A novel synthesis of a key intermediate for (+)-biotin from L-aspartic acid

Article abstract of DOI:10.1055/s-2002-20035

The aldol reaction of an N-Cbz-3-amino-4-butanolide 4, derived from L-aspartic acid, with formaldehyde gave the trans-disubstituted 3-amino-4-butanolide 5 stereoselectively. Following protection of the hydroxyl group of 5, amidation and oxidation provided the β-substituted L-asparagine derivative 6. The Hofmann rearrangement of 6 with sodium hypochlorite in the presence of sodium hydroxide and subsequent hydrogenation gave the bicyclic lactone 11, which upon dibenzylation and thionation, gave the thiolactone 2, a key intermediate for the synthesis of (+)-biotin (1).

Full text of DOI:10.1055/s-2002-20035

PAPER
361
A Novel Synthesis of a Key Intermediate for (+)-Biotin from L-Aspartic Acid
Synthesisof
a
K
eyInte
a
rmediate fo
s
r
(
+)-Bio
atin hiko Seki,* Toshiaki Shimizu, Koichi Inubushi
Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
Fax +81(6)63002816; E-mail: m-seki@tanabe.co.jp
Received 30 October 2001; revised 7 December 2001
imidazolidin-2-one moiety of (+)-biotin (1) might be
Abstract: The aldol reaction of an N-Cbz-3-amino-4-butanolide 4,
formed by the Hofmann rearrangement of the protected
amide 6, which is obtained from the lactone 5 through
protection of the hydroxyl group, ring-opening with am-
derived from L-aspartic acid, with formaldehyde gave the trans-dis-
ubstituted 3-amino-4-butanolide 5 stereoselectively. Following pro-
tection of the hydroxyl group of 5, amidation and oxidation
provided the -substituted L-asparagine derivative 6. The Hofmann monia and oxidation of the hydroxymethyl group. Re-
rearrangement of 6 with sodium hypochlorite in the presence of so-
dium hydroxide and subsequent hydrogenation gave the bicyclic
moval of the protective groups of the resultant
imidazolidin-2-one derivative 7 and subsequent dibenzy-
lactone 11, which upon dibenzylation and thionation, gave the thi-
lation and thionation should give the desired thiolactone
olactone 2, a key intermediate for the synthesis of (+)-biotin (1).
2.
Key words: vitamins, stereoselective synthesis, amino acids, aldol
reaction, rearrangement
O
O
NHCbz
CO2H
HN
NCbz
CO2H
(+)-Biotin (1) is a water-soluble vitamin isolated in 19411
and has received much attention as a synthetic target be-
cause of its useful biological properties for human nutri-
tion and animal health.2 Since the first total synthesis of 1
was accomplished about fifty years ago, a number of syn-
thetic routes have been devised.3 Among them, the meth-
od utilizing the thiolactone 2 as a key intermediate is
considered to be one of the most expedient approaches to
1. Some practical synthetic methods of 2 have been devel-
oped, which involve the ones based on diastereomeric4 or
enzymatic resolution,5 chiral pool method with L-cysteine
as a starting material,6 and asymmetric synthesis.7 How-
ever, no approach starting from readily accessible L-
aspartic acid has been reported. As a part of our synthetic
studies utilizing L-aspartic acid (3) as a starting material
for biologically active compounds,8 we report herein a
novel synthesis of 2 from 3 (Figure 1).
H2N
BOMO
2
Hofmann
rearrangement
OBOM
6
7
1. protection
2. amidation
3. oxidation
HO
NHCbz
NHCbz
3
O
O
O
aldol
reactIon
O
4
5
Scheme 1
The N-Cbz-3-amino-4-butanolide 4 was prepared accord-
ing to the literature9 from N-Cbz-L-aspartic acid 8 through
formation of an acid anhydride followed by regioselective
reduction of the -aminocarbonyl group (Scheme 2).
Yoda and co-workers have reported a stereoselective hy-
droxymethylation at C-2 of an (S)-N-Boc-3-amino-4-bu-
tanolide.10 The method was applied to the Cbz derivative
4 to provide the desired trans-disubstituted N-Cbz-3-ami-
no-4-butanolide 5 with a high stereoselectivity (trans/
cis = 12:1). The diastereoselectivity was determined by
the 1H NMR spectrum. The enantiomeric integrity of 5 is
assured because the reactions of electrophiles with dian-
ions generated from N-Cbz-3-amino-4-butanolide deriva-
O
O
HN
NH
O
NH2
BnN
NBn
OH
HO
O
S
CO2H
S
O
2
3
1
Figure 1
We envisioned the synthetic route outlined in Scheme 1. tives have been reported to proceed without any
The required consecutive asymmetric centers at C-3a and racemization.11 The hydroxyl group of 5 was protected as
C-6a of (+)-biotin (1) were planned to be set by stereose- a benzyloxymethyl ether (BOM ether) and was allowed to
lective introduction of a hydroxymethyl group at C-2 of react with aqueous ammonia in methanol to provide the
the N-Cbz-3-amino-4-butanolide 4 derived from 3. The amide alcohol 10. The Hofmann rearrangement of 10
failed because of the poor solubility. We thus decided to
use the acid derivative 6 with higher solubility than 10.
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0361,0364,ftx,en;F08301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Oxidation of the hydroxymethyl group of 10 was conduct-
ed using Jones’ reagent to give the acid 6. Treatment of 6
with aqueous sodium hypochlorite in the presence of so-

362
M. Seki et al.
PAPER
dium hydroxide12 expectedly resulted in a clear solution.
Upon stirring at 55 °C for 50 minutes, a clean rearrange-
ment and a spontaneous cyclization took place to give the
desired cyclic urea 7 in good yield. The cis configuration
of 7 is ensured because the Hofmann rearrangement pro-
ceeds with retention of the configuration.12 Removal of
the protective groups of 7 by hydrogenation provided the
bicyclic lactone 11. The structure of 11 was confirmed by
an X-ray crystallographic analysis (Figure 2).13 The com-
pound 11 was treated with benzyl bromide in the presence
of sodium hydride followed by heating with potassium
thioacetate in DMF4a providing the desired thiolactone 2
in good yield (Scheme 2). The product 2 obtained by the
present method revealed its identity with an authentic
sample with respect to mp, IR, 1H NMR, mass spectra and
specific rotation14 {mp 122–123 °C; [ ]D25 +90.5 (c = 1.0,
25
CHCl3)}{Lit.4a mp 125–127 °C; [ ]D +91.3 0.9 (c =
1.0, CHCl3)}.
NHCbz
O
NHCbz
OH
a9
b
HO
O
O
O
4
8
O
NHCbz
R
Figure 2 ORTEP II Diagram of Compound 1113
RO
NHCbz
f
d
H2N
O
O
BOMO
1
Melting points are uncorrected. H NMR spectra were recorded
with tetramethylsilane as an internal standard. Optical rotations
were measured at the indicated temperature with a sodium lamp (D
line, 589 nm). Silica gel column chromatography was performed us-
ing Kieselgel 60 (E. Merck). THF was distilled from sodium/ben-
zophenone ketyl. Other solvents and reagents were used as
received.
5: R = H
9: R = BOM
10: R = CH2OH
6: R = CO2H
c
e
O
O
O
BnN
NBn
HN
NH
HN
NCbz
g
h
CO2H
O
O
X
O
(2R,3S)-3-Benzyloxycarbonylamino-2-hydroxymethyl-4-butan-
olide (5)
OBOM
12: X = O
2: X = S
11
7
i
To a solution of i-Pr2NH (33 mL) in THF (90 mL) was added BuLi
(1.6 mol/L in hexane, 150 mL, 0.24 mol) at –78 °C under N2 and the
mixture was stirred at 0 °C for 15 min. To the resulting solution was
added 4 (21 g, 89 mmol) in THF (180 mL) at –78 °C and the mixture
was stirred at the same temperature for 1 h. Monomeric formalde-
hyde solution was prepared according to the literature16 by using
paraformaldehyde (20.3 g), p-toluenesulfonic anhydride (3.3 g) and
THF (450 mL), and was added dropwise to the enolate solution at –
78 °C. The mixture was stirred at –78 °C for 1 h. To the mixture was
added 10% aq citric acid (500 mL) and the mixture was extracted
with EtOAc. The extracts were washed with H2O, dried (MgSO4)
and evaporated. The residue (trans/cis = 12:1, determined from the
1H NMR spectrum: The C-2 proton of the trans-isomer appeared at
= 2.70–2.75 and that of cis-isomer at 2.82–2.87) was purified by
silica gel column chromatography (hexane–EtOAc–CHCl3, 1:1:1)
and subsequent crystallization by adding i-Pr2O to give 5 (14.7 g,
Scheme 2 Reagents and conditions: a: i) Ac2O, ii) NaBH4, THF, iii)
HCl, 95%; b: i) LDA, THF, ii) HCHO, –78 °C, 62%, trans/cis = 12:
1; c: BOMCl, i-Pr2NEt, THF, quant.; d: NH4OH, MeOH, 58%; e: Jo-
nes’ reagent, acetone, 76%; f: NaOCl, NaOH, H2O, 70%; g: H2,
Pd(OH)2/C, MeOH, 80%; h: BnBr, NaH, DMF, 84%; i: AcSK, DMF,
92%
In conclusion, a novel synthesis of the (+)-biotin key in-
termediate 2 from L-aspartic acid was accomplished. The
compound 2 was synthesized in 11% overall yield and in
9 steps from readily accessible N-Cbz-L-aspartic acid 8.
As the compound 2 has been converted to (+)-biotin (1) in
3 steps by our reported procedure,15 (+)-biotin (1) is now
accessible in 12 steps from 8. The present method is effi-
cient in terms of ready availability of the starting material
and high stereoselectivities of the aldol reaction and the
Hofmann rearrangement to form the required consecutive
chiral centers. The present synthetic scheme would enable
access to a variety of (+)-biotin analogs, which would
have interesting biological properties.
20
62%) as colorless crystals; mp 89–92 °C; [ ]D –1.3 (c = 1.0,
MeOH).
IR (KBr): 3316, 1765, 1703 cm–1.
1H NMR (CDCl3): = 7.30–7.40 (m, 5 H), 5.15–5.21 (br, 1 H), 5.11
(s, 2 H), 4.40–4.62 (m, 2 H), 3.92–4.13 (m, 3 H), 2.70–2,75 (m, 1
H).
SIMS: m/z = 266 (M+ + 1).
Synthesis 2002, No. 3, 361–364 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of a Key Intermediate for (+)-Biotin
363
Anal. Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C,
58.92; H, 5.37; N, 5.42.
0.312 mmol) at 10 °C. The mixture was stirred at 10 °C for 1 h and
at 55 °C for 50 min. The mixture was acidified by adding 1 N aq
HCl and extracted with EtOAc. The extracts were washed with
H2O, dried (MgSO4) and evaporated to give 7 (69.6 mg, 70%) as a
colorless oil; [ ]D20 –3.1 (c = 0.4, MeOH).
(2R,3S)-3-Benzyloxycarbonylamino-2-benzyloxymethoxy-me-
thyl-4-butanolide (9)
To a solution of 5 (2.96 g, 11.2 mmol) in THF (60 mL) were added
i-Pr2NEt (8.8 mL, 50.4 mmol) and BOMCl (3.5 mL, 25.5 mmol) at
10 °C, and the mixture was stirred at 10 °C for 1 h and at 25 °C for
2 h. The mixture was washed with water, dried (MgSO4) and evap-
orated. The residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 10:1 to 4:1 to 2:1) to give 9 (4.5 g, quant.) as
a colorless oil; [ ]D20 –2.6 (c = 0.9, MeOH).
IR (Nujol): 1782, 1738 cm–1.
1H NMR (CDCl3): = 7.26–7.39 (m, 10 H), 5.64 (s, 1 H), 5.12–5.30
(m, 2 H), 4.77 (d, J = 9.7 Hz, 1 H), 4.74 (s, 2 H), 4.58 (s, 2 H), 4.05–
4.11 (m, 1 H), 3.79–3.82 (m, 1 H), 3.44–3.49 (m, 1 H).
SIMS: m/z = 415 (M+ + 1).
Anal. Calcd for C21H22N2O7: C, 60.86; H, 5.35; N, 6.76. Found: C,
61.21; H, 5.45; N, 6.99.
IR (Nujol): 3335, 1782, 1721 cm–1.
1H NMR (CDCl3): = 7.26–7.52 (m, 10 H), 5.10–5.20 (m, 3 H),
4.62–4.75 (m, 2 H), 4.53–4.62 (m, 3 H), 4.41–4.45 (m, 1 H), 3.87–
3.98 (m, 3 H), 2.69–2.79 (m, 1 H).
(3aS,6aR)-Tetrahydro-1H-furo[3,4-d]imidazole-2,4-dione (11)
A mixture of 7 (100 mg, 0.24 mmol), 10% Pd(OH)2/C (dry) (20 mg)
in MeOH (1 mL) and H2O (0.2 mL) was hydrogenated in Parr ap-
paratus at r.t. for 17 h under 3.5 kg/cm2 of H2. The mixture was fil-
tered and the filtrate was evaporated. The residue was crystallized
by adding MeOH and Et2O to provide 11 (27 mg, 80%) as colorless
crystals; mp 159–161 °C; [ ]D20 +62.0 (c = 1.0, MeOH).
SIMS: m/z = 386 (M+ + 1).
Anal. Calcd for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C,
65.10; H, 6.32; N, 3.26.
(2R,3S)-3-Benzyloxycarbonylamino-2-benzyloxymethoxy-me-
thyl-4-hydroxy-butanamide (10)
IR (KBr): 3246, 1777, 1691 cm–1.
1H NMR (DMSO-d6): = 4.11–4.17 (m, 1 H), 4.29–4.48 (m, 3 H),
6.85 (s, 1 H), 7.37 (s, 1 H).
SIMS: m/z = 143 (M+ + 1).
To a solution of 9 (1.64 g, 4.3 mmol) in MeOH (33 mL) was added
concd aq NH3 (8.4 mL) at 10 °C and the mixture was stirred at 20 °C
for 2 h. The mixture was evaporated and the residue was purified by
silica gel column chromatography (CHCl3–MeOH, 7:1) to give 10
(989 mg, 58%) as colorless crystals; mp 165–168 °C; [ ]D20 –8.3 (c
= 0.18, MeOH).
Anal. Calcd for C5H6N2O3: C, 42.26; H, 4.26; N, 19.71. Found: C,
42.44; H, 4.12; N, 19.69.
IR (KBr): 1688, 1660 cm–1.
(3aS,6aR)-1, 3-Dibenzyltetrahydro-1H-furo[3,4-d]imidazole-
2,4-dione (12)
1H NMR (CDCl3): = 7.43 (s, 1 H), 7.29–7.36 (m, 10 H), 7.12 (d,
J = 7.6 Hz, 1 H), 6.95 (s, 1 H), 5.01 (s, 2 H), 4.59–4.64 (m, 2 H),
4.43–4.51 (m, 2 H), 3.65–3.72 (m, 2 H), 3.56–3.59 (m, 1 H), 3.15–
3.42 (m, 3 H), 2.51–2.65 (m, 1 H).
To a suspension of NaH (63.7% in mineral oil, 113 mg, 3 mmol) in
DMF (2 mL) were added 11 (142 mg, 1 mmol) and benzyl bromide
(0.36 mL, 3 mmol) at 0 °C and the mixture was stirred at r.t. for 17
h. To the mixture was added H2O and the product was extracted
with EtOAc. The combined extracts were washed with H2O, dried
(MgSO4) and evaporated. The residue was crystallized by adding
Et2O and hexane to afford 12 (271 mg, 84%) as colorless crystals;
mp 120–121 °C (Lit.4a mp 120–121 °C). [ ]D20+58.0 (c, 1.0, ben-
zene) {Lit.4a [ ]D20+58.2 (c, 1.0, benzene)}.
SIMS: m/z = 403 (M+ + 1).
Anal. Calcd for C21H26N2O6: C, 62.69; H, 6.51; N, 6.96. Found: C,
62.72; H, 6.71; N, 6.82.
(2S,3R)-3-Aminocarbonyl-2-benzyloxycarbonylamino-4-benz-
yloxymethoxybutanoic Acid (6)
IR (KBr): 1775, 1706 cm–1.
To a solution of 10 (697 mg, 1.73 mmol) in acetone (7 mL) was add-
ed dropwise Jones’ reagent [prepared from CrO3 (3.5 g), H2O (25
mL) and conc. H2SO4 (3.05 mL), 4.2 mL] over 1 h at 10 °C. The ex-
cess reagent was destroyed by adding i-PrOH and the mixture was
diluted with EtOAc. The mixture was washed with H2O, dried
(MgSO4) and evaporated. The residue was crystallized by adding i-
Pr2O to give 6 (548 mg, 76%) as colorless crystals; mp 124–126 °C;
[ ]D20 –14.4 (c = 0.1, MeOH).
1H NMR (CDCl3): = 7.23–7.40 (m, 10 H), 5.06 (d, J = 16 Hz, 1
H), 4.64 (d, J = 16 Hz, 1 H), 4.38 (d, J = 16 Hz, 1 H), 4.35 (d, J = 16
Hz, 1 H), 4.03–4.17 (m, 3 H), 3.92 (d, J = 8 Hz, 1 H).
SIMS: m/z = 323 (M+ + 1).
(3aS,6aR)-1, 3-Dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-
2,4-dione (2)
IR (KBr): 1693, 1652 cm–1.
The compound 2 was synthesized in 92% yield from 12 according
to the known procedure;4a mp 122–123 °C (Lit.4a mp 125–127 °C);
1H NMR (DMSO-d6): = 12.4–12.7 (br s, 1 H), 7.56 (d, J = 9.6 Hz,
1 H), 7.47 (s, 1 H), 7.27–7.36 (m, 10 H), 6.93 (s, 1 H), 4.96–5.05
(m, 2 H), 4.59–4.64 (m, 2 H), 4.37–4.51 (m, 3 H), 3.64–3.71 (m, 2
H), 2.92–2.97 (m, 1 H).
25
25
[ ]D +90.5 (c = 1.0, CHCl3) {Lit.4a [ ]D +91.3 0.9 (c = 1.0,
CHCl3)}. Optical purity: >99% ee [HPLC: CHIRALPAK AD, hex-
ane–EtOH (85:15), 225 nm, 40 °C, 0.8 mL/min].
IR (KBr): 1696, 1680 cm–1.
SIMS: m/z = 417 (M+ + 1).
1H NMR (CDCl3): = 7.09–7.45 (m, 10 H), 5.04 (d, J = 16 Hz, 1
H), 4.69 (d, J = 16 Hz, 1 H), 4.32–4.40 (m, 2 H), 4.09–4.17 (m, 1
H), 3.81 (d, J = 8 Hz, 1 H), 3.24–3.43 (m, 2 H).
Anal. Calcd for C21H24N2O7: C, 60.57; H, 5.81; N, 6.73. Found: C,
60.41; H, 6.01; N, 6.80.
SIMS: m/z = 339 (M+ + 1).
(4R,5S)-1-Benzyloxycarbonylamino-4-benzyloxymethoxy-me-
thylimidazolidin-2-one-5-carboxylic Acid (7)
To a solution of 0.1 mol/L aq NaOH (2.4 mL, 0.24 mmol) was add-
ed 6 (100 mg, 0.24 mmol) followed by aq NaOCl (8 wt%) (290 mg,
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(8) For reviews on the utilization of aspartic acid to drug
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Synthesis 2002, No. 3, 361–364 ISSN 0039-7881 © Thieme Stuttgart · New York