Regioselective synthesis of polyketide-type phenols by formal [3+3]-cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with 3-oxoorthoesters

Article abstract of DOI:10.1055/s-0028-1083524

A variety of 4-methoxysalicylates and related polyketide-type phenols are regioselectively prepared by the first formal [3+3]-cyclocondensations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-oxoorthoesters.

Full text of DOI:10.1055/s-0028-1083524

LETTER
2671
Regioselective Synthesis of Polyketide-Type Phenols by Formal [3+3]-
Cyclocondensations of 1,3-Bis(silyloxy)-1,3-butadienes with 3-Oxoorthoesters
R
egioselective Synthes
a
is of Polyk
t
etide-T
h
ype Phenolsias Lubbe,a Jörg-Peter Gütlein,a Helmut Reinke,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse, Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
E-mail: peter.langer@uni-rostock.de
b
Received 4 June 2008
Recently, we reported7 a regioselective synthesis of 4-hy-
droxy- and 6-hydroxysalicylates by cyclization of 1,3-
bis(silyloxy)-1,3-butadienes with 3,3-dimethoxypen-
tanoyl chloride. However, this method is limited so far to
the synthesis of ethyl-substituted derivatives. Herein, we
report a new and convenient synthesis of 4-methoxysali-
cylates and related polyketide-type phenols by what are,
to the best of our knowledge, the first formal [3+3]-cyclo-
condensations of 1,3-bis(silyloxy)-1,3-butadienes with 3-
oxoorthoesters.8 This method provides a rather general
and regioselective approach to a wide range of substituted
salicylates which are not readily available by other meth-
ods.
Abstract: A variety of 4-methoxysalicylates and related
polyketide-type phenols are regioselectively prepared by the first
formal [3+3]-cyclocondensations of 1,3-bis(trimethylsilyloxy)-1,3-
butadienes with 3-oxoorthoesters.
Key words: arenes, cyclizations, regioselectivity, silyl enol ethers
Many pharmacologically important, naturally occurring
phenols are biosynthetically derived from poly(b-
oxo)carboxylic acids (polyketides).1 Harris and co-work-
ers reported the biomimetic synthesis of various 1,3,5,7-
tetracarbonyl compounds and their higher homologues
based on condensations of 1,3-dicarbonyl dianions or
1,3,5-tricarbonyl trianions with carboxylic acid deriva-
tives.2 These products are unstable and rapidly undergo an
intramolecular aldol condensation to give polyhydroxy-
lated arenes.
Chan and Brownbridge developed3 a convenient synthesis
of salicylates by cyclocondensation of 1,3-bis(silyloxy)-
1,3-butadienes, masked 1,3-dicarbonyl dianions,4 with 3-
silyloxy-2-en-1-ones. In recent years, we have extended
the scope of this chemistry and studied its application to
the synthesis of a variety of functionalized arenes.5 In
most reactions developed so far, the products, functional-
ized salicylates, contain no functional group located at
carbon atoms C4 and C6. This is a severe limitation, since
naturally occurring, polyketide-derived phenols contain a
free or masked hydroxyl group at one of these positions.
The 3-oxoorthoesters 4a–j were prepared following a
known procedure in two steps (Scheme 1, Table 1). The
AlCl3-mediated reaction9a–9c of 1,1-dichloroethene (2)
with acid chlorides 1a–j afforded the 3,3,3-trichloroke-
tones 3a–j. The reaction9d of the latter with methanol af-
forded the 3-oxoorthoesters 4a–j in good overall yields
(except for 4f). The synthesis of 4a9d,e and 4c9d has been
previously reported. 1,3-Bis(trimethylsilyloxy)-1,3-buta-
dienes 5a–c,e,h–j were prepared from the corresponding
b-ketoesters in two steps.3 Dienes 5d,f,g were prepared
from the corresponding 1,3-diketones in one step.10
O
Cl
Cl
O
i
+
Cl
R
Cl
Cl
R
Cl
1a–j
2
3a–j
Chan and Stössel were the first to report6 an elegant ap-
proach to 4-hydroxysalicylates by Lewis acid mediated
formal [5+1]-cyclization of 1-methoxy-1,3,5-tris(trimeth-
ylsilyloxy)-1,3,5-hexatriene with acid chlorides or imida-
zolides. However, the preparative scope of this method is
limited by the availability of the 1,3,5-tris(silyl enol
ether). In fact, trienes derived from substituted 3,5-di-
oxoalkanoates and from 1,3,5-triketones, proved to be un-
stable and could not be successfully employed. Therefore,
only methyl salicylates containing a hydrogen atom locat-
ed at carbon atoms C3 and C5 can be prepared by this
method.
NaOMe
ii
O
OMe
MeO
MeO
R
4a-j
Scheme 1 Synthesis of 4a–j. Reagents and conditions: (i) AlCl3,
CH2Cl2, 20 °C, 2–14 h; (ii) MeOH, 20 °C, 2–14 h.
The TiCl4-mediated cyclization of 4a with 1,3-bis(trime-
thylsilyloxy)-1,3-butadiene 5a regioselectively afforded
4-methoxysalicylate 6a (Scheme 2). The formation of the
isomeric 6-methoxysalicylate was not observed. The best
yields were obtained when 5a, 4a and TiCl4 were em-
ployed in a stoichiometric ratio of 2:1:1 and when the re-
action was carried out in a relatively concentrated solution
[c(4a) = 0.5 M].
SYNLETT 2008, No. 17, pp 2671–2673
x
x
.x
x
.2
0
0
8
The formation of 6a can be explained by TiCl4-mediated
attack of the terminal carbon atom of 5a onto the ortho-
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083524; Art ID: D20608ST
© Georg Thieme Verlag Stuttgart · New York

2672
M. Lubbe et al.
LETTER
Table 1 Synthesis of 4a–j
The TiCl4-mediated cyclization of 3-oxoorthoesters 4a–j
with 1,3-bis(trimethylsilyloxy)-1,3-butadienes 5a–j af-
forded the 4-methoxysalicylates 6a–v in moderate to good
yields with very good regioselectivity (Scheme 3,
Table 2).11 A wide range of products could be successful-
ly prepared. This includes salicylic acid esters 6a–
c,e,g,j,k,m–t,v and 6-acyl-3-methoxyphenols 6d,f,h,i,l,u.
The substituents R2 attached to carbon atom C3 of the
1,3,4
R
Yield (%) of 3a Yield (%) of 4a
a
b
c
d
e
f
Me
75
86
77
97
92
82
95
94
92
96
88
94
62
66
53
30
93
86
79
92
Et
n-Pr
Ph
TMSO
R2
OTMS
R3
4-ClC6H4
c-Pr
OH
O
5a–j
R2
i
R3
+
g
h
i
c-Bu
MeO
R1
O
OMe
c-Pent
c-Hex
(CH2)2(c-Pent)
6a–v
R1
MeO
MeO
4a–j
j
Scheme 3 Synthesis of 6a–v. Reagents and conditions: (i) 1. TiCl4
(1.0 equiv), CH2Cl2, –78 to 20 °C, 14 h; 2. HCl (10%).
a Yields of isolated products.
Table 2 Synthesis of 6a–v
TMSO
OTMS
OMe
OH
O
4
5
6
R1
R2
R3
Yield (%)
of 6a
5a
+
TiCl4
i
OMe
a
a
b
b
c
c
c
c
c
d
d
d
e
f
a
b
c
d
a
d
e
f
a
b
c
d
e
f
Me
H
OMe
OMe
OMe
Me
44
47
56
30
42
40
53
48
35
31
33
58
34
48
52
50
67
71
67
88
63
67
OMe
O
MeO
Me
MeO
MeO
6a (44%)
Me
Et
Me
4a
_
_
TiOCl2
HCl
Et
Me
H
+ H2O
TiCl4,
TMSOMe
5a
Et
Cl3
Ti
n-Pr
H
OMe
Me
O
O
TMSO
O
n-Pr
H
OMe
OMe
Me
MeO
MeO
g
h
i
n-Pr
OMe
H
OMe
Ph
MeO
Me
TiCl4
O
C
A
n-Pr
H2O
g
a
e
d
a
h
i
n-Pr
Me
H
Et
OH
O
HCl,
TMSOMe
j
Ph
OMe
OMe
Me
OMe
Me
OTiCl3
k
l
Ph
OMe
H
MeO
B
Ph
Scheme 2 Possible mechanism of the formation of 6a. Reagents
and conditions: (i) 1. TiCl4 (1.0 equiv), CH2Cl2, –78 °C → 20 °C, 14
h; 2. HCl (10%).
m
n
o
p
q
r
s
4-ClC6H4
c-Pr
H
OMe
Oi-Pr
OMe
Oi-Bu
Oi-Pr
OMe
Oi-Pr
OMe
Me
H
f
c-Pr
n-Pr
H
ester to give intermediate A, subsequent cyclization by at-
tack of the central carbon atom of the dicarbonyl moiety
onto the double bond (intermediate B), aromatization (in-
termediate C) and hydrolysis upon aqueous workup. The
TiCl4-mediated reaction of 5a with trimethyl orthoacetate
has been previously reported.8 Alternatively, the cyclo-
condensation may proceed by TiCl4-mediated transforma-
tion of 4a into 4,4-dimethoxy-3-buten-2-one, conjugate
addition of the terminal carbon atom of 5a onto the latter
and subsequent cyclization. The conjugate addition fol-
lows the mechanism earlier suggested for the cyclization
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-
alkoxy- and 3-silyloxy-2-en-1-ones.3,5
g
h
h
i
j
c-Bu
c-Pent
c-Pent
c-Hex
c-Hex
c-Hex
(CH2)2(c-Pent)
h
i
H
n-Pr
H
h
i
i
t
n-Pr
H
i
d
h
u
v
j
H
Oi-Pr
a Yields of isolated products.
Synlett 2008, No. 17, 2671–2673 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of Polyketide-Type Phenols
2673
C. M.; Roberson, J. S.; Harris, T. M. J. Am. Chem. Soc. 1976,
98, 5380. (d) Harris, T. M.; Hay, J. V. J. Am. Chem. Soc.
1977, 99, 1631. (e) Hubbard, J. S.; Harris, T. M.
Tetrahedron Lett. 1978, 47, 4601. (f) Sandifer, R. M.;
Bhattacharya, A. K.; Harris, T. M. J. Org. Chem. 1981, 46,
2260. (g) Gilbreath, S. G.; Harris, C. M.; Harris, T. M. J. Am.
Chem. Soc. 1988, 110, 6172.
benzene system include, besides hydrogen, alkyl groups
and the methoxy group. Various substituents can be intro-
duced at carbon atom C6 (substituent R1). This includes
alkyl, aryl and various cycloalkyl groups. It is noteworthy
that the cyclopropyl, cyclobutyl, cyclopentyl and cyclo-
hexyl group proved to be compatible with the reaction
conditions. No decrease of the yield was observed despite
the steric hindrance of these groups. The cyclopropyl
group was not cleaved during the reaction. The synthesis
of cycloalkyl-substituted arenes by formal [3+3]-cycliza-
tions has, to the best of our knowledge, not been reported
to date.
(3) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
(4) For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
(5) For a review of formal [3+3]-cyclizations of 1,3-bis(silyl
enol ethers), see: Feist, H.; Langer, P. Synthesis 2007, 327.
(6) (a) Chan, T.-H.; Stössel, D. J. Org. Chem. 1988, 53, 4901.
(b) Chan, T.-H.; Stössel, D. J. Org. Chem. 1986, 51, 2423.
(7) Sher, M.; Langer, P. Synlett 2008, 1050.
(8) The TiCl4-mediated reaction of 5a (2 equiv) with trimethyl
orthoacetate has been reported to give a homophthalate by
2:1 condensation and subsequent aldol reaction:
The configuration of all products was established by spec-
troscopic methods (2D NMR). The structure of 6j was in-
dependently confirmed by X-ray crystal structure analysis
(Figure 1).12
Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J.
Can. J. Chem. 1983, 61, 688.
(9) (a) Wilson, B. D. Synthesis 1992, 283. (b) Heilbron, I.;
Jones, E. R. H.; Julia, M. J. Chem. Soc. 1949, 1434.
(c) Searles, S.; Sanchez, R. A.; Soulen, R. L.; Kundinger,
D. G. J. Org. Chem. 1967, 32, 2655. (d) Banville, J.;
Brassard, P. J. Chem. Soc., Perkin Trans. 1 1976, 1852.
(e) Barker, D.; Brimble, M. A.; Do, P.; Turner, P.
Tetrahedron 2003, 59, 2441.
(10) Krägeloh, K.; Simchen, G. Synthesis 1981, 30.
(11) Typical Procedure for the Synthesis of Methyl 2-hydroxy-
4-methoxy-6-(n-propyl)benzoate (6e): To a CH2Cl2
solution (2 mL) of 4c (0.191 g, 1.0 mmol) and 5a (0.521 g,
2.0 mmol) was added TiCl4 (0.11 mL, 1.0 mmol) at –78 °C
under an argon atmosphere. The temperature of the reaction
mixture was allowed to rise to 20 °C during 14 h with
stirring. To the mixture was added hydrochloric acid (10%,
10 mL). The organic and the aqueous layer were separated
and the latter was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. After column
chromatography (silica gel; heptanes–EtOAc, 1:1), 6e was
obtained as a colorless oil (92 mg, 42%); Rf 0.88 (heptanes–
EtOAc, 1:1). 1H NMR (250 MHz, CDCl3): d = 11.73 (s, 1 H,
OH), 6.33 (s, 1 H, ArH), 6.30 (s, 1 H, ArH), 3.93 (s, 3 H,
OMe), 3.38 (s, 3 H, OMe), 2.83 (t, 3J = 7.7 Hz, 2 H, ArCH2),
1.49–1.63 (m, 2 H, CH2CH3), 0.95 (t, 3J = 7.4 Hz, 3 H, Me).
13C NMR (63 MHz, CDCl3): d = 172.0 (C=O), 165.5, 163.9
(CO), 147.7 (C), 110.7 (CH), 104.6 (C), 98.7 (CH), 55.3,
51.8 (OMe), 38.9 (ArCH2), 24.9 (CH2CH3), 14.2 (Me). IR
(ATR): 2956 (br m), 2871 (w), 2846 (w), 1649 (s), 1611 (s),
1575 (s) cm–1. MS (EI, 70 eV): m/z (%) = 224 (33) [M+], 192
(100), 164 (34), 135 (45). Anal. Calcd for C12H16O4
(224.26): C, 64.27; H, 7.19. Found: C, 64.27; H, 7.39.
(12) CCDC 690564 contains all crystallographic details of this
publication and is available free of charge at
Figure 1 ORTEP plot of 6j
In conclusion, a variety of 4-methoxysalicylates and relat-
ed polyketide-type phenols were prepared by what are, to
the best of our knowledge, the first [3+3]-cyclizations of
1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-oxoortho-
esters. The scope and application of this methodology are
currently being studied.
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern is gra-
tefully acknowledged.
References and Notes
(1) (a) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18,
380. (b) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. Rev.
2005, 34, 677. (c) Römpp-Lexikon Naturstoffe; Fugmann,
B., Ed.; Georg Thieme Verlag: Stuttgart / New York, 1997.
(2) For a review, see: (a) Harris, T. M.; Harris, C. M.
Tetrahedron 1977, 33, 2159. See also: (b) Murray, T. P.;
Harris, T. M. J. Am. Chem. Soc. 1972, 94, 8253. (c) Harris,
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ; Fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
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