More recently, this laboratory has been exploring the
utilization of 1,2- and 1,3-hydroxy azides as nitrogen ring-
expansion reagents.7 This technique allows for the high-yield
synthesis of N-substituted lactams from ketones in a one-
pot, two-reaction protocol. The key reaction is enabled by
the initial formation of a hemiketal, dehydration to an
oxonium ion, intramolecular attack by the now-attached azido
group, and rearrangement along with the loss of nitrogen
(Scheme 1). Notably, the intermolecular reaction of simple
The use of chiral hydroxy azides would permit the
extension of this chemistry to the synthesis of chiral lactams
in enantiomerically pure form. A few such examples were
noted in the original disclosure; thus, 2-phenyl-2-azidoethanol
combined with 4-tert-butylcyclohexanone to afford lactam
having ds ) ca. 88%.7 Still more promising results (90%
yield, 97.5% ds) were obtained when a single example of a
chiral 1,3-azido alcohol was used with the same substrate,
but the particular reagent used ((2S,4R)-2-azido-4-hydroxy-
pentane) was expensive to prepare. We now wish to present
a 1,3-hydroxy azide that is trivially obtained from a com-
mercially available chiral starting material, gives superior
reactions over the previously published examples (with
respect to rate, yield, and selectivity), and leads to a
remarkable level of 1,7-diastereomeric control in lactam
formation.
Scheme 1
As shown in Scheme 2, (R)-3-chloro-1-phenylpropanol
reacts with sodium azide to provide azide 1 in excellent yield
and g99% ee (HPLC; Chiracel OD-H). BF3‚OEt2 was added
to a mixture of 1 and 4-methylcyclohexanone in CH2Cl2 at
Scheme 2
(non-hydroxy) azides fails under the same conditions.8 A
hydrolytic workup then releases a lactam identical to that
which would have resulted from direct reaction of the azide
portion of the molecule. This procedure is described as “in
situ tethering” because the carbon-oxygen linkage is formed
and released without additional synthetic operations.
(7) (a) Gracias, V.; Milligan, G. L.; Aube´, J. J. Am. Chem. Soc. 1995,
117, 8047-8048. (b) Gracias, V.; Milligan, G. L.; Aube´, J. J. Org. Chem.
1996, 61, 10-11. (c) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube´, J.
Tetrahedron 1997, 53, 16241-16252. (d) For an application of this
methodology to an attempted alkaloid synthesis, see: Vidari, G.; Tripolini,
M.; Novella, P.; Allegraucci, P.; Garlaschelli, L. Tetrahedron: Asymmetry
1997, 8, 2893-2903.
-82 °C, and the reaction allowed to warm to room
temperature. Hydrolysis of the resulting iminium ether with
KOH afforded a mixture of lactams 3a/4a in 98% yield and
93% ds (HPLC). In contrast, the corresponding reaction of
4-methylcyclohexanone with 2-phenyl-2-azidoethanol in ca.
20:1 cyclohexanone/CH2Cl2 proceeded only in 74% ds (81%
yield) and required temperatures of about -5 °C for
satisfactory conversions (reaction not shown).9 A survey of
reactions of 1 with a variety of substituted ketones shows
that excellent selectivity is preserved for substituted cyclo-
hexanones but that there is room for improvement with four-
(8) Aube´, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992, 57,
1635-1637.
(9) Representative Procedure. A solution of (R)-3-azido-1-phenylpro-
panol (205 mg, 1.15 mmol) and 4-methylcyclohexanone (188 mg, 1.68
mmol) in 3 mL of CH2Cl2 was cooled to -82 °C (ether/dry ice bath), and
BF3‚OEt2 (0.56 mL, 4.48 mmol) was added dropwise. The reaction was
allowed to come to room temperature over a period of 48 h. The resulting
crude iminium ether was diluted with Et2O (5 mL) and hydrolyzed with
50% KOH (1 mL) added dropwise over 5 min. The solution was stirred for
30 min and partitioned between CH2Cl2 (20 mL) and H2O (10 mL). The
layers were separated, and the water layer was extracted with CH2Cl2 (2 ×
10 mL). The combined organic layers were washed with NH4Cl (5 mL),
dried (MgSO4), filtered, and concentrated. HPLC analysis of the crude
reaction mixture showed a 93:7 ratio of diastereomeric lactams. Flash
chromatography (1:1 f 9:1 EtOAc/MeOH) gave 3a and 4a as transparent
oils in a combined yield of 296 mg (98%). TLC (1:1 hexane/EtOAc): Rf(3a)
) 0.15, Rf(4a) ) 0.20; HPLC tR major (3a) ) 19.9 min, tR minor (4a) )
18.2 min (Chirobotic T; 90% hexane/EtOH; flow rate 1 mL/min; UV 254
nm). Major diastereomer (3a): [R]D ) -4.2 (c 1.02, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.99 (d, J ) 6.6, 3H), 1.12-1.31 (m, 3H), 1.62-
1.75 (m, 1H), 1.76-1.98 (m, 4H), 2.42-2.61 (m, 2H), 3.12 (dt, J ) 14.2,
4.4 Hz, 1H), 3.24 (dd, J ) 6.5, 15.2 Hz, 1H), 3.51 (dd, J ) 10.9, 15.2 Hz,
1H), 4.09-4.19 (m, 1H), 4.62 (m, 1H), 7.21-7.28 (m, 1H), 7.31-7.39 (m,
4H); 13C NMR (100.6 MHz, CDCl3) δ 22.6, 31.4, 35.7, 36.1, 37.2, 37.7,
45.7, 49.3, 69.8, 125.5, 127.0, 128.3, 144.1, 177.1; MS (EI) m/e 262 (M+
+ 1), 244(100); HRMS m/e calcd for C16H24NO2 (M+ + 1) 262.1807, found
(M+ + 1) 262.1798. Minor diastereomer (4a): 1H NMR (400 MHz, CDCl3)
δ 0.97 (d, J ) 6.5 Hz, 3H), 1.18-1.30 (m, 2H), 1.65-1.95 (m, 5H), 2.50-
2.56 (m, 2H), 3.01 (m, 1H), 3.32 (dd, J ) 15.1, 5.9 Hz, 1H), 3.47 (J )
15.1, 11.0 Hz, 1H), 4.10-4.25 (m, 1H), 4.53 (br d, J ) 10.4 Hz, 1H),
4.75-4.85 (m, 1H), 7.21-7.29 (m, 1H), 7.29-7.39 (m, 4H); 13C NMR
(100.6 MHz, CDCl3) δ 22.6, 31.3, 35.7, 35.8, 36.3, 37.5, 44.9, 48.4, 69.6,
125.7, 127.0, 128.2, 144.1, 177.2; MS (EI) m/e 262 (M+ + 1), 244; HRMS
m/e calcd for C16H24NO2 (M+ + 1) 262.1807, found (M+ + 1) 262.1797.
496
Org. Lett., Vol. 1, No. 3, 1999