Regio- and diastereoselective synthesis of lissoclinolide analogues by Lewis acid catalyzed cyclization of the first 1,5-bis(trimethylsilyloxy)-1,3,5-hexatrienes with oxalyl chloride

Article abstract of DOI:10.1055/s-2001-12327

The Lewis acid catalyzed cyclization of 1,5-bis(trimethylsilyloxy)-1,3,5-hexatrienes with oxalyl chloride resulted in formation of polyunsaturated butenolides.

Full text of DOI:10.1055/s-2001-12327

LETTER
523
Regio- and Diastereoselective Synthesis of Lissoclinolide Analogues by Lewis
Acid Catalyzed Cyclization of the First 1,5-Bis(trimethylsilyloxy)-1,3,5-
hexatrienes with Oxalyl Chloride
Peter Langer,* Ilia Freifeld
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: planger@uni-goettingen.de
Received 19 January 2001
oxidation of the resulting alcohols afforded the aldehydes
Abstract: The Lewis acid catalyzed cyclization of 1,5-bis(trimeth-
ylsilyloxy)-1,3,5-hexatrienes with oxalyl chloride resulted in for-
mation of polyunsaturated butenolides.
3
1
a-d in good yields. Wittig reaction afforded the protected
,5-ketoesters 4a-d9 which were deprotected and
transformed into the novel silyl dienol ethers 6a-d in
high yields. Deprotonation of 6a-d with LDA/HMPTA at
Key words: butenolides, cyclizations, oxalic acid, regioselectivity,
silyl enol ethers
7
8 °C and subsequent addition of Me SiCl resulted in
3
formation of the desired 1,5-bis(trimethylsilyloxy)-1,3,5-
hexatrienes 7a-d in good yields. For the synthesis of 7a-c
a spirocyclic acetal was used as the protecting group. In
case of the synthesis of 7d, this group could not be
chemoselectively removed without destruction of the
molecule. This problem was eventually solved by the use
of the dimethylacetal protecting group.
Polyunsaturated
prominent natural products such as freelingyne, dihydro-
freelingyne, lissoclinolide, and dihydroxerulin, are of
-alkylidenebutenolides, including
1
high pharmacological relevance. Lissoclinolide, for in-
stance, exhibits antibiotic activity against Gram-positive
2
bacteria and dihydroxerulin has proven to be an impor-
tant nontoxic inhibitor in the biosynthesis of cholesterol.3
-
Alkylidenebutenolides have been prepared so far by
O
R'O OR'
O
O
4
5
R1
Wittig reactions, stereospecific -eliminations, or lac-
tonizations of 2-en-4-ynoic acids and related methods.
We have recently reported a new approach to -alkyl-
R1
a
OR
6
OR
R = Me, Et
a-c (R' = _CH2 _)
1d (R' = CH3)
1
7
idenebutenolides based on cyclizations of 1,3-dicarbonyl
dianions and 1,3-bis(trimethylsilyloxy)-1,3-butadienes,
electroneutral dianion equivalents, with oxalic acid di-
electrophiles. Herein, we wish to report an extension of
this methodology to the synthesis of polyunsaturated
b
8
O
R'O
R'O OR'
c
OR'
R1
R1
OH
H
3a-d
2a-d
-
alkylidenebutenolides which relies on the first cycliza-
tions of 1,5-bis(trimethylsilyloxy)-1,3,5-hexatrienes, a
previously unknown substance class, with oxalyl chlo-
ride. The butenolides prepared represent important ana-
logues and synthetic precursors to pharmacologically
relevant natural products such as lissoclinolide.
d
O
O
O
R'O OR'
e
R1
R1
OR2
OR2
4
a-d
5a-d
f
OH
O
O
O
HO
O
OSiMe3
O
OSiMe3
OSiMe3
OR2
O
g
R1
R1
OR2
Dihydrofreelingyne
Lissoclinolide
7a-d
6a-d
7
7
a: R1 = Me, R = Me
2
7c: R1 = H, R = Me
2
O
O
1
2
7d: R = OMe, R2 = Et
1
b: R = Et, R = Et
Dihydroxerulin
Scheme 1 Synthesis of 1,5-Bis(trimethylsilyloxy)-1,3,5-hexatri-
enes 7a-d. a: 1a-c: (CH OH) , p-TosOH, toluene, Dean-Stark-trap,
2
2
+
reflux, 12 h, 77 80%; 1d: (MeO) CH, Amberlite IR-120 , 20 °C,
Despite many potential applications, 1,5-bis(trimethylsi-
lyloxy)-1,3,5-hexatrienes have to our knowledge not been
previously prepared. These new synthetic building blocks
were prepared as follows (Scheme 1): acetalization of
3
6
2%; b: HAl(Bu-i) , CH Cl , 78 °C, 1 h, 60 92%; c: oxalyl chlo-
2 2 2
2
ride, DMSO, NEt3, 78 °C, 78 95%; d: Ph P=CHCO R , THF,
2
8
3
2
0 °C, 1 h, 42 72%; e: 5a-c: p-TosOH, acetone, reflux, 12 h, 65
4%; 5d: TFA, CH Cl , 95%; f: Me SiCl, NEt , C H , 20 °C, 24 h,
2
2
3
3
6
6
the corresponding -ketoesters afforded the acetals 1a-d; 77 98%; g: 1) 1.5 equiv. LDA, HMPTA, THF, 78 °C, 1 h,
reduction of the ester group and subsequent Swern 2) Me SiCl, 78 20 °C, 4 h, 70 93%.
3
Synlett 2001 No. 4, 523–525 ISSN 0936-5214 © Thieme Stuttgart · New York

5
24
P. Langer, I. Freifeld
LETTER
Reaction of triene 7a with oxalyl chloride in the presence
O
OMe
O
δ = 5.85
of 0.5 equiv. of trimethylsilyl-trifluoromethanesulfonate
δ = 6.43
OH
J = 14 Hz
δ = 6.87
7
c, 10
(
Me SiOTf)
-
resulted in formation of the desired
alkylidenebutenolide 8a.11 Likewise, cyclization of
trienes 7b-d with oxalyl chloride afforded the butenolides
b-d. Complex mixtures were obtained when no Lewis
J = 14 Hz
3
O
OH
OMe
O
δ = 6.07
O
O
8
Z-8c
E-8c
acid was added or when stoichiometric amounts of TiCl4
were used. The formation of butenolides 8a-d proceeded
with very good regioselectivity and (except for 8c) with
very good diastereoselectivity in favor of the products
containing a Z-configured exocyclic double bond.
δ = 5.81
NOE
Me
J = 14 Hz
O
OH
OMe
O
O
8a
O
Cl
O
R1
O
O
The formation of butenolides 8a-d can be explained by
the following working hypothesis (Scheme 2): oxalyl
OSiMe3
OSiMe3
OR2
Cl
OH
R1
OR2
O
0.5 eq. Me SiOTf
CH2Cl2, _78 °C
3
chloride is activated by Me SiOTf and subsequently at-
7a-d
8a-d
3
tacked by the terminal carbon atom of the 1,5-bis(trimeth-
ylsilyloxy)-1,3,5-hexatriene to give intermediate A.
Intramolecular silyl-migration resulted in formation of in-
termediate B and generation of an ester function (interme-
diate C). The product is formed by attack of the oxygen
atom onto the activated carboxylic chloride, expulsion of
+
Me3SiOTf
oxalyl chloride
Me3SiCl
_
_
Me3SiOTf
Me3SiCl
+
_
Me3
Si
+
O
Cl
Me3Si
OH
O
+
O
O
OSiMe3
_
OTf
OR2
O
O
OR2
Me SiCl and regeneration of the catalyst.
3
1
_
R
SiMe3
R1
Cl
OTf
The high regioselectivity for the first condensation step
suggests that for trienes 7a-d the highest electron density
is present at the terminal carbon atom. The regioselectivi-
ty of the cyclization step can be explained based on stereo-
A
C
Me3
Si
SiMe3
O
O
O
OH
12
+
OR2
electronic considerations: the formation of a five-mem-
_
OTf
Cl
R1
bered ring by acylation of the carbon of an enol requires
approach of the electrophile perpendicular to the plane of
B
Scheme 2 Synthesis of polyunsaturated -alkylidenebutenolides the double bond; in contrast, acylation of the oxygen re-
8
a-d
quires approach in the plane of the enol. In case of five-
membered rings, approach of the electrophile to the car-
bon atom of the enol is, thus, sterically difficult compared
to its approach in the plane to the oxygen. The Z-selectiv-
ity of the formation of butenolides 8a-b and 8d can be ex-
Table Synthesis of butenolides 8a-d
1
plained by the steric influence of the substituent R .
3
Me SiO
OSiMe
3
3
Me SiO
OSiMe3
O
O
O
a
b
OMe
O
OMe
3
Me SiO
OMe
9
10
11
a
1
b
By H NMR of the products. Isolated yield
c
The configuration of the products was determined as fol-
lows: For all butenolides, the J = 14 Hz coupling be-
O
OH
O
OH
O
OH
3
MeO
MeO
2 (keto:enol = 2:1)
O
O
O
O
tween the hydrogen atoms 2 -H and 3 -H suggests that the
corresponding double bond exhibits E-configuration.
Similar coupling constants have been previously observed
1
Scheme 3 Synthesis of butenolide 12. a: Me SiCl, NEt , ZnCl ,
3
3
2
4
for related butenolides. The geometry of the exocyclic
CH Cl , 20 °C, 90%; b: 1) LDA, THF, 78 °C, 1 h, 2) Me SiCl,
2
2
3
double bond C-5 C-1 was determined by NOESY mea-
surements and by analysis of the chemical shifts ( H
78 20 °C, 4 h, 84%; c: oxalyl chloride, 0.3 eq. Me SiOTf, CH Cl ,
78 20 °C, 12 h, 55%.
3 2 2
1
NMR) of the hydrogen atoms 1 -H (for 8a-d) and 4-H (for
8
c) following the general rule that the signals of E-config-
The use of 1,3,5-tris(trimethylsilyloxy)-1,3-5-hexatrienes
in our cyclization reaction was next studied (Scheme 3).
Triene 11 was prepared by conversion of methyl
ured -alkylidenebutenolides are shifted downfield rela-
tive to the signals of the respective Z-configured isomers.4
Synlett 2001, No. 4, 523–525 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Regio- and Diastereoselective Synthesis of Lissoclinolide Analogues
525
3
1
,5-dioxohexanoate 9 into the 1,3-bis(trimethylsilyloxy)-
,3-butadiene 10 which was subsequently transformed
Tetrahedron Lett. 1998, 7799; (c) Xu, C.; Negishi, E.-i.
Tetrahedron Lett. 1999, 431.
(7) For -alkylidenebutenolide syntheses from our laboratory,
1
3
into 11. The Me SiOTf-catalyzed cyclization of triene
1
lide 12 with very good regio- and E-diastereoselectivity.
The product resides as a 2:1-mixture of keto-enol-tau-
3
see: (a) Langer, P.; Stoll, M. Angew. Chem. Int. Ed. 1999, 38,
1 with oxalyl chloride afforded the -alkylidenebuteno-
1803; (b) Langer, P.; Schneider, T.; Stoll, M. Chem. Eur. J.
2000, 6, 3204; (c) Langer, P.; Eckardt, T.; Stoll, M. Org. Lett.
2000, 2991; (d) Langer, P.; Eckardt, T. Synlett 2000, 844;
tomers (in acetone-d ). It is important to note that buteno-
lides 12 and 8c both contain a hydrogen atom at the -
position of the ring (4-H). However, only butenolide 12
(e) Langer, P.; Saleh, N. N. R. Org. Lett. 2000, 3333.
(8) For 1,3-bis(trimethylsilyloxy)-1,3-butadienes, see: (a) Chan,
T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun. 1979,
6
578; (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc.
(
containing an additional carbonyl group) was formed
1980, 102, 3534; (c) Hagiwara, H.; Kimura, K.; Uda, H. J.
with high E-diastereoselectivity, whereas 8c was obtained
as a mixture of isomers. The selectivity observed for the
formation of 12 can be explained by the dipol-dipol repul-
Chem. Soc., Chem. Commun. 1986, 860; (d) Molander, G. A.;
Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830. For 1-
trimethylsilyloxy-1,3-dienes, see: (e) Hoffman, R. V.; Kim,
H.-O. J. Org. Chem. 1991, 56, 1014 and references cited
therein.
1
4
sion between the oxygen atoms or alternatively by the
formation of a stabilizing intramolecular hydrogen bond
C H(4) O in the product.
(
9) For the preparation of ketoester 5c, see: Barrett, A. G. M.;
Carr, R. A. E.; Finch, M. A. W.; Florent, J.-C.; Richardson, G.;
Walshe, N. D. A. J. Org. Chem. 1986, 51, 4254.
In summary, we have reported the first synthesis of
1
,5-bis(trimethylsilyloxy)-1,3,5-hexatrienes. The cycliza- (10) For the use of Me SiOTf in the reaction of simple silyl enol
3
tion of these compounds with oxalyl chloride allows for a
direct, regio- and diastereoselective synthesis of polyun-
saturated -alkylidenebutenolides under mild conditions.
The efficiency of this process is remarkable, if one consid-
ers that the oxalic acid unit is prone to several drawbacks
in reactions with nucleophiles. The butenolides prepared
represent important analogues and synthetic precursors to
pharmacologically relevant natural products such as lisso-
clinolide.
ethers with monofunctional acetals, see: Murata, S.; Suzuki,
M.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 3248. See also
ref. 8d.
(
11) Typical experimental procedure for the preparation of
butenolides 8: To a CH Cl solution (10 mL) of oxalyl
2
2
chloride (0.62 mmol, 80 mg) and of 1,5-bis(trimethylsilyl-
oxy)-1,3,5-hexatriene 7a (0.52 mmol, 156 mg) was added a
CH Cl solution (1 mL) of Me SiOTf (0.31 mmol, 70 mg)
1
5
2
2
3
at 78 °C. The temperature of the reaction mixture was
allowed to rise to 20 °C during 12 h. After stirring for 2 h at
2
0 °C the reaction mixture was extracted with a saturated
aqueous solution of NaCl (20 mL) and with a solution of HCl
10%, 20 mL). The organic layer was separated and the
aqueous layer was extracted with CH Cl (2 20 mL). The
(
Acknowledgement
2
2
P. L. thanks Professor A. de Meijere for his support. Financial sup-
port from the Fonds der Chemischen Industrie (Liebig scholarship
and funds for P. L.) and from the Deutsche Forschungsgemeinschaft
is gratefully acknowledged.
combined organic extracts were dried (MgSO ), filtered and
4
the solvent of the filtrate was removed in vacuo. The residue
was purified by column chromatography (silica gel, ether/
petroleum ether = 1:2 2:1) to give butenolide 8a as a yellow
1
solid (60 mg, 55%). H NMR (CDCl , 250 MHz): 2.03 (s, 3
3
H, CH ), 3.78 (s, 3 H, OCH ), 5.81 (d, J = 12 Hz, 1 H, 1 -H),
3
3
References and Notes
6
1
.00 (d, J = 14 Hz, 1 H, 3 -H), 7.76 (dd, J = 14 Hz, J = 12 Hz,
1
3
H, 2´-H). C NMR (CDCl , 50 MHz): 7.21 (CH ), 52.78
(
(
(
(
1) (a) Reviews: Rao, Y. S. Chem. Rev. 1976, 76, 625;
3
3
(
OCH ), 105.53 (CH, C-1 ), 120.93 (C), 122.16 (CH, C-3 ),
(
(
b) Pattenden, G. Prog. Chem. Nat. Prod. 1978, 35, 133;
c) Knight, D. W. Contemp. Org. Synth. 1994, 1, 287.
3
1
36.17 (CH, C-2 ), 141.86, 152.58, 164.45, 166.94 (C). MS
+
(
EI, 70 eV): 210 (M , 66), 179 (43), 95 (100), 83 (43), 57 (40).
2) (a) Gallo, C. G.; Coronelli, C.; Vigevani, A.; Lancini, G. C.
Tetrahedron 1969, 25, 5677; (b) Pagani, H.; Lancini, G.;
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3) Kuhnt, D.; Anke, T.; Besl, H.; Bross, M.; Herrmann, R.;
Mocek, U.; Steffan, B.; Steglich, W. J. Antibiot. 1990, 43,
+
The exact molecular mass m/z = 210.0528 ±2 mDa (M ) was
confirmed by HRMS (70 eV, EI). All compounds were
characterized by spectroscopic methods and gave correct
elemental analyses and/ or high resolution mass spectra.
12) Baldwin, J. E.; Kruse, L. I. J. Chem. Soc., Chem. Commun.
(
1
413.
4) (a) Siegel, K.; Brückner, R. Chem. Eur. J. 1998, 4, 1116;
b) Görth, F. C.; Brückner, R. Synthesis 1999, 1520; for
butenolides containing only one double bond in the
alkylidene side-chain, see for example: (c) Knight, D. W.;
Pattenden, G. J. Chem. Soc. Perkin Trans 1 1979, 62;
d) Ingham, C. F.; Massy-Westropp, R. A.; Reynolds, G. D.;
1977, 233.
(
(
13) Chan, T. H.; Stossel, D. J. Org. Chem. 1986, 51, 2423.
14) (a) Rhoads, S. J.; Holder, R. W. Tetrahedron 1969, 25, 5443;
(
(
b) Miller, B.; Margulies, H.; Drabb Jr., T.; Wayne, R.
-
Tetrahedron Lett. 1970, 3801; (c) Cambillau, C.; Sarthou, P.;
Bram, G. Tetrahedron Lett. 1976, 281; (d) Seebach, D.
Angew. Chem. Int. Ed. Engl. 1988, 27, 1624.
(
Thorpe, W. D. Aust. J. Chem. 1975, 28, 2499.
(
15) For the decarbonylation during the cyclization of glycols with
(
(
5) (a) Goerth, F.; Umland, A.; Brückner, R. Eur. J. Org. Chem.
oxalyl chloride, see: Iida, T.; Itaya, T. Tetrahedron 1993, 49,
1
1
998, 1055; (b) v. d. Ohe, F.; Brückner, R. Tetrahedron Lett.
998, 1909; (c) Hanisch, I.; Brückner, R. Synlett 2000, 374.
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(
Article Identifier:
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1
Synlett 2001, No. 4, 523–525 ISSN 0936-5214 © Thieme Stuttgart · New York