, 5 mL of MeCN and 0.51 g (1.5 mmol) of Fmoc-OSu were
added to the solution at 0 °C. After stirring for 12 h at room tem-
perature, the solution was adjusted to pH 2 with 5% NaHCO3 solu-
tion. After stirring overnight at room temperature, the solution was
acidified with 10% aqueous HCl solution and, after stirring for 1 h,
the reaction mixture was extracted with EtOAc (3 ꢁ 20 mL). The
combined organic layer was dried over Na2SO4 and evaporated,
and the crude product obtained was purified by flash chromatogra-
phy on a silica gel column (n-hexane/EtOAc = 9:1, Rf = 0.35), result-
ing in a white crystalline product. Isolated compound: 0.40 g
azatricyclo[5.1.1.02,5]nonan-4-one 7
To a stirred solution of 0.30 g (1.8 mmol) of (1R,2R,5S,7R)-8,8-
dimethyl-3-azatricyclo[5.1.1.02,5]nonan-4-one
2 and dry THF
(10 mL), Et3N (0.47 g, 4.6 mmol), di-tert-butyl dicarbonate (0.51 g,
2.3 mmol) and a catalytic amount of DMAP (20 mg) were added.
After stirring for 6 h at room temperature (the reaction was mon-
itored by means of TLC), the mixture was evaporated to dryness.
The oily residue obtained was purified by flash chromatography
on a silica gel column (n-hexane/EtOAc = 9:1), which resulted in
a white crystalline product. Compound 7: 0.43 g (89%); mp: 64–
(63%); mp: 160–162 °C; ½a D20
ꢂ
¼ þ2:0 (c 0.25, MeOH); 1H NMR
66 °C; ½a 2D0
ꢂ
¼ ꢀ41:1 (c 0.5, MeOH); 1H NMR (CDCl3) d (ppm): 0.89
(CDCl3) d (ppm): 0.84 (3H, s), 1.23 (3H, s), 1.71 (1H, d,
(3H, s), 1.31 0.89 (3H, s), 1.35 (1H, d, J = 11.6 Hz), 1.50 (9H, s),
1.81–2.00 (2H, m), 2.14–2.25 (2H, m), 2.51–2.57 (1H, m), 3.29
(1H, dd, J = 6.2, 10.3 Hz), 4.27 (1H, dd, J = 4.0, 5.6 Hz). 13C NMR
(CDCl3) d (ppm): 20.5 (Me), 24.3 (CH2), 25.5 (CH2), 27.3 (Me),
28.7 ((Me)3C), 39.8 (Cq), 42.1 (CH), 42.5 (CH), 44.1 (CH), 55.5
(CH), 83.4 (Cq), 148.6 (C@O), 170.5 (C@O). IR = 2926, 1803, 1707,
1349, 1156 cmꢀ1. Anal. Calcd for C15H23NO3 (265.35): C, 67.90;
H, 8.74; N, 5.28. Found: C, 68.16; H, 8.54; N, 5.35.
J = 10.4 Hz), 1.81–2.25 (5H, m), 3.08 (1H, t, J = 9.1 Hz), 4.00–4.47
(4H, m), 7.24–7.75 (8H, m). 13C NMR (CDCl3) d (ppm): 20.8, 24.8,
26.8, 28.8, 39.1, 39.6, 39.9, 46.9, 47.9, 50.8, 68.2, 120.6, 125.6,
125.9, 127.7, 128.3, 142.0, 142.1, 144.5, 144.8, 158.7, 180.2.
IR = 3260, 2908, 1711, 1652, 1414, 1332, 1201, 741 cmꢀ1. Anal.
Calcd for C25H27NO4 (405.49): C, 74.05; H, 6.71; N, 3.45. Found:
C, 74.19; H, 6.45; N, 3.53.
4.14. (1S,2S,3R,5S)-2-(9H-Fluoren-9-yl-methoxy-
carbonylamino)-6,6-dimethylbicyclo[3.1.1]heptane-3-
carboxylic acid 23
4.11. (1R,2R,3S,5R)-(2-tert-Butoxycarbonylamino)-6,6-
dimethylbicyclo[3.1.1]heptane-3-carboxylic acid 8
At first, 0.66 g (3 mmol) of (1R,2R,3S,5R)-2-amino-6,6-di-
methylbicyclo[3.1.1]heptane-3-carboxylic acid hydrochloride 5 was
dissolved in 5 mL of distilled water at 0 °C and the pH of the solu-
tion was adjusted to pH 8 with 3% NaOH solution in the presence of
bromothymol blue as indicator. Next 5 mL of dioxan and 0.72 g
(3.3 mmol) of Boc2O were added, and the reaction mixture was
stirred at room temperature, with the pH being maintained at 8
with 3% NaOH solution. After stirring for 6 h at room temperature,
the solution was cooled to 0 °C, acidified with 5% aqueous HCl solu-
tion to pH 5, and extracted with CHCl3 (3 ꢁ 50 mL). The combined
organic layer was dried (Na2SO4) and evaporated, and the white
crystalline product obtained was recrystallized from n-hexane.
The NMR measurements on the product revealed the presence of
two rotamer populations in a ratio of 12:88. Isolated compound:
The (1S,2S,3R,5S) = enantiomer 23 was synthesized analogously
to 9, from the (1S,2S,3R,5S)-enantiomer 18; ½a D20
¼ ꢀ2:0 (c 0.25,
ꢂ
MeOH); all the spectroscopic data and the mp were similar to those
for the (1R,2R,3S,5R)-enantiomer 9. Anal. Calcd for C25H27NO4
(405.49): C, 74.05; H, 6.71; N, 3.45. Found: C, 74.23; H, 6.51; N,
3.57.
4.15. (1S,2S,3R,5S)-2-Dimethylamino-6,6-dimethyl-
bicyclo[3.1.1]heptane-3-carboxylic acid hydrochloride 10
At first, 0.50 g (2.27 mmol) of amino acid hydrochloride 5 was
dissolved in 15 mL of distilled water, followed by the addition of
0.43 g (5.0 mmol) of 35% HCHO solution and 0.20 g of 10% Pd/C cat-
alyst. The mixture was stirred at room temperature and 10 bar un-
der a H2 atmosphere for 12 h. The mixture was then filtered and
the filtrate was evaporated to dryness. The resulting crystalline
product was triturated with acetone, and then filtered off. Isolated
0.52 g (61%); mp: 151–153 °C; ½a D20
ꢂ
¼ þ46:0 (c 0.5, MeOH); 1H
NMR (CDCl3) d (ppm) of major rotamer: 0.88 (3H, s), 1.24 (3H, s),
1.47 (9H, s), 1.75 (1H, d, J = 10.6 Hz), 1.84–1.99 (3H, m), 2.20–
2.31 (2H, m), 3.21 (1H, dt, J = 2.5, 10.1 Hz), 4.31 (1H, t,
J = 10.1 Hz), 7.33 (1H, d, J = 10.1 Hz), 11.30 (1H, br s). 13C NMR
(CDCl3) d (ppm): 20.6 (Me), 24.5 (CH2), 26.5 (Me), 27.5 (CH2),
28.6 (CMe3), 39.0 (CH), 39.3 (Cq), 39.6 (CH), 46.7 (CH), 50.5 (CH),
81.4 (CMe3), 155.8 (NC@O), 179.8 (C@O). IR = 3255, 2914, 1711,
1654, 1407, 1171 cmꢀ1. Anal. Calcd for C15H25NO4 (283.36): C,
63.58; H, 8.89; N, 4.94. Found: C, 63.79; H, 8.41; N, 5.19.
compound: 0.50 g (89%); mp: 144–145 °C; ½a D20
¼ þ10:7 (c 0.505,
ꢂ
MeOH); 1H NMR (CDCl3) d (ppm): 0.89 (3H, s), 1.35 (3H, s), 1.62
(1H, d, J = 11.1 Hz), 2.03–2.10 (1H, m), 2.21–2.56 (4H, m), 2.88
(3H, s), 2.92 (3H, s), 3.51 (1H, t, J = 9.3 Hz), 3.76 (1H, d,
J = 8.6 Hz). 13C NMR (CDCl3) d (ppm): 19.4 (Me), 23.4 (CH2), 25.9
(Me), 29.5 (CH2), 34.3 (CH), 39.3 (CH), 40.3 (CH), 40.4 (Cq), 42.3
(Me), 44.1 (Me), 67.2 (CH), 179.9 (C@O). IR = 2952, 1709, 1458,
1186 cmꢀ1. Anal. Calcd for C12H22ClNO2 (247.76): C, 58.17; H,
8.95; N, 5.65. Found: C, 58.23; H, 8.69; N, 5.37.
4.12. (1S,2S,3R,5S)-(2-tert-Butoxycarbonylamino)-6,6-
dimethylbicyclo[3.1.1]heptane-3-carboxylic acid 22
4.16. Ethyl (1R,2R,3R,5R)-2-amino-6,6-dimethyl-
The (1S,2S,3R,5S)-enantiomer 22 was synthesized analogously
to 8, from the (1S,2S,3R,5S) = amino acid hydrochloride enantiomer
bicyclo[3.1.1]heptane-3-carboxylate hydrochloride 11
18; ½a 2D0
ꢂ
¼ ꢀ44:1 (c 0.5, MeOH); all the spectroscopic data and the
To a solution of 0.23 g (10 mmol) of Na in 30 mL of dry EtOH,
1.05 g (5 mmol) of the base form of ethyl (1R,2R,3S,5R)-2-amino-
mp were similar to those for the (1R,2R,3S,5R)-enantiomer 8. Anal.

Z. Szakonyi et al. / Tetrahedron: Asymmetry 19 (2008) 2296–2303
2301
6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylate hydrochloride 4
was added in one portion. The solution was stirred at room tem-
perature until the isomerization was complete (approximately
4 h; the isomerization process was monitored by means of TLC
and GC). The solution was then evaporated to approximately
5 mL, diluted with ice-cold water (50 mL) and extracted with
EtOAc (3 ꢁ 50 mL). The combined organic layer was dried over
Na2SO4 and evaporated, and the hydrochloride salt 11, prepared
from the resulting amino ester base with a 15% solution of anhy-
drous HCl in dry EtOH, was recrystallized from iPr2O. Isolated com-
2.99–3.07 (1H, m), 4.08 (1H, d, J = 8.6 Hz). 13C NMR (CDCl3) d
(ppm): 19.1 (Me), 23.0 (CH2), 25.8 (Me), 27.4 (CH2), 38.2 (CH),
39.4 (CH), 39.8 (Cq), 43.4 (CH), 52.4 (CH), 177.7 (C@O). IR = 2913,
1716, 1511, 1247 cmꢀ1. Anal. Calcd for C10H18ClNO2 (219.71): C,
54.67; H, 8.26; N, 6.38. Found: C, 54.79; H, 8.39; N, 6.21.
4.20. (1S,2S,3S,5S)-2-Amino-6,6-dimethylbicyclo[3.1.1]heptane-
3-carboxylic acid hydrochloride 21
The 1S,2S,3S,5S enantiomer 21 was synthesized analogously to
13, from the 1S,2S,3S,5S amino ester enantiomer 20;
pound: 0.85 g (69%); mp: 147–148 °C; ½a D20
¼ ꢀ32:4 (c 0.5, MeOH);
ꢂ
1H NMR (CDCl3) d (ppm): 0.88 (3H, s), 1.34 (3H, s), 1.36 (3H, t,
J = 7.1 Hz), 1.56 (1H, d, J = 11.1 Hz), 2.05 (1H, dd, J = 9.1, 13.6 Hz),
2.10–2.23 (2H, m), 2.35–2.46 (2H, m), 3.05 (1H, dd, J = 9.1,
18.1 Hz), 4.10 (1H, d, J = 89.6 Hz), 4.33 (2H, dd, J = 7.1, 14.1 Hz).
13C NMR (CDCl3) d (ppm): 13.8 (Me), 19.1 (Me), 23.0 (CH2), 25.8
(CH), 27.5 (CH2), 38.4 (CH), 39.3 (Me), 39.7 (Cq), 43.4 (CH), 52.3
(CH), 63.0 (CH2), 175.9 (C@O). IR = 2926, 1734, 1509, 1292,
1193 cmꢀ1. Anal. Calcd for C12H22ClNO2 (247.76): C, 58.17; H,
8.95; N, 5.65. Found: C, 58.35; H, 8.78; N, 5.79.
½
a 2D0
ꢂ
¼ þ30:1 (c 0.5, MeOH); all the spectroscopic data and the
mp were similar to those for the (1R,2R,3R,5R)-enantiomer 13.
Anal. Calcd for C10H18ClNO2 (219.71): C, 54.67; H, 8.26; N, 6.38.
Found: C, 54.83; H, 8.35; N, 6.19.
4.21. (1R,2R,3R,5R)-(2-tert-Butoxycarbonylamino)-6,6-
dimethylbicyclo[3.1.1]heptane-3-carboxylic acid 14
Compound 14 was synthesized analogously to 8, from 0.66 g
(3 mmol) of (1R,2R,3R,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]-
heptane-3-carboxylic acid hydrochloride 13. Isolated compound:
4.17. Ethyl (1S,2S,3S,5S)-2-amino-6,6-dimethyl-
bicyclo[3.1.1]heptane-3-carboxylate hydrochloride 20
0.55 g (65%); mp: 85–87 °C; ½a D20
ꢂ
¼ ꢀ43:3 (c 0.5, MeOH); 1H NMR
(CDCl3)
d (ppm): 0.94 (3H, s), 1.23 (3H, s), 1.35 (1H, d,
The (1S,2S,3S,5S) enantiomer 20 was synthesized analogously to
J = 10.1 Hz), 1.43 (9H, s), 1.94–2.21 (5H, m), 2.53–2.64 (1H, m),
4.26–4.36 (1H, m), 4.73 (1H, br s). 13C NMR (CDCl3) d (ppm):
20.1, 24.1, 27.2, 28.4, 29.0, 40.2, 40.4, 42.7, 46.7, 52.1, 81.0, 155.7,
179.8. IR = 3336, 2923, 1711, 1659, 1366, 1176 cmꢀ1. Anal. Calcd
for C15H25NO4 (283.36): C, 63.58; H, 8.89; N, 4.94. Found: C,
63.84; H, 8.99; N, 5.26.
11, from the 1S,2S,3R,5S enantiomer amino ester 19; ½a D20
¼ þ31:0
ꢂ
(c 0.5, MeOH); all the spectroscopic data and the mp were similar
to those for the 1R,2R,3R,5R enantiomer 11. Anal. Calcd for
C12H22ClNO2 (247.76): C, 58.17; H, 8.95; N, 5.65. Found: C, 58.27;
H, 8.72; N, 5.83.
4.18. (1R,2R,3R,5R)-2-Amino-6,6-dimethyl-
4.22. (1S,2S,3S,5S)-(2-tert-Butoxycarbonylamino)-6,6-
bicyclo[3.1.1]heptane-3-carboxylic acid 12
dimethylbicyclo[3.1.1]heptane-3-carboxylic acid 24
At first, 0.23 g (1.09 mmol) of the base liberated from ethyl
(1R,2R,3R,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carb-
oxylate hydrochloride 11 was dissolved in a mixture of 10 mL of
dioxan and 10 mL of distilled water, and the solution was heated
at 80 °C with monitoring by means of TLC. When the reaction
was complete (indicated by elimination of the starting ester), the
mixture was evaporated to dryness and the resulting white crystal-
line product was triturated with acetone, filtered off, and recrystal-
lized from an acetone/water mixture. Isolated compound: 0.13 g
The (1S,2S,3S,5S)-enantiomer 24 was synthesized analogously
to 14, from 0.66 g (3 mmol) of (1S,2S,3S,5S)-2-amino-6,6-dim-
ethylbicyclo[3.1.1]heptane-3-carboxylic acid hydrochloride 21
prepared as above, ½a D20
¼ þ41:1 (c 0.5, MeOH); all the spectro-
ꢂ
scopic data and the mp were similar to those for the
(1R,2R,3R,5R)-enantiomer 14. Anal. Calcd for C15H25NO4 (283.36):
C, 63.58; H, 8.89; N, 4.94. Found: C, 63.71; H, 9.13; N, 5.15.
4.23. (1R,2R,3R,5R)-2-(9H-Fluoren-9-yl-methoxy-
carbonylamino)-6,6-dimethylbicyclo[3.1.1]heptane-3-
carboxylic acid 15
(65%); mp: 250–252 °C; ½a D20
ꢂ
¼ ꢀ42:7 (c 0.5, MeOH); 1H NMR
(CDCl3)
d (ppm): 0.82 (3H, s), 1.26 (3H, s), 1.49 (1H, d,
J = 10.8 Hz), 1.83–1.93 (1H, m), 1.98–2.11 (2H, m), 2.20–2.30 (2H,
m), 2.61–2.70 (1H, m), 3.90 (1H, d, J = 8.6 Hz). 13C NMR (CDCl3) d
(ppm): 19.1 (Me), 22.8 (CH2), 25.8 (Me), 28.1 (CH2), 39.7 (CH),
39.9 (Cq), 40.6 (CH), 43.4 (CH), 53.6 (CH), 181.5 (C@O). IR = 2924,
1624, 1552, 1404 cmꢀ1. Anal. Calcd for C10H17NO2 (183.25): C,
65.54; H, 9.35; N, 7.64. Found: 65.21; H, 9.87; N, 7.19.
The (1R,2R,3R,5R)-enantiomer 15 was synthesized analogously
to 9, from the (1R,2R,3R,5R)-amino acid hydrochloride enantiomer
13; mp: 155–157 °C; ½a D20
ꢂ
¼ ꢀ4 (c 0.25, MeOH); 1H NMR (CDCl3) d
(ppm): 0.90 (3H, s), 1.20 (3H, s), 1.34 (1H, d, J = 10.6 Hz), 1.81–2.14
(5H, m), 2.56–2.62 (1H, m), 4.17 (1H, t, J = 6.5 Hz), 4.28–4.46 (3H,
m), 4.97 (1H, br s), 7.20–7.80 (8H, m). 13C NMR (CDCl3) d (ppm):
20.1, 24.2, 27.2, 28.4, 32.1, 40.2, 42.6, 46.7, 47.9, 52.5, 67.5,
120.6, 125.8, 127.7, 128.3, 142.0, 144.6, 148.5, 179.8.); IR = 3340,
4.19. (1R,2R,3R,5R)-2-Amino-6,6-dimethyl-
bicyclo[3.1.1]heptane-3-carboxylic acid hydrochloride 13
2926, 1693, 1536, 1450, 1252, 739 cmꢀ1
. Anal. Calcd for
At first, 0.74 g (3.0 mmol) of ethyl (1R,2R,3R,5R)-2-amino-6,6-
dimethylbicyclo[3.1.1]heptane-3-carboxylate hydrochloride 11
was dissolved in a 10% solution of aqueous HCl, and the solution
was stirred at room temperature for 48 h (the reaction was moni-
tored by means of 1H NMR). When the hydrolysis was complete,
the solution was evaporated to dryness and the resulting crystal-
line product was triturated with acetone, and then filtered off.
C25H27NO4 (405.49): C, 74.05; H, 6.71; N, 3.45. Found: C, 74.27;
H, 6.52; N, 3.49.
4.24. (1S,2S,3S,5S)-2-(9H-Fluoren-9-yl-methoxy-
carbonylamino)-6,6-dimethylbicyclo[3.1.1]heptane-3-
carboxylic acid 25
Compound 13: 0.56 g (85%); mp: 241–242 °C; ½a D20
ꢂ
¼ ꢀ32:6 (c
The (1S,2S,3S,5S)-enantiomer 25 was synthesized analogously
to 15, from the (1S,2S,3S,5S)-amino acid hydrochloride enantiomer
0.5, MeOH); 1H NMR (CDCl3) d (ppm): 0.88 (3H, s), 1.34 (3H, s),
1.56 (1H, d, J = 11.1 Hz), 2.05 (1H, dd, J = 8.8, 13.8 Hz), 2.13 (1H,
dd, J = 4.8, 9.8 Hz), 2.20 (1H, t, J = 5.5 Hz), 2.35–2.45 (2H, m),
21; ½a 2D0
¼ þ6 (c 0.25, MeOH); all the spectroscopic data and the
ꢂ
mp were similar to those for the 1R,2R,3R,5R enantiomer 15. Anal.

2302
Z. Szakonyi et al. / Tetrahedron: Asymmetry 19 (2008) 2296–2303
Calcd for C25H27NO4 (405.49): C, 74.05; H, 6.71; N, 3.45. Found: C,
74.23; H, 6.49; N, 3.57.
39.3, 40.0, 40.4, 47.2, 49.6, 54.2, 62.0, 79.9, 127.8, 129.3, 130.0,
136.4, 156.1, 172.0, 175.3. IR = 3306, 2923, 2852, 1744, 1681,
. Anal. Calcd for C26H38N2O5
(458.59): C, 68.10; H, 8.35; N, 6.11. Found: C, 68.45; H, 8.01; N,
6.43.
1500, 1330, 1160, 1042 cmꢀ1
4.25. Ethyl (2S,10R,20R,30S,50R)-2-[(20-tert-butoxy-
carbonylamino)-60,60-dimethylbicyclo[3.1.1]heptane-30-
carbonyl)]amino-3-phenylpropionate 26
4.28. Ethyl (2S,10S,20S,30S,50S)-2-[[(20-tert-butoxy-
carbonylamino)-60,60-dimethylbicyclo[3.1.1]heptane-30-
carbonyl)]amino]-3-phenylpropionate 29
At first, 0.05 g of Et3N and 0.065 g of isobutyl chloroformate
were added to
a solution of 0.14 g (0.49 mmol) of the
(1R,2R,3S,5R)-Boc-protected amino acid 8 in 5 mL of dry THF at
ꢀ10 °C with vigorous stirring. After stirring for 10 min, 2 mL of a
dry THF solution of 0.095 g (0.49 mmol) of (S)-phenylalanine ethyl
ester was added dropwise to the mixture at ꢀ10 °C. The mixture
was stirred at room temperature for a further 5 h, and then evap-
orated to dryness. The resulting crude oily product was dissolved
in CHCl3 (30 mL), and the organic solution was washed first with
an ice-cold 5% solution of NaHCO3 (20 mL), and then with an ice-
cold 5% aqueous HCl solution (20 mL). The organic layer was next
dried over Na2SO4 and evaporated, and the oily product obtained
was purified by flash chromatography on a silica gel column (n-
hexane/EtOAc = 6:1, Rf = 0.35). Isolated compound: 0.15 g (67%),
The (2S,10S,20S,30S,50S)-enantiomer 29 was synthesized analo-
gously to 26, from 0.14 g (0.49 mmol) of the (1S,2S,3S,5S)-enantio-
mer 24. Isolated compound: 0.10 g (45%); mp: 186–188 °C;
½
a 2D0
ꢂ
¼ þ18 (c 0.25, MeOH); 1H NMR (CDCl3) d (ppm): 0.93 (3H,
s), 1.21 (3H, t, J = 7.1 Hz), 1.22 (3H, s), 1.26 (9H, s), 1.31 (1H, d,
J = 11.1 Hz), 1.94–2.18 (5H, m), 2.29 (1H, m), 3.08 (1H, dd, J = 6.0,
14.1 Hz), 3.20 (1H, dd, J = 6.0, 14.1 Hz), 4.13 (2H, dd, J = 7.1,
14.1 Hz), 4.23–4.32 (1H, m), 4.66 (1H, br s), 4.81–4.91 (1H, m),
6.89 (1H, br s), 7.09–7.30 (5H, m). 13C NMR (CDCl3) d (ppm):
14.8, 20.1, 23.4, 27.2, 29.0, 29.4, 30.0, 32.6, 38.5, 40.3, 43.7, 47.2,
54.3, 62.0, 80.3, 127.5, 129.0, 130.0, 137.0, 156.0, 172.6, 174.1.
IR = 3310, 2926, 1692, 1645, 1557, 1182 cmꢀ1. Anal. Calcd for
C26H38N2O5 (458.59): C, 68.10; H, 8.35; N, 6.11. Found: C, 68.39;
H, 8.05; N, 6.28.
viscous oil; ½a 2D0
ꢂ
¼ þ22:5 (c 0.5, MeOH); 1H NMR (CDCl3) d
(ppm): 0.88 (3H, s), 1.22 (6H, s overlapped with t), 1.36 (9H, s),
1.62–2.20 (7H, m), 3.01 (1H, dt, J = 3.5, 10.1 Hz), 3.10 (1H, dd,
J = 3.5, 10.1 Hz), 3.21 (1H, dd, J = 3.5, 10.1 Hz), 4.14 (2H, q, J = 7.1,
14.1 Hz), 4.35 (1H, t, J = 10.0 Hz), 4.74 (1H, q, J = 6.1, 12.1 Hz),
5.28 (1H, d, J = 10.1 Hz), 6.19 (1H, d, J = 6.5 Hz), 7.9 (2H, d,
J = 7.1 Hz), 7.20–7.30 (3H, m). 13C NMR (CDCl3) d (ppm): 14.7
(Me), 20.9 (Me), 25.4 (CH2), 26.8 (Me), 29.0 (CMe3), 29.8 (CH2),
38.6 (CH2), 39.8 (Cq), 40.0 (Me), 40.5 (CH), 46.9 (CH), 49.5 (CH),
54.5 (CH), 62.1 (CH2), 79.6 (CMe3), 127.7 (CHar), 129.1 (CHar),
130.1 (CHar), 136.7 (Cq), 156.1 (C@O, Boc), 171.6 (C@O), 175.4
(C@O). IR = 3411, 2978, 1711, 1497, 1366, 1161, 701 cmꢀ1. Anal.
Calcd for C26H38N2O5 (458.59): C, 68.10; H, 8.35; N, 6.11. Found:
C, 67.76; H, 8.53; N, 6.38.
Acknowledgement
We are grateful to the Hungarian Research Foundation (OTKA
No. NF69316) for financial support.
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½
a 2D0
ꢂ
¼ ꢀ15 (c 0.25, MeOH); 1H NMR (CDCl3) d (ppm): 0.79 (3H,
s), 1.19 (3H, t, J = 7.1 Hz), 1.20 (3H, s), 1.30 (1H, d, J = 10.5 Hz),
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