Synthesis of isotetronic acids by cyclization of 1,3-bis(trimethylsilyloxy) alk-1-enes with oxalyl chloride

Article abstract of DOI:10.1016/j.tetlet.2005.09.137

Isotetronic acids were regioselectively prepared by cyclization of 1,3-bis(trimethylsilyloxy)alk-1-enes with oxalyl chloride.

Full text of DOI:10.1016/j.tetlet.2005.09.137

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8129–8131
Synthesis of isotetronic acids by cyclization of
1,3-bis(trimethylsilyloxy)alk-1-enes with oxalyl chloride
Rudiger Dede,a,b Lars Michaelisb and Peter Langera,c,
*
¨
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bInstitut fu¨r Chemie und Biochemie, Ernst-Moritz-Arndt Universita¨t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
cLeibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e. V. (IfOK), Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 4 August 2005; revised 20 September 2005; accepted 21 September 2005
Available online 7 October 2005
Abstract—Isotetronic acids were regioselectively prepared by cyclization of 1,3-bis(trimethylsilyloxy)alk-1-enes with oxalyl chloride.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Isotetronic acids and butenolides are of great pharmaco-
logical relevance and occur in a number of natural prod-
ucts:1 for example, (+)-leptosphaerin represents a
metabolite of the marine ascomycete Leptosphaeria
oraemaris2a and compound WF-3681 represents an
aldose reductase inhibitor produced by Chaetomella
raphigera.2b Isotetronic acid derivatives have been
used also as key intermediates during the synthesis of
available starting materials. The reactions proceed in
good yields and with very good regioselectivity and are
convenient to be carried out.
Oxalyl derivatives represent useful synthetic building
blocks for the synthesis of oxygen heterocycles: Saal-
frank and co-workers have reported the synthesis of
2,3-dioxo-2,3-dihydrofurans by cyclization of 1,3-dicar-
bonyl compounds with oxalyl chloride.8 We have
reported an efficient approach to a-hydroxy-c-alkylid-
enebutenolides by cyclization of 1,3-bis-silyl enol
ethers—masked 1,3-dicarbonyl dianions—with oxalyl
chloride.9 Herein, we wish to report a convenient
one-pot synthesis of isotetronic acids by what are,
to the best of our knowledge, the first cyclizations of
oxalyl chloride with 1,3-bis(trimethylsilyloxy)alk-1-enes,
which can be regarded as masked dianions of 3-
hydroxyesters.10
(ꢀ)-tetrodotoxin,3a
6-thiosialic
and
neuraminic
acids,3b–e nactins4a or erythronolide A.4b Ascorbic acid
derivatives5a represent synthetic precursors of (+)- and
(ꢀ)-eldanolide,5b antileukaemic lignans, such as (+)-
trans-burseran5c and (ꢀ)-isostegane,5c (+)- and (ꢀ)-ste-
ganacin,5d (ꢀ)-verrucarinolactone5e and chrysanthemic
acid analogues. Although a number of synthetic
approaches to isotetronic acids are known,6,7 the devel-
opment of new and efficient methods is of considerable
current interest. The methodology reported herein pro-
vides a convenient and inexpensive approach to a vari-
ety of functionalized isotetronic acids fromreadily
The cyclization of oxalyl chloride with 1,3-bis(trimeth-
ylsilyloxy)alk-1-ene 2a, available by reaction of the
dianion of 1a with trimethylchlorosilane,11 afforded
the isotetronic acid 3a. After careful optimization of
the reaction conditions (Table 1), 3a was isolated in
up to 54% yield. Interestingly, the best results were
obtained when the reaction was carried out without
the presence of a Lewis acid (entry 7, 1:1 stoichio-
metry, 18 h, ꢀ78 ! 20 ꢁC, c = 0.1 M).12 In contrast,
the cyclization of 1,3-bis-silyl enol ethers with oxalyl
chloride requires the use of catalytic amounts of
Me3SiOTf.9 On the other hand, the reaction of 1,3-
bis-silyl enol ethers with simple acid chlorides proceeds
best in the absence of Lewis acid;13 the same is true for
Me
HN
Ph
OH
O
H
O
HO
O
O
O
O
HO
HO
(+)-Leptosphaerin
WF-3681
Keywords: Butenolides; Cyclizations; Isotetronic acids; Oxalyl chlo-
ride; Silyl enol ethers.
*
Corresponding author. Tel.: +49 381 498 6410; fax: +49 381 498
6412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.137

8130
R. Dede et al. / Tetrahedron Letters 46 (2005) 8129–8131
Table 1. Optimization of the synthesis of 3a
Entry
Lewis acid (equiv)
(COCl)2 (equiv)
c (2a) [M]
t [h], T [ꢁC]
% (3a)a
1
2
3
4
5
6
7
8
9
Me3SiOTf (0.5)
Me3SiOTf (0.5)
Me3SiOTf (0.5)
Me3SiOTf (1.0)
Me3SiOTf (4.0)
Me3SiOTf (4.0)
None
BF3ÆOEt2 (2.0)
TiCl4 (2.0)
TiCl4 (2.0)
2.0
2.5
1.3
1.3
4.3
4.3
1.0
1.3
1.3
1.3
0.12
0.075
0.15
0.12
0.03
0.03
0.10
0.12
0.12
0.12
0.5, ꢀ78; 96, 20
0.5, ꢀ78; 2, 50
18, 20
51
14
50
53
30
23
54
40
0b
0b
0.5, ꢀ78; 96, 20
72, ꢀ78 ! 20
72, 0 ! 20
18, ꢀ78 ! 20
0.5, ꢀ78; 96, 20
72, ꢀ78 ! 20
72, ꢀ78 ! 20
10
a Isolated yields.
b Complex mixture.
the condensation of simple silyl ketene acetals with
oxalyl chloride.14
Bu
Bu
O
OEt
O
OEt
O
i
O
The preparative scope of our methodology was studied
(Scheme 1, Table 2). The 1,3-bis(trimethylsilyloxy)alk-
1-enes 2a–k were prepared by generation of the dianions
of the 3-hydroxyalkanoates 1a–k, which are available
by aldol reaction of ethyl and methyl acetate with the cor-
responding aldehydes. The alkyl-substituted isotetronic
acids 3a–i were prepared from 2a–i. All products were
isolated (except for 3h) in good yields. The cyclization
O
OTf
O
OH
3f
4 (84%)
ii
Bu
PhB(OH)2
OEt
O
O
O
Ph
5 (76%)
Scheme 2. Synthesis of 5. Reagents and conditions: (i) Tf2O, pyridine,
ꢀ78 ! ꢀ10 ꢁC; (ii) Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), dioxane,
reflux.
OH
1a-k
ii
O
O
i
O
+
R1
R2
R2
R1
of 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,4-pentadiene (2j)
with oxalyl chloride afforded the vinyl-substituted isote-
tronic acid 3j. The phenyl-substituted isotetronic acid
3k was prepared from1-ethoxy-1,3-bis(trimethylsilyl-
oxy)-3-phenylprop-1-ene (2k). All transformations were
carried out without the presence of a Lewis acid.
Cl
O
R1
R2
O
Cl
Me3SiO
R1
OSiMe3
R2
O
O
iii
The hydroxy group of the isotetronic acid was success-
fully functionalized by transition metal catalyzed
cross-coupling reactions: for example, 3f was trans-
formed into enol triflate 4. The Suzuki reaction of 4 with
phenylboronic acid afforded butenolide 5 in good yield
(Scheme 2).
O
OH
3a-k
2a-k
Scheme 1. Synthesis of isotetronic acids 3a–k. Reagents and condi-
tions: (i) LDA, THF, 5 min, ꢀ78 ꢁC; (ii) (1) LDA (2.2 equiv), THF,
1 h, ꢀ78 ꢁC, (2) Me3SiCl (2.5 equiv), ꢀ78 ! 20 ꢁC, 24 h; (iii) (COCl)2
(1.0 equiv), ꢀ78 ! 20 ꢁC, 18 h.
Our current studies are directed towards the synthesis
of enantiomerically pure isotetronic acids from enantio-
merically pure 3-hydroxyesters.
Table 2. Products and yields
3
R1
R2
% (3)a
Acknowledgement
a
b
c
d
e
f
Me
Me
Et
nPr
iPr
nBu
iBu
OEt
OMe
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OEt
OEt
54
52
77
71
54
75
63
19
61
34
62
Financial support fromthe Deutsche Forschungsge-
meinschaft is gratefully acknowledged.
g
h
i
References and notes
tBu
nHex
CH@CH2
Ph
1. For reviews of butenolides, see: (a) Rao, Y. S. Chem. Rev.
1976, 76, 625; (b) Pattenden, G. Prog. Chem. Nat. Prod.
1978, 35, 133; (c) Knight, D. W. Contemp. Org. Synth.
1994, 1, 287.
j
k
a Isolated yields.

R. Dede et al. / Tetrahedron Letters 46 (2005) 8129–8131
8131
2. (a) Pallenberg, A. J.; White, J. D. Tetrahedron Lett. 1986,
5591; (b) Namiki, T.; Nishikawa, M.; Itoh, Y.; Uchida, I.;
Hashimoto, M. Tetrahedron Lett. 1987, 1400.
3. (a) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125,
11510; (b) Mack, H.; Brossmer, R. Tetrahedron 1998, 54,
4521; (c) Mack, H.; Brossmer, R. Tetrahedron Lett. 1992,
33, 1867; (d) Lafont, D.; Hoch, M.; Schmidt, R. R. J.
Carbohydr. Chem. 1986, 5, 601; (e) Holmquist, L. Acta
Chem. Scand. 1971, 25, 712.
4. (a) Barrett, A. G. M.; Sheth, H. G. J. Org. Chem. 1983, 48,
5017; for the synthesis of erythronolide A, see: (b) Stork,
G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987, 109, 1564–
1565.
5. (a) Vekemans, J. A. J. M.; Franken, G. A. M.; Dapperens,
C. W. M.; Godefroi, E. F. G. J. Org. Chem. 1988, 53, 627;
(b) Vigneron, J. P.; Meric, R.; Larcheveque, M.; Debal,
A.; Lallemand, J. Y.; Kunesch, G.; Zagetti, P.; Gallois, M.
Tetrahedron 1984, 40, 3521; (c) Tomioka, K.; Ishiguro, T.;
Iitaka, Y.; Koga, K. Tetrahedron 1984, 40, 1303; (d)
Tomioka, K.; Sato, F.; Koga, K. Heterocycles 1982, 17,
311; (e) Mann, J.; Thomas, A. J. Chem. Soc., Chem.
Commun. 1985, 737.
(50.0 mmol) was prepared by addition of nBuLi
(20.5 mL, 51.3 mmol, 2.5 M solution in hexanes) to a
THF solution (50 mL) of diisopropylamine (5.06 g,
50.0 mmol) at 0 ꢁC. After stirring for 1 h, the solution
was cooled to ꢀ78 ꢁC and ethyl 3-hydroxyheptanoate (1f)
(3.92 g, 22.5 mmol) was added. After stirring for 1 h at
ꢀ78 ꢁC, trimethylchlorosilane (6.11 g, 56.2 mmol) was
added and the solution was allowed to warmto 20 ꢁC
within 24 h. The solvent and volatile compounds were
removed in vacuo and the residue was dissolved in hexane
and filtered under inert atmosphere. The filtrate was
concentrated in vacuo to give 1-ethoxy-1,3-bis(trimethyl-
silyloxy)hept-1-ene (2f) (7.17 g, 100%) as a clear yellow
liquid, which was used without further purification. 1H
NMR (CDCl3, 300 MHz): d = 4.37–4.45 (m, 1H,
CHCH2), 3.72 (q, J = 7.1 Hz, 2H, OCH2), 3.51 (d, J =
9.0 Hz, 1H, CHCHCH2), 1.20–1.60 (m, 9H, CH2CH2CH2,
OCH2CH3), 0.86–0.94 (m, 3H, CH2CH2CH3), 0.23 (s, 9H,
Si(CH3)3), 0.16 (s, 9H, Si(CH3)3); 13C NMR (CDCl3,
75 MHz): d = 155.96 (C), 81.02, 68.60 (CH), 62.81
(OCH2), 39.29, 28.14, 22.55 (CH2), 14.32, 14.11 (CH3),
0.47, 0.31 (Si(CH3)3); MS (EI, 70 eV): m/z (%) = 317.8
(M+, 0.15), 260.7 (42), 230.7 (11), 188.7 (13), 146.3 (25),
142.9 (100), 110.0 (19), 102.6 (12), 75.3 (35), 73.5 (77), 55.2
(13), 28.0 (20).
3
3
6. Enders, D.; Dyker, H.; Leusink, F. R. Chem. Eur. J. 1998,
4, 311, and references cited therein.
7. (a) Bonadies, F.; Scarpati, M. L. Gazz. Chim. Ital. 1983,
113, 421; (b) Amer, A.; Ventura, M.; Zimmer, H. J.
Heterocycl. Chem. 1983, 20, 359; (c) Wiley, R. H.; Kim, K.
S. J. Org. Chem. 1973, 38, 3582; (d) Cocker, W.; Ladwa, P.
H.; McMurry, T. B. H.; Ntamila, M. S. J. Chem. Soc. (C)
1971, 9, 1708; (e) Stacy, G. W.; Cleary, J. W.; Gortatow-
ski, M. J. J. Am. Chem. Soc. 1957, 79, 1451; (f) Stacy, G.
W.; Wagner, G. D. J. Am. Chem. Soc. 1952, 74, 909.
8. (a) Saalfrank, R. W.; Lutz, T. Angew. Chem. 1990, 102,
1064; Angew. Chem., Int. Ed. Engl. 1990, 29, 1041; (b)
Saalfrank, R. W.; Lutz, T.; Hoerner, B.; Guendel, J.;
Peters, K.; von Schnering, H. G. Chem. Ber. 1991, 124,
2289.
9. (a) Langer, P.; Stoll, M. Angew. Chem. 1999, 111, 1919;
Angew. Chem., Int. Ed. 1999, 38, 1803; (b) Langer, P.;
Schneider, T.; Stoll, M. Chem. Eur. J. 2000, 6, 3204; (c)
Langer, P.; Eckardt, T.; Schneider, T.; Go¨bel, C.; Herbst-
Irmer, R. J. Org. Chem. 2001, 66, 2222; (d) Ahmed, Z.;
Langer, P. J. Org. Chem. 2004, 69, 3753; for a-hydroxy-
maleic anhydrides, see: (e) Ullah, E.; Langer, P. Synlett
2004, 2782.
10. For reactions of silyl ketene acetals derived from3-
hydroxyesters, see: (a) Ohtake, H.; Imada, Y.; Murahashi,
S.-I. J. Org. Chem. 1999, 64, 3790; (b) Hattori, K.;
Yamamoto, H. Bioorg. Med. Chem. Lett. 1993, 11, 2337;
(c) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50,
3099; (d) Caron, B.; Brassard, P. Tetrahedron 1993, 49,
771; (e) Gu, J. H.; Terada, M.; Mikami, K.; Nakai, T.
Tetrahedron Lett. 1992, 33, 1465; (f) Hoffman, R. V.; Kim,
H. O. J. Org. Chem. 1991, 56, 6759; (g) Shirai, F.; Nakai,
T. Tetrahedron Lett. 1988, 29, 6461; (h) Guanti, G.; Banfi,
L.; Narisano, E. Tetrahedron 1988, 44, 5553; (i) Guanti,
G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987, 28,
4335.
12. Typical procedure for the preparation of isotetronic acids
3a–k. To a CH2Cl2 solution (10 mL) of 2f (322 mg,
1.01 mmol) was added a CH2Cl2 solution of oxalyl
chloride (2 M, 0.505 mL, 1.01 mmol) at ꢀ78 ꢁC. The
temperature of the reaction mixture was allowed to rise
to 20 ꢁC within 16 h. Ether (60 mL) and brine (20 mL)
were added, the organic and the aqueous layer were
separated and the latter was extracted with ether
(3 · 30 mL). The combined organic layers were washed
with water (10 mL), dried (Na2SO4) and filtered. The
filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/
ether = 1:1) to give 3f (173 mg, 75%) as slightly orange
crystals. IR (KBr, cmꢀ1): m ¼ 3330 (br, w), 2960 (m), 2935
~
(m), 2870 (w), 1780 (s), 1708 (s), 1662 (m), 1443 (m), 1378
(w), 1336 (m), 1301 (m), 1226 (m), 1183 (m), 1138 (m) 1103
1
(m), 1018 (w), 770 (w); H NMR (CDCl3, 300 MHz): d =
8.6–7.6 (s, br, 1H, OH), 5.11 (dd, 3J1 = 7.9 Hz, 3J2 =
2.9 Hz, 1H, CH), 4.30–4.48 (m, 2H, OCH2), 2.00–2.20 (m,
1H, CHCHAHB), 1.50–1.70 (m, 1H, CHCHAHB), 1.45–
3
1.25 (m, 7H, CH3CH2CH2), 0.91 (dd, J1 = 3J2 = 7.1 Hz,
3H, OCH2CH3); 13C NMR (CDCl3, 75 MHz): d = 165.86,
164.54, 152.13, 118.71 (C), 78.28 (CH), 61.86 (OCH2),
32.66, 26.30, 22.20 (CH2), 14.07, 13.71 (CH3); MS
(EI, 70 eV): m/z (%) = 227.8 (M+, 3), 182.8 (43), 171.8
(25), 142.9 (100), 125.9 (33), 114.1 (92), 113.1 (89), 96.8
(46), 85.8 (52), 69.8 (71), 41.0 (60), 29.0 (90), 27.9 (47), 27
(47). All products were prepared in racemic form. All
products were characterized spectroscopically and gave
correct elemental analyses and/or high resolution mass
spectra.
13. Nguyen, V. T. H.; Reim, S.; Langer, P. Tetrahedron Lett.,
in press.
11. Typical procedure for the preparation of 1,3-bis(trimethyl-
14. Heurtaux, B.; Lion, C.; Le Gall, T.; Mioskowski, C.
J. Org. Chem. 2005, 70, 1474.
silyloxy)alk-1-enes 2a–k.
A THF solution of LDA