Pyranocyclopropanyl sugar amino acids, a new class of constrained (di)peptide isosteres

Article abstract of DOI:10.1016/j.tetasy.2009.03.009

The design, synthesis and application of oxabicyclo[4.1.0]heptane amino acids as conformationally restricted sugar amino acid dipeptide isosteres are reported.

Full text of DOI:10.1016/j.tetasy.2009.03.009

Tetrahedron: Asymmetry 20 (2009) 945–951
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Tetrahedron: Asymmetry
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Pyranocyclopropanyl sugar amino acids, a new class of constrained
(di)peptide isosteres
*
Martijn D. P. Risseeuw, Gijs A. van der Marel, Herman S. Overkleeft, Mark Overhand
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The design, synthesis and application of oxabicyclo[4.1.0]heptane amino acids as conformationally
restricted sugar amino acid dipeptide isosteres are reported.
Received 24 February 2009
Accepted 4 March 2009
Available online 6 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
On the occasion of the 65th birthday of
Professor George Fleet
1. Introduction
2. Results and discussion
Sugar amino acids (SAAs) are hybrid structures with elements
from both carbohydrates and amino acids embedded in their struc-
ture.1 They are used to construct both peptidomimetics and
glycomimetics and the resulting oligomers2 are subjected to con-
formational analysis, biological activity assays or both.3 Peptidom-
imetics can be obtained by incorporation of a specific SAA in an
oligopeptide sequence at a predesigned position whereas glycom-
imetics are accessed by the assembly of oligomers composed of
SAA monomers exclusively. Carbohydrates constitute a highly
diverse class of compounds with numerous structural and configu-
rational variations. They are often relatively inexpensive and offer
ample synthetic potential to create carbohydrate-derived com-
pounds with desirable functionalities. These combined properties
are the basis of the extensive literature on the synthesis and appli-
cation of SAAs in carbohydrate and peptide chemistries.4 An attrac-
tive feature of carbohydrates as a starting point in amino acid
design is the potential to adapt the functional groups inherent to
the parent saccharide and that remain after installment of the
amine and carboxylate groups. Alkylation of SAA hydroxy groups1,4
may tune solubility and conformational behavior or bring desirable
pharmacophores to a predetermined site in oligomers assembled
from them. In a specific class of SAAs and the subject of this paper,
the functional diversity of monosaccharides is utilized to introduce
added conformational constraint through the annulation of an
extra ring.
We5 and others6 have reported on the design of dioxabicy-
clo[3.3.0]octane SAAs, dioxabicyclo[3.2.0]heptane SAAs, dioxabicy-
clo[3.2.1]heptane SAAs, dioxabicyclo[4.4.0]decane SAAs as well as
spiro-furanofuran SAAs. A logical extension of these series is the
oxabicyclo[4.1.0]heptane SAAs and oxabicyclo[3.1.0]hexane SAAs,
especially when taking into account the literature precedent7 on
the efficient and often asymmetric cyclopropanations one can per-
form on glycals derived from furanoses and pyranoses. Several
groups have reported on the rhodium(II)-catalyzed cyclopropana-
tion of protected D-glucal with ethyl diazoacetate and we consid-
ered this reaction as a good starting point in the generation of
oxabicyclo[4.1.0]heptane SAAs as a new class of carbohydrate-de-
rived d amino acids. Both benzyl and silyl protective groups are
reportedly compatible with these conditions. Indeed, when we
treated 1,2-anhydro-3,4-tri-O-benzyl-6-O-(tert)butyldimethylsi-
lyl-D
-glucose 18 with ethyl diazoacetate and Rh2OAc4 (5 mol %,
Scheme 1) in methylene chloride we obtained alpha-exo ester 2
as an inseparable mixture of two diastereoisomers. The configura-
tion of these could not be established at this stage, but proton NMR
indicated the presence of a major isomer in a ratio of about 10:1.
Fluoride-mediated removal of the silyl protective group proceeded
uneventfully and at this stage the mixture of diastereomers was
readily separated by silica gel chromatography. The major stereo-
mer (58% over the two steps) was determined by NMR spectros-
copy as the alpha-exo derivative 3, the expected stereoisomer
considering the literature data on the rhodium(II)-catalyzed cyclo-
propanation of perbenzylated or persilylated glucal with ethyl
diazoacetate.9 Mitsunobu reaction of 3 with hydrazoic acid (tri-
phenylphosphine, diethylazodicarboxylate, toluene, 85% yield) fol-
lowed by saponification of the ester (LiOH, dioxane, 82% yield) gave
azido-acid 6 in four steps with an overall yield of 40% based on glu-
cal 1.
* Corresponding author.
E-mail address: overhand@chem.leidenuniv.nl (M. Overhand).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.009

946
M. D. P. Risseeuw et al. / Tetrahedron: Asymmetry 20 (2009) 945–951
OH
O
O
O
O
O
TBDMSO
TBDMSO
BnO
ii
HO
BnO
i
O
BnO
BnO
+
OEt
BnO
OEt
O
OBn
OBn
OBn
OEt
2
1
3
4
iii
H
H
H
H
O
O
O
O
N3
N3
BnO
iv
OH
OEt
BnO
OBn
OBn
6
5
Scheme 1. Reagents and conditions: (i) Ethyl diazoacetate, Rh2OAc4 (5 mol %), CH2Cl2; (ii) TBAF, THF (3 58%, 4 8%, two steps); (iii) HN3, PPh3, DEAD, toluene (85%); (iv) LiOH,
dioxane (82%).
H
H
H
H
O
O
O
O
TBDMSO
i
TBDMSO
ii
OEt
OH
3
BnO
BnO
OBn
OBn
7
8
iii
O
H
H
H
O
O
TBDMSO
iv,v
HO
BnO
NHBoc
NHBoc
BnO
H
OBn
OBn
9
10
Scheme 2. Reagents and conditions: (i) TBDMSCl, imidazole, DMF (95%); (ii) LiOH, dioxane (79%); iii) DPPA, Et3N, tBuOH
D (72%); (iv) TBAF, THF (95%); (v) 2 equiv H2CrO4
(1 M), acetone (86%).
In an alternative strategy, resilylation of the enantiopure oxabi-
cyclo[4.1.0]heptane 3 (TBDMSCl, imidazole, dioxane, 95%, Scheme
2) opened the way to the synthesis of the inversed (relative to 6)
SAA 10 featuring a Curtius rearrangement as the key step. Saponi-
fication of fully protected compound 7 (LiOH, dioxane) gave car-
boxylate 8 in 79% yield. Treatment of 8 with diphenylphosphoryl
azide and triethylamine in tert-butyl alcohol at reflux gave with
retention of configuration, secondary amine 9 in 72% yield. Elabo-
ration of the primary alcohol in 9 (TBAF-mediated desilylation fol-
lowed by Jones oxidation) gave a second oxabicyclo[4.1.0]heptane
SAA 10 in 80% yield over the last two steps.
Both bicyclo-SAA entities were next subjected to a sequence of
homo-oligomerization reactions to arrive at two tetrameric gly-
comimetics 13 (Scheme 3) and 17 (Scheme 4). Selective reduction
of azide in 5 (Lindlar’s catalyst, ethanol) followed by condensation
(HATU, DiPEA, DMF) with carboxylate 6 gave fully protected dimer
11 (74%, two steps, Scheme 3). Lindlar reduction of the azide in 11
gave amine 12a whereas saponification of the ester in 11 gave car-
boxylate 12b, both in good yield. Condensation of 12a and 12b fi-
nally gave tetramer 13, which was purified to homogeneity by
HPLC (13% yield).
over the two steps based on 10. Removal of the Boc-protective
group in one portion of 10 to give 16a (TFA, DCM) and removal
of the ester group in another portion of 10 gave 16b employing tri-
methyltin hydroxide as the base in ethylene chloride (as this re-
agent gave the best yield, 95%).10 Compounds 16a and 16b were
condensed to give tetrasaccharide mimic 17 in 18% yield after
HPLC purification.
3. Conclusion
The NMR analysis of the purified tetramers revealed the pres-
ence of a single product in both examples and we can conclude
that both oxabicyclo[4.1.0]heptanes SAAs 6 and 10 can be sub-
jected to condensation reactions inherent to peptide chemistry
without unexpected complications. Our strategy should be readily
transposable to glycals derived from other pyranoses and likely
also furanoses, thus bringing
a whole panel of oxabicy-
clo[4.1.0]heptane SAAs and oxabicyclo[3.1.0]hexane SAAs for
installment in both peptidomimetics and glycomimetics within
reach.
For the construction of tetramer 17, a sample of acid 10 was
esterified (TMS–diazomethane, methanol, toluene, 99%) to give
the fully protected oxabicyclo[4.1.0]heptane 14. Removal of the
tert-butyloxycarbonyl group in 14 (trifluoroacetic acid, methylene
chloride) and subsequent condensation of the resulting TFA–amine
salt with 10 (HATU, DiPEA, DCM, DMF) gave dimer 15 in 68% yield
4. Experimental
4.1. General
Solvents and reagents were used as provided. Analysis of linear-
protected tetramers was performed on a Jasco HPLC-system

M. D. P. Risseeuw et al. / Tetrahedron: Asymmetry 20 (2009) 945–951
947
O
H
H
O
O
N
H
O
i, ii
R1
BnO
H
5
OR2
BnO
H
OBn
BnO
= N3, R2 = Et
1
11
R
iii
12a R1 = NH2, R2 = Et
12b R1 = N3, R2 = H
iv
v
O
H
H
H
O
O
O
N
H
O
H
R3O
NH
R3O
HN
H
OR3
OR3
O
H
H
R3O
O
H
O
OR3
13
R3O
R1
R3O
OR2
Scheme 3. Reagents and conditions: (i) H2, Lindlar’s cat. EtOH; (ii) 6, HATU, DIPEA, DMF (74%, two steps); (iii) H2, Lindlar’s cat. EtOH; (iv) LiOH, dioxane (76%); (v) HATU,
DIPEA, DMF (13%, two steps). R1 = N3, R2 = Et, R3 = Bn.
O
O
H
H
H
H
O
O
R1
RO
NHBoc
N R2
H
ii
BnO
BnO
OBn
OBn
2
10
14
R = OMe, R2 = Boc
R = H
1
15
i
iii
R = Me
iv
16a R1 = OMe, R2 = H
16b R1 = OH, R2 = Boc
v
O
O
O
O
H
H
H
O
H
O
O
H
H
R1
R3O
O
N
H
N
N
NHR2
H
H
R3O
R3O
H
R3O
H
OR3
OR3
OR3
OR3
17
Scheme 4. Reagents and conditions: (i) TMS–diazomethane, methanol, toluene (quant.); (ii) first TFA/DCM (1:1 v/v) then 10, HATU, DIPEA DCM, DMF (68%); (iii) TFA/DCM
(1:1 v/v); (iv) Me3SnOH ClCH2CH2Cl (95%); (v) HATU, DIPEA DCM, DMF R1 = OMe, R2 = Boc, R3 = Bn (19%).
(detection simultaneously at 214 nm) coupled to a Perkin Elmer
Sciex API 165 mass instrument with a custom-made Electronspray
Interface (ESI). An analytical Alltima CN column (Alltech,
a ‘lock mass’. The high resolution mass spectrometer was cali-
brated prior to measurements with a calibration mixture (Ther-
mo Finnigan).
150 Â 4.6 mm, 5
lm) was used in combination with buffers A:
H2O, B: MeCN, and C: 1.0% TFA in H2O.
4.1.1. (1S,3R,4S,5R,6S,7S)-Ethyl 4,5-bis(benzyloxy)-3-hydroxy-
methyl)-2-oxabicyclo[4.1.0]heptane-7-carboxylate 3
NMR spectra were recorded on a Bruker DMX600 using deuter-
ated solvents. All carbon spectra are proton-decoupled. CD3OH was
used as provided. Chemical shifts (d) are given in ppm, relative to
the solvent peak of CD3OH; 3.31 ppm in 1H spectra, 49.0 ppm in
13C spectra. Coupling constants are given in hertz.
IR spectra were recorded on a Perkin Elmer Paragon 1000 FT-IR
Spectrometer.
High resolution mass spectra were recorded by direct injec-
tion (2 lL of a 2 lM solution in water/acetonitrile; 50/50; v/v,
and 0.1% formic acid) on a mass spectrometer (Thermo Finnigan
LTQ Orbitrap) equipped with an electro spray ion source in posi-
tive mode (source voltage 3.5 kV, sheath gas flow 10, capillary
temperature 250 °C) with resolution R = 60,000 at m/z 400 (mass
range m/z = 150–2000) and dioctylphthalate (m/z = 391.28428) as
Compound 17 (9.7 g, 22.0 mmol) was coevaporated with toluene
(2 Â 50 mL), taken up in CH2Cl2 (250 mL) and Rh2OAc4 (200 mg,
0.45 mmol) was added. The solution was placed under an argon
atmosphere. Under vigorous stirring ethyl diazoacetate (7.0 mL,
7.5 g, 66 mmol) was added slowly over 6 h. Stirring was continued
for an hour after which the mixture was filtered and concentrated
in vacuo. The residue was purified by silica gel chromatography
(0?15% EtOAc in light petroleum). This yielded product 2 contam-
inated with a minor stereoisomer and considerable amounts of
diethyl fumarate. This mixture was taken up in THF (250 mL) and
tetrabutylammonium fluoride (22 mL, 1 M in THF) was added after
which the mixture was stirred for 2 h. The reaction mixture was
diluted with ethyl acetate (400 mL) and washed with water

948
M. D. P. Risseeuw et al. / Tetrahedron: Asymmetry 20 (2009) 945–951
(3 Â 300 mL) and saturated aqueous NaCl. The organic layer was
dried on Na2SO4 and concentrated in vacuo. Purification of the res-
idue by silica gel chromatography (0?30% EtOAc in light petro-
leum) yielded the product 3 as an oil (5.28 g, 12.8 mmol, 58% two
steps) and minor amounts (0.363 g, 0.88 mmol, 4%) of a stereoiso-
mer of undetermined configuration. 1H NMR (CDCl3): d 1.23 (t,
3H, J = 10.8 Hz), 1.80 (m, 1H), 2.00 (m, 1H), 2.59 (b, 1H), 3.49 (m,
1H), 3.65 (m, 1H), 3.78 (m, 2H), 3.95 (dd, 1H, J = 2.4 Hz, J = 7.6 Hz),
4.09 (q, 2H, J = 7.2 Hz), 4.54–4.73 (m, 4H), 7.20–7.31 (m, 10H). 13C
NMR (CDCl3): d 13.95, 23.32, 23.86, 57.64, 60.49, 61.66, 71.26,
73.21, 74.36, 75.12, 76.25, 127.53, 127.58, 127.63, 128.15, 128.22,
137.43, 137.77, 171.43. Exact mass calculated for (C24H28
[a]
D = +54.8 (c 1.0, CHCl3). IR = cmÀ1 2870 (w), 2360 (w), 2095
(vs), 1685 (vs), 1455 (m), 1280 (bm), 1090 (s), 525 (vs).
4.1.4. (1S,3R,4S,5R,6S,7S)-Ethyl 4,5-bis(benzyloxy)-3-((tert-
butyldimethylsilyloxy)methyl)-2-oxabicyclo[4.1.0]heptane-7-
carboxylate 7
Compound 3 (2.1 g, 5.1 mmol) was coevaporated with toluene
(2 Â 20 mL) and taken up in DMF (50 mL). To the solution were
added imidazole (0.48 g, 7.0 mmol) and tert-butylchlorodimeth-
ylsilane (0.845 g, 5.6 mmol) and the mixture was stirred under
an argon atmosphere for 1 h. The reaction mixture was diluted
with diethyl ether (200 mL) and washed with water (3 Â 100 mL)
and saturated aqueous NaCl (100 mL). The organic layer was dried
on Na2SO4 and concentrated in vacuo. Chromatography of the res-
idue (0?15% EtOAc in light petroleum) yielded the product 7
(2.55 g, 4.85 mmol, 95%) as a colorless oil. 1H NMR (CDCl3): d
0.08 (2 Â s, 6H), 0.93 (s, 9H), 1.27 (t, 3H, J = 7.2 Hz), 1.80 (m, 1H),
1.95 (m, 1H), 3.56 (m, 1H), 3.69 (t, 1H, J = 6.8 Hz), 3.77 (m, 2H),
3.86 (dd, 1H, J = 4.4 Hz, J = 10.8 Hz), 4.14 (m, 2H), 4.63–4.82 (m,
4H), 7.29–7.38 (m, 10 H). 13C NMR (CDCl3): d À5.47, À5.33,
14.18, 18.21, 24.91, 25.03, 25.84, 57.81, 60.58, 62.57, 71.44,
73.54, 75.07, 76.51, 77.17, 127.65, 127.71, 127.85, 128.33, 128.38,
137.83, 138.27, 171.60. Exact mass calculated for (C30H43O6S-
O6 + H)+ = 413.19587, mass found: 413.19583. [
a]D = +20 (c 1.0,
CHCl3). IR = cmÀ1 3500 (wb), 2870 (w), 1718 (vs), 1180 (m), 1090
(s), 530 (vs).
4.1.2. (1S,3R,4S,5R,6S,7S)-Ethyl 3-(azidomethyl)-4,5 bis(benzyl-
oxy)-2-oxabicyclo[4.1.0]heptane-7-carboxylate 5
Hydrazoic acid solution (Caution: HN3 is volatile, highly toxic,
and explosive!): Sodium azide (4.0 g, 61.5 mmol) was dissolved
in water (10 mL). Toluene (50 mL) was added and the resulting bi-
phasic system was cooled on ice to 0 °C. Under vigorous stirring,
concentrated sulfuric acid (8 mL) was added dropwise. After
30 min of stirring, the organic layer was separated and stored on
anhydrous Na2SO4.
i + H)+ = 527.28234, mass found: 527.28226. [
a]D = +25.4 (c 1.0 in
CHCl3). IR = cmÀ1 2930 (w), 2855 (w), 2360 (w), 2340 (w), 1718
(vs), 1120 (s), 1090 (s), 835 (vs), 530 (vs).
Compound 3 (2.4 g, 5.8 mmol) was coevaporated with toluene
(2 Â 20 mL) and taken up in toluene (60 mL). To the reaction mix-
ture were added triphenylphosphine (3.0 g, 11.6 mmol), diethyl-
azodicarboxylate (5.3 mL 40% in toluene, 11.6 mmol), and 5 mL of
the freshly prepared hydrazoic acid stock solution. Stirring was
continued for 1 h during which the appearance of the reaction mix-
ture shifted from clear and bright yellow to turbid and colorless.
The mixture was concentrated in vacuo and the residue was puri-
fied by silica gel chromatography (0?15% EtOAc in light petro-
leum). This provided the product 5 (2.04 g, 4.9 mmol, 85%) as an
oil. 1H NMR (CDCl3): d 1.24 (t, 3H, J = 7.2 Hz), 1.83 (m, 1H), 2.01
(dd, 1H, J = 2 Hz, J = 5.6 Hz), 3.28 (dd, 1H, J = 3.6 Hz, J = 13.2 Hz),
3.45 (t, 1H, J = 6.0 Hz), 3.52 (m, 1H), 3.62 (m, 1H), 3.80 (dd, 1H,
J = 5.2 Hz), 3.94 (dd, 1H, J = 1.6 Hz, J = 7.2 Hz), 4.12 (m, 2H), 4.56
(d, 2H, J = 11.6 Hz), 4.71 (dd, 2H, J = 2.4 Hz, J = 11.2 Hz), 7.20–7.36
(m, 10H). 13C NMR (CDCl3): d 14.07, 23.70, 23.86, 51.13, 57.04,
60.65, 71.36, 73.17, 73.24, 75.09, 75.32, 127.64, 127.77, 128.32,
128.37, 137.38, 137.56, 171.30. Exact mass calculated for (C24H27N3
4.1.5. (1S,3R,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-3-((tert-butyl
dimethylsilyloxy)methyl)-2-oxabicyclo[4.1.0]heptane-7-
carboxylic acid 8
Compound 7 (2.3 g, 4.4 mmol) in THF (50 mL) was treated with
aqueous LiOH (4.5 mL, 4 M). Stirring was continued for 16 h. The
mixture was neutralized by the addition of amberlite IR-120 (H+
form) resin. The resin was removed by filtration and the filtrate
was diluted with ethyl acetate (100 mL). The solution was washed
with 10% aqueous citric acid (2 Â 50 mL) and saturated aqueous
NaCl (50 mL). The organic layers were dried on Na2SO4 and concen-
trated in vacuo. Chromatography on silica gel (0? 100% [1% HOAc
in EtOAc] in light petroleum) yielded the product 8 (1.74 g,
3.48 mmol, 79%) as a colorless syrup. 1H NMR (CDCl3): d 0.12
(2 Â s, 6H), 0.98 (s, 9H), 1.89 (m, 1H), 1.99 (m, 1H), 3.61 (m, 1H),
3.73 (t, 1H, J = 6.8 Hz), 3.80 (m, 2H), 3.89 (dd, 1H, J = 4.4 Hz,
J = 11.2 Hz), 4.07 (dd, 1H, J = 1.4 Hz, J = 7.2 Hz), 4.66–4.84 (m, 4H),
7.32–7.43 (m, 10 H). 13C NMR (CDCl3): d À5.46, À5.33, 18.21,
24.86, 25.84, 58.44, 62.57, 71.51, 73.53, 74.88, 76.41, 76.81,
127.68, 127.74, 127.78, 127.85, 128.08, 128.33, 128.40, 137.69,
138.16, 177.81. Exact mass calculated for (C28H38O6S-
O6 + H)+ = 438.20235, mass found: 438.20226. [
a]D = +43.4 (c 1.0,
CHCl3). IR = cmÀ1 2870 (w), 2095 (vs), 1720 (vs), 1280 (bm), 1180
(m), 1090 (s), 530 (vs).
4.1.3. (1S,3R,4S,5R,6S,7S)-3-(Azidomethyl)-4,5-bis(benzyloxy)
2-oxabicyclo[4.1.0]heptane-7-carboxylic acid 6
i + H)+ = 499.25104, mass found: 499.25104. [
a]D = +21.8 (c 1.0,
CHCl3). IR = cmÀ1 2930 (w), 2855 (w), 1690 (vs), 1455 (s), 1255
(m), 1090 (vs), 835 (vs).
Compound 5 (1.81 g, 4.14 mmol) in THF (50 mL) was treated
with aqueous LiOH (4.0 mL, 4.0 M). Stirring was continued for
16 h. The mixture was neutralized by the addition of amberlite
IR-120 (H+ form) resin. The resin was removed by filtration and
the filtrate was diluted with ethyl acetate (100 mL). The solution
was washed with 1 M HCl (2 Â 50 mL) and saturated aqueous NaCl
(50 mL). The organic layers were dried on Na2SO4 and concentrated
in vacuo. Chromatography on silica gel (0? 100% [1% HOAc in
4.1.6. tert-Butyl(1S,3R,4S,5R,6S,7S)-4,5-bis(benzyloxy)-3-((tert-
butyldimethylsilyloxy)methyl)-2-oxabicyclo[4.1.0]heptane-7-
ylcarbamate 9
Compound 8 (1.55 g, 3.11 mmol) was coevaporated with tolu-
ene (2 Â 20 mL) and taken up in tert-butanol (60 mL). To this solu-
tion were added freshly activated molecular sieves (rods, 4 Å),
diphenylphosphoryl azide (0.94 g, 3.42 mmol), and triethylamine
(0.346 g, 3.42 mmol). Stirring was continued, while gentle heating
at reflux and under an argon atmosphere for 20 h. The reaction
mixture was filtered, concentrated in vacuo, and taken up in ethyl
acetate (150 mL). This solution was washed with 1 M HCl (100 mL)
and saturated aqueous NaHCO3 (100 mL). The organic layer was
dried on Na2SO4 and concentrated in vacuo. Chromatography of
the residue on silica gel (0?25% EtOAc in light petroleum) yielded
the product 9 (1.28 g, 2.24 mmol, 72%) as a colorless syrup. 1H
EtOAc] in light petroleum) yielded the product
6 (1.39 g,
3.40 mmol, 82%) as a colorless syrup. 1H NMR (CDCl3): d 1.87 (m,
1H), 2.02 (m, 1H), 3.28 (dd, 1H, J = 3.6 Hz, J = 13.2 Hz), 3.44–3.53
(m, 2H), 3.61 (m, 1H), 3.80 (dd, 1H, J = 1.2 Hz, J = 6 Hz), 4.00 (dd,
1H, J = 2.0 Hz, J = 7.2 Hz), 4.53–4.71 (m, 4H), 7.16–7.42 (m, 10 H),
11.05 (b, 1H). 13C NMR (CDCl3): d 23.62, 24.84, 51.03, 57.74,
71.42, 73.20, 73.23, 74.87, 75.03, 76.69, 127.70, 127.79, 127.84,
127.87, 128.36, 128.42, 137.24, 137.45, 171.62. Exact mass calcu-
lated for (C22H23N3O6 + Na)+ = 432.15299, mass found: 432.15294.

M. D. P. Risseeuw et al. / Tetrahedron: Asymmetry 20 (2009) 945–951
949
NMR (CDCl3): d 0.05 (2 Â s, 6H), 0.89 (s, 9H), 1,21 (m, 1H), 1.44 (s,
9H), 2.61 (m, 1H), 3.53 (dd, 1H, J = 1.2, J = 7.6 Hz), 3.57–3.80 (m,
5H), 4.60–4.89 (m, 5H), 7.21–7.41 (m, 10H). 13C NMR (CDCl3): d
À5.45, À5.36, 18.22, 25.47, 25.89, 28.34, 34.57, 56.13, 63.41,
71.24, 73.41, 75.77, 76.68, 78.79, 79.58, 127.44, 127.76, 127.89,
128.21, 128.25, 138.63, 138.74, 155.87. Exact mass calculated for
(C32H47NO6Si + NH4)+ = 588.35445, mass found: 588.35407.
1.84 (m, 1H), 1.92 (m, 1H), 2.03 (dd, 1H, J = 2.4 Hz, J = 5.6 Hz),
3.25 (dd, 1H, J = 3.6 Hz, J = 12.8 Hz), 3.36 (t, 1H, J = 5.5 Hz), 3.44
(t, 1H, J = 5.2 Hz), 3.46–3.61 (m, 5H), 3.78 (m, 1H), 3.82 (m, 1H),
3.86 (dd, 1H, J = 1.6 Hz, J = 7.2 Hz), 3.91 (dd, 1H, J = 2.0 Hz,
J = 7.2 Hz), 4.11 (q, 2H, J = 7.2 Hz), 4.51–4.72 (m, 8H), 5.97 (m,
1H), 7.22–7.35 (m, 20H). 13C NMR (CDCl3): d 14.10, 22.48, 23.40,
23.69, 25.70, 40.12, 51.10, 55.84, 57.06, 60.69, 71.13, 71.44,
72.37, 72.85, 73.06, 73.46, 74.19, 75.29, 75.37, 75.54, 127.61,
127.67, 127.72, 127.81, 127.85, 127.96, 128.36, 128.42, 137.41,
137.49, 137.55, 169.92, 171.42. Exact mass calculated for
[a]
D = +39.0 (c 1.0, CHCl3). IR = cmÀ1 2930 (w), 2365 (w), 1720
(vs), 1455 (m), 1365 (m), 1255 (m), 1095 (s), 835 (s), 525 (vs).
4.1.7. (1S,3R,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-7-((tert-butyl-
oxycarbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carboxylic
acid 10
(C46H50N4O9 + H)+ = 803.36506,
mass
found:
803.36552.
[a]
D = +18 (c 1.0, CHCl3). IR = cmÀ1 2870 (w), 2350 (w), 2100 (s),
1720 (bs), 1455 (m), 1295 (w), 1180 (w), 1075 (s), 750 (s), 525 (vs).
Chromic acid stock solution (1.0 M) (Caution: Chromic acid is
corrosive, toxic, and carcinogenic!): Concentrated sulfuric acid
(9 mL, 162 mmol) is taken up in water (50 mL). To this solution
CrO3 (10 g, 100 mmol) is added and the bright red solution is stir-
red until all solids are completely dissolved. The solution is diluted
with water to a total volume of 100 mL.
4.1.9. (1S,3R,4S,5R,6S,7S)-3-(((1S,3R,4S,5R,6S,7S)-3-(Azido-
methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-car-
boxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]
heptane-7-carboxylic acid 12b
Compound 11 (145 mg, 0.18 mmol) in dioxane/MeOH (2.5 mL,
Compound 8 (1.11 g, 1.95 mmol) in THF (20 mL) was treated
with tetrabutylammonium fluoride (2.2 mL, 1 M in THF) and stir-
ring is continued for 2 h. The reaction mixture was diluted with
ethyl acetate (50 mL) and washed with water (2 Â 50 mL). The or-
ganic fraction is dried on Na2SO4 and concentrated in vacuo. Chro-
matography on silica gel (0?60% ethylacetate in light petroleum)
yielded the product (0.483 g, 1.85 mmol, 95%) as a white foam.
The obtained alcohol (0.512 g, 1.12 mmol) was taken up in acetone
(20 mL). The solution was cooled on ice and a freshly prepared
chromic acid stock solution (2.3 mL, 2.3 mmol) added. Stirring
was continued for 16 h during which the color of the reaction mix-
ture shifted from bright orange to green. The reaction mixture was
diluted with ethyl acetate (60 mL) and washed with 1 M HCl
(2 Â 30 mL) and saturated aqueous NaCl (30 mL). The organic layer
was dried on Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (0?100% [1% HOAc
in EtOAc] in light petroleum) yielding product 10 (0.451 g,
0.96 mmol, 86%) as a white foam. 1H NMR (CDCl3): d 1.28 (m,
1H),1.43 (s, 9H), 2.89 (m, 1H), 3.85–3.87 (m, 2H), 3.94–3.96 (m,
1H), 4.30 (d, 1H, J = 3.2 Hz), 4.59–4.64 (m, 4H), 7.21–7.32 (m, 10
H). 13C NMR (CDCl3): d 24.71, 28.35, 33.49, 56.05, 71.24, 72.20,
76.07, 127.54, 127.59, 127.76, 128.29, 128.38, 129.84, 137.72,
138.02, 175.01. Exact mass calculated for (C26H31NO7 + -
4:1 v/v) was treated with aqueous LiOH (500 lL, 4 M). After stirring
for 16 h the reaction mixture was neutralized by the addition of
amberlite IR-120 (H+ form) resin. The resin was filtered off and the
filtrate was diluted with ethyl acetate (20 mL). The solution was
washed with 10% aqueous citric acid (2 Â 10 mL) and saturated
aqueous NaCl (10 mL). The organic layers were dried on Na2SO4
and concentrated in vacuo. The residue was purified by gel filtration
(LH-20, MeOH) giving the product 12b (109 mg, 0.14 mmol, 76%) as
an off white foam. 1H NMR (CDCl3): d 1.71–2.31 (m, 4H), 3.23–4.22
(m, 10H), 4.50–4.72 (m, 8H), 6.02 (m, 1H), 7.10–7.51 (m, 20H). 13C
NMR (CDCl3): d 22.54, 23.38, 24.43, 25.74, 29.59, 40.18, 51.11,
55.90, 57.56, 71.20, 71.48, 72.45, 72.90, 73.11, 73.50, 74.08, 75.13,
75.28, 75.44, 127.68, 127.74, 127.80, 127.89, 128.03, 128.44,
128.50, 130.0, 137.34, 137.50, 170.28, 176.40. Exact mass calculated
for (C44H47N4O9 + H)+ = 775.33376, mass found: 775.33423.
[a]
D = +41 (c 2.0, CHCl3). IR = cmÀ1 2870 (w), 2095 (s), 2100 (s),
1650 (m), 1455 (m), 1280 (bm), 1195 (b), 1075 (s), 735 (s), 695 (s).
4.1.10. (1S,3R,4S,5R,6S,7S)-Ethyl 3-(((1S,3R,4S,5R,6S,7S)-3-
(((1S,3R,4S,5R,6S,7S)-3-(((1S,3R,4S,5R,6S,7S)-3-(azidomethyl)-
4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-carbox-
amido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-
7-carboxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]
heptane-7-carboxamido)methyl)-4,5-bis(benzyloxy)-2-oxabi-
cyclo[4.1.0]heptane-7-carboxylate 13
Compound 11 (97 mg, 0.12 mmol) in ethanol (3 mL) was trea-
ted with Lindlar’s catalyst (10 mg). The reaction mixture was stir-
red vigorously and hydrogen gas was bubbled through for 5 h. The
dark grey catalyst was removed by filtration and the filtrate con-
centrated in vacuo.
Na)+ = 492.19927, mass found: 492.19929. [
a]D = +43.0 (c 1.0,
CHCl3). IR = cmÀ1 2980 (w), 2350 (w), 1720 (vs), 1455 (m), 1395
(m), 1255 (w), 1075 (s), 750 (s), 525 (vs).
4.1.8. (1S,3R,4S,5R,6S,7S)-Ethyl 3-(((1S,3R,4S,5R,6S,7S)-3-(azido-
methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]heptane-7-car-
boxamido)methyl)-4,5-bis(benzyloxy)-2-oxabicyclo[4.1.0]
heptane-7-carboxylate 11
Compound 5 (183 mg, 0.42 mmol) in ethanol (10 mL) was trea-
ted with Lindlar’s catalyst (30 mg). The reaction mixture was stir-
red vigorously and hydrogen gas was bubbled through for 5 h. The
dark grey catalyst was removed by filtration and the filtrate con-
centrated in vacuo.
In a separate vessel, compound 12b (101 mg, 0.13 mmol) in
DMF (5 mL) was treated with HATU (46 mg, 0.12 mmol) and DIPEA
(63 lL, 0.36 mmol). After stirring for 5 min, the reaction mixture
was added to the crude amine in the other vessel. The reaction
mixture was stirred for 16 h after which the solution was diluted
with ethyl acetate (20 mL), washed with 10% aqueous citric acid
(2 Â 10 mL) and saturated aqueous NaCl (10 mL). The organic frac-
tion was dried on Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by RP-HPLC using a gradient of acetonitrile in
water containing 1% TFA, providing the tetramer 13 (24 mg,
In a separate vessel, compound 6 (207 mg, 0.51 mmol) in DMF
(5 mL) was treated with HATU (175 mg, 0.46 mmol) and DIPEA
(260 lL, 1.50 mmol). After stirring for 5 min, the reaction mixture
was added to the crude amine in the other vessel. The resulting
mixture was stirred for 16 h after which the solution was diluted
with ethyl acetate (50 mL), washed with 10% aqueous citric acid
(2 Â 25 mL) and saturated aqueous NaCl (25 mL). The organic frac-
tion was dried on Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by gel filtration (LH-20, MeOH) giving the
product (249 mg, 0.31 mmol, 74%) as an off-white foam. 1H NMR
(CDCl3): d 1.25 (t, 3H, J = 4.0 Hz), 1.70 (dd, 1H, J = 2.0 Hz, 6.0 Hz),
15.6 l
mol, 13%) as a white foam. 1H NMR (CDCl3): d 1.21–1.30
(m, 3H), 1.68–2.06 (m, 8H), 3.27–4.16 (m, 26H), 4.50–4.77 (m,
16H), 5.95 (m, 3H), 7.28–7.35 (m, 40H). 13C NMR (CDCl3): d
14.24, 22.60, 22.81, 23.71, 23.91, 25.59, 26.07, 40.40, 40.51,
44.92, 51.50, 56.15, 56.20, 57.24, 60.28, 60.80, 65.50, 71.44,
71.52, 71.75, 72.58, 72.67, 72.80, 73.01, 73.15, 73.35, 73.54,
73.86, 74.74, 74.79, 74.93, 75.67, 75.89, 76.04, 76.11, 76.68,

950
M. D. P. Risseeuw et al. / Tetrahedron: Asymmetry 20 (2009) 945–951
76.99, 77.32, 80.47, 81.80, 102.50, 110.07, 127.72, 127.82, 127.87,
127.96, 128.13, 128.30, 128.52, 128.56, 128.57, 137.64, 137.74,
137.83, 170.03, 170.13, 171.43. Exact mass calculated for
(C90H96N6O17 + H)+ = 1533.69047, mass found: 1533.69190.
out further purification. 1H NMR (CDCl3): d 1.20–1.35 (m, 11H),
1.42 (s, 9H), 3.0 (m, 1H), 3.50 (m, 1H), 3.60 (m, 1H), 3.80 (m, 1H),
3.95 (m, 1H), 4.10–4.20 (m, 3H), 4.35 (m, 1H), 4.50–4.80 (m, 9H),
7.20–7.40 (m, 20H). 13C NMR (CDCl3): d 24.96, 28.36, 33.49,
55.45, 70.98, 71.80, 72.72, 73.48, 75.50, 76.75, 76.79, 77.00,
77.21, 127.44, 127.63, 127.68, 127.84, 127.88, 127.92, 128.26,
128.33, 128.35, 128.40, 128.50, 138.03, 138.30, 171.48. Mass found
[a]
D = +36 (c 0.1, CHCl3). IR = cmÀ1 3285 (w), 2920 (w), 2880 (w),
2100 (w), 1722 (w), 1635 (s), 1565 (s), 1560 (s), 1495 (w), 1455
(m), 1360 (w), 1075 (bs), 1025 (m), 875 (w), 735 (s), 695 (s).
for ((C47H52N2O11 + H)+ = 821.1. [ D = +46 (c 0.1, CHCl3). IR = cmÀ1
a]
4.1.11. (1S,3R,4S,5R,6S,7S)-Methyl 4,5-bis(benzyloxy)-7-((tert-
butyloxycarbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carbox-
ylate 14
3300 (w), 2925 (w), 1705 (m), 1700 (m), 1680 (m), 1650 (m), 1495
(w), 1455 (w), 1365 (w), 1250 (w), 1070 (bs), 1025 (s), 730 (s), 695
(s).
Compound 10 (0.217 g, 0.462 mmol) was taken up in a mixture
of toluene (3 mL) and methanol (1 mL). To this mixture was added
trimethylsilyldiazomethane (1.5 mL, 2 M in hexanes, 3.0 mmol)
and stirring was continued for 1 h. The reaction mixture was con-
centrated in vacuo and used without further purification. The
methyl ester 14 (0.225 g, 0.462 mmol, quantitative) was obtained
as a pale yellow foam. 1H NMR (CDCl3): d 1.35 (m, 1H), 1.41 (s,
9H), 2.89 (m, 1H), 3.57 (s, 3H), 3.86–3.90 (m, 3H), 4.29 (t, 1H,
J = 1.6), 4.54–4.62 (m, 5H),7.24–7.33 (m, 10 H). 13C NMR (CDCl3):
d 24.74, 28.35, 33.37, 51.75, 56.22, 71.33, 72.01, 72.13, 73.66,
76.15, 79.58, 127.61, 127.76, 128.27, 128.37, 137.76, 138.06,
155.84, 170.91. Exact mass calculated for (C27H33NO7 + NH4)+ =
4.1.14. (1S,3S,4S,5R,6S,7S)-Methyl 4,5-bis(benzyloxy)-7-
(1S,3S,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-((1S,3S,4S,5R,6S,7S)-4,5-
bis(benzyloxy)-7-((1S,3S,4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-(tert-
butoxy-carbonylamino)-2-oxabicyclo[4.1.0]heptane-3-carbox-
amido)-2-oxabicyclo[4.1.0]heptane-3-carboxamido)-2-
oxabicyclo[4.1.0]heptane-3-carboxamido)-2-
oxabicyclo[4.1.0]heptane-3-carboxylate 17
Compound 15 (102 mg, 0.12 mmol) was treated with TFA/
CH2Cl2 (1:1, v/v). Stirring was continued for 30 min, the reaction
mixture concentrated and the residue coevaporated with toluene
(10 mL). The obtained crude product 16a was condensed with
pre-activated compound 16b (110 mg, 0.13 mmol) using HATU
501.25953, mass found: 501.25944. [a]D = +73.4 (c 1.0, CHCl3).
IR = cmÀ1 2980 (w), 2350 (w), 1752 (m), 1720 (vs), 1455 (m),
1365 (m), 1250 (w), 1141 (vs), 1075 (s), 735 (s), 695 (vs).
(46 mg, 0.12 mmol) and DIPEA (65 lL, 0.37 mmol) in DMF/CH2Cl2
(5 mL, 1:1, v/v). The reaction mixture was stirred for 16 h after
which the solution was diluted with ethyl acetate (20 mL), washed
with 10% aqueous citric acid (2 Â 10 mL) and saturated aqueous
NaCl (10 mL). The organic fraction was dried on Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by RP-HPLC
using a gradient of acetonitrile in water containing 1% TFA, to give
the tetramer (32 mg, 0.021 mmol, 18%) as a white foam. 1H NMR
(CDCl3): d 1.21–1.35 (m, 4H), 1.42 (s, 9H), 2.85–2.98 (m, 4H),
3.55 (s, 3H), 3.57–3.72 (m, 6H), 3.87–3.91 (m, 3H), 4.05–4.13 (m,
6H), 4.31 (d, J = 3 Hz, 1H), 4.51–4.72 (m, 17H), 6.32–6.38 (m, 3H),
7.15–7.31 (m, 40H). 13C NMR (CDCl3): d 22.64, 24.42, 24.86,
24.89, 25.10, 28.36, 29.32, 29.63, 29.67, 32.46, 32.81, 32.87,
33.64, 51.86, 55.41, 55.44, 55.84, 55.86, 71.21, 71.24, 71.31,
71.52, 71.83, 72.23, 72.88, 73.00, 73.61, 73.71, 75.61, 75.67,
76.07, 76.79, 77.00, 77.22, 77.26, 79.97, 125.10, 125.30, 127.57,
127.61, 127.65, 127.70, 127.75, 127.78, 127.81, 127.83, 127.85,
127.93, 127.96, 128.01, 128.03, 128.22, 128.27, 128.34, 128.36,
128.40, 128.43, 129.03, 137.71, 138.00, 138.06, 138.07, 138.10,
138.19, 138.24, 170.99, 171.35, 171.39. Mass found for
4.1.12. (1S,3R,4S,5R,6S,7S)-Methyl 4,5-bis(benzyloxy)-7-((1S,3R,-
4S,5R,6S,7S)-4,5-bis(benzyloxy)-7-(tert-butoxy-carbonylamino)-
2-oxabicyclo[4.1.0]heptane-3-carboxamido)-2-oxabicyclo-
[4.1.0]heptane-7-carboxylate 15
Compound 14 (203 mg, 0.42 mmol), was taken up in TFA/
CH2Cl2 (10 mL, 1:1, v/v), and allowed to stand for 30 min. The solu-
tion was concentrated and the residue was coevaporated once with
toluene (10 mL).
In a separate vessel, compound 10 (221 mg, 0.47 mmol) was ta-
ken up in DMF/CH2Cl2 (5 mL, 1:1, v/v). To this solution were added
HATU (171 mg, 0.45 mmol) and DIPEA (235 lL, 1.35 mmol). After
stirring for 5 min the reaction mixture was added to the crude
amine in the other vessel. The resulting mixture was stirred for
16 h after which the solution was diluted with ethyl acetate
(20 mL), washed with 10% aqueous citric acid (2 Â 10 mL) and sat-
urated aqueous NaCl (10 mL). The organic fraction was dried on
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by gel filtration (LH-20, MeOH) giving the product 15 (242 mg,
0.29 mmol, 68%) as an off white foam. 1H NMR (CDCl3): d 1.20–1.42
(m, 11H), 2.76–2.99 (m, 3H), 3.62–4.74 (m, 15H), 6.62 (m, 1H),
7.23–7.47 (m, 20H). 13C NMR (CDCl3): d 24.32, 24.99, 25.60,
28.26, 29.52, 32.44, 33.66, 35.62, 38.46, 51.68, 55.70, 55.78,
56.53, 71.09, 71.23, 71.90, 72.11, 72.72, 73.80, 74.03, 74.11,
75.65, 76.08, 77.50, 78.43, 79.65, 127.09, 127.44, 127.56, 127.66,
127.71, 127.76, 127.81, 128.02, 128.12, 128.23, 128.28, 129.72,
137.65, 137.96, 138.08, 138.22, 138.71, 155.70, 170.85, 171.16. Ex-
act mass calculated for (C48H54N2O11 + H)+ = 835.38004, mass
((C90H96N4O19–Boc) + H)+ = 1438.9.
[a]D = +24 (c 0.1, CHCl3).
IR = cmÀ1 3305 (w), 2920 (w), 2800 (w), 1680 (s), 1660 (s), 1650
(s), 1520 (m), 1455 (m), 1360 (w), 1090 (s), 850 (w), 730 (s), 695
(s).
Acknowledgments
We thank Nico Meeuwenoord and Hans van den Elst for the
HPLC and HRMS data. We thank Fons Lefeber and Kees Erkelens
for the NMR data.
found: 835.38077. [a]
D = +36 (c 1.0, CHCl3). IR = cmÀ1 2870 (w),
2365 (s), 1680 (s), 1455 (m), 1250 (bw), 1070 (s), 735 (s), 695 (s).
References
4.1.13. (1S,3S,4S,5R,6S,7S)-4,5-Bis(benzyloxy)-7 ((1S,3S,4S,5R,6S,
7S)-4,5-bis(benzyloxy)-7-(tert-butoxy-carbonylamino)-2-oxa-
bicyclo[4.1.0]heptane-3-carbox-amido)-2-oxabicyclo[4.1.0]
heptane-3-carboxylic acid 16b
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treated with Me3SnOH (290 mg, 1.6 mmol) and the solution was
heated at 85 °C for 16 h. The reaction mixture was concentrated
in vacuo and coevaporated with toluene. The product 16b
(125 mg, 0.15 mmol, 95%) obtained as a white foam is used with-
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did not determine the stereochemistry of this minor isomer 4 (formed in 8%
over the two steps) since we felt that the limited accessibility of this isomer
following this particular route made it less useful in the generation of SAAs.
10. The use of LiOH to hydrolyse the ester in the dimer stage gave partial
epimerization at the
aÀH next to the COOH group.