pathway to the structurally related natural product Xyloketal
D.4
o-methyleneacetoxy-phenol (6b) from salicylaldehyde.6a
Perhaps as a consequence, reports of potential o-methylene-
acetoxy-phenols to serve as o-quinone methide synthons are
limited to base-promoted chemistry, followed by in situ
nucleophilic Michael addition.6b We have been unable to find
reports of their use for o-quinone methide generation under
purely thermal conditions.
As part of our continuing efforts directed toward the
biomimetic synthesis of complex natural products derived
from functionalized o-quinone methides,2 we became inter-
ested in developing methodology that would allow ready
access to structures such as 1.
Initially we considered that the most convenient procedure
to allow the formation of the desired o-quinone methide
would be dehydration of the corresponding hydroxymethyl-
orcinol derivative (4).2b However, upon reduction of the
corresponding aldehydic precursor, compound 4 was found
to be unstable and rapidly decomposed under the reaction
conditions. To address this problem, we reasoned that suitable
protection of the phenolic positions may prevent premature
decomposition.
To this end, known diacetate 59 was prepared, which we
hoped could be reduced to its alcohol, so that such a
compound might facilitate o-quinone methide formation
under thermal conditions from an o-methyleneacetoxy-phenol
(6a), itself generated via a transesterfication mechanism.
Although such o-methyleneacetoxy-phenols, e.g., 6b, (Scheme
1), have been described in the literature, members of this
In practice, the transfer of the phenolic acetate to the
adjacent benzyl alcohol group occurred during the reduction
of 5 with borane-DMS complex. Gratifyingly, this strategy
permitted us to prepare and isolate a stable precursor (6a)10
for the generation of the benzopyran core of 1 using the
o-quinone methide pathway. Thus, simple heating of 6a in
the presence of (()-4,5-dihydro-2,4-dimethylfuran afforded
acetylalboatrin (7) as the major product (63% yield), acetyl-
epi-alboatrin11 (5% yield), and an inseparable mixture [3:2]
of diastereoisomers (8)4 (25% yield). Deacylation of 7
yielded the desired (()-Alboatrin, for which spectral data
was identical to the natural material [1H, 13C].7,8 The struc-
ture of 1 was also confirmed by X-ray analysis and was
found to be in agreement with Murphy’s proposal (Figure
2).12
Scheme 1. Synthesis of (()-Alboatrin
Figure 2. X-ray structure of 1 and 6a.
The proton NMR of 6a displayed a sharp signal at 8.23
ppm, characteristic of a hydrogen bond between the phenolic
OH and the benzylic acetate, which was confirmed by the
X-ray crystal structure of 6a (Figure 2).12 This hydrogen bond
may facilitate the elimination of acetic acid upon heating
through a six-membered ring transition state, furnishing the
o-quinone methide under relatively mild conditions.
The described methodology required no added acid, base,
or catalyst for the formation of the hetero-Diels-Alder
adduct, and the elimination of acetic acid was not found to
be detrimental to the reaction.
class of compounds have been reported as being labile
structures that “can be conserved for several days in dilute
solution but polymerize rapidly as soon as they are pure”.6b
Their reported synthesis is likewise unattractive; for example,
Loubinoux has reported the need for a six-step synthesis of
To further demonstrate the versatility of this methodology,
several benzopyran cores have been prepared with a range
of dienophiles (Table 1). The reaction times, temperatures
required, and yields obtained compare favorably with those
(7) Ichiara, A.; Nonaka, M.; Sakamura, S.; Sato, R.; Tajimi, A. Chem.
Lett. 1988, 27.
(8) Graham, S. R.; Murphy, J. A.; Kennedy, A. R. J. Chem. Soc., Perkin
Trans. 1 1999, 3071.
(9) Gruneiro, E. M.; Gros, E. G. An. Asoc. Quim. Argent. 1971, 59, 259.
We obtained 5 in two steps starting from orcinol: (a) POCl3 (1 equiv),
(DMF), -10 °C to room temperature, 2 h, 38%; (b) pyridine (2.2 equiv),
AcCl (1.1 equiv), DCM, 0 °C then to room temperature, 2 h, AcCl (1.1
equiv), 0 °C then to room temperature, 2 h, 71%.
(10) Mp ) 95-96 °C. Stable at room temperature for over 4 months.
(11) Deacylated to epi-alboatrin.8
(12) Atomic coordinates for 1 and 6a are available upon request from
the Cambridge Crystallographic Data Center, University Chemical Labora-
tory, Lensfield Road, Cambridge CB2 1EW (Deposition numbers: (1)
CCDC 239364, (6a) CCDC 237660).
3618
Org. Lett., Vol. 6, No. 20, 2004
Rodriguez, Raphael
