Enantioselective formal synthesis of tridemethylisovelleral

Article abstract of DOI:10.1016/j.tetlet.2006.11.122

A simple and efficient synthetic route to the bicyclic α,β-unsaturated β-keto ester methyl (3aS,7aS)-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate, a versatile intermediate in the synthesis of biologically active unsaturated 1,4-dialdehydes, is described. The synthesis includes a chirality introducing nonenzymatic asymmetric desymmetrization (ADS) reaction of a cyclic meso-anhydride 4 and a modified Hofmann method for preparing exocyclic dienes. The ester was synthesized in a moderate overall yield (19%) from 6 and with an excellent enantioselectivity (>90%).

Full text of DOI:10.1016/j.tetlet.2006.11.122

Tetrahedron Letters 48 (2007) 635–638
Enantioselective formal synthesis of tridemethylisovelleral
*
Daniel R o¨ me, Martin Johansson and Olov Sterner
Division of Organic Chemistry, Lund University, PO Box 124, S-22100 Lund, Sweden
Received 11 October 2006; revised 8 November 2006; accepted 17 November 2006
Available online 11 December 2006
Abstract—A simple and efficient synthetic route to the bicyclic a,b-unsaturated b-keto ester methyl (3aS,7aS)-6-oxo-2,3,3a,6,7,7a-
hexahydro-1H-indene-5-carboxylate, a versatile intermediate in the synthesis of biologically active unsaturated 1,4-dialdehydes, is
described. The synthesis includes a chirality introducing nonenzymatic asymmetric desymmetrization (ADS) reaction of a cyclic
meso-anhydride 4 and a modified Hofmann method for preparing exocyclic dienes. The ester was synthesized in a moderate overall
yield (19%) from 6 and with an excellent enantioselectivity (>90%).
ꢀ
2006 Elsevier Ltd. All rights reserved.
(
+)-Isovelleral (1), a thoroughly studied fungal meta-
diene and maleic anhydride. ADS reactions are powerful
methods of establishing several stereocentres in a single
symmetry-breaking operation. Considerable attention
bolite found in the fruit bodies of Lactarius vellereus,
possesses potent antimicrobial and cytotoxic activities.
1
4
The biological activities are linked to the presence of an
unsaturated 1,4-dialdehyde moiety and a cyclopropane
ring. The rationally designed synthetic racemic analog
tridemethylisovelleral (2) proved to be an even more
potent compound with antitumour properties in sub-
has been given to the use of prochiral cyclic anhydrides,
which are readily available through the Diels–Alder
reaction of maleic anhydride and suitable dienes as
substrates. The catalytic ADS of cyclic anhydrides often
5
utilizes bis-cinchona derived catalysts such as hydro-
2
nanomolar concentrations. Because of these results
quinine (anthraquinone-1,4-diyl) diether ((DHQ) AQN)
2
we desired to prepare 2 in enantiomerically pure form
since (+)-isovelleral and its stereoisomers have been
shown to possess significantly different biological activi-
and hydroquinidine (anthraquinone-1,4-diyl) diether
((DHQD) AQN).
2
1
a
ties (Fig. 1). Inspired by the pseudo-C -symmetry of 2
This synthetic methodology could possibly also be used
in the synthesis of other marasmanes or terpenoids with
compounds such as 3 as key intermediates.
2
(
Scheme 1) we were interested in studying the possibility
of utilizing a nonenzymatic asymmetric desymmetriza-
3
tion (ADS) reaction in the synthesis of this compound.
A symmetry-breaking hydrolytic opening of a meso-
anhydride would lead to a non-racemic ester carboxylic
acid. The meso-anhydride could be formed through a
diastereoselective Diels–Alder reaction between a 1,3-
Preparation of the meso-anhydride for the ADS reaction
required an efficient method for the synthesis of dimeth-
ylene compound 6. Exocyclic 1,3-dienes are especially
interesting and useful compounds, but have proven to
be quite difficult to prepare since they easily rearrange
to more substituted conjugated alkenes. Exocyclic
6
dienes are usually formed via a Hofmann elimination,
7
CHO
CHO
CHO
CHO
or by some other pyrolysis reaction, but can also be
8
synthesized via vinylogous Peterson olefination, E2-
9
10
elimination and allene dimerization. A prerequisite
for the Hofmann elimination is the presence of a
hydroxide counter-ion, which is usually obtained from
the corresponding halide with moist silver oxide. Ion-ex-
2
1
Figure 1.
11
change resins have in some cases been used instead of
silver oxide to effect ion exchange, since the oxide is light
sensitive and expensive. The resins themselves are quite
expensive too, but they are very stable and recyclable.
*
Corresponding author. Tel.: +46 708678687; fax: +46 462228209;
e-mail: martin.johansson@organic.lu.se
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.122

636
D. R o¨ me et al. / Tetrahedron Letters 48 (2007) 635–638
CHO
CHO
CHO
CHO
CO Me
2
O
C2
2
3
O
O
CO Me
2
+
O
O
CO H
2
O
O
6
7
4
5
Scheme 1. Retrosynthetic analysis.
As a part of this project we were interested in exploring
the formation of exocyclic dienes without the use of
silver reagents.
an analogous manner from the corresponding diacid
(14).
In order to convert 5 into ketoester 3, the carbon–car-
bon double bond had to be reduced (Scheme 3).
Although tetra-substituted alkenes are known to be
resistant towards standard hydrogenation conditions,
substrates similar to 5 have been reduced with Adam’s
The synthesis of the dienes studied in this investigation
began with the bromination of b-keto ester 8, which in
turn was subjected to a Favorskii rearrangement and
recrystallized to give diacid 9 in a 74% yield (Scheme
1
2
15
2
). Diacid 9 was then converted directly to diol 10 with
catalyst in dry THF. These conditions effected the de-
borane dimethyl sulfide complex in the presence trimeth-
sired reduction with an excellent stereoselectivity and
without any ring opening or reduction of the cyclic
anhydride to afford 16. There are several ADS-catalysts
available, however, many are required in stoichiometric
1
3
ylborate. Treatment of crude 10 with phosphorus
tribromide gave crude 11, which was immediately con-
verted into the bis-quaternary ammonium bromide
7
a
1
2
with an excess of ethanolic trimethylamine at
amounts. The catalyst (DHQD) AQN is effective even
2
1
00 ꢁC. The bromide counter-ion was exchanged for
at low concentrations (<10 mol %) and was considered
for the desired transformation. In the event, the
4
hydroxide using a strong basic ion-exchange resin
DOWEX 550A OH). The resin was activated prior to
(
(DHQD) AQN-catalyzed ADS methanolysis of 16
2
14
16
use and could be used again after regeneration. Ther-
mal decomposition of the bis-quaternary ammonium
hydroxide 13 gave the desired diene 6 in an acceptable
yield. The presence of the diene was confirmed by
NMR and by preparation of the Diels–Alder adduct
with maleic anhydride. Crude 6 was reacted with maleic
anhydride in benzene at room temperature to provide
meso-anhydride 5 in an excellent yield. 1,1-Dimethyl-
afforded 4 in more than 90% enantiomeric excess
and in a good yield. Mono-acid 4 was then conveniently
converted into the corresponding acid chloride with oxa-
lyl chloride in toluene with a constant purge of nitrogen,
to remove produced hydrochloric acid. Subsequent cat-
alytic hydrogenation with Pd/C and 2,6-lutidine, used to
lower the catalyst activity, in THF at 40 psi and room
1
7
temperature afforded aldehyde 17, which was directly
3
,4-bis-methylene-cyclopentane (15) was prepared in
converted to the corresponding trimethylsilylenol ether.
CO Et
CO H
2
2
a
b
OH
OH
c
Br
Br
O
CO H
2
8
9
10
11
NMe Br
d
3
e
NMe OH
3
f
NMe Br
3
NMe OH
3
1
2
6
13
O
O
O
CO H
g
2
CO H
2
5
1
4
15
ÆSMe
Scheme 2. Reagents and conditions: (a) (i) Br
rt, overnight; (c) PBr
, ꢀ10 ꢁC ! rt ! 85 ꢁC, overnight; (d) NMe
OH, H O; (f) pyrolysis, 200 mmHg, 130–200 ꢁC, 30% from 12; (g) maleic anhydride, benzene, rt, 2 d, 99%.
2
, CHCl
3
, 0 ꢁC to rt, overnight; (ii) KOH, H
2
O, 0 ꢁC to rt, 74%; (b) BH
(33% in EtOH), sealed tube 100 ꢁC, overnight, 47% from 10; (e) DOWEX 550A
3
2
, B(OMe) , THF, 0 ꢁC to
3
3
3
2

D. R o¨ me et al. / Tetrahedron Letters 48 (2007) 635–638
637
O
O
CO Me
2
b
c,d
a
O
O
CO H
2
O
O
4
5
16
CO Me
CO Me
CO Me
2
2
2
e,f
g
CHO
O
O
17
18
3
Scheme 3. Reagents and conditions: (a) Pt
rt, overnight; (d) Pd/C, H
CH Cl
2
O, H
2
(1 atm), THF, rt, overnight; (b) (DHQD)
2
AQN, MeOH, Et
2
O, ꢀ18 ꢁC, 3 d; (c) (COCl)
2
, toluene,
, MeOH/
2
(40 psi), 2,6-lutidine, THF, overnight; (e) ZnCl , Et N, TMSCl, benzene, rt (0.5 h) to 40 ꢁC, overnight; (f) O
(4:1), ꢀ7 ꢁC, 39% from 5; (g) (i) PhSeCl, pyridine, CH Cl , 0 ꢁC, 0.5 h; (ii) 35% H , CH Cl , 0 ꢁC, 0.5 h, 48%.
2
3
3
2
2
2
2
2
O
2
2
2
Attempts to form the silylenol ether by conventional
methods, for example, using a base and then chlorotri-
methylsilane, failed. However, enolization of aldehyde
5. Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996,
5, 448.
3
6
. (a) Blomquist, A. T.; Wolinsky, J.; Meinwald, Y. C.;
Longon, D. T. J. Am. Chem. Soc. 1956, 77, 6057–6063; (b)
Nguyet, A. L.; Jones, M., Jr.; Bickelhaupt, F.; De Wolf,
W. H. J. Am. Chem. Soc. 1989, 111, 8491–8493; (c)
Sustmann, R.; Daute, P.; Sauer, R.; Sommer, A.; Traha-
novsky, W. S. Chem. Ber. 1989, 122, 1551–1558.
1
7 in the presence of chlorotrimethylsilane using trieth-
1
8
ylamine-zinc chloride complex was successful, and the
1
9
product was immediately ozonolyzed to yield b-keto
ester 18 in a 39% yield and 6 steps from 5. Introduction
of the a,b-unsaturation in 18 to yield a,b-unsaturated b-
7
. (a) Bailey, W. J.; Sorenson, W. R. J. Am. Chem. Soc. 1989,
76, 5421–5423; (b) Bartlett, P. D.; Wingrove, A. S.;
Owyang, R. J. Am. Chem. Soc. 1968, 90, 6067–6070.
2
keto ester 3 was done as previously described using
PhSeCl and hydrogen peroxide. Keto ester 3 was ob-
2
0
tained in a 90% enantiomeric excess and 3 has previ-
8. Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–
1.
6
ously been transformed to the target dialdehyde 2 in a
2
9. Barco, A.; Benetti, S.; Casolari, A.; Menfredini, S.; Pollini,
2
5% overall yield.
G. P.; Polo, E.; Zanirato, V. Tetrahedron 1989, 45, 3935–
3
944.
In summary, we have developed a facile method for the
asymmetric synthesis of an important intermediate in
the synthesis of biologically active dialdehydes utilizing
a nonenzymatic asymmetric desymmetrization (ADS)
reaction. We have also shown that reactive exocylic
dienes can be readily synthesized from quatenary amines
using recyclable ion-exchange resins, eliminating the
need for expensive silver salts.
1
0. Hegedus, L. S.; Kambe, N.; Ishii, Y.; Mori, A. J. Org.
Chem. 1985, 50, 2240–2243.
1. Martin, H. D.; Mayer, B. Tetrahedron Lett. 1979, 2351–
1
2
352.
12. (a) Wilkening, D.; Mundy, B. P. Synth. Commun. 1984, 14,
227–238; (b) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.;
Stull, P. D. J. Org. Chem. 1989, 54, 817–824.
3. Hanessian, S.; Ugolini, A.; Dub e´ , D.; Glamyan, A. Can. J.
Chem. 1984, 62, 2146–2147.
1
1
4. Activation/regeneration of ion-exchange resin: The resin
should be activated prior to use according to the method
described by the supplier, DOWEX 550A OH; regenerant,
Acknowledgement
4
–8% NaOH; rinse requirement, 2–5 Bed volumes; tem-
Financial support from the Swedish Natural Science
Council is gratefully acknowledged.
perature, ambient or up to 60 ꢁC.
1
1
5. Ishizumi, K.; Antoku, F.; Maruyama, I.; Kojima, A.
European Patent Application 1986, EP 86-104190, CAN
1
06-33119.
6. Based on the enantiomeric excess of the final product 3 ee
was determined using chiral chromatography: Daicel
CHIRAL PAK AD-RH column (4.6 · 150 mm, particle
size 5 lM), Waters 2705 Separations Module, Waters 2996
Photodiode Array Detector and acetonitrile/water eluent.
References and notes
1
. (a) Anke, H.; Sterner, O. Planta Med. 1991, 57, 344–346;
b) Sterner, O.; Bergman, R.; Kihlberg, J.; Wickberg, B. J.
(
Nat. Prod. 1985, 48, 279–288; (c) Sterner, O.; Carter, R.;
Nilsson, L. Mutat. Res. 1987, 188, 169–174; (d) Gustafs-
son, J.; Jonassohn, M.; Kahnberg, P.; Anke, H.; Sterner,
O. Nat. Prod. Lett. 1997, 9, 253–258.
17. Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J. E.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1993, 34,
2593–2596.
18. Simoneau, B.; Brassard, P. Tetrahedron 1988, 44, 1015–
1022.
2
3
4
. Aujard, I.; R o¨ me, D.; Arzel, E.; Johansson, M.; De Vos,
D.; Sterner, O. Bioorg. Med. Chem. 2005, 13, 6145–
19. (a) Arai, Y.; Hayashi, Y.; Yamamoto, M.; Takayema, H.;
Koizumi, T. J. Chem. Soc., Perkin Trans. 1 1988, 3133–
3140; (b) Corey, E. J.; Peterson, R. T. Tetrahedron Lett.
1985, 26, 5025–5028.
6
150.
. (a) Spivey, A. C.; Andrews, B. I. Angew. Chem., Int. Ed.
001, 40, 3131–3134; (b) Willis, M. C. J. Chem. Soc.,
2
Perkin Trans. 1 1999, 1765–1784.
. (a) Chen, Y.; Tian, S. K.; Deng, L. J. Am. Chem. Soc.
20. Methyl
indene-5-carboxylate (3). PhSeCl (201 mg, 1.05 mmol)
was dissolved in CH Cl (30 ml) and cooled to 0 ꢁC.
Pyridine (89 ll, 1.10 mmol) was added and the orange
(3aS,7aS)-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-
2
000, 122, 9542–9543; (b) Hiratake, J.; Yamamoto, Y.;
2
2
Oda, J. J. Chem. Soc., Chem. Commun. 1985, 1717–1719.

638
D. R o¨ me et al. / Tetrahedron Letters 48 (2007) 635–638
trated and chromatographed to give 3 (75 mg, 0.39 mmol,
solution turned yellow. The resulting mixture was stirred
for 15 min at 0 ꢁC and 18 (191 mg, 0.97 mmol) in CH Cl
3.5 ml) was added. The solution was stirred for an
additional 15 min. The reaction mixture was washed with
M aqueous HCl (2 · 15 ml), cooled to 0 ꢁC and 35%
aqueous H (70 ll) was added. An additional amount of
H O (70 ll) was added after 10 min and again after
1
2
2
48%) and recovered 18 (32 mg, 0.16 mmol, 17%):
H
(
NMR (400 MHz, CDCl ) d 1.41 (1H, m), 1.68 (1H, m),
3
1.71 (2H, m), 1.87 (1H, m), 2.07 (1H, m), 2.48 (1H, m),
2
2.60 (1H, m), 2.62 (1H, m), 2.94 (1H, m), 3.82 (3H, s), 7.49
1
3
2
O
2
(1H, d, J = 3.8 Hz); C NMR CDCl
24.3, 30.6, 31.1, 37.9, 40.2, 41.5, 52.2, 131.1, 158.8,
165.1, 194.9; HRMS (FAB): for calcd
3
(100 MHz) d
2
2
20 min. After a further 10 min, H
2
O (10 ml) was added
11 15 3
C H O
20
+
and the layers were separated. The organic layer was
195.1021 [M+H] ; found 195.1030. ½aꢁ ꢀ52 (c 0.04,
D
washed with saturated aqueous NaHCO , dried, concen-
CHCl ).
3
3