Synthetic studies on d-biotin, part 8: An efficient chemoenzymatic approach to the asymmetric total synthesis of d-biotin via a polymer-supported PLE-mediated desymmetrization of meso-symmetic dicarboxylic esters

Article abstract of DOI:10.1002/adsc.200404311

A practical chemoenzymatic method for the asymmetric total synthesis of d-biotin (1) starting from the commercially available cis-1,3-dibenzyl-2- imidazolidone-4,5-dicarboxylic acid (2) has been developed. The key step of the synthesis is the highly enantioselective hydrolysis of meso-dicarboxylic esters by a polymer-supported pig liver esterase and introduction of a formyl group at the C-4 position in 4 via a Grignard reaction. The polymer-supported PLE can be recovered quantitatively from the reaction mixture by simple filtration and reused without significant loss of activity.

Full text of DOI:10.1002/adsc.200404311

FULL PAPERS
Synthetic Studies on d-Biotin, Part 8:[1] An Efficient
Chemoenzymatic Approach to the Asymmetric Total Synthesis of
d-Biotin via a Polymer-Supported PLE-Mediated
Desymmetrization of meso-Symmetic Dicarboxylic Esters
Fen-Er Chen,a,* Xu-Xiang Chen,b Hui-Fang Dai,a Yun-Yan Kuang,a Bin Xie,a
Jian-Feng Zhaoa
a
Department of Chemistry, Fudan University, Shanghai, 200433, Peopleꢀs Republic of China
Fax: (þ86)-21-65641-740, e-mail: rfchen@fudan.edu.cn
b
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016, Peopleꢀs Republic of China
Received: October 11, 2004; Accepted: January 3, 2005
Dedicated to Prof. Yuguo Zhong on the occasion of his 70th birthday and his retirement.
Abstract: A practical chemoenzymatic method for the via a Grignard reaction. The polymer-supported
asymmetric total synthesis of d-biotin (1) starting PLE can be recovered quantitatively from the reac-
from the commercially available cis-1,3-dibenzyl-2- tion mixture by simple filtration and reused without
imidazolidone-4,5-dicarboxylic acid (2) has been de- significant loss of activity.
veloped. The key step of the synthesis is the highly
enantioselective hydrolysis of meso-dicarboxylic es- Keywords: d-biotin; desymmetrization; enzyme catal-
ters by a polymer-supported pig liver esterase and in- ysis; kinetic resolution; polymer-supported PLE; vita-
troduction of a formyl group at the C-4 position in 4 min H
Introduction
excess (x98%) in the presence of chiral oxazaborolidine
catalyst[1] or polymer-supported chiral oxazaborolidine
Although marked advances in the total synthesis of d-bi- catalyst.[6] The chromatographic purification of the chi-
otin (1) in the last 55 years have been achieved,[2] the ral hydroxylactam was needed, thus making the two ap-
1949 Goldberg and Sternbach 14-step approach, utiliz- proaches very difficult for large-scale synthesis. As a re-
ing (3aS, 6aR)-thiolactone 6 as a key intermediate, is still sult, the development of efficient and practical methods
relevant today, with minor improvements, for large- that exhibit high enantioselectivity is still a highly desir-
scale syntheses.[3] The undesirability of involving an in- able yet exclusive goal in the asymmetric synthesis of d-
termediate resolution progress, which required the recy- biotin.
cling of a large amount of resolving agents in the prepa-
In a wide variety of asymmetric methods, enzymatic
ration of the chiral building block, (3aS, 6aR)-lactone 5, asymmetric hydrolysis has become a very powerful
has provided an impetus to search for alternatives. For method in the development of strategies for the asym-
example, Matsukiꢀs group reported[4] the example of a metric synthesis of various natural products.[7] In partic-
one-pot enantioselective reduction of the meso-anhy- ular, esterases, such as pig liver esterase (PLE), are now
dride of 2 to 5 with 90% ee. However, this approach re- widely used in asymmetric organic synthesis, notably in
quired the use of a large excess of Noyoriꢀs BINAL-H the desymmetrization of meso compounds.[8] In this way,
complexes. Choi et al.[5] have reported a catalytic asym- prochiral diesters can be hydrolyzed to enantiomerically
metric synthesis of 5 with modified Cinchona alkaloids enriched hemiesters in up to quantitative yield.[9] In
via enantioselective methanolysis of the meso-anhy- 1982, Iriuchijima and co-workers[10] realized the first
dride of 2 and a one-pot chemoselective reduction PLE-catalyzed asymmetric hydrolysis of prochiral die-
with high enantioselectivity (90% ee). But this method sters 3 into the corresponding (4S,5R)-hemiester 4 as a
required the very expensive dihydroquinidine phe- precursor for the formation of (3aS,6aR)-lactone 5 to
nanthryl ether (DHQD-PHN) as catalyst. Very recently, perform an asymmetric total synthesis of 1. However,
we reported the enantioselective reduction of the meso- the efficiency of biocatalyst recovery and recycling be-
cyclic imide into hydroxylactam as a key chiral building comes a critical feature for the economical viability of
block to prepare 5 in excellent yield and enantiomeric an industrial process based on such an enzyme. There-
Adv. Synth. Catal. 2005, 347, 549–554
DOI: 10.1002/adsc.200404311
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fore, a practical means of separating the biocatalyst be- expected, the (4S,5R)-hemiester 4 was achieved in a
fore work-up has to be devised. Obviously, immobiliza- yield of 90% with an enantiomeric excess of 91%, which
¼
tion of PLE would offer a solution to this problem.
was then upgraded to 98.5% ee by recrystallization
In continuation of our continued interest in develop- from toluene. The enantiomeric purity of 4 was deter-
ing new and practical routes for the total synthesis of mined by chiral HPLC and 1H NMR analysis of the dia-
1, we to report herein an efficient and more economical stereoisomers of (S)-1-(1-naphthyl)-ethylamine ob-
method for the asymmetric synthesis of 1, which in- tained by treatment of 4 with (S)-1-(1-naphthyl)-ethyl-
volves the polymer-supported PLE-catalyzed hydrolysis amine according to the literature procedure.[8c] The abso-
of 3 into the (4S,5R)-hemiester 4 and the assembly of the lute configuration of 4 (CCDC no. 249374) was verified
formyl group at the C-4 position in (3aS,6aR)-thiolac- by X-ray diffraction analysis (Figure 1). Significantly, af-
tone 6 via a Grignard reaction.
ter the asymmetric hydrolysis was completed, the poly-
mer-supported PLE used could be conveniently recov-
ered from the reaction mixture by simple filtration fol-
lowed by washing with 0.1 M aqueous phosphate buffer.
One of the most useful features of polymer-supported
Results and Discussion
The present synthetic route to 1 is outlined in Scheme 1. enzyme catalyst is its ability to be recycled.[12] To show
The known meso-dicarboxylic diester 3 was prepared in that the immobilized PLE can be recycled for a number
95% yield by heating commercially available cis-1,3-di- of times, the hydrolysis of 3 using the polymer-supported
benzyl-2-imidazoidione-4,5-dicarboxylic acid (2) and PLE was repeated four times. As shown in Table 1, the
methanol in benzene with a catalytic amount of H2SO4 enzyme-catalyzed hydrolysis proceeded smoothly with-
with azeotropic removal of water.
out any decrease of the enantiomeric excess of 4 in every
With the prochiral meso-dicarboxylic diesters 2 in cycle, clearly indicating the reusability of the polymeric
hand, the next crucial step of our approach to 1 was enzyme without loss of catalytic performance. Also, the
the enantioselective hydrolysis of 3 into the (4S,5R)- rate of hydrolysis was increased with each successive cy-
hemiester 4 with the immobilized PLE on Eupergit cle of the enzyme. This reaction went to completion
Cꢂ.[11] The reaction was conducted in 0.1 M aqueous within 45 h when the enzyme was first employed. Only
phosphate buffer suspensions at 30 8C for 45 h, which 36 h in the second cycle (entry 2) and 29 h in the third cy-
were adjusted and kept constant at pH 8 by the continu- cle (entry 3). Complete conversion in the fourth cycle
ous addition of 1 M aqueous NaOH using a pH stat. As was observed after only 25 h (entry 4). This may be ow-
Scheme 1. Synthetic scheme for the total synthesis of d-biotin (1). Reaction conditions: a) CH3OH, H2SO4, benzene, reflux, 6 h,
95%; b) polymer-supported PLE, 0.1 M aqueous phosphate, 0.1 M aqueous NaOH, pH 8, 45 h, 30 8C, then 1 M aqueous HCl,
90%; c) LiEt3BH, THF, 0 8C to r.t., 6 h, then 1 M aqueous HCl, 45 8C, 1 h, 88%; d) EtOC(S)SK, DMA, 125 8C, 7 h, 70%; e)
CH3OCH2MgI, n-Bu2O, toluene, 45 8C to 15 8C, 3 h, then 0 8C to r.t., 1 M aqueous HCl, reflux, 3 h, 78%; f) (EtO)2P(O)CH2-
¼
CH CHCO2CH3, Ba(OH)2 ·0.8 H2O, dioxane, H2O, 70 8C, 2.5 h, 90%; g) 1 M aqueous KOH, CH3OH, n-Bu4NBr, r.t., 8 h, then
1 M aqueous HCl; h) H2, Pd(OH)2/C, AcOEt, 10 atm, 15 h, r.t., 82% (from 8 to 10); i) 47% aqueous HBr, reflux, 42 h; j) (i)
diphosgene, 3 M aqueous KOH, n-Bu4NBr, toluene, r.t., 6.5 h; (ii) 2 M aqueous HCl, 82% (from 10 to 1).
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Table 1. Recycling of polymer-supported PLE in the asym-
metric hydrolysis of 3 in 0.1 M aqueous phosphate buffer at
308C.
Run
Reaction time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
45
36
29
25
90
90.5
91
91
91
90.5
91
90
[a]
Yields refer to crude products
[b]
Determined by HPLC analysis of the diastereomeric (S)-
1-(1-naphthyl)ethylamides prepared from 4 and (S)-1-(1-
naphthyl)ethylamine, using a Daicel column (Chiralpak
OD, hexane/i-PrOH, 4: 1).
ester 8 was the only product of this reaction. Treatment
of 8 with potassium hydroxide in methanol in the pres-
ence of n-Bu4NBr (TBAB) effected a one-step transfor-
mation involving the positional isomerization of the
conjugated double bond of 5-side chain, hydrolysis and
Figure 1. Molecular structure of (4S,5R)-hemiester 4 (CCDC
No. 249374) in the crystal. The thermal ellipsoids are drawn
at the 30% probability level.
ing to a preadjustment of the conformation of the en- acidification. The resulting crude 3,5-dienyl acid 9
zyme by incorporation of water molecules after catalytic upon hydrogenation in ethyl acetate at 308C and 10
hydrolysis.
atm of H2 using Pd(OH)2/C catalyst led stereospecifical-
Chemoselective reduction of the ester group of 4 with ly to dibenzyl-biotin 10 in 82% yield based on 8.
super-hydride (LiEt3BH) in THF at room temperature
Finally, transformation of 10 into 1 was performed in
for 2.5 hours, followed by acid-catalyzed lactonization three steps in a similar way to our previous procedure.[6]
afforded (3aS,6aR)-lactone 5 in 88% yield with 96.5% Heating 10 with 47% aqueous HBr at reflux for 42 hours
enantiomeric excess. The lactone was increased up to
via a one-pot debenzylation and ring opening reaction
x99% ee by recrystallization from ethanol, which was gave rise to the diamine·2 HBr salt. Non-purified 11
treated with potassium O-ethyl dithiocarbonate was subjected to the phase-transfer-catalyzed ring clos-
[EtOC(S)SK] in anhydrous N,N-dimethylacetamide ing reaction upon treatment with diphosgene in the
(DMA) at 125 8C for 7 hours to provide the desired presence of 3 M aqueous KOH and a catalytic amount
(3aS,6aR)-thiolactone 6 in 80% yield.
of TBAB in toluene at room temperature for 6.5 hours
The introduction of the formyl group was carried out to afford the desired d-biotin (1) in 82% yield
by the addition of the Grignard reagent, derived from io-
domethyl methyl ether[13] and magnesium, to 6 in
n-Bu2O/toluene (1:1) at 15 8C and subsequent treatment
with 1 M aqueous HCl at reflux via dehydration/hydroly-
Conclusion
sis in a one-pot procedure to afford the (3aS,4R,6aR)-al-
dehyde 7 exclusively in 78% yield. It should be noted
that the Grignard reaction of 6 is dependent upon the re-
action solvent. In THF, the yield of 7 was 45%, but the
use of ether considerably improved the yield to 63%.
The stereochemistry of (3aS,4R,6aR)-aldehyde 7 was
obvious from the lack of vicinal coupling between the
protons a and b to the aldehyde, clearly indicating that
C-4–Ha and C-3–Ha are anti-disposed, and a b-orienta-
tion of the hydroxy group at C-4 in 7.
In summary, we have developed an efficient synthesis of
d-biotin (1) starting from readily accessible cis-1,3-di-
benzyl-2-imidazolidone-4,5-dicarboxylic acid in about
25% overall yield. Notable features include the enzy-
matic desymmetrization of meso-dicarboxylic esters 3
with polymer- supported PLE to prepare the key chiral
(4S,5R)-monoester 4 and introduction of a formyl group
in 4 via a modified Grignard reaction. This procedure
should permit the practical large-scale preparation of
d-biotin.
The Horner–Emmons reaction of 7 in dioxane at
70 8C with diethyl 3-methoxycarbonyl-2-propenylidine
phosphonate using activated barium hydroxide catalyst
C-200 [Ba(OH)2 ·0.8 H2O][14] under interfacial solid-liq-
uid conditions following Sinisterraꢀs conditions provid-
ed the (E,E)-2,4-dienyl ester 8 in 90% yield as a single
Experimental Section
General Remarks
1
13
isomer. Comparison of the H and CNMR data of 8
Commercially available reagents were used as received. DMA
with literature data[15] revealed that the (E,E)-2,4-dienyl was distilled over CaH2 and stored under N2 over 3 ꢃ mo-
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lecular sieves. THF, n-Bu2O and toluene were dried with Na/
benzophenone and stored over Na wire under N2. Iododimeth-
yl methyl ether[13] was prepared through the treatment of an ex-
cess of the dimethyl acetal of formaldehyde with trimethylsilyl
iodide. Polymer-supported PLE[11] and C-200 catalyst[14] were
prepared according to the literature procedures. Analytical
TLC was carried out with silica gel GF254 plates (Qingdao,
Haiyang, China).
Melting points were measured with a WRS-1 digital melting
point apparatus and are uncorrected. IR spectra were recorded
on a Nicolet FI-IR 300 spectrometer. NMR spectra were re-
corded on a Bruker AMX 300 (1H NMR: 300 MHz, 13C:
100 MHz) spectrometer with TMS as internal standard. Mass
spectra were obtained on an HP-5988A spectrometer by direct
inlet at 70 eV. Optical reactions were measured on a Perkin-El-
mer 241 MC polarimeter
1H, J¼15.4), 7.19–7.36 (m, 10H), 13.4 (s, 1H); 13C NMR
(CDCl3): d¼46.8, 47.1, 53, 56.8, 57, 57.5, 128, 128.8, 128.96,
129.02, 135.7, 159.8, 168.8, 171; MS (EI): m/z (%)¼368 (Mþ,
3), 3336 (10), 323 (4), 309 (7), 277 (2.6), 264 (9.4), 134 (6), 91
(100), 65 (12).
(3aS,6aR)-1, 3-Dibenzyltetrahydro-4H-furo[3,4-d]-
imidazole-2,4(1H)-dione (5)
To a stirring solution of 4 (17.2 g, 45 mmol) in THF (280 mL)
was added dropwise LiEt3BH (1.0 M in 155 mL THF,
155 mmol) at 0 8C. After being stirred at the same temperature
for 30 min, the reaction mixture was allowed to warm up to
room temperature, and stirred for 5.5 h, monitoring the reac-
tion by TLC. Then 1 M aqueous HCl (200 mL) was added
with stirring at 45 8C for 1 h. After cooling to room tempera-
ture, the resulting mixture was extracted with EtOAc (4ꢀ
55 mL). The combined organic layers were washed with satu-
rated aqueous NaCl (3ꢀ400 mL) and H2O (3ꢀ400 mL), and
dried over Na2SO4. Evaporation of the solvent under reduced
pressure gave the crude product, which was purified by recrys-
tallization from EtOH to afford pure 5 as a white crystalline
powder; yield: 12.75 g (88%); mp 119–121 8C; [a]2D5: þ61.3 (c
Dimethyl cis-1,3-Dibenzyl-2-imidazolidine-4,5-
dicarboxyate (3)
A mixture of 2 (283.2 g, 0.8 mol), CH3OH (162 mL, 4 mol),
conc. H2SO4 (4 mL, 75.1 mmol), and benzene (650 mL) was
stirred at reflux using a Dean–Stark apparatus for 6 h. After
the removal of solvent under vacuum, the residue was diluted
with H2O (400 mL) and EtOAc (400 mL). The organic layer
was separated, and the aqueous layer was extracted with
EtOAc (3ꢀ100 mL). The combined organic layers were wash-
ed with 2 M Na2CO3 (3ꢀ50 mL) and H2O (4ꢀ50 mL), dried
over (Na2SO4) and evaporated under reduced pressure to
give the crude product which was recrystallized from CH3OH
to afford the pure 3 as a white crystalline powder; yield:
290.3 g (95%); mp 111–112 8C (Lit.[10] mp 109–112 8C); IR
(KBr): v¼1749, 1735, 1700 cmꢁ1; 1H NMR (CDCl3): d¼3.65
(s, 6H), 4.07 (d, 4H, J¼14.75 Hz), 4.98 (d, 2H, J¼14.95 Hz),
7.20–7.30 (10H); MS (EI): m/z (%)¼382 (Mþ, 7.62), 325
(1.1), 264 (1.8), 291 (11), 91 (100).
0
2.0, CHCl3) {Lit.[1] mp 120–121 8C; [a]2D5: þ61.5 (c 2.0,
CHCl3)}; IR (KBr): v¼1785, 1704, 1416, 1210 cmꢁ1; 1H NMR
(CDCl3): d¼3.59 (s, 3H), 4.03–4.14 (m, 4H), 4.97 (d, 1H, J¼
14.8 Hz). 5.07 (d, 1H, J¼14.8 Hz). 7.20–7.40 (m, 10H), 10.52
(br s, 1H);13C NMR (CDCl3): d¼45.5, 47.1, 53, 54.6, 70.2,
128.1, 128.3, 128.4, 128.9, 129, 129.1 136.1, 136.2, 158.4; MS
(EI): m/z (%)¼322 (Mþ, 24.5), 264 (6.91), 231 (6.94), 187
(16.1), 91 (100).
(3aS, 6aR)-1,3-Dibenzylthiotetrahedro-4H-thieno[3,4-
d]imidazole-2,4(1H)-dione (6)
A stirred mixture of 5 (19.3 g, 60 mmol), potassium O-ethyl di-
thiocarbonate (11.5 g, 72 mmol) and DMA (130 mL) was heat-
ed at 1258C for 7 h under N2. The reaction mixture was cooled
to room temperature and diluted with H2O (120 mL) and tol-
uene (180 mL). The organic layer was separated and the aque-
ous layer was extracted with toluene (3ꢀ30 mL). The com-
bined organic layers were washed with saturated aqueous
NaCl (3ꢀ45 mL) and H2O (4ꢀ30 mL), dried over Na2SO4,
and evaporated under reduced pressure to give the crude prod-
uct which was purified by recrystallization from EtOAc to af-
ford the pure 6; yield: 16.2 g (80%); mp125–1268C; [a]2D0:
þ90.2 (c 1.0, CHCl3) {Lit.[17] mp 125–1278C; [a]2D0: þ90.8 (c
(4S,5R)-1, 3-Dibenzyl-5-(methoxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic Acid (4)
To a suspension of 3 (19.1 g, 50 mmol) in a mixture of 0.1 M
phosphate buffer (pH 8, 1.0 L) and CH3OH (800 mL) was add-
ed polymer-supported PLE (408 units, 6.0 mg). The reaction
mixture was stirred at 30 8C for 45 h. The pH value of reaction
mixture was kept at 8 by addition of 1 M NaOH. The reaction
was stopped by adjusting the pH to 9. The polymeric-supported
PLE catalyst was filtered and washed several times with 0.1 M
phosphate buffer and stored in a buffer suspension for reuse.
The combined aqueous layer was acidified to pH 2.0 with 1
M HCl and extracted with EtOAc (4ꢀ150 mL). The combined
organic layers were washed with H2O (3ꢀ100 mL) and satu-
rated aqueous NaCl (3ꢀ80 mL), dried over Na2SO4, and
evaporated under reduced pressure to give the crude 4 as a
white solid; yield: 16.6 g (90%), mp 145–148 8C, [a]2D5: þ6.688
(c 1.0, DMF). Recrystallization from toluene afforded pure 4
as a white crystalline powder; yield: 14.7 g (80%); mp 150–
1
1.0, CHCl3)}; IR (KBr): v¼1705, 1694, 1425, 1226 cmꢁ1; H
NMR (CDCl3); d¼3.27 (dd. 1H, J¼2.2, 12.8 Hz), 3.38 (dd,
1H, J¼5.5, 12.8 Hz), 3.80 (d, 1H, J¼8.1 Hz), 4.13 (ddd, 1H,
J¼2.2, 5.5, 8.1 Hz), 4.35, 4.36, 4.68, 5.04 (4ꢀd, 4H, J
¼15.2 Hz), 7.28–7.335 (m, 10H); MS (EI): m/z (%)¼338
(Mþ, 17), 310 (23), 277 (9), 264 (65).
(3aS,4R,6aR)-1,3-Dibenzyl-4-formyl-1H-
tetrahydrothieno[3,4-d]imidazole-2(3H)-one (7)
151 8C, [a]2D5: þ7.31 (c 1.0, DMF) {Lit.[16] mp 149–150 8C,
20
¼
[a]D : ꢁ27.6 (c 1.0, DMF)}; IR (KBr): v 3257, 1963, 1706,
1450, 1256, 1237, 770 cmꢁ1; H NMR (CDCl3): d¼3.54 (s,
Iodomethyl methyl ether (3.44 g, 20 mmol) was added to a stir-
red suspension of magnesium (6.32 g, 0.26 mol) in a mixture n-
1
3H), 4.00–4.15 (m, 4H), 4.66 (d, 1H, J¼15.4 Hz), 4.77 (d,
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Bu2O (35 mL) and toluene (35 mL) at 458C under a nitrogen
atmosphere, when reaction has started, the remaining iodo-
methyl methyl ether (41.3 g, 0.24 mol) in a mixture of n-Bu2O
(125 mL) and toluene (125 mL) was added dropwise within
45 min. Stirring was continued at 458C for 1 h, followed by
cooling to 158C and dropwise addition of a solution of 6
(33.8 g, 0.1 mol) in toluene (380 mL) at 158C. The reaction
mixture was stirred 3 h at this temperature, 2 M aqueous HCl
(200 mL) was added and mixture was refluxed with stirring
for 3 h. After cooling to room temperature, the organic layer
was separated and the aqueous layer was extracted with tol-
uene (4ꢀ50 mL). The combined organic layers were washed
with saturated aqueous NaHCO3 (4ꢀ55 mL), saturated aque-
ous NaCl (3ꢀ40 mL) and H2O (4ꢀ45 mL) and dried over
Na2SO4. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography on
silica gel using EtOAc-petroleum ether (1:2) to afford the
pure 7 as a colorless oil; yield: 24.6 g (70%); [a]2D2: ꢁ61.2 (c
1.0, CHCl3) {Lit.[15] [a]D20: ꢁ60 (c 0.9, CHCl3)}; IR (nujol): v¼
2939, 1706, 1693, 1605, 1594, 1502, 1452, 1250 cmꢁ1; 1H NMR
(CDCl3): d¼2.27 (dd, 1H, J¼12.9, 4.76 Hz), 2.64 (d, 1H, J¼
12.9), 3.60 (s, 1H), 4.13 (dd, 1H, J¼7.8, 4.75 Hz), 4.17 (d, 1H,
J¼15.4 Hz), 4.34 (d, 1H, J¼7.95 Hz), 4.36 (d, 1H, J¼
15.4 Hz), 4.46 (d, 1H, J¼15.4 Hz), 4.67 (d, 1H, J¼15.4 Hz),
7.18–7.35 (m, 10H); 13C NMR (CDCl3): d¼34.7, 46.4, 47.2,
59.3, 60.6, 62, 127.6, 127.7, 127.8, 128.65, 128.71, 136.8, 137,
159.8, 189.9; MS (EI): m/z (%)¼352 (Mþ, 5), 323 (5), 277
(93), 264 (6), 91 (100), 65 (6).
(3aS,4S,6aR)-1, 3-Dibenzyltetrahydro-1H-thieno[3,4-
d]imidazole-2(3H)-one-4-ylpentanoic Acid (10)
1 M aqueous KOH (143 mL) and a catalytic amount of TBAB
were added to a solution of 8 (13 g, 30 mmol) in CH3OH
(130 mL) at room temperature for 8 h. Then, the solvent was
evaporated under reduced pressure to dryness. 1 M HCl
(235 mL) and CH2Cl2 (200 mL) were added with stirring at
5–108C, the organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3ꢀ40 mL). The combined organic
layers were washed with saturated aqueous NaCl (3ꢀ45 mL)
and H2O (3ꢀ45 mL), and dried over Na2SO4. The solvent
was evaporated. The residue was dissolved in EtOAc
(125 mL) and hydrogenated under 10 atm of H2 in the presence
of Pd(OH)2/C (1.1 g) at room temperature for 15 h. After the
reduction was completed, the reaction mixture was filtered
through a pad of celite, which was washed with EtOAc (3ꢀ
10 mL). The filtrate was evaporated under reduced pressure
to give the crude product, which was purified by recrystalliza-
tion from i-PrOH/petroleum ether (bp 60–908C, 1:2) to afford
the pure 10; yield: 10.4 g (82%); mp 91–938C; [a]2D3: ꢁ26.6 (c 1.0,
CH3OH) {Lit.[18] mp 91–928C; [a]D23: ꢁ26.8 (c 1.0, CH3OH)}; IR
(KBr): v¼29.28, 1726, 1664, 1433, 1366, 1230, 1178, 951,
1
754 cmꢁ1; H NMR (CDCl3): d¼1.59–1.64 (m, 6H), 2.33 (t,
2H, J¼6.55 Hz), 2.70 (4ꢀd, 2H, J¼2.35, 4.38 Hz), 3.08
(m,1H), 3.91 (dd, 1H, J¼5.55 Hz), 3.98 (m, 1H), 4.03, 4.15,
4.75, 5.00 (4ꢀd, 4H, J¼14.9, 15.1 Hz), 7.24–7.36 (m, 10H);
MS (EI): m/z (%)¼423 (Mþ, 37.3), 289 (18.3), 238 (10.8), 198
(2.4), 106 (49.3), 91 (100).
d-Biotin (1)
A stirred mixture of 10 (42.4 g, 0.1 mol) and 47% HBr
(275 mL) was heated at reflux for 42 h. The cooled reaction
mixture was extracted with toluene (3ꢀ60 mL) to remove
the benzyl bromide and some impurities, and the toluene was
then concentrated under reduced pressure to dryness. A solu-
tion of 3 M aqueous KOH (350 mL) and TBAB (1.5 g) were
added to the residue and stirring was continued for 15 min at
room temperature. A solution of diphosgene (59.4 g, 0.3 mol)
in toluene (400 mL) was added dropwise over a period of
30 min, and the reaction mixture was stirred at room tempera-
ture for 6.5 h. The pH value of the reaction mixture was kept
within the range 9–10 by addition of 3 M aqueous KOH. H2O
(200 mL) was added to the reaction mixture. The organic layer
was separated, theaqueous layer was acidified topH 2with 2M
aqueous HCl with stirring to give a precipitate which was re-
crystallized from H2O to afford the pure 1 as a white crystalline
powder; yield: 20.1 g (82%); mp 231–2338C, [a]2D2: þ91.2 (c 1.0,
0.1 M NaOH) {Lit.[19] mp 232–2338C; [a]2D2: þ91.2 (c 1.0, 0.1 M
NaOH)}; IR (KBr): v¼3306–3243, 2704–2500, 1706,
1666 cmꢁ1; 1H NMR (DMSO-d6): d¼1.31–1.62 (m, 6H), 2.18
(t, 2H, J¼7.3 Hz), 2.58 (dd, 1H, J¼1.7 Hz), 2.81 (dd, 1H, J¼
4.8, 12.5 Hz), 3.15 (m, 1H), 4.18 (m, 1H), 4.35 (m, 1H), 6.38
(s, 1H), 6.48 (s, 1H), 11.9 (br s, 1H); MS (EI): m/z (%)¼245
(Mþ þ1, 15), 227 (9), 184 (25), 112 (26), 97 (100), 85 (66).
(3aS,4R,6aR)-1,3-Dibenzyl-4-[(1E,3E)-4-
methoxycarboxyl-1,3-butandienyl]-1H-
tetrahydrothieno [3,4-d]imidazole-2(3H)-one (8)
A mixture of 7 (35.2 g, 0.1 mmol), diethyl 3-methoxycarbonyl-
2-propenylidinephosphonate (23.6 g, 0.1 mmol), C-200 cata-
lyst (9.66 g, 52 mmol) dioxane (120 mL), and H2O (2.0 mL)
was stirred at 708C for 2.5 h. After cooling to room tempera-
ture, 1.0 M aqueous HCl (75 mL) and CH2Cl2 (150 mL) were
added. The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (3ꢀ45 mL). The combined organic lay-
ers were washed with saturated aqueous NaHCO3 (3ꢀ45 mL)
and H2O (3ꢀ45 mL), and dried over MgSO4. The solvent was
evaporated under reduced pressure and the residue was puri-
fied by column chromatography on silica gel using EtOAc-pe-
troleum ether (1:2) to afford the pure 8 as a colorless oil; yield:
39 g (90%); [a]D22: þ86 (c 1.0, CH3OH) {Lit.[15] [a]D22: þ85.51 (c
¼
1.16, CH3OH)}; IR (nujol): v 3020, 2920, 1700, 1650, 1600,
1
1510, 1450, 1370, 1260, 1150, 1020 cmꢁ1; H NMR (C6D6):
d¼7.25 (m, 11H), 5.76 (d, 1H, J¼15.2 Hz), 5.53 (dd, 1H, J¼
15.2, 10.78 Hz), 4.67 (t, 2H, J¼15.2 Hz), 3.42 (s, 3H), 3.27
(dd, 1H, J¼8.89, 3.86 Hz), 2.35 (dd, 1H, J¼12.25, 4.3 Hz),
2.22 (dd, 1H, J¼12.25, 5.8 Hz); 13C NMR (CDCl3): d¼36.7,
37.0, 46.3, 46.7, 51.3, 55.1, 61.5, 65.9, 121.7, 127.5, 127.95,
128.5, 129.6, 136.7, 136.8, 138.6, 142.7, 158.9, 166.6; MS (EI):
m/z (%)¼434 (Mþ, 43), 402 (7), 277 (100), 264(13), 187 (15),
155 (9), 91 (76).
X-Ray Structure Analysis of Compound 4
Crystals of C20H20N2O5 (Mw: 368.38) suitable for X-ray analy-
sis were obtained from EtOAc/cyclohexane (1:1). A colorless
Adv. Synth. Catal. 2005, 347, 549–554
asc.wiley-vch.de
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
553

Fen-Er Chen et al.
FULL PAPERS
monoclinic crystal of dimensions 0.25ꢀ0.15ꢀ0.10 mm was
mounted on a Rigaku AFC7R diffractometer. Determination
of the cell parameters was performed by least-squares refine-
ment of 25 reflections. The compound crystallized in the mono-
clinic system, space group P21 with a¼5.750 (2), b¼9.302 (2),
c¼17.014 (4) ꢃ, b¼93.92 (3)8, v¼907.9 (4) ꢃ3, T¼295 (2) K,
Chim. Acta 1983, 66, 2501; i) S. Masamune, S. V. Asrov
Ali, D. L. Smitman, D. S Garvey, Angew. Chem. 1980,
92, 573; j) M. Schmeider, N. Engel, H. Boensmann, An-
gew. Chem. Int. Ed. Engl. 1984, 23, 64; k) D. Arlt, M. Jau-
telat, R. Lantzsch, Angew. Chem. Int. Ed. Engl. 1981,
#20#93, 719; l) Y. I. F. Wang, C. S. Chen, G. Girdaukas,
C. J. Sih, J. Am. Chem. Soc. 1984, 106, 3695; m) M. Harre,
P. Raddatz, R. Walenta, E. Winterfeldt, Angew. Chem.
1982, 94, 496.
Z¼2, m(Mo-Ka)¼0.098 mmꢁ1
,
Dcalcd. ¼1.348 g
cmꢁ3
,
F(000)¼388 reflections were collected in the range of 1.20<
q<25.178 using Mo-Ka radiation (graphite monochromator,
l¼0.71073 ꢃ), w-2 scan mode. The structure was solved by di-
rect methods and expanded using difference Fourier tech-
niques and refined by full-matrix least-square to R¼0.0520,
Rw¼0.1210 with w¼1/[s2 (Foþ(0.1035P2 þ1.3711P))R
[where P¼(Fo2 þ2Fc2)/3] by using the 1729 observed reflec-
tions having I>2.00s(I) for 247 parameters refined. All non-
hydrogen atoms were refined anisotropically.
[8] a) P. Mohr, N. Waespe- Sarcevic, C. Tamm, K. Gawron-
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The crystallographic data has been deposited in Cambridge
Crystallographic Data Centre with depository number
249374.Copies of the data can be obtained free of charge on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax: int. codeþ44(1223)336–033; E-mail: deposit@ccdc.
cam.ac.uk].
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554
ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 549–554