A versatile route for the stereoselective synthesis of oxybiotin

Article abstract of DOI:10.1016/j.tetasy.2008.05.008

An efficient 10-step synthesis of oxybiotin, an oxygen analogue of biotin, is disclosed starting from 3,4,6-tri-O-benzyl-d-glucal.

Full text of DOI:10.1016/j.tetasy.2008.05.008

Tetrahedron: Asymmetry 19 (2008) 1372–1375
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A versatile route for the stereoselective synthesis of oxybiotin q
Lingala Vijaya Raghava Reddy a, Golla Narayana Swamy b, Arun K. Shaw a,
*
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Department of Chemistry, Sri Krishnadevaraya University, Anantapur 515 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2008
Accepted 13 May 2008
An efficient 10-step synthesis of oxybiotin, an oxygen analogue of biotin, is disclosed starting from 3,4,6-
tri-O-benzyl-D-glucal.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Bani Talapatra on her
70th birthday
1. Introduction
O
O
S
Carbohydrates represent the single most abundant class of
organic compounds associated with living matter. They can be con-
sidered as an important resource for synthetic organic chemists
due to the wealth of functional, conformational, and stereochemi-
cal information associated with them.1 The advantages of using
carbohydrates include that they display a high density of func-
tional groups, are available as single enantiomers, and contain
multiple sites for attachment of recognition groups.2 Hence, for
the past few decades, the generation of enantiopure, biologically
active natural and non-natural products from readily available
carbohydrates has become a topic of intensive research activity.3,4
Recently, we have accomplished a practical and efficient meth-
od for the stereoselective synthesis of jaspine B, a marine natural
HN
NH
HN
NH
CO2H
CO2H
O
Biotin 1
2
Oxybiotin
Figure 1.
ship to biotin and its ability to replace biotin as an essential metab-
olite for various species of microorganisms and higher animals.8
Hoffman achieved the first total synthesis of oxybiotin in its dl-
form.9 Later, Ohrui et al.10 reported the total synthesis of optically
product, starting from 3,4,6-tri-O-benzyl-D-galactal utilizing the
active (+)-oxybiotin in 19 steps starting from D-glucose. It showed
intramolecular asymmetric ring opening (ARO) of the 2,3-epoxy
alcohol as a pivotal step.5 While working on the synthesis of jas-
pine B, we envisioned that some more biologically important com-
pounds having the tetrahydrofuran backbone can be easily
synthesized by using the glycal derived enantiopure THFs6 as key
intermediates. In this endeavor, we adeptly developed a general
biotin-like activity for several species of bacteria, yeast, rats, and
chickens.11 Afterwards, only Popsavin et al. have devoted much
effort toward its synthesis starting from D-xylose and D-arabinose
as chiral sources.12–16 Notably, among the numerous biotin
analogues, the only one which has been shown to exhibit growth
promoting activity without being transformed into biotin is
oxybiotin.17 This shows that oxybiotin is intrinsically active.
Our retrosynthetic plan (Fig. 2) relies on the consecutive
approach toward the synthesis of trisubstituted THF domains, a
method recently developed by us.6a The THF domain 4 is easily
available in a single step from glucal-derived allylic alcohol involv-
ing the intramolecular ARO of the in situ formed enantiomerically
pure 2,3-epoxy alcohol, and carries the right stereochemistry at C1
of the tetrahydrofuran.
stereoselective method for the synthesis of c-azido tetrahydrofu-
ran carboxylic acids starting from glycals.7 As a part of our contin-
uing efforts to fully explore and exploit our recently synthesized
versatile THF’s6a toward the synthesis of biologically important
compounds, we herein report the stereoselective synthesis of oxy-
biotin using one of the THFs as an enantiopure key intermediate.
Oxybiotin is an oxygenated analogue of biotin in which the sul-
fur atom is replaced by oxygen (Fig. 1). This oxygen analogue of
biotin has been named oxybiotin, because of its structural relation-
The isopropylidene protected side-chain diol at C1 of 4 can be
easily transformed into an aldehyde group for introduction of the
valeric acid side chain. The replacement of hydroxyl functionalities
at C2 and C3 by the nitrogen atoms in an SN2 fashion can provide
the required ureido system of the oxybiotin.
q CDRI Communication No. 7479.
* Corresponding author. Tel.: +91 9415403775.
E-mail address: akshaw55@yahoo.com (A. K. Shaw).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.008

L. V. R. Reddy et al. / Tetrahedron: Asymmetry 19 (2008) 1372–1375
1373
propenylidene) triphenylphosphorane gave the expected dienoate
9 as an inseparable mixture of isomers (1H NMR).
O
O
(CH2)4CO2Me
(CH2)4CO2H
The catalytic hydrogenation of the C2 benzyl and two double
bonds in the side chain of 9 over Pd(OH)2 in methanol was carried
out to obtain 3 in a single step. Although the specific rotation
HO
OH
NH
HN
3
{½a 2D8
¼ ꢁ26:6 (c 0.42, CHCl3)} of the sample is different from the
ꢀ
O
2
literature value {½a D28
ꢀ
¼ ꢁ39:4 (c 1.0, CHCl3)},16 the IR, 1H, and
13C NMR data are consistent with structure 3. However, the phys-
ico-chemical data of the 3,4-ditriflate 10 prepared from 3 by using
triflic anhydride and pyridine in dichloromethane under dry condi-
tion is in full agreement with the reported values.16 The crude 3,4-
ditriflate 10 was then treated with sodium azide in HMPA to afford
the corresponding diazido derivative 11 as the only reaction prod-
uct (68% yield for two steps).
OBn
O
O
H
O
O
BnO
BnO
HO
OBn
4
5
Figure 2. Retrosynthetic pathway.
In a one-step sequence, diazide 11 was hydrogenated in the
presence of catalytic amount of PtO2 to the intermediate diamine
12, which was subsequently protected with triphosgene to obtain
the methyl ester of the oxybiotin 13. Treatment of 13 with 1 M
NaOH followed by neutralization with properly cleaned Amberlyst
15 resin18 furnished the target compound 2 in quantitative yield
(Scheme 2). The physical and spectroscopic data of the title com-
pound are in good agreement with the literature values.
2. Results and discussion
The synthesis of oxybiotin began with an inexpensive starting
material 3,4,6-tri-O-benzyl- -glucal to obtain the THF domain 4
D
in a one-pot process, as shown in Scheme 1. The isopropylidene
in domain 4 was then smoothly converted to an aldehyde group
in a single step using 1.3 equiv of periodic acid. Notably, aldehyde
8 could be easily stored for long periods unlike the intermediate
aldehyde used by Popsavin et al.16 The Wittig olefination of the
crude aldehyde 8 with the freshly prepared 3-(carbomethoxy-2-
3. Conclusion
In conclusion, a versatile approach for the synthesis of oxybio-
tin, the analogue of biotin, was achieved starting from 3,4,6-tri-
O
OBn
O
OH
H
OH
H
O
O
iii
BnO
BnO
CHO
i
ii
OH
BnO
BnO
H
OBn
OBn
OBn
HO
4
7
6
5
Scheme 1. Synthesis of 4. Reagents and conditions: (i) HgSO4 (cat.), 0.01 N H2SO4, 1,4-dioxane, 0 °C–rt, 8 h; (ii) NaBH4 (0.5 equiv), CeCl3ꢂ7H2O (1.0 equiv), EtOH, 0 °C–rt, 3 h,
57% for two steps; (iii) Ti(O-i-Pr)4 (1.0 equiv),
L-(+)-DET (1.2 equiv), t-BuOOH (2.0 equiv), MS 4 Å, CH2Cl2, ꢁ25 °C to 0 °C, 2.5 h, satd citric acid in acetone, 2 h, 51%.
CO2Me
O
CHO
O
H2, Pd(OH)2,
H5IO6 (1.3 equiv.),
Ph3P:CHCH:CHCO2Me, CH2Cl2,
2 h, 65% for two steps
4
MeOH, rt, 24 h,
98%
EtOH, 3 h
HO
OBn
OBn
HO
8
9
O
O
(CH2)4CO2Me
O
(CH2)4CO2Me
(CH2)4CO2Me
NaN3, HMPA, rt, 1.5 h,
68% for two steps
Tf2O, Py, CH2Cl2,
0°C, 1.5 h
HO
OH
N3
N3
TfO
OTf
10
3
11
O
O
(CH2)4CO2Me
(CH2)4CO2Me
(Cl3CO)2CO, Et3N,
H2, PtO2,
NaOH, H2O, rt, 24 h,
2
0°C, 2 h, then rt, 21 h,
66% for two steps
CH2Cl2, rt,
22 h
then Amberlyst 15, rt,
1 h, 98%.
H2N
NH2
NH
HN
12
O
13
Scheme 2. Synthesis of oxybiotin 2.

1374
L. V. R. Reddy et al. / Tetrahedron: Asymmetry 19 (2008) 1372–1375
O-benzyl-
D
-glucal. It is noteworthy that key intermediate THF
phosphorane (1.23 g, 3.4 mmol) was added in one portion
(15 mL) and left for stirring. After 1.5 h of stirring, change in color
of the reaction mixture from yellow to orange was observed. The
solvent was evaporated under reduced pressure and passed
through a short column to furnish 338 mg of pure compound 9
as a mixture of diastereomers.
domain 4,6a which can be prepared in multi-gram scale, showed
its versatility toward the synthesis of compounds of biological
importance.
4. Experimental
4.1. General
Oil, eluent for column chromatography: EtOAc/hexane (1/5, v/
v), Rf 0.48 (1/2 EtOAc/hexane). IR (neat, cmꢁ1): 3432 (–OH str),
1712 (C@O, ester), 1647, 1520, 1437 (C@C str), 1216. 1H NMR
(300 MHz, CDCl3) d 2.67, 2.72 (2d, 2H, –OH and –OHD), 3.70–3.77
(m, 7H, CO2Me, CO2MeD, H-3), 3.86–3.90 (m, 2H, H-5a, HD-5a),
4.09–4.13 (m, 2H, H-5b, HD-5b), 4.26 (br s, 2H, H-4, HD-4) 4.40 (t,
J = 6.4 Hz, 1H, HD-2) 4.54–4.69 (m, 4H, CH2Ph, CH2PhD) 4.83 (t,
J = 7.8 Hz, 1H, H-2) 5.78 (t, J = 8.5 Hz, 1H, H-10) 5.88–6.07 (m, 3H,
HD-10, H-40, HD-40) 6.29 (t, J = 11.2 Hz, 1H, H-20), 6.42 (dd, J = 11.8,
15.2 Hz, 1H, HD-20), 7.28–7.39 (m, 11H, ArH, ArDH, HD-30), 7.69
(dd, J = 12.3, 15.1 Hz, 1H, H-30); 13C NMR (75 MHz, CDCl3) d 51.9
(CO2Me), 70.1 (C-4), 70.2 (CD-4), 73.4 (CH2Ph), 73.7 (CD-5), 73.9
(C-5), 76.3 (C-2), 80.2 (CD-2), 83.7 (CD-3), 84.1 (C-3), 122.0 (CD-
40), 123.72 (C-40), 128.3 (ArH), 128.4 (ArDH), 128.6 (ArH), 128.8
(ArDH), 128.9 (ArH), 129.0 (ArDH), 129.5 (CD-20), 130.0 (C-20),
137.2 (Arqc), 137.6 (C-10), 139.5 (C-30), 140.1 (CD-10), 143.9 (CD-
30), 167.4 (CO2Me), 167.6 (CO2MeD); mass (ESI-MS) m/z 304, found
343 [M+K]+. DART-HRMS: calcd for [M+1]+Å, C17H21O5, m/z
305.13890, measured 305.13840.
CH2Cl2 was distilled from calcium hydride. Ti(O-i-Pr)4, (+)-
diethyltartrate, 6.0 M solution of t-BuOOH in nonane, triflic anhy-
dride, sodium azide, and triphosgene were purchased from Aldrich
Chemical Co., whereas 5 was synthesized in a laboratory. All the
products were characterized by 1H, 13C, IR, ESI-MS, EI-HRMS, and
DART-HRMS (C, H, O, N, S).
Analytical TLC was performed using 2.5 ꢃ 5 cm plates coated
with a 0.25 mm thickness of silica gel (60F-254), and visualization
was accomplished with CeSO4, or in some cases 30% (v/v) H2SO4 in
MeOH and subsequent charring over the hotplate. 1H NMR spectra
were recorded at 300 MHz with TMS as the internal reference. 13
C
NMR spectra were recorded at 75 MHz with CDCl3, D2O, or DMSO-
d6 as the internal reference. Chemical shifts were given in parts per
million downfield from internal standard Me4Si. IR spectra were
recorded on Perkin–Elmer 881 and FTIR-8210 PC Shimadzu Spec-
trophotometers. Mass spectra were recorded on a JEOL JMS-600H
high-resolution spectrometer using EI mode at 70 eV. Optical rota-
tions were determined on an Autopol III polarimeter using a 1 dm
cell at 28 °C; concentrations mentioned are in g/100 mL.
To the mixture of pure dienoate 9 (338 mg, 1.1 mmol) in dry
methanol, degassed with argon, was added 10% Pd(OH)2 on carbon
(30 mg). The resulting mixture was stirred under 1 atm H2 using a
balloon at room temperature for 24 h. After the completion of the
reaction (TLC), the catalyst was filtered, washed with methanol
twice, and the filtrate was concentrated to afford the diol 3 as a
colorless oil.
4.2. Procedure for the preparation of the Wittig salt
½
a 2D8
ꢀ
¼ ꢁ26:6 (c 0.42, CHCl3), Rf 0.26 (Et2O). IR (neat, cmꢁ1):
To a solution of PPh3 (1 equiv) in toluene was added methyl 4-
bromocrotonate (1 equiv) in toluene and the reaction was left for
stirring at rt overnight. The precipitate formed was filtered,
washed with toluene thrice, and dried. The salt thus obtained
was dissolved in water, and to it 10% NaOH was added dropwise
until the yellow precipitate of the ylide formed (solution should
be alkaline). The ylide was filtered, washed with water, dried,
and used for the reaction.
3405 (O–H str), 1726 (C@O, ester). 1H NMR (300 MHz, CDCl3) d
1.37–1.71 (m, 6H, 3 ꢃ CH2), 2.32 (t, J = 7.2 Hz, 2H, CH2CO2Me),
3.42–3.71 (br s, 8H, CO2CH3, 2 ꢃ OH, H-2, H-3 and H-5a), 4.05
(dd, J = 4.6, 9.7 Hz, 1H, H-5b), 4.17 (br s, 1H, H-4); 13C NMR
(75 MHz, CDCl3 + CCl4) d 25.2, 25.7 and 33.3 (3 ꢃ CH2), 34.3
(CH2CO2Me), 51.9 (CO2CH3), 71.4 (C-4), 73.0 (C-5), 76.3 (C-2),
82.3 (C-3), 174.5 (CO2CH3); mass (EI-MS) m/z 218, found 219
[M+1]+Å. DART-HRMS: calcd for [M+1]+Å, C10H19O5, m/z 219.12325,
measured 219.12275.
4.2.1. (2R,3R,4R)-3-(Benzyloxy)-4-hydroxytetrahydrofuran-2-
carbaldehyde 8
A
solution of 46a (500 mg, 1.70 mmol) and periodic acid
4.2.3. Methyl 5-((2S,3S,4R)-3,4-bis(trifluoromethylsulfonyloxy)
tetrahydrofuran-2-yl)pentanoate 10
(504 mg, 2.21 mmol) in 10 mL of dry ethyl acetate was allowed
to stir at room temperature for 1.5 h. After the completion of reac-
tion (TLC), the reaction mixture was quenched with saturated solu-
tion of NaHCO3 and extracted with ethyl acetate (3 ꢃ 15 mL). The
combined organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure to afford 380 mg of crude alde-
hyde 8 (>95% pure from 1H NMR) as a colorless syrup which was
immediately used for the next step. IR (neat, cmꢁ1): 3402 (O–H
str), 2926 (@C–H str), 1738 (C@O str), 1631, 1456, (C@C str),
1216, 1114, 1066 (C–O str). 1H NMR (300 MHz, CDCl3) d 3.92–
4.10 (m, 3H, H-3 and H-5), 4.19 (dd, J = 4.3, 8.9 Hz, 1H, H-4), 4.30
(dd, J = 1.0, 5.5 Hz, 1H, H-2), 4.64, 4.74 (2d, J = 11.7 Hz, 2H, CH2Ph),
7.32–7.41 (m, 5H, ArH), 9.69 (d, J = 1.3 Hz, 1H, –CHO); 13C NMR
(75 MHz, CDCl3) d 70.6 (C-5), 73.2 (CH2Ph), 74.1 (C-4), 79.9 (C-3),
85.6 (C-2), 128.4 (ArC), 128.8 (ArC), 129.1 (ArC), 136.9 (Ar qC),
201.3 (–CHO). DART-HRMS: calcd for ½M+NH4þꢀ, C12H18N1O4 m/z
240.12358, measured 240.12530.
To the precooled (ꢁ10 °C) solution of 3 (242 mg, 0.90 mmol) in
dry CH2Cl2 and pyridine (0.36 mL, 4.5 mmol) was added dropwise,
a cooled solution of trifluoromethane–sulfonic anhydride (0.9 mL,
5.4 mmol). The temperature of the reaction mixture was raised
to 0 °C and then left for stirring for 1.5 h. After the completion of
reaction (TLC), the reaction mixture was neutralized with 10 mL
of saturated NaHCO3 and extracted with CH2Cl2 (3 ꢃ 15 mL), dried,
evaporated, and as such used for the next step without purification.
A small amount of the compound was purified on silica gel column
chromatography to obtain the physical data of 10.
Oil, eluent for column chromatography: EtOAc/hexane (2/25,
v/v), ½a 2D8
¼ ꢁ36:6 (c 0.18, CHCl3), Rf 0.68 (CH2Cl2). IR (neat,
ꢀ
cmꢁ1): 1730 (C@O, ester), 1425, 1217 (SO2), 1144 (C–F). 1H NMR
(300 MHz, CDCl3) d 1.45–1.77 (m, 6H, 3 ꢃ CH2), 2.34 (t, J = 2.9 Hz,
2H, CH2CO2Me), 3.69 (s, 3H, CO2CH3), 4.04–4.14 (m, 2H, H-5a,
H-2), 4.35 (dd, 1H, J = 5.3, 11.1 Hz, H-5b), 4.86 (t, 1H, J = 6.0 Hz,
H-3), 5.32 (dd, J = 4.9, 9.7 Hz, 1H, H-4). 13C NMR (75 MHz,
CDCl3 + CCl4) d 24.8, 25.0 and 31.8 (3 ꢃ CH2), 34.0 (CH2CO2Me),
51.9 (CO2CH3), 69.7 (C-5), 79.7 (C-2), 81.6 (C-4), 84.0 (C-3), 116.6
(CF3SO2), 120.8 (CF3SO2), 174.1 (CO2CH3). EI-HRMS: calcd for
[M+1]+Å, C12H17F6O9S2, m/z 483.0218, measured 483.0211.
4.2.2. Methyl 5-((2S,3S,4R)-3,4-dihydroxytetrahydrofuran-2-yl)
pentanoate 3
To the solution of aldehyde 8 (380 mg, 1.71 mmol) in CH2Cl2,
freshly prepared 3-(carbomethoxy-2-propenylidene) triphenyl-

L. V. R. Reddy et al. / Tetrahedron: Asymmetry 19 (2008) 1372–1375
1375
4.2.4. Methyl 5-((2S,3S,4R)-3,4-diazidotetrahydrofuran-2-yl)
pentanoate 11
water and the whole aqueous solution was co-evaporated with tol-
uene to give 2. Recrystallization of the crude product from water
gave 40 mg of pure 2 as silky white crystals. Mp: 185–187 °C,
To a solution of 10 (300 mg, 0.62 mmol) dissolved in a minimal
amount of HMPA (2 mL) was added an excess amount of NaN3
(1.0 g, 15.5 mmol) and left for stirring at room temperature. After
1.5 h of stirring, the reaction mixture was diluted with 20 mL of
water and extracted with 1:1 benzene–hexane (3 ꢃ 15 mL). The
combined organic layer collected was dried and evaporated to give
the crude azide, which on column chromatography gave the pure
compound 11 as a yellow oil. Oil, eluent for column chromatogra-
½
a 2D8
ꢀ
¼ þ57:2 (c 0.10, 1 M NaOH), IR (KBr, cmꢁ1): 3401 (COOH),
1704 (COOH), 1673 (NHCONH). 1H NMR (300 MHz, D2O): d 1.40–
1.63 (m, 6H, 3 ꢃ CH2), 2.34 (t, J = 7.2 Hz, 2H, CH2CO2H), 3.53–3.60
(m, 2H, H-2 and H-5a), 3.81 (d, J =10.3 Hz, 1H, H-5b), 4.29 (dd,
J = 3.9, 8.6 Hz, 1H, H-3), 4.45 (dd, J = 4.1, 8.6 Hz, 1H, H-4). 13C
NMR (75 MHz, Me2SO-d6): d 25.3, 25.9 and 28.9 (3 ꢃ CH2), 34.2
(CH2CO2H), 57.2 (C-4), 58.7 (C-3), 74.3 (C-5), 82.7 (C-2), 163.2
(NHCONH), 175.1 (CO2H); EI-HRMS: calcd for (M+Å) C10H16N2O4,
m/z 228.1110, measured 228.1104. EI-HRMS: calcd for [M+ÅꢁOH],
phy: EtOAc/hexane (3/20, v/v), ½a D28
¼ þ31:3 (c 0.15, CHCl3), Rf 0.28
ꢀ
(CH2Cl2). IR (neat, cmꢁ1): 2105 (–N3 str) 1731 (C@O, ester). 1H NMR
(300 MHz, CDCl3) d 1.39–1.48 (m, 2H, –CH2), 1.64–1.74 (m, 4H,
2 ꢃ CH2) 2.34 (t, J = 7.3 Hz, 2H, CH2CO2Me), 3.67 (s, 3H, CO2CH3),
3.80 (dd, 1H, J = 7.2, 9.0 Hz, H-5a), 3.86–3.92 (m, 1H, H-2), 3.99–
4.04 (m, 2H, H-3 and H-5b), 4.25 (m, 1H, H-4). 13C NMR (75 MHz,
CDCl3) d 25.1, 25.9 and 30.1 (3 ꢃ CH2), 34.1 (CH2CO2Me), 51.9
(CO2CH3), 63.4 (C-4), 65.6 (C-3), 68.9 (C-5), 81.2 (C-2), 174.3
(CO2Me); mass (ESI-MS) m/z 268, found 269 [M+1]+Å. DART-HRMS:
calcd for [M+1]+Å, C10H17N6O3, m/z 269.13621, measured
269.13360. DART-HRMS: calcd for [M+NH4]+Å, C10H20N7O3, m/z
286.16276, measured 286.15899.
C10H15N2O3, m/z 211.1083, measured 211.1099.
Acknowledgments
We are thankful to Sophisticated Analytical Instrument Facility,
CDRI for providing spectral data, and Mr. A. K. Pandey for technical
assistance. L.V.R.R. thanks CSIR, New Delhi for financial support.
References
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4.2.5. Methyl ester of oxybiotin 13
A 50 mL round-bottomed flask was charged with 85 mg of azide
11 (0.3 mmol), 10 mL of CH2Cl2, and 15 mg of PtO2. The reaction
mixture was stirred under 1 atm hydrogen for 21 h. After the com-
plete consumption of starting material, the reaction mixture was
cooled to 0 °C and to it were added Et3N (0.13 mL, 0.93 mmol)
and a solution of triphosgene (69 mg, 0.23 mmol) in dry CH2Cl2.
After stirring for 2 h under the same temperature, the reaction
mixture was left for stirring at room temperature. After 21 h, the
catalyst was filtered off and washed thrice with CH2Cl2. Concentra-
tion of the filtrate under vacuum provided the crude residue which
on column chromatography afforded pure 13. Oil, eluent for col-
umn chromatography: methanol/EtOAc (2/25, v/v), ½a D28
¼ þ35:3
ꢀ
(c 0.20, CHCl3), Rf 0.29 (Me2CO). IR (neat, cmꢁ1): 3020 (NH), 1710
(CO2Me, NHCONH). 1H NMR (300 MHz, CDCl3) d 1.37–1.70 (m,
6H, 3 ꢃ CH2), 2.33 (t, J = 7.3 Hz, 2H, CH2CO2Me), 3.43 (br s, 1H, H-
2), 3.52 (dd, J = 3.5, 9.7 Hz, 1H, H-5a), 3.65 (s, 3H, CO2CH3), 3.89
(d, J = 9.9 Hz, 1H, H-5b), 4.19–4.21 (m, 1H, H-3), 4.35 (br s, 1H,
H-4), 5.90 and 6.09 (2 ꢃ br s, 1H each, 2 ꢃ NH). 13C NMR
(75 MHz, CDCl3) d 25.2, 25.9 and 28.8 (3 ꢃ CH2), 34.1 (CH2CO2Me),
51.8 (CO2CH3), 57.9 (C-4), 59.4 (C-3), 74.6 (C-5), 83.0 (C-2), 163.6
(NHCONH), 174.6 (CO2Me). mass (ESI-MS) m/z 242, found 243
[M+1]+Å; EI-HRMS: calcd for [M+1]+Å, C11H18N2O4 242.1267, mea-
sured 242.1261.
13. Miljkovic´, D.; Popsavin, V.; Harangi, J.; Batta, G. J. Serb. Chem. Soc. 1989, 54,
163–165.
14. Popsavin, V.; Benedekovic´, G.; Popsavin, M.; Miljkovic´, D. Carbohydr. Res. 2002,
337, 459–465.
15. Popsavin, V.; Benedekovic´, G.; Popsavin, M. Tetrahedron Lett. 2002, 43, 2281–
2284.
´
´
16. Popsavin, V.; Benedekovic, G.; Popsavin, M.; Divjakovic, V.; Armbruster, T.
Tetrahedron 2004, 60, 5225–5235.
17. McCoy, R. H.; McKibben, J. N.; Axelrod, A. E.; Hofmann, K. J. Biol. Chem. 1948,
176, 1319–1326 and references cited therein.
18. Amberlyst 15 beads (ꢄ100 gm) as received were soaked for 2 h in 500 mL of
deionized water. After the 2 h soaking, the beads were placed in a glass
column. Deionized water was passed through the column until the effluents
ran clear. Six bed volumes of 10% (electronic grade) hydrochloric acid were
passed through the column with a 10 min residence time for each bed. Finally,
a large volume of deionized water was passed through the column until the
conductivity of the water going into the column was the same as the effluents
leaving the column. At this point the beads were considered ready for use and
dried (see U.S. Patent 5,936,071).
4.2.6. (+)-Oxybiotin 2
A freshly prepared 1 M solution of NaOH (2 mL) was added to
13 (55 mg, 0.2 mmol) and stirred for 24 h at room temperature.
The reaction mixture was diluted with water and neutralized with
properly cleaned Amberlyst-15 resin (3 g) catalyst by stirring at
room temperature for an additional 1 h. The reaction mixture
was filtered, the resin was washed with a minimal amount of