Scheme 1. Total Synthesis of (-)-Xyloketal A
Figure 1. Molecular structure and retrosynthetic analysis of
xyloketal A.
cally stable cis-fused bicyclic acetal moieties of the natural
product. It was also appreciated that the stereochemistry of
the acetal formation reactions would be directed by the steric
influence of the stereogenic C4-methyl substituent of the
reactive intermediate 4. In principle, this reactive intermediate
could be generated on ionization of the corresponding chiral
nonracemic alcohol 3.7 To demonstrate this synthetic objec-
tive, a method was developed for the preparation of a
precursor to the chiral nonracemic alcohol 3. Thus, the
methyl ester 11 was prepared from the known oxazolidinone
5 (Scheme 1).8
Deprotonation of the oxazolidinone 5 in a mixture of
tetrahydrohydrofuran and hexamethylphosphoramide (HMPA,
∼10%) with lithium diisopropylamide (LDA, 1.5 equiv), and
on subsequent reaction with propargyl bromide (4 equiv) at
-78 °C for 20 h, afforded the oxazolidinone 6 in good yield
(77%) and as a single diastereoisomer.9 This oxazolidinone
was then reduced with lithium aluminum hydride to afford
the known chiral nonracemic alcohol 7.10,11 This acetylenic
alcohol was in turn converted to the known endo-cyclic
dihydrofuran 8 on heating with a substoichiometric amount
of sodium amide followed by thermal isomerization of the
corresponding exo-cyclic dihydrofuran.4b,12
To prepare the required methyl ester 11, the dihydrofuran
8 was reacted (based on literature procedures) with trichlo-
roacetyl chloride and pyridine.13,14 This afforded a readily
separable mixture of the desired trichloroketone 9 (45%
yield) and a substantial quantity of the regioisomeric trichlo-
roketone 10 (46% yield).15 Presumably, the latter compound
was formed via isomerization of the endo-cyclic dihydrofuran
8 to the corresponding exo-cyclic dihydrofuran under the
reaction conditions. To suppress the formation of the
regioisomeric trichloroketone 10, the reaction was repeated
at -78 °C. This resulted in the isolation of the trichloroketone
9 in very good yield (93%). Subsequent methanolysis of the
trichloroketone 9 afforded the methyl ester 11 in excellent
(6) Krohn and co-workers have attempted the synthesis of xyloketal A
(1) from racemic 5-hydroxy-4-methyl-3-methylenepentan-2-one and phlo-
roglucinol. In this instance, the desired tris-adducts were isolated in 6%
yield as a mixture of eight diastereoisomers, see: (a) Krohn, K.; Riaz, M.;
Flo¨rke, U. Eur. J. Org. Chem. 2004, 1261. In this paper, an asymmetric
synthesis of (-)-xyloketal D via a conjugate addition reaction of 2,4-
dihydroxyacetophenone to the (4R)-enantiomer of the aforementioned ketone
was also described. In addition, Krohn and co-workers reported the synthesis
of demethyl analogues of the xyloketal natural products in this paper. For
a preliminary communication of this work, see: (b) Krohn, K.; Riaz, M.
Tetrahedron Lett. 2004, 45, 293.
(7) We have established, in simplified model systems, that this novel
triple electrophilic aromatic substitution reaction and subsequent bicyclic
acetal formation process can be promoted with a variety of acidic reagents
in the presence of anhydrous magnesium sulfate, see: Pettigrew, J. D.;
Wilson, P. D. J. Org. Chem. 2006, 71, 1620.
(12) The final reaction product was contaminated with a small amount
of the corresponding exo-cyclic dihydrofuran (<7%).
(13) (a) Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagawa, M. Synthesis
1986, 1016. (b) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer,
P. Synthesis 1991, 483.
(14) A direct one-step procedure for the synthesis of dihydrofuran esters
from the corresponding dihydrofurans has been reported, see: Stetter, H.;
Lorenz, G. Chem. Ber. 1985, 118, 1115. However, in our hands, a complex
mixture of reaction products was obtained when the dihydrofuran 8 was
employed as a reaction substrate.
(8) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
(9) For reports on the use of HMPA in alkylation reactions of derivatives
of oxazolidinone chiral auxiliaries, see: (a) Fadel, A. Tetrahedron:
Asymmetry 1994, 5, 531. (b) Versteeg, M.; Bezuidenhoudt, B. C. B.;
Ferreira, D.; Swart, K. J. J. Chem. Soc., Chem. Commun. 1995, 1317. (c)
Versteeg, M.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron 1999, 55,
3365.
(10) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(11) For an alternative synthesis (employing a resolution procedure) and
proof of absolute stereochemistry of the chiral nonracemic alcohol 7, see
ref 4b.
(15) The trichloroketone 10 was isolated as a single geometrical isomer.
The geometry of the double bond was not determined but it is reasonable
to assume, based on electronic and steric considerations, that it is trans.
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Org. Lett., Vol. 8, No. 7, 2006