An efficient and practical procedure for Strecker reaction: A highly diastereoselective synthesis of a key intermediate for (+)-biotin

Article abstract of DOI:10.1016/j.tetlet.2004.07.034

Treatment of α-amino aldehyde 2, which was prepared through Moffatt oxidation of the corresponding β-amino alcohol 5, with aqueous sodium bisulfite allowed clean conversion to a water-soluble bisulfite adduct 6 [>99% conversion, 89% yield (two steps)]. The aqueous solution of 6 was treated with benzylamine followed by easy-handling NaCN to effect the Strecker reaction to afford α-amino nitrile 3 with high diastereoselectivity and in high yield (syn/anti = 11:1, 95% assay yield). Both the compounds syn-3 and anti-3 were converted to a key intermediate 4 for (+)-biotin through S,N-carbonyl migration in high yields.

Full text of DOI:10.1016/j.tetlet.2004.07.034

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6579–6581
An efficient and practical procedure for Strecker reaction: a highly
diastereoselective synthesis of a key intermediate for (+)-biotin
b
b
Masahiko Seki,a, Masanori Hatsuda and Shin-ichi Yoshida
*
aExport & Import Group, Purchasing Department, Logistics Division, Tanabe Seiyaku Co., Ltd, 3-2-10, Dosho-Machi,
Chuo-Ku, Osaka 541-8505, Japan
bProcess Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd, 3-16-89, Kashima, Yodogawa-Ku, Osaka 532-8505, Japan
Received 29 June 2004; revised 7 July 2004; accepted 9 July 2004
Available online 24 July 2004
Abstract—Treatment of a-amino aldehyde 2, which was prepared through Moffatt oxidation of the corresponding b-amino alcohol
5, with aqueous sodium bisulfite allowed clean conversion to a water-soluble bisulfite adduct 6 [>99% conversion, 89% yield (two
steps)]. The aqueous solution of 6 was treated with benzylamine followed by easy-handling NaCN to effect the Strecker reaction to
afford a-amino nitrile 3 with high diastereoselectivity and in high yield (syn/anti = 11:1, 95% assay yield). Both the compounds syn-3
and anti-3 were converted to a key intermediate 4 for (+)-biotin through S,N-carbonyl migration in high yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The Strecker reaction has gained considerable attention
due to its significance in the synthesis of a-amino acid
derivatives from aldehydes.1 In our synthetic studies
on (+)-biotin (1),2 a syn-selective Strecker reaction of
a-amino aldehyde 2 to b-amino-a-amino nitrile syn-3
was required to allow an access to thiolactone 4, a key
intermediate for 1.2j However, our previously reported
procedure2j has suffered from such drawbacks as need
for employing expensive trimethylsilyl cyanide
(TMSCN). Although, as a solution to the problem, we
initially attempted to use HCN, which was generated
by the treatment of NaCN with acetic acid (2 ! 3,
77% yield, syn/anti = 11:1), it was hard to apply to a
large scale preparation due to difficulty in handling toxic
and low-boiling HCN. Taylor and co-workers have re-
ported that the Strecker reaction takes place by the
treatment of bisulfite adducts of achiral aldehydes with
inexpensive and easy-handling NaCN.3 However, to
the best of our knowledge, there have not been any re-
ports on the diastereoselective Strecker reaction of the
bisulfite adducts of chiral aldehydes with an asymmetric
centre a to the carbonyl group. We envisioned a possible
use of the protocol for our diastereoselective synthesis
employing the chiral a-amino aldehyde 2. The use of
the bisulfite adduct may have an additional and signifi-
cant advantage of easy purification due to the water sol-
ubility. Reported herein are the successful results of
highly diastereoselective Strecker reaction of the bisul-
fite adduct 6 employing NaCN.
O
O
O
O
Bn
Bn
HN
NH
N
BnN
NBn
N
S
S
NHBn
CHO
O
S
CO2H
S
CN
1
2
syn-3
4
In our initial study, conversion of a-amino aldehyde 2 to
the corresponding bisulfite adduct 6 was undertaken. b-
Amino alcohol 5 was allowed to the Moffatt oxidation
employing DCC4 in the presence of TFA and pyridine
to effect a clean conversion to a-amino aldehyde 2
(90% yield).2j The resulting solution of 2 in AcOEt
was treated with sodium bisulfite (1.1equiv) in water
to provide the bisulfite adduct 6 in 99% conversion. As
expected, a simple work-up involving extraction and
separation provided 6 pure enough for the subsequent
step (Scheme 1).
The Strecker reaction of 6 was the next subject for our
investigation. The aqueous solution of 6 (vide supra) was
treated with benzylamine in a biphasic system involv-
ing CH2Cl2 and water at 20ꢁC for 2 h. The resulting
*
Corresponding author. Tel.: +81-6-6205-5498; fax: +81-6-6205-
5178; e-mail: m-seki@tanabe.co.jp
5
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.034

6580
M. Seki et al. / Tetrahedron Letters 45 (2004) 6579–6581
O
Ph
O
O
Bn
Bn
Bn
N
O
a
b
N
N
N
OH
N
S
Bn
S
S
OH
N
.
OH
90%
99%
HCl
NHBn
DMF
120oC, 5 h
Ph
S
CHO
S
SO3Na
5
2
6
CONH2
CONH2
O
S
.
anti-7 HCl
9
Bn
c
N
NHBn
CN
95%
O
syn-3
syn/anti = 11:1
>99% ee
Bn
Bn
N
N
4
91%
CONH2
SH
10
Scheme 1. Reagents and conditions: (a) DCC, TFA, pyridine, DMSO,
AcOEt, 50ꢁC, 3h; (b) NaHSO3, AcOEt, H2O, 20ꢁC, 18h; (c) (i)
BnNH2 (1.7equiv), CH2Cl2, 20ꢁC, 2h, (ii) NaCN (1.2equiv), 8–20ꢁC
20h, (iii) NaHSO3 (0.3equiv), NaCN (0.3equiv), 20ꢁC, 1.5h.
Scheme 3.
reaction mixture and filtration. The oily anti-isomer
anti-7 solidified by converting to HCl salt and was ob-
tained in 7% yield without tedious purification such as
silica-gel column chromatography. According to our re-
ported procedure,2j syn-7 was allowed to undergo the
ring transformation from 2-thiazolidinone to 2-imidazo-
lidinone through S,N-carbonyl migration and subse-
quent hydrolysis to give thiol carboxylic acid 8 in 95%
yield. The compound 8 obtained was cyclized and isom-
erized to thiolactone 4 in 93% yield. In contrast, the anti-
isomer anti-7ÆHCl was directly converted to 4 in 91%
yield with heating at a higher temperature (120ꢁC)
through the S,N-carbonyl migration followed by spon-
taneous cyclization (Scheme 3). The structure of 4 ob-
tained either from syn-7 or anti-7ÆHCl was fully
characterized by comparison with an authentic sample
mixture involving an imine (Scheme 4, compound 13)
and a bisulfite adduct of the imine (Scheme 4, com-
pound 14) was treated with NaCN (1.2equiv) at 8ꢁC
and the whole was stirred at ambient temperature for
20h. To complete the reaction were added NaCN
(0.3equiv) and sodium bisulfite (0.3equiv) and the mix-
ture was further stirred for 1.5h. Then, 10% aq NaOH
was added and the organic phase was washed with
water to completely remove the toxic cyanide to provide
a-amino nitrile 3 as a solution of CH2Cl2 with high dia-
stereoselectivity and in high yield (syn/anti = 11:1, 95%
assay yield).6 The ee value of 3 was confirmed to be
>99% ee by HPLC analysis.7 It should be noted that,
during the reaction, the reaction mixture was always ba-
sic and evolution of HCN gas in the reaction flask was
much less than that observed in the reaction employing
NaCN/AcOH.8
1
with respect to IR, H NMR and MS spectra and the
ee value of 4 was confirmed to be >99% ee by HPLC.9
The resulting CH2Cl2 solution of 3 was directly allowed
to amidation employing H2O2, K2CO3 and DMSO
(Scheme 2).2j The reaction smoothly proceeded even in
a mixed solvent of DMSO and CH2Cl2 to afford the cor-
responding amide 7 in quantitative yield. The syn-isomer
syn-7 was obtained as solids by just adding water to the
The plausible mechanism of the present reaction is de-
picted in Scheme 4. The compound 6 solidified by con-
centrating the aqueous solution and the relative
O
S
O+
O
Bn
H
N
S
N
SO3Na
Bn
CHO
H
H
O
Bn
N
12
2
d
S
.
anti-3
anti-7 HCl
syn-3
+
+
NHBn
syn/anti = 11:1
O
O
O
CONH2
Bn
Bn
Bn
N
N
syn-7
93%
N
BnNH2
S
S
S
7%
N
NHBn
OH
SO3Na
Bn
e
95%
H
SO3Na
14
g
91%
O
+ NaHSO3
13
6
Bn
Bn
N
N
f
4
O
S
S
H
O
93%
Bn
CO2H
N
NaCN
SH
N
CN
NHBn
CN
syn-3
8
N+
Bn
Bn
H
Scheme 2. Reagents and conditions: (d) (i) H2O2, K2CO3, DMSO/
CH2Cl2, 20ꢁC, 2.5h, (ii) H2O, filtration, (iii) for the filtrate: HCl; (e) (i)
DMF, 90ꢁC, 1h, (ii) HCl; (f) DCC, TFA, pyridine, CHCl3, 5ꢁC––
reflux, 5h; (g) 120ꢁC, 5h DMF.
Na2SO3
+
15
Scheme 4.

M. Seki et al. / Tetrahedron Letters 45 (2004) 6579–6581
6581
solution can be washed with aq NaOH for complete
removal of the toxic cyanide.
configuration of 6 was confirmed to be syn by X-ray
crystallographic analysis.10 The syn-isomer 6 may be
formed through a Felkin–Ahn model11 in which sodium
bisulfite attacks the re-face of the carbonyl group. The
adduct 6 was treated with benzylamine in a 0.75:1.0 mix-
ture of D2O and CD2Cl2. A mixture of free imine 13 and
bisulfite adduct of the imine 14 (13/14 = 61:39) was
formed in nearly quantitative yield, as determined by
1H NMR analysis. The relative configuration of 14
should be anti in consideration of the structure of syn-
32j that may be formed through the similar transition
state controlled by a Houk model.12 It is noteworthy
that any racemization did not occur during the reaction
partly because of the partial trap of the imine 13 as the
bisulfite adduct 14.
6. Preparation of 3 through the formation of the bisulfite
adduct and the Strecker reaction therewith: To a solution
of b-amino alcohol 5 (40g, 0.18mol) in a mixed solvent of
AcOEt (90mL) and DMSO (90mL) were successively
added pyridine (2.92mL, 0.036mol), TFA (2.78mL,
0.036mol) and DCC (44.4g, 0.22mol) at <43ꢁC. After
stirring the mixture at 50ꢁC for 3h, AcOEt (200mL) was
added and the mixture was cooled in an ice bath. The
precipitated DCU was filtered and the filtrate was washed
with 12% aq NaCl (200mL). The aqueous layer was
extracted with AcOEt (100mL) and the combined organic
phases were washed with 12% aq NaCl (200mL). The
AcOEt solution contained a-amino aldehyde 2 (35.9g,
90%) [HPLC; Capcell Pak C18 SG 120A (Shiseido),
15cm · 4.6mm, 15mM Na2HPO4/CH3CN = 5:1, 1mL/
min, 40ꢁC, 220nm]. To the compound
2 (35.9g,
In conclusion, an efficient and practical synthesis of a
key intermediate for (+)-biotin was worked out through
novel and highly diastereoselective Strecker reaction
employing bisulfite adduct of a-amino aldehyde and
easy-handling NaCN. The ease of operation, the use
of inexpensive reagents and mild reaction conditions
of the present method would permit facile access to b-
amino-a-amino nitriles involving an intermediate for
(+)-biotin.
0.162mol) in AcOEt were added water (80mL) and
sodium bisulfite (18.6g, 0.178mol) and the mixture was
stirred at 20ꢁC for 30min. After the solution was
concentrated under reduced pressure, AcOEt (80mL)
was added to the residue. The mixture was stirred at
20ꢁC for 17h and the aqueous layer involving bisulfite
adduct 6 (35.4g, 0.16mol) was suspended in CH2Cl2
(106mL). To the suspension was added benzylamine
(23.2g, 0.27mol) and the mixture was stirred at 20ꢁC for
2h. The mixture was cooled down to 8ꢁC and NaCN
(9.4g, 0.19mol) was added. After stirring the mixture at
20ꢁC for 20h, NaHSO3 (5.0g, 0.048mol) and NaCN
(2.35g, 0.048mol) were added and the mixture was stirred
for 1.5h. To the mixture was added 10% aq NaOH
(40mL). The organic phase was separated and washed
with water (40mL). The aqueous layer was extracted with
CH2Cl2 (40mL) and combined extracts were dried over
anhydrous MgSO4 and filtration to afford a-amino nitrile
3 (51.1g, 95%) in CH2Cl2 as a mixture of syn- and anti-
isomers [syn/anti = 11:1, HPLC; L-Column ODS (Shima-
dzu), 0.01M KH2PO4 buffer (pH = 3)/CH3CN = 55:45,
1mL/min, 40ꢁC, 225nm].
References and notes
1. (a) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92,
889; (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539; (c)
Gro¨ger, H. Chem. Rev. 2003, 103, 2795.
2. (a) Shimizu, T.; Seki, M. Tetrahedron Lett. 2000, 41, 5099;
(b) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42, 429;
(c) Shimizu, T.; Seki, M. Tetrahedron Lett. 2002, 43, 1039;
(d) Mori, Y.; Seki, M. Heterocycles 2002, 58, 125; (e)
Mori, Y.; Seki, M. J. Org. Chem. 2003, 68, 1571; (f) Seki,
M.; Hatsuda, M.; Mori, Y.; Yamada, S. Tetrahedron Lett.
2002, 43, 3269; (g) Seki, M.; Mori, Y.; Hatsuda, M.;
Yamada, S. J. Org. Chem. 2002, 67, 5527; (h) Seki, M.;
Shimizu, T.; Inubushi, K. Synthesis 2002, 361; (i) Mori,
Y.; Kimura, M.; Seki, M. Synthesis 2003, 2311; (j) Seki,
M.; Kimura, M.; Hatsuda, M.; Yoshida, S.; Shimizu, T.
Tetrahedron Lett. 2003, 44, 8905; (k) Kimura, M.; Seki, M.
Tetrahedron Lett. 2004, 45, 1635; (l) Kimura, M.; Seki, M.
Tetrahedron Lett. 2004, 45, 3219.
3. (a) Taylor, H. M.; Hauser, C. R. In Org. Synth.; Wiley:
New York, 1973; Collect. Vol. 5, p 437; (b) Leblanc, J.-P.;
Gibson, H. W. J. Org. Chem. 1994, 59, 1072.
4. Although large scale disposal of dicyclohexylurea (DCU)
after the reaction can be an important issue to be solved,
DCU is recovered by simple filtration and converted back
to DCC according to the known procedure (see: Stevens,
C. L. J. Org. Chem. 1967, 32, 2895).
7. HPLC conditions: Chiralcel AD-H (Daicel), hexane/
EtOH = 90:10, 0.8mL/min, 225nm, 40ꢁC.
8. After the reaction, the concentration of HCN gas in the
reaction flask was 50ppm. Nonetheless, the reaction
should be conducted in a well-ventilated draft.
9. HPLC conditions: Chiralcel AD (Daicel), hexane/
EtOH = 85:15, 0.8mL/min, 225nm, 40ꢁC.
10. The X-ray data of 6 have been deposited to Cambridge
Crystallographic Data Centre.
11. (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
1991, 537; (b) Anh, N. T. Top. Curr. Chem. 1980, 88, 114.
12. (a) In the possible stable conformation of 15, the imino
group might orient to the opposite direction as does the
carbonyl group in 12 due to the presence of an N-benzyl
group on the imine. Houk, K. N.; Paddon-Row, M. N.;
Rondan, N. G.; Wu, Y.-D.; Brown, F. K.; Spellmeyer,
D.C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Sci. 1986, 231,
1108; (b) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero,
T. J. Org. Chem. 1996, 61, 9028.
5. Dichloromethane (CH2Cl2) is classified as a class 2 solvent
according to ICH guidelines. However, the use of CH2Cl2
is required to dissolve a-amino nitrile syn-3: whose