Total synthesis of (±)-xyloketal D and model studies towards the total synthesis of (-)-xyloketal A

Article abstract of DOI:10.3987/com-03-s(p)37

A stereoselective total synthesis of (±)-xyloketal D (±-2) has been achieved using a cycloaddition reaction of an ortho-quinone methide and a dihydrofuran as a key step. Preliminary model studies towards the total synthesis of xyloketal A (1) are also reported.

Full text of DOI:10.3987/com-03-s(p)37

HETEROCYCLES, Vol. 62, 2004, pp. 445 - 452
Received, 30th July, 2003, Accepted, 8th September, 2003, Published online, 27th October, 2003
TOTAL SYNTHESIS OF (±)-XYLOKETAL D AND MODEL STUDIES
TOWARDS THE TOTAL SYNTHESIS OF (-)-XYLOKETAL A
Jeremy D. Pettigrew, Jason A. Bexrud, Rebecca P. Freeman, and Peter D.
Wilson*
Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, British Columbia, Canada V5A 1S6
E-mail: pwilson@sfu.ca
Abstract – A stereoselective total synthesis of (±)-xyloketal D (±-2) has been
achieved using a cycloaddition reaction of an ortho-quinone methide and a
dihydrofuran as a key step. Preliminary model studies towards the total
synthesis of xyloketal A (1) are also reported.
INTRODUCTION
Xyloketals A (1) and D (2) are two of the metabolites that were isolated from a mangrove fungus of the
Xylaria species (Ascomycota). The molecular structures of these natural products were determined by
extensive spectroscopic studies and by X-Ray crystallography. Xyloketal A (1) has a unique chiral,
C3-symmetric molecular structure and was shown to be an inhibitor of acetylcholine esterase (Figure 1).1
O
Me
Me
O
O
OH
Me
Me
H
H
H
Me
O
O
O
O
O
Me
Me
O
Me
1
2
H
Me
Figure 1. Molecular structures of xyloketals A (1) and D (2).
Retrosynthetic analysis of xyloketal D (2) suggested that it could be prepared by a [4+2] cycloaddition
reaction of the ortho-quinone methide (3) and the dihydrofuran (4) (Scheme 1).2 It was anticipated that
this inverse electron demand Diels-Alder reaction would afford the target compound in a regio- and
stereoselective manner.3 The Mannich base (5) could serve as a precursor for the generation of the

ortho-quinone methide (3).4 Alkylation, oxidation, and photochemical reactions have been used to
generate ortho-quinone methides from the Mannich bases of phenols.2, 5
O
OH
O
OH
O
OH
Me
Me
H
- R2NH
Me
NR2
OH
Me
Me
+
Me
O
O
O
O
Me
2
3
4
5
Scheme 1. Proposed synthesis of xyloketal D (2).
In a similar fashion, it can be envisioned that xyloketal A (1) could be prepared from the Mannich base
(7) and three equivalents of the dihydrofuran (4) (Scheme 2).6 This unprecedented and direct synthetic
process would involve the stepwise generation and subsequent cycloaddition reaction of a series of
ortho-quinone methide reaction intermediates [c.f. structure (6)].
O
Me
Me
R N
2
R N
2
OH
O
OH
Me
Me
H
H
- R NH
- 2 x R NH
2
2
NR
2
+
3 x
Me
O
O
HO
O
O
O
HO
OH
Me
O
Me
4
1
6
7
R N
R N
2
2
H
Me
Scheme 2. Proposed synthesis of xyloketal A (1).
RESULTS AND DISCUSSION
The Mannich base (9) was prepared in good yield and as a single regioisomeric product from
2,4-dihydroxyacetophenone (8), formaldehyde, and morpholine. (Scheme 3).4 The structure of the
compound (9) and the regioselectivity of the aromatic substitution reaction were determined by analysis
1
of the H NMR spectrum. The aromatic protons of the product (9) were strongly coupled (J=8.9 Hz)
which indicated that they were located on adjacent carbon atoms.4 In order to determine the feasibility
of the proposed cycloaddition reaction, commercially available 4,5-dihydro-2-methylfuran (10) was
employed as a model substrate. On heating the Mannich base (9) and the dihydrofuran (10) (3
equivalents) with methyl iodide (1.05 equivalents) in benzene at reflux for 5 days, the xyloketal D
analogue (±-11) was isolated in 43% yield.2, 5a Increasing the number of equivalents of methyl iodide
lowered the yield of this reaction. This was caused by competing methylation reactions of one or more
of the phenol groups of the Mannich base (9). The structure of the product and the regioselectivity of
this cycloaddition reaction were determined on the basis of a sharp, downfield chemical shift (~13 ppm)
of the unreacted phenolic proton. This indicated that the phenol group was adjacent to the carbonyl
substituent.1 In addition, the 13C NMR spectrum showed a resonance that could be assigned to the

acetal carbon (C-2). The stereochemistry of the ring junction was assigned as cis based on the
observation of a NOE contact between the bridgehead methyl group and H-6. In addition, a NOE
contact was observed between H-7β and the bridgehead methyl group.
O
OH
O
OH
O
OH
HN
H
7
5
10
O
Me
O
Me
Me
Me
N
6
4
16
1
O
13
O
O
MeI, PhH
, 5 d (43%)
CH O, H O, MeOH
2
2
OH
OH
14
Me
∆
∆, 3 h (82%)
10
(±-11)
8
9
Scheme 3. Synthesis of (±)-11-norxyloketal D (±-11).
The racemic dihydrofuran (±-4) was prepared by modification of known synthetic procedures from the
alcohol (±-12) in order to attempt the synthesis of (±)-xyloketal D (±-2) (Scheme 4).7 The alcohol
(±-12) was prepared in two steps, by standard synthetic methods, from propionic acid.8
o
1) LDA, HMPA, THF, 0 C to rt, 1 h;
Me
Me
Me
o
1) NaNH , ∆, 2 h (66%)
HCCCH Br, 0 C to rt, 3 h (63%)
2
2
OH
OH
o
Me
O
(±-4)
2) LiAlH , THF, 0 C to rt, 16 h (74%)
2) ∆, 16 h (87%)
4
O
(±-12)
Scheme 4. Synthesis of racemic dihydrofuran (±-4).
The cycloaddition reaction of the Mannich base (9) with the dihydrofuran (±-4) (3 equivalents) afforded
(±)-xyloketal D (±-2), (±)-5-epi-xyloketal D (±-5-epi-2), and the diastereomeric (±)-spiroacetals (±-13) as
a mixture of products (11:1:3:3) in a combined yield of 54% (Scheme 5). It was possible to separate
these compounds by repeated chromatography and the spectral data for synthetic (±)-xyloketal D (±-2)
were in agreement with those reported for the natural product.1 Thus, the relative stereochemistry of the
major reaction product was firmly established. The formation of the (±)-spiroacetal products (±-13) in
this reaction can be attributed to the isomerization and subsequent reaction of the corresponding
exocyclic double bond isomer of dihydrofuran (±-4). It is of interest that a spiroacetal product was not
identified in the cycloaddition reaction of 4,5-dihydro-2-methylfuran (10). Thus, it appears that the
additional methyl substituent decreases the reactivity of the endocyclic double bond of the dihydrofuran
(±-4) in this cycloaddition reaction.
Me
O
OH
O
OH
O
OH
11
Me
5
8
H
7
Me
7
O
(±-4)
Me
N
Me
6
Me
17
6
4
17
1
O
1
O
O
14
14
Me
11
(±-5-epi-2)
5
O
+
+
OH
15
15
O
Me
MeI, PhH
4
10
9
(±-13)
(±-2)
∆, 5 d (54%)
Scheme 5. Synthesis of (±)-xyloketal D (±-2), diastereomer (±-5-epi-2), and (±)-spiroacetals (±-13).
The feasibility of using this cycloaddition strategy to prepare (-)-xyloketal A (1) was then demonstrated
successfully in a model study (Scheme 6). The Mannich base (15) was prepared by adaptation of a

literature procedure from phloroglucinol (14), dibenzyl amine, and formaldehyde.6a A mixture of the
Mannich base (15), 4,5-dihydro-2-methylfuran (10) (9 equivalents), and methyl iodide (3 equivalents)
was heated at reflux to afford an inseparable mixture (1:4) of the desired symmetric xyloketal A analogue
(±-16) and the diastereomer (±-17). This mixture of compounds was fully characterized by
spectroscopic methods. Of note, the MS (CI) contained the parent molecular ion (M+H) as well as
daughter ions that can be attributed to fragmentation by retro Diels-Alder reactions. In addition, a large
signal for an ion that corresponded to the dihydrofuran (10) was observed. The 13C NMR spectrum also
clearly showed four signals that corresponded to the acetal carbons that would be expected for an
inseparable mixture of compounds (±-16) and (±-17). The yield of this reaction (19%) is indeed
respectable when one considers that this direct process involves nine individual reactions (three
alkylation reactions, three elimination reactions, and three subsequent cycloaddition reactions).
O
Me
O
H
H
O
O
O
Me
O
Me
Bn2N
HO
OH
OH
(±-16)
H
10
Bn2NH
Me
O
NBn2
O
CH2O, H2O, EtOH
rt, 24 h (93%)
MeI, PhH
, 24 h (19%)
Me
O
HO
OH
OH
15
∆
14
H
H
Bn2N
7
5
6
4
1
O
O
O
Me
O
Me
10
(±-17)
H
Scheme 6. Synthesis of xyloketal A analogues (±-16) and (±-17).
We anticipate that the synthesis and use of the chiral, non-racemic (4R)-dihydrofuran (4) in this
cycloaddition reaction will afford (-)-xyloketal A (1) in a diastereoselective manner. It is expected that
this process will be controlled by the stereogenic centre of dihydrofuran (4). It remains to be
determined if this process will be complicated by the formation of spiroacetal reaction byproducts. In
view of this possibility, other synthetic routes to prepare this novel natural product are also being
investigated.
EXPERIMENTAL
Mps were measured on a Gallenkamp capillary melting point apparatus and are uncorrected. IR spectra
were recorded as evaporated films (EF) or as KBr discs (KBr) using a Perkin Elmer 599B IR
1
spectrophotometer. NMR experiments were carried out on Bruker AMX 400 (400.1 MHz for H and

1
100.6 MHz for 13C), Varian AS500 (125.7 MHz for 13C) and Bruker AMX 600 (600.1 MHz for H)
spectrometers. Chemical shifts (δ) are listed in parts per million downfield from tetramethylsilane using
the NMR solvent peak as an internal reference. MS were recorded on a Hewlett Packard 5985 GC-mass
spectrometer using chemical ionization (CI) with isobutene. Microanalyses (Anal.) were performed on
a Carlo Erba Model 1106 CHN analyzer.
3-Morpholin-4-yl-methyl-2,4-dihydroxyacetophenone (9)
To a solution of 2,4-dihydroxyacetophenone (8) (504 mg, 3.31 mmol) in methanol (9 mL) at rt were
added morpholine (315 µL, 3.61 mmol) and an aqueous formaldehyde solution (37% w/v, 290 µL, 3.58
mmol). The reaction mixture was heated at reflux for 3 h and then concentrated in vacuo to afford a
cream colored solid. Purification by column chromatography (ether:hexanes, 1:1) afforded the title
compound (9) as a white solid (687 mg, 83%). mp 100-102 °C (ether:hexanes). Rf=0.22
(ether:hexanes, 4:1). IR (EF) 3432, 2948, 2854, 1615, 1493, 1274, 1260, 1116, 1060, 817 cm-1. MS
(CI) 252 (M+H, 100%), 88 (24%). 1H NMR (400 MHz, CDCl3) δ: 2.53 (3H, s, Me), 2.65 (4H, m,
NCH2), 3.78 (4H, m, OCH2), 3.87 (2H, s, ArCH2), 6.36 (1H, d, J=8.9 Hz, H-5), 7.57 (1H, d, J=8.9 Hz,
H-6), 8.64 (1H, br s, 4-OH), 13.15 (1H, s, 2-OH). 13C NMR (100 MHz, CDCl3) δ: 26.14, 52.98, 53.93,
66.76, 106.85, 108.54, 112.81, 131.89, 162.70, 165.98, 202.67. Anal. Calcd for C13H17NO4: C, 62.14;
H, 6.82; N, 5.57. Found: C, 61.84; H, 6.95; N, 5.25.
(±)-11-Norxyloketal D (±-11)
To a solution of the Mannich base (9) (199 mg, 0.792 mmol) in benzene (8 mL) at rt were added
4,5-dihydro-2-methylfuran (10) (220 µL, 2.41 mmol) and methyl iodide (52 µL, 0.84 mmol). The
resultant solution was heated at reflux until TLC analysis indicated that the Mannich base had completely
reacted (5 d). The reaction mixture was then cooled to rt, filtered, and concentrated in vacuo.
Purification by column chromatography (hexanes:ether, 16:1) afforded the title compound (±-11) as a
white solid (86 mg, 43%). mp 104-105 °C (hexanes:ether). Rf=0.25 (hexanes:ether, 4:1). IR (EF)
3487, 2973, 2938, 2904, 1621, 1491, 1421, 1370, 1330, 1271, 1177, 1107, 1086, 1004, 852 cm-1. MS
(CI) 249 (M+H, 100%). 1H NMR (400 MHz, CDCl3) δ: 1.54 (3H, s, Me-10), 1.74 (1H, m, H-5), 2.08
(1H, m, H-5′), 2.47 (1H, m, H-6), 2.54 (3H, s, Me-16), 2.75 (1H, dd, J=17.9, 6.4 Hz, H-7β), 3.02 (1H, dd,
J=17.9, 1.1 Hz, H-7α), 3.98 (1H, apparent q, J=8.6 Hz, H-4), 4.06 (1H, apparent dt, J=9.5, 2.9 Hz, H-4′),
6.37 (1H, d, J=8.8 Hz, H-15), 7.52 (1H, d, J=8.8 Hz, H-14), 13.09 (1H, s, OH). 13C NMR (100 MHz,
CDCl3) δ: 19.55, 22.39, 22.25, 28.62, 39.73, 67.09, 106.23, 107.51, 108.85, 113.30, 130.18, 159.73,
163.11, 202.82. Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.85; H, 6.61.

(±)-4,5-Dihydro-2,4-dimethylfuran (±-4)7
The alcohol (±-12) (3.95 g, 40.3 mmol) and sodium amide (150 mg, 3.84 mmol) were heated at reflux for
2 h. Direct distillation of the reaction mixture afforded the exocyclic double bond isomer of the title
compound as a colorless liquid (2.60 g, 66%). A sample of this material (1.20 g, 12.2 mmol) was
heated at reflux for 16 h and then distilled to afford the title compound (±-4) as a colorless liquid (1.04 g,
87%). bp ~100 ºC. IR (EF) 2961, 2875, 1674, 1453, 1383, 1243, 1043, 1008, 886 cm-1. MS (CI) 99
(M+H, 100%). 1H NMR (400 MHz, C6D6) δ: 0.84 (3H, d, J=6.6 Hz, Me-4), 1.68 (3H, apparent t, J=1.5
Hz, Me-2), 2.76 (1H, m, H-4), 3.71 (1H, dd, J=8.7, 6.5 Hz, H-5), 4.21 (1H, dd, J=9.5, 8.6 Hz, H-5′), 4.43
(1H, m, H-3). 13C NMR (100 MHz, C6D6) δ: 13.59, 20.88, 37.88, 77.19, 101.39, 154.99.
(±)-Xyloketal D (±-2), (±)-5-epi-xyloketal D (±-5-epi-2) and (±)-spiroacetals (±-13)
To a solution of the Mannich base (9) (177 mg, 0.704 mmol) in benzene (7 mL) at rt were added the
dihydrofuran (±-4) (207 mg, 2.11 mmol) and methyl iodide (46 µL, 0.74 mmol). The resultant solution
was heated at reflux until TLC analysis indicated that the Mannich base had completely reacted (5 d).
The reaction mixture was then cooled to rt, filtered, and concentrated in vacuo. Purification by column
chromatography (dichloromethane:ether, 40:1) afforded a mixture (11:1:3:3) of (±)-xyloketal D (±-2),
(±)-5-epi-xyloketal D (±-5-epi-2), and (±)-spiroacetals (±-13) as a yellow oil (99 mg, 54%). Further
column chromatography (hexanes:ether, 4:1 on TLC grade silica gel) afforded an inseparable mixture
(11:1) of (±)-xyloketal D (±-2) and (±)-5-epi-xyloketal D (±-5-epi-2) as a pale cream solid and an
inseparable mixture (1:1) of the two (±)-spiroacetals (±-13) as a pale cream solid. (±)-Xyloketal D (±-2)
and (±)-5-epi-xyloketal D (±-5-epi-2): mp 66-67 °C (hexanes:ether). Rf=0.24 (hexanes:ether, 4:1).
IR (EF) 3399, 2968, 2898, 1621, 1491, 1421, 1382, 1370, 1332, 1272, 1117, 1070, 1006 cm-1. MS (CI)
263 (M+H, 100%). 1H NMR (400 MHz, CDCl3) for (±)-xyloketal D (±-2) δ: 1.08 (3H, d, J=6.5 Hz,
Me-11), 1.52 (3H, s, Me-10), 1.98 (1H, ddd, J=11.3, 6.3, 1.2 Hz, H-6), 2.06 (1H, m, H-5), 2.53 (3H, s,
Me-17), 2.71 (1H, dd, J=17.9, 6.2 Hz, H-7), 2.96 (1H, d, J=18.0, H-7′), 3.56 (1H, apparent t, J=8.4 Hz,
H-4), 4.20 (1H, apparent t, J=8.3 Hz, H-4′), 6.36 (1H, d, J=8.9 Hz, H-15), 7.52 (1H, d, J=8.9 Hz, H-14),
13.10 (1H, s, OH). 13C NMR (100 MHz, CDCl3) for (±)-xyloketal D (±-2) δ: 15.76, 17.98, 22.68, 26.09,
35.10, 46.96, 74.28, 106.11, 108.25, 108.77, 113.12, 130.00, 159.49, 162.90, 202.65. Anal. Calcd for
C15H18O4: C, 68.68; H, 6.92. Found: C, 68.88; H, 6.85. (±)-Spiroacetals (±-13): mp 57-59 °C
(hexanes:ether). Rf=0.32 (hexanes:ether, 4:1). IR (EF) 3464, 2958, 2863, 1625, 1491, 1421, 1370,
1332, 1270, 1246, 1136, 1060, 1017, 853 cm-1. 1H NMR (400 MHz, CDCl3) δ: 1.10 (3H, d, J=6.6 Hz,
Me-11), 1.18 (3H, d, J=6.6 Hz, Me-11), 1.55 (2H, dd, J=12.8, 9.5 Hz, 2 × H-6), 2.00 (5H, m, 3 × H-7, 2 ×
H-5), 2.28 (1H, dd, J=13.4, 9.5 Hz, H-6), 2.36 (1H, dd, J=12.9, 7.3 Hz, H-6), 2.46 (1H, m, H-7), 2.54

(3H, s, Me-17), 2.55 (3H, s, Me-17), 2.78 (4H, m, 4 × H-8), 3.54 (1H, t, J=7.7 Hz, H-4), 3.64 (1H, t,
J=8.4 Hz, H-4), 4.09 (1H, t, J=7.9 Hz, H-4), 4.21 (1H, t, J=7.9 Hz, H-4), 6.34 (1H, d, J=8.9 Hz, H-15),
6.37 (1H, d, J=9.0 Hz, H-15), 7.50 (1H, d, J=8.9 Hz, H-14), 7.51 (1H, d, J=8.9 Hz, H-14), 13.01 (1H, s,
OH), 13.02 (1H, s, OH). 13C NMR (100 MHz, CDCl3) δ: 16.29, 16.54, 17.67, 18.04, 26.13, 29.37,
29.65, 31.93, 33.04, 45.17, 45.34, 75.01, 75.36, 108.12, 108.86, 108.95, 109.98, 110.17, 113.18, 113.26,
129.56, 129.59, 159.60, 162.25, 202.70, 202.73. Anal. Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C,
68.47; H, 7.16.
2,4,6-Tris[dibenzylaminomethyl]phloroglucinol (15)
To a solution of phloroglucinol (14) (3.00 g, 23.8 mmol) in ethanol (100 mL) at rt were added
dibenzylamine (14.2 mL, 78.5 mmol) and an aqueous formaldehyde solution (37% w/v, 6.0 mL, 74
mmol). The reaction mixture was stirred overnight and the resultant precipitate was then collected by
filtration, washed with ethanol (3 × 15 mL), and dried in vacuo to afford the title compound (15) as a
white powder (16.68 g, 93%). mp 156-160 °C (ethanol). Rf=0.70 (hexanes:ether, 4:1) IR (KBr)
3454, 3093, 3067, 3031, 2897, 2830, 2794, 1743, 1630, 1491, 1450, 1383, 1352, 1254, 1115 cm-1. MS
(CI) 212 (96%), 198 (100%), 89 (18%). 1H NMR (400 MHz, CDCl3) δ: 3.60 (12H, s, 6 × PhCH2), 3.78
(6H, s, 3 × ArCH2), 7.22-7.33 (30H, m, ArH). 13C NMR (100 MHz, CDCl3) δ: 49.24, 57.83, 99.50,
110.27, 127.39, 128.47, 129.57, 137.19, 155.90. Anal. Calcd for C51H51N3O3: C, 81.24; H, 6.82; N,
5.57. Found: C, 81.21; H, 7.04; N, 5.62.
(±)-11-Trinorxyloketal A (±-16) and (±)-2,6-epi -11,11′,11′′-trinorxyloketal A (±-17)
To a solution of the Mannich base (15) (754 mg, 1.00 mmol) in benzene (10 mL) at rt were added
4,5-dihydro-2-methylfuran (10) (820 µL, 8.99 mmol) and methyl iodide (190 µL, 3.05 mmol). The
resultant solution was heated at reflux until TLC analysis indicated that the Mannich base had completely
reacted (24 h). The reaction mixture was then cooled to rt, filtered, and concentrated in vacuo.
Purification by repetitive column chromatography (hexanes:ether, 1:1 then dichloromethane:ether, 18:1)
afforded the title compounds (±-16) and (±-17) as a mixture of diastereomers (1:4) as a solid white foam
(78 mg, 19%). mp 145-147 ºC [from petroleum ether (35-60 ºC)]. Rf=0.43 (ether:hexanes, 4:1), 0.27
(dichloromethane:ether, 9:1). IR (EF) 2983, 2933, 2894, 1617, 1460, 1380, 1106, 1004 cm-1. MS (CI)
415 (M+H, 8%), 331 (9%), 253 (13%), 169 (28%), 85 (100%). 1H NMR (600 MHz, C6D6) δ: 1.44, 1.45,
1.47 (3 × 3H of compound (±-17), s, Me-10, 10′, 10′′), 1.48 (9H of compound (±-16), s, Me-10), 1.51 (6H,
m, H-5), 1.65 (6H, m, H-5), 1.95 (6H, m, H-6), 2.73 (6H, m, H-7), 3.05 (6H, m, H-7), 3.62 (6H, m, H-4),
3.89 (6H, m, H-4). 13C NMR (125 MHz, C6D6) δ: 20.81, 20.84, 20.88, 22.80, 22.93, 23.07, 23.22,
29.34, 29.36, 40.64, 40.66, 40.69, 66.56, 66.57, 66.59, 99.43, 99.57, 99.63, 99.65, 106.78, 106.91, 106.95,

107.12, 150.81, 150.88, 150.89, 151.07. Anal. Calcd for C24H30O6: C, 69.54; H, 7.30. Found: C, 69.34;
H, 7.30.
ACKNOWLEDGEMENTS
We wish to thank the Natural Sciences and Engineering Research Council of Canada (NSERC) and
Simon Fraser University for financial support. JDP would like to thank NSERC for a PGSA
1
postgraduate scholarship. We are grateful to Professor Yongcheng Lin for providing a copy of the H
NMR spectrum of xyloketal D for comparison purposes.
This paper is dedicated to Professor Leo A. Paquette on the occasion of his 70th birthday.
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