Total synthesis of tropinone using 1,3-dipolar cycloaddition of cyclic azomethine ylide and phenyl vinyl sulfone as the key step

Article abstract of DOI:10.1007/s10600-010-9581-x

Total synthesis of tropinone from the readily available piperidone 2 is described. The rapid assembly of the tropane skeleton was achieved by 1,3-dipolar cycloaddition of cyclic azomethine ylide 3 to phenyl vinyl sulfone.

Full text of DOI:10.1007/s10600-010-9581-x

Chemistry of Natural Compounds, Vol. 46, No. 2, 2010
TOTAL SYNTHESIS OF TROPINONE USING 1,3-DIPOLAR
CYCLOADDITION OF CYCLIC AZOMETHINE YLIDE
AND PHENYL VINYL SULFONE AS THE KEY STEP
Joydev K. Laha
UDC 547.94
Total synthesis of tropinone from the readily available piperidone 2 is described. The rapid assembly of the
tropane skeleton was achieved by 1,3-dipolar cycloaddition of cyclic azomethine ylide 3 to phenyl vinyl
sulfone.
Keywords: tropane alkaloids, tropinone, phenyl vinyl sulfone, 1,3-dipolar cycloaddition, cyclic azomethine ylide.
Tropane alkaloids possessing the intriguing structural feature of the 8-azabicyclo[3.2.1]octane (tropane) skeleton are
endowed with a variety of biological activities ꢀ1ꢁ. The first synthesis of tropinone (1), a simple tropane alkaloid, was reported
by Willstatter in an extended series of transformations starting from cycloheptanone ꢀ2ꢁ. Soon thereafter, Robinson devised an
efficient, elegant approach involving the condensation of succinaldehyde, methylamine, and the calcium salt of 1,3-acetone
dicarboxylic acid affording 1 in 42% yield ꢀ3ꢁ. Recently, Mikami et al. reported the synthesis of 1 via a tandem (domino) ene-
type reaction of acetone silyl enol ether with an imminium ion ꢀ4ꢁ.
Our continued efforts to develop an efficient route to the stereoselective construction of the tropane skeleton by
1
,3-dipolar cycloaddition of endocyclic non-stabilized azomethine ylide to a racemic ꢀ5ꢁ or chiral ꢀ6ꢁ dipolarophile provided
a unique platform to apply this methodology to the total synthesis of tropane alkaloids. Herein, we describe the synthesis of 1
from an inexpensive piperidone 2 using 1,3-dipolar cycloaddition of a suitably functionalized cyclic azomethine ylide 3,
generated in situ fromꢂꢃ,ꢃꢄ-bis(trimethylsilyl)-N-methylpiperidine 4 by treatment with Ag(I)F, to phenyl vinyl sulfone as the
key step ꢀ7ꢁ.
O
O
O
O
O
4O
7
O1
9
O
O
a
b
c
d
e
N
Boc
N
Boc
N
Boc
TMS
TMS
N
Me
TMS
TMS
N
Boc
TMS
2
5
6
7
4
Me
H
Me
N
SO Ph
2
N
O
O
1
f
PhO2S
6
8%
N
Me
H
5
H
O
6
O
O
3
8
1
a. ethylene glycol, PPTS, benzene reflux, 87%; b. TMEDA, s-BuLi, TMSCl, –78ꢅC, 86%; c. TMEDA, s-BuLi, TMSCl,
40ꢅC, 62%; d. 1. TFA, CH Cl , room temperature, 2. HCHO, NaBH CN, gl CH COOH, room temperature, 66%;
–
2
2
3
3
e. Ag(I)F, CH Cl , room temperature; f. 6% Na–Hg, Na HPO 4H O, MeOH, room temperature, 65%
2
2
2
4
2
Scheme 1
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune-411008, India, e-mail:
jlaha@rics.bwh.harvard.edu. Published in Khimiya Prirodnykh Soedinenii, No. 2, pp. 213–215, March–April, 2010. Original
article submitted September 12, 2008.
0
254
0009-3130/10/4602-0254 2010 Springer Science+Business Media, Inc.

The synthesis of 1 from the commercially available piperidone 2 is shown in Scheme 1. Refluxing a mixture of 2,
ethylene glycol, and pyridinium p-toluene sulfonate (PPTS) in benzene gave 5 in 87% isolated yield.
Following our previous protocol ꢀ6bꢁ, treatment of 5 with s-BuLi at –78ꢅC for 2 h in the presence of
N,N,Nꢄ,Nꢄ-tetramethylethylenediamine (TMEDA), followed by the addition of TMSCl, gave 6 in 86% isolated yield. Several
experiments were carried out to optimize the synthesis of 7. The best condition entails treatment of 6 with s-BuLi at –40ꢅC for
1
h, followed by the addition of TMSCl, yielding 7 in 62% isolated yield. Treatment of 7 with TFA in CH Cl at room
2 2
temperature afforded the free-base crude amine, which was subjected to reductive methylation with 37% aqueous formaldehyde
in the presence of NaBH CN and glacial acetic acid. Thus, compound 4 was obtained from 7 in 66% isolated yield (two steps).
3
The effective generation of cyclic azomethine ylide 3 and subsequent cycloaddition to the dipolarophile involved addition of
a solution of 4 in anhydrous CH Cl to a stirred mixture of Ag(I)F and phenyl vinyl sulfone in anhydrous CH Cl under argon.
2
2
2
2
1
Upon flash chromatography of the crude mixture, only cycloadduct 8 was isolated in 68% yield. In the H NMR spectra of 8,
the H-6 endo-proton appeared at ꢆ 3.90 as a doublet of a doublet (J = 10.7, 5.9 Hz,), which is indicative of exo-orientation of
1
1
the sulfonyl functionality. Furthermore, this assignment was confirmed by 2D H– H COSY experiment. Desulfonylation of
, carried out by stirring a buffered solution of 8 and 6% sodium-amalgam in methanol, and subsequent in situ deprotection of
8
the ketal group afforded 1 in 65% isolated yield.
In conclusion, we have synthesized tropinone (1) in a short sequence of steps using a novel 1,3-dipolar cycloaddition
chemistry involving a cyclic azomethine ylide 3 and phenyl vinyl sulfone. The methodology is sufficiently flexible to initiate
a complex total synthesis of tropane alkaloids.
EXPERIMENTAL
8
-Methyl-7,9-bis(trimethylsilyl)-1,4-dioxa-8-azaspiro[4.5]decane (4). A stirred solution of 7 (3.88 g, 10.0 mmoL)
in anhydrous CH Cl (40 mL) was treated dropwise with TFA (5.70 g, 50.0 mmoL) at 0ꢅC over 30 min. After stirring at room
2
2
temperature for 4 h, the reaction mixture was basified with 10% aqueous NaOH solution under ice-cold conditions. The
organic layer was separated, washed with brine, dried (Na SO ), and concentrated to give a crude amine that was utilized in
2
4
the next step. A stirred solution of the crude amine in CH CN (120 mL) was treated with 37% aqueous formalin (1.5 mL)
3
followed by NaBH CN (1.71 g, 27.3 mmoL). After stirring at room temperature for 15 min, the reaction mixture was neutralized
3
with glacial acetic acid followed by basification with NH OH, affording a solution which upon extraction with hexane gave a
4
yellow liquid. Chromatographic purification of the crude product [silica, ethyl acetate–hexane (3:97)] gave a colorless viscous
–
1
1
liquid (2.00 g, 66% yield). C H NO Si . IR (CHCl , ꢇ , cm ): 2940, 1263; H NMR (200 MHz, CDCl , ꢆ, ppm, J/Hz):
1
4
31
2
2
3
max
3
1
3
0
2
.12 (18H, s), 1.72 (4H, d, J = 7.2), 2.45 (3H, s), 2.48 (2H, t, J = 5.8), 3.92 (4H, s); C NMR (50 MHz, CDCl , ꢆ, ppm): 28.6,
8.7, 42.1, 52.8, 64.1, 108.4; mass (m/z): 301 (M ); FAB-MS: obsd 301.1889, calcd 301.1893.
3
+
tert-Butyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (5).Amixture of 2 (10.0 g, 50.2 mmoL), ethylene glycol
(
3.70 g, 60.3 mmoL), and PPTS (1.20 g, 5.02 mmoL) was refluxed in benzene for 8 h under Dean-Stark conditions. The
solvent was evaporated, and the residue thus obtained was dissolved in excess ethyl acetate. The solution was washed with
water, brine, and dried (Na SO ). Chromatographic purification of the crude reaction mixture [silica, hexane–EtOAc (2.5:1.5)]
2
4
–
1
1
afforded a viscous liquid (10.6 g, 87% yield). C H NO . IR (CHCl , ꢇ , cm ): 2974, 1697, 1421; H NMR (200 MHz,
CDCl , ꢆ, ppm, J/Hz): 1.45 (9H, s), 1.70 (4H, t, J = 5.6), 3.50 (4H, t, J = 6.2), 3.98 (4H, s); C NMR (50 MHz, CDCl , ꢆ,
ppm): 28.1, 34.7, 41.6, 64.0, 79.0, 106.8, 154.3; Mass (m/z): 243 (M ).
1
2
21
4
3
max
1
3
3
3
+
tert-Butyl-7-(trimethylsilyl)-1,4-dioxa-8-azaspiro-[4.5]decane-8-carboxylate (6). A solution of 5 (4.90 g,
0.1 mmoL) in anhydrous ether (40 mL) was treated with TMEDA (2.79 g, 24.1 mmoL) followed by s-BuLi (1.5 M solution
2
in cyclohexane, 16.1 mL, 24.1 mmoL) at –78ꢅC over 15 min. After stirring the reaction mixture at –78ꢅC for 2 h, TMSCl
2.61 g, 24.1 mmoL) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was
quenched with saturated aqueous NH Cl followed by the usual work up, affording a crude mixture which upon distillation (bp
(
4
–
1
1
7
5–80ꢅC/0.5 mm) gave a colorless oil (5.45 g, 86% yield). IR (CHCl , ꢇ , cm ): 2940, 1691, 1423; H NMR (200 MHz,
CDCl , ꢆ, ppm): 0.10 (9H, s), 1.45 (9H, s), 1.58–1.62 (2H, m), 1.70–1.80 (2H, m), 3.50–3.75 (3H, m), 4.02 (4H, s); C NMR
3 max
1
3
3
(
50 MHz, CDCl , ꢆ, ppm): –0.9, 28.3, 35.4, 35.5, 44.1, 45.2, 64.0, 64.3, 78.9, 107.3, 154.7; mass (m/z): 316 (M+H); FAB-MS:
3
obsd 315.1861, calcd 315.1866 (C H NO Si).
1
5
29
4
tert-Butyl-7,9-bis(trimethylsilyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (7). A solution of 6 (3.66 g,
1.6 mmoL) in anhydrous ether (30 mL) was treated dropwise with TMEDA (1.60 g, 13.9 mmoL) followed by s-BuLi (1.5 M
1
in cyclohexane, 9.3 mL, 13.9 mmoL) at –78ꢅC over 15 min. After 15 min, the temperature was raised to –40ꢅC over 30 min.
255

After stirring for 1 h at this temperature, TMSCl (1.50 g, 13.9 mmoL) was added. Work-up followed by chromatography of the
–
1
1
crude mixture gave a colorless liquid (2.80 g, 62% yield). IR (CHCl , ꢇ , cm ): 2973, 1692, 1430; H NMR (200 MHz,
3
max
1
3
CDCl , ꢆ, ppm): 0.15 (18H, s), 1.40 (9H, s), 1.60–1.80 (4H, m), 2.50–2.60 (2H, m), 3.85 (4H, s); C NMR (50 MHz, CDCl3,
3
ꢆ, ppm): –1.32, –0.68, 28.47, 35.11, 36.07, 45.06, 46.07, 64.26, 79.04, 108.22, 155.86; mass (m/z): 388 (M + H); FAB-MS:
obsd 387.2256, calcd 387.2261 (C H NO Si ).
1
8
37
4
2
8
-Methyl-6-(phenylsulfonyl)-8-azaspiro-[bicyclo[3.2.1]octane-3,2ꢄ-[1,3]dioxolane] (8). A stirred suspension of
Ag(I)F (1.50 g, 0.010 moL) (previously dried under vacuum at 40ꢅC) and phenyl vinyl sulfone (1.00 g, 5.90 mmoL) in
anhydrous CH Cl (15 mL) was treated dropwise with a solution of 4 (1.50 g, 5.00 mmoL) in CH Cl (30 mL) over 15 min.
2
2
2
2
Chromatographic purification of the crude residue [silica, CHCl –methanol 98:2] gave a yellow solid (1.10 g, 68% yield). Mp
3
–
1
1
1
2
65–167ꢅC; IR (CHCl , ꢇ , cm ): 2925, 1275, 1125; H NMR (500 MHz, CDCl , ꢆ, ppm, J/Hz): 1.50–1.60 (2H, m),
3 max 3
.10–2.20 (2H, m), 2.25–2.45 (2H, m), 2.45 (3H, s), 3.40 (1H, m), 3.65 (4H, m), 3.90 (1H, dd, J = 10.7, 5.9), 4.20 (1H, t,
J = 8.0), 7.55 (2H, t, J = 7.8), 7.65 (1H, t, J = 7.8), 7.90 (2H, d, J = 7.8); C NMR (75 MHz, CDCl , ꢆ, ppm): 30.5, 35.9, 36.1,
7.1, 59.5, 60.2, 63.6, 64.9, 67.2, 107.1, 128.3, 129.3, 133.7, 139.3; mass (m/z): 323 (M ); FAB-MS obsd 323.1196, calcd
1
3
3
+
3
3
23.1191 (C H NO S).
1
6
21
4
8
-Methyl-8-azabicyclo[3.2.1]octan-3-one (1). A solution of 8 (0.500 g, 1.54 mmoL) and NaH PO ·H O (0.700 g,
2 4 2
6
.19 mmoL) in anhydrous methanol (15 mL) was treated with 6% sodium amalgam (1.5 g). After stirring at room temperature
for 2 h, the reaction mixture was poured into water and the aqueous layer was extracted with CHCl . Chromatographic
3
purification of the crude mixture [silica, CHCl –methanol 98:2] gave a brown solid (0.14 g, 65% yield). Mp 40ꢅC (lit. ꢀ3ꢁ
3
–
1
1
mp 42.5ꢅC). C H NO. IR (CHCl , ꢇ , cm ): 3018, 2952, 1714; H NMR (200 MHz, CDCl , ꢆ, ppm): 1.50–1.65 (2H, m),
.05–2.20 (4H, m), 2.45 (3H, s), 2.55–2.70 (2H, m), 3.35–3.50 (2H, m); C NMR (50 MHz, CDCl , ꢆ, ppm): 27.4, 37.9, 47.2,
8
13
3
max
3
1
3
2
6
3
0.5, 208.8.
ACKNOWLEDGMENT
The author thanks Dr. Ganesh Pandey for helpful advice on this work.
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1
2
3
4
5
6
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