Synthetic studies on (+)-biotin, part 151: A chiral squaramide-mediated enantioselective alcoholysis approach toward the total synthesis of (+)-biotin

Article abstract of DOI:10.1248/cpb.59.488

An efficient stereocontrolled total synthesis of (+)-biotin (1) has been achieved via the intermediacy of Roche's lactone 5 starting from cis-1,3-dibenzyl-2-imidazole-4,5-dicarboxylic acid (2). The bifunctional cinchona alkaloid-derived squaramide-promoted enantioselective alcoholysis was utilizing as a tool for the construction of two contiguous stereocenters of C-3a and C-6a in biotin molecular with excellent enantioselectivity. In addition, the 4-carboxybutyl side chain was assembled by first using C4+C1 approach via a novel tricyclic thiophanium salt intermediate.

Full text of DOI:10.1248/cpb.59.488

488
Note
Chem. Pharm. Bull. 59(4) 488—491 (2011)
Vol. 59, No. 4
1)
ꢀ
Synthetic Studies on ( )-Biotin, Part 15 : A Chiral Squaramide-Mediated
ꢀ
Enantioselective Alcoholysis Approach toward the Total Synthesis of ( )-
Biotin
Xu-Xiang CHEN,a Fei XIONG,a,b Han FU,a Zhi-Qian LIU,a and Fen-Er CHEN*,a,b
a Fudan-DSM Joint Laboratory for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University;
Shanghai 200433, People’s Republic of China: and b Institutes of Biomedical Sciences, Fudan University; Shanghai
200031, People’s Republic of China.
Received November 16, 2010; accepted January 13, 2011; published online January 21, 2011
An efficient stereocontrolled total synthesis of (ꢀ)-biotin (1) has been achieved via the intermediacy of
Roche’s lactone 5 starting from cis-1,3-dibenzyl-2-imidazole-4,5-dicarboxylic acid (2). The bifunctional cinchona
alkaloid-derived squaramide-promoted enantioselective alcoholysis was utilizing as a tool for the construction of
two contiguous stereocenters of C-3a and C-6a in biotin molecular with excellent enantioselectivity. In addition,
the 4-carboxybutyl side chain was assembled by first using C4ꢀC1 approach via a novel tricyclic thiophanium
salt intermediate.
Key words (ꢀ)-biotin; cinchona alkaloid-derived squaramide; enantioselective alcoholysis; tricyclic thiophanium salt
Over the past two decades, significant progress in methods for the enantioselective desymmetrization of 3 ap-
organocatalysis has been achieved by mark advances in the pling methanol as nuclophiles frequently suffer from one or
enantioselective desymmetrization of meso and other prochi- more of the following problems: extended reaction times at
ral compounds. Well known in the respect is the catalytic reduced temperature, lower enantioselectivity and difficulties
asymmetric desymmetrization of meso-cyclic anhydride via with organocatalyst preparation etc. The finding of novel cat-
the addition of an alcohol nuclophile, which represents a alysts and new protocols for the enantioselective methanoly-
simple and elegant method for the preparation of syntheti- sis of 3 into the key intermediate (3aS,6aR)-lactone 5 to com-
cally pliable hemiester with the generation of either single or plete the commercial asymmetric total synthesis of 1 still re-
multiple stereocenters with high levels of enantiocontrol in mains challenge. Our continued interest in the development
one symmetry-breaking operation.2—13) While naturally-oc- of practical asymmetric total synthesis of 1 based upon the
curring cinchona alkaloids such as quinine, quinidine and chiral Lewis acid-catalyzed enantioselective anhydride
their variants have been demonstrated to serve as practical desymmetrization has prompted us to investigate an facile
organocatalysts for the enantioselective alcoholysis of five- organocatalytic enantioselective methanolysis approach to-
and six-membered meso-cyclic anhydrides since the pioneer- ward 1 starting from cis-1,3-dibenzyl-2-imidazole-4,5-dicar-
ing works by Oda and colleagues14,15) in the late 1980s.
boxylic acid (2) by utilizing our newly developed bifunc-
In recent years, our group has made many significant ef- tional cinchona alkaloid-derived squaramide IV20)-promoted
forts to explore the utility of various chiral amine (I—III, enantioselective methanolysis of 3 for the construction of 5
Fig. 1)-mediated enantioselective methanolysis8,16,17) as a and a novel C4ꢀC1 strategy for the introduction of the 4-car-
more effective strategy for the preparation of (3aS,6aR)-lac- boxybutyl side chain at C-4 position of (3aS,6aR)-thiolactone
tone (Roche’s lactone, 5) from the meso-cyclic anhydride 3 6. Herein, we reported the details of our investigations on
along Hoffmann Roche lactone-thiolactone route developed this subject.
by Goldberg and Sternbach in 1949 to complete the stereo-
controlled total synthesis of (ꢀ)-biotin 1.18,19) However, de- Results and Discussion
spite the indisputable advances that have been made, these
Our stereocontrolled total synthesis of (ꢀ)-biotin (1) was
undertaken starting from cis-1,3-dibenzyl-2-imidazoledone-
4,5-dicarboxylic acid (2) as outlined in Chart 1. Treatment of
2 in boiling toluene in the presence of a catalytic amount of
MeSO3H with azeotropic removal of water for 4 h led to the
desired meso-cyclic anhydride 3 in almost quantitatively
yield.
We next set out to prepare the key chiral intermediate
(4S,5R)-hemiester 4 from meso-cyclic anhydride 3 by a cat-
alytic enantioselective methanolysis strategy using a bifunc-
tional cinchona alkaloid-based squaramide IV. In our initial
studies, the asymmetric desymmetrization of 3 upon treat-
ment with 3 eq of methanol in the presence of 5 mol% cata-
lyst IV in methyl tert-butyl ether (MTBE) at room tempera-
ture resulted in (4S,5R)-hemiester 4 in excellent yield with
very low enantioselectivity (only 50% ee, Table 1, entry 1). It
has been reported that the stoichiometric amount of organo-
Fig. 1. Structure of Chiral Amine Organocatalysts
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: rfchen@fudan.edu.cn

April 2011
489
Fig. 2. The Proposed Transition-State Model for the Squaramide Medi-
ated Enantioselective Methanolysis Reaction
Reagents and conditions: a) MeSO3H, toluene, reflux, 4 h, 98%; b) MeOH, cata-
lyst VI (110 mol%), r.t., 24 h, 96%, 99% ee; c) BER, CaCl2, EtOH, r.t., 24 h; then
5% HCl, 55 °C, 0.5 h, 95% (over two steps); d) PhCOSK, DMF, 150 °C, 2 h, 85%;
e) BrMg(CH2)4OEt, THF, reflux, 2 h; then 30% H2SO4, reflux, 3 h, 95%; f) H2,
10% Pd/C, iso-PrOH, 110 °C, 60 atm, 12 h, 98%; g) conc. HCl, 88% HCO2H, re-
flux, 5 h, 90%; h) NaCN, DMSO, 90 °C, 3 h, 95%; i) 48% HBr, reflux, 10 h, 80%.
Fig. 3. The NOE Observed for 7 in the NOESY Spectrum
Chart 1. The Synthetic Route to (ꢀ)-Biotin 1
addition, the catalyst IV was easily recovered quantitatively
Table 1. Optimization of Reaction Conditions in the Asymmetric and no significant loss in the catalysis activity and enantiose-
Methanolysis of 3 Catalyzed by Chiral Squaramide IVa)
lectivity was observed when it was reused up to ten times.
To account for the observed stereochemical outcome of
this reaction, a transition state model was proposed and is de-
picted in Fig. 2. The NH group of the squaramide IV moiety
are expected to form hydrogen-bonding interaction with the
carbonyl group to active the electrophile (anhydride 3) and
the quinuclidine group is believed to simultaneously act as a
general base to active the nucleophile (methanol).
Catalyst
loading
(%)
Yieldb)
(%)
eec)
(%)
Entry
Solvent
The resulting chiral hemiester 4 was subjected to regiose-
lective reduction with Borohydride anion exchange resin
(BER, 3.3 mmol BH4ꢁ/g) in the presence of anhydrous CaCl2
in EtOH for 18 h, subsequent acid-catalyzed lactonization with
5% HCl for 30 min at 55 °C to furnish the desired (4S,5R)-lac-
tone 5 in 95% overall yield with 98.5% enantiomeric excess.
The resin could be recovered from reaction mixture by simple
filtration followed by washing with 5% aq. NaOH and H2O
after the reduction went to completion. It is well documented
that the recovered resin in this reaction could be regenerated to
the original BER (3.3 mmol BH4ꢁ/g) without much loss of ac-
1
2
3
4
5
6
7
8
9
5
30
50
MTBE
MTBE
MTBE
MTBE
MTBE
Et2O
THF
Toluene
CH2Cl2
95
96
97
96
98
97
96
96
97
50
60
70
74
96
80
85
63
65
80
110
110
110
110
110
a) Unless otherwise noted, all reactions were performed with 5 mmol of 3 and
15 mmol of methanol in 1.65 l solvents. b) Yield of isolated product 4. c) Deter- tivity upon treatment of KBH4 in H2O according to the BER
preparation procedure.22) The conversion of 5 into the desired
(3aS,6aR)-thiolactone 6 was achieved in 85% yield via a thio-
mined by chiral HPLC analysis using chiralcel OJ-H column (hexane/IPA/TFAꢂ
92/8/0.2, lꢂ220 nm, 0.5 ml/min)
lactonization by heating of potassium benzothioate (PhCOSK)
catalyst has found to constitute the key features for a highly in anhydrous dimethylformamide (DMF) at 150 °C for 2 h.
efficient methanolytic desymmetrization of meso-cyclic an-
With the (3aS,6aR)-thiolactone 6 in hand, installation of
hydride in complex total synthesis due to the bulky size and C4 side chain at C-4 position of 6 was efficiently carried out
the presence of multiple polar and basic functionalities of an- by the reaction of 6 with Grignard reagent derived from 1-
hydrides.8,10) We also observed that anhydride 3 reacted very bromo-4-ethoxybutane in anhydrous tetrahydrofuran (THF)
well leading to the corresponding product 4 in 98% yield and subsequent dehydration with 30% H2SO4 at refulxing
with 96% ee when the catalyst loading increased from 5 to temperature for 3 h, affording (Z)-alkene ether 7 in an overall
110 mol% (Table 1, entries 1 and 5). The stereochemistry of yield of 95%. The (Z)-configuration of 7 was unequivocally
4 was confirmed by comparision with the specific optical ro- characterized by nuclear Overhauser effect spectroscopy
tation value reported in our laboratory.21) It is noteworthy that (NOESY) experiment, which showed the NOE correlation
the stereochemical outcome of the methanolysis is strongly between H3a and Ha, as depicted in Fig. 3.
affected by the solvent used in the anhydride desymmetriza-
The resulting unsaturated ether 7 further on high pressure
tion. A low enantioselectivity was obtained in the anhydride hydrogenation (60 atm) at 110 °C for 12 h by the use of a cat-
desymmetrization when other solvents including Et2O, alytic amount of 10% Pd/C in iso-PrOH provided (3aS,4S,
tetrahydrofuran (THF), toluene and CH2Cl2 was used instead 6aR)-saturated ether 8 in almost quantitative yield. Tricyclic
of methyl tert-butyl ether (MTBE) (Table 1, entries 6—9). In thiophanium salt 9 was formed in 90% isolated yield via the

490
Vol. 59, No. 4
were dried over Na2SO4 and concentrated in vacuo to afford 5 as a white
solid (3.06 g, 95% yield). mp 119.4—120.1 °C; [a]D25.3 ꢀ61.2 (cꢂ2.0,
CHCl3) [lit.26) mp 120—121 °C; [a]D25 ꢀ61.5 (cꢂ2.0, CHCl3)]. IR (KBr) n:
3031, 2919, 1775, 1706, 1415, 1365, 1237, 1209, 1146, 970, 754, 700, 639,
527 cmꢁ1. 1H-NMR (CDCl3) d: 3.92 (d, 1H, Jꢂ8.0 Hz), 4.09—4.16 (m, 3H),
4.37 (dd, 2H, Jꢂ10.4, 15.2 Hz), 4.63 (d, 1H, Jꢂ15.2 Hz), 5.05 (d, 1H,
Jꢂ15.2 Hz), 7.24—7.36 (m, 10H). 13C-NMR (CDCl3) d: 45.2, 46.9, 52.4,
54.3, 70.1, 127.8, 128.0, 128.2, 128.7, 128.8, 129.0, 135.9, 136.0, 158.1,
172.7. MS (ESI) m/z: 345.2 (MꢀNa)ꢀ.
cleavage/chlorination/cyclization/salt fromation in a one-pot
procedure upon treatment of 8 with concentrated HCl in
formic acid at reflux for 5 h. Treatment of 9 with sodium
cyanide in dimethyl sulfoxide (DMSO) at 90 °C for 3 h al-
lowed the direct conversion into the desired (3aS,4S,6aR)-ni-
trile 10 in 95% yield. The absolute configuration of 10 was
validated by comparison with the reported values of the spe-
cific rotation.23) Final one-pot hydrolysis and debenzylation
of 10 was effected in 48% HBr for 10 h to provide (ꢀ)-biotin
(1) in 80% yield, which is identical in all respects with our
previous reported values.24)
In conclusion, we have developed a novel highly enantio-
selective organocatalytic approach to the total synthesis of
(ꢀ)-biotin (1) in an overall yield of 48% starting from the
known cis-1,3-dibenzyl-2-imidazoledone-4,5-dicarboxylic
acid (2), which exhibit advantages over the existing synthetic
routes to 1 in terms of the high enantioselectivity, overall
yield and the practicality on large-scale production.
Procedure for the Synthesis of 6 A mixture of 5 (3.22 g, 10 mmol),
potassium benzothioate (1.92 g, 12 mmol) and anhydrous DMF (30 ml) was
stirred at 150 °C under argon atmosphere for 2 h. After cooling to room tem-
perature, the resulting mixture was poured into H2O (30 ml) and extracted
three times with CH2Cl2 (3Åꢃ30 ml). The combined organic phases were
washed successively with brine (30 ml) and H2O (30 ml), dried over Na2SO4,
and evaporated the solvent to give the crude product which was then purified
by recrystallization from iso-propanol to afford the pure 6 as a white solid
(2.87 g, 85% yield). mp 125.5—126.2 °C; [a]D25.3 ꢀ90.1 (cꢂ1.0, CHCl3)
[lit.23) mp 125—126 °C; [a]D25 ꢀ90.2 (cꢂ1.0, CHCl3)]. IR (KBr) n: 3030,
2934, 2889, 1703, 1697, 1453, 1412, 1361, 1218, 1148, 1051, 997, 903,
1
808, 698, 647, 581, 485 cmꢁ1. H-NMR (CDCl3) d: 3.28 (dd, 1H, J ꢂ12.4,
2.0 Hz), 3.37 (dd, 1H, Jꢂ12.4, 5.6 Hz), 3.81 (d, 1H, Jꢂ8.0 Hz), 4.15—4.11
(m, 1H), 4.36 (d, 1H, Jꢂ14.8 Hz), 4.37 (d, 1H, Jꢂ15.6 Hz), 4.68 (d, 1H,
Jꢂ15.6 Hz), 5.03 (d, 1H, Jꢂ14.8 Hz), 7.37—7.26 (m, 10H). 13C-NMR
(CDCl3) d: 33.0, 45.2, 46.5, 55.8, 62.1, 127.73, 127.91, 128.0, 128.66,
Experimental
General Procedures 1H- and 13C-NMR spectra were recorded on a
Bruker Avance 400 spectrometer (400, 100 MHz, respectively) in CDCl3 or 128.78, 128.87, 136.2, 136.4, 158.2, 203.4. MS (ESI) m/z: 361.1 (MꢀNa)ꢀ.
DMSO-d6 using tetramethylsilane (TMS) or DMSO (1H d 2.49) and CDCl3
Procedure for the Synthesis of 7 To a suspension of Magnesium pow-
(13C d 77.0) or DMSO-d6 (13C d 39.5) as internal standards. IR spectra were der (2.9 g, 120 mol) in anhydrous THF (20 ml) was added a catalytic amount
recorded on a JASCO FT/IR-4200 spectrometer. Mass spectra were recorded
on a Waters Quattro Micromass instrument using electrospray ionization
(ESI) techniques. Optical rotations were obtained on a JASCO P1020 digital
polarimeter. Melting points were measured with a WRS-1B digital melting
point apparatus and are uncorrected. Unless otherwise notes all reactions
were conducted in oven dried glassware under inert atmosphere of dried Ar
of iodine under nirogen atmosphere and the mixture was heated to reflux.
The soloution of 1-bromo-4-ethoxybutane (21.4 g, 120 mmol) in anhydrous
THF (20 ml) was added dropwise and the resulting mixture was kept stirring
at reflux for 1 h. The solution of compound 6 (20 g, 59 mmol) in anhydrous
THF (200 ml) was added into the reaction mixture at 25 °C. After stirring for
2 h at reflux, the mixture was cooled to 0 °C before 30% H2SO4 (100 ml) was
or N2. THF was distilled from sodium/benzophenone, toluene, CH2Cl2 from added. After further stirring at reflux for 3 h, the mixture was extracted with
calcium hydride and DMF from calcium hydride under reduced pressure. CH2Cl2 (3ꢃ60 ml). The combined organic phases were washed successively
The alcohols used were purified accorded to standard methods,25) other with brine (30 ml), sat. aq NaHCO3 (30 ml) and H2O (30 ml), dried over
reagents were obtained from commercial sources and used as received.
Procedure for the Synthesis of 3 A mixture of 2 (10 g, 28 mmol),
CH3SO3H (0.04 g, 0.42 mmol), toluene (200 ml) was stirred under reflux
with azeotropic removal of water for 4 h. After cooled to room temperature,
Na2SO4, and evaporated the solvent to give the crude product which was
then purified by chromatography on a silica gel column (AcOEt/petroleum
ether (PE)ꢂ1/1) to give 7 as a yellow oil (23.7 g, 95% yield). IR (KBr) n:
1
3062, 3028, 2929, 1700, 1604, 1448, 1357, 1114, 1076, 750, 701 cmꢁ1. H-
the precipitated colorless crystals was filtered and dried at 70 °C in vacuo for NMR (CDCl3) d: 1.18 (t, 3H, Jꢂ7.0 Hz), 1.64 (m, 2H, Jꢂ6.99 Hz), 2.13 (m,
4 h to give the pure product 3 as a white powder (9.22 g, 98% yield). mp 2H), 2.95 (m, 2H), 3.37 (t, 2H, Jꢂ6.49 Hz), 3.43 (q, 2H, Jꢂ7 Hz), 4.02 (m,
237.1—237.6 °C [lit.1) mp 237.1—237.8 °C]. IR (KBr) n: 1805, 1740, 1687, 1H), 4.02, 4.22, 4.80, 4.96 (dddd, 4H, Jꢂ15.71, 15.29 Hz), 4.27 (d, 1H,
1227 cmꢁ1 1H-NMR (CDCl3) d: 4.15 (s, 2H), 4.18 (s, 2H), 4.22 (d, 1H, Jꢂ7.70 Hz), 5.48 (t, 1H, Jꢂ7.19 Hz), 7.21—7.36 (m, 10H). MS (ESI) m/z:
.
Jꢂ14.8 Hz), 5.15 (d, 1H, Jꢂ14.8 Hz), 7.15—7.35 (m, 10H). MS (ESI) m/z: 422.1 (Mꢀ1)ꢀ.
337.4 (Mꢀ1)ꢀ.
Procedure for the Synthesis of 8 A suspension of compound 7 (29.5 g,
Procedure for the Synthesis of 4 Methanol (0.5 g, 15 mmol) was added
dropwise into a suspension of 3 (1.68 g, 5 mmol) and catalyst VI (3.5 g,
5.5 mmol) in MTBE (1.65 l) at 25 °C under argon atmosphere. Upon com-
pletion of the addition the reaction mixture was stirred for 24 h at room tem-
perature and then evaporated in vacuo. The residue was washed with 10%
aq. Na2CO3 (3ꢃ10 ml) and the organic phase was dried over Na2SO4 and
concentrated to recover the catalyst VI. The combined aqueous phases was
adjusted to pH 5 use 2 M HCl, then extracted with AcOEt (3ꢃ10 ml). The
combined organic phases was dried over Na2SO4, filtred and concentrated in
vacuo to yield the crude product, which was then purified by recrystalliza-
tion from AcOEt to give the methyl monoester 4 as a white solid (1.77 g,
96% yield); eeꢂ99%. mp 149.7—150.4 °C; [a]D25.2 ꢀ7.22 (cꢂ1.0, DMF)
70 mmol), 10% Pd/C (7 g) in iso-propanol (160 ml) was stirred at 110 °C
under hydrogen pressure of 60 atm for 12 h, and then filtred through Celite.
The filtrate was evaporated under reduced pressure to give the crude prod-
uct, which was purified by recrystallization from CCl4/cyclohexane to afford
pure 8 (29.1 g, 98% yield). mp 62—63 °C; [a]D25 ꢁ27.6 (cꢂ1.0, EtOH). IR
1
(KBr) n: 1679, 1462, 1452, 1425, 1236, 1105, 700 cmꢁ1. H-NMR (CDCl3)
d: 1.21 (t, 3H, Jꢂ7.04 Hz), 1.54 (m, 6H), 2.65 (dddd, 1H, Jꢂ3.16, 5.84 Hz),
3.05 (m, 1H), 3.38 (m, 2H), 3.45 (q, 2H, Jꢂ7.05 Hz), 3.80 (dd, 1H,
Jꢂ5.40 Hz), 3.93 (m, 1H), 3.93, 4.10, 4.70, 5.10 (dddd, 4H, Jꢂ15.21,
15.17 Hz), 7.14—7.32 (m, 10H). MS (ESI) m/z: 424 (Mꢀ1)ꢀ.
Procedure for the Synthesis of 9 A mixture of compound 8 (12.7 g,
30 mmol), conc. HCl (18 g) and 88% aq. HCO2H (40 ml) was heated to re-
[lit.21) mp 150—151 °C; [a]D25 ꢀ7.31 (cꢂ1.0, DMF)]. IR (KBr) n: 3258, flux for 5 h and then evaporated under reduced pressure. The residue was pu-
2943, 1756, 1713, 1449, 1411, 1252, 968, 799, 598, 458 cmꢁ1 1H-NMR rified by recrystallization from acetone to get 9 as a white solid (11.2 g, 90%
.
(CDCl3) d: 3.63 (s, 3H), 4.13—4.04 (m, 4H), 4.98 (d, 1H, Jꢂ14.8 Hz), 5.09
yield). IR (KBr) n: 3447, 2931, 1683, 1608, 1443, 1067 cmꢁ1
.
1H-NMR
(d, 1H, Jꢂ14.8 Hz), 6.85 (br s, 1H), 7.36—7.19 (m, 10H). 13C-NMR
(CDCl3) d: 1.6—2.2 (m, 6H), 4.0—4.1 (m, 2H), 3.45—3.6 (m, 1H), 4.3—
(CDCl3) d: 46.80, 46.89, 52.6, 56.7, 57.3, 127.93, 127.98, 128.56, 128.64, 4.35 (m, 1H), 4.48 (dd, 1H, Jꢂ5.97 Hz), 4.44 (dd, 1H, Jꢂ6.99 Hz), 4.95 (dd,
128.79, 128.85, 135.52, 135.57, 159.5, 168.5, 171.7. MS (ESI) m/z: 391.1 1H, Jꢂ6.02 Hz), 3.95, 4.15, 4.92, 5.2 (dddd, 4H, Jꢂ15.21, 15.17 Hz), 7.1—
(MꢀNa)ꢀ.
7.32 (m, 10H). MS (ESI) m/z: 414 (Mꢀ1)ꢀ.
Procedure for the Synthesis of 5 To a stirred solution of 4 (3.68 g,
10 mmol) and anhydrous CaCl2 (1.11 g, 10 mmol) in anhydrous ethanol
(52 ml) was added BER (6.7 g, 20 mmol) at 0 °C. Stirring was continued at
the same temperature for 1 h, the reaction mixture was allowed to warm up
to room temperature and stirred for another 18 h at 25 °C. The resulting mix-
ture was filtred and the filtrate was concentrated. The residue was treated
with 5% aq. HCl (37 ml) at 55 °C. After 30 min at this temperatue, the solu-
Procedure for the Synthesis of 10 A mixture of compound 9 (8.29 g,
20 mmol), NaCN (2.45 g, 50 mmol) and DMSO (100 ml) was stirred at
90 °C for 3 h. After cooling to room temperature, the reaction mixture was
extracted with Toluene (3ꢃ30 ml). The combined organic phases was
washed successively with brine and H2O and dried over Na2SO4. Evapora-
tion of the solvent gave the crude product, which was purified by recrystal-
lization from iso-PrOH to obtain pure 10 as a white solid (7.70 g, 95%
tion was extracted with CH2Cl2 (3ꢃ30 ml). The combined organic phases yield). mp 93—94 °C; [a]D25 ꢁ67.1 (cꢂ1.0, DMSO) [lit.23) mp 93—94 °C;

April 2011
491
[a]D25 ꢁ67.3 (cꢂ1.0, DMSO)]. IR (KBr) n: 1679, 2270, 1451, 1237,
8) Wang S. X., Chen F. E., Adv. Synth. Catal., 351, 547—552 (2009).
9) Youk S. H., Oh S. H., Rho H. S., Lee J. E., Lee J. W., Song C. E.,
Chem. Commun., 2009, 2220—2222 (2009).
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(2010).
701 cmꢁ1 1H-NMR (CDCl3) d: 1.58—1.75 (m, 6H), 2.34 (t, 2H), 2.71
.
(dddd, 2H, Jꢂ2.34, 4.39 Hz), 3.06 (m, 1H), 3.89 (dd, 1H, Jꢂ5.56 Hz), 3.96
(m, 1H), 4.03, 4.15, 4.75, 5.00 (dddd, 4H, Jꢂ15.07, 15.08 Hz), 7.22—7.38
(m, 10H). MS (ESI) m/z: 405 (Mꢀ1)ꢀ.
11) Wakchaure V. N., List B., Angew. Chem. Int. Ed., 49, 4136—4139
(2010).
12) Manzano R., Andres J. M., Muruzabal M. D., Pedrosa R., J. Org.
Chem., 75, 5417—5420 (2010).
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1985, 1717—1719 (1985).
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Trans. 1, 1987, 1053—1058 (1987).
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Procedure for the Synthesis of 1 A mixture of compound 8 (12 g,
30 mmol) and 47% aq HBr (300 ml) was heated to reflux with vigorous stir-
ring. After 10 h the reaction mixture was extracted with toluene (3ꢃ30 ml),
the aqueous phase was separated and concentrated in vacuo to get the crude
product. The residue was purified by recrystallization from H2O to give pure
1 as a white crystalline powder (5.8 g, 80% yield). mp 231.1—232.0 °C;
[a]D25 ꢀ91.3 (cꢂ1.0, 0.1 N NaOH) [lit.27) mp 232—233 °C; [a]D21.9 ꢀ91.2
(cꢂ1.0, 0.1 N NaOH)]. IR (KBr) n: 3359, 3308, 2961, 2469, 1941, 1707,
1480, 1318, 1270, 1154, 1015, 842, 753, 651 cmꢁ1 1H-NMR (DMSO) d:
.
1.37—1.30 (m, 2H), 1.62—1.41 (m, 4H), 2.20 (t, 2H, Jꢂ7.6 Hz), 2.57 (d,
1H, J ꢂ12.4 Hz), 2.82 (dd, 1H, J ꢂ12.4, 5.2 Hz), 3.12—3.07 (m, 1H),
4.15—4.11 (m, 1H), 4.30 (dd, 1H, J ꢂ7.6, 5.2 Hz), 6.33 (s, 1H), 6.40 (s,
1H), 11.9 (s, 1H). 13C-NMR (CDCl3) d: 25.0, 28.52, 28.57, 33.9, 40.0, 55.8,
59.6, 61.5, 163.1, 174.8. MS (ESI) m/z: 267 (MꢀNa)ꢀ.
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Acknowledgments We gratefully acknowledge the financial support
from the DSM Nutritional Products Ltd. in Switzerland.
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