A biomimetic type expedient approach to the tricyclic core of xyloketals. Application to a short, stereocontrolled synthesis of alboatrin and a remarkable epi to natural isomerisation

Article abstract of DOI:10.1016/j.tetlet.2009.01.086

An expedient synthesis of the linear tetrahydrofurano benzopyran ring system of xyloketals is described involving an ortho ester Claisen rearrangement and an intramolecular cationic cyclisation. This strategy was applied for a short, stereocontrolled and

Full text of DOI:10.1016/j.tetlet.2009.01.086

Tetrahedron Letters 50 (2009) 1431–1434
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A biomimetic type expedient approach to the tricyclic core of xyloketals.
Application to a short, stereocontrolled synthesis of alboatrin and a remarkable
epi to natural isomerisation
*
Debayan Sarkar, Subrata Ghosh, Ramanathapuram V. Venkateswaran
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient synthesis of the linear tetrahydrofurano benzopyran ring system of xyloketals is described
involving an ortho ester Claisen rearrangement and an intramolecular cationic cyclisation. This strategy
was applied for a short, stereocontrolled and high yield synthesis of the phytotoxic metabolite alboatrin.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 September 2008
Revised 23 December 2008
Accepted 10 January 2009
Available online 20 January 2009
Keywords:
Xyloketals
Tetrahydrofurano benzopyran
Ortho ester Claisen rearrangement
Intramolecular cationic cyclisation
Alboatrin
Xyloketals are a group of novel, structurally unique, closely re-
lated natural products originating from a mangrove fungus of the
xylaria species which enclose a highly labile internal ketal in the
form of a tetrahydrofurano benzopyran in their structural inlay.1
Xyloketal A 1, a representative compound belonging to this group
possesses a distinctive C3-symmmetric molecular structure. This is
also a potent inhibitor of acetyl choline esterase and considered a
lead compound in the treatment of Alzheimer’s disease.2 Xyloketal
D 2 is a simpler structural sibling of 1 incorporating a single linear
tricyclic network. In view of their unusual structural features and
associated biological properties, xyloketals have emerged as
attractive targets for synthesis.3 We have initiated a comprehen-
sive programme towards their synthesis and have looked at devel-
oping a convenient method for the linear tricyclic ring system
embedded in these compounds. The core structural motif as in 2
along with an identical stereochemical disposition of the three
contiguous stereogenic centres is also present in alboatrin 3, a phy-
totoxic metabolite isolated from the culture filtrate of Verticillium
alboatrum4 This inhibits the root growth of the host plant (Maris
Kabul) and causes vascular-wilt disease in alfalfa. The originally as-
signed structure was later corrected to 3 involving inversion of the
configuration of the secondary methyl group at C-3.5a Representa-
tive syntheses of 3 have also been reported.4,5 We had previously
disclosed a synthesis of 3 in which an intra-molecular ketene–al-
kene cycloaddition followed by an oxidative ring expansion served
as the key steps for the development of the tricyclic ring system.6
Low yields in crucial steps and the need to separate the mixture of
products in the initial aromatic Claisen rearrangement step af-
fected the overall yield profile in the synthesis. Prompted by our
interest to develop an expeditious synthetic route to the xyloke-
tals, we now present a convenient synthesis of the central tricyclic
ring system, and demonstrate the efficacy of the strategy by appli-
cation to a short, stereocontrolled and high yield synthesis of
alboatrin. In the course of the synthesis, we have also observed a
remarkable case of isomerisation of the epi- to the natural isomer,
which enabled a further improvement in the total overall yield.
Retrosynthetically, we envisaged the generation of the tricyclic
ring system of xyloketals through a cationic intramolecular cyclisa-
tion of a properly hydroxyethyl substituted benzopyran 4, the
annulation providing the thermodynamically more stable cis ring
junction in a hydrindane-like system. This alcohol 4 was to be
available from a Johnson orthoester Claisen rearrangement of the
chromenol 5, which was to be accessed from the chromone carbox-
ylate 6, obtainable from the o-hydroxyacetophenone 7 by a stan-
dard procedure (Scheme 1). Initially we decided to test the
efficacy of this hypothesis by applying it to the synthesis of a linear
unsubstituted tricyclic model compound. Reduction of the known
ethyl chromone-2-carboxylate 87 employing a combination of so-
dium cyanoborohydride and boron trifluoride etherate8 furnished
the chromene carboxylate 9 through a chemoselective deoxygen-
* Corresponding author. Tel.: +91 33 24734971; fax: +91 33 24732805.
E-mail addresses: ocrvv@iacs.res.in, drvenkatesh46@yahoo.com (R.V. Venkates-
waran).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.086

1432
D. Sarkar et al. / Tetrahedron Letters 50 (2009) 1431–1434
O
H
11
OH
O
10
H
O
H
O
O
4
5
8
3
6
4a
8a
3a
2
7
1
9
O
O
O
H
H
HO
O
O
12
3
O
1
2
H
H
H+
R
R
:OH
H+
O
O
4
O
O
O
C2H5C(OEt) 3
R
R
R
OH
O
OH
O
COOEt
7
5
6
Scheme 1.
ation in about 74% yield. The absence of the benzylic ketone in the
IR and the appearance of a doublet at d 3.53 in the 1H NMR for the
benzylic methylene group alongwith the expected splitting of the
olefinic proton into a triplet attested to the formation of the de-
sired chromene carboxylate.
furnish the tricyclic ketal 13 incorporating the basic structural net-
work of the xyloketals (Scheme 2). The structure was amply sup-
ported by the appropriate features in the 1H NMR spectrum
showing a strong singlet at d 1.58 for the angular methyl group
and appropriate features for the methylene protons.10 The cis ring
juncture to this product has been assigned based on previous
precedents in the synthesis3 of xyloketals and was further sup-
ported from nuclear Overhauser enhancement (NOE) studies
which showed a strong connection between the angular methyl
group and the angular hydrogen at C-3a.
With the demonstrated success of our projected approach to the
xyloketal core through a synthesis of the model compound, we
decided to first apply the methodology to a synthesis of alboatrin.
The point of departure was the known resacetophenone 14.11 The
interaction of this with methyl iodide in refluxing acetone with
added potassium carbonate achieved the selective methylation of
the less encumbered phenolic group to provide the methyl ether
15. An intra-molecular hydrogen bonding between the carbonyl
oxygen and the adjacently placed phenolic group in 14 renders
the distal phenolic function more reactive resulting in this selectiv-
ity. Condensation of the methyl ether 15 with diethyl oxalate fol-
lowed by dehydration of the resultant 2-hydroxy chromanone
furnished the desired chromone carboxylate 16 in an overall 90%
yield.10 Exposure of this keto-ester to the previously tried combi-
nation of sodium cyanoborohydride and boron trifluoride etherate
accomplished the chemoselective removal of the carbonyl oxygen
and afforded the chromene carboxylate 17, but in a low yield
(25%).10 In an effort to improve the yield of this product, 16 was
subjected to total hydrogenation to the chromane carboxylate 18
in 95% yield. The double bond was then reinstated taking advan-
tage of the ester functionality through phenyl selenylation fol-
lowed by oxidative elimination, which ensured the smooth re-
introduction of the double bond to furnish the unsaturated ester
17 in very good overall yield (83%) (Scheme 3).
The interaction of this ester with LAH in ether delivered the
allylic alcohol 10 in excellent yield. Refluxing a homogenous mix-
ture of this alcohol and triethyl orthoacetate in xylene in the pres-
ence of a catalytic amount of propionic acid resulted in the
expected ortho ester Claisen rearrangement9 to furnish the rear-
ranged ester 11 in 96% yield. The structure of this product was duly
attested by the appropriate features in the 1H NMR spectrum, par-
ticularly the two broad singlets at d 4.27 and 4.60 for the exo-
methylene protons.10 The reaction of ester 11 with LAH achieved
the reduction of the ester function to the corresponding alcohol
12 in excellent yields properly set up for the proposed intramolec-
ular cyclisation. In the event, the mild acid treatment of a THF solu-
tion of this alcohol ensured the expected cationic cyclisation to
O
a
R
O
R= CO2C2H5
O
CO2C2H5
8
9
b
10
R= CH2OH
c
H
e
4
5
8
3
6
7
3a
9a
4a
8a
R
2
1
9
O
O
O
10
13
R= CO2C2H5
11
Proceeding with the synthesis, the chromene carboxylate 17
was reduced with LAH and furnished the allylic alcohol 19 in
93% yield, which was subjected to the Johnson orthoester Claisen
rearrangement employing triethyl orthopropionate to obtain a
rearranged product incorporating the desired secondary methyl
d
12 R= CH2OH
Scheme 2. Reagents and conditions: (a) BF3ÁEt2O, NaCNBH3, THF, reflux, 3 h,74%;
(b) LAH, THF, À40 °C to 0 °C, 1 h, 92%; (c) CH3C(OEt)3, C2H5COOH(Cat.), xylene,
140 °C, 6 h, 96%; (d) LAH, THF, 0 °C, 1 h, 97%; (e) H2SO4(Cat.), THF, 0 °C–rt, 2 h, 96%.

D. Sarkar et al. / Tetrahedron Letters 50 (2009) 1431–1434
1433
O
O
b
c
f
OEt
OEt
OH
O
RO
OH
MeO
MeO
O
MeO
O
O
d
16
O
17
19
14 R = H
15
a
e
R = Me
g
OEt
O
MeO
18
O
MeO
R
H
H
H
i
OEt
h
O
H
O
OH
O
MeO
O
RO
O
O
MeO
H
Me
Me
20a R =
20b R =
22
23 R = Me
3 R = H
Ref.5
j
O
OEt
21
Scheme 3. Reagents and conditions: (a) K2CO3, acetone, MeI, reflux, 3 h, 92%; (b) (i) NaH, (CO2C2H5)2, THF, 0 °C–rt, 8 h; (ii) PTSA, C6H6, reflux, overall yield 90%; (c) BF3ÁEt2O,
NaCNBH3, THF, reflux, 4 h, 25%; (d) Pd/C, H2, C2H5OH, 3 h, 95%; (e) (i) LDA, PhSeBr, THF, À78 °C, 92%; (ii) H2O2, CH2Cl2/THF (2:1), 0 °C–rt, 90%; (f) LAH, THF, À40 °C to 0 °C, 1 h,
93%; (g) C2H5C(OEt)3, C2H5COOH(Cat.), xylene, 140 °C, 6 h, 97%; (h) LAH, THF, 0 °C, 1 h, 90%; (i) H2SO4(Cat.), THF, 0 °C–rt, 2 h, 96%; (j) BBr3, CH2Cl2, À78 °C, 1 h, 80%.
group also. Thus, refluxing a homogenous mixture of the alcohol
and triethyl orthopropionate in xylene in the presence of a cata-
lytic amount of propionic acid delivered the rearranged c,d unsat-
H
H
R
c
3
MeO
a
O
O
urated ester(s) 20 as a mixture of two diastereomers in 9:1 ratio in
97% total yield (Scheme 3). These were separated by column chro-
matography, and the structure of the major isomer was assigned as
20a10 considering the chair-like conformation for the intermediate
allyl enol ether 21 involving very few interactions.9 The final con-
firmation of the assignment, however, depended on its conversion
to alboatrin itself. Reduction of the ester 20a with LAH furnished
the alcohol 22 in 90% yield. When this alcohol was subjected to
mild acid treatment, it underwent an intramolecular cationic cyc-
lisation as before to afford the methyl ether 23 of alboatrin as
the only isolated product in 96% yield. The melting point and spec-
tral features (1H and 13C NMR) of this material were identical with
our previously synthesised sample.5 Demethylation of this to
alboatrin 3 having already been reported,5,12 this concluded a
short, high yield synthesis of the metabolite (Scheme 3). The syn-
thesis further substantiated the structural and stereochemical
assignment to the Claisen rearrangement product 20a.
Murphy and co-workers, in their synthesis of alboatrin, had ob-
tained epi-alboatrin 26 as the major product.5 epi-Alboatrin dif-
fered from its natural counterpart chiefly in its spectral features.
In the 1H NMR spectrum, the C-3 secondary methyl protons dis-
played an upfield shift, appearing as a doublet at d 0.88 arising
from the shielding by the aromatic ring in the convex conformation
of the molecule. We had obtained the diasteromer 20b10 as a minor
component in the orthoester Claisen rearrangement, and decided
to utilize this for a synthesis of epi-alboatrin 26 employing the
same sequence of reactions as detailed above for the synthesis of
alboatrin. LAH reduction of the ester 20b furnished the alcohol
24 in 90% yield. When this was subjected to mild acid treatment
it afforded O-methyl-epi-alboatrin 25 in near quantitative yields.
As anticipated, in the 1H NMR spectrum of 2510, the C-3 secondary
methyl protons appeared as a doublet at d 0.84. When 25 was sub-
jected to demethylation with BBr3, the only product isolated in 80%
yield was not epi-alboatrin 26, but alboatrin 3 (Scheme 4). The iden-
tity was established from spectral comparison with an authentic
sample. This was indeed an unusual and unique case of isomerisa-
tion and is thought to proceed through a remarkable tandem ring
RO
O
R= CO 2C2H5
R= CH 2OH
20b
24
R= Me
R= H
25
26
d
Scheme 4. Reagents and conditions: (a) LAH, THF, 0 °C, 1 h, 90%; (b) H2SO4(Cat.),
THF, 0 °C–rt, 2 h, 96%; (c) BBr3, CH2Cl2, À78 °C, 1 h, 80%; (d) EtSNa, DMF, 6 h, 86%.
opening and re-cyclisation process. We suggest that the primary
process is the cleavage of the internal ketal to furnish a dihydrofu-
ran phenol intermediate which undergoes a protonation with con-
comitant anti-addition of the phenolic moiety to finally deliver 3
(Scheme 5). Interestingly the protonation takes place syn to the
secondary methyl group at C-3. Ichihara et al., in their synthesis
of 34, had implicated a similar dihydrofuran intermediate. How-
ever, based on the subsequent revision of the configuration of
the methyl group at C-3, their conclusion relating to protonation
anti to this methyl group also needs revision. Support for this pro-
posal accrued from aborting the demethylation of 25 midway. A
H
H
..
O
MeO
O
O
MeO
O
BBr3
BBr2
H
3
O
MeO
O
BBr2
Scheme 5.

1434
D. Sarkar et al. / Tetrahedron Letters 50 (2009) 1431–1434
5. (a) Graham, S. R.; Murphy, J. A.; Kennedy, A. R. J. Chem. Soc., Perkin Trans. 1 1999,
3071–3073; (b) Rodriguez, R.; Mosses, J.; Cowley, A.; Baldwin, J. E. Org. Biomol.
Chem. 2005, 3, 3488–3495.
6. Biswas, B.; Sarkar, D.; Venkateswaran, R. V. Tetrahedron 2008, 64, 3212–3216.
7. Walenzyk, T.; Carola, C.; Buchholz, H.; Konig, B. Tetrahedron 2005, 61, 7366–
7377.
work-up of the reaction furnished a mixture of alboatrin 3 and o-
methyl alboatrin 23, indicating a primary ring cleavage followed
by re-cyclisation prior to demethylation. Another aspect of great
interest and encouragement that emerged from these observations
was that the stereochemistry of the Claisen rearrangement product
20 was irrelevant for the final outcome of the synthesis. Indeed,
when a mixture of both the isomers 20a and 20b was subjected
to the sequence of reactions involving LAH reduction, acid treat-
ment and demethylation, alboatrin 3 was the sole product isolated
in an excellent overall yield. To circumvent the problem of epimer-
isation under Lewis acid conditions, demethylation of 25 was tried
with sodium ethyl mercaptide. This afforded the expected epi-
alboatrin 2610 in 86% yield as the only product. 1H NMR spectral
data which matched with the reported5a values attested to the
identity of the product. epi-Alboatrin also when treated with BBr3
under previously stated demethylation conditions fully isomerised
to alboatrin.
In summary, we have developed a very efficient and stereocon-
trolled route to the linear tricyclic network of the xyloketals by
employing a diastereoselective Claisen rearrangement and an
intramolecular cationic cyclisation as the key steps, and demon-
strated their efficacy by applying the methodology to a short, high
yield synthesis of the phytotoxic metabolite alboatrin. The synthe-
sis affords the final product in nine steps from the resacetophenone
14 in an overall yield of 44%. A unique case of isomerisation of the
epi to the natural isomer under Lewis acid conditions has also been
observed. It is anticipated that with appropriate modifications in
the substitution pattern in the aromatic ring, this route will serve
as a convenient access to the xyloketals.
8. Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A.; Yelamaggad, C. V. Tetrahedron
Lett. 1995, 36, 2347–2350.
9. (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brockson, T. J.; Li, T.;
Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741–743; (b)
Bartlett, P. D. Tetrahedron 1980, 36, 2–72; (c) Daub, G. W.; Shanklin, P. L.;
Tata, C. J. Org. Chem. 1986, 51, 3402–3405; (d) Fukuda, Y.; Okamoto, Y.
Tetrahedron 2002, 58, 2513–2521; (e) Srikrishna, A.; Ramachary, D. B.
Tetrahedron Lett. 2002, 43, 2765–2768; (f) Martin Castro, A. M. Chem. Rev.
2004, 104, 2939–3002.
10. All new compounds reported here gave analytical and spectral data consistent
with assigned structures. Selected spectral data: For 11: 1H NMR (300 MHz,
CDCl3) d 1.25 (t, J = 6.9 Hz, 3H); 2.4 (dd, J = 8.0, 15.6 Hz, 1H); 2.59 (dd, J = 6.6,
15.6 Hz, 1H), 2.65 (dd, J = 6.6, 15.6 Hz, 1H); 2.99 (dd, J = 4.8, 15.6 Hz, 1H); 3.18–
3.11 (m, 1H); 4.17 (q, J = 6.9 Hz, 2H); 4.27 (s, 1H); 4.60 (s, 1H); 6.90 (t,
J = 7.8 Hz, 2H); 7.04 (d, J = 7.2 Hz, 1H); 7.15 (t, J = 7.5 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 14.2, 30.6, 32.7, 37.0, 60.7, 89.8, 115.8, 120.7, 121.5, 127.9,
129.2, 152.4, 157.8, 171.7. For 13: 1H NMR (300 MHz, CDCl3) d 1.58 (s, 3H);
1.73–1.80 (m, 1H); 2.02–2.07 (m, 1H); 2.42–2.48 (m, 1H); 2.79 (d, J = 16.6 Hz,
1H); 3.06 (dd, J = 5.7, 16.6 Hz, 1H); 3.88–4.02 (m, 2H); 6.83–6.89 (m, 2H); 7.06–
7.14 (m, 2H). 13C NMR (75 MHz, CDCl3) d 23.2, 26.3, 28.8, 41.1, 66.8, 107.1,
117.0, 119.4, 120.7, 127.7, 129.3, 153.4. For 16: mp 132–134 °C; IR (KBr) mmax
1645 cmÀ1, 1737 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.35 (t, J = 6.9 Hz, 3H);
;
2.72 (s, 3H);3.80 (s, 3H); 4.37 (q, J = 6.9 Hz, 2H); 6.66 (s, 1H), 6.77 (s, 1H); 6.88
(s, 1H); 13C NMR (75 MHz, CDCl3) d 14.2, 22.9, 55.8, 62.8, 98.8, 116.36, 117.2,
117.4, 142.8, 150.4, 159.5, 160.8, 163.4, 179.4. HRMS (EI) Found: MH+,
263.0928; C14H14O5 requires; MH+ 263.0921. For 17: IR (Neat) mmax
1732 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.28 (t, J = 7.2 Hz, 3H); 2.09 (s, 3H);
.
3.29 (d, J = 4.2 Hz, 2H); 3.66 (s, 3H); 4.23 (q, J = 7.2 Hz, 2H); 6.13 (t, J = 4.2 Hz,
1H); 6.37 (s, 1H); 6.38 (s, 1H). 13C NMR (75 MHz, CDCl3) d 14.6, 19.6, 22.8, 55.7,
61.8, 99.7, 109.4, 110.6, 112.4, 138.3, 141.8, 152.1, 159.2, 162.1. HRMS (ESI)
Found: M+Na+, 271.0946; C14H16O4 requires; M+Na+, 271.0946. For 20a: IR
(Neat) mmax 1732 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.16 (d, J = 6.9 Hz, 3H);
.
1.26 (t, J = 7.2 Hz, 3H); 2.2 (s, 3H); 2.52–2.57 (m, 1H); 2.70 (d, J = 4.8 Hz, 2H);
2.86–2.89 (m, 1H); 3.74 (s, 3H); 4.10 (q, J = 6.9 Hz, 2H); 4.17 (s, 1H); 4.56 (s,
1H); 6.33 (s, 1H); 6.38 (s, 1H). 13C NMR (75 MHz, CDCl3) d 14.5, 15.2, 19.6, 24.1,
39.2, 41.0, 55.6, 60.8, 90.9, 99.1, 110.1, 111.3, 137.8, 153.7 157.3, 159.3, 175.8.
HRMS (EI) Found: MH+, 291.1589; C17H22O4 requires; MH+ 291.1598. For 20b:
Acknowledgements
We sincerely acknowledge financial support from the Depart-
ment of Science and Technology, Government of India. D.S. and
S.G. thank the Council of Scientific and Industrial Research, New
Delhi, for Senior Research fellowships.
IR (Neat) 1732 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.19 (d, J = 6.9 Hz, 3H); 1.24
.
(t, J = 7.2 Hz, 3H); 2.14 (s, 3H); 2.43–2.47 (m, 1H); 2.61 (dd, J = 2.4, 16.2 Hz,
1H); 2.73 (dd, J = 5.1, 16.2 Hz, 1H); 2.82–2.87 (m, 1H); 3.74 (s, 3H); 4.13 (q,
J = 7.2 Hz, 2H); 4.25 (s, 1H); 4.66 (s, 1H); 6.30 (s, 1H); 6.38 (s, 1H). 13C NMR
(75 MHz, CDCl3) d 14.4, 16.4, 19.4, 26.3, 39.7, 39.8, 55.3, 60.6, 92.7, 98.7, 109.9,
111.1, 138.1, 153.3, 155.4, 158.8, 176.0. For 25: Colourless solid. Mp 54–55 °C;
1H NMR (300 MHz, CDCl3) d 0.83 (d, J = 6.9 Hz, 3H), 1.51 (s, 3H), 2.21 (s, 3H),
2.43–2.53 (m, 2H); 2.68–2.70 (m, 2H); 3.58 (t, J = 8.1 Hz, 1H), 3.71 (s, 3H), 4.12
(t, J = 8.1 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 6.35 (s, 1H). 13C NMR (75 MHz, CDCl3)
d 14.1, 19.4, 20.8, 24.3, 35.5, 43.8, 55.2, 74.8, 100.1, 107.9, 109.4, 113.1, 136.8,
155.2, 158.7; HRMS (EI) Found: MH+, 249.1484, C15H20O3 requires 249.1485.
For 26: colourless solid. Mp 145–148 °C; 1H NMR (300 MHz, CDCl3) d 0.84 (d,
J = 6.8 Hz, 3H); 1.53 (s, 3H); 2.19 (s, 3H); 2.44–2.55 (m, 2H); 2.68–2.69 (m, 2H);
3.57 (t, J = 6.7 Hz, 1H); 4.12 (t, J = 7.9 Hz, 1H); 5.9 (br s, 1H); 6.32 (s, 1H); 6.35
(d, J = 2.1, 1H). 13C NMR (75 MHz, CDCl3) d 13.9, 19.2, 20.6, 24.4, 35.5, 44.0,
74.80, 102.2, 108.1, 110.3, 112.8, 136.8, 155.0, 155.2.
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