R2Zn, Cyclic Enones, N-tert-Butanesulfinyl Imines
2.25 (m, 1H), 1.95 (m, 1H), 1.70 (m, 3H), 1.44 (m, 1H), 1.23 (s,
9H), 1.01 (d, J ) 6.9, 3H), 0.96 (d, J ) 6.9, 3H); 13C NMR δ
222.5, 140.3, 128.5 (CH), 127.8 (CH), 127.6 (CH), 60.6 (CH), 57.6
(CH), 55.9, 45.3 (CH), 39.6 (CH2), 28.9 (CH), 22.8 (CH3), 21.5
(CH2), 21.4 (CH3), 17.2 (CH3); IR ν (cm-1) 3272 (broad), 2956
(s), 1724 (s), 1454, 1068 (s); HRMS (MALDI) Calcd for
C19H29NNaO2S [M + Na]+ 358.1817. Found 358.1812.
By simply choosing the appropriate ligand (L1 vs ent-L1)/chiral
sulfinimine combination (Rs vs Ss), the present methodology
allows access to four diastereomeric ꢀ-amino ketones in
enantiomerically pure form, when cyclohexenone or cyclohep-
tenone are used. Moreover, excellent regioselectivities and
isolated yields were obtained for the Baeyer-Villiger oxidation
of some five- and six-membered ring ꢀ-amino ketones obtained
by the present methodology. This Baeyer-Villiger transforma-
tion greatly expands the synthetic utility of the methodology
disclosed in this work since the resulting aminolactones 6 are
versatile building blocks for synthetic applications.
General Procedure for Baeyer-Villiger Oxidation of ꢀ-Ami-
noketones. To a solution of ꢀ-aminoketones 3 or 5 (0.34 mmol) in
CH2Cl2 (2 mL) was added MCPBA (300 mg, 1.20 mmol) at 0-5
°C, and the mixture was stirred at the same temperature. After 30
min, finely ground NaHCO3 (100 mg, 1.20 mmol) was added, and
the suspension was concentrated to give a solid residue. The solid
was allowed to stand for 3 h at room temperature, a small volume
of CH2Cl2 was added to the mixture, and the suspension was
carefully concentrated to a solid. When the reaction was not
completed, the process of dissolution and evaporation was repeated.
After completion (TLC monitoring), the reaction was quenched by
diluting with EtOAc (10 mL) and adding a solution of Na2SO3 (800
mg) in H2O (10 mL). After stirring for 15 min at room temperature,
the phases were separated and the aqueous phase extracted with
more EtOAc (2 × 10 mL). The combined organic layers were
washed with a saturated solution of NaHCO3, followed by brine.
The organic layers were dried over MgSO4, and the solution was
concentrated in vacuo and chromatographied on silica gel (hexane/
EtOAc) to afford the pure corresponding ꢀ-aminolactone.
Experimental Section
General Procedure for the Tandem Conjugate Addition-
Mannich Reaction. Cu(OTf)2 (6 mg, 0.016 mmol), phosphoramidite
L1 (18 mg, 0.032 mmol), the enone 1 (0.75 mmol), and the
corresponding sulfinimine 2 (0.50 mmol) were suspended in CH2Cl2
(4.0 mL), and the suspension was stirred at room temperature for
15 min before cooling to -40 °C. A solution of R1 Zn (1.50 mL,
2
1.0 M in toluene) was added dropwise, and the reaction mixture
was allowed to reach -20 °C while stirring overnight (12-14 h).
The reaction was quenched at -20 °C by adding a saturated solution
of NH4Cl in 1:1 H2O/MeOH (1.50 mL), and the mixture was stirred
for 15 min at room temperature. The resulting precipitate was
filtered through a short pad of celite, and after evaporation of
solvents, 1H NMR analysis of the crude sample was performed to
determine the imine conversion and diasteromeric ratio of products.
Purification by silica gel column chromatography, using EtOAc/
hexane, gave the analytically pure compound.
(6S,7S,1′R)-N-(tert-Butylsulfonyl)-6-methyl-7-(1-amino-3-phenyl-
propyl)oxepan-2-one (6a). Following the general procedure, after
workup, column chromatography purification was carried out using
2:1 hexane/ethyl acetate, affording 107 mg (83% yield) of a
20
colorless foam with >99:1 dr according to GC: [R]D +73.1 (c
1.0, CHCl3); GC tr (major) ) 21.96 min; 1H NMR δ 7.28 (m, 2H),
7.16 (m, 3H), 4.53 (d, J ) 10.2, 1H, 1H), 4.37 (dd, J ) 9.05, 2.0,
1H), 3.70 (m, 1H), 2.98 (m, 1H), 2.60 (m, 3H), 1.95 (m, 1H),
1.90-1.55 (m, 6H), 1.45 (s, 9H), 1.40 (m, 1H), 0.87 (d, J ) 6.8,
3H); 13C NMR δ 175.4, 141.4, 128.7 (CH), 128.6 (CH), 126.3 (CH),
87.6 (CH), 60.2, 56.0 (CH), 37.2 (CH2), 34.8 (CH), 33.8 (CH2),
33.1 (CH2), 30.5 (CH2), 24.4 (CH3), 21.7 (CH2), 17.4 (CH3); IR ν
(cm-1) 3295 (broad), 2928, 1731 (s), 1454 (s), 1127; MS (EI) m/z
(%) 382.1 (2, M+ + 1), 381.1 (3, M+), 254 (15), 156 (9), 134 (100),
117 (6), 91 (25), 70 (5), 57 (45); HRMS (EI) Calcd for C20H31NO4S
[M]+ 381.1974. Found 381.1925.
(RS,2S,3S,1′R)-N-(tert-Butylsulfinyl)-3-methyl-2-(1-amino-3-phe-
nylpropyl)cyclohexanone (3 h). Following the general procedure,
but using 2 mmol of starting N-sulfinimine 2e, after workup,
chromatography on silica gel eluting first with 3:1 and then 2:1
hexane/ethyl acetate afforded 630 mg (91% yield) of 3h as a
colorless oil: [R]D20 -27.7 (c 0.92, CHCl3); Rf 0.19 (1:1 n-hexane/
EtOAc); 1H NMR δ 7.26 (m, 3H), 7.17 (m, 2H), 4.64 (d, J ) 10.8,
1H), 3.28 (t, J ) 11.0, 1H), 2.90 (m, 1H), 2.80 (dd, J ) 11.7, 3.9,
1H), 2.53 (m, 1H), 2.30 (m, 2H), 1.95 (m, 1H), 1.77 (m, 1H), 1.60
(m, 3H), 1.44 (m, 1H), 1.26 (s, 9H), 0.83 (d, J ) 6.4, 3H); 13C
NMR δ 213.9, 141.9, 128.7 (CH), 128.5 (CH), 126.0 (CH), 61.7
(CH), 56.3 (CH), 56.2, 42.6 (CH2), 36.6 (CH), 34.2 (CH2), 33.0
Acknowledgment. This work was generously supported by
the Spanish Ministerio de Educacio´n y Ciencia (MEC; Con-
solider Ingenio 2010-CSD2007-00006 and CTQ-2007-65218).
J.C.G.-G. thanks the Spanish MEC for a Juan de la Cierva
contract.
(CH2), 32.0 (CH2), 25.5 (CH2), 22.9 (CH3), 19.4 (CH3); IR ν (cm-1
)
3301 (broad), 2956 (s), 2867 (m), 1697 (s), 1455 (m), 1066 (s);
MS (MALDI) m/z 372 [M + Na]+. HRMS (MALDI) Calcd for
C20H31NNaO2S [M + Na]+ 372.1973. Found 372.1979.
(RS,2R,3S,1′R)-N-(tert-Butylsulfinyl)-3-isopropyl-2-(1-amino-1-
phenylmethyl)cyclopentanone (5c). Following the general proce-
dure, sulfinimine 2a (209 mg, 0.53 mmol) and cyclopentenone 1c
(60 µL, 0.70 mmol) were used. After workup, purification by
chromatography on silica gel was carried out using first 3:1 and
then 7:3 hexane/ethyl acetate, affording 152 mg (83% yield) of a
colorless oil with 94:6 dr according to 1H NMR: [R]D20 -112.7 (c
3.00, CHCl3); 1H NMR δ 7.30 (m, 3H), 7.15 (m, 2H), 5.95 (d, J )
8.7, 1H), 4.57 (dd, J ) 8.7, 5.1, 1H), 2.79 (dd, J ) 9.3, 5.1, 1H),
Supporting Information Available: Experimental proce-
dures, full characterization, copies of 1H and 13C NMR spectra
of all compounds, and X-ray crystal data for compound 4. This
material is available free of charge via the Internet at
JO802812W
J. Org. Chem. Vol. 74, No. 6, 2009 2553