Aromatic annulation of alicyclic α,β-unsaturated aldehydes: Synthesis of chirally substituted tetrahydronaphthalenes

Article abstract of DOI:10.1055/s-1998-1663

Chiral 2-tetrahydronaphthalene-carboxylic acid derivatives 3, 6, and 9 were prepared by functionalization of enantiopure terpenic unsaturated aldehydes 1, 4, 7 with triphenyl-(α-carbethoxy-β-carboxyethyl)-phosphonium betaine, followed by a cyclization reaction promoted by ethyl chloroformate under basic conditions.

Full text of DOI:10.1055/s-1998-1663

April 1998
SYNLETT
365
Aromatic Annulation of Alicyclic α,β-Unsaturated Aldehydes: Synthesis of Chirally
Substituted Tetrahydronaphthalenes
Elisabetta Brenna,* Claudio Fuganti, Stefano Serra
Dip. di Chimica del Politecnico, Centro CNR per la Chimica delle Sostanze Organiche Naturali,Via Mancinelli 7, 20131 Milano, Italy
Fax: 39 2 23993080. E-mail: brenna@dept.chem.polimi.it
Received 22 December 1997
Abstract: Chiral 2-tetrahydronaphthalene-carboxylic acid derivatives 3,
6, and 9 were prepared by functionalization of enantiopure terpenic
unsaturated aldehydes 1, 4,
7
with triphenyl-(α-carbethoxy-β-
carboxyethyl)-phosphonium betaine, followed by a cyclization reaction
promoted by ethyl chloroformate under basic conditions.
The interest in various terpenoid natural products showing
a
1
tetrahydronaphthalene basic structure has recently stimulated the
research of new methods for the aromatic annulation of alicyclic
2
precursors. In the past years the development of this synthetic strategy,
alternative to the classical procedure starting from aromatic substrates,
has brought to various approaches based, for example, on the Diels
3
4
Alder reactions of o-quinodimethanes and 2-pyrones, or on the
1d,
5
intramolecular ring closure of α-oxoketeneacetals,
and 1,5-
1c,6
dicarbonyl derivatives.
An efficient route for the synthesis of these chiral
tetrahydronaphthalenes has to show high control on the
a
regiochemistry of the cyclization step, and to preserve the configuration
of the existing stereocentres. These requisites could be conveniently
7
satisfied by a synthetic procedure that we have recently improved to
prepare 4-aryl-3-hydroxy-benzoic acid derivatives from α,β-unsaturated
aromatic aldehydes and dimethyl succinate. The use of alicyclic
aldehydes showing an endocyclic conjugated double bond would give
benzoannulated compounds.
Thus, in this work we report the application of this cyclization route to
3 6
,
9
the synthesis of chiral tetrahydronaphthalenes
, and , starting from
In this work we have clearly shown that the base-promoted cyclization
1 4
7
enantiopure unsaturated aldehydes
, , and (Scheme 1).
of mono ester mono acid derivatives of alicyclic α,β-unsaturated
aldehydes
can
be
used
to
prepare
optically
active
In order to investigate the potentiality of the cyclization method as an
aromatic annulation procedure, we chose as starting materials
2a
tetrahydronaphthalenes in satisfactory yields. It is known that only a
few methods of aromatic annulation can be used to add an aromatic ring
to a non-aromatic chiral ring, since epimerization of stereocentres is a
major problem. The synthetic route we have proposed is regiospecific, it
preserves the configuration of the existing stereocentres, and it involves
only two simple and mild reaction steps. Furthermore, it affords 4-
hydroxy-2-tetrahydronaphthalene carboxylic acid derivatives, whose
functional groups can be easily manipulated, to give valuable precursors
for the synthesis of natural products. For example, the saponification
of derivative 3, followed by the conversion of the carboxylic group into
a methyl substituent would give an isomer of the norsesquiterpene (+)-
ligudentanol, whose total synthesis has been recently published.
1
7
commercially available (-)-perillaldehyde ( ), and (-)-myrtenal ( ),
4
1
together with the bicyclic substrate , which was easily prepared from
by treatment with HBr in acetic acid, followed by reaction with
8
potassium t-butoxide.
The first step required the preparation of mono ester mono acid
7
substrates 2, 5, and 8. In our previous work this conversion had been
achieved in good yields by Stobbe condensation of the starting
unsaturated aldehydes with dimethyl succinate. However, this synthetic
approach was unsuccessful when applied to aliphatic aldehydes 1, 4,
and 7. Thus, we changed our strategy and prepared the desired
compounds 2, 5, and 8 by Wittig olefination with triphenyl-(α-
2a
2b
9, 10
carbethoxy-β-carboxyethyl)-phosphonium betaine.
2 5 8
, , and with ethyl chloroformate in the
Treatment of intermediates
References and Notes
3 6
, , and
presence of triethylamine afforded the tetrahydronaphthalenes
11
(1) a) Ohashi, M.; Maruishi, T.; Kakisawa, H. Tetrahedron Lett.,
9
, with the phenol group protected. Reaction of these latter substrates
1968
;
, 6, 719 b) Rowe, J.W.; Toda, J.K. Chem. Ind. (London),
with ethanolic sodium hydroxide easily allowed the quantitative
recovery of the corresponding phenolic parent compounds.
1969
, 922; c) Takaki, K.; Ohsugi, M.; Okada, M.; Yasumura, M.;
1984
, 741; d) Dieter,
Negoro, K. J. Chem. Soc. Perkin Trans. I,
3 6
, ,
Thus, a simple two step route gave chiral tetrahydronaphthalenes
1985
R.K.; Jenkitkasemwong Lin, Y. Tetrahedron Lett.,
1989
, 39;
9
and in satisfactory overall yields, in the presence of easily available
reagents. The mild reactions conditions did not produce racemization
and allowed the isolation of optically active benzoannulated products.
Furthermore, as the key cyclization step proceeded through a 1,6-
e) Corey, E.J.; Carpino, P. J. Am. Chem. Soc.,
, 111, 5472;
f) Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, Y. J. Am.
1991
Chem. Soc.
, 113, 5402.
(2) a) Corey, E.J.; Palani, A. Tetrahedron Lett.,
1997
, 38, 6087.
7
1997
, 38, 2397;
electrocyclic reaction of a ketene intermediate, a regiospecific ring
closure process was assured.
b) Haddad, N.; Salman, H. Tetrahedron Lett.,

366
LETTERS
SYNLETT
1
(3) Funk, R.L.; Vollhardt, K.P.C. Chem. Soc. Rev., 1980, 9, 41.
C, 69.04; H, 7.97. Found: C, 69.41; H, 7.99. H NMR δ 0.85 (s,
3H, CCH ), 1.15 - 1.45 (t + s, 6H, CCH + COOCH CH ), 2.0 -
(4) Boger, D.L.; Mullican, M.D. Tetrahedron Lett., 1983, 24, 4939,
3
3
2
3
2.55 (m, 6H, aliphatic hydrogens of the cyclohexane ring), 3.54 (s,
2H, CH COOH), 4.22 (q, 2H, J = 7.1 Hz, COOCH CH ), 5.88 (m,
and references cited therein.
2
2
3
(5) a) Tius, M.A., Tetrahedron Lett. , 1981, 22, 3335; b) Singh, G.;
Ila, H.; Junjappa, H., Tetrahedron Lett., 1984, 25, 5095.
1H, CHC=C endocyclic), 7.20 (s, 1H, CHC=C); EI-MS m/z 279
+
+
+
+
(M +1), 278 (M ), 261 (M -OH), 233 (M -COOH), 217, 189,
(6) a) Tius, M.A.; Thurkauf, A. J. Org. Chem., 1983, 48, 3839, and
references cited therein; b) Boger, D.L.; Mullican, M.D. J. Org.
Chem., 1980, 45, 5002.
-1
161, 145, 117, 91; FT-IR (nujol): ν (cm ) 1650, 1710.
(11) General procedure for the cyclization reaction of intermediates 2,
5, and 8 to afford 3, 6, and 9:
(7) Brenna, E.; Fuganti, C.; Perozzo, V.; Serra, S. Tetrahedron, 1997,
53, 15029.
Ethyl chloroformate (2.1 eq, 42 mmoles) was added to a 0.5 M
solution of the suitable mono acid mono ester derivative (1 eq, 20
mmoles) in THF (40 ml); then, triethylamine (3 eq, 60 mmoles)
was added dropwise, keeping the temperature under 20°C. The
reaction mixture was stirred at room temperature for 15 min, then
treated with 5% HCl aq., and extracted with diethyl ether. The
organic phase was dried over sodium sulfate, and concentrated
under reduced pressure. The residue was chromatographed on a
silica gel column, eluting with hexane - ethyl acetate (9:1- 3:1).
Ethyl 4-[(ethoxycarbonyl)oxy]-6-isopropenyl-5,6,7,8-tetrahydro-
(8) Büchi, G.; Hofheinz, W.; Paukstelis, J.V. J. Am. Chem. Soc.,
1969, 91, 6473.
(9) Hudson, R.F.; Chopard, P.A. Helv. Chim. Acta, 1963, 46, 2178.
(10) General Procedure for the Wittig olefination of aldehydes 1, 4,
and 7 to give intermediates 2, 5 , and 8:
Triphenyl-(α-carbethoxy-β-carboxy-ethyl)phosphonium betaine
(1.2 eq, 60 mmoles) was added in one portion to a 0.5 M solution
of the suitable aldehyde (1 eq, 50 mmoles) in dry benzene (100
ml). After stirring at 50°C for 48h, the reaction mixture was
treated with water and extracted with ethyl acetate. The organic
phase was dried on sodium sulphate, and concentrated under
reduced pressure. The residue was chromatographed on a silica
gel column, eluting with hexane-ethyl acetate (5:1 - 1:1).
2-naphthalenecarboxylate (3). Yield: 85%. Anal. Calcd for
20
C
H
O : C, 68.66; H, 7.28. Found: C, 68.77; H, 7.24. [α]
= -
19 24
5
D
1
50.4° (c 1.1, CHCl ); H NMR δ 1.35 (2t, 6H, 2COOCH CH ),
3
2
3
1.80 (s, 3H, CH C=C), 1.90 - 3.0 (m, 7H, aliphatic hydrogens of
3
the cyclohexane ring), 4.35 (2q, 4H, 2COOCH CH ), 4.77 (m,
2
3
4-(4-Isopropenyl-1-cyclohexenyl)-3-(ethoxycarbonyl)-3-butenoic
1H, CHH=C), 4.82 (m, 1H, CHHC=C), 7.61 (s, 1H, aromatic
+
acid (2). Yield: 45%. Anal. Calcd for C
7.97. Found: C, 69.29; H, 7.86. H NMR δ 1.32 (t, 3H, J = 7.1 Hz,
H
O : C, 69.04; H,
hydrogen), 7.72 (s, 1H, aromatic hydrogen); EI-MS m/z 332 (M ),
16 22
4
1
+
-1
287 (M - OEt), 245, 217, 192, 145, 115; FT-IR (nujol): ν (cm )
1721, 1762.
COOCH CH ), 1.4 - 1.55 (m, 2H, aliphatic hydrogens of
2
3
cyclohexane ring ), 1.75 (s, 3H, CH C=C), 2.0-2.4 (m, 5H,
aliphatic hydrogens of cyclohexane ring), 3.58 (m, 2H,
Ethyl 7-[(ethoxycarbonyl)oxy]-1,1-dimethyl-1a,2,3,7 b-tetra-hy-
dro-1H-cyclopropa[a]-naphthalene-5-carboxylate (6)
3
CH COOH), 4.22 (q, 2H, J = 7.1 Hz, COOCH CH ), 4.72 (m, 2H,
88%. Anal. Calcd for C
H
O : C, 68.66; H, 7.28. Found: C,
2
2
3
19 24
5
20
1
C=CH ), 6.00 (m, 1H, CH=C endocyclic), 7.31 (s, 1H, CH=C);
68.79; H, 7.34. [α]
= + 43.7° (c 1.3, CHCl ); H NMR δ 0.71
2
D
3
+
+
+
+
EI-MS m/z 278 (M ), 261 (M -OH), 233 (M -COOH), 232 (M -
EtOH), 217, 204, 189, 161, 145, 136, 117, 99; FT-IR (nujol): ν
(cm ) 1645, 1708.
(s, 3H, CCH ), 1.22 (s, 3H, CCH ), 1.0 - 1.65 (2t + m, 8H,
3 3
2COOCH CH + 2 aliphatic hydrogens of the cyclohexane ring),
2
3
-1
2.1 - 2.95 (m, 4H, aliphatic hydrogens of the cyclohexane ring),
4.35 (2q, 4H, 2COOCH CH ), 7.64 (s, 1H, aromatic hydrogen),
4-(7,7-Dimethylbicyclo[4.1.0]
hept-2-en-3yl)-3-(ethoxy-carbo-
2
3
+
+
nyl)-3-butenoic acid (5). Yield: 47%. Anal. Calcd for C
C, 69.04; H, 7.97. Found: C, 69.32; H, 7.79. H NMR δ 0.95 (s,
H
O :
7.68 (s, 1H, aromatic hydrogen); EI-MS m/z 332 (M ), 287 (M -
OEt), 273, 260, 245, 217; FT-IR (nujol): ν (cm ) 1719, 1764.
16 22
4
1
-1
3H, CCH ), 0.98 - 1.10 (m, 2H, aliphatic hydrogens of the
Ethyl 6-[(ethoxycarbonyl)oxy]-10,10-dimethyltricyclo
[7.1.1.0 ]undeca-2(7),3,5-triene-4-carboxylate (9)
3
2,7
cyclohexane ring), 1.15 (s, 3H, CCH ), 1.31 (t, 3H, J = 7.2 Hz,
3
COOCH CH ), 1.75 - 2.30 (m, 4H, aliphatic hydrogens of the
90%. Anal. Calcd for C
H
O : C, 68.66; H, 7.28. Found: C,
2
3
19 24
5
20
1
cyclohexane ring), 3.55 (m, 2H, CH COOH), 4.20 (q, 2H, J = 7.2
68.53; H, 7.31. [α]
= -14.6° (c 1.1, CHCl ); H NMR δ 0.64 (s,
2
D
3
Hz, COOCH CH ), 6.23 (d, 1H, J = 4.6 Hz, CHC=C endocyclic),
3H, CCH ), 1.3 - 1.5 (t +s, 6H, CCH + COOCH CH ), 2.2 - 3.0
3 3 2 3
2
3
+
+
7.27 (s, 1H, CHC=C); EI-MS m/z 278 (M ), 262 (M -H O), 232,
(m, 6H, aliphatic hydrogens of the cyclohexane ring), 4.35 (2q,
4H, 2 COOCH CH ), 7.52 (d, 1H, J = 1.6 Hz, aromatic
2
+
-1
(M -EtOH), 217, 189, 183, 161, 145, 117; FT-IR (nujol): ν (cm )
2
3
1650, 1705.
4-(6,6-Dimethylbicyclo[3.1.1]
nyl)-3-butenoic acid (8). Yield: 41%. Anal. Calcd for C
hydrogen), 7.66 (d, 1H, J = 1.6 Hz, aromatic hydrogen); EI - MS
+
+
+
hept-2-en-2yl)-3-(ethoxy-carbo-
O :
m/z 333 (M +1), 332 (M ), 287 (M - OEt), 261, 245, 216, 171,
-1
H
145; FT-IR (nujol): ν (cm ) 1720, 1762.
16 22
4