An improved synthesis of a key intermediate for (+)-biotin from d-mannose

Article abstract of DOI:10.1016/j.carres.2007.06.029

An efficient and reproducible process for the synthesis of methyl 2,3,4,5-tetradeoxy-7,8-O-isopropylidene-d-arabino-nanonate (2), a key intermediate in the total synthesis of (+)-biotin (1), starting from readily available d-mannose is described. The cruc

Full text of DOI:10.1016/j.carres.2007.06.029

Carbohydrate Research 342 (2007) 2461–2464
Note
An improved synthesis of a key intermediate
for (+)-biotin from D-mannose
Fen-Er Chen,* Jian-Feng Zhao, Fang-Jun Xiong, Bin Xie and Ping Zhang
Fudan-DSM Joint Laboratory for Synthetic Methods and Chiral Technology, Department of Chemistry,
Fudan University, Shanghai 200433, People’s Republic of China
Received 9 May 2007; received in revised form 19 June 2007; accepted 22 June 2007
Available online 18 July 2007
Abstract—An efficient and reproducible process for the synthesis of methyl 2,3,4,5-tetradeoxy-7,8-O-isopropylidene-D-arabino-nan-
onate (2), a key intermediate in the total synthesis of (+)-biotin (1), starting from readily available D-mannose is described. The
crucial part of this synthesis was the development of a practical route to a novel O-benzyl protected unsaturated ester methyl (benzyl
5,6,7,8-tetradeoxy-2,3-O-isopropylidene-a-D-lyxo-nona-5,7-dienofuranosid) uronate (7), allowing the one-step preparation of
hydroxy ester methyl 5,6,7,8-tetradeoxy-2,3-O-isopropylidene-a-D-lyxo-nanofuranuronate (8) by the catalytic debenzylation and
hydrogenation over palladium on carbon catalyst. This procedure requires no chromatographic purification, which makes it ideal
for synthetic preparation on an industrial scale.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: (+)-Biotin; Methyl 2,3,4,5-tetradeoxy-7,8-O-isopropylidene-D-arabino-nanonate; D-Mannose; Horner–Emmons olefination; Chiral pool
Carbohydrates are especially useful starting materials
for the total synthesis of chiral natural products because
they provide an almost unlimited combinatorial source
of stereocenters, and allow facile introduction of nitro-
gen after activation–substitution of hydroxyl groups.1
A large effort has been devoted to the development of
elegant methods for the total synthesis of (+)-biotin
(1) (Fig. 1), a water-soluble vitamin, based on a carbo-
hydrate approach to generate the (+)-biotin skeleton
with excellent stereocontrol. Of the various chiron strat-
egies described toward this vitamin synthesis,2 the syn-
thetic methods utilizing methyl 2,3,4,5-tetradeoxy-7,8-
O-isopropylidene-D-arabino-nanonate (2) as a key inter-
mediate seems to be one of the most expedient approach
to 1 to date.
Some synthetic methods for 2, using carbohydrates
including D-mannose,3 D-arabinose,4 and D-glucose,5
have been developed. Among them, one of the very con-
venient approaches which attracted our attention is the
D-mannose process developed by Ohrui and Emoto3
However, one of the serious limitations in this procedure
is the formation of considerable amount of a side prod-
uct, triphenylphosphine oxide, on use of Wittig reaction
as a key step toward introduction of the desired C4 side
chain into 1-O-benzoyl-2,3-isopropylidene-a-D-lyxo-
pentodialdo-1,4-furanose, making it very difficult for
large-scale production.
As a part of our continuing program to explore a
practical total synthesis of 1,6 herein, we disclose an im-
proved and scalable method for the preparation of 2
starting from commercially available D-mannose.
Our strategy for the preparation of 2 is depicted in
Scheme 1. 2,3:5,6-Di-O-isopropylidene-a-D-mannofura-
nose (3) was readily prepared in 88% yield by treatment
O
HN NH
H
H
H
COOH
S
1
Figure 1.
*
Corresponding author. Tel./fax: +86 21 65643811; e-mail: rfchen@
fudan.edu.cn
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.06.029

2462
F.-E. Chen et al. / Carbohydrate Research 342 (2007) 2461–2464
Me2
C
Me2
C
OH
O
O
O
O O
a
c
b
HO
HO
OH
OH
HO
O
BnO
O
O
O
O CMe2
O CMe2
3
4
D-mannose
Me2
C
Me2
C
Me2
C
O
O
O
O
O
O
d
e
BnO
OH
BnO
CHO
BnO
COOMe
O
O
O
OH
5
6
7
Me2
Me2
C
C
O
O
O O
f
g
OHC
HO
HO
COOMe
COOMe
O
8
9
Me2
C
O
O
h
HO
COOMe
HO
2
Scheme 1. Reagents and conditions: (a) Acetone, FeCl3, rt, 4 h, 88%; (b) KOH, BnBr, PEG-600, THF, rt, overnight, 90.3%; (c) 70%HOAc, rt, 18 h,
˚
97.5%; (d) silica gel-supported NaIO4, CH2Cl2, 0 ꢁC, 1.5 h, 99.5%; (e) (EtO)2POCHCH@CHCOOMe, MS 4 A, LiOHÆH2O, THF, reflux, 12 h, 80%;
(f) 5% Pd/C, EtOH/HOAc, 1 atm H2, rt, 18 h, 90%; (g) NaOMe, MeOH, 0 ꢁC, 15 min; (h) NaBH4, MeOH, rt, 2 h, 96.4% (two steps from 8).
of D-mannose with an excess acetone in the presence of a
catalytic amount of anhydrous FeCl3 according to the
procedure described by Singh et al.7 The phase trans-
fer-catalyzed O-benzylation of hydroxyl group at C-1
in 3 with benzyl bromide and powdered KOH in THF
using a catalytic amount of polyethylene glycols 600
(PEG-600) was carried out to provide a crystalline
benzyl ether 4 in 90.3% yield. Hydrolytic removal of
the 5,6-O-isopropylidene group was regioselectively
achieved with 70% aqueous acetic acid at 25 ꢁC for
18 h to afford the desired diol 5 as a single product in
almost quantitative yield. It is worth mentioning that
several attempts to this deprotection at elevated reaction
temperature (50–70 ꢁC) failed to give any product, and
decreasing the concentration of acetic acid to 40% low-
ered the yield of 5 considerably. Shing’s protocol8 using
Silica Gel-supported sodium metaperiodate in CH2Cl2
was eventually found to effect the oxidative cleavage of
the glycol in 5 to give the expected aldehyde 6 in quan-
titative yield. The Horner–Emmons olefination of 6 in
anhydrous THF with diethyl 3-methoxycarbonyl-2-
at room temperature led to the corresponding saturated
hemiacetal 8 in 90% isolated yield. Treatment of 8 with
50% sodium methoxide in methanol at 0 ꢁC, followed by
the reduction of the resulting aldehyde 9 with sodium
borohydride at room temperature for 2 h, furnished
methyl 2,3,4,5-tetradeoxy-7,8-O-isopropylidene-D-ara-
bino-nanonate (2) in 96.4% yield (two steps from 8).
In summary, an efficient and convenient synthesis
of methyl 2,3,4,5-tetradeoxy-7,8-O-isopropylidene-D-
arabino-nanonate (2) amenable to scale-up has been
accomplished in an overall yield of 53% starting form
D-mannose by utilizing cheap and readily available
reagents and by applying simple experimental proce-
dures. Further developments of (+)-biotin (1) using this
key intermediate are in process and will be reported in
due course.
1. Experimental
1.1. General methods
˚
propenylidine using MS 4 A as catalyst in the presence
of LiOHÆH2O under reflux for 12 h worked well to give
a,b-unsaturated esters 7 as an inseparable mixture of
several E- and Z-isomers. One-pot catalytic debenzyla-
tion and hydrogenation of the resulting 7 with 5% Pd/
C in mixed solvents of ethanol/glacial acetic acid (1:1)
Melting points were determined on a WRS-1 digital
melting point apparatus and uncorrected. IR spectra
were recorded on a JASCO FT/IR-4200 spectrometer.
NMR spectra were taken on a Bruker AVANCEII
400 MHz spectrometer using TMS as an internal stan-

F.-E. Chen et al. / Carbohydrate Research 342 (2007) 2461–2464
2463
dard. Mass spectra were measured on Agilent Technol-
ogies 6890 N. Optical rotations were recorded with a
JASCO P-1020 Polarimeter at 25 ꢁC. All chemicals
and solvents were of reagent grade and were used with-
out further purification, silica gel-supported NaIO4
reagent was prepared according to the method of Shing
et al.8
4.66 (d, 1H, J 6.0 Hz), 4.86 (dd, 2H, J 3.6, 6.0 Hz),
5.12 (s, 1H), 7.30 (m, 5H); 13C NMR (100 MHz,
CDCl3): d 137.4, 128.5, 128.0, 127.9, 112.7, 105.6,
84.9, 80.2, 79.4, 70.5, 69.3, 64.5, 25.9, 24.6. GC–MS:
(m/z, %): 295 (MꢁCH3)+, 246, 222, 91 (100).
1.4. Benzyl 2,3-O-isopropylidene-a-D-lyxo-pentodialdo-
1,4-furanoside (6)
1.2. Benzyl 2,3:5,6-di-O-isopropylidene-a-D-mannofur-
anoside (4)
To a vigorously stirred suspension of silica gel-sup-
ported NaIO4 reagent (110 g) was added a soln of 5
(17.05 g, 55 mmol) in CH2Cl2 (700 mL) at room temper-
ature. The reaction mixture was stirred at 0 ꢁC for 1.5 h,
and filtered. The residue was washed twice with MeOH
(400 mL). The combined filtrates were concentrated
under diminished pressure and allowed to stand at
5 ꢁC overnight to give 6 (15.2 g, 99.5%) as a white solid
and was pure enough to be used immediately for the
To a vigorously stirred suspension of powdered KOH
(10.0 g, 0.18 mol), PEG-600 (0.2 g) and
3 (26 g,
0.1 mol) in THF (200 mL) was added benzyl bromide
(17.1 g, 0.1 mol) in one portion. The reaction mixture
was stirred overnight at room temperature. CH2Cl2
(200 mL) and water (200 mL) were added into the reac-
tion mixture, the organic phase was separated, washed
with water (150 mL), dried (MgSO4) and concentrated
under diminished pressure. The crude product a yellow-
ish syrup became solid on storing in the cold. Recrystal-
lization of the crude product from petroleum ether
(60–90 ꢁC) afford pure 4 (31.6 g, 90.3%) as a white solid.
25
next step. Mp 81.4–82.7 ꢁC, lit.:10 mp 81–82 ꢁC; ½aꢀD
+28 (c 1.0, acetone); IR(KBr): m 2935, 1750, 1377,
1
1211, 1092, 864, 749, 699 cmꢁ1; H NMR (400 MHz,
CDCl3): d 1.28 (s, 3H), 1.43 (s, 3H), 4.43 (d, 1H, J
4.8 Hz), 4.52 (d, 1H, J 11.6 Hz), 4.69 (d, 1H, J
6.0 Hz), 4.70 (d, 1H, J 11.6 Hz), 5.09 (dd, 1H, J 4.8,
6.0 Hz), 5.31 (s, 1H), 7.31 (m, 5H), 9.67 (s, 1H); 13C
NMR (100 MHz, CDCl3): d 197.6, 136.8, 128.5, 128.0,
127.9, 113.9, 105.9, 84.7, 84.1, 80.9, 69.3, 25.8, 24.5.
GC–MS: (m/z, %): 295 (MꢁCH3)+, 246, 222, 91 (100).
25
Mp 54.9–55.6 ꢁC, lit.:9 mp 55–56 ꢁC; ½aꢀD +74.8 (c 1.0,
25
acetone), lit.:9 ½aꢀD +76.5 (c 1.0, acetone); IR(KBr): m
2988, 2933, 1380, 1086, 737, 517 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 1.32 (s, 3H); 1.38 (s, 3H), 1.45
(s, 3H), 1.46 (s, 3H), 3.97 (dd, 1H, J 6.4, 8.8 Hz), 3.98
(dd, 1H, J 3.6, 6.8 Hz), 4.10 (dd, 1H, J 5.5 Hz,
1.0 Hz), 4.40 (m, 1H), 4.49 (d, 1H, J 12 Hz), 4.64 (d,
1H, J 12 Hz), 4.66 (d, 1H, J 6.0 Hz), 4.79 (dd, 1H, J
3.6, 6.0 Hz), 5.07 (s, 1H), 7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 137.3, 128.4, 128.0, 127.8, 112.5,
109.2, 105.7, 85.1, 80.5, 79.6, 73.1, 69.1, 66.9, 26.8,
25.9, 25.2, 24.5. GC–MS: (m/z, %): 335 (MꢁCH3)+,
229, 214, 91 (100).
1.5. Methyl (benzyl 5,6,7,8-tetradeoxy-2,3-O-isopropyl-
idene-a-D-lyxo-nona-5,7-dienofuranosid) uronate (7)
˚
Activated MS 4 A (25 g, beads, 4–8 mesh) and LiOHÆ
H2O (2.21 g, 52.5 mmol) were added to a vigorously
stirred soln of 6 (13.9 g, 50 mmol) and methyl diethyl-
4-phosphonocrotonate (12.4 g, 52.5 mmol) in THF
(500 mL). The reaction mixture was heated under reflux
for 12 h, and filtered. The filtrate was evaporated under
diminished pressure. The residual oil was dissolved in
EtOAc (200 mL), washed with water (3 · 80 mL), dried
(MgSO4). The solvent was concentrated under dimin-
ished pressure to a dark brown syrup, which was crystal-
lized from aq CH3OH to afford 7 (14.4 g, 80%) as a
1.3. Benzyl 2,3-O-isopropylidene-a-D-mannofuranoside
(5)
A soln of 4 (21 g, 12 mmol), glacial AcOH (91 mL), and
water (39 mL) was stirred for 18 h at room temperature,
and concentrated under diminished pressure. The resi-
due was dissolved in EtOAc (200 mL), washed sequen-
tially with satd aq NaHCO3 (2 · 50 mL), water
(2 · 20 mL), and brine (2 · 30 mL), dried (MgSO4),
and the solvent was concentrated under diminished pres-
sure to a colorless oil which was crystallized upon cool-
ing to afford 5 (18.1 g, 97.5%) as a white solid. Mp 59.4–
25
yellow solid. Mp 41.7–43.4 ꢁC, ½aꢀD +9.5 (c 1.0,
acetone); IR(KBr): m 2990, 2918, 1719, 1619, 1497,
;
1376, 1232, 860, 702 cmꢁ1 1H NMR (400 MHz,
CDCl3): d 1.30 (s, 3H), 1.44 (s, 3H), 3.75 (s, 3H), 4.50
(d, 1H, J 12 Hz), 4.56 (dd, 1H, J 3.6, 6.8 Hz), 4.68 (d,
1H, J 5.6 Hz), 4.69 (d, 1H, J 12 Hz), 4.72 (dd, 1H, J
3.6, 5.6 Hz), 5.13 (s, 1H), 5.93 (d, 1H, J 15.2 Hz), 6.21
(dd, 1H, J 6.8. 15.2 Hz), 6.46 (dd, 1H, J 11.2,
15.2 Hz), 7.31 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 167.1, 143.7, 135.6, 137.2, 131.2, 128.4, 127.8,
127.6, 122.0, 112.7, 105.3, 85.3, 81.3, 80.3, 69.0, 51.5,
26.0, 24.8. GC–MS: (m/z, %): 360 (M+), 246, 222, 91
(100).
25
61.0 ꢁC, lit.:9 mp 60–61 ꢁC; ½aꢀD +88.6 (c 1.0, acetone),
25
lit.:9 ½aꢀD +90 (c1.0, acetone); IR(KBr): m 3520, 3364,
3063, 2934, 1736, 1454, 1381, 1207, 1085, 893,
735 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.33 (s,
;
3H), 1.47 (s, 3H), 2.01 (s, 1H), 2.76 (s, 1H), 3.66 (m,
1H), 3.82 (m, 1H), 3.96 (dd, 1H, J 3.6, 8.0 Hz), 4.02
(m, 1H), 4.50 (d, 1H, J 12 Hz), 4.62 (d, 1H, J 12 Hz),

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F.-E. Chen et al. / Carbohydrate Research 342 (2007) 2461–2464
1.6. Methyl 5,6,7,8-tetradeoxy-2,3-O-isopropylidene-
a-D-lyxo-nanofuranuronate (8)
Acknowledgment
This work was supported by the DSM Nutritional
Products Ltd in Switzerland.
Compound 7 (13 g, 36.1 mmol) dissolved in a mixture of
EtOH (75 mL) and glacial AcOH (75 mL) was hydroge-
nated under 1 atm of H2 in the presence of 5% Pd/C
(2.6 g). After stirring at room temperature for 24 h, the
reaction mixture was filtered through a pad of Celiteꢂ
and the filtrate was concentrated under diminished pres-
sure. The residual syrup was solidified upon on storing
in the cold storage to afford 8 (8.9 g, 90%) as a pale-
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yellow solid. Mp 50.4–52.0 ꢁC, ½aꢀD +17.6 (c 1.0,
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1
1202, 1066, 875 cmꢁ1; H NMR (400 MHz, CDCl3): d
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A soln of 8 (8.22 g, 30 mmol) in anhyd MeOH (100 mL)
and 50% sodium methoxide (0.54 g, 5 mmol) was stirred
at 0 ꢁC for 15 min, sodium borohydride (2.28 g,
60 mmol) was added into the resulting aldehyde 9,
stirring was continued at room temperature for an
additional 2 h, the excess sodium borohydride was
carefully quenched by the addition of glacial AcOH
(3 mol) after cooling to ꢁ40 ꢁC, and extracted CH2Cl2
(3 · 60 mL). The combined organic extracts were
washed sequentially with satd aq NaHCO3 (2 ·
50 mL), water (2 · 35 mL), and brine (2 · 30 mL) and
dried (MgSO4). The solvent was concentrated under
diminished pressure to afford 2 as a pale yellow oil
25
25
D
(7.25 g, 96.4%); ½aꢀD +13.8 (c 1.92, CHCl3), lit.:3 ½aꢀ
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;
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(400 MHz, CDCl3): d 1.38 (s, 3H), 1.50 (s, 3H), 1.401–
1.747 (m, 6H), 2.34 (t, 2H, J 7.6 Hz), 2.69 (s, 2H), 3.67
(s, 1H), 3.73 (m, 1H), 3.78 (t, 2H, J 5.2 Hz), 4.05 (dd,
1H, J 3.2, 6.8 Hz), 4.22 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 174.0, 108.2, 79.2, 77.3, 68.8, 61.0, 51.3,
34.6, 33.4, 27.2, 25.3, 24.9, 24.7. GC–MS: (m/z, %):
261 (MꢁCH3)+, 243, 227, 59 (100).