noteworthy in the NOE measurements was that the angular
methyl substituent and the phenyl sulfone ortho protons each
displayed a strong contact with H-9. Thus, as expected,8 the
stereochemical course of the cycloaddition reaction featured
approach of the diene from the â-face of the dienophile.
Cycloadducts resulting from other modes of addition were
not detected. Hence, the desired relationship between C-9
and C-10 is established during the Diels-Alder reaction with
apparent complete stereochemical control.
Scheme 4 a
Ketosulfone 23 was treated with lithium naphthalenide16
to generate the required enolate, which was methylated
through the action of methyl iodide (see Scheme 6).
a Key: (a) p-TsNHNH2, PPTS, THF, 92%; (b) n-BuLi, THF,
PhSSPh, -78 to -40 °C, 94%; (c) n-BuLi, -78 to -20 °C, 42%
(74% based on conversion); (d) SeO2, pyridine, 95:5 EtOH-H2O,
reflux, 78%; (e) m-CPBA, CH2Cl2, 0 °C to rt; DMP, pyridine,
CH2Cl2, 0 °C to rt, 91%.
Scheme 6 a
procedures to afford ketone 14,12 thus establishing the anti
fusion required of the AB ring junction. The ketone function
was then reduced using the Huang-Minlon modification of
the Wolff-Kischner reaction, thereby generating compound
15.12 Deketalization of this product gave 16.
The stage was set for incorporation of the enabling dieno-
philic functionality (see Scheme 4). Accordingly, tosylhy-
drazone 17 was prepared. R-Sulfenylation of this material
efficiently provided 18 as an approximately 2:1 mixture of
diastereomers. These converged, via a Shapiro olefination
reaction, to thioenol ether 19.13 Selenium dioxide-mediated
allylic oxidation of this compound gave alcohol 2014 in good
yield. Adjustment of the oxidation level to that required was
best carried out by first converting the thioether to a sulfone,
followed by oxidation of the resulting crude alcohol to the
corresponding ketone, thus providing compound 21.
Compound 21 served as the dienophile component in a
Diels-Alder reaction using, for the purposes of demonstra-
tion, the readily accessible diene 2215 (Scheme 5). In the
a Key: (a) Li+(C10H8)-, THF, -78 °C ; MeI, -78 °C to rt, 66%;
(b) LiAlH4, Et2O, -78 to 0 °C; TBAF, THF, 0 °C to rt, 86%; (c)
H2NNH2‚H2O, KOH, tri(ethylene glycol), 200 °C, 77%.
C-Alkylated material (24) was obtained in reasonable yield,
along with the corresponding O-alkylated compound (ap-
proximately 2.3:1, respectively). At this stage, we were
unable to establish unambiguously the critical stereochem-
istry at C-8, due to the lack of resolution of relevant proton
signals at 500 MHz. We were, however, able to deduce this
information using a derivative of this compound. Hence, the
C-alkylated compound (now known to be 24) was treated
with lithium aluminum hydride, followed by exposure of the
product to TBAF, thereby affording keto alcohol 25.
The key signals in keto alcohol 25 were suitably resolved
Scheme 5
1
in its H NMR spectrum at 500 MHz. A number of useful
(8) For leading studies on stereoselective Diels-Alder addition to 4a-
methyl-trans-4a,5,6,7,8,8a-hexahydro-1H-naphthalen-2-ones, see: Grieco,
P. A.; Garner, P.; He, Z. Tetrahedron Lett. 1983, 24, 1897-1900. Sicherer-
Roetman, A.; Jansen, B. J. M.; de Groot, A. Tetrahedron Lett. 1984, 25,
2593-2596.
(9) For leading studies on synthesis via vinyl sulfones, see: Meyers, D.
J.; Fuchs, P. L. J. Org. Chem. 2002, 67, 200-204 and other papers in that
series.
(10) Available from Aldrich, catalog number M6,515-7.
(11) Ciceri, P.; Demnitz, J. Tetrahedron Lett. 1997, 38, 389-390.
(12) Mewshaw, R. E.; Taylor, M. D.; Smith, A. B., III. J. Org. Chem.
1989, 54, 3449-3462.
(13) Cf.: Nakai, T.; Mimura, T. Tetrahedron Lett. 1979, 531-534.
(14) A single diastereomer of undetermined relative configuration at C-7
was obtained.
event, the resulting cycloadduct exhibited spectral charac-
1
teristics consistent with ketosulfone 23. The H and 13C
assignment was conducted using a combination of COSY,
HMQC, DEPT, and NOE difference spectroscopy. Especially
(7) Approaches involving different strategies have also been reported.
See: Dauben, W. G.; Kessel, C. R.; Kishi, M.; Somei, M.; Tada, M.;
Guillerm, D. J. Am. Chem. Soc. 1982, 104, 303-305. Wiebel, J.-M.;
Heissler, D. Tetrahedron Lett. 1994, 35, 473-476.
(15) Ireland, R. E.; Thompson, W. J. J. Org. Chem. 1979, 44, 3041-
3052.
(16) Cf.: Azuma, T.; Yanagida, S.; Sakurai, H.; Sasa, S.; Yoshino, K.
Synth. Commun. 1982, 12, 137-140.
Org. Lett., Vol. 5, No. 8, 2003
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