Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part VI: Synthesis and incorporation of the novel polyhydroxylated 5-aminocyclopent-1-enecarboxylic acids into peptides

Article abstract of DOI:10.1016/j.tetasy.2010.05.052

The first total synthesis of enantiopure methyl (3aR,4S,5S,6R,6aS)-4- benzyloxycarbonylamino-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3] dioxole-5-carboxylate has been carried out according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines. This approach is based on an intramolecular cyclization that leads to 2-oxabicyclo[2.2.1]heptane derivatives. E1cb elimination of the methoxy substituent was observed when attempting to incorporate these β-amino acid into peptides. As a result, the synthesis and incorporation of the first polyhydroxylated 5-aminocyclopent-1-enecarboxylic acid into peptides were developed.

Full text of DOI:10.1016/j.tetasy.2010.05.052

Tetrahedron: Asymmetry 21 (2010) 2021–2026
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereocontrolled transformation of nitrohexofuranoses into
cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part VI: Synthesis and
incorporation of the novel polyhydroxylated 5-aminocyclopent-1-enecarboxylic
acids into peptides
*
*
Fernando Fernández, Begoña Pampín, Marcos A. González, Juan C. Estévez , Ramón J. Estévez
Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of enantiopure methyl (3aR,4S,5S,6R,6aS)-4-benzyloxycarbonylamino-6-hydroxy-
2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-5-carboxylate has been carried out according to
our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines. This
approach is based on an intramolecular cyclization that leads to 2-oxabicyclo[2.2.1]heptane derivatives.
E1cb elimination of the methoxy substituent was observed when attempting to incorporate these b-amino
acid into peptides. As a result, the synthesis and incorporation of the first polyhydroxylated 5-aminocyclo-
pent-1-enecarboxylic acid into peptides were developed.
Received 12 May 2010
Accepted 21 May 2010
Available online 4 August 2010
Ó 2010 Published by Elsevier Ltd.
1. Introduction
We are currently interested in the development of practical ste-
reocontrolled syntheses of biologically and pharmacologically rel-
Peptides play a crucial role in biology. However, their use as
therapeutic agents suffers from their poor metabolic stability and
transport properties1 together with their limited structural diver-
sity, which is related to the limited number of secondary structures
and backbones resulting from the small number of proteinogenic
amino acids.2 Accordingly, a great deal of work has been carried
out in recent years which aimed at the synthesis of unnatural ami-
no acids. This represents the first step for the introduction of ele-
ments of diversity for the development of peptidomimetics with
high levels of diversity and the capability to generate highly or-
dered structures that may act as new drugs and overcome the
pharmacological limitations of proteins.3
Cyclic b-amino acids, in particular cyclopentyl b-amino acids,
have become a hot topic in the synthetic and medicinal chemistry
as a result of their present interest as stabilizers of peptide confor-
mations—a property that has been related to the high tendency of
their homopolymers to fold in rigid secondary structures in short
peptide sequences.4 Accordingly, several procedures for the syn-
thesis of these systems have been developed. However, the panel
of known cyclopentane b-amino acids is limited, probably due to
the lack of efficient methods for the stereocontrolled preparation
of their polysubstituted derivatives, which remains a challenge
for synthetic chemists.5
evant polysubstituted carba- and aza-sugar derivatives from
nitrosugars.6 In this context, we have developed a stereocontrolled
route to polyhydroxylated cyclopentyl b-amino acids with the aim
of opening up opportunities to access lipophililic or hydrophilic
b-peptides, with the hydroxy substituents either protected or
unprotected. This approach allowed us to synthesize the first poly-
hydroxylated trans-2-aminocyclopentanecarboxylic acid6b from
D
-glucose and the first polyhydroxylated cis-2-aminocyclopentane-
carboxylic acid6f from
L-idose. Herein, we report the application of
this synthetic strategy for the preparation of the polysubstituted
cyclopentane b-amino acid 1, a structurally complex cyclopen-
tane-based b-amino acid of interest in order to obtain new insights
into b-peptides.
2. Results and discussion
The preparation of amino acid 1 from D-glucose was initially at-
tempted according to the synthetic plan depicted in Scheme 1,
which involved the early introduction of a methoxy substituent
at C-3. Treatment of compound 5, obtained from diacetone-D-glu-
cose 4 following a known procedure,7 with TBDPSCl and imidazole
yielded derivative 68 due to selective protection of the hydroxy
group at C-6 (Scheme 2). Benzylation of the hydroxyl group at C-
5 of compound 6 with sodium hyride and benzyl bromide gave
intermediate 7 in 81% yield. Subsequent deprotection of the hydro-
xy group at C-6 of this compound by treatment with TBAF9 was fol-
lowed by a second reaction sequence which aimed at replacing the
* Corresponding authors.
E-mail address: ramon.estevz@usc.es (R.J. Estévez).
0957-4166/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2010.05.052

2022
F. Fernández et al. / Tetrahedron: Asymmetry 21 (2010) 2021–2026
OR
O
6
O2N
O
O
O
OMe
5
O
O
O
1
O
O
4
BnO
NO2
OBn
3
2
O
CbzHN
CO2Me
HO
RO
OTf
O
1
2 a: R=Me, b: R=Bn
3 a: R=Me, b: R=Bn
4
Scheme 1. Synthetic plan for the preparation of amino acid 1 from
D-glucose.
TBDPSO
BnO
HO
TBDPSO
O
O
O
iii
i
ii
O
O
O
O
O
HO
HO
O
O
O
MeO
MeO
MeO
MeO
5
6
7
HO
BnO
I
O2N
BnO
O
O
O
iv
v
vi
O
O
O
BnO
O
MeO
MeO
MeO
8
9
10
OMe
6
O2N
BnO
O2N
BnO
O2N
O
O
5
O
OH
OH
O
O
viii
ix
vii
1
4
O
BnO
NO2
OBn
3
2
MeO
OH
MeO
OTf
O
11
12
3a
2a
Scheme 2. Reagents and conditions: (i) TBDPSCl, imidazole, DMF, ꢀ20 °C, 1 h, 87%; (ii) NaH, BnBr, NBu4I, DMF, 0 °C?rt, 24 h, 81%; (iii) TBAF, THF, rt, 17 h, 97%; (iv) imidazole,
Ph3P, I2, toluene, 85 °C, 4 h, 90%; (v) NaNO2, phloroglucinol, DMSO, rt, 96 h, 65%; (vi) TFA/H2O (1:1), rt, 15 h; (vii) Br2, BaCO3, dioxane/H2O (2:1), rt, 15 h (80% from 10); (viii)
Tf2O, pyridine, CH2Cl2, ꢀ30 °C, 1 h; (ix) TBAF, THF, rt, 12 h (36% from 12).
free hydroxy group of the resulting compound 8 with a nitro group.
Accordingly, treatment of primary alcohol 8 under Appel10 condi-
tions provided the iodo derivative 9, from which our key nitrosugar
derivative 10 was easily obtained in 65% yield by displacement of
the iodide by nitrite in the presence of phloroglucinol.11
Reaction of compound 10 with trifluoroacetic acid and water,
followed by anomeric oxidation of the resulting lactol 11 with bro-
mine and barium carbonate, afforded the lactone 12 as a yellowish
oil. Treatment of this compound with triflic anhydride in pyridine
furnished the desired triflate 3a, which was maintained under vac-
uum overnight and then directly reacted with TBAF in THF to pro-
mote an intramolecular cyclization that provided the desired
bicyclic nitrolactone 2a in only 36% yield.
under the reaction conditions, compounds 2a and 13 should be in
equilibrium with their common nitronate 14, but the thermody-
namically more stable compound 2a should be favoured over com-
pound 13, in which the nitro and benzyloxy groups are eclipsed.
This explains the highly remarkable stereoselectivity of the cycliza-
tion of nitronate of 3a.
The yield achieved in this intramolecular cyclization of 3a was
substantially lower than the 75% yield previously reported for a
similar cyclization of C-3 O-benzylated nitronate 3b to the bicyclic
lactone 2b (Scheme 1).6b This result led us to discard our initial
plans for the preparation of our synthetic objective 1 from 3a, via
2a, in favour of an alternative route as outlined in Scheme 4.
Accordingly, trihydroxylated cyclopentane b-amino acid derivative
The stereochemical outcome of this key step leading to com-
pound 2a was explained, as for previous similar cases,6b with the
assumption that both bicyclic compounds 2a and 13 should be
formed from the nitronate of compound 3a (Scheme 3). However,
15 was prepared from diacetone-D-glucose 4 as previously re-
ported (Scheme 4) and subsequent treatment with 2,2-dimethoxy-
propane in dry acetone gave 16 as a result of the selective
protection of its cis-1,2-diol system. Finally, the reaction of this
compound with methyl iodide, using silver(I) oxide as a base,12 re-
sulted in the efficient methylation of its free hydroxy group, a pro-
OMe
cess that allowed our target compound
1 to be obtained.
Compound 1 was easily identified from its analytical and spectro-
scopic properties. Following this approach, compound 1 was ob-
tained in 13% overall yield after a 15-step sequence.
O
2a
NO2
OBn
OMe
O
6
O2N
In order to investigate the incorporation of this amino acid
derivative 1 into peptides, a freshly isolated sample of this com-
pound was subjected to diverse basic hydrolysis conditions with
the aim of obtaining the corresponding carboxylic acid. However,
the formation of b-amino acid derivative 17 was observed in all
cases (Scheme 5); this constitutes the first reported example of this
novel class of cyclopentene based b-amino acid. The formation of
17 probably involved an E1cb elimination of methanol, followed
by hydrolysis of the methoxycarbonyl moiety.
O
5
O
O
1
OMe
OBn
4
BnO
O
3
O
N
2
MeO
OTf
H
H
O
O
14
3a
O
OBn
NO2
13
Scheme 3.

F. Fernández et al. / Tetrahedron: Asymmetry 21 (2010) 2021–2026
2023
OBn
O2N
O
O
O
O
i
Ref. 6b
O
O
O
BnO
NO2
OBn
O
HO
BnO
O
OTf
O
4
3b
2b
OH
O
O
O
HO
CbzHN
OH
CO2Me
OH
OMe
ii
iii
iv
CbzHN
CO2Me
CbzHN
CO2Me
1
15
16
Scheme 4. Reagents and conditions: (i) TBAF, THF, rt, 6 h (75%, two steps); (ii) see Ref.6b (three steps, 39% from 2b); (iii) 2,2-DMP, PTSA, MgSO4, acetone, rt, 13 h, 88%; (iv) MeI,
Ag2O, CH3CN, 50 °C, 60 h, 93%.
O
O
O
O
O
O
O
O
OMe
i
ii
+
CbzHN
CO2Me
CbzHN
CO2H
H2N
CO2H
H2N
CO2H
1
17
18a
18b
ii
O
O
O
O
O
O
O
O
OMe
OMe
CO2Me
iv
iii
v
H2N
CO2Me
CbzGlyHN
CbzGlyHN
CO2H
CbzGlyHN
COGlyOMe
19
20
21
22
Scheme 5. Reagents and conditions: (i) NaOH, THF, rt, 2 h, 90%; (ii) H2, Pd/C, EtOAc, rt, 2 h; (iii) Cbz-Gly-OH, DIEA, TBTU, CH2Cl2, rt, 12 h (88% from 1); (iv) NaOH, THF, rt, 2 h;
(v) H-Gly-OMeꢁHCl, DIEA, TBTU, CH2Cl2, rt, 12 h (65% from 20).
Compound 17 is an amino acid of interest as a novel scaffold in b-
peptide chemistry due to the extra rigidity provided by its endocy-
clic carbon–carbon double bond. As a result, we decided to study the
incorporation of 17 into peptides. Accordingly, we first tried to re-
move selectively the benzyloxycarbonyl group by catalytic hydro-
genation but an inseparable 1:1 mixture of compounds 18a and
18b was obtained due to simultaneous hydrogenation of the car-
bon–carbon double bond. However, satisfactory results were
achieved by the early incorporation of a glycine subunit in the N-ter-
minus of b-amino acid derivative 1. Thus, catalytic hydrogenation of
1 provided the expected cyclopentylamine 19, which upon treat-
ment with benzyloxycarbonylglycine, TBTU and DIEA gave dipep-
tide 20 in 88% yield for the last two steps. Subsequent treatment
of this compound with base led to the expected dipeptide 21, which
was finally reacted with glycine methyl ester hydrochloride under
the same coupling conditions as for 19. This sequence allowed us
to obtain the desired tripeptide 22 in 65% yield for the last two steps.
Work aiming at the preparation of diverse 5-aminocyclopent-1-
enecarboxylic acids as an initial stage in the study of the structural,
physical and biological properties of their oligomers is currently in
progress. Specifically, we are interested in establishing how the ex-
tra rigidity of the cyclopentane ring, due to the presence of a car-
bon–carbon double bond, can influence the folding properties.
4. Experimental
Melting points were determined using a Kofler Thermogerate
apparatus and are uncorrected. Specific rotations were recorded
on a JASCO DIP-370 optical polarimeter. Infrared spectra were re-
corded on a MIDAC Prospect-IR spectrophotometer. Nuclear mag-
netic resonance spectra were recorded on a Bruker DPX-250
spectrometer. Mass spectra were obtained on a Hewlett–Packard
5988A mass spectrometer. Elemental analyses were obtained from
the Elemental Analysis Service at the University of Santiago de
Compostela. Thin layer chromatography (TLC) was performed
using Merck GF-254 type 60 silica gel and ethyl acetate/hexane
mixtures as eluants; the TLC spots were visualized with Hanessian
mixture. Column chromatography was carried out using Merck
type 9385 silica gel. Compounds 5, 6, 14, 3b, 2b and 15 were pre-
pared by following known procedures.
3. Conclusion
In conclusion, we have adapted our strategy for the stereocon-
trolled synthesis of polyhydroxylated cyclopentane b-amino acids
from nitro sugars6a and applied it to the preparation of methyl
(3aR,4S,5S,6R,6aS)-4-benzyloxycarbonylamino-6-hydroxy-2,2-di-
methyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-5-carboxylate
1, a new member of this family of amino acids. Basic hydrolysis of 1
was accompanied by elimination of methanol. This allowed us to
access the first reported polyhydroxylated 5-aminocyclopent-1-
enecarboxylic acid and to develop a specific protocol for its incor-
poration into peptides.
4.1. 6-O-tert-Butyldiphenylsilyl-1,2-O-isopropylidene-3-O-
methyl-a-D-glucofuranose 6
Compound 5 (6.11 g, 26.08 mmol) was dissolved in dry DMF
(55 mL) and cooled to ꢀ20 °C. Imidazole (3.55 g, 52.26 mmol)
and TBDPSCl (6.8 mL, 26.13 mmol) were added and the mixture

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F. Fernández et al. / Tetrahedron: Asymmetry 21 (2010) 2021–2026
0
was stirred at room temperature for 1 h. The starting material had
been consumed (TLC, EtOAc/hexane 1:1) and the solvent was con-
centrated in vacuo. The residue was dissolved in EtOAc (30 mL) and
washed with H2O (3 ꢂ 50 mL). The organic layer was dried with
Na2SO4 and concentrated to dryness. The crude product was puri-
fied by flash column chromatography (EtOAc/hexane 1:5) to afford
4); 4.53 (d, 1H, JH,H = 11.2 Hz, CHPh); 4.54 (d, 1H, J2,1 = 3.9 Hz, H-
0
2); 4.70 (d, 1H, JH,H = 11.2 Hz, CHPh); 5.84 (d, 1H, J1,2 = 3.9 Hz, H-
1); 7.24–7.34 (m, 5H, 5 ꢂ H-ar). 13C NMR (CDCl3, ppm): 25.7;
26.2; 56.8; 61.6; 71.9; 75.5; 78.7; 80.5; 83.0; 104.5; 111.2;
127.3; 127.9; 137.9. IR (NaCl,
m/z, %): 325 (50, [M+H]+); 91 (100, [CH2Ph]+). Anal. Calcd for
C17H24O6: C, 62.95; H, 7.46. Found: C, 63.06; H, 7.61.
m
max, cmꢀ1): 3495 (br, OH). MS (CI,
compound
6
(10.76 g, 22.76 mmol, 87%) as
a
yellowish oil.
½
a 2D2
ꢃ
¼ ꢀ44:6 (c 1.1, CHCl3). 1H NMR (CDCl3, ppm): 1.07 (s, 9H,
3 ꢂ CH3); 1.31 (s, 3H, CH3); 1.41 (s, 3H, CH3); 2.87 (d, 1H,
JOH,5 = 7.0 Hz, OH); 3.41 (s, 3H, OCH3); 3.84–3.87 (m, 2H, H-3 + H-
5); 3.99–4.14 (m, 2H, H-6a + H-6b); 4.27 (dd, 1H, J4,5 = 7.9 Hz,
J4,3 = 3.0 Hz, H-4); 4.57 (d, 1H, J2,1 = 3.6 Hz, H-2); 5.89 (d, 1H,
J1,2 = 3.6 Hz, H-1); 7.34–7.41 (m, 6H, 6 ꢂ H-ar); 7.61–7.67 (m, 4H,
4 ꢂ H-ar). 13C NMR (CDCl3, ppm): 19.7; 26.0; 26.4; 26.6; 57.7;
65.2; 68.6; 78.9; 81.4; 84.0; 104.9; 111.3; 127.5; 127.6; 129.5;
4.4. 5-O-Benzyl-6-deoxy-6-iodo-1,2-O-isopropylidene-3-O-
methyl- -glucofuranose 9
a-D
Imidazole (1.16 g, 16.98 mmol), Ph3P (3.19 g, 12.26 mmol) and
I2 (3.13 g, 12.26 mmol) were added to a stirred solution of com-
pound 8 (1.53 g, 4.72 mmol) in toluene (17 mL) and the mixture
was stirred at 85 °C for 4 h. After the starting material had been
consumed (TLC, EtOAc/hexane 1:2) the reaction mixture was al-
lowed to cool down to room temperature, concentrated in vacuo
and then partitioned between CH2Cl2 (45 mL) and saturated aq
NaHCO3 (45 mL). The aqueous layer was extracted with CH2Cl2
(3 ꢂ 45 mL) and the resulting organic layer was dried with Na2SO4
and evaporated to dryness. The crude product was purified by flash
column chromatography (EtOAc/hexane 1:9) to afford compound 9
(1.84 g, 4.25 mmol, 90% yield), which was recrystallized from Et2O/
129.6; 132.6; 132.9; 135.3; 135.4. IR (NaCl, m
max, cmꢀ1): 3559 (br,
OH); 1115 (st, Si–O–C). MS (CI, m/z, %): 474 (8, [M+H]+); 339
t
(100, [MꢀHꢀ BuꢀPh]+). Anal. Calcd for C26H36O6Si: C, 66.07; H,
7.68. Found: C, 65.87; H, 7.99.
4.2. 5-O-Benzyl-6-O-tert-butyldiphenylsilyl-1,2-O-
isopropylidene-3-O-methyl-a-D-glucofuranose 7
To a suspension of NaH (1.47 g, 36.69 mmol, 60% dispersion in
mineral oil) in dry DMF (120 mL) at 0 °C was added dropwise a
hexane to give a white solid. Mp 62–64 °C. ½a D22
¼ ꢀ62:9 (c 1.0,
ꢃ
CHCl3). 1H NMR (CDCl3, ppm): 1.31 (s, 3H, CH3); 1.49 (s, 3H,
CH3); 3.36 (s, 3H, OCH3); 3.45–3.51 (m, 2H, H-5 + H-6b); 3.59
(dd, 1H, J6a,6b = 10.9 Hz, J6a,5 = 2.7 Hz, H-6a); 3.82 (d, 1H,
J3,4 = 3.0 Hz, H-3); 4.13 (dd, 1H, J4,5 = 8.5 Hz, J4,3 = 3.0 Hz, H-4);
solution of compound
6 (11.54 g, 24.46 mmol) in dry DMF
(130 mL). When the evolution of hydrogen had ceased, NBu4I
(1.18 g, 3.18 mmol) and BnBr (4.4 mL, 36.69 mmol) were added.
The mixture was allowed to warm up to room temperature and
then stirred at room temperature for 24 h. The starting material
had been consumed (TLC, EtOAc/hexane 1:5); MeOH (14 mL) was
added and the mixture was stirred for 1 h. The solvent was par-
tially removed in vacuo, Et2O was added and the mixture was fil-
tered through a pad of Celite. The solvent was evaporated to
dryness and the crude product was purified by flash column chro-
matography (EtOAc/hexane 1:8) to afford compound 7 (11.15 g,
0
4.46 (d, 1H, JH,H = 10.9 Hz, CHPh); 4.56 (d, 1H, J2,1 = 3.5 Hz, H-2);
0
4.74 (d, 1H, JH,H = 10.9 Hz, CHPh); 5.83 (d, 1H, J1,2 = 3.5 Hz, H-1);
7.31–7.37 (m, 5H, 5 ꢂ H-ar). 13C NMR (CDCl3, ppm): 10.7; 26.9;
27.4; 58.0; 72.2; 73.3; 81.7; 81.9; 83.5; 105.3; 112.5; 128.3;
128.5; 128.8; 130.0. IR (NaCl, m
max, cmꢀ1): no characteristic bands
MS (CI, m/z, %): 435 (100, [M+H]+); 91 (20, [CH2Ph]+). Anal. Calcd
for C17H23IO5: C, 47.02; H, 5.34. Found: C, 47.12; H, 5.28.
19.81 mmol, 81%) as a yellow oil: ½a D24
ꢃ
¼ ꢀ44:4 (c 1.0, CHCl3). 1H
4.5. 5-O-Benzyl-6-deoxy-1,2-O-isopropylidene-3-O-methyl-6-
nitro-a-D-glucofuranose 10
NMR (CDCl3, ppm): 1.05 (s, 9H, 3 ꢂ CH3); 1.29 (s, 3H, CH3); 1.53
(s, 3H, CH3); 3.34 (s, 3H, OCH3); 3.85–3.94 (m, 3H, H-3 + H-5 + H-
6b); 4.06 (dd, 1H, J6a,6b = 13.0 Hz, J6a,5 = 3.3 Hz, H-6a); 4.37 (dd,
1H, J4,5 = 9.1 Hz, J4,3 = 3.0 Hz, H-4); 4.55 (d, 1H, J2,1 = 3.6 Hz, H-2);
To a solution of compound 9 (2.85 g, 6.56 mmol) in dry DMSO
(45 mL) were added phloroglucinol (2.13 g, 13.11 mmol) and
NaNO2 (1.04 g, 15.08 mmol). The mixture was stirred at room tem-
perature for 96 h. The starting material had been consumed (TLC,
EtOAc/hexane 1:3) and the reaction mixture was partitioned be-
tween EtOAc (80 mL) and brine (80 mL). The aqueous layer was ex-
tracted with EtOAc (3 ꢂ 80 mL) and the combined organic layers
were dried with Na2SO4 and evaporated to dryness. The crude
product was purified by flash column chromatography (EtOAc/
hexane 1:2) to afford compound 10 (1.51 g, 4.26 mmol, 65%),
which was recrystallized from EtOAc/hexane. Mp 89–91 °C.
0
0
4.57 (d, 1H, JH,H = 11.2 Hz, CHPh); 4.86 (d, 1H, JH,H = 11.2 Hz,
CHPh); 4.87 (d, 1H, J1,2 = 3.6 Hz, H-1); 7.27–7.36 (m, 11H, 11 ꢂ H-
ar); 7.70–7.77 (m, 4H, 4 ꢂ H-ar). 13C NMR (CDCl3, ppm): 19.1;
26.1; 26.5; 26.7; 57.3; 64.1; 72.6; 76.6; 78.1; 80.9; 83.5; 105.1;
111.3; 127.3; 127.5; 127.6; 128.1; 129.4; 129.5; 133.3; 133.4;
135.5; 135.6; 138.6. IR (NaCl,
(CI, m/z, %): 564 (7, [M+H]+); 91 (100, [CH2Ph]+). Anal. Calcd for
33H42O6Si: C, 70.43; H, 7.52. Found: C, 70.29; H, 7.69.
m
max, cmꢀ1): 1105 (st, Si–O–C). MS
C
4.3. 5-O-Benzyl-1,2-O-isopropylidene-3-O-methyl-
a
-D
-
½
a 1D7
ꢃ
¼ ꢀ46:7 (c 1.0, CHCl3). 1H NMR (CDCl3, ppm): 1.30 (s, 3H,
glucofuranose 8
CH3); 1.46 (s, 3H, CH3); 3.37 (s, 3H, OCH3); 3.80 (d, 1H,
J3,4 = 3.0 Hz, H-3); 4.17 (dd, 1H, J4,5 = 7.6 Hz, J4,3 = 3.0 Hz, H-4);
4.52–4.78 (m, 6H, H-2 + H-5 + H-6a + H-6b + CH2Ph); 5.85 (d, 1H,
J1,2 = 3.9 Hz, H-1); 7.26–7.32 (m, 5H, 5 ꢂ H-Ar). 13C NMR (CDCl3,
ppm): 25.9; 26.5; 57.0; 73.2; 73.4; 77.3; 79.0; 80.6; 82.9; 104.7;
Compound 7 (5.70 g, 10.13 mmol) was dissolved in dry THF
(75 mL) and stirred with TBAF (20.3 mL, 20.3 mmol, 1 M solution
in THF) at room temperature for 17 h. The starting material had
been consumed (TLC, EtOAc/hexane 1:2) and the solvent was re-
moved under reduced pressure. The residue was dissolved in
CH2Cl2 (150 mL) and washed with H2O (3 ꢂ 150 mL). The organic
layer was dried with Na2SO4 and evaporated in vacuo. The crude
product was purified by flash column chromatography (EtOAc/
hexane 2:3) to afford compound 8 (3.19 g, 9.83 mmol, 97% yield)
111.8; 127.6; 127.8; 128.2; 137.1. IR (NaCl,
m
max, cmꢀ1): 1557,
1379 (st, NO2). MS (CI, m/z, %): 354 (23, [M+H]+); 91 (100,
[CH2Ph]+). Anal. Calcd for C17H23NO7: C, 57.78; H, 6.56; N, 3.96.
Found: C, 57.87; H, 6.57; N, 3.98.
4.6. 5-O-Benzyl-6-deoxy-3-O-methyl-6-nitro-D-glucono-1,4-
as a yellowish oil. ½a D22
ꢃ
¼ ꢀ35:7 (c 1.0, CHCl3). 1H NMR (CDCl3,
lactone 12
ppm): 1.28 (s, 3H, CH3); 1.38 (s, 3H, CH3); 2.83 (br s, 1H, OH);
3.31 (s, 3H, OCH3); 3.70–3.92 (m, 3H, H-5 + H-6a + H-6b); 3.81 (d,
1H, J3,4 = 3.0 Hz, H-3); 4.23 (dd, 1H, J4,5 = 8.5 Hz, J4,3 = 3.0 Hz, H-
Compound 10 (2.37 g, 6.73 mmol) was treated with a mixture
of TFA/H2O (1:1, 110 mL) and the mixture was stirred at room tem-

F. Fernández et al. / Tetrahedron: Asymmetry 21 (2010) 2021–2026
2025
perature for 15 h. The starting material had been consumed (TLC,
EtOAc/hexane 1:1). After the solvent was evaporated in vacuo
and the residue was coevaporated with toluene (3 ꢂ 50 mL) to give
the corresponding intermediate 12 as a clear gum, which was used
in the next step without further purification. This crude product
was dissolved in dioxane/H2O (2:1, 120 mL). BaCO3 (1.46 g,
7.40 mmol) and then Br2 (0.87 mL, 16.82 mmol) were added and
the reaction mixture was stirred for 15 h at room temperature with
the exclusion of light. After the starting material had been con-
sumed (TLC, EtOAc/hexane 3:2), the reaction was quenched with
saturated aq Na2S2O3 (until the mixture was colourless) and the
mixture was then extracted with EtOAc (3 ꢂ 200 mL). The com-
bined organic extracts were dried over Na2SO4 and evaporated to
dryness. The crude product was purified by flash column chroma-
tography (EtOAc/hexane 1:1) to afford compound 12 (1.67 g,
red at room temperature for 13 h. After the starting material had
been consumed (TLC, CH2Cl2/MeOH 15:1), the reaction mixture
was concentrated to dryness. The resulting residue was diluted
with CHCl3 (15 mL) and washed with brine (3 ꢂ 15 mL). The organ-
ic layer was dried over Na2SO4 and concentrated to dryness. The
crude product was purified by flash column chromatography
(EtOAc/hexane 1:1) to afford compound 16 (0.10 g, 0.27 mmol,
88% yield) as a colourless oil. ½a D23
ꢃ
¼ þ70:0 (c 1.0, CHCl3). 1H
NMR (CDCl3, ppm): 1.25 (s, 3H, CH3); 1.40 (s, 3H, CH3); 2.96–3.05
(m, 1H, H-1); 3.69 (s, 4H, OCH3 + OH); 4.39–4.44 (m, 1H, H-5);
4.51–4.53 (m, 1H, H-3); 4.55–4.57 (m, 1H, H-2); 4.66–4.69 (m,
0
1H, H-4); 5.07 (d, 1H, JH,H = 12.0 Hz, CHPh); 5.11 (d, 1H,
0
JH,H = 12.0 Hz, CHPh); 5.56 (m, 1H, NH); 7.28–7.34 (m, 5H, 5 ꢂ H-
ar). 13C NMR (CDCl3, ppm): 24.4; 26.0; 52.3; 55.8; 58.6; 67.0;
78.1; 84.3; 85.4; 112.1; 128.2; 128.5; 136.1; 155.5; 171.0. IR (NaCl,
5.36 mmol, 80% from 10) as a yellowish oil: ½a D25
ꢃ
¼ þ30:8 (c 1.4,
m
max, cmꢀ1): 3427 (br, NH + OH); 1727 (st, C@O); 1679 (st, N–C@O).
CHCl3). 1H NMR (CDCl3, ppm): 3.45 (s, 3H, OCH3); 3.87 (br s, 1H,
OH); 4.08–4.15 (m, 1H, H-5); 4.54–4.80 (m, 7H, H-2 + H-3 + H-
4 + H-6a + H-6b + CH2Ph); 7.23–7.35 (m, 5H, 5 ꢂ H-ar). 13C NMR
(CDCl3, ppm): 58.1; 71.2; 74.2; 74.6; 75.8; 78.1; 81.8; 128.0;
MS (CI, m/z, %): 366 (42, [M+H]+); 350 (77, [MꢀCH3]+); 91 (100,
[CH2Ph]+). Anal. Calcd for C18H23NO7: C, 59.17; H, 6.34; N, 3.83.
Found: C, 59.24; H, 6.15; N, 4.01.
128.1; 128.4; 136.4; 174.6. IR (NaCl,
m
max, cmꢀ1): 3443 (br, OH);
4.9. Methyl (3aR,4S,5S,6R,6aS)-4-benzyloxycarbonylamino-6-
methoxy-2,2-dimethyl-tetrahydro-3aH-
cyclopenta[d][1,3]dioxole-5-carboxylate 1
1793 (st, C@O); 1555, 1380 (st, NO2). MS (CI, m/z, %): 312 (8,
[M+H]+); 91 (100, [CH2Ph]+). Anal. Calcd for C14H17NO7: C, 54.02;
H, 5.50; N, 4.50. Found: C, 53.86; H, 5.75; N, 4.41.
A solution of compound 16 (0.03 g, 0.08 mmol) in CH3CN (1 mL)
was treated with MeI (0.08 mL, 1.31 mmol) and Ag2O (0.04 g,
0.18 mmol) and the mixture was stirred at 50 °C for 60 h. After
the starting material had been consumed (TLC, EtOAc/hexane
1:2) and the mixture was filtered through a pad of Celite and evap-
orated in vacuo. The crude product was purified by flash column
4.7. (1S,4S,5S,6R,7R)-6-Benzyloxy-7-methoxy-5-nitro-2-
oxabicyclo[2.2.1]heptan-3-one 2a
Compound 12 (0.26 g, 0.84 mmol) was dissolved in dry CH2Cl2
(8.5 mL) and the solution was then cooled down to ꢀ30 °C under
argon. Pyridine (0.2 mL, 2.53 mmol) and Tf2O (0.22 mL,
1.26 mmol) were added and the mixture was stirred at ꢀ30 °C
for 1 h. After the starting material had been consumed (TLC,
EtOAc/hexane 1:2), the reaction mixture was diluted with CH2Cl2
(30 mL), washed with 10% aq HCl (30 mL) and brine (30 mL). The
organic layer was dried over Na2SO4 and evaporated to dryness,
affording the corresponding intermediate 3a as a clear gum,
which was used in the next step without further purification after
storing it under vacuum overnight. Next, TBAF (0.92 mL, 1 M solu-
tion in THF) was added to a solution of the crude product obtained
above in THF (8.5 mL) and the resulting mixture was stirred under
argon for 12 h. The starting material had been consumed (TLC,
EtOAc/hexane 1:2). The solvent was evaporated and the residue
was dissolved in CH2Cl2 (30 mL). The solution was washed with
H2O (3 ꢂ 30 mL) and the organic layer was dried over Na2SO4
and evaporated to dryness. The crude product was purified by
flash column chromatography (EtOAc/hexane 1:4) to afford com-
pound 2a (0.09 g, 0.30 mmol, 36% from 12) as a yellow oil.
chromatography (EtOAc/hexane 1:2) to afford compound
1
(0.03 g, 0.08 mmol, 93% yield) as a colourless oil. ½a D17
¼ ꢀ13:6 (c
ꢃ
1.5, CHCl3). 1H NMR (CDCl3, ppm): 1.26 (s, 3H, CH3); 1.39 (s, 3H,
CH3); 2.94–2.97 (m, 1H, H-1); 3.40 (s, 3H, OCH3); 3.71 (s, 3H,
OCH3); 4.18–4.21 (m, 1H, H-2); 4.52–4.61 (m, 3H, H-3 + H-4 + H-
0
0
5); 5.07 (d, 1H, JH,H = 12.9 Hz, CHPh); 5.13 (d, 1H, JH,H = 12.9 Hz,
CHPh); 5.28 (br s, 1H, NH); 7.31–7.39 (m, 5H, H-ar). 13C NMR
(CDCl3, ppm): 24.0; 25.8; 51.7; 53.6; 57.1; 58.1; 66.3; 82.5; 83.6;
86.3; 112.0; 127.7; 127.8; 128.0; 136.0; 155.1; 170.5. IR (NaCl,
m
max, cmꢀ1): 3342 (br, NH); 1742 (st, C@O); 1630 (st, N–C@O).
MS (CI, m/z, %): 380 (74, [M+H]+); 244 (46, [MꢀCO2Bn]+); 91
(100, [CH2Ph]+). Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64; N,
3.69. Found: C, 59.94; H, 6.84; N, 3.60.
4.10. (3aR,4S,6aS,E)-4-benzyloxycarbonylamino-2,2-dimethyl-
4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-5-carboxylic acid
17
½
a 2D4
ꢃ
¼ ꢀ8:4 (c 1.2, CHCl3). 1H NMR (CDCl3, ppm): 3.23 (s, 3H,
To a solution of compound 1 (0.03 g, 0.08 mmol) in THF (0.8 mL)
was added 1 M aqueous NaOH (0.4 mL) and the mixture was stir-
red at room temperature for 2 h. After the starting material had
been consumed (TLC, EtOAc/hexane 1:3), the mixture was neutral-
ized with DOWEX 50W-X4, filtered and evaporated in vacuo. The
crude product was purified by flash column chromatography
(EtOAc/hexane 1:1) to afford compound 17 (0.024 g, 0.07 mmol,
OCH3); 3.98–4.00 (m, 1H, H-1); 4.10–4.12 (m, 1H, H-6); 4.48–
4.50 (m, 1H, H-7); 4.74–4.77 (m, 1H, H-4); 4.76 (d, 1H,
0
0
JH,H = 12.0 Hz, CHPh); 4.84 (d, 1H, JH,H = 12.0 Hz, CHPh); 4.95–
4.98 (m, 1H, H-5); 7.30–7.43 (m, 5H, 5 ꢂ H-ar). 13C NMR (CDCl3,
ppm): 49.8; 57.5; 72.3; 79.8; 82.0; 83.4; 84.4; 127.8; 128.1;
128.4; 136.5; 169.3. IR (NaCl, m
max, cmꢀ1): 1805 (st, C@O); 1555,
1381 (st, NO2). MS (CI, m/z, %): 294 (11, [M+H]+); 91 (100,
[CH2Ph]+). Anal. Calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78.
Found: C, 57.15; H, 5.18; N, 4.53.
90% yield) as a clear oil. ½a D24
ꢃ
¼ ꢀ12:6 (c 1.8, CHCl3). 1H NMR
(CDCl3, ppm): 1.20 (s, 3H, CH3); 1.32 (s, 3H, CH3); 4.65–4.79 (m,
2H, H-3 + H-4); 4.86–4.93 (br s, 1H, H-5); 5.04 (d, 1H,
0
0
JH,H = 12.2 Hz, CHPh); 5.15 (d, 1H, JH,H = 12.2 Hz, CHPh); 5.73 (br
s, 1H, NH); 6.60 (s, 1H, H-2); 7.28–7.41 (m, 5H, H-ar); 11.15 (br
s, 1H, CO2H). 13C NMR (CDCl3, ppm): 24.3; 25.6; 52.9; 68.1; 83.5;
84.2; 112.6; 127.9; 128.0; 128.2; 136.2; 137.9; 142.6; 154.8;
4.8. Methyl (3aR,4S,5S,6R,6aS)-4-benzyloxycarbonylamino-6-
hydroxy-2,2-dimethyl-tetrahydro-3aH-
cyclopenta[d][1,3]dioxole-5-carboxylate 16
169.2. IR (NaCl, m
max, cmꢀ1): 3328 (br, NH); 1725 (st, C@O); 1636
Compound 15 (0.10 g, 0.31 mmol) was dissolved in dry acetone
(3 mL). MgSO4 (0.11 g, 0.91 mmol), 2,2-DMP (4.6 mL, 37.41 mmol)
and p-TSA (catalytic amount) were added and the mixture was stir-
(st, N–C@O). MS (CI, m/z, %): 334 (15, [M+H]+); 242 (59,
[MꢀCH2Ph]+); 91 (100, [CH2Ph]+). Anal. Calcd for C17H19NO6: C,
61.25; H, 5.75; N, 4.20. Found: C, 61.47; H, 5.91; N, 4.10.

2026
F. Fernández et al. / Tetrahedron: Asymmetry 21 (2010) 2021–2026
4.11. Methyl (3aR,4S,5S,6R,6aS)-4-benzyloxycarbonylgly-
cylamino-6-methoxy-2,2-dimethyl-tetrahydro-3aH-cyclope-
nta[d][1,3]dioxole-5-carboxylate 20
CH3); 1.40 (s, 3H, CH3); 3.68 (s, 3H, OCH3); 3.75–3.90 (m, 4H, H-
30 + H-40 + CH2-Gly); 4.08–4.26 (m, 2H, CH2-Gly); 4.56–4.60 (m,
1H, H-50); 5.09 (br s, 2H, CH2Ph); 5.15 (br s, 1H, NH); 5.27 (br s,
1H, NH); 5.74 (br s, 1H, NH); 6.71 (s, 1H, H-20); 7.29–7.41 (m,
5H, H-ar). 13C NMR (CDCl3, ppm): 25.6; 27.3; 41.1; 44.5; 52.4;
58.9; 67.2; 83.1; 84.7; 111.9; 128.0; 128.3; 128.5; 136.0; 138.4;
To a degassed solution of compound 1 (0.05 g, 0.13 mmol) in
EtOAc (1.5 mL) was added 10% Pd/C (0.05 g, 10% w/w) and the mix-
ture was stirred under hydrogen at room temperature for 2 h. After
the starting material had been consumed (TLC, EtOAc/hexane 1:3),
the mixture was filtered through a pad of Celite and concentrated
to dryness. The crude amine 19 was dissolved in CH2Cl2 (1 mL) and
added to a solution of Cbz-Gly-OH (0.036 g, 0.17 mmol), TBTU
(0.055 g, 0.17 mmol) and DIEA (0.07 mL, 0.40 mmol) in CH2Cl2
(1 mL) and the mixture was stirred under argon at room tempera-
ture for 12 h. After the starting material had been consumed (TLC,
CH2Cl2/MeOH 9:1), the mixture was diluted with CH2Cl2 (5 mL)
and washed with 10% aq HCl (10 mL), saturated aq NaHCO3
(10 mL) and brine (10 mL). The organic layer was dried over
Na2SO4 and concentrated to dryness. The crude product was puri-
fied by flash column chromatography (EtOAc/hexane 1:1) to afford
compound 20 (0.051 g, 0.116 mmol, 88% from 1) as a colourless oil.
141.2; 156.7; 163.6; 170.3; 170.4. IR (NaCl, m
max, cmꢀ1): 3310 (br,
NH); 1725 (st, C@O); 1664 (st, N–C@O); 1535 (st, N–C@O). MS
i
(CI, m/z, %): 462 (9, [M+H]+); 296 (10, [MꢀCH2Phꢀ PrO2]+); 91
(100, [CH2Ph]+). Anal. Calcd for C22H27N3O8: C, 57.26; H, 5.90; N,
9.11. Found: C, 57.49; H, 6.15; N, 9.27.
Acknowledgements
We thank the Spanish Ministry of Science and Innovation for
financial support (CTQ2009-08490) and for an F.P.U. grant to Fer-
nando Fernández Nieto.
References
a 1D5
ꢃ
¼ ꢀ19:2 (c 1.3, CHCl3). 1H NMR (CDCl3, ppm): 1.24 (s, 3H,
1. (a) Perlow, D. S.; Paleveda, W. J.; Colton, C. D.; Zacchei, A. G.; Tocco, D. J.; Hoff,
D. R.; Vandlen, R. L.; Gerich, J. E.; Hall, L.; Mandarino, L.; Cordes, E. H.; Anderson,
P. S.; Hirschmann, R. Life Sci. 1984, 34, 1371; (b) Veber, D. F.; Freidinger, R. M.
Trends Neurosci. 1985, 392; (c) Stein, W. D. The Movement of Molecules Across
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2. (a) Creighton, T. E. Proteins: Structures and Molecular Properties, 2nd ed.;
Freeman: New York, 1993; (b) Spatola, A. F. In Chemistry and Biochemistry of
Amino Acids, Peptides and Proteins; Weinstein, B., Ed.; Dekker: New York, 1983;
Vol. 7, p 267; (c) Latham, P. W. Nat. Biotechnol. 1999, 17, 755.
3. (a) Patch, J. A.; Barron, A. E. Curr. Opin. Chem. Biol. 2002, 6, 872; (b) Cheng, R. P.;
Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219; (c) Seebach, D.;
Hook, D. F.; Glattli, A. Biopolymers 2006, 84, 23; (d) Goodman, C. M.; Choi, S.;
Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252.
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Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893; (c) Fülöp, F.; Martinek, T.
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½
CH3); 1.37 (s, 3H, CH3); 2.90 (br s, 1H, H-1); 3.38 (s, 3H, OCH3);
0
3.71 (s, 3H, OCH3); 3.84 (d, 2H, JH,H = 5.5 Hz, CH2-Gly); 4.20–4.25
(m, 1H, H-2); 4.48–4.58 (m, 2H, H-3 + H-4); 4.78–4.88 (m, 1H, H-
5); 5.13 (br s, 2H, CH2Ph); 5.43 (br s, 1H, NH); 6.58 (d, 1H,
JNH,5 = 7.7 Hz, NH); 7.30–7.42 (m, 5H, H-ar). 13C NMR (CDCl3,
ppm): 24.1; 25.7; 44.3; 52.1; 53.5; 56.6; 57.4; 67.0; 82.8; 84.0;
86.7; 112.0; 127.9; 128.1; 128.4; 136.0; 156.5; 168.8; 170.3. IR
(NaCl, m
max, cmꢀ1): 3307 (br, NH); 1720 (st, C@O); 1653 (st, N–
C@O); 1530 (st, N–C@O). MS (CI, m/z, %): 437 (60, [M+H]+); 379
i
(74, [Mꢀ PrO]+); 91 (100, [CH2Ph]+). Anal. Calcd for C21H28N2O8:
C, 57.79; H, 6.47; N, 6.42. Found: C, 57.60; H, 6.25; N, 6.17.
5. (a)Enantioselective Synthesis of b-Amino Acids; Juaristi, E., Soloshonok, V. A., Eds.;
Wiley-Interscience: New York, 2005; (b) Ortuño, R. M.; Moglioni, A. G.;
Moltrasio, G. Y. Curr. Org. Chem. 2005, 9, 237; (c) Davies, S. G.; Smith, A. D.;
Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833; (d) Miller, J. A.; Nguyen, S. T.
Mini-Rev. Org. Chem. 2005, 2, 39.
4.12. Methyl 2-((3aR,4S,6aS,E)-4-(2-(benzyloxycarbonyl-
glycylamino)acetamido)-2,2-dimethyl-4,6a-dihydro-3aH-
cyclopenta[d][1,3]dioxole-5-carbamido)acetate 22
6. (a) Fernández, F.; Estévez, A. M.; Estévez, J. C.; Estevez, R. J. Tetrahedron:
Asymmetry 2009, 20, 892; (b) Fernández, F.; Estévez, J. C.; Sussman, F.; Estévez,
R. J. Tetrahedron: Asymmetry 2008, 19, 2907; (c) Otero, J. M.; Soengas, R. G.;
Estévez, J. C.; Estévez, R. J.; Watkin, D.; Evinson, E. L.; Nash, R. J.; Fleet, G. W. J.
Org. Lett. 2007, 9, 623; (d) Otero, J. M.; Fernández, F.; Estévez, J. C.; Estévez, R. J.
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Soengas, R. G.; Estévez, J. C.; Estévez, R. J.; Maestro, M. A. Tetrahedron:
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Compound 20 (0.051 g, 0.116 mmol) was dissolved in THF
(1.2 mL) and treated with 1 M aq NaOH (0.6 mL) at room temper-
ature for 2 h. The starting material had been consumed (TLC,
EtOAc/hexane 1:1) and the mixture was neutralized with DOWEX
50W-X4, filtered and evaporated in vacuo. The resulting crude
unsaturated carboxylic acid 21 was dissolved in CH2Cl2 (2 mL)
and reacted with TBTU (0.049 g, 0.152 mmol) and DIEA (0.06 mL,
0.35 mmol) under argon at room temperature. After 15 min H-
Gly-OMe-HCl (0.019 g, 0.152 mmol) was added and the mixture
stirred for a further 12 h. After complete consumption of the start-
ing material (TLC, EtOAc), the reaction mixture was diluted with
CH2Cl2 (5 mL) and washed with 10% aq HCl (10 mL), saturated aq
NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried
over Na2SO4 and evaporated to dryness. The crude product was
purified by flash column chromatography (EtOAc) to afford com-
pound 22 (0.035 g, 0.076 mmol, 65% from 20) as a colourless oil.
12. Greene, A. E.; Drian, C. L.; Crabbe, P. J. Am. Chem. Soc. 1980, 102, 7583.
½
a 1D6
ꢃ
¼ ꢀ10:3 (c 1.1, CHCl3). 1H NMR (CDCl3, ppm): 1.32 (s, 3H,