Application of an intramolecular Stetter reaction to access trans,syn,trans-fused pyrans

Article abstract of DOI:10.1055/s-0028-1087519

The use of a commercially available thiazolium salt facilitated an intramolecular Stetter reaction between an aliphatic aldehyde and an acrylate unit, which delivered a trans,syn-fused bicyclic pyranone in high yield as a single diastereomer. The pyranone

Full text of DOI:10.1055/s-0028-1087519

LETTER
233
Application of an Intramolecular Stetter Reaction to Access trans,syn,trans-
Fused Pyrans
I
ntramolecular St
h
etter Reactio
r
n
to
A
cc
i
ess tran
s
s
,
syn
,
tran
t
s
-Fuse
o
d
P
yrans pher S. P. McErlean,*a Anthony C. Willisb
a
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
Fax +61(2)93513329; E-mail: C.McErlean@chem.usyd.edu.au
b
Research School of Chemistry, The Australian National University, Canberra, ACT 0200, Australia
Received 19 September 2008
O
R1
O
R1
Abstract: The use of a commercially available thiazolium salt fa-
cilitated an intramolecular Stetter reaction between an aliphatic al-
dehyde and an acrylate unit, which delivered a trans,syn-fused
bicyclic pyranone in high yield as a single diastereomer. The pyra-
none was used to synthesize a trans,syn,trans-fused polycyclic
ether array and was ring expanded to give the corresponding ox-
epanone.
R2
R2
2
1
Scheme 1 Intramolecular Stetter reaction of aliphatic substrates
Key words: carbenes, diastereoselectivity, fused-ring systems, ring
closure, umpolung
Table 1 Intramolecular Stetter Reaction of Aliphatic Substrates
R1
R2
Yield (%)a
The direct addition of an aldehyde onto a Michael accep-
tor to give a 1,4-dicarbonyl system was reported in the
early 1970’s by Stetter and co-workers.1 The reversal in
conventional reactivity of the aldehyde unit (umpolung2)
was brought about by the action of catalytic cyanide.
However, that initial protocol was only useful for aromat-
ic aldehydes. In order to affect such a coupling between
aliphatic aldehydes and Michael acceptors, Stetter mim-
icked the thiazolium unit found in co-enzyme B1. Depro-
tonation of simple, commercially available thiazolium
salts generated carbenes, which underwent addition to al-
dehydes. Proton transfer then generated acyl anion equiv-
alents (Breslow intermediates3), which underwent
addition to unsaturated ketones, esters, and nitriles to de-
liver 1,4-oxoketones, ketoesters, and ketonitriles, respec-
tively. The potential power of this new catalytic
methodology for the intramolecular generation of ring
systems lay dormant for many years. Until the work of
Ciganek in 19954 – more than twenty years after the initial
report – only a single example of an intramolecular Stetter
reaction had been disclosed.5
COPh
CO2Et
CO2Et
H
60
0
H
CO2Et
97
a Yields as quoted by Rovis et al.7
stance, while the formation of six-membered rings from
aliphatic aldehydes and unsaturated ketones is known,12
the corresponding reaction involving unsaturated esters
has proved elusive. Rovis demonstrated that only highly
activated malonate-derived diesters participated in this
ring closure (Scheme 1, Table 1),7 and that the readily ac-
cessible and synthetically valuable ethyl acrylate unit was
not electrophilic enough to undergo the intramolecular
Stetter reaction.
We became interested in utilizing the intramolecular
Stetter reaction for the (re)iterative generation of
trans,syn,trans-fused pyran architectures of the type com-
monly found in polycyclic ethers of marine origin.13 It
was our intention to use the economical ethyl acrylate unit
as the Michael acceptor. This ambitious plan not only uti-
lized an unreactive a,b-unsaturated ester but one that suf-
fered the additional deactivating effect of possessing a
b-oxygen substituent.
Interest in the catalytic intramolecular Stetter reaction has
been rekindled by attempts to render the procedure enan-
tioselective. Enders pioneered this new push, generating
chiral thiazolium salts for use in intra- and intermolecular
Stetter reactions.6 And the mantle has since been taken up
by Rovis,7,8 Johnson,9 Scheidt,10 and others11 who have
developed high-yielding procedures which give highly
enantioenriched products.
At the outset of this work we were intrigued by a number
of questions: i) could we overcome the barrier to intramo-
lecular Stetter reactions between such unactivated esters
and aliphatic aldehydes by the presence of an existing
ring; ii) would the newly formed ring be stable given that
it would possess a b-alkoxy ester; and iii) would achiral
catalysts provide useful levels of diastereomeric (i.e., sub-
strate) control?
Despite the potential of this methodology to give rapid ac-
cess to ring systems, it possesses some limitations. For in-
SYNLETT 2009, No. 2, pp 0233–0236
x
x.
x
x.
2
0
0
8
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087519; Art ID: D33108ST
© Georg Thieme Verlag Stuttgart · New York
We set about answering these questions using a cyclo-
hexane-based system as a model for naturally occurring

234
C. S. P. McErlean, A. C. Willis
LETTER
H
H
Table 2 Conditions for the Intramolecular Stetter Reaction
OH
allylMgBr
CuCl
O
N
Br
Cl
Ph
N
BF4
Ph
93%
N
N
N
HO
3
4
N
S
N
1. O3, DMS
2. HS(CH2)3SH
BF3⋅OEt2
11
10
9
Entry Salt (mol%)Solvent
Base
Temp Yield of 8
(°C)
73%
(%)b
H
H
H
O
HCCCO2Et
OH
CO2Et
1
2
9a (30)
9 (30)
9 (30)
9 (30)
9 (30)
toluene
toluene
EtOH
KHMDS r.t.
0
S
NMM
S
88%
Et3N
Et3N
Et3N
Et3N
60
60
r.t.
40
0
S
S
H
6
5
3
0
MeI,
NaHCO3
96%
4
CH2Cl2
CH2Cl2
0
H
H
H
H
5
23
0
O
O
CO2Et
CO2Et
Table 2
6
10a (100) toluene
KHMDS r.t.
O
O
H
7
8
7
10 (30)
11 (30)
CH2Cl2
toluene–EtOH
Et3N
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
40
70
110
70
67
r.t.
67
67
0
Scheme 2 Synthesis of pyranone 8
8
29
trace
0
9
11 (100) toluene
11 (100) EtOH
11 (100) THF
11 (100) THF
pyran arrays (Scheme 2). As such, cyclohexene oxide 3
was reacted with allylmagnesium bromide to deliver the
known secondary alcohol 414 in good yield. Ozonolytic
cleavage of the alkene and treatment with propanedithiol
in the presence of boron trifluoride diethyl etherate deliv-
ered the dithiane 5. Michael addition of the alcohol to eth-
yl propiolate in the presence of N-methylmorpholine gave
the expected E-configured alkene 6.15 The aldehyde unit
was then unmasked to reveal the precursor 7 of the antic-
ipated intramolecular Stetter reaction. Initially, the triazo-
lium salts 9 and 10 described by Rovis were evaluated as
potential catalysts for effecting the desired ring closure
(Table 2).8 Disappointingly, the optimized conditions of
Rovis using either 9 or 10 in toluene with KHMDS as a
base failed to deliver the desired pyranone 8. After sur-
veying several base and solvent combinations, the desired
pyranone was eventually isolated in low yield, but omi-
nously, the bulk of the material had decomposed under the
basic reaction conditions.
10
11
12
13
14
54
29c
44
98
11 (30)
THF
11 (150) THF
a For synthesis, see ref. 8.
b Yield of isolated compound after chromatography.
c Reaction was halted after 48 h.
newly formed pyranone was assigned on the basis of NOE
experiments (see Supporting Information). The stereo-
chemical outcome of the reaction can be rationalized by
noting that the syn-pyranone is more thermodynamically
stable than the corresponding trans-isomer.16 Given the
basic nature of the carbene reagent and the presence of
DBU in the reaction mixture, the initial reaction products
may be converted into the more stable product by epimer-
ization or by an elimination–addition sequence. Alterna-
tively, we cannot rule out the possibility that the product
is the kinetic outcome of Stetter addition to the E-alkene.
Switching from a triazolium to a thiazolium-based car-
bene reagent gave immediate improvement (Table 2, en-
try 8). Using a mixed solvent system to ensure dissolution
of the thiazolium salt 11 and triethylamine as the base, the
desired pyranone 8 was isolated in a 29% yield along with
starting material in which the unsaturated ester was
present as a mixture of geometric isomers. This suggested
that triethylamine was interfering with the acrylate unit
and that use of a non-nucleophilic base would be advanta-
geous. With DBU as the base and THF as the solvent (en-
try 11), the desired pyranone 8 was isolated as the sole
product in 54% yield. To the best of our knowledge, this
is the first example of an intramolecular Stetter reaction
between an aliphatic aldehyde and an unactivated ester to
deliver a six-membered ring.
We next sought to improve the yield of the process
(Table 2). Lowering the reaction temperature resulted in
an unacceptable decrease in the rate of reaction, which
was incomplete after 2 days. As entry 13 shows, the reac-
tion proceeded with a substoichiometric amount of the
thiazolium salt, but in reduced yield. Given the commer-
cial availability and low cost of the reagent we did not
consider this a serious limitation. Indeed, increasing the
amount of thiazolium salt to 1.5 equivalents gave the desired
pyranone 8 in 98% yield.17
As expected, hydride reduction of the ketone 8 at low tem-
perature was stereoselective, delivering alcohol 12
(Scheme 3).18 X-ray crystallographic analysis of the cor-
Gratifyingly, 8 existed as a single diastereomer. The syn
relationship of the protons adjacent to the O atom of the
Synlett 2009, No. 2, 233–236 © Thieme Stuttgart · New York

LETTER
Intramolecular Stetter Reaction to Access trans,syn,trans-Fused Pyrans
235
H
O
H
CO2Et
H
H
H
H
H
H
O
O
CO2Et
CO2Et
OH
NaBH4
94%
O
O
H
CO2Et
H
H
H
O
8
16
12
O
3. HCCCO2Et
NMM
4. MeI, NaHCO3
53%
1. DiBAL-H
2. HS(CH2)3SH
BF3⋅OEt2
53%
17
H
H
H
TMSCHN2
BF3⋅OEt2
O
CO2Et
43%
11
O
H
O
H
H
O
H
O
O
(1.5 equiv)
DBU
8
Scheme 4 Oxepanone synthesis
81%
O
O
H
H
H
H
H
CO2Et
14
15
trans,syn,trans-fused polyether array and ring expanded
to the corresponding oxepanone. Further studies on sub-
strate-controlled, intramolecular Stetter reactions and
their application to the synthesis of natural products will
be reported in due course.
CO2Et
Scheme 3 Iterative synthesis of a polycyclic ether array
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
(1) (a) Stetter, H.; Kuhlmann, H. Angew. Chem., Int. Ed. Engl.
1974, 13, 539. (b) Stetter, H. Angew. Chem., Int. Ed. Engl.
1976, 15, 639. (c) Stetter, H. Org. React. 1991, 40, 407.
(2) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(3) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(4) Ciganek, E. Synthesis 1995, 1311.
(5) Trost, B. M.; Shuey, C. D.; DiNinno, F. Jr.; McElain, S. S.
J. Am. Chem. Soc. 1979, 101, 1284.
Figure 1 X-ray crystal structure of compound 13
(6) (a) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv.
Chim. Acta 1996, 79, 1899. (b) Enders, D.; Balensiefer, T.
Acc. Chem. Res. 2004, 37, 534.
responding 3,5-dinitrobenzoate 13 established unambigu-
ously the trans,syn,trans stereochemistry of the bicyclic
pyran (Figure 1).19,20
(7) Rovis, T.; Kerr, M. S. Synlett 2003, 1934.
(8) (a) Read de Alaniz, J.; Kerr, M. S.; Moore, J. L.; Rovis, T.
J. Org. Chem. 2008, 73, 2033. (b) Kerr, M. S.;
Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298. (c) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004,
126, 8876. (d) Rovis, T.; Read de Alaniz, J. J. Am. Chem.
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10, 691.
(10) (a) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am.
Chem. Soc. 2004, 126, 2314. (b) Mattson, A. E.; Bharawaj,
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5715.
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107, 5606.
The alcohol 12 was then carried through another iteration
of the ring-forming sequence to deliver the tricyclic com-
pound 15, which could serve as the substrate for further
iterations.
Having demonstrated that the intramolecular Stetter reac-
tion provided access to a stable pyranone product and that
the reaction displayed a high level of diastereocontrol, we
turned our attention to the question of ring size
(Scheme 4). Disappointingly, the corresponding ox-
epanone 17 was not produced by subjecting the homolo-
gous aldehyde 16 to the conditions used previously.
However, pyranone 8 could be ring expanded in the
known fashion by the action of trimethylsilyldi-
azomethane to deliver the seven-membered ring.21
(12) (a) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem. Commun.
2007, 1922. (b) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.;
Gibe, R.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47,
944.
(13) For polycyclic ethers, see: (a) Bowden, B. Toxin Rev. 2006,
25, 137. (b) Inoue, M. Chem. Rev. 2005, 105, 4379. (c) Lin,
Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.;
In summary, we report the first example of an intramolec-
ular Stetter reaction between an aliphatic aldehyde and an
acrylate unit to access a trans,syn-fused pyranone as a
single diastereomer. This compound was progressed to a
Synlett 2009, No. 2, 233–236 © Thieme Stuttgart · New York

236
C. S. P. McErlean, A. C. Willis
LETTER
Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc.
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M.; Covelo, B.; Gómeza, G.; Fall, Y. Tetrahedron Lett.
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(o) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T.
Tetrahedron 2002, 58, 1853.
residue was subjected to flash chromatography, eluting with
10% EtOAc in hexanes, to give 8 (57 mg, 98%) as a clear oil.
IR (CHCl3): nmax = 3093, 2977, 2931, 1735, 1720, 1450,
1396, 1288, 1172, 1103, 1026 cm–1. 1H NMR (300 MHz,
CDCl3): d = 4.29 (1 H, dd, J = 6.0, 5.7 Hz), 4.14 (2 H, q, J =
7.2 Hz), 3.36 (1 H, ddd, J = 9.9, 9.9, 4.5 Hz), 2.87 (1 H, dd,
J = 16.5, 5.4 Hz), 2.62 (1 H, dd, J = 16.5, 6.3 Hz), 2.55 (1 H,
dd, J = 15.5, 4.5 Hz), 2.15 (1 H, dd, J = 15.5, 12.3 Hz), 2.05–
1.99 (1 H, m), 1.85–1.62 (4 H, m), 1.37–1.06 (4 H, m), 1.25
(3 H, t, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): d = 206.6
(C), 171.0 (C), 80.5 (CH), 79.7 (CH), 60.7 (CH2), 45.1
(CH2), 42.9 (CH), 35.3 (CH2), 32.0 (CH2), 31.7 (CH2), 24.9
(CH2), 24.6 (CH2), 14.2 (CH3). HRMS: m/z calcd for
C13H21O4 [M + H+]: 241.14344; found: 241.14383.
(18) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc.
1996, 118, 8158.
(19) (a) For the synthesis of compound 13 see Supporting
Information. (b) CCDC 702838 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
(14) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982,
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
104, 2444.
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(16) Betancort, J. M.; Martín, V. S.; Padrón, J. M.; Palazón, J. M.;
Ramírez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570.
(17) Synthesis of Compound 8
(20) (a) A crystalline p-bromobenzoate derivative of a similar
fused bicyclic system has been reported.20b Therefore,
alcohol 12 was converted into the corresponding p-bromo-
benzoate but that compound failed to provide crystals
suitable for X-ray crystallographic analysis. (b) Nicolaou,
K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am.
Chem. Soc. 1989, 111, 5330.
(21) (a) Shioiri, T.; Hashimoto, N.; Aoyama, T. Tetrahedron Lett.
1980, 21, 4619. (b) Mori, Y.; Yaegashi, K.; Furukawa, H.
J. Am. Chem. Soc. 1997, 119, 4557. (c) Mori, Y.; Nogami,
K.; Hayashi, H.; Noyori, R. J. Org. Chem. 2003, 68, 9050.
To a solution of aldehyde 7 (58 mg, 0.24 mmol) in THF (2
mL) was added thiazolium salt 11 (90 mg, 0.36 mmol) and
DBU (54 mL, 0.36 mmol). The mixture was stirred under
reflux for 16 h, poured onto H2O (30 mL), and extracted with
EtOAc (4 × 10 mL). The combined organic phases were
dried over Na2SO4, the solvent was evaporated, and the
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