First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5- dimethyl-2(3H)-naphthalenone

Article abstract of DOI:10.1016/S0957-4166(99)00349-3

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl- 2(3H)-naphthalenone (-)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure

Full text of DOI:10.1016/S0957-4166(99)00349-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3365–3370
First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-
hexahydro-4a,5-dimethyl-2(3H)-naphthalenone
Xavier Cuesta, Asensio González and Josep Bonjoch ∗
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 6 July 1999; accepted 10 August 1999
Abstract
The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone(−)-1 is descri-
bed for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers
enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by
an intramolecular aldol reaction gives the bicyclic enone (−)-1. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
As part of our current research program directed to the synthesis of biologically interesting terpene
derivatives, we required an efficient method for the preparation of (4aS,5R)-hexahydro-4a,5-dimethyl-
2(3H)-naphthalenone (−)-1. Several methods have been used to prepare 4,4a,5,6,7,8-hexahydro-4a,5-
dimethyl-2(3H)-naphthalenone (rac-1),1–8 but only two enantioselective routes that give the enantiomer
(4aR,5S)-(+)-1 have been reported recently9,10 (Scheme 1). In the first approach, Paquette et al.9 take
advantage of the Wieland–Mischer ketone11 as a chiral intermediate and introduce the methyl group at
C-5 in a six-step sequence. In the second approach, Jenniskens and deGroot10 use a bicyclic system,
prepared from carvone,12 in which the isopropenyl group must be removed. Although compound (−)-1
could also be prepared under identical conditions, using (−)-Wieland–Mischer ketone or (−)-carvone as
chiral starting materials,13 we wanted to find a more practical and economic route.
In this paper we describe a short and cheap synthesis for (−)-1, which does not require chromatographic
purification in any step. The interest of bicyclic enone (−)-1 lies in its potential as a chiral building block
for the enantioselective synthesis of terpenes with the same absolute configuration, such as nominine14
and aspernomine15 as well as others of so far unknown absolute configuration, but with the same relative
cis relationship between the methyl groups, such as nakamurol-A16 or related compounds with the
thelepogane skeleton.17
∗
Corresponding author. E-mail: bonjoch@farmacia.far.ub.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00349-3

3366
X. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 3365–3370
Scheme 1.
2. Results and discussion
The synthesis is outlined in Scheme 2 and takes advantage of Piers’ results reported for the racemic
series,2a described 30 years ago but not exploited in the terpene field. The use of the Piers enol lactone 5
as precursor of 1 allows excellent purification of the cis-diastereoisomer, removing by crystallization the
minor quantities of the trans-epimer that in other approaches to 1 proves remarkably troublesome.
Scheme 2. Reagents and conditions: (i) NaOMe, ethyl formate, MeOH; (ii) N-methylaniline, reflux; (iii) LDA, MeI; (iv)
tert-BuOK, ethyl 3-bromopropionate, tert-BuOH; (v) 10% HCl, reflux; then 10% NaOH, reflux; (vi) AcONa, Ac2O; (vii) MeLi,
Et2O; then KOH, MeOH, reflux. Compound 3 is a 2.5:1 mixture of trans- and cis-epimers, respectively. For the formation of 4,
the diastereoselection is 7:1. Compound 5, available in enantiopure form, is formed together with its epimer at C-4a (7:1 ratio)
in 94% combined yield
Starting from the commercially available (R)-3-methylcyclohexanone, the α-N-methylanilinomethyl-
ene derivative 218 was obtained in 78% overall yield by formylation at C-6 and subsequent treatment
with N-methylaniline. Regioselective formation of 2 can be accounted for considering that the initial
formylation takes place under thermodynamic control and is governed by the 1,3-allylic strain in the
enolate formation step. Treatment of 2 with LDA and methyl iodide furnished the intermediate 3,19–21
which was a diastereomeric mixture in a 2.5:1 ratio, the diequatorial isomer (2S,3R) being the major
one. Ketone 3 was alkylated with ethyl bromopropionate to give the corresponding α,α-disubstituted
ketone, which, without further purification, was converted to 4.22 The result of the alkylation process
means that the preferred approach of the electrophilic reagent is from the opposite side of the enolate
anion to where the methyl group is placed. However, it cannot be ruled out that the reaction occurs via an

X. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 3365–3370
3367
E1cB elimination and Michael addition under thermodynamic control.23 Keto acid 4 was a 7:1 cis:trans
diastereoisomeric mixture, which could be separated after its transformation into the corresponding enol
lactone 5. Purification of the diastereoisomeric cis- and trans-5 was achieved by crystallization, the cis-
isomer being easily separated using hexane as solvent. Treatment of enantiopure 5 with methyl lithium
followed by intramolecular aldol condensation gave the bicyclic enone (−)-1. The yield for this final
step is 60%. This is not surprising as methyl lithium is acting as a competitive base and gives back
either starting material 5 or the acid 4 (via ketene formation).23 According to the NMR data, which
were assigned unequivocally by 2D NMR experiments (COSY, HSQC24), (−)-1 adopts the conformation
depicted in Fig. 1.
Figure 1. 13C NMR data of 1 (HSQC based assignment)
In conclusion, we have reported an efficient and stereoselective route to the interesting chiral building
block (−)-1, assembling very efficient classical procedures that allow work on a multigram scale. The
seven-step sequence from (R)-3-methylcyclohexanone to (−)-1 includes the blocking of the ketone α-
position, two successive alkylations, a deprotecting step, enol lactone formation, and methyl lithium
addition followed by aldol cyclization in 25% overall yield. In addition, the entire synthetic procedure
to (−)-1 was performed without any chromatographic separation of diastereomers or other undesired
materials.
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded in CDCl3 solution at 200 MHz, or at 500 MHz when noted,
and 50.3 MHz, respectively. In addition, 2D NMR COSY and HSQC experiments were performed on
a Varian XL-500 instrument. Chemical shifts are reported as δ values (ppm) relative to internal Me4Si.
Infrared spectra were recorded on a Nicolet 205 FT-IR spectrophotometer. Optical rotations were taken
on a Perkin–Elmer Model 241 polarimeter with a 1 ml (L=1 dm) cell. TLC was performed on SiO2 (silica
gel 60 F254, Merck). Chromatography refers to flash column chromatography and was carried out on SiO2
(silica gel 60, SDS, 230–400 mesh). All reactions were carried out under an argon atmosphere with dry,
freshly distilled solvents under anhydrous conditions, unless otherwise noted. Drying of organic extracts
during the work-up of reactions was performed over anhydrous Na2SO4.
3.2. (5R)-5-Methyl-2-(N-methylanilinomethylene)cyclohexanone 2
To a solution of sodium methoxide, prepared from Na (20 g, 0.88 g-atom) and MeOH, in toluene
(500 ml) was added slowly for 30 min a mixture of (3R)-3-methylcyclohexanone (50 g, 0.45 mmol)
and ethyl formate (71.6 ml, 0.88 mol). The reaction mixture was shaken for 17 h, ice-water was added,

3368
X. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 3365–3370
basified with concentrated HCl and extracted with ether. The dried organic extract gave (5R)-5-methyl-2-
1
(hydroxymethylene)cyclohexanone (60.5 g), which was used in the next step without purification. H
NMR 1.02 (d, J=6.2 Hz, 3H), 1.12–1.34 (m, 1H), 1.74–1.88 (m, 2H), 1.99 (dd, J=18, 10 Hz, 1H),
2.31–2.49 (m, 3H), 8.69 (d, J=1.8 Hz, 1H); 13C NMR 21.2 (CH3), 22.4(CH2), 27.6 (CH), 30.6 and
39.2 (CH2), 108.1 (C), 184.1 (C), 187.5 (CH).
A solution of the above hydroxymethylene derivative (60.5 g, 0.43 mol), N-methylaniline (49 ml, 0.44
mol) and benzene (750 ml) was heated at reflux in a Dean–Stark apparatus for 13 h. The solvent was
removed and the resulting oil was purified by distillation, bp 158–160°C/0.3 mmHg, to give 218 (79 g,
1
78% for the two steps), which solidified on standing: H NMR 0.96 (d, J=6.2 Hz, CH3), 1.05–1.15 (m,
1H), 1.6–2.15 (m, 5H), 2.45 (dm, J=15 Hz, 1H), 3.42 (s, NMe), 7.0–7.1 (m, 3H), 7.3 (m, 2H), 7.57 (s,
_CH); 13C NMR 21.7 (CH3), 26.3 (C-4), 29.3 (C-5), 31.6 (C-3), 42.2 (NCH3), 47.1 (C-6), 110.8 (C-2),
121.1, 123.7, 128.6, 145.7 (Ar), 144.8 (_CH), 198.9 (C-1).
3.3. (2RS,3R)-2,3-Dimethyl-6-(N-methylanilinomethylene)cyclohexanone 3
To a solution of LDA (1.6 M in cyclohexane, 30.8 ml, 49.3 mmol) in THF (60 ml) at 0°C was added
a solution of ketone 2 (10.76 g, 47 mmol) in THF (100 ml). The solution was stirred for 35 min, methyl
iodide (10.3 ml, 164 mmol) was added and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into a mixture of aqueous NaHCO3 solution–water–ether. The organic layer
was separated and the aqueous phase was extracted with ether. The organic extracts were concentrated
to give an oil which was distilled to furnish 3, as a mixture of diastereomers in a 2.5:1 ratio (10.4 g,
91%): bp 175°C/0.1 mmHg; major isomer (2S,3R): 1H NMR 1.01 (d, J=6.2 Hz, CH3), 1.20 (d, J=7 Hz,
CH3), 3.40 (s, NCH3), 7.0–7.1 (m, 3H), 7.25–7.35 (m, 2H), 7.54 (t, J=1.4 Hz, _CH); 13C NMR 15.5
and 20.8 (CH3), 26.1 (C-4), 30.9 (C-5), 36.0 (C-3), 42.0 (NCH3), 49.6 (C-2), 111.3 (C-6), 120.9, 123.7,
128.8 (Ar), 144.7 (_CH), 201.7 (C-1). Minor signals for the isomer 2R,3R were observed at 12.8 and
16.0 (CH3), 32.6 and 46.7 (CH), and 202.8 (CO).
3.4. (1S,2R)-1,2-Dimethyl-6-oxocyclohexanepropanoic acid 4
The ketone 3 (20 g, 87 mmol) was added to tert-BuOH (200 ml) containing potassium tert-butoxide
(29.4 g, 0.26 mol) and the resulting solution was stirred at room temperature for 20 min. Ethyl 3-
bromopropionate (38.8 ml, 0.30 mol) was added slowly and the mixture was stirred for 1 day. The
solvent was removed and the residue was partitioned between ice-water and ether. The aqueous phase
was extracted with ether and the combined organic extracts were dried and concentrated to give an oil,
which, without purification, was treated with a 10% HCl solution (150 ml) and the mixture was heated at
reflux for 30 min. The mixture was cooled and extracted with ether. The organic phase was concentrated
and treated with a 10% NaOH solution (150 ml) and the mixture was heated at reflux for 45 min. The
mixture was cooled, acidified with 6N HCl solution and extracted with ether. The organic phase was
dried and concentrated to give an oil which by distillation gave the carboxylic acid 4 and its epimer in
1
C-1 in a 7:1 ratio (8.2 g, 71%): bp 144–146°C/0.1 mmHg; IR (neat) 2700–3500, 1735, 1705; H NMR
0.94 (d, J=6.6 Hz, CH3), 1.04 (s, CH3), 1.6–1.9 (m, 5H), 1.95–2.1 (m, 2H), 2.2–2.45 (m, 4H), 11.0 (br,
1H, COOH); 13C NMR 15.3 and 18.4 (CH3), 24.5, 28.9, 29.1, 30.0 and 38.0 (CH2), 38.4 (CH), 51.2 (C),
179.6 (COOH), 215.4 (CO).

X. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 3365–3370
3369
3.5. (4aS,5R)-3,4,4a,5,6,7-Hexahydro-4a,5-dimethyl-2H-1-benzopyran-2-one 5
A solution of keto acid 4 (14.1 g, 71 mmol) in Ac2O (320 ml) containing sodium acetate (3 g, 36 mmol)
was heated at reflux for 2 h. The solvent was evaporated and the crude was partitioned between water
and ether. The organic extracts were washed with aqueous NaHCO3 solution, dried and concentrated. The
resulting crude was distilled to give enol lactone 5 (12.1 g, 94%), which corresponds to a 7:1 mixture
22
of cis- and trans-isomers, respectively. Crystallization with hexane of this mixture gave pure 5: [α]D
+153.6 (c 1, CHCl3); IR (neat) 1756, 1683; 1H NMR (500 MHz, COSY) 0.91 (d, J=6.5 Hz, 3H, 5-CH3),
1.00 (s, 3H, 4a-CH3), 1.48 (m, 2H, H-6), 1.6 (m, 2H, H-5 and H-4), 1.85 (dt, J=13, 5.2 Hz, H-4eq), 2.06
(m, 2H, H-7), 2.60 (dd, J=9.2, 5 Hz, 2H, H-3), 5.26 (t, J=4 Hz, 1 H, H-8); 13C NMR (50 MHz, HSQC)
15.0 (5-CH3), 17.1 (4a-CH3), 22.8 (C-7), 26.2 (C-6), 27.6 (C-3), 30.6 (C-4), 34.7 (C-4a), 39.0 (C-5),
106.0 (C-8), 154.3 (C-8a), 168.2 (C-2). Anal. calcd for C11H16O2: C, 73.30; H, 8.95. Found: C, 73.05;
H, 9.03.
Previous to the crystallization process minor signals corresponding to the C-4a epimer were observed
in the 13C NMR spectrum of distilled 5: 14.6, 20.7, 23.7, 25.8, 26.5, 27.8, 35.0, 37.8, 152.9 and 168.9.
3.6. (4aS,5R)-4,4a,5,6,7,8-Hexahydro-4a,5-dimethyl-2(3H)naphthalenone 1
To a solution of enol lactone 5 (5.2 g, 29 mmol) in ether (50 ml) cooled to −25°C was quickly added
MeLi (1.6 M in ether, 29.1 ml, 46.5 mmol). The resulting solution was stirred at this temperature for 1.5
h and the reaction mixture was poured into 1 N HCl (25 ml) and the product was extracted with ether. To
the concentrated organic extract was added a 2.5 N aqueous solution of KOH (30 ml) and MeOH (270
ml) and the mixture was warmed at reflux for 2 h. MeOH was evaporated and the crude was partitioned
between water and ether. The organic extracts were concentrated and distilled to give 3 g (60%, 65%
based on recovered 4) of enone (−)-1: [α]D −183 (c 1.63, CHCl3); lit.9 for (+)-1: [α]D +185.6 (c
22
22
1
1.63, CHCl3); IR (neat) 1675, 1615; H NMR (500 MHz, COSY) 0.92 (d, J=6 Hz, 5-CH3), 1.11 (s,
4a-CH3), 1.45 (m, 3H, H-5, H-6 and H-7), 1.55 (m, 1H, H-6), 1.73 (td, J=14, 5 Hz, H-4ax), 1.87 (m, 1H,
H-7), 2.03 (ddd, J=14, 5, 3.5 Hz, H-4eq), 2.25 (dm, J=14.5 Hz, H-8eq), 2.33 (m, 2H, H-8ax and H-3eq),
2.43 (ddd, J=16.5, 14, 5, H-3ax), 5.74 (s, H-1); 13C NMR (75 MHz, HSQC) 15.0 (5-CH3), 15.8 (4a-CH3),
26.3 (C-7), 30.3 (C-6), 33.2 (C-8), 33.8 (C-3), 35.3 (C-4), 38.8 (C-4a), 43.0 (C-5), 123.8 (C-1), 171.1
(C-8a), 199.4 (C-2).
From the aqueous layer, after acidification and extraction with ether, 500 mg of keto acid 4 was
recovered.
Acknowledgements
Support for this research was provided by DGES (Spain) through Grant PB97-0877 and a fellowship
to X.C. Thanks are also due to the ‘Comissionat per a Universitats i Recerca’ (Catalonia) for Grant
1997SGR-00166. The laboratory work by undergraduate student Sandra Díaz is gratefully acknowledged.
References
1. Berger, C.; Franck-Neuman, M.; Ourisson, G. Tetrahedron Lett. 1968, 3451–3452.
2. (a) Piers, E.; Britton, R. W.; de Waal, W. Can. J. Chem. 1969, 47, 4307–4312. (b) See also Pinder, A. R.; Torrence, A. K.
J. Chem. Soc. (C) 1971, 3410–3414.

3370
X. Cuesta et al. / Tetrahedron: Asymmetry 10 (1999) 3365–3370
3. Kelly, R. B.; Zamecnik, J.; Beckett, B. A. Can. J. Chem. 1972, 50, 3455–3464.
4. Zoretic, P. A.; Golen, J. A.; Saltzman, M. D. J. Org. Chem. 1981, 46, 3554–3555.
5. Boeckman Jr., R. Tetrahedron 1983, 39, 925–934; Boeckman Jr., R.; Blum, D. M.; Ganem, B. Org. Synth. 1978, 58,
158–163.
6. Huffman, J. W.; Potnis, S. M.; Satish, A. V. J. Org. Chem. 1985, 50, 4266–4270.
7. Dancer, R. J.; Haynes, R. K.; Loughlin, W. A.; Vonwiller, S. C. Aust. J. Chem. 1990, 43, 1375–1389.
8. Duhamel, P.; Dujardin, G.; Hennequin, L.; Poirier, J.-M. J. Chem. Soc., Perkin Trans. 1 1992, 387–396.
9. Paquette, L. A.; Wang, T.-Z.; Philippo, C. M. G.; Wang, S. J. Am. Chem. Soc. 1994, 116, 3367–3374.
10. Jenniskens, L. H. D.; de Groot, A. Tetrahedron 1998, 54, 5617–5622.
11. Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T. Synthesis 1990, 53–56, and references cited therein.
12. Verstegen-Haaksma, A. A.; Swarts, H. J.; Jansen, B. J. M.; de Groot, A. Tetrahedron 1994, 50, 10073–10082.
13. In fact, we have synthesized (−)-1 from (−)-Wieland–Mischer ketone using the procedure described by Paquette for (+)-1.
14. Rinderknecht, B. L.; Gloer, J. B.; Dowd, P. F.; Wicclow, D. T. J. Org. Chem. 1989, 54, 2530–2532.
15. Staub, G. M.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Am. Chem. Soc. 1992, 114, 1015–1017.
16. Shoji, N.; Umeyama, A.; Teranaka, M.; Arihara, S. J. Nat. Prod. 1996, 59, 448–450.
17. Iwagawa, T.; Kaneko, M.; Okamura, H.; Nakatani, M.; van Soest, R. W. M. J. Nat. Prod. 1998, 61, 1310–1312.
18. Guest, I. G.; Hugues, C. R.; Ramage, R.; Sattar, A. J. Chem. Soc., Chem. Commun. 1973, 526–527.
19. Compound 3 was also synthesized from (−)-pulegone by methylation20 and a retroaldol process following the procedure
of Tori21 (50% for the two steps) and further formylation and treatment with N-methylaniline (77% for the two steps,
operating in a 0.22 mol scale). The overall yield is lower than that obtained from (R)-3-methylcyclohexanone and the
sequence involves four steps, instead of the three required in the route depicted in Scheme 2.
20. Lee, R. A.; McAndrews, C.; Patel, K. M.; Reusch, W. Tetrahedron Lett. 1973, 965–968.
21. Tori, M.; Uchida, N.; Sumida, A.; Furuta, H.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1 1995, 1513–1517.
22. For an enantioselective synthesis of the corresponding methyl ester, which appeared when the work had been done, see:
Tori, M.; Hisazumi, K.; Wada, T.; Sono, M.; Nakashima, K. Tetrahedron: Asymmetry 1999, 10, 961–971.
23. We acknowledge a reviewer’s suggestions concerning this question.
24. Bodenhausen, G.; Ruben, D. J. Chem. Phys. Lett. 1980, 69, 185–189.