A new synthesis of the 2,2,3,5,6,6-substituted tetrahydropyran aplysiapyranoid A and its 5-epimer

Article abstract of DOI:10.1016/S0040-4039(03)01468-0

The vanadium(V)-catalyzed oxidation of bromide in the presence of methyl (E)-2-(1-hydroxy-1-methylethyl)-5-phenyl-4-hexenoate furnished 5,6-trans-5-bromo-6-phenyl-2,2,6-trimethyl-3- methyloxycarbonyltetrahydropyran, which was converted into the marine nat

Full text of DOI:10.1016/S0040-4039(03)01468-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6091–6093
A new synthesis of the 2,2,3,5,6,6-substituted tetrahydropyran
aplysiapyranoid A and its 5-epimer
Jens Hartung* and Marco Greb
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received 31 March 2003; revised 12 May 2003; accepted 12 June 2003
Abstract—The vanadium(V)-catalyzed oxidation of bromide in the presence of methyl (E)-2-(1-hydroxy-1-methylethyl)-5-phenyl-
4-hexenoate furnished 5,6-trans-5-bromo-6-phenyl-2,2,6-trimethyl-3-methyloxycarbonyltetrahydropyran, which was converted
into the marine natural product aplysiapyranoid A and its 5-epimer, via a short sequence of decarboxylative bromination and
transition metal-based procedures for transforming a phenyl into a chlorovinyl substituent.
© 2003 Elsevier Ltd. All rights reserved.
Aplysiapyranoids A–D are monoterpene-derived sec-
ondary metabolites, which have been isolated from the
midgut gland of the sea hare Aplysia kurodai.1,2 Due to
their cytotoxic profile towards several human tumor cell
lines, in association with their restricted availability
from natural sources, aplysiapyranoids have become
attractive targets in organic synthesis.3–5 In order to
provide adequate quantities of these compounds for
succeeding biological experiments it was desired to
develop a new synthesis, which was based on a catalytic
procedure for constructing the bromofunctionalized tet-
rahydropyran nucleus from a suitable bishomoallylic
alcohol. Further, it was considered useful to design an
approach that would allow an application of polar and
free radical reactions for subsequent functional group
interconversions in order to establish a straightforward
access to a wider range of analogues of heterocycle 1 in
future investigations. In regard of these prerequisites,
styrene derivative 2 was chosen as substrate for a new
synthesis of aplysiapyranoid A (1) and its 5-epimer
epi-1 (Fig. 1).†,‡ A phenyl substituent is known to
exhibit a comparatively strong polar effect in elec-
trophilic bromination reactions of olefins and thus was
thought to significantly favor a 6-endo-selective ring
closure reaction in the initial step.6 Introduction of the
second bromo substituent into the heterocyclic core was
expected to be feasible via a decarboxylative free radi-
cal bromination.7 A subsequent oxidative degradation
of the phenyl into a carbonyl functionality8 then would
provide an appropriate starting point for constructing
the (E)-configured chlorovinyl substituent of target
compounds 1 and epi-1.
† Satisfactory analytical data were obtained for all new compounds
prepared in this study. The present communication reports on a
proof of concept. Therefore it has been restricted to the synthesis of
racemic aplysiapyranoid A (1) and epi-1.
‡ Methyl (E)-2-(1-hydroxy-1-methylethyl)-5-phenyl-4-hexenoate (2)
was prepared by esterification of 4-benzoyl butyric acid (CH3OH,
CHCl3, TsOH, 61°C), selective methylation (CH3MgI, Et2O, 20°C),
treatment of this crude product with TsOH in a mixture of C6H6
and CH3OH (oil bath: 95°C), and subsequent a-alkylation (LDA,
THF, −78°C, then acetone): 1H NMR (CDCl3, 250 MHz): l=1.29
(2 s, 6H), 2.03 (s, 3H), 2.30–2.44 (br. s, 1H), 2.43–2.77 (m, 2H), 2.55
(mc, 1H), 3.68 (s, 3H), 5.67 (tq, J=6.7 Hz, J=1.5 Hz, 1H),
7.21–7.36 (m, 5H). 13C NMR (CDCl3, 63 MHz): l=16.0, 26.8,
27.0, 29.2, 51.6, 55.7, 71.0, 124.8, 125.7, 126.8, 128.2, 137.0, 143.8,
176.1. C16H22O3 (262.34): calcd C, 73.25; H, 8.45; found: C, 73.72;
H, 8.33.
Figure 1. Concept for the construction of aplysiapyranoid A
(+)-(1).
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01468-0

6092
J. Hartung, M. Greb / Tetrahedron Letters 44 (2003) 6091–6093
Thus,
methyl
(E)-2-(1-hydroxy-1-methylethyl)-5-
chemoselective transformation of both diastereomers of
6. However, it should be added that the conversion of
starting material 6 ceased at some point. It was not
possible to resume its oxidation by adding further
RuCl3 or supplementary NaIO4 to the reaction mixture.
Since separation of likewise prepared carboxylic acids
from unreacted substrate 6 at that stage of the synthesis
was tedious and associated with loss of substantial
amounts of oxidation product, the crude material was
treated with MeOH and DIC to provide esters 7 and
epi-7, which were purified by chromatography (Scheme
3). Reduction of the ester functionality in 7 and epi-7
using DIBAH in hexanes/CH2Cl2 afforded the corre-
sponding aldehydes. Treatment of these products with
CrCl2 and CHCl3 furnished target compounds 1 and
phenyl-4-hexenoate (2)‡ was treated on a 15 g scale with
tert-butyl hydroperoxide (TBHP), pyridinium hydro-
bromide and 5 mol% of catalyst VOL(OEt)(EtOH)
[L=N-(2-hydroxyphenyl)salicylidenimine dianion]9,10
to furnish 43% of 6-endo-bromocyclized product 3 (3,5-
cis:3,5-trans=80:20) besides 15% of tetrahydrofuran 4
(cis:trans=34:66, Scheme 1).11 Substituents at C5 and
C6 in both diastereomers of 3 exhibited relative trans-
configuration. Formation of 5-(1-phenyl-1-hydroxy-1-
ethyl)-substituted
tetrahydrofurans
or
the
corresponding tetrahydropyranols as side products,
which might have originated from a competing direct
vanadium(V)-catalyzed oxygenation of substrate 2, was
not observed.11 It is worth mentioning that treatment of
a solution of alkenol 2 in CH2Cl2 (20°C or 40°C) with
the standard reagent for conducting 6-endo-selective
ring
closure
reactions,
i.e.
2,4,4,6-tetra-
bromocyclohexadienone,3–5,12,13 provided 5,6-trans-
configured tetrahydropyran 3 in yields that remained
below 20%. Surprisingly, the diastereoselectivity for a
likewise obtained product 3 with regard to substitution
at C3 and C5 was reversed (3,5-cis:3,5-trans=26:74,
not shown in Scheme 1).
Saponification of methyl ester 3 using LiOH in aqueous
dimethoxyethane (DME) furnished upon neutralization
the corresponding carboxylic acid (3,5-cis:3,5-trans=
80:20, 93%, not shown in Scheme 2). Treatment of the
latter compound with N-hydroxypyridine-2(1H)thione
(PTOH) and diisopropylcarbodiimide (DIC) provided
mixed anhydride 5 (Scheme 2).7 Photolysis of alkyl
radical precursor 5 in the presence of BrCCl3 led to the
formation of dibromide 6 (3,5-cis:3,5-trans=50:50, 52%
starting from the carboxylic acid derivative of 3).
For completion of both syntheses, separated dibro-
mides 3,5-trans-6 and 3,5-cis-6 were treated with the
reagent combination of RuCl3 and NaIO4 in order to
transform in both instances the phenyl substituent into
a carboxyl group (Scheme 3). Since this procedure had
originally been developed for preparing carboxylic acids
from less functionalized aromatic hydrocarbons,8 we
were pleased to notice that it was also suitable for a
Scheme 2. Formation of 3,5-dibromo-2,2,6,6-substituted tet-
rahydropyran 6 from heterocyclic ester 3. Reagents and condi-
tions: (a) LiOH, DME, H2O, 20°C (93%); (b) PTOH, DIC,
CH2Cl2; (c) BrCCl3, C6H6, hw, 20°C (52% for steps b and c).
Scheme 1. Application of the vanadium(V)-catalyzed oxida-
tion of bromide in the 6-endo-selective bromocyclization of
styrene-derived alcohol 2. Reagents and conditions: (a) TBHP
(1.1 equiv.), C5H5N·HBr (1.5 equiv.), VOL(OEt)(EtOH) [5
mol%, L=N-(2-hydroxyphenyl)salicylidenimine dianion)],9,10
CH3CN, 20°C.
Scheme 3. Completion of the synthesis of aplysiapyranoid A
(1) and epi-1, both as racemates. Reagents and conditions: (a)
RuCl3, NaIO4, CCl4, CH3CN, H2O, 20°C; (b) CH3OH, DIC,
CH2Cl2 (36% for 3,5-trans-6“7, 46% for 3,5-cis-6“epi-7); (c)
DIBAH in hexanes, CH2Cl2, −78°C; (d) CrCl2, CHCl3, THF,
61°C (33% for 7“1, 22% for epi-7“epi-1).

J. Hartung, M. Greb / Tetrahedron Letters 44 (2003) 6091–6093
6093
epi-1.§,14 The sample of aplysiapyranoid A (1) was
contaminated with a minor amount of its dechlorinated
derivative (4%) and 10% of starting aldehyde, which
could be separated from 1 by column chromatography.
The final step from the synthesis of epi-1 was not
associated with similar complications.
Klu¨h, undergraduate research participant, for technical
assistance.
References
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The observation that only moderate yields were attain-
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comment. This fact had been noted for the
chloroethenylation step in the synthesis of (+)-1 in an
earlier report.3 According to our experience, this issue
has to be associated with the significant steric crowding
in 2,2,3,5,6,6-substituted tetrahydropyrans that some-
times rendered seemingly elementary reactions into
troublesome processes.
In summary, we have devised a new synthesis of
aplysiapyranoid A (1) and its isomer epi-1, both as
racemates. The selected strategy supplements the exist-
ing approach.3 It offers potential for future syntheses of
new aplysiapyranoid derivatives, since it takes profit
from a transition metal-catalyzed oxidation in the
bromine cyclization step and enables the preparation of
related compounds under mild and neutral conditions
using radical-based transformations.
7. Motherwell, W. B.; Imboden, C. In Radicals in Organic
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Acknowledgements
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Generous financial support was provided by the
Deutsche Forschungsgemeinschaft (Grants, Ha 1705/6-
1 and 8-1) and the Fonds der Chemischen Industrie.
Further, we express our gratitude to Mrs. Katharina
§ 1: 1H NMR (CDCl3, 400 MHz): l=1.38 (s, 3H), 1.43 (s, 6H),
2.61–2.68 (m, 2H), 4.39 (dd, J=7.8, 5.0 Hz, 1H, CHBr), 4.47 (dd,
J=6.2, 4.0 Hz, 1H, CHBr), 6.14 (d, J=13.8 Hz, 1H), 6.18 (d,
J=13.8 Hz, 1H). 13C NMR (CDCl3, 101 MHz): l=27.3, 28.7, 29.0,
37.3, 54.6, 55.1, 75.8, 76.0, 118.4, 138.4. epi-1: 1H NMR (CDCl3,
400 MHz): l=1.36 (s, 3H), 1.47 (s, 3H), 1.53 (s, 3H), 2.59–2.70 (m,
2H), 3.87 (mc, 2H, 2 CHBr), 6.09 (d, J=13.1 Hz, 1H), 6.29 (d,
J=13.1 Hz, 1H). 13C NMR (CDCl3, 101 MHz): l=22.1, 23.3, 30.4,
38.3, 52.8, 53.9, 76.8, 77.1, 119.9, 137.8.