References
<A NAME="RD20802ST-1A">1a</A>
Adams DJ.
Simpkins NS.
Smith TJN.
Chem. Commun.
1998,
1605
<A NAME="RD20802ST-1B">1b</A> For our full report of
this work, see:
Adams DJ.
Blake AJ.
Cooke PA.
Gill CD.
Simpkins NS.
Tetrahedron
2002,
58:
4603 ; this issue of the journal is dedicated
entirely to chiral base chemistry and is an excellent source of
leading references in the area
For recent asymmetric syntheses
of paroxetine, see:
<A NAME="RD20802ST-2A">2a</A>
de Gonzalo G.
Brieva R.
Sanchez VM.
Bayod M.
Gotor V.
J.
Org. Chem.
2001,
66:
8947
<A NAME="RD20802ST-2B">2b</A>
Cossy J.
Mirguet O.
Gomez Pardo D.
Desmurs J.-R.
Tetrahedron Lett.
2001,
42:
7805
<A NAME="RD20802ST-2C">2c</A>
Johnson TA.
Curtis MD.
Beak P.
J. Am. Chem. Soc.
2001,
123:
1004
<A NAME="RD20802ST-2D">2d</A>
Liu LT.
Hong P.-C.
Huang H.-L.
Chen S.-F.
Wang C.-LW.
Wen Y.-S.
Tetrahedron: Asymmetry
2001,
12:
419
<A NAME="RD20802ST-2E">2e</A>
Amat M.
Bosch J.
Hidalgo J.
Canto M.
Perez M.
Llor N.
Molins E.
Miravitlles C.
Orozco M.
Luque J.
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2000,
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3074
<A NAME="RD20802ST-3A">3a</A>
Rama Rao R.
Singh AK.
Varaprasad CVNS.
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1991,
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4393
<A NAME="RD20802ST-3B">3b</A>
Goehring RR.
Greenwood TD.
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Rogers TG.
Wolfe JF.
J. Med. Chem.
1990,
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926
<A NAME="RD20802ST-4">4</A>
Bambridge K.
Begley MJ.
Simpkins NS.
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1994,
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3391
<A NAME="RD20802ST-5">5</A>
1-Benzyl-4-(4-fluorophenyl)-3-methyl
-piperidine-2,6-dione 5e: A solution
of the chiral bis-lithium amide base 8 was prepared by dropwise addition of
a solution of n-BuLi (1.0 mL, of a 1.6
M in hexanes, 1.60 mmol) to the chiral diamine (342 mg, 0.81 mmol)
in THF (4 mL) at -78 °C. The resulting red coloured
solution was warmed to room temperature for 20 min before cooling
to -78 °C and addition via cannula, to a stirred
solution of the starting imide 4 (200 mg,
0.67 mmol) in THF (10 mL) at ca. -78 °C (internal
temperature). The mixture was stirred for 45 min at this temperature
before being diluted with THF (14 mL). Excess methyl iodide (3 mL)
was then added, the mixture warmed to -40 °C (internal temperature)
and then stirred at this temperature for 4 h. The reaction mixture
was quenched with saturated aqueous NH4Cl (10 mL) and
extracted into Et2O (3 × 20 mL). The extracts
were washed sequentially with 2 M HCl (3 × 60 mL), saturated
aqueous NaHCO3 (60 mL) and brine (60 mL). The combined
extracts were then dried (MgSO4) and concentrated under
reduced pressure to yield a crude product which was purified by
flash column chromatography on silica gel (40% Et2O
in petroleum ether) to give the product as an off white solid (128
mg, 64%), mp 115-118 °C; [α]D
22 -21
(c = 1.02 in CHCl3);
IR (CHCl3)/cm-1:
1726 (C=O), 1681 (C=O), 1606 (Ar), 1512 (Ar); δH (400
MHz, CDCl3): 1.11 (3 H, d, J = 7
Hz, CH3), 2.72 (1 H, dq, J = 11
Hz, 7 Hz, CHCH3), 2.78 [1
H, dd, J = 18 Hz, 13 Hz, C(O)CH2ax],
2.94 (1 H, m, CHAr), 2.94 [1 H, dd, J = 18
Hz, 4 Hz, C(O)CH2eq], 4.97 (1 H, d, J = 14 Hz, NCHHPh),
5.02 (1 H, d, J = 14 Hz, NCHHPh), 7.02 (2 H, m), 7.11 (2 H, m), 7.29
(3 H, m) and 7.38 (2 H, m); δC (125 MHz, CDCl3):
14.4 (CH3), 40.8 [C(O)CH2],
41.9 (CHAr), 43.4 (NCH2Ph), 43.5 (CHCH3), 116.1
(J
C-F = 21.5 Hz,
CH), 127.6 (CH), 128.5 (CH), 128.6 (CH), 128.9 (CH), 136.3 (C),
137.3 (C), 162.1 (d, J
C-F = 246 Hz,
C), 171.0 (C=O) and 174.5 (C=O); HRMS(EI) Found: [M]+ 311.1334,
C19H18NO2F requires 311.1322.
The
enantiomeric excess was determined by HPLC analysis using a Chiralcel
OD column with 5% i-PrOH in
hexane as eluant, at a flow rate of 0.8 mL/min, using UV
detection at 215 nm. Retention times were 49.8 min(minor) and 59.5 min(major).
1-Benzyl-4-(4-fluorophenyl)-2,6-dioxo-piperidine-3-carboxylic
acid methyl ester 5i:
The
reaction was carried out as described above, starting with imide 4 (200 mg, 0.67 mmol) and quenching of
the intermediate enolate with excess methyl cyanoformate (0.11 mL).
After 30 min at -78 °C the mixture was worked
up as described above to give a crude product which was purified by
flash column chromatography on silica gel (30% EtOAc in
petroleum ether followed by DCM) to give the product 5i as
a white solid (168 mg, 71%), mp 137-139 °C; [α]D
28 -31 (c = 0.74 in CHCl3);
IR (CHCl3)/cm-1:
1749 (C=O), 1729 (C=O), 1680 (C=O), 1608
(Ar), 1512 (Ar); δH (400 MHz, CDCl3):
2.82 [1 H, dd, J = 17.5
Hz, 11, C(O)CH2ax], 3.02 [1 H, dd, J = 17.5 Hz, 4.5 Hz, C(O)CH2eq],
3.65 (3 H, s, OCH3), 3.68 (1 H, ddd, J = 11
Hz, 11 Hz, 4.5 Hz, CHAr), 3.81 (1 H, d, J = 11
Hz, CHCO2Me), 4.96 (1 H, d, J = 14
Hz, NCHHPh), 5.03 (1 H, d, J = 14, NCHHPh),
7.00 (2 H, m), 7.13 (3 H, m), 7.29 (2 H, m), 7.37 (2 H, m); δC (125
MHz, CDCl3): 37.5 (CHAr), 38.8 [C(O)CH2], 43.5 (NCH2Ph), 52.9
(OCH3), 56.4 (CHCO2Me),
116.2 (d, J
C-F = 21.5
Hz, CH), 127.8 (CH), 128.4 (CH), 128.6 (CH), 129.1 (CH), 134.4 (C),
136.5 (C), 163.5 (d, J
C-F = 247
Hz, C), 168.1 (C=O), 168.3 (C=O), 170.1 (C=);
HRMS(EI): Found: [M]+ 355.1220,
C20H18NO4F requires 355.1220.
The
enantiomeric excess was determined by HPLC analysis using a Chiralcel
OD column with 3% EtOH in hexane as eluant, at a flow rate
of 0.8 mL/min, using UV detection at 215 nm. Retention
times were 75.8 min(minor) and 88.5 min(major).
<A NAME="RD20802ST-6">6</A>
The use of bis-lithiated
base 8 may seem to invite the formation
of unwanted products 7 but we achieved
much poorer yields of desired compounds 5 by
using the base in mono-lithiated form.
<A NAME="RD20802ST-7">7</A>
Kamikawa T.
Hayashi T.
Tetrahedron
1999,
55:
3455
<A NAME="RD20802ST-8">8</A>
Gotov B.
Schmalz H.-G.
Org. Lett.
2001,
3:
1753
<A NAME="RD20802ST-9">9</A> Many syntheses of paroxetine use
this approach, see for example:
Yu MS.
Lantos I.
Peng Z.-Q.
Yu J.
Cacchio T.
Tetrahedron
Lett.
2000,
41:
5647 ;
see also ref. and references
therein
<A NAME="RD20802ST-10">10</A>
The reported values for paroxetine
include [α]D
20 -75.5
(c = 1.2, MeOH) for >97:3
er,
[2c]
and [α]D
22 -80.8
(c = 1.25, MeOH) via enantiopure
intermediates.
[2e]
