process described by Deng and co-workers. The improved
organocatalysts OPQD and OPQ can be easily prepared and
are highly enantioselective in the kinetic resolution of
UNCAs and in the desymmetrization of meso-anhydrides.
Processes for the preparation of (S)-N-Boc-propargylglycine
24 and the key intermediate 26 for â-amino acid BAY 10-
8888/PLD-118 using these new catalysts were successfully
performed on multikilogram scale.
2.01-2.20 (m, 1H), 2.20-2.30 (m, 1H), 2.71-3.13 (m, 4H),
3.25-3.40 (m, 1H), 3.80-4.05 (m, 2H), 3.92 (s, 3H), 5.00-
5.40 (m, 5H), 5.85-6.15 (m, 2H), 7.29-7.45 (m, 3H), 8.03
(d, J ) 9.2 Hz, 1H), 8.74 (d, J ) 4.6 Hz, 1H). 13C NMR
(CDCl3): δ 21.7, 26.6, 28.3, 40.2, 49.7, 50.3, 55.6, 59.8,
70.1, 80.9, 101.0, 114.3, 116.8, 118.7, 121.5, 127.2, 131.7,
134.3, 140.7, 144.5, 144.5, 147.5, 157.5. HRMS (M + H)+
Calcd for C23H29N2O2: 365.2229. Found: 365.2316.
O-Propargylquinidine (OPQD): yield ) 92%; 1H NMR
(CDCl3): δ 1.20-1.40 (m, 1H), 1.43-1.60 (m, 2H), 1.72-
1.83 (m, 1H), 2.00-2.13 (m, 1H), 2.18-2.34 (m, 1H), 2.46
(t. J ) 2.4 Hz, 1H), 2.70-2.97 (m, 3H), 3.04-3.16 (m, 1H),
3.21-3.35 (m, 1H), 3.87-3.95 (m, 1H), 3.93 (s, 3H), 4.24
(dd, J ) 16.0, 2.3 Hz, 1H), 5.05-5.16 (m, 2H), 5.36 (d, J
) 4.0 Hz, 1H), 6.02-6.17 (m, 1H), 7.33-7.45 (m, 3H), 8.03
(d, J ) 9.8 Hz, 1H), 8.77 (d, J ) 4.5 Hz, 1H). 13C NMR
(CDCl3): δ 22.6, 26.7, 28.2, 40.2, 49.4, 50.1, 55.6, 56.4,
59.9, 74.9, 79.4, 79.8, 101.1, 114.4, 119.0, 121.6, 127.4,
131.7, 140.7, 143.8, 144.5, 147.4, 157.6. HRMS (M + H)+
Calcd for C23H27N2O2: 363.2073. Found: 363.2144.
O-tert-Butoxycarbonylmethylquinidine: yield ) 55%;
1H NMR (CDCl3): δ 1.20-1.40 (m, 1H), 1.44 (s, 9H), 1.50-
1.58 (m, 1H), 1.67-1.90 (m, 2H), 2.16-2.30 (m, 2H), 2.70-
3.00 (m, 3H), 3.05-3.16 (m, 1H), 3.28-3.40 (m, 1H), 3.77
(d, J ) 15.9 Hz, 1H), 3.93 (s, 3H), 3.95 (d, J ) 15.9 Hz,
1H), 5.07-5.14 (m, 2H), 5.33 (br, 1H), 6.09-6.22 (m, 1H),
7.28-7.44 (m, 3H), 8.03 (d, J ) 9.2 Hz, 1H), 8.75 (d, J )
4.1 Hz, 1H). 13C NMR (CDCl3): δ 22.2, 26.5, 28.1, 28.4,
40.3, 49.5, 50.1, 55.6, 55.6, 60.0, 66.9, 81.5, 101.0, 114.4,
119.0, 121.7, 127.3, 131.7, 140.7, 143.6, 144.5, 147.4, 157.7,
168.5. HRMS (M + H)+: Calcd for C26H35N2O4: 439.2629.
Found: 439.2616.
Large-Scale Procedure for O-Propargylquinine (OPQ).
Under N2 atmosphere in a glass-lined reactor, a solution of
quinine (130 kg, 400 mol) in DMF (460 kg) was added below
20 °C to a NaH (35.2 kg, 880 mol, 60% in mineral oil)
suspension in DMF (220 kg) over a period of 2 h.
(CAUTION: there have been explosive accidents in NaH-
DMF mixtures, and evaluation of the reaction hazard and
the safety treatment have been reported.19 Buckley and co-
workers reported that the NaH-DMF mixtures were ob-
served to self-heat beginning as low as 26 °C by ARC
(accelerating rate calorimeter) analysis.19a,20 DeWall reported
observing that an exothermic reaction involving NaH-DMF
started to occur at about 40 °C only in the stainless steel
reactor.19b Kinoshita and co-workers concluded that the
reaction hazard in NaH-DMF mixtures was suppressed
dramatically when the weight ratio of NaH to DMF was
below 0.16 and the reaction temperature maintained at less
than 60 °C by ARC analysis and Dewar vessels methods.19d
Moreover these workers recommended to use NaH-DMI
(1,3-dimethyl-2-imidazolidinone) mixtures to avoid hazard-
ous NaH-DMF ones. Our reaction conditions in NaH-DMF
Experimental Section
General. Starting materials were obtained from com-
mercial suppliers and were used without further purification
unless otherwise mentioned. Dry solvents were used as
purchased. HPLC analyses were performed on a Shimadzu
14A liquid chromatograph equipped with a UV detector.
1
NMR spectra were obtained at 270 MHz for H NMR and
67.5 MHz for 13C NMR. All coupling constants are reported
in Hertz (Hz). Melting points were determined in open
capillary tubes and uncorrected. N-Z-Phenylalanine UNCA
156a and 5-methylenetetrahydrocyclopenta[c]furan-1,3-dione
(25)17 were synthesized according to the literature procedure.
(DHQD)2AQN and (DHQ)2AQN were purchased from
Aldrich and used without further purification.
General Procedure for Synthesis of O-Alkylated Qui-
nidine. Under N2 atmosphere, NaH (400 mg, 10 mmol, 60%
in mineral oil) was added at 0 °C to a solution of quinidine
(1.62 g, 5 mmol) in DMF (30 mL). After cessation of H2
evolution, alkyl halide (6 mmol) was added dropwise over
a period of 30 min, while maintaining the temperature below
0 °C, followed by stirring for 3 h at room temperature. Water
(50 mL) was added to quench the reaction, followed by
extraction with toluene (50 mL). The toluene layer was
washed with brine (20 mL), concentrated, and purified on
silica gel chromatography (25:25:1) hexanes/acetone/di-
ethylamine) to afford O-alkylated quinidine as a colorless
oil (52-92%).
1
O-Methylquinidine: yield ) 52%; H NMR (CDCl3):
δ 1.10-1.25 (m, 1H), 1.50-1.70 (m, 2H), 1.70-1.80 (m,
1H), 2.15-2.45 (m, 2H), 2.70-3.05 (m, 4H), 3.39 (s, 3H),
3.50-3.62 (m, 1H), 4.00 (s, 3H), 5.05-5.20 (m, 2H), 5.52
(br, 1H), 6.02-6.15 (m, 1H), 7.29-7.45 (m, 3H), 8.04 (d, J
) 9.2 Hz, 1H), 8.75 (d, J ) 4.6 Hz, 1H). 13C NMR
(CDCl3): δ 20.3, 25.5, 28.0, 39.2, 49.0, 49.7, 56.2, 57.2,
59.5, 80.9, 100.9, 115.4, 118.2, 122.0, 127.1, 131.6, 139.1,
143.0, 144.4, 147.2, 158.0. HRMS (M + H)+ Calcd for
C21H27N2O2: 339.2072. Found: 339.2113.
O-Benzylquinidine: yield ) 66%; 1H NMR (CDCl3): δ
1.20-1.60 (m, 3H), 1.70-1.80 (m, 1H), 2.02-2.15 (m, 1H),
2.20-2.30 (m, 1H), 2.65-2.91 (m, 3H), 3.00-3.15 (m, 1H),
3.20-3.35 (m, 1H), 3.89 (s, 3H), 4.38 (d, J ) 11.6 Hz, 1H),
4.48 (d, J ) 11.6 Hz, 1H), 4.90-5.05 (m, 2H), 5.25 (br,
1H), 5.87-6.02 (m, 1H), 7.27-7.47 (m, 8H), 8.05 (d, J )
9.2 Hz, 1H), 8.76 (d, J ) 4.3 Hz, 1H). 13C NMR (CDCl3):
δ 22.4, 26.6, 28.2, 40.1, 49.5, 50.1, 55.6, 60.1, 71.2, 80.8,
101.1, 114.2, 119.0, 121.6, 127.4, 127.6, 127.8, 128.2, 131.7,
137.7, 140.6, 144.5, 144.6, 147.5, 157.5. HRMS (M + H)+
Calcd for C27H31N2O2: 415.2386. Found: 415.2405.
(19) (a) Buckley, J.; Webb, R. L.; Laird, T.; Ward, R. J. Chem. Eng. News 1982,
60 (28), 5. (b) DeWall, G. Chem. Eng. News 1982, 60 (37), 5 and 43. (c)
Laird, T. Chem. Ind. 1986, 17, 134. (d) Kinoshita, N.; Takeuchi, H.; Kawai,
N. Proc. Annu. Meet. Jpn. Soc. Saf. Eng. 2000, Abstr. 15.
(20) Thermal stability: A review of methods and interpretation of data. Rowe,
S. M. Org. Process Res. DeV. 2002, 6, 877.
1
O-Allylquinidine: yield ) 72%; H NMR (CDCl3): δ
1.16-1.30 (m, 1H), 1.40-1.60 (m, 2H), 1.70-1.80 (m, 1H),
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
613