Synthesis of xyloketal A, B, C, D, and G analogues

Article abstract of DOI:10.1021/jo052371+

A series of demethyl analogues of the natural products xyloketal A, B, C, D, and G have been prepared in a notably direct manner from 3-hydroxymethyl-2- methyl-4,5-dihydrofuran and a series of corresponding phenols. These syntheses featured a boron trifluoride diethyl etherate-promoted electrophilic aromatic substitution reaction as a key step. In the case of the synthesis of analogues of xyloketal A, the process was found to be highly efficient (up to 93% yield). The optimized isolated yield of these reaction products is remarkable in view of the fact that this transformation involves, minimally, six individual reactions. Moreover, these synthetic studies provide significant insight into the possible biogenic origin of the xyloketal natural products.

Full text of DOI:10.1021/jo052371+

Synthesis of Xyloketal A, B, C, D, and G Analogues
Jeremy D. Pettigrew and Peter D. Wilson*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe, Burnaby,
British Columbia V5A 1S6, Canada
pwilson@sfu.ca
ReceiVed NoVember 16, 2005
A series of demethyl analogues of the natural products xyloketal A, B, C, D, and G have been prepared
in a notably direct manner from 3-hydroxymethyl-2-methyl-4,5-dihydrofuran and a series of corresponding
phenols. These syntheses featured a boron trifluoride diethyl etherate-promoted electrophilic aromatic
substitution reaction as a key step. In the case of the synthesis of analogues of xyloketal A, the process
was found to be highly efficient (up to 93% yield). The optimized isolated yield of these reaction products
is remarkable in view of the fact that this transformation involves, minimally, six individual reactions.
Moreover, these synthetic studies provide significant insight into the possible biogenic origin of the
xyloketal natural products.
Introduction
conditions, confirmed the common biogenic origin of all of these
novel secondary metabolites.2 The xyloketals incorporate identi-
cal 5,6-bicyclic acetal moieties that are fused to an aromatic
core. In all cases, the hydrogen atoms of the cis-ring junctions
of the bicyclic acetals are syn to the stereogenic methyl
substituents at C5 of the five-membered rings.4
Xyloketal A (1) has a unique and remarkable C3-symmetric
molecular structure that incorporates three bicyclic acetal
moieties. In the solid state, this molecule adopts a bowl-shaped
conformation that is presumably enforced by anomeric effects.1
Xyloketal B (2) and the minor C2-symmetric component,
xyloketal C (3) [that also readily rearranges to xyloketal B (2)
in solution], incorporate two bicyclic acetal moieties.5 Xyloketal
D (4) and the corresponding regioisomer, xyloketal G (7), are
the simplest members of this family of natural products in that
they only contain one bicyclic acetal moiety. The isolation and
structural characterization of xyloketal E (5), an additional
derivative of xyloketal B (2) [cf. xyloketal F (6)], suggests that
In 2001, Lin and co-workers reported the isolation and
structural characterization of five related natural products,
xyloketal A (1), B (2), C (3), D (4), and E (5), from a mangrove
fungus of the Xylaria species (Figure 1).1 More recently, Lin
and co-workers have reported the isolation and structural
characterization of two additional members of this family of
natural products, xyloketal F (6) and G (7).2,3 The molecular
structures and relative stereochemistries of these natural products
were determined by extensive spectroscopic studies and by
X-ray crystallography.1-3 The absolute stereochemistries of
xyloketal A (1), D (4), F (6), and G (7) were determined by
interpretation of their CD spectra. The absolute stereochemistries
of the remaining members of this family of natural products
were assigned by analogy. In addition, the semisynthesis of the
C2-symmetric natural product, xyloketal F (6), from xyloketal
B (2), on condensation with formaldehyde under acidic reaction
(1) Lin, Y.; Wu, X.; Feng, S.; Jiang, G.; Luo, J.; Zhou, S.; Vrijmoed, L.
L. P.; Jones, E. B. G.; Krohn, K.; Steingro¨ver, K.; Zsila, F. J. Org. Chem.
2001, 66, 6252.
(2) Wu, X. Y.; Liu, X. H.; Lin, Y. C.; Luo, J. H.; She, Z. G.; Houjin, L.;
Chan, W. L.; Antus, S.; Kurtan, T.; Elsa¨sser, B.; Krohn, K. Eur. J. Org.
Chem. 2005, 4061.
(4) Herein, the numbering scheme is based on that described by Lin and
co-workers (see refs 1 and 3).
(5) Xyloketal B (2) is presumably more stable than the regioisomeric
natural product, xyloketal C (3), because destabilizing dipole-dipole
interactions are minimized. In addition, xyloketal B (2) in principle can
also form a hydrogen bonded dimer in solution [cf. xyloketal F (6), see ref
2].
(3) Wu, X.; Liu, X.; Jiang, G.; Lin, Y.; Chan, W.; Vrijmoed, L. L. P.
Chem. Nat. Compd. 2005, 41, 27.
10.1021/jo052371+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/27/2006
1620
J. Org. Chem. 2006, 71, 1620-1625

Synthesis of Xyloketal A, B, C, D, and G Analogues
FIGURE 2. Synthesis of (()-11-norxyloketal D (8, R ) H), (()-
xyloketal D (4, R ) Me), and the xyloketal A analogues 9 and 10.7
Of note, the synthesis of (()-xyloketal D (4, R ) Me), although
highly diastereoselective (11:1), was complicated by the forma-
tion of diastereoisomeric spiroacetals. These byproducts resulted
from a nonstereoselective cycloaddition reaction (presumably
following isomerization of the dihydrofuran 14 under the
reaction conditions) of the corresponding exo-cyclic dihydro-
furan. This complicating factor resulted in the formation of a
highly complex mixture of reaction products on attempting the
total synthesis of (()-xyloketal A (1).7
We have subsequently reported the asymmetric syntheses of
(-)-xyloketal D (4) and its enantiomer on preparing both
enantiomers of 4,5-dihydro-2,4-dimethylfuran 14.8,9 These total
syntheses confirmed the absolute stereochemistry of the natural
product and thus the absolute stereochemistry of the xyloketals.
Krohn and co-workers have also reported an asymmetric total
synthesis of (-)-xyloketal D (4) from (3R)-3-methylbutyrolac-
tone and 2,4-dihydroxyacetophenone.10 This synthesis featured
the conjugate addition reaction of the latter aromatic phenol to
an R,â-unsaturated ketone [(4R)-5-hydroxy-4-methyl-3-meth-
ylenepentan-2-one], that was elaborated from the butyrolactone,
on heating at reflux in toluene.11,12 In addition, these researchers
have also described the synthesis of demethyl analogues of
xyloketal A (1) and B (2) (as well as a corresponding mono-
adduct) as mixtures of diastereoisomers from a model R,â-
unsaturated ketone and phloroglucinol.13 The ratio of these
products was dependent on the ratio of the reactants employed
and the reaction time.
FIGURE 1. Molecular structures of xyloketal A (1), B (2), C (3), D
(4), E (5), F (6), and G (7).
(4R)-4,5-dihydro-2,4-dimethylfuran (or the corresponding hy-
droxyketone) is the common biogenic precursor to all of these
natural products. In the case of xyloketal E (5), it reasonable to
conclude that this natural product is formed by a direct
substitution reaction of the electron-rich aromatic ring of
xyloketal B (2) on protonation of the aforementioned dihydro-
furan precursor.6 Xyloketal A (1) has also been shown to be a
potent inhibitor of acetylcholine esterase and so it represents
an important lead compound for the treatment of neurological
diseases.1,2 In addition, xyloketal A (1), B (2), and F (6) have
been shown to have L-calcium channel blocking activity.2 Thus,
the total synthesis of these natural products and structural
analogues is of notable significance.
We have previously reported the synthesis of (()-11-
norxyloketal D (8, R ) H), the first total synthesis of
(()-xyloketal D (4, R ) Me), and the synthesis of the two
possible diastereoisomers of the tris-demethyl analogue of
xyloketal A (9 and 10) (Figure 2).7 These syntheses featured
the cycloaddition reactions of appropriately functionalized
o-quinone methides (generated by methylation of the readily
available and corresponding Mannich bases 11 and 12) and the
dihydrofurans 13 and 14. The Mannich base substrates 11 and
12 were prepared in one step from the corresponding com-
mercially available aromatic phenols, 2,4-dihydroxyacetophe-
none and phloroglucinol (1,3,5-trihydroxybenzene), respectively.
(8) Pettigrew, J. D.; Freeman, R. P.; Wilson, P. D. Can. J. Chem. 2004,
82, 1640.
(9) We have also outlined an alternative approach for the synthesis of
the xyloketal natural products based on a novel phenylboronic acid-mediated
condensation reaction of R,â-unsaturated aldehydes with aromatic phenols,
see: Pettigrew, J. D.; Cadieux, J. A.; So, S. S. S.; Wilson, P. D. Org. Lett.
2005, 7, 467.
(10) (a) Krohn, K.; Riaz, M. Tetrahedron Lett. 2004, 45, 293. (b) Krohn,
K.; Riaz, M.; Flo¨rke, U. Eur. J. Org. Chem. 2004, 1261.
(11) This alternative high-yielding synthesis was also diastereoselective
(8.5:1.5). However, the reported racemic synthesis of xyloketal D (4) and
its diastereoisomer (80% combined yield) was also complicated by the
formation of a diastereomeric mixture of the regioisomeric bicylic acetals
(9%, combined yield). One of these latter diastereoisomers corresponds to
xyloketal G (7) (see refs 10b and 3).
(12) These researchers have also described the synthesis of demethyl
analogues of xyloketal D (4) and G (7) from a model R,â-unsaturated ketone
and 2,4-dihydroxyacetophenone (see ref 10b).
(13) Krohn and co-workers have also attempted the synthesis of xyloketal
A (1) from racemic 5-hydroxy-4-methyl-3-methylenepentan-2-one and
phloroglucinol. In this instance, the desired tris-adducts were isolated in
6% yield as a mixture of eight diastereoisomers (the corresponding mono-
and bis-adducts were also isolated) (see ref 10b).
(6) The stereochemistry of the quaternary benzylic center of xyloketal
E (5), if this natural product is formed by an electrophilic aromatic
substitution reaction of xyloketal B (2) and (4R)-4,5-dihydro-2,4-dimeth-
ylfuran, is opposite to what would be predicted on the basis of simple steric
arguments. However, the level of diastereoselectivity of this proposed
reaction is not predictable and it is possible that an epimer of xyloketal E
(5) is also produced metabolically.
(7) Pettigrew, J. D.; Bexrud, J. A.; Freeman, R. P.; Wilson, P. D.
Heterocycles 2004, 62, 445.
J. Org. Chem, Vol. 71, No. 4, 2006 1621

Pettigrew and Wilson
SCHEME 1. Synthesis of 3-Hydroxymethyl-2-methyl-4,5-
dihydrofuran 20a
a Reagents and conditions: (a) HCl (g), methanol, reflux, 4 days then
distill; (b) H2SO4 (cat.), distill, 19% (over two steps); (c) LiAlH4, ether, 0
°C to room temperature, 20 min, 96%.
FIGURE 3. Retrosynthetic analysis of xyloketal A (1).
When we initiated our studies toward the total synthesis of
the xyloketals, via o-quinone methide intermediates, we had also
realized that xyloketal A (1) could in principle be prepared by
a triple electrophilic aromatic substitution reaction of phloro-
glucinol 15 and the reactive intermediate 17 (Figure 3). The
initial adducts of these substitution reactions would then be
expected to rearrange, under the reaction conditions, to afford
the thermodynamically stable cis-fused bicyclic acetal moieties
of the natural product. The desired reactive intermediate 17 in
this reaction could, in principle, be generated by ionization of
the corresponding chiral nonracemic alcohol 16. In a similar
manner, xyloketal B (2) and C (3) could be prepared by
executing selective double electrophilic aromatic substitution
reactions of phloroglucinol 15 with the same reactive intermedi-
ate. In addition, xyloketal D (4) and the regioisomer, xyloketal
G (7), could be prepared from the corresponding aromatic
phenol, 2,4-dihydroxyacetophenone. In all of these reactions,
it would be expected that the stereochemistry of the acetal
formation reactions (that involve protonation of the dihydrofuran
moieties) would be controlled, based on steric arguments, by
the C4-methyl substituent of the parent alcohol 16. Biogenically,
the alcohol 16 could be derived from (4R)-4,5-dihydro-2,4-
dimethylfuran 14 on reaction with a formaldehyde equivalent.14
In this paper, we describe the synthesis of analogues of
xyloketal A (1), B (2), C (3), D (4), and G (7) from a model
3-(hydroxymethyl)dihydrofuran and a series of appropriate
aromatic phenols. We believe that the exceedingly efficient and
facile synthesis of these analogues, described herein, possibly
reflects the biogenic origin of the xyloketal natural products.15
TABLE 1. Synthesis of Xyloketal A Analogues 9 and 10
acid promoter
(equiv)
temp
(°C)
yielda of
9 and 10 (%)
entry
1
2
3
4
5
6
7
8
BF3‚Et2O (2.7)
BF3‚Et2O (2.7)
BF3‚Et2O (1.3)
BF3‚Et2O (1.0)
BF3‚Et2O (0.5)
BF3‚Et2O (0.25)
HF (cat.)
0
-78
36
35
69
93
77
77
77
71
0
0
0
0
0
0
p-TsOH (1.0)
a Combined isolated yield of xyloketal A analogues 9 and 10 after
purification by flash chromatography.
relatively unstable compound and so it was used immediately
in subsequent experiments. The ester 19 was prepared from the
commercially available lactone 18 on heating in methanol in
the presence of hydrogen chloride (which was bubbled into the
reaction mixture) and following redistillation of the resultant
product from a catalytic amount of concentrated sulfuric acid.16
The initial reaction conditions selected for the triple electro-
philic aromatic substitution reaction of phloroglucinol 15 with
the alcohol 20 were based on a report by Razdan and co-workers
on the synthesis of ∆1-tetrahydrocannabinol (THC) from p-men-
tha-2,8-dienol and olivetol.18 A two-fold excess of the unstable
alcohol 20 was employed per phenolic reaction site and the
initial reaction involved stirring a mixture of the phloroglucinol
15 (1 equiv) and the alcohol 20 (6 equiv), in ether at 0 °C, in
the presence of anhydrous magnesium sulfate and boron
trifluoride diethyl etherate (2.7 equiv) (Table 1, entry 1).18,19
The known xyloketal A analogues 9 and 10 were formed rapidly
Results and Discussion
Synthesis of Xyloketal A Analogues. The required model
3-(hydroxymethyl)dihydrofuran, the alcohol 20, was prepared
by reduction of the known ester 19 with lithium aluminum
hydride (Scheme 1).16,17 Of note, the volatile alcohol 20 is a
(14) The isolation of xyloketal F (6) suggests, as commented on by Lin
and co-workers (and demonstrated by semisynthesis), that a formaldehyde
equivalent is involved in the biosynthesis of this particular natural product
(see ref 2). It can also be inferred that a formaldehyde equivalent could
also be involved in additional steps in the biosynthesis of the xyloketals in
view of this new synthetic proposal.
(15) After the reports of our original syntheses of xyloketal D (4) (see:
ref 7 and 8), Lin and co-workers have also commented that the biosynthesis
of the xyloketals involves o-quinone methide intermediates (see ref 3). In
view of the findings reported in this paper, in addition to our earlier
observations, we believe that this conclusion is incorrect. Of note, the R,â-
unsaturated ketone reported by Krohn and co-workers is a synthetic
equivalent of the alcohol 16 (see ref 10). We believe that the former
compound is not directly involved in the biosynthesis of the xyloketal natural
products because relatively forcing conditions are required for this compound
to react (nor was the reactivity of this compound influenced by the addition
of acids, vide infra) and in view of the isolation of xyloketal E (5). However,
the potentially biogenic route described by Krohn and co-workers cannot
be discounted at this time.
(17) The preparation of the alcohol 20 by direct reaction of commercially
available 2-methyl-4,5-dihydrofuran 13 with formaldehyde or related
synthetic equivalents, under various reaction conditions, was unsuccessful.
(18) Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem. Soc.
1974, 96, 5860. Of note, the cosolvent, dichloromethane, was not used in
these studies because of the poor solubility of phloroglucinol 15 in
chlorinated solvents.
(19) Boron trifluoride diethyl etherate has also been employed as a Lewis
acid in the electrophilic aromatic substitution reaction of phloroglucinol
15 and 2-methylbut-3-en-2-ol, see: (a) Collins, E.; John, G. D.; Shannon,
P. V. R. J. Chem. Soc., Perkin Trans. 1 1975, 96. In addition, a key step
in a total synthesis of the natural product, alboatrin, has involved a boron
trifluoride diethyl etherate-promoted electrophilic aromatic substitution
reaction of orcinol with 2,4-dimethyl-3-hydroxymethylfuran, see: (b)
Ichiara, A.; Nonaka, M.; Sakamura, S.; Sato, R.; Tajimi, A. Chem. Lett.
1988, 27.
(16) (a) Korte, F.; Machleidt, H. Chem. Ber. 1957, 90, 2137. (b) Gollnick,
K.; Knutzen-Mies, K. J. Org. Chem. 1991, 56, 4017.
1622 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of Xyloketal A, B, C, D, and G Analogues
SCHEME 2. Synthesis of Substituted Analogues of
Xyloketal B (24 and 25) and Xyloketal C (26 and 27)
and the limiting starting material, phloroglucinol 15, was
consumed in less than 15 min.7,10b These compounds were
isolated, in pure form and in reasonable yield (36%), as an
inseparable mixture of two diastereoisomers (2:7, respectively).
The corresponding mono- and bis-adducts were not isolated
from this reaction. In addition, no evidence for the formation
of these intermediates (by thin-layer chromatography) was
observed during the course of the reaction. It would be expected
that these more substituted and electron-rich intermediates would
react at a faster rate than the limiting starting material,
phloroglucinol 15.
To improve the efficiency of this new reaction, it was repeated
at a lower temperature (-78 °C) (Table 1, entry 2). However,
the desired products were isolated in essentially the same yield
and diastereoselectivity after 15 min. In this instance, as in the
initial experiment, phloroglucinol 15 was completely consumed
and highly polar or polymeric reaction byproducts were also
formed. Thus, it was decided to systematically decrease the
number of equivalents of boron trifluoride diethyl etherate and
explore the use of different acid promoters. On employing boron
trifluoride diethyl etherate (1.3 equiv), at 0 °C, a dramatic
improvement in the isolated yield of the xyloketal A analogues
9 and 10 (69%) was recorded (Table 1, entry 3). Moreover, the
use of boron trifluoride diethyl etherate (1.0 equiv, ∼0.3 equiv
per phenolic reaction site) led to an exceptionally clean synthetic
transformation and the isolation of the xyloketal A analogues 9
and 10 in excellent yield (93%) (Table 1, entry 4). The isolated
yield of these reaction products is truly remarkable in view of
the fact that this transformation involves, minimally, six
individual reactions. Decreasing the number of equivalents of
boron trifluoride diethyl etherate further resulted in the isolation
of the desired reaction products in lower yield (Table 1, entries
5 and 6). However, it was found that concentrated hydrofluoric
acid (which could have been involved in the reactions described
above) and p-toluenesulfonic acid also promoted this reaction
in good yield (Table 1, entries 7 and 8).20 Of note, the desired
C3-symmetric diastereoisomer [that has the same relative
stereochemistry as xyloketal A (1)] was the minor component
in all of these reactions. However, we anticipate that the
stereochemistry of the C4-methyl substituent of the chiral
nonracemic alcohol 16 will correctly direct the diastereoselec-
tivity of the triple condensation reactions (in an absolute sense)
on attempting the total synthesis of xyloketal A (1).
trihydroxybenzoate 22 was prepared from the corresponding
commercially available carboxylic acid, 2,4,6-trihydroxybenzoic
acid 21.22 In the first instance, the methyl ester 22 (1 equiv)
was reacted with the alcohol 20 (4 equiv), boron trifluoride
diethyl etherate (1 equiv), and magnesium sulfate in ether and
the resultant mixture was allowed to warm from 0 °C to room
temperature over 4 h (Scheme 2). On subsequent purification
of the crude reaction mixture by flash chromatography, the
mono-adduct 23 (6%) and a mixture (3:3:1) of the substituted
xyloketal B analogues 24 and 25 as well as the substituted
xyloketal C analogues 26 and 27 (50%, combined yield) were
isolated. The latter minor components were formed as a mixture
of diastereoisomers (∼1:1).5
On performing the above reaction for an extended period of
time (36 h), a mixture (5:5:1) of the substituted xyloketal B
analogues 24 and 25 as well as the substituted xyloketal C
analogues 26 and 27 was isolated (51%, combined yield). In
this instance, none of the monoadduct 23 was present in the
crude reaction mixture and less of the unstable xyloketal C
analogues 26 and 27 were isolated as they were presumably
converted to the substituted xyloketal B analogues 24 and 25
during the extended reaction time.5 The substituted xyloketal
B analogues 24 and 25 could also be separated from the
substituted xyloketal C analogues 26/27, in this instance,
following further purification by flash chromatography. It was
subsequently found that the above products could be prepared
in improved yield (58%) on decreasing the amount of boron
trifluoride diethyl etherate employed in the process (0.7 equiv,
∼0.3 equiv per phenolic reaction site) and on performing the
reaction for 46 h. Of note, the slower rate and lower isolated
yields of these latter reactions reflect the decreased reactivity
of the less electron-rich phenol 22 (as compared to phloroglu-
cinol 15).
Synthesis of Xyloketal B and C Analogues. It was consid-
ered that analogues of xyloketal B and C could be prepared by
decreasing the number of equivalents of the alcohol 20 employed
in the above optimized reaction with phloroglucinol 15.
However, given the relative instability of this alcohol and the
observed propensity for the preferential formation of the tris-
adducts 9 and 10 (as well as to prepare the xyloketal B and C
analogues in acceptable yield), it was decided to temporarily
block one of the reaction sites of phloroglucinol 15. For this
purpose, a methyl ester blocking group was selected because it
was expected that this substituent could be removed by a
decarboxylative saponification reaction.21 Thus, methyl 2,4,6-
The synthesis of the known bis-demethyl analogues of
xyloketal B (28 and 29) was subsequently accomplished on
(22) Methyl 2,4,6-trihydroxybenzoate 22 was prepared from the car-
boxylic acid 21, on reaction with dimethyl sulfate and sodium bicarbonate,
according to a literature procedure, see: Carvalho, C. F.; Russo, A. V.;
Sargent, M. V. Aust. J. Chem. 1985, 38, 777.
(20) None of the desired products were formed on performing the
reactions at room temperature in the absence of an acid promoter or in the
presence of acetic acid.
(21) For recent references regarding the facile decarboxylative saponi-
fication reactions of ortho-phenolic esters, see: (a) Hu, H.; Harrison, T. J.;
Wilson, P. D. J. Org. Chem. 2004, 69, 3782. (b) Kang, Y.; Mei, Y.; Du,
Y.; Jin, Z. Org. Lett. 2003, 5, 4481. (c) Kurdyumov, A. V.; Hsung, R. P.;
Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935.
J. Org. Chem, Vol. 71, No. 4, 2006 1623

Pettigrew and Wilson
SCHEME 3. Synthesis of Analogues of Xyloketal B (28 and
29)
methyl-4,5-dihydrofuran and a series of corresponding phenols
via electrophilic aromatic substitution reactions that were
promoted by boron trifluoride diethyl etherate. In the case of
the synthesis of analogues of xyloketal A, the process was found
to be highly efficient (up to 93% yield). This remarkable
transformation involves six individual reactions (i.e., three
electrophilic aromatic substitution reactions and three subsequent
acetal formation reactions). Analogues of xyloketal B and C
were prepared from methyl 2,4,6-trihydroxybenzoate and ana-
logues of xyloketal D and G were also prepared from 2,4-
dihydroxyacetophenone. The lower isolated yields of the desired
analogues, in these instances, reflected the decreased reactivity
of these phenolic substrates toward electrophilic aromatic
substitution reactions. Although all of these syntheses were
nondiastereoselective, it would be expected that the stereo-
chemistry of the acetal formation reactions would be controlled
by the C4-methyl substituent of the corresponding chiral
nonracemic alcohol that is required for the total synthesis of
the xyloketal natural products. The results of our studies toward
this ultimate objective will be reported in due course.
SCHEME 4. Synthesis of Analogues of Xyloketal D (8) and
Xyloketal G (31)
Experimental Section
(()-11-Trinorxyloketal A (9) and (()-2,6-epi-11,11′,11′′-
Trinorxyloketal A (10).7,10b To a suspension of phloroglucinol 15
(38 mg, 0.30 mmol, 1 equiv), a solution of alcohol 20 in ether
[(3.0 mL, 1.8 mmol, 6 equiv) prepared from the corresponding ester
19 (854 mg, 6.01 mmol) in ether (10 mL)], and anhydrous
magnesium sulfate (0.25 g) in ether (2 mL) at 0 °C was added
boron trifluoride diethyl etherate (38 µL, 0.30 mmol, 1 equiv). The
resultant mixture was stirred at 0 °C for 15 min. The reaction
mixture was then filtered and the filter-cake was washed with ether
(3 × 10 mL). The combined filtrates were washed with water (3
× 10 mL), dried over anhydrous magnesium sulfate, and concen-
trated in vacuo. Purification by flash chromatography with ether:
hexanes (3:1) as the eluant afforded a mixture (2:7) of the title
compounds 9 and 10 (115 mg, 93%) as a solid white foam.
Recrystallization of the title compounds 9 and 10 from petroleum
ether, on slow evaporation of the solvent afforded an analytically
pure mixture (2:7) of the title compounds 9 and 10 as a white solid.
Rf 0.32, ether:hexanes (3:1); mp 139-143 °C, petroleum ether [lit.7
mp 144-145 °C, petroleum ether for a mixture (1:4) of the title
compounds 9 and 10 and lit.10b mp 155-157 °C, for a mixture
(1:4) of the title compounds 9 and 10]; 1H NMR (400 MHz, C6D6)
δ 1.44 (s, 3H), 1.45 (s, 3H), 1.47 (s, 3H), 1.48 (s, 9H, corresponding
to the symmetrical minor isomer 9), 1.51 (m, 3H), 1.65 (m, 3H),
1.94 (m, 3H), 2.74 (m, 3H), 3.05 (m, 3H), 3.62 (m, 3H), 3.90 (m,
3H); 13C NMR (101 MHz, C6D6) δ 20.8, 20.9, 22.9, 23.0, 23.2,
23.3, 29.4, 29.5, 66.57, 66.59, 99.7, 99.8, 106.9, 107.0, 107.1, 107.2,
150.86, 150.93, 151.0, 151.1; IR (ef) 2981, 2936, 2885, 2852, 1617,
1455, 1371, 1179, 1105, 1003 cm-1; MS (CI) m/z (rel intensity)
415 (M + H, 31), 414 (M, 15), 373 (10), 331 (100), 97 (9), 43
(32). Anal. Calcd. for C24H30O6: C, 69.54; H, 7.30. Found: C,
69.34; H, 7.48.
(()-11,11′-Dinorxyloketal B 13-Methylcarboxylate (24), (()-
2,6-epi-11,11′-Dinorxyloketal B 13-Methylcarboxylate (25), and
the (()-11,11′-Dinorxyloketal C 13-Methylcarboxylates (26/27).
To a suspension of the methyl ester 22 (139 mg, 0.76 mmol, 1
equiv), a solution of alcohol 20 [(4 mL, 3.0 mmol, 4 equiv) prepared
from the corresponding ester 19 (1.07 g, 7.5 mmol) in ether (10
mL)], and anhydrous magnesium sulfate (0.75 g) in ether (10 mL)
at 0 °C was added boron trifluoride diethyl etherate (63 µL, 0.50
mmol, 0.7 equiv). The resultant mixture was allowed to warm to
room temperature and was stirred for 46 h. The reaction mixture
was then filtered and the filter-cake was washed with ether (3 ×
15 mL). The combined filtrates were washed with water (3 × 20
mL), dried over anhydrous magnesium sulfate, and concentrated
executing a facile and high yielding decarboxylative saponifica-
tion reaction (96%) of a mixture (1:1) of the substituted
xyloketal B analogues 24 and 25 (Scheme 3).10b,21
Synthesis of Xyloketal D and G Analogues. In a similar
way to that described above, the synthesis of the xyloketal D
and G analogues 8 and 31 was undertaken from the correspond-
ing commercially available phenol, 2,4-dihydroxyacetophenone
30 (Scheme 4). Accordingly, the acetophenone 30 (1 equiv)
was reacted with the alcohol 20 (2 equiv), boron trifluoride
diethyl etherate (0.3 equiv), and magnesium sulfate in ether.
On allowing the reaction mixture to warm from 0 °C to room
temperature over 46 h and following purification of the crude
reaction mixture by flash chromatography, the known xyloketal
D analogue 8 [13% (41% brsm)] and the xyloketal G analogue
31 [11% (34% brsm)] were isolated.7,10b A substantial quantity
of the unreacted acetophenone 30 (62%) was also recovered.
In view of the relatively poor reactivity of this particularly
less electron-rich phenol, the above reaction was repeated with
an increased amount of alcohol 20 (4 equiv). In this instance,
the xyloketal D analogue 8 [17% (54% brsm)] and the xyloketal
G analogue 31 [10% (32% brsm)] were isolated in slightly
improved combined yield. In addition, the unreacted acetophe-
none 30 (68%) was also recovered from the crude reaction
mixture. No further attempts were made to improve the yield
of this less facile and nonregioselective reaction in view of the
fact that xyloketal D (4) and G (7) are minor metabolites and
that no biological activity has been reported for these natural
products.
Conclusions
A potentially biomimetic synthesis of analogues of the
xyloketal natural products has been demonstrated. A series of
demethyl analogues of xyloketal A, B, C, D, and G were
prepared in a notably direct manner from 3-hydroxymethyl-2-
1624 J. Org. Chem., Vol. 71, No. 4, 2006

Synthesis of Xyloketal A, B, C, D, and G Analogues
in vacuo. Purification by flash chromatography with dichlo-
romethane:ether (12:1) as the eluant afforded a mixture (5:5:1) of
the title compounds 24, 25, and 26/27 (165 mg, 58%) as a solid
white foam. Further purification by flash chromatography with
dichloromethane:ether (19:1) as the eluant afforded a mixture (1:
1) of the analytically pure title compounds 24 and 25 as a solid
white foam. Title compounds 24 and 25 (1:1): Rf 0.21, dichlo-
romethane:ether (19:1); mp 137-138 °C, dichloromethane:ether;
1H NMR (500 MHz, CDCl3) δ 1.51 (s, 3H), 1.52 (s, 3H), 1.53 (s,
6H), 1.73 (m, 4H), 2.05 (m, 4H), 2.41 (m, 4H), 2.63 (apparent dt,
J ) 17.0, 7.0 Hz, 2H), 2.70 (apparent dt, J ) 17.3, 7.0 Hz, 2H),
2.83 (apparent ddd, J ) 17.0, 8.1, 2.2 Hz, 2H), 2.93 (apparent ddd,
J ) 17.3, 3.6, 1.5 Hz, 2H), 3.90 (s, 2 × 3H), 3.98 (m, 8H); 13C
NMR (126 MHz, CDCl3) δ 19.7, 19.8, 20.26, 20.30, 22.5, 22.6,
22.8, 22.9, 28.58, 28.62, 29.4, 29.5, 39.8, 40.07, 40.14, 52.1, 66.81,
66.84, 96.18, 96.22, 98.3, 98.4, 99.5, 107.5, 107.6, 107.76, 107.83,
153.7, 153.8, 156.3, 156.4, 160.79, 160.81, 172.1; IR (ef) 3425
(br), 2981, 2898, 2852, 1648, 1615, 1338, 1227, 1177, 1105, 1002
cm-1; MS (CI) m/z (rel intensity) 377 (M + H, 8), 376 (M, 4), 345
(15), 293 (100), 85 (11), 43 (17). Anal. Calcd. for C20H24O7: C,
63.82; H, 6.43. Found: C, 63.93; H, 6.54. Title compounds 24,
(1.0 g) in ether (10 mL) at 0 °C was added boron trifluoride diethyl
etherate (63 µL, 0.50 mmol, 0.3 equiv). The resultant mixture was
allowed to warm to room temperature and was stirred for 46 h.
The reaction mixture was then filtered and the filter-cake was
washed with ether (3 × 15 mL). The combined filtrates were
washed with water (3 × 20 mL), dried over anhydrous magnesium
sulfate, and concentrated in vacuo. Purification by flash chroma-
tography with a gradient of dichloromethane:ether (99:1 to 98:2)
as the eluant afforded the title compound 8 [63 mg, 17% (54%
brsm)] as a white solid (on evaporation from petroleum ether), the
title compound 31 [37 mg, 10% (32% brsm)] as a white solid (also
on evaporation from petroleum ether), and the unreacted acetophe-
none 30 (158 mg, 68%). Title compound 8: Rf 0.48, dichlo-
romethane:ether (99:1); mp 103-105 °C, petroleum ether [lit.7 mp
104-105 °C, hexanes:ether and lit.10b mp 114-116 °C]; 1H NMR
(400 MHz, CDCl3) δ 1.54 (s, 3H), 1.74 (m, 1H), 2.08 (m, 1H),
2.47 (m, 1H), 2.54 (s, 3H), 2.75 (dd, J ) 17.9, 6.4 Hz, 1H), 3.02
(dd, J ) 17.9, 1.1 Hz, 1H), 3.98 (apparent q, J ) 8.5 Hz, 1H),
4.06 (apparent td, J ) 9.5, 2.9 Hz, 1H), 6.37 (d, J ) 8.9 Hz, 1H),
7.52 (d, J ) 8.9 Hz, 1H), 13.10 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 19.4, 22.2, 26.1, 28.5, 39.6, 66.9, 106.1, 107.4, 108.7,
113.1, 130.0, 159.6, 162.9, 202.6; IR (ef) 3232 (br), 2987, 2930,
2897, 1622, 1491, 1420, 1370, 1330, 1271, 1177, 1107, 1085, 1004,
852 cm-1; MS (CI) m/z (rel intensity) 249 (M + H, 100), 231 (30).
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.38; H,
6.81. Title compound 31: Rf 0.35, dichloromethane:hexanes (99:
1); mp 131-133 °C, petroleum ether [lit.10b mp 134-135 °C]; 1H
NMR (500 MHz, CDCl3) δ 1.58 (s, 3H), 1.73 (m, 1H), 2.05 (m,
1H), 2.48 (m, 1H), 2.54 (s, 3H), 2.77 (dd, J ) 16.3, 1.2 Hz, 1H),
3.00 (dd, J ) 16.3, 5.4 Hz, 1H), 3.97 (m, 2H), 6.36 (s, 1H), 7.44
(s, 1H), 12.37 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 23.0, 25.3,
26.2, 28.0, 40.7, 66.9, 104.5, 108.1, 110.4, 114.4, 132.2, 160.4,
163.3, 202.3; IR (ef) 3399 (br), 2988, 2927, 2899, 1650, 1615, 1494,
1390, 1364, 1284, 1160, 1099, 1074, 1000 cm-1; MS (CI) m/z (rel
intensity) 249 (M + H, 100), 248 (M, 26), 231 (30), 165 (7), 43
(59). Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.60;
H, 6.65.
1
25, and 26/27 (5:5:1): mp 48-51 °C, dichloromethane:ether; H
NMR [500 MHz, CDCl3 (additional signals observed for the title
compounds 26/27)] δ 1.20 (s, 3H), 1.22 (s, 3H), 1.59 (m), 1.87
(m), 3.56 (m). Anal. Calcd for C20H24O7: C, 63.82; H, 6.43.
Found: C, 63.58; H, 6.60.
(()-11,11′-Dinorxyloketal B (28) and (()-2,6-epi-11,11′-Di-
norxyloketal B (29).10b To a suspension of the esters 24 and 25
(1:1, 57 mg, 0.15 mmol) in methanol (2 mL) and water (2 mL)
was added an aqueous solution of sodium hydroxide (2 M, 0.75
mL). The resultant mixture was heated at reflux for 6 h and then
allowed to cool to room temperature. The reaction mixture was
then diluted with ethyl acetate (30 mL). The resultant solution was
washed with a saturated aqueous solution of ammonium chloride
(2 × 8 mL) and brine (8 mL), dried over anhydrous sodium sulfate,
and concentrated in vacuo. Purification by flash chromatography
with dichloromethane:ether (17:3) as the eluant afforded a mixture
(1:1) of the title compounds 28 and 29 (46 mg, 96%) as a white
solid. Rf 0.29, ether:hexanes (17:3); mp 236 °C dec, dichlo-
romethane:ether [lit.10b mp 244-245 °C dec, for a mixture (1:1) of
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) and
Simon Fraser University for financial support. We also wish to
acknowledge the Canadian Foundation for Innovation (CFI),
the British Columbia Knowledge Development Fund (BCKDF),
and AstraZeneca Canada, Inc. for support of our research
program. J.D.P. thanks Simon Fraser University for a special
graduate entrance scholarship as well as NSERC for postgradu-
ate scholarships (PGS-A and PGS-D).
1
the title compounds 28 and 29]; H NMR (500 MHz, CDCl3) δ
1.52 (s, 3H), 1.53 [2 × (s, 3H)], 1.54 (s, 3H), 1.79 (m, 4H), 2.04
(m, 4H), 2.42 (m, 4H), 2.64 (dd, J ) 17.1, 6.3 Hz, 2H), 2.73 (m,
2H), 2.88 (m, 4H), 3.94 (m, 4H), 4.03 (m, 4H), 5.88 (s, 1H), 5.92
(s, 1H), 6.16 (s, 1H), 6.17 (s, 1H); 13C NMR (126 MHz, CDCl3) δ
20.0, 20.08, 20.12, 22.5, 22.6, 22.8, 28.9, 29.00, 29.04, 40.0, 40.1,
40.3, 66.69, 66.71, 66.8, 95.91, 95.94, 98.5, 98.7, 99.4, 99.5, 106.67
106.72, 106.8, 106.9, 151.9, 152.13, 152.16, 152.2, 153.2, 153.3;
IR (ef) 3364 (br), 2981, 2933, 2896, 2848, 1618, 1509, 1453, 1381,
1175, 1131, 1106, 1082, 1002 cm-1; MS (CI) m/z (rel intensity)
319 (M + H, 15), 318 (M, 30), 277 (32), 235 (5), 180 (8), 85 (18),
43 (100). Anal. Calcd. for C18H22O5: C, 67.91; H, 6.97. Found:
C, 67.55; H, 7.09.
Supporting Information Available: General experimental
details, experimental procedures, and full product characterization
data for all of the compounds synthesized, 1H and 13C NMR spectra
for compounds 19, 20, 9, 10, 22-25, 28, 29, 8, and 31, as well as
selected COSY and HMQC spectra for compounds 24, 25, 28, 29,
and 31. This material is available free of charge via the Internet at
http://pubs.acs.org.
(()-11-Norxyloketal D (8) and (()-10-Norxyloketal G (31).7,10
To a suspension of the 2,4-dihydroxyacetophenone 30 (230 mg,
1.51 mmol, 1 equiv), a solution of the alcohol 20 [(7.5 mL, 6.0
mmol, 4 equiv) prepared from the corresponding ester 19 (1.14 g,
8.03 mmol) in ether (10 mL)], and anhydrous magnesium sulfate
JO052371+
J. Org. Chem, Vol. 71, No. 4, 2006 1625