Bicyclic O,P ligands for catalytic asymmetric 1,4-addition to α,β-unsaturated ketones

Article abstract of DOI:10.1002/adsc.200303238

A new class of bicyclic O,P ligands has been prepared and evaluated in the 1,4-addition to α,β-unsaturated ketones. The best results with the bicyclic ligand were obtained using a lower catalyst loading than what has been reported with similar ligands whe

Full text of DOI:10.1002/adsc.200303238

FULL PAPERS
Bicyclic O,P Ligands for Catalytic Asymmetric 1,4-Addition to
a,b-Unsaturated Ketones
Stefan A. Modin,a Pedro Pinho,b Pher G. Anderssona,*
a
Department of Organic Chemistry, Uppsala University, Box 599, 751 24 Uppsala, Sweden
Fax: (þ46)-18-471-3818, e-mail: Pher.Andersson@kemi.uu.se
b
Medivir AB, Lunastigen 7, 141 44 Huddinge, Sweden
E-mail: Pedro.Pinho@medivir.se
Received: December 20, 2003; Accepted: March 10, 2004
Abstract: A new class of bicyclic O,P ligands has gands when adding a Grignard reagent to 2-cyclo-
been prepared and evaluated in the 1,4-addition to hexenone.
a,b-unsaturated ketones. The best results with the bi-
cyclic ligand were obtained using a lower catalyst Keywords: asymmetric catalysis; cuprates; heterocy-
loading than what has been reported with similar li- cles; Michael addition; O,P ligands
Introduction
Results and Discussion
Enantioselective conjugate addition of carbon nucleo- Ligands 2a and b are readily available from amino alco-
philes to a,b-unsaturated ketones has been a challenge hol 3 which, in turn, is conveniently prepared in three
to organic chemists for a long time. One way to achieve steps from (S)-(À)-1-phenylethylamine, ethyl glyoxy-
this is to use a stoichiometric amount of copper together late and cyclopentadiene by a diastereoselective aza-
with a chiral ligand, which results in a stereoselective ad- Diels Alder reaction.[12] The rigid 2-azanorbornyl deriv-
dition (Figure 1).
atives formed therefrom can be formed in both enan-
Much attention has been focused on the possibility to tiomers and on a large scale[13] and have proven to be
obtain a catalytic system for the reaction.[1 10] In previ- very successful as ligands in a number of catalytic asym-
ous work by Tomioka,[11] promising results have been metric reactions.[14 18] Boc protection of the amine and
obtained using the proline-derived ligand 1, see Fig- tosylation of the alcohol gave 5. The introduction of
ure 2.
the diphenylphosphinoyl group proved to be difficult,
since neither the use of NaPPh2, derived from chlorodi-
phenylphosphine and sodium, nor LiPPh2 ¥BH resulted
3
in acceptable yields of the desired product. However, re-
action of tosylate 5 with LiPPh2, prepared from PPh3 and
lithium metal in THF,[19] gave 6 in 77% isolated yield. N-
Deprotection and subsequent acylation then afforded li-
gands 2a and b in high yields, Scheme 1.
Figure 1. Typical Michael addition.
The ligands were evaluated in the enantioselective
1,4-addition to 7 as outlined in Table 1.
As can be seen in Table 1 the bicyclic ligand 2a shows a
different reaction behaviour compared with the proline-
derived ligand 1. Using the conditions that have been re-
ported to give the best results with ligand 1 led to almost
no product at all when 2a was used as the chiral ligand.
However, it was found that the counter ion of the copper
salt had a profound effect on both yield and selectivity of
the catalyst. The use of CuCl resulted in 54% yield and
41% ee. The selectivity was further improved when
Figure 2. Pyrrolidine and azanorbornyl derivatives used as
chiral ligands in asymmetric 1,4-addition.
We now report on the synthesis of the new bicyclic li- CuBr was used (entry 6), while CuBr¥Me2S resulted in
gands2a and bandtheirapplicationin the copper-catalysed decreased enantioselectivity (25% ee, entry 7) but
addition of a Grignard reagent to a,b-unsaturated ketones. gave exclusively 1,4 addition.[20] One difference between
Adv. Synth. Catal. 2004, 346, 549 553
DOI: 10.1002/adsc.200303238
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
549

Stefan A. Modin et al.
FULL PAPERS
son for this behaviour is not known to us. Best results
were obtained with CuI that gave the product in 71%
ee and 73% yield (entry 5). It should be noted that these
results were obtained using only 4.7 mol % of the chiral
ligand. Attempts to further decrease catalyst loading did
not give satisfactoryresults. The use ofligand 2b resulted
in similar enantioselectivities as 2a but gave a higher de-
gree of 1,2 addition.
Ligands 1 and 2a were also evaluated in a reaction us-
ing chalcone as substrate. However, as can be seen in Ta-
ble 2, it is evident that these ligands are unsuitable for
chalcones as they give a racemic product.
Scheme 1. (a) Et3N, Boc 2O THF, rt, 88%; (b) TsCl, pyridine,
CH2Cl2, 08C to rt, 97%; (c) LiPPh2, THF 08C to rt, 77%; (d)
HCl, THF, reflux; (e) Et3N, t-BuCOCl, CH2Cl2, 08C to rt, >
98% (two steps): (f) Et3N, AcCl, CH2Cl2, 08C to rt, 83% (two
steps).
Conclusion
Two new chiral bicyclic O,P ligands have been pre-
the two different catalysts is their behaviour when de- pared and evaluated in the enantioselective 1,4-addi-
creasing the ligand loading. Going down from tion to a,b-unsaturated systems. It was found that, at
34 mol % to 17 mol % of ligand 1 gave both lower yield lower catalyst loadings, these new bicyclic ligands per-
and ee while ligand 2b gave higher yield and ee. The rea- formed better than the earlier reported proline-de-
Table 1. Addition of BuMgCl to 2-cyclohexenone promoted by ligands 1, 2a and 2b.
Entry
Ligand
Mol % Ligand
Copper(I) Salt
Yield [%][a]
ee [%][b]
Config.[b]
Selectivity
1,4: 1,2[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
34
17
34
17
4.7
17
17
17
17
34
17
17
9.5
17
CuI
CuI
CuI
CuI
55[d]
35
8.3
44
73
28
74
54
43
28
41
55
26
25
79
S
S
4.0: 1
4.8: 1
1.6: 1
1.9: 1
>10: 1
45
[e]
28
28
2a
2a
2a
2a
1
2a
2a
2a
2a
2b
72
71
55
25
41
12
50
59
56
28
52
R
R
R
R
R
S
R
R
R
R
R
CuI
CuBr
CuBr¥Me2S
CuCl
CuCN
CuCN
CuCN
CuCN[g]
CuCN
CuCN
1.2: 1
[f]
4.9: 1
2.8: 1
1.4: 1
2.0: 1
2.3: 1
2.3: 1
0.8: 1
[a]
Isolated yield after flash chromatography (deactivated silica gel, pentane/EtOAc).
Determined by specific optical rotation (see Experimental Section).
Determined by H NMR [1,4]/[1,2].
No quantitative separation.
Yield too low to be able to determine ee.
No [1,2] addition could be detected.
[b]
[c]
[d]
[e]
[f]
1
[g]
17 mol % TMSCl added before adding Grignard reagent.
Table 2. Addition of BuMgCl to chalcone promoted by ligands 1 or 2a.
Entry
Ligand
Mol % Ligand
Copper(I) Salt
Yield [%][a]
ee [%][b]
Selectivity[c]
17.6
1
2
2a
1
17
17
CuCN
CuCN
12
71
rac
rac
[a]
Isolated yield after flash chromatography (deactivated silica gel, pentane/EtOAc).
Determined by HPLC analysis on a chiral column (ChiralCel OD-H).
Determined by H NMR [1,4]/[1,2].
[b]
[c]
1
550
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Catalytic Asymmetric 1,4-Addition to a,b-Unsaturated Ketones
FULL PAPERS
tion, pyridine (2.0 mL, 24.8 mmol) was added followed by ad-
dition of tosyl chloride (2.4 g, 12.6 mmol) as a solution in CH2
Cl2 (20 mL). The mixture was allowed to stir overnight at rt.
The reaction mixture was diluted with CH2Cl2 (20 mL), washed
with brine (2ꢀ10 mL) and water (10 mL), dried with MgSO4,
filtered and evaporated to give crude 5. Flash chromatography
[silica, pentane/EtOAc (100/0 to 80/20)] gave 5 as a colourless
oil; yield: 3.88 g (97%); Rf ¼0.82 (EtOAc/pentane: 60/40);
[a]2D0: þ65.5 (c 1.11, CHCl3); IR (neat): n¼1698, 1366,
rived ligand 1. Further studies on this class of ligands
are in progress.
Experimental Section
General Remarks
1
1177 cmÀ1; H NMR (CDCl3; mixture of rotamers): d¼1.22
Liquid chromatography was carried out on a chiral column
(Daicel ChiralCel OD-H), using a 254 nm UV detector and a
flow rate of 0.5 mL/min (i-PrOH/hexane: 1/99). Flash chroma-
tography was performed on silica gel (Matrex 60A, 37 70 mm).
When mentioned, deactivated silica gel means that it was treat-
ed with 5% Et3N in pentane and the column was eluted with the
same solvent mixture until the exiting eluent was basic to pH
paper. Analytical TLC was carried out on precoated plates,
SIL G-60 UV254, purchased from Macherey-Nagel. Slow addi-
tion was made using a syringe pump. Polarimetry was per-
formed on a Perkin Elmer 241 polarimeter. Infrared spectra
were obtained from a Perkin-Elmer 1760 FTIR. 1H and
13C NMR were obtained either on a Varian Gemini 200, a Var-
ian XL 300 or a Varian Unity 400 using the residual peak from
(m, 2H), 1.32 [s, 9H, C(CH3)3], 1.39 [s, 9H, C(CH3)3], 1.65 (m,
8H), 2.43 (s, 6H), 2.51 (m, 2H), 3.30 (m, 1H), 3.44 (m, 1H),
3.64 (t, 1H), 3.77 (t, 1H), 4.10 (m, 6H), 7.33 (m, 4H, tosyl),
7.77 (m, 4H, tosyl); 13C NMR (mixture of rotamers): d¼21.6,
27.2, 28.3, 28.4, 29.6, 30.1, 33.8, 34.6, 38.6, 39.2, 56.7, 57.6,
61.5, 61.7, 68.4, 68.6, 79.8, 127.9, 129.8, 133.0 and 145.2; MS
(EI): m/z (rel. intensity)¼281 (Mþ Boc,<1%), 53 (17), 54
(30), 65 (28), 66 (32), 67 (100), 68 (74), 77 (11), 78 (10), 79
(14), 80 (68), 81 (17), 82 (12), 94 (72), 108 (54), 112 (29), 138
(17), 153 (66); anal. calcd. for C19H27NO5S: C 59.82, H 7.13, N
3.67; found: C 59.05, H 7.19, N 3.61.
1
CHCl3 d¼7.26 for H or CDCl3 d¼77.0 for 13C as reference.
(1S,3R,4R)-3-[(Diphenylphosphanyl)-methyl]-2-
azabicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (6)
Unless otherwise noted, materials were obtained from com-
mercial suppliers and used without any further purification.
THFand diethyl ether were distilled from a sodium-benzophe-
none solution. Dichloromethane was distilled from CaH2. 2-
Cyclohexenone was dried with MS 4 ä, distilled under vacuum
and stored over MS 4 ä.
In a two-necked round-bottomed flask equipped with
a condenser, a solution of triphenylphosphine (2750 mg,
10.48 mmol) in THF (6 mL) was prepared under argon. Lithi-
um metal (146 mg, 20.96 mmol) was added under a flow of ar-
gon and the mixture was stirred at rt until the metal was dis-
solved and the solution turned deep red. Then tert-butyl chlor-
ide (1.1 mL, 10.48 mmol) was added dropwise to quench the
phenyllithium. This solution was then added dropwise via a sy-
ringe to a solution of 5 (1.00 g, 2.62 mmol) in THF (5 mL) un-
der argon at 08C. The reaction mixture was then stirred for 2 h
at rt and quenched with methanol (6 mL) and the solvents were
evaporated. Flash chromatography [silica, pentane/EtOAc
(100/0 to 90/10)] gave 6 as a white solid; yield: 800 mg (77%);
Rf ¼0.75 (EtOAc/pentane: 20/80); mp 113 1158C; [a]2D0:
(1S,3R,4R)-3-Hydroxymethyl-2-
azabicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (4)
In a 250-mL round-bottomed flask, a solution of Boc2O (3.5 g,
16.2 mmol) in THF (20 mL) was prepared under argon. To this
solution triethylamine (4.0 ml, 28.4 mmol) was added. Then
3
[12] was added dropwise as a solution in THF (20 mL). The re-
action mixture was stirred at rt for 5 h. The reaction mixture
was then diluted with diethyl ether (10 mL), washed with brine
(2ꢀ10 mL), water (10 mL), dried with MgSO4, filtered and
evaporated to give crude 4. Flash chromatography [silica, pen-
tane/EtOAc (95/5 to 40/60)] gave 4 as pale yellow oil; yield: 4 g
(88%); Rf ¼0.57 (EtOAc/pentane: 60/40); [a]2D0: þ71.6 (c 0.87,
þ92.8 (c 1.08, CHCl3); IR (neat): n¼2224, 1591, 1484 cmÀ1
;
1H NMR (CDCl3; mixture of rotamers): d¼1.30 (m, 4H),
1.43 [s, 9H, C(CH3)3], 1.50 [s, 9H, C(CH3)3], 1.60 (m, 6H),
1.90 (m, 4H), 2.6 (s, 1H), 2.7 (s, 1H), 2.73 (m, 1H, CHP), 2.95
(m, 1H, CHP), 3.28 (m, 1H, CHP), 3.46 (m, 1H, CHP), 4.10
(s, 3H), 4.23 (s, 3H), 7.25 7.55 (m, 16H), 7.64 (m, 4H);
13C NMR (mixture of rotamers): d¼27.6, 28.5, 29.6, 30.2,
32.1, 32.2, 32.7, 32.9, 33.9, 34.6, 40.4, 40.8, 40.9, 56.9, 57.7, 61.9,
62.2, 78.8, 79.4, 128.2, 128.4, 128.4, 128.6, 132.4, 132.6 132.7,
132.9, 133.0, 154.5; 31P NMR: d¼ À21.86, À21.32; MS (EI):
m/z (rel. intensity)¼295 (Mþ B oc, 5%), 68 (18), 183 (26),
185 (11), 199 (30), 200 (100), 201 (17); anal. calcd. for
C24H30NO2P: C 72.89, H 7.65, N 3.54; found: C 72.86, H 7.79,
N 3.46.
CHCl3); IR (neat): n¼3420, 1697, 1670, 1397, 1165 cmÀ1
;
1H NMR (CDCl3): d¼1.24 (m, 2H), 1.45 [s, 9H, C(CH3)3],
1.65 (m, 4H), 2.28 (s, 1H), 3.45 (m, 1H), 3.56 (m, 2H), 4.08 (s,
1H), 4.46 (m, 1H); 13C NMR: d¼27.9, 28.4, 29.7, 35.7, 39.7,
57.9, 66.6, 67.3, 80.2, 157.4; MS (EI): m/z (rel. intensity)¼227
(Mþ, 1%), 68 (42), 96 (15), 112 (18), 140 (100), 196 (26); anal.
calcd. for C12H21NO3: C 63.41, H 9.31, N 6.16; found: C 62.94,
H 9.74, N 6.20.
(1S,3R,4R)-3-(Toluene-4-sulfonyloxymethyl)-2-
azabicyclo[2.2.1]heptane-2-carboxylic Acid tert-Butyl
Ester (5)
(1S,3R,4R)-1-{3-[(Diphenylphosphanyl)-methyl]-2-
azabicyclo[2.2.1]hept-2-yl}-2,2-dimethylpropan-1-one (2a)
In a 250-mL round-bottomed flask, a solution of 4 (2.4 g,
10.5 mmol) in CH2Cl2 (20 mL) was cooled to 08C. To this solu-
In a 100-mL round-bottomed flask, a solution of 6 (1.7 g,
4.3 mmol) under nitrogen and conc. HCl (2.5 mL, 30.1 mmol)
Adv. Synth. Catal. 2004, 346, 549 553
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Stefan A. Modin et al.
FULL PAPERS
in THF (40 mL) was allowed to reflux over night. The reaction
mixture was cooled to 08C and 20% NaOH (aqueous) was add-
ed until pH 10. The phases were separated and the aqueous
phase was extracted with CH2Cl2 (4ꢀ10 mL). The combined
organic phases were washed with brine (20 mL), dried with
MgSO4, filtered and evaporated. The crude was dissolved in
CH2Cl2 under argon and cooled to 08C. Triethylamine
(1.5 mL, 10.8 mmol) followed by pivaloyl chloride (0.90 mL,
7.31 mmol) were added. The reaction mixture was allowed to
stir overnight at rt. The solvent was evaporated and flash chro-
matography [silica, pentane/EtOAc (100/0 to 90/10)] gave 2a as
a white solid; yield: 1.6 g (99%); Rf ¼0.75 (EtOAc/pentane: 20/
80); [a]2D0: þ54.5 (c 1.03, CHCl3); mp 105 1068C; IR (neat):
Catalytic Conjugate Addition of Butylmagnesium
Chloride to 2-Cyclohexenone (Table 1, Entry 11)
In a 50-mL round-bottomed flask, a solution of 2a (45.45 mg,
0.120 mmol) and CuCN (5.58 mg, 0.0623 mmol) in diethyl
ether (8 mL) was stirred under nitrogen at rt for 20 min. The
mixture was then cooled to À788C and butylmagnesium chlor-
ide (420 mL, 0.840 mmol) was added. After stirring for 20 min
2-cyclohexenone (70 mL, 0.700 mmol), in diethyl ether
(2 mL) was added during 15 min. The reaction mixture was stir-
red until completion according to TLC (EtOAc/pentane: 10/
90) and then quenched with saturated aqueous NH4Cl
(10 mL) and 22% NH4OH (aqueous) (10 mL). The blue solu-
tion was stirred for 30 min and the layers were separated.
The aqueous phase was extracted with ether (3ꢀ20 mL).
The organic phases were combined and washed with 10%
aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL),
water (10 mL) and brine (10 mL). The organic phase was dried
with MgSO4, filtered and evaporated to give the crude product.
Flash chromatography [deactivated silica, pentane/EtOAc
(100/0 to 90/10)] gave 8 as a colourless oil;[21] yield: 44 mg
(41%). The ee was determined from the optical rotation as
specified previously.[3]
n¼2973, 1617, 1407 cmÀ1
;
1H NMR (CDCl3): d¼1.24 (m,
9H), 1.33 (m, 2H), 1.5 1.7 (m, 4H), 1.92 (m, 1H), 2.74 (s,
1H), 3.18 (m, 1H), 3.66 (m, 1H), 4.47 (s, 1H), 7.24 7.42 (m,
8H), 7.69 (m, 2H); 13C NMR: d¼27.0, 27.4, 27.9, 30.1, 32.2,
35.5, 39.3, 58.9, 63.0, 128.2, 128.3, 128.4, 128.5, 132.6, 132.7,
132.9, 133.0, 176.0; 31P NMR: d¼ À20.67; MS (EI): m/z (rel. in-
tensity)¼379 (Mþ, 1%), 67 (10), 95 (39), 96 (14), 155 (11), 177
(14), 178 (100), 179 (16), 183 (44), 185 (13), 201 (40), 202 (46),
203(10), 215 (18); anal. calcd. for C24H30NOP: C 75.96, H 7.97,
N 3.69; found: C 74.53, H 7.30, N 4.11.
Acknowledgements
We thank the Swedish Research Council for generous financial
support.
(1S,3R,4R)-1-{3-[(Diphenylphosphanyl)-methyl]-2-
azabicyclo[2.2.1]hept-2-yl}-ethanone (2b)
In a 25-mL round-bottomed flask, a solution of 6 (201.7 mg,
0.510 mmol) and conc. HCl (0.30 mL, 3.6 mmol) in THF
(10 mL) was allowed to reflux overnight under nitrogen. The
reaction mixture was cooled to 08C and quenched with 20%
NaOH (aqueous) until pH 10. The phases were separated
and the aqueous phase was extracted with CH2Cl2 (4ꢀ
10 mL). The combined organic phases were washed with brine
(20 mL), dried with MgSO4, filtered and solvent evaporated.
The crude residue was dissolved in CH2Cl2 (8 mL) under argon
and cooled to 08C. Triethylamine (0.5 mL, 3.59 mmol) and ace-
tyl chloride (0.166 mL, 2.33 mmol) were added in this order.
The reaction mixture was allowed to stir overnight at rt. The
solvent was evaporated and flash chromatography (deactivat-
ed silica, EtOAc/pentane: 75/25) gave 2b as a white solid; yield:
142.43 mg (83%); Rf ¼0.30 (EtOAc/pentane: 75/25); mp 143
1458C; [a]2D0: þ99.3 (c 1.02, CHCl3); IR (neat): n¼2969,
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1636, 1434, 1417 cmÀ1; H NMR (CDCl3): d¼1.2 1.37 (m,
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Catalytic Asymmetric 1,4-Addition to a,b-Unsaturated Ketones
FULL PAPERS
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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