â,γ-Unsaturated N,N-Diisopropylamides
J . Org. Chem., Vol. 64, No. 13, 1999 4797
room temperature. To this solution was added ether, and the
solution was dried (MgSO4) and the solvent removed (aspira-
tor).
the structural assignment. Molecular ion calcd for C9H14O3
170.09430, found m/e ) 170.0957, error ) 8 ppm; IR (neat,
cm-1) 3508, O-H; 1759, CdO; 300 1H MHz NMR (CDCl3, ppm)
δ 3.97 (1H, dd, J ) 11.6, 5.2 Hz) 2.46 (1H, q, J ) 7.0 Hz) 2.01-
1.87 (4H, m) 1.69-1.62 (3H, m) 1.52-1.25 (2H, m) 1.20 (3H,
d, J ) 7.0 Hz).
Gen er a l TMEDA-Med ia ted Osm yla tion P r oced u r e.5 To
a stirred solution of the alkene and TMEDA (1.1-1.5 equiv)
at -78 °C was added OsO4 (solution in CH2Cl2), and the
solution turned dark. After stirring for 2 h the reaction was
tested for the presence of the starting alkene by TLC. Once
the alkene was consumed, the osmate ester was reduced with
1:1 saturated NaHSO3/THF (10 mL) (reflux, 2 h). Brine was
added, and the resulting solution was extracted with EtOAc
(3×). The combined organic extracts were then dried (MgSO4)
and evaporated (aspirator) to give the crude product.
Diols 2a (Ma jor ) a n d 2b (Min or ). The general NMO
procedure (rt) using 11 (213 mg, 0.90 mmol), NMO (126 mg,
1.1 mmol), and OsO4 (0.25 mL of a 2.5% v/v solution in t-BuOH,
0.02 mmol, Aldrich) afforded 254 mg (99%) of a 3.2:1 diaste-
reomer ratio (2a (major):2b (minor)) that was >90% diols. The
residue was purified by flash chromatography on EM silica
gel 60 (33 × 1.6 cm, 50 mL and then 8 mL fractions). Fractions
13-16 gave 52 mg of 2b (21%) and fractions 18-25 afforded
165 mg of 2a (68%); 4:1 CH2Cl2/ether eluent; analytical TLC
on EM silica gel 60, 4:1 CH2Cl2/ether, Rf ) 0.50 (2b, minor),
Rf ) 0.45 (2a , major). Ma jor d ia st er eom er 2a . r a c-
(2R,1′S,2′S)-2-(1′,2′-Dih yd r oxycycloh exyl)-N,N-d iisop r o-
p ylp r op a n a m id e: solid; molecular ion calcd for C15H29NO3
271.21470, found m/e ) 271.2146, error ) 0 ppm; IR (neat,
Enantiomerically enriched 3 was prepared by the same
sequence starting from (R)-1 of 96% ee and performing the
lactonization on 98 mg of enantiomerically enriched diol 2a
to give 50 mg (82%) of (3R,3aS,7aS)-3 after chromatography
as described above, oil, ([R]25 ) -46, c ) 0.05).
D
La cton iza tion of th e Min or Diol 2b. r a c-(3R,3a R,7a R)-
3a -Hyd r oxy-3-m eth ylh exa h yd r oben zofu r a n -2-on e (4). To
r a c-2b (25 mg, 0.09 mmol) was added 0.27 mL of a 10% H2-
SO4 solution (v/v) (5 equiv), and the mixture was heated to
reflux for 2 h. The acid layer was extracted with ether (3 × 2
mL). The combined organic layers were dried (MgSO4) and
evaporated (aspirator) to give 13 mg of an oil. 1H NMR analysis
indicated a 3.5:1 ratio of 4:2b with no sign of 3. An isomeric
product was also present (ca. 10%; Rf ) 0.47 in 1:1 EtOAc:
hexane), identified as the ketone derived from pinacol rear-
rangement of 2b. The structure of the pinacol contaminant
was confirmed by correlation with 29b (see Supporting Infor-
mation).4 The residue was purified by preparative layer
chromatography on EM silica gel 60 (20 × 20 × 0.02 cm), 4:1
CH2Cl2/ether eluent (Rf ) 0.36), which afforded 9 mg (60%) of
4 as an oil. Analytical TLC on EM silica gel 60, Rf ) 0.37.
Molecular ion calcd for C9H14O3 170.09430, found m/e )
170.0944, error ) 1 ppm; IR (neat, cm-1) 3482, O-H; 1757,
CdO; 300 MHz NMR (CDCl3, ppm) δ 4.11 (1H, dd, J ) 11.8,
4.8 Hz) 2.55 (1H, q, J ) 7.7 Hz) 2.04-1.25 (9H, m) 1.20 (3H,
d, J ) 7.7 Hz).
Elim in a tion of En a n tiom er ica lly En r ich ed 3 to 57
Usin g SOCl2/P yr id in e. To a solution of (3R,3aS,7aS)-3 (45
mg, 0.26 mmol) in 0.5 mL of pyridine at 0 °C was added thionyl
chloride (60 µL, 0.79 mmol). After 15 min the reaction was
warmed to room temperature and the solution was stirred for
30 min. Ether (5 mL) was added, and the resulting solution
was extracted with 1.5 N HCl (3 × 3 mL). The ether layer
was dried (MgSO4) and evaporated to an oil. The initial residue
was purified by flash chromatography (13 × 1 cm, 2 mL
fractions), 9:1 hexane:ether. Fractions 8-10 gave 2 mg of the
minor lactone 6. Fractions 13-17 gave 30 mg (75%) of pure
(S)-5 ([R]25D ) +54, c ) 0.03). Comparison of a racemic sample
of 57 and the enantiomerically enriched (S)-5 by HPLC on a
chiral stationary phase (93:3 hexane/EtOH, (R,R)-Whelk-O 1
(Regis), flow ) 1.0 mL/min, tR19.3 min (R), 20.1 min (S))
established that the ee was greater than 90% favoring the (S)
enantiomer. Baseline resolution could not be achieved, but an
authentic 95:5 mixture of enantiomers prepared from the
enriched and racemic samples showed a clear inflection point
for 90% ee that was absent in the enriched sample (>90% ee).
To establish the structure of 6, a similar experiment was
performed starting with racemic racemic 3 and r a c-6 was
obtained as an oil; analytical TLC on EM silica gel 60, 1:1
hexane/ether, Rf ) 0.59. Molecular ion calcd for C9H12O2
152.08370, found m/e ) 151.0758; M - 1, 151.0758; IR (neat,
cm-1) 1756, CdO; 300 MHz 1H NMR (CDCl3, ppm) δ 5.55 (1H,
br s) 4.86-4.76 (1H, m) 3.20-3.09 (1H, m) 2.36-2.27 (1H, m)
2.19-2.09 (2H, m) 2.00-1.89 (1H, m) 1.69-1.52 (1H, m) 1.47-
1.33 (1H, m) 1.31 (3H, d, J ) 6.9 Hz).
1
cm-1) 3442, O-H; 3236, O-H; 1604, CdO; 300 MHz H NMR
(CDCl3, ppm) δ 6.46 (1H, s) 4.08 (1H, sept, J ) 6.6 Hz) 3.60-
3.39 (2H, m) 2.82 (1H, q, J ) 7.2 Hz) 2.50 (1H, br s) 1.90-
1.42 (6H, m) 1.41-1.22 (14H, m) 1.18 (3H, d, J ) 7.0 Hz); 13
C
NMR (75 MHz, CDCl3, ppm) δ 177.5 s, 74.7 s, 73.4 d, 48.5 d,
45.9 d, 37.2 d, 30.8 t, 29.9 t, 21.2 t, 21.2 t, 20.9 q, 20.8 q, 20.2
q, 20.2 q, 12.7 q. Min or d ia ster eom er 2b. r a c-(2R,1′R,2′R)-
2-(1′,2′-Dih yd r oxycycloh exyl)-N,N-d iisop r op ylp r op a n a -
m id e: colorless oil; molecular ion calcd for
C15H29NO3
271.21470, found m/e ) 271.2155, error ) 3 ppm; IR (neat,
1
cm-1) 3419, O-H; 3263, O-H; 1604, CdO; 300 MHz H NMR
(CDCl3, ppm) δ 5.20 (1H, br s) 4.25-4.05 (1H, m) 3.80-3.40
(2H, m) 3.71 (1H, ddd, J ) 9.9, 4.4, 2.2 Hz) 2.91 (1H, q, J )
7.2 Hz) 1.79-1.32 (14H, m) 1.29-1.19 (9H, m); 13C NMR (75
MHz, CDCl3, ppm) δ 176.7 s, 74.4 s, 70.2 d, 49.2 d, 46.3 d,
35.5 d, 29.8 t, 23.1 t, 21.3 t, 21.1 q, 20.6 q, 20.5 q, 14.5 q.
P r ep a r a tion of 2a Usin g TMEDA/OsO4. To a solution of
11 (272 mg, 1.15 mmol) and TMEDA (208 µL, 1.38 mmol) in
2.0 mL of CH2Cl2 at -78 °C was added OsO4 (350 mg, 1.38
mmol) in CH2Cl2 (2 × 1.0 mL). After 2 h, TLC analysis
indicated 1 had been consumed. The solution was allowed to
warm to room temperature, and the solvent was evaporated
to produce a brown residue. After the addition of 10 mL of
THF, 1.6 g of NaHSO3, and 0.75 mL of water, the solution
was heated to reflux for 2 h. The solution was then diluted
with ether (30 mL), dried (MgSO4), and evaporated to a green
oil (314 mg). 1H NMR assay of this residue indicated a 11:1
diastereomer ratio and >95% conversion to diols. The residue
was purified by flash chromatography on EM silica gel 60 (23
× 1.6 cm, 7 mL fractions; 4/1, CH2Cl2/ether eluent). Fraction
11 gave 11 mg of a mixture of 2a and 2b. Fractions 12-33
gave 253 mg (82%) of pure 2a .
Lacton ization of Diol 2a. r a c-(3R,3aS,7aS)-3a-Hydr oxy-
3-m eth ylh exa h yd r oben zofu r a n -2-on e (3) a n d (3R,3a S,-
7a S)-3. To r a c-2a (200 mg, 0.74 mmol) in 1.8 mL of dioxane
was added 1.6 mL of a 10% H2SO4 solution (v/v) (4 equiv), and
the solution was heated to reflux for 9 h. The acid layer was
extracted with ether (3 × 10 mL). The combined organic layers
were dried (MgSO4) and evaporated (aspirator) to give 126 mg
of a white solid. 1H NMR analysis indicated >90% conversion
to product. Crystallization of the initial product from ether
afforded 77 mg of 3 (62%). The mother liquor (44 mg) was
purified by flash chromatography on EM silica gel 60 (11 × 1
cm, 4:1 CH2Cl2/ether eluent, 3 mL fractions, 25 mL prerun).
Fractions 4-7 gave 24 mg of 3 (19%). The materials were
combined to afford 101 mg (81%) as a white crystalline solid.
Pure r a c-3 was obtained by crystallization from ether/
hexane, mp 120.0-121.0 °C. X-ray crystallography confirmed
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM44724).
Su p p or tin g In for m a tion Ava ila ble: X-ray data tables
for 3, 17a , and 19. NMR spectra. Procedures and characteriza-
tion for 14a , 18a ,b 19, 15-17, 21-23, and 25-29, and
correlations with 30-32. This material is available free of
J O990119U