Asshown in Scheme 3, the allylic alkylation nucleophile 3
waspreparedfrom known isocyanate5 which was obtained
from trans-cinnamic acid via Curtius rearrangement.3 In
the critical coupling step, 5 was exposed to the lithium
enolate derived from ethyl acetate at -78 °C to afford 3 in
55% yield (four steps).
Scheme 2. Synthesis of Key Intermediate 4
Next, the Pd(0)-catalyzed coupling reaction between 3
and 4 was investigated using various palladium catalysts
and phosphine ligands. After considerable experimenta-
tion, the optimal conditions for accessing 125 with high
efficiency and excellent regio- and stereocontrol were
determined to be a combination of an allylpalladium(II)
chloride dimer and dppf.6 Gratifyingly, heating of 12 led to
pyridine ring formation7 and afforded the advanced inter-
mediate 2 in 66% yield.
Scheme 4. Synthesis of 4-Hydroxy-2-pyridone 2
protection as the TBDPS ether to afford 7. Overall, the
conversion of (þ)-pulegone to 7 was carried out in 60%
yield over five steps, with purification only required in the
final step. Ozonolysis of 7 furnished trans-cyclopentanone
8 (88% yield) which was converted to 9 by R-selenenyla-
tion/oxidation/elimination (80% yield, two steps). The
derived enone 9 underwent iodination/dehydrohalogenation
to provide the vinyl iodide, which was subsequently employed
in a Stille coupling with Me4Sn, affording trans-cyclopente-
none 10 in quantitative yield. After screening several reduc-
tants, DIBAL was selected for the subsequent stereoselective
1,2-reduction to produce the desired β-allyl alcohol 11 in 66%
yield. As a note, the undesired R-allyl alcohol was also ob-
tained (30% yield) and could be recycled to 11 via Dess-
Martin oxidation followed by DIBAL reduction. Treatment
of 11 with methyl chloroformate provided the key intermedi-
ate for the allylic alkylation 4,5 in quantitative yield.
With 2 in hand, the stage was set for the intramolecular
iodocyclization. A C-4 regioselective cyclization was re-
quired for the total synthesis of 1; however, undesi-
red iodocyclization at the C-2 position as a concomitant
reaction was also considered due to the 4-hydroxy-2-
pyridone 2 tautomeric equilibrium as depicted in Scheme
4. To the best of our knowledge, only a few regioselective
reactions of 4-hydroxy-5-phenyl-2-pyridones have been
reported8 in which C-4 position-selective cyclization pro-
ceeds preferentially, but the respective reaction mechan-
isms are not clear. At the outset, treatment of 2 with I2 in
CH2Cl2 at rt furnished the undesired iodocyclized
(3) (a) Jones, L. W.; Mason, J. P. J. Am. Chem. Soc. 1927, 49, 2528–
2536. (b) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989, 54,
224–228.
Scheme 3. Synthesis of the Allylic Alkylation Nucleophile 3
(4) (a) Marx, J. N.; Norman, L. R. J. Org. Chem. 1975, 11, 1602–
1606. (b) Wolinsky, J.; Chan, D. J. Org. Chem. 1965, 30, 41–43.
(5) The relative stereochemical configurations were confirmed by
NOE experiments on each compound; also see the Supporting
Information.
(6) (a) Acharya, H. P.; Kobayashi, Y. Tetrahedron 2006, 62, 3329–
3343. (b) Hoke, M. E.; Brescia, M. R.; Bogaczyk, S.; Deshong, P. J. Org.
Chem. 2002, 67, 327–335.
(7) (a) Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54, 5852–5853. (b)
Zhang, Q.; Rivkin, A.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 5774–
5781.
€
(8) (a) Intramolecular 1,4-addition: Furstner, A.; Feyen, F.; Prinz,
H.; Waldmann, H. Angew. Chem., Int. Ed. 2003, 42, 5361–5364. (b)
Intramolecular lactonization and nonregioselective intramolecular cy-
clization: Snider, B. B.; Che, Q. Org. Lett. 2004, 6, 2877–2880.
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