SCHEME 4. Stereoselective Synthesis of (+)-Lasubine II
(R)-2,3-Dihydro-2-(3,4-dimethoxyphenyl)-1-(4-tolylsulfonyl)-
pyridin-4(1H)-one (1): A solution of 3 (70.9 mg, 0.056 mmol)
and AgClO
the dark at room temperature under argon for 2 h then treated with
a solution of imine 2 (350 mg, 1.10 mmol) in CH Cl (10 mL).
4 2 2
(23 mg, 0.11 mmol) in CH Cl (6 mL) was stirred in
2
2
The reaction mixture was stirred at room temperature for 5 min
and cooled to -20 °C before it was treated with Danishefsky’s
diene (300 µL, 1.50 mmol) and stirred at -20 °C for 12 h. TFA (1
mL) was added and the mixture was stirred at room temperature
for an additional 30-60 min. The reaction mixture was neutralized
SCHEME 5. Stereoselective Synthesis of (+)-Lasubine I
with saturated aqueous NaHCO
MgSO , and filtered. After evaporation of the solvent, the residue
was purified by flash chromatography (EtOAc/hexane 4:1) to afford
(302 mg, 71%, 94% ee, pale yellow solid). Mp: 52-54 °C (Et O).
), >99% ee. HPLC: Daicel Chiralcel
OD, n-hexane/i-PrOH 70:30, flow 0.8 mL/min, 290 nm, (S)-1 t
3 2 2
, extracted with CH Cl , dried over
4
1
2
20
[R]
D
+29 (c 0.24, CHCl
3
R
)
1
1
1
2
R
8.4 min, (R)-1 t ) 30.0 min. H NMR (300 MHz): δ 7.75 (dd,
H, J ) 8.3, 1.4 Hz, H-6), 7.58 (d, 2H, J ) 8.5 Hz, Ar), 7.22 (d,
H, J ) 8.5 Hz, Ar), 6.75-6.60 (m, 3H, Ar), 5.46 (d, 1H, J ) 6.9
Hz, H-2), 5.40 (d, 2H, J ) 8.3 Hz, H-5), 3.80 (s, 3H, CH
s, 3H, CH O), 2.79 (dd, 1H, J ) 16.6, 6.9 Hz, CH ), 2.64 (d, 1H,
J ) 16.6 Hz, CH ). C NMR (75 MHz): δ
90.8, 149.0, 148.9, 144.9, 142.3, 135.7, 129.9, 129.4, 127.0, 118.9,
10.8, 109.6, 108.1, 57.4, 55.8, 55.6, 41.6, 21.5. IR (CH Cl
3
O), 3.76
(
3
2
13
2
), 2.38 (s, 3H, CH
3
1
1
2
5
2
2
): ν
+
937, 1672, 1597, 1519, 1268, 1169, 1053. MS (EI+): 387 (M ,
+
7), 232 (M - Ts, 36), 164 (100), 91 (45). HRMS (EI+) calcd
5
for C20H21NO S 387.1140, found 387.1131.
(
R)-2,3-Dihydro-2-(3,4-dimethoxyphenyl)pyridin-4(1H)-one
4): To a suspension of 1 (350 mg, 0.90 mmol) of 94% ee and
activated zinc dust (1.30 g, 20 mmol) in THF (5 mL) was added a
saturated aqueous solution of NH Cl (5 mL). The mixture was
(
4
stirred at room temperature for 24 h, diluted with a 1:1 AcOEt/
hexane mixture, and filtered through Celite. The organic layer was
separated and concentrated under reduced pressure to afford 4 (203
mg, 97%, pale yellow solid). Recrystallization from acetone/pentane
gave 4 with >99% ee (156 mg, 77%). Mp: 164-165 °C (acetone/
iodobutane (NaH, THF) provided the required N-functionalized
chloro-derivative 8 in 75% yield (Scheme 5). However, all
attempts to carry out the radical cyclization of this substrate
under thermal (Bu3SnH, AIBN, benzene, reflux) or photochemi-
cal (Bu3SnH, Hg, 120 V, 400 nm, 35 °C) conditions failed,
leading to only traces of the quinolizidine derivative. To improve
the reactivity of the radical precursor, the iodo derivative 9 was
prepared in almost quantitative yield by reaction of 8 with NaI
in acetone. The treatment of the iodo derivative 9 under standard
20
pentane). [R]
D
-110 (c 0.05, acetone), >99% ee. HPLC: Daicel
1
9
Chiralcel OD, n-hexane/i-PrOH 70:30, flow 0.8 mL/min, 310 nm,
1
(S)-4 t ) 13.6 min, (R)-4 t ) 22.9 min. H NMR (CD Cl , 300
R
R
2
2
MHz): δ 7.25 (t, 1H, J ) 7.0 Hz, Ar), 6.95-6.82 (m, 3H, Ar +
H-6), 5.08 (s ancho, 1H, NH), 5.00 (d, 1H, J ) 7.5 Hz, H-5), 4.66
(
dd, 1H, J ) 14.8, 4.8 Hz, H-2), 3.82 (s, 3H, CH
CH O), 2.68 (dd, 1H, J ) 16.2, 14.8 Hz, CH ), 2.43 (ddt, 1H, J )
16.2, 4.8, 1.2 Hz, CH , 75 MHz): δ 191.8,
50.8, 149.5, 149.3, 132.8, 118.8, 111.6, 110.0, 99.4, 58.4, 55.9,
5.0. IR (KBr): ν 3224, 3046, 1611, 1572, 1538, 1514, 1253, 1134.
3
O), 3.80 (s, 3H,
3
2
radical cyclization conditions (Bu3SnH, AIBN, benzene, reflux)
13
yielded the quinolizidine ketone 10,20 exclusively as the trans
2
2 2
). C NMR (CD Cl
1
4
isomer (69%), along with a minor amount of the noncyclized
5
a,b
reduction product 11 (16%). Finally, as previously reported,
+
MS (EI+): 233 (M , 94), 164 (100). HRMS (EI+) calcd for
233.1052, found 233.1054.
R)-1-(tert-Butoxycarbonyl)-2,3-dihydro-2-(3,4-dimethoxyphe-
nyl)pyridin-4(1H)-one (5): To a solution of 4 (100 mg, 0.43 mmol,
99% ee), Et N (148 µL, 1.07 mmol), and DMAP (5.0 mg) in
CH Cl (8 mL) was added (Boc) O (234.0 mg, 1.07 mmol). The
the stereoselective carbonyl reduction of 10 with L-selectride
afforded (+)-lasubine I in good yield21 (Scheme 5).
In conclusion, we have developed a concise, stereodivergent,
and highly stereoselective synthesis of (+)-lasubines I and II
from a common enantiopure N-tosyl 2,3-dihydropyridone. This
key intermediate was obtained by applying a novel Cu-catalyzed
asymmetric aza-Diels-Alder protocol between N-tosyl imines
and Danishefsky’s diene.
13 3
C H15NO
(
>
3
2
2
2
mixture was stirred at room temperature for 6 h and a saturated
aqueous solution of NH Cl (5 mL) was added. The organic layer
4
was separated and the aqueous phase was extracted with CH Cl
2
2
(10 mL). The combined organic phase was washed with brine, dried
over MgSO , and filtered. After evaporation of the solvent, the
residue was purified by flash chromatography (AcOEt/hexane 1:4)
4
Experimental Section
The quinolizidine ketones 7 and 10 and lasubines I and II have
been previously described in the literature. See the Supporting
Information for experimental procedures and characterization data.
to afford 5 (141.7 mg, 99%, pale yellow solid). Mp: 91-93 °C.
20
1
[R]
D
3
-143 (c 0.30, CHCl ). H NMR (200 MHz): δ 7.85 (d,
1
7
3
1
H, J ) 8.3 Hz, H-6), 6.80-6.64 (m, 3H, Ar), 5.58 (d, 1H, J )
.5 Hz, H-2), 5.26 (d, 1H, J ) 8.3 Hz, H-5), 3.70 (s, 3H, CH O),
.68 (s, 3H, CH O), 3.06 (dd, 1H, J ) 16.4, 7.5 Hz, CH ), 2.71 (d,
H, J ) 16.4 Hz, CH ), 1.41 (s, 9H, t-Bu). C NMR (50 MHz):
3
(
19) For a review on intramolecular 1,4-radical cyclizations, see: Zhang,
W. Tetrahedron 2001, 57, 7237-7262.
20) The enantiomer of ketone 10 has been previously described; see
refs 5a and 5b.
3
2
13
2
(
δ 192.2, 151.3, 149.0, 148.5, 142.5, 131.3, 118.1, 110.9, 109.3,
106.6, 83.5, 55.6, 55.0, 41.5, 27.8. IR (CH Cl ): ν 3057, 2983,
1724, 1668, 1605, 1518, 1266, 1151. MS (EI+): 333 (M , 31),
21) [R] D +6.2 (c 0.34, MeOH); lit. (-)-lasubine I [R]25D -6.5 (c 2.60,
2
5
(
2
2
25
+
MeOH), see ref 5b; [R] D -7.0 (c 0.37, MeOH), see ref 5c.
1
0296 J. Org. Chem., Vol. 72, No. 26, 2007