Total synthesis of (+/-)-cytisine via the intramolecular heck cyclization of activated N-alkyl glutarimides.

Article abstract of DOI:10.1021/ol006765t

[reaction:see text] A synthesis of racemic cytisine 1 has been developed utilizing an intramolecular Heck cyclization to prepare the bridged tricyclic intermediate 2. The cyclization employs activated glutarimide-derived ketene aminals 3 (X = P(O)OEt(2) or SO(2)CF(3)) and represents the first use of such intermediates in metal-catalyzed processes.

Full text of DOI:10.1021/ol006765t

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4205-4208
Total Synthesis of (±)-Cytisine via the
Intramolecular Heck Cyclization of
Activated N-Alkyl Glutarimides
Jotham W. Coe
Pfizer Global Research and DeVelopment, Pfizer Inc., Groton, Connecticut 06340
coejw@groton.pfizer.com
Received October 23, 2000
ABSTRACT
A synthesis of racemic cytisine 1 has been developed utilizing an intramolecular Heck cyclization to prepare the bridged tricyclic intermediate
2. The cyclization employs activated glutarimide-derived ketene aminals 3 (X ) P(O)OEt2 or SO CF3) and represents the first use of such
2
intermediates in metal-catalyzed processes.
The natural product (-)-cytisine, (1, as depicted), a member
of the lupin alkaloid family,1 is an important probe in
nicotinic acetylcholine receptor research.2 It displays high
affinity at neuronal nicotinic receptors,3 yet elicits weak
agonist properties in cells expressing these receptors.4
Though found ubiquitously in nature,5 it is currently expen-
sive and available only in small quantities commercially.
Elegant syntheses of cytisine appeared in the 1950s by van
Tamelen,6 Bohlmann,7 and Govindachari.8 These efforts
served to confirm its structure and establish efficient strate-
gies for its construction; however, the syntheses are lengthy
and suffer from low overall yields. To further probe the
chemistry and biology of (-)-cytisine, we sought a synthetic
source of the material. Herein we describe a concise 6-step
synthesis of racemic cytisine from cyclopent-3-enylmethanol
4.9
Our strategy features the intramolecular Heck cyclization10
of glutarimide-derived ketene aminals, 3, to construct the
tricyclic carbon skeleton of cytisine, 2. A variety of lactam-
derived ketene aminal derivatives have recently appeared in
methodological and total synthetic studies. Isobe,11 Comins,12
(1) (a) Isolation: Partheil, A. Arch. Pharm. (Weinheim, Ger.) 1894, 232,
161. (b) Structure determination: Ing, H. R. J. Chem. Soc. 1932, 2778.
(2) (a) Barlow, R. B.; McLeod, L. J. Br. J. Pharmacol. 1969, 35, 161-
174. (b) McDonald, I. A.; Cosford, N.; Vernier, J.-M. Annual Reports in
Medicinal Chemistry; Academic Press: New York, 1994; Vol. 30, pp 41-
50. (c) Schmitt, J. D.; Bencherif, M. Annual Reports in Medicinal Chemistry;
Academic Press: New York, 2000; Vol. 35, pp 41-52. (d) Eur. J.
Pharmacol. 2000, 393, Issues 1-3, 1-340.
(3) (a) Pabreza, L. A.; Dhawan, S.; Kellar, K. J. Mol. Pharmacol. 1991,
39, 9-12. (b) Hall, M.; Zerbe, L.; Leonard, S.; Freedman, R. Brain Res.
1993, 600, 127-133. (c) Happe, H. K.; Peters, J. L.; Bergman, D. A.;
Murrin, L. C. Neuroscience 1994, 62, 929-944.
(7) (a) Bohlmann, F.; English, A.; Ottawa N.; Sander, H.; Weise, W.
Chem. Ber. 1956, 89, 792-799. For preleminary discussion, see: (b)
Bohlmann, F.; Ottawa, N.; Keller, R. Liebigs Ann. Chem. 1954, 587, 162-
176. (c) Bohlmann, F.; English, A.; Ottawa N.; Sander, H.; Weise, W.
Angew. Chem. 1955, 67, 708.
(8) Govindachari T. R.; Rajadurai, S.; Subramanian, M.; Thyagarajan,
B. S. J. Chem. Soc. 1957, 3839.
(4) (a) Luetje, C. W.; Patrick, J. J. Neuroscience 1991, 11, 837-845.
(b) Papke, R. L.; Heinemann, S. F. Mol. Pharmacol. 1994, 45, 142-149.
(5) Ing, H. R. J. Chem. Soc. 1931, 2195. See also, refs 6-8.
(6) (a) van Tamelem, E. E.; Baran, J. S. J. Am. Chem. Soc. 1955, 77,
4944-4955. (b) van Tamelem, E. E.; Baran, J. S. J. Am. Chem. Soc. 1956,
78, 2913-2914. (c) van Tamelem, E. E.; Baran, J. S. J. Am. Chem. Soc.
1958, 80, 4659-4670.
(9) This alcohol is readily available as described. See: (a) Depre´s, J.-
P.; Greene, A. E. J. Org. Chem. 1984, 49, 928-931; Org. Synth. 1997, 75,
195-200. For more recent approaches, see: (b) Nugent, W. A.; Feldman,
J.; Calabrese, J. C. J. Am. Chem. Soc. 1995, 117, 8992-8998. (c) Mar´ınez,
L. E.; Nugent, W. A.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 7963-
7966. (d) Briot, A.; Bujard, M.; Gouverneur, V.; Nolanz, S. P.; Mioskowski,
C. Org. Lett. 2000, 2, 1517-1519.
10.1021/ol006765t CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/07/2000

Scheme 1a
a (a) 1.0 equiv of glutarimide, 1.0 equiv of t-BuOK, 68 °C, THF 1 h, then 0.9 equiv of mesylate of 4, cat. DMF, cat. n-Bu4NI; (b) 1 equiv
of LHMDS, THF, 0 to 23 °C; (c) see text, Supporting Information; (d) 2.5 mol % of Pd(OAc)2, 5 mol % of P(o-tol)3, 1.5 equiv of TEA,
CH3CN, 83 °C, 24 h; (e) 10-20 equiv of activated MnO2, benzene, 80 °C, 3 h; (f) (CH3)3NO‚2H2O, cat. OsO4, CH2Cl2; (g) 1 equiv of
NaIO4, EtOH, H2O, 30 min, then aqueous NH4OH, H2, Pd(OH)2, 48-72 h.
Murai,13 and Speckamp14 introduced vinyl trifluoromethane-
sulfonates (vinyl triflates, X ) SO2CF3) of N-acyllactams
for transition metal catalyzed processes, and additional
examples have appeared.15 Nicolaou subsequently reported
phosphate activation of both N-acyllactam16 and lactone17
derivatives (vinyl phosphates, X ) P(O)OR2). Phosphate-
activated intermediates were found to be more robust than
the corresponding triflates. Recently N-alkyl ketene aminal
triflates and phosphates derived from N-alkyl lactam precur-
sors were applied to asymmetric syntheses.18 Herein we
extend this approach to include examples of participation
by cyclic imide derived ketene aminals in transition metal
catalyzed processes.
The synthesis begins with the N-alkyl glutaramide 5,
prepared from cyclopent-3-enylmethanol 4a by alkylation
of the corresponding mesylate19 4b with glutarimide (KO-
t-Bu, THF, 68 °C, 24 h, 78-91%, Scheme 1).20 Treatment
of 5 with LHMDS in THF (0 °C to rt) provides a poorly
soluble enolate (3a, X ) Li). Our initial studies employed
triflate activation (PhN(SO2CF3)2, -78 to 0 oC, 1 h)21 which
provided dihydropyridone 3b (X ) SO2CF3) in low yield
(<10%). The improved conditions reported by Comins
provided little advantage (5-Cl-2-N(SO2CF3)2-pyridine, -78
to 0 oC, THF, 1 h, 24%).22 Under standard Heck conditions23
(2.5 mol % of Pd(OAc)2, 5 mol % of P(o-tol)3, 1.5 equiv of
TEA, CH3CN, 83 °C, 24 h), 3b was readily converted to
the key tricyclic dihydropyridone 6 (52%).
(10) For leading references, see: (a) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (b) Shibasaki, M.; Boden, C.
D. J.; Kojima, A. Tetrahedron 1997, 53, 7371-7395. (c) Ashimori, A.;
Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6477-6487. (d) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488-6499.
Spectroscopic analysis (COSY and decoupling studies)
supported the tricyclic skeletal structure of 6. Confirmation
was obtained by single-crystal X-ray diffraction analysis of
the crystalline derivative 7, a 1:1 adduct obtained by reaction
of 6 with N-bromosuccinimide in CH2Cl2 or THF (Scheme
1). This result unambiguously defines the [3.2.1]-bridged
tricyclic skeleton of 7, derived from cis-addition of NBS to
N-acyl enamine 6 from the least hindered face.
With an established route to the nucleus, we focused on
alternative methods for ketene aminal activation. Treatment
of lithium enolate 3a (X ) Li) with ClP(O)(OEt)2 (1 equiv,
THF, -78 to 20 °C) resulted in complete conversion to
(11) (a) (Z ) N-COPh, R ) SO2CF3) Okita, T.; Isobe, M. Synlett 1994,
589-590. (b) Okita, T.; Isobe, M. Tetrahedron 1995, 51, 3737-3744.
(12) Z ) N-CO2Ph or N-COPh, R ) SO2CF3) Foti, C. J.; Comins, D. L.
J. Org. Chem. 1995, 60, 2656-2657.
(13) Z ) N-CO2-t-Bu, R ) SO2CF3) Tsushima, K.; Hirade, T.; Hasegawa,
H.; Murai, A. Chem. Lett. 1995, 9, 801-2.
(14) Z ) N-SO2-p-tol, R ) SO2CF3) (a) Bernabe´, P.; Rutjes, F. P. J. T.;
Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1996, 37, 3561-3564.
(b) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
3592-3596. (c) Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
Lett. 1996, 37, 8257-8260.
(15) (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. Org. Lett. 2000, 2,
1241-1242. (b) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha, J, K. J. Org.
Chem. 1998, 63, 3810-3811. (c) Ha, J. D.; Lee, D.; Cha, J, K. J. Org.
Chem. 1997, 62, 4550-4551.
(16) Z ) N-CO2-t-Bu, N-CO2Ph, R ) P(O)(OPh3)2) Nicolaou, K. C.;
Shi, G.-Q.; Namoto, K.; Bernal, F. Chem. Commun. 1998, 1757-1758.
(17) P(O)(OPh3)2) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Ga¨rtner,
P.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 5467-5468.
(18) Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J.
J. Am. Chem. Soc. 1999, 121, 593-594.
(19) (a) Opitz, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 107-123.
(b) King, J. F.; Lee, T. W. S. J. Am. Chem. Soc. 1969, 91, 6524-6525.
(c) O’Donnell, C. J.; Burke, S. D. J. Org. Chem. 1998, 63, 8614-
8616.
(20) For a closely related alkylation, see: Brosius, A. D.; Overman, L.
E. J. Org. Chem. 1997, 62, 440-441.
(21) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-
982.
(22) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302, and ref 12.
(23) Heck, R. F. In Organic Reactions; Wiley: New York, 1982; Vol.
27, p 345.
4206
Org. Lett., Vol. 2, No. 26, 2000

ketene aminal phosphate 3c (X ) P(O)(OEt)2). This material
was routinely used without further purification, requiring only
simple evaporation of solvent from the crude reaction
mixture.24 Our initial attempts to cyclize 3c were hampered
by the presence of residual THF. Exchange of solvent to
CH3CN and introduction of base and catalyst (1.5 equiv of
TEA, 2 mol % of Pd(OAc)2, 4 mol % of P(o-tol)3, 60 °C,
24 h) resulted in smooth conversion to bicyclic adduct 6 in
57% isolated yield.25 Glutarimide 5 was recovered from the
reaction (20-30%), presumably arising from hydrolysis of
the phosphate ester. Other phosphate esters (Ph, i-Pr) and
methods of preparation were explored but offered no
measurable advantage. Ultimately, generation of the inter-
mediate ketene aminal phophate 3c (X ) P(O)(OEt)2) in
toluene (KHMDS, 0 to 20 °C, 30 min, treatment with
ClP(O)(OEt)2 at -78 to 20 °C, 1 h) followed by in situ Heck
cyclization provided a one-pot preparation of 6 from 5 (1.5
equiv of TEA, 2.5 mol % of Pd(OAc)2 and 5 mol % of 9,
110 °C, 5 d, 52%, see Scheme 2 below).
react.26 Efforts to effect allylic bromination led to products
derived from N-acyl enamine addition, such as 7, and
attempts to efficiently convert these to pyridone 2 were
unsuccessful. Difficulties have been observed in related
oxidations of dihydropyrrones and NH-dihydropyridones.27
Ultimately MnO2 was found to be mild and effective, cleanly
and reproducibly converting 6 to crystalline 2 (10-20 equiv,
benzene, 80 °C, 3 h, 74%).26b
Finally, the piperidine ring was introduced in a two-pot
operation using standard literature techniques. Dihydroxyl-
ation of olefin 2 was accomplished in 85% isolated yield
((CH3)3NO‚2H2O, cat. OsO4, CH2Cl2).28 Filtration of the
crude reaction mixture through a silica pad avoids extraction
of the water-soluble diol 8 and produces crystalline material.
Direct conversion of diol 8 to (()-cytisine is accomplished
by a one-pot procedure: oxidative cleavage (NaIO4, EtOH,
H2O, 3 h), followed by treatment with 30% aqueous NH4OH
solution and catalytic hydrogenation (H2, Pd(OH)2) for 48
to 72 h provides racemic cytisine 1, in 57% yield after
chromatography.29
Scheme 2a
Preliminary studies on the influence of chiral ligands in
the cyclization event have been promising (Scheme 2).
Though Heck cyclization with BINAP as ligand did not
progress under the conditions we studied, the Pfaltz ligand
9 successfully catalyzed the reaction of triflate 3b to provide
6.30 This product was determined to be 22% ee after
conversion to cytisine. Phosphate ester 3c provided es-
sentially racemic material under similar conditions (4% ee
favoring the opposite antipode). Further work may uncover
suitable ligands and conditions to induce useful enantio-
selection.31
We have established a protecting group free, 6-step, 16%
overall yield synthesis of racemic cytisine from readily
available starting materials. The key step features the novel
(26) For related examples of dihydropyridone-pyridone oxidations,
see: (a) Meyers, A. I.; Nolen, R. L.; Collington, E. W.; Narwid, T. A.;
Strickland, R. C. J. Org. Chem. 1973, 38, 1974-1983. (b) Hagen, T. J.;
Cook, J. M. Tetrahedron Lett. 1988, 29, 2421-2424. (c) Singh, B. Synthesis
1985, 305-306. (d) Markgraf, J. H.; Synder, S. A.; Vosburg, D. A.
Tetrahedron Lett. 1998, 39, 1111-1112.
(27) (a) Victory, P.; Sempere, J.; Borrell, J. I.; Crespo, A. J. Chem. Soc.,
Perkin Trans. 1 1989, 2269-2272. (b) Also see: Ireland, R. E.; Anderson,
R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs, S.;
Wilcox, C. S. J. Am. Chem. Soc. 1983, 105, 1988-2006.
a (a) KHMDS, THF, 0 °C to rt, 1/2 h; (b) 5-Cl-2-N-(SO2CF3)-
2-pyridine, -78 °C to rt, 1.5 h, 24%.; (c) 2.5 mol % of Pd(OAc)2,
5 mol % of 9, 1.5 equiv of i-Pr2NEt, toluene, 110 °C, 18 h, 52%;
(d) KHMDS, THF, 0 °C to rt, 1/2 h; (e) ClP(O)(OEt)2, -78 °C to
rt 1.5 h; (f) 2.5 mol % of Pd(OAc) , 5 mol % of 9, 1.5 equiv of
2
i-Pr2NEt, toluene, 110 °C, 18 h, 52% from 5.
(28) Without pyridine, see: Nomura, K.; Okazaki, K.; Hori, K.; Yoshii,
E. J. Am. Chem. Soc. 1987, 109, 3402-3408. With pyridine, see: (a) Ray,
R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449-450. (b) Lodge, E.
P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353-3361.
(29) (a) Emerson, W. S. In Organic Reactions; Wiley: New York, 1982;
Vol. 4, Chapter 3. (b) Bols, M.; Persson, M. P.; Butt, W. M.; Jørgensen,
M.; Christensen, P.; Hansen, L. T. Tetrahedron Lett. 1996, 37, 2097-2100.
(c) Evans, D. A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986, 108,
2478-2479. (d) Kawaguchi, M.; Ohashi, J.; Kawakami, Y.; Yamamoto,
Y.; Oda, J. Synthesis 1985, 701-703. (e) Fray, A. H.; Augeri, D. J.;
Kleinman, E. F. J. Org. Chem. 1988, 53, 896-899. (f) Wolin, R.; Wang,
D.; Kelly, J.; Afonso, A.; James, L.; Kirschmeier, P.; McPhail, A. T. Bioorg.
Med. Chem. Lett. 1996, 6, 195-200. (g) Meyers, A. I.; Nguyen, T. H.
Tetrahedron Lett. 1995, 36, 5873-5876.
Identifying an efficient dehydrogenation of 6 to pyridone
2 was initially an obstacle (Scheme 1). DDQ was capricious,
as various conditions and reaction times produced product
of poor quality in yields below 50%. Chloranil failed to
(24) The recovered yield of 5 was not enhanced when chromatographi-
cally pure 3c was employed.
(25) Early experiments established the requirement that THF be exhaus-
tively removed from the ketene aminal phosphate to allow a reasonable
Heck cyclization rate. Azeotropic removal with CH3CN (3×) under nitrogen
gave reproducible results. Use of argon atmosphere, however, under the
azoetropic conditions and during the subsequent Heck reaction prevented
Heck cyclization. Introduction of a nitrogen atmosphere to the argon-purged
reaction after 24 h initiated the Heck cyclization. Indeed, reaction in air
(CaCO3 tube) progressed rapidly, albeit causing decomposition of the air-
sensitive cycloadduct and vinyl Heck intermediate. This observation sug-
gests that catalytic oxygen is required to generate the active palladium
catalyst.
(30) (a) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 200-202. (b) Koch, G.; Lloyd-Jones, G. C.; Loiseleur, O.; Pfaltz,
A.; Pretot, R.; Schaffner, S.; Schnider, P.; von Matt, P. Recl. TraV. Chim.
Pays-Bas 1995, 114, 206-210. (c) Ripa, L.; Hallberg, A. J. Org. Chem.
1997, 62, 595-602.
(31) An efficient resolution is known. See ref 6.
Org. Lett., Vol. 2, No. 26, 2000
4207

use of glutarimide derived ketene aminal phosphate as an
activated substituent for an intramolecular Heck cyclization
process.32
Acknowledgment. We thank B. T. O’Neill, J. Lyssakatos,
M. G. Vetelino, P. R. Brooks, R. A. Volkmann, D. Kemp,
and E. J. Corey for lively discussion and encouragement and
J. Bordner and D. Decosta for X-ray analysis.
(32) Experimental Procedures: Unless otherwise noted, all materials
were purchased from commercial sources. Anhydrous solvents were used
as provided (in Sure/Seal bottles) and reactions were performed under a
dry nitrogen atmosphere. Thin-layer chromatography was performed with
EM Separations Technology silica gel F254. Silica gel chromatography was
carried out with J. T. Baker 40 µm silica gel according to Still’s procedure
(Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923). All
OL006765T
was added (50 mL) and the product was extracted with Et2O (5 × 40 mL).
The organic layer was washed with H2O (2 × 20 mL), a saturated aqueous
NaHCO3 solution (2 × 20 mL), and a saturated aqueous NaCl solution (50
mL) and then dried over Na2SO4. This mixture was filtered through a 1 in.
silica pad eluting with Et2O to remove baseline color. The filtrate was
concentrated and purified by chromatography on silica gel eluting with 12%
Et2O/CH2Cl2 to provide 6 as an oil (3.25 g, 57% yield) (TLC 10% EtOAc/
CH2Cl2 Rf 0.40): 1H NMR (CDCl3) δ 5.97 (m, 2H), 4.82 (dd, 5.8, 2.3 Hz,
1H), 3.68 (dd, 12.7, 1.5 Hz, 1H), 3.21 (dd, 12.7, 3.4 Hz, 1H), 3.05 (dd, 5.0,
2.5 Hz, 1H), 2.85 (dd, J ) 5.0, 2.8, 1H), 2.43 (m, 2H), 2.24 (m, 1H), 2.08
(m, 2H), 1.73 (d, J ) 10.3 Hz, 1H); 13C NMR (CDCl3) δ 135.23, 134.24,
100.47, 43.93, 43.52, 38.91, 37.58, 31.55, 19.26; GCMS m/e 175 (M+).
Preparation of 7: Dihydropyridone 6 (175 mg, 1.0 mmol) was stirred
in CH2Cl2 (10 mL) and treated dropwise with NBS (178 mg, 1.0 mmol) in
CH2Cl2 (10 mL). A 10 min concentration affords an oily solid which
crystallized. X-ray analysis confirmed the structure as the 1:1 adduct, 7
(TLC (EtOAc) Rf 0.36): 1H NMR (CDCl3) δ 6.16 (dd, J ) 5.8, 3.0 Hz,
1H), 5.96 (dd, J ) 5.8, 3.2 Hz, 1H), 4.38 (dd, J ) 5.2, 3.2 Hz, 1H), 4.25
(m, 2H), 2.75-2.04 (aliphatic, 11 H), 1.48 (d, J ) 11.2 Hz, 1H).
1
glassware was flame dried under dry nitrogen purge before use. H NMR
spectra were collected at 400 MHz with residual CHCl3 as standard (7.26
ppm). Melting points are uncorrected. All spectroscopic data for known
compounds was in complete accord with literature values.
Preparation of 4b: Cyclopent-3enylmethanol9 (4a, 18.0 g, 184 mmol)
and triethylamine (22.5 g, 222 mmol) were stirred in CH2Cl2 (300 mL) at
0 °C under nitrogen and treated with methanesulfonyl chloride (23.2 g,
202 mmol) over 15 min. After 15 min at 0 °C the reaction was poured into
H2O (150 mL), the layers were separated, and the organic layer was washed
with H2O (2 × 50 mL). The aqueous layer was extracted with CH2Cl2 (2
× 30 mL), and the combined organic layer was washed with a saturated
aqueous NaHCO3 solution (2 × 50 mL) and a saturated aqueous NaCl
solution (50 mL). The organic layer was dried through a cotton plug and a
1 in. silica gel pad to remove polar impurities. The filtrate was concentrated
to afford mesylate 4b (32.3 g, 100%) which was used without further
purification (TLC 25% EtOAc/hexanes Rf 0.60): 1H NMR (CDCl3) δ 5.68
(br s, 2H), 4.14 (d, J ) 8 Hz, 2H), 3.03 (s, 3H), 2.7 (m, 1H), 2.63-2.45
(m, 2H), 2.35-2.10 (m, 2H).
Preparation of 2: A dispersion of dihydropyridone 6 (1.58 g, 9.03 mmol)
and activated MnO2 (14.3 g, 165 mmol) were stirred in benzene (75 mL)
and warmed under reflux for 3 h. The reaction mixture was filtered while
hot through a Celite pad and eluted with EtOAc (400 mL). Concentration
afforded pyridone 2 as an oil which crystallized on standing (1.16 g, 74%)
Preparation of 5: Glutarimide (15.4 g, 136 mmol) and KO-t-Bu (15.3
g, 136 mmol) were dispersed in THF (600 mL) under nitrogen and warmed
under reflux for 1 h. To this mixture were added DMF (1 mL), n-Bu4NI (1
g), and mesylate 4b (21 g, 119 mmol) in THF (20 mL). The resulting
mixture was stirred at this temperature for 24 h and then treated with
additional DMF (25 mL). After 4 d the mixture was cooled, poured into
H2O (200 mL), and extracted with EtOAc (3 × 100 mL). The organic
extracts were washed with H2O (2 × 100 mL) and saturated aqueous NaCl
solution (100 mL), dried over Na2SO4 and filtered through a 1 in. silica
pad to remove baseline material. The concentrated product was filtered
through a silica gel pad (3.5 × 5 in.) eluting with CH2Cl2 to generate 5 as
an oil that crystallizes (18 g, 78%): mp 32-33 °C (TLC 25% EtOAc/
1
(TLC 5% MeOH/CH2Cl2 Rf 0.50): mp 64-66.5 °C; H NMR (CDCl3) δ
7.12 (dd, J ) 9.0, 7.0 Hz, 1H), 6.36 (dd, J ) 9.0, 1.0 Hz, 1H), 6.03 (dd,
5.5, 3.0 Hz, 1H), 5.95 (dd, 5.5, 3.0 Hz, 1H), 5.83 (dd, J ) 7.0, 1.0 Hz,
1H), 3.67 (Abq, ∆ν1-3 ) 17.5 Hz, J ) 15.5 Hz, 2H), 3.31 (dd, J ) 4.0, 3.3
Hz, 1H), 3.06 (m, 1H), 2.16 (m, 1H), 1.87 (d, J ) 10.5 Hz, 1H); 13C NMR
(CDCl3) δ 138.40, 136.09, 133.28, 118.07, 103.34, 44.92, 43.85, 37.44,
36.09. GCMS m/e 173 (M+). Anal. Calcd for C11H11NO: C, 76.28; H,
6.40; N, 8.09; Found C, 76.21; H, 6.19; N, 7.95.
Preparation of 8: Pyridone 2 (228 mg, 1.32 mmol) and trimethylamine-
N-oxide dihydrate (161 mg, 1.45 mmol) were stirred under nitrogen in
CH2Cl2 (20 mL) with OsO4 (0.32 mL of a 2.5 wt % solution in t-BuOH,
0.003 mmol, 0.24 mol %) for 36 h. The solution was filtered through a
silica pad (1.5 × 2 in.) eluting with 19/1 CH2Cl2/CH3OH and the filtrate
was concentrated to provide 8 as white granular solid (232 mg, 85%) (TLC
5% MeOH/CH2Cl2 Rf 0.34): 1H NMR (CDCl3) δ 7.28 (dd, J ) 9.0, 7.0
Hz, 1H), 6.41 (dd, J ) 9.0, 1.0 Hz, 1H), 6.04 (d, J ) 7.0 Hz, 1H), 4.13 (br
s, 2H), 3.95 (d, J ) 15.2 Hz, 1H), 3.77 (dd, J ) 15.2, 4.8 Hz, 1H), 3.09 (br
s, 1H), 2.62 (br s, 1H), 2.29 (m, 1H), 1.62 (d, J ) 12.0 Hz, 1H).
Preparation of racemic 1: A solution of diol 8 (256 mg, 1.24 mmol)
in EtOH/H2O (3/1, 40 mL) was magnetically stirred in a Parr bottle and
treated with a solution of NaIO4 (265 mg, 1.24 mmol) in H2O (2 mL). The
resulting white dispersion was stirred 3 h, the stir bar was removed, and a
37% NH4OH solution (30 mL) and Pd(OH)2 (87 mg, 10% on C) were
introduced. The mixture was shaken u der 50 psi of hydrogen for 72 h and
then filtered through a Celite pad and eluted with ethanol. The filtrate was
concentrated to an oily residue, dissolved in CH3OH (30 mL), treated with
silica gel (3 g), and concentrated to a powder. This powder was transferred
onto a silica gel column and eluted with 92/7/1 CH2Cl2/CH3OH/(37%
NH4OH) to provide 1 as a clear oil which crystallizes (135 mg, 57%) (TLC
92/7/1 CH2Cl2/CH3OH/(37% NH4OH) Rf 0.50): mp 139-142 °C (lit. 146-
147 °C);8c 1H NMR (CD3OD) δ 7.46 (dd, J ) 9.0, 7.0 Hz, 1H), 6.42 (d, J
) 9.0 Hz, 1H), 6.27 (d, J ) 7.0 Hz, 1H), 4.05 (d, J ) 15.2 Hz, 1H), 3.90
(dd, J ) 15.2, 6.3 Hz, 1H), 3.29 (br s, 2H), 2.98 (m, 4H), 2.34 (br s, 1H),
1.99 (m, 1H); GCMS m/e 190 (M+); APCI MS m/e 191 (M+ + 1). Anal.
Calcd for 7 C11H14N2O‚H2O: C, 68.52; H, 7.47; N, 14.53. Found C, 68.64;
H, 7.10; N, 14.22.
1
hexanes Rf 0.37); H NMR (CDCl3) δ 5.64 (br s, 2H), 3.79 (d, J ) 8 Hz,
2H), 2.65 (t, J ) 6.6 Hz, 4H), 2.70 (m, 1H), 2.38-2.32 (m, 2H), 2.05-
2.00 (m, 2H), 1.92 (m, 2H); GCMS m/e 193 (M+). Anal. Calcd for C11H15-
NO2: C, 68.37; H, 7.82; N, 7.25. Found C, 67.90; H, 7.58; N, 7.26.
Preparation of 3c: 1,1,1,3,3,3-Hexamethyldisilazane (7.15 mL, 33.9
mmol) was stirred in anhydrous THF (40 mL) under nitrogen at 0 °C and
treated with 2.5 M n-BuLi in hexanes (13.2 mL, 32.9 mmol) over 2 min.
After 20 min, glutarimide 5 (6.23 g, 32.3 mmol) in anhydrous THF (40
mL) was introduced over 5 min by cannula. The resulting thick slurry was
stirred for 5 min at 0 °C and then allowed to warm with stirring to ambient
temperature over a 30 min. It was then cooled to -78 °C and treated with
chloro diethylphosphate (4.81 mL, 32.3 mmol) in anhydrous THF (15 mL)
over 2 min. The mixture was stirred for 10 min at -78 °C and allowed to
warm to ambient temperature over 1.5 h. This solution was concentrated
on the rotary evaporator while a nitrogen atmosphere was maintained. The
resulting oil was dried under reduced pressure for 2 h (0.01 mm). Data for
enol phosphate (3c) (TLC 10% EtOAc/CH2Cl2 Rf 0.12): 1H NMR (CDCl3)
δ 5.54 (br s, 2H), 5.13 (t, J ) 5.0 Hz, 1H), 3.81 (m, 6H), 2.79 (m, 1H),
2.32-2.26 (m, 2H), 2.18 (t, J ) 7.7 Hz, 2H), 2.12-2.07 (m, 2H), 1.65 (m,
2H), 0.90 (t, J ) 7.0 Hz, 6H); APCI MS m/e 330 (M+ + 1).
Preparation of 6: The above enol phosphate 3c (32.3 mmol) was
dissolved in anhydrous CH3CN (100 mL, distilled from CaH) under nitrogen
and treated with freshly distilled triethylamine (6.75 mL, 48.4 mL), tri-o-
tolylphosphine (393 mg, 1.29 mmol), and palladium(II) acetate (145 mg,
0.65 mmol). The resulting mixture was stirred and warmed in an oil bath
to 60 °C for 24 h. After cooling, the volatiles were removed in vacuo. H2O
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Org. Lett., Vol. 2, No. 26, 2000