Short and practical synthesis of O-(p-Biphenoyl)-N-tosyl-allo-threonine- derived oxazaborolidinone catalyst

Article abstract of DOI:10.1021/jo0522299

O-(p-Biphenoyl)-N-tosyl-(L)-allo-threonine methyl ester is synthesized in three steps (65% overall yield) starting from commercially available (L)-allo-threonine methyl ester hydrochloride by N-acylation followed by N,O-acyl migration with inversion of th

Full text of DOI:10.1021/jo0522299

SCHEME 1. OXB-Catalyzed Asymmetric Michael and
Diels-Alder Reactions
Short and Practical Synthesis of
O-(p-Biphenoyl)-N-tosyl-allo-threonine-Derived
Oxazaborolidinone Catalyst
Toshiro Harada* and Chieko Inui
Department of Chemistry and Materials Technology,
Kyoto Institute of Technology, Matsugasaki, Sakyo-ku,
Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
ReceiVed October 27, 2005
Herein, we wish to report a practical four-step synthesis of OXB
2 that provides an easy access to this useful Lewis acid catalyst.
The Elliot method involves thionyl chloride-mediated cy-
clization of benzamide derivative 3 with inversion of the carbinol
carbon to oxazoline 4, which is then fully hydrolyzed by
treatment with hot aqueous HCl to give allo-threonine (eq 1).
O-(p-Biphenoyl)-N-tosyl-(L)-allo-threonine methyl ester is
synthesized in three steps (65% overall yield) starting from
commercially available (L)-allo-threonine methyl ester hy-
drochloride by N-acylation followed by N,O-acyl migration
with inversion of the â carbinol carbon and N-tosylation.
Treatment of the methyl ester with dibromophenylborane
gives oxazaborolidinone 1, which can be used as a Lewis
acid catalyst for the asymmetric Michael and Diels-Alder
reactions.
If the selective CdN bond cleavage of 4 can be achieved under
milder conditions, hydrolysis of 4 would afford the O-acyl
derivative of allo-threonine methyl ester, realizing overall N,O-
acyl group transfer with the inversion of the carbinol carbon.
Such a possibility was examined for N-(p-biphenoyl) derivative
6 (Scheme 2).
Asymmetric Lewis acid-catalyzed reactions of conjugated
enones are challenging due to nonselective metal coordination
of the sterically and electronically similar lone pairs of the
carbonyl oxygen.1 Recent reports from this laboratory have
disclosed allo-threonine-derived oxazaborolidinone (OXB) 2 is
an efficient Lewis acid catalyst for asymmetric reaction of
simple acyclic enones (Scheme 1). In the presence of OXB 2
(10-20 mol %), the asymmetric Michael reaction2 and Diels-
Alder reaction3 proceed with the high enantioface selection of
the enones to give the products of high enantiopurity. While
catalyst 2 can be prepared simply by mixing (L)-allo-threonine
derivatives 1 with dichlorophenylborane, the preparation of
ligand 1 required a multistep synthetic route. According to the
method reported by Elliot,4 (L)-allo-threonine is prepared in three
steps by the inversion of the â carbinol carbon of (L)-threonine
methyl ester hydrochloride (5). The amino acid is converted
into 1 by an additional four-step sequence involving N-
tosylation, protection of the carboxylic acid moiety as a benzyl
ester, O-acylation, and final deprotection by hydrogenolysis.
SCHEME 2. Synthesis of OXB Catalyst 2
The reaction of hydrochloride 5 with p-biphenoyl chloride
in the presence of triethylamine in CH2Cl2 at room temperature
afforded N-acyl derivative 6 in 74% yield. After treatment of 6
with thionyl chloride (9 equiv) for 24 h, the concentrate of the
mixture was dissolved in water and stood at room temperature
for 4 days to give anticipated N,O-acyl migration product 7.5
The initial product of the reaction of 6 with thionyl chloride
might be oxazoline hydrochloride 9, which underwent hydrolysis
(1) (a) Hawkins, J. M.; Nambu, M.; Loren, S. Org. Lett. 2003, 5, 4293.
(b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. (d)
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800.
(2) (a) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku,
A. Org. Lett. 2001, 3, 2101. (b) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki,
H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68,
10046. (c) Harada, T.; Adachi, S.; Wang, X. Org. Lett. 2004, 6, 4877.
(3) Singh, R. S.; Harada, T. Eur. J. Org. Chem. 2005, 3433.
(4) Elliot, D. F. J. Chem. Soc. 1950, 62.
10.1021/jo0522299 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/07/2006
J. Org. Chem. 2006, 71, 1277-1279
1277

N-(p-Biphenoyl)-(L)-threonine Methyl Ester (6). To a mixture
of (L)-threonine methyl ester hydrochloride (4.6 g, 30 mmol) in
CHCl3 (20 mL) at room temperature was added dropwise triethyl-
amine (9.9 mL, 71 mmol). To the resulting solution at 0 °C was
added dropwise a suspension of 4-biphenylcarbonyl chloride (6.5
g, 30 mmol). The resulting mixture was stirred at room temperature
for 3 h. The mixture was poured into water and extracted twice
with CHCl3. The organic layers were washed with water (2×), 1
N aqueous HCl, and 5% aqueous NaHCO3, dried over MgSO4, and
concentrated in vacuo to give 6 as a colorless solid, which was
used in the next step without further purification (7.0 g, 74%): mp
181-183 °C; 1H NMR (500 MHz, CDCl3) δ 1.31 (3H, d, J ) 6.4
Hz), 2.32 (2H, br), 3.80 (3H, s), 4.48 (1H, dq, J ) 2.4 and 6.4
Hz), 4.86 (1H, dd, J ) 2.4 and 8.7 Hz), 7.04 (1H, br d, J ) 8.7
Hz), 7.39 (1H, m), 7.46 (2H, m), 7.60 (2H, m), 7.65 (2H, d, J )
8.3 Hz), 7.92 (2H, d, J ) 8.3 Hz); 13C NMR (125.8 MHz, CDCl3)
δ 20.1, 52.7, 57.6, 68.3, 127.2, 127.3, 127.7, 128.0, 128.9, 132.3,
139.9, 144.7, 167.6, 171.6; IR (KBr disk) 1747, 1639, 1261, 1107,
743 cm-1. Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47.
Found: C, 68.98; H, 6.03; N, 4.54.
O-(p-Biphenoyl)-N-tosyl-(L)-allo-threonine Methyl Ester (8).
N-(p-Biphenoyl) derivative 6 (7.2 g, 23 mmol) was added portion-
wise to a stirred thionyl chloride (15 mL, 0.21 mol) cooled with
an ice bath such that the temperature did not exceed 5 °C. After
being stirred at room temperature for 24 h, the mixture was
concentrated in vacuo. Dichloromethane (200 mL) and hexane (100
mL) were added to the residue and subsequently removed in vacuo.
This was repeated again to remove excess thionyl chloride. The
resulting solid was finely ground with a mortar, suspended in water
(100 mL), and stirred vigorously for 4 days at room temperature
to give the suspension of 7. During this time, aliquots were removed
to monitor the hydrolysis reaction by TLC (50% ethyl acetate in
hexane) after treatment with 5% aqueous NaHCO3 and extraction
with CH2Cl2. Spectral data of O-(p-biphenoyl)-allo-threonine methyl
ester (free base of 7): mp 181-183 °C; 1H NMR (500 MHz,
CDCl3) δ 1.41 (3H, d, J ) 6.4 Hz), 1.68 (2H, br), 3.78 (3H, s),
3.89 (1H, br), 5.39 (1H, m), 7.40 (1H, m), 7.47 (2H, m), 7.62 (2H,
m), 7.66 (2H, d, J ) 8.4 Hz), 8.10 (2H, d, J ) 8.4 Hz).
under weakly acidic conditions through tetrahedral intermediate
10 to produce 7 by selective C-N+ bond cleavage (eq 2).
Although the product 7 can be isolated as a free base, the
aqueous suspension of 7 obtained from 6 was subjected to the
tosylation reaction under the Schotten-Baumann conditions. The
product 8 was isolated by recrystallization from ethyl acetate
and hexane in 88% overall yield from 6. Although selective
hydrolysis of the methyl ester moiety of 6 with aqueous LiOH
failed owing to the competing reaction at the p-biphenylcar-
oboxylate moiety, the conversion of 6 to ligand 2 could be
achieved by demethylation with iodotrimethylsilane in 82%
yield.6 Thus, the preparation of chiral ligand 1 was achieved in
four steps from commercially available hydrochloride 5 in 52%
overall yield.
A more straightforward and convenient method for the
preparation of OXB catalyst 2 would be the direct use of methyl
ester 6 as a precursor. Indeed, when methyl ester 6 was treated
with dichlorophenylborane in CH2Cl2 at room temperature, the
1
formation of OXB 1 was detected by H NMR analysis of the
crude concentrate.7 However, the full conversion of 6 was not
attained even after prolonged reaction time. Gratifyingly, clean
formation of 2 was observed by using dibromophenylborane
instead. The activity of the catalyst prepared by the present
method was confirmed in a representative asymmetric Michael
reaction (eq 3).
Dichloromethane (46 mL) and Na2CO3 (12 g, 12 mmol) were
added to the above suspension of 7. To the resulting mixture at
room temperature was added portionwise p-toluenesulfonyl chloride
(5.3 g, 28 mL). After being stirred for 24 h, the mixture was
extracted twice with CH2Cl2 (2 × 50 mL). Organic layers were
washed with 1 N aqueous HCl followed by filtration of the
precipitate formed. The filtrate was washed with 5% aqueous
NaHCO3, dried over Na2SO4, and concentrated in vacuo. The
residue was recrystallized from ethyl acetate and hexane to give
In summary, a short and practical synthesis of OXB catalyst
2 has been developed from commercially available (L)-allo-
threonine methyl ester hydrochloride by utilizing N,O-acyl
transfer with inversion of the â carbinol carbon and demeth-
ylation/oxazaborolidinone-ring formation of ester 8 with dibro-
mophenylborane. The present method provides an easy access
to the efficient Lewis acid catalyst for asymmetric Michael and
Diels-Alder reactions of acyclic enones.
1
8.2 g (88% yield) of 8: mp 127-128 °C, H NMR (500 MHz,
CDCl3) δ 1.39 (3H, d, J ) 6.5 Hz), 2.36 (3H, s), 3.58 (3H, s), 4.31
(1H, dd, J ) 4.3 and 9.6 Hz), 5.30 (1H, dq, J ) 4.4 and 6.5 Hz),
5.44 (1H, br d, J ) 9.6 Hz), 7.24 (2H, d, J ) 8.2 Hz), 7.40 (1H,
m), 7.47 (2H, m), 7.61-63 (4H, m), 7.71 (2H, d, J ) 8.2 Hz),
8.03 (2H, J ) 8.3 Hz); 13C NMR (125.8 MHz, CDCl3) δ 15.9,
21.5, 52.8, 58.9, 70.9, 127.0, 127.2, 128.2, 128.3, 128.9, 129.7,
130.3, 136.6,139.9, 143.8, 146.0, 165.4, 169.5, 174.8; IR (KBr disk)
1742, 1710, 1165, 1153, 748, 683 cm-1. Anal. Calcd for C25H25-
NO6S: C, 64.22; H, 5.39; N, 2.99. Found: C, 64.44; H, 5.24; N,
3.06.
Experimental Section
General. Dichloromethane and chloroform was dried and
distilled over CaH2 and P2O5, respectively. (L)-Threonine methyl
ester hydrochloride was prepared from (L)-threonine by treatment
with thionyl chloride in methanol.8 Dibromophenylborane was
prepared according to the literature procedure9 and stored as a
dichloromethane solution.
O-(p-Biphenoyl)-N-tosyl-(L)-allo-threonine (1). To a solution
of 8 (2.00 g, 4.28 mmol) in dry chloroform (5 mL) was added
iodotrimethylsilane (3.4 mL, 24 mmol). The resulting mixture was
heated at 80 °C for 6 h. The resulting mixture was poured into
water and extracted twice with ethyl acetate, washed successively
with water (2×), aqueous 10% Na2S2O3, and water, dried over Na2-
SO4, and concentrated in vacuo. The residue was recrystallized from
benzene and hexane to give 1.60 g (82% yield) of 1.2a
(5) (a) Wakamiya, T.; Tarumi, Y.; Shiba, T. Bull. Chem. Soc. Jpn. 1974,
47, 2686. (b) Dutta, P. K.; Chaudhuri, C.; Mandal, S. B.; Banerjee, A. K.;
Pakrashi, S. C.; Achari, B. J. Chem. Res., Synop. 1991, 201.
(6) Jung, M. F.; Lyster, M. A. J. Am. Chem. Soc. 1977, 99, 968.
(7) Conversion of methyl esters to carboxylic acids with trichloroborane
has been reported: Manchand, P. S. J. Chem. Soc., Chem. Commun. 1971,
667.
(8) Anderson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62,
7364.
(9) Haubold, W.; Herdtle, J.; Gollinger, W.; Einholz, W. J. Organomet.
Chem. 1986, 315, 1.
Oxazaborolidinone 2. To a solution of methyl ester 8 (0.14 g,
0.30 mmol) in CH2Cl2 (1.8 mL) under nitrogen atmosphere at room
1278 J. Org. Chem., Vol. 71, No. 3, 2006

temperature was added a CH2Cl2 solution of dibromophenylborane
(1.17 M, 0.256 mL, 0.30 mmol). After being stirred for 1 h, the
mixture was concentrated in vacuo to give 2, which was identified
ment [Grant-in-Aid for Scientific Research (No. 14044051)] is
gratefully acknowledged.
1
2a
by H NMR (see the Supporting Information).
Supporting Information Available: 1H NMR spectra of 2. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
Acknowledgment. Financial support from the Ministry of
Education, Science, Sports and Culture of the Japanese Govern-
JO0522299
J. Org. Chem, Vol. 71, No. 3, 2006 1279