A short, efficient synthesis of the chiral auxiliary (+)-8- phenylneomenthol

Article abstract of DOI:10.1016/S0040-4039(00)00594-3

(+)-8-Phenylneomenthol 2, the structure of which was confirmed by X-ray analysis of its 3,5-dinitrobenzoate, was efficiently prepared from commercially available (-)-8-phenylmenthol 3 by oxidation with the Sarett reagent, followed by L-Selectride reduction of the (+)-8-phenylmenthone 6 thus formed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00594-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4123–4125
A short, efficient synthesis of the chiral auxiliary
(+)-8-phenylneomenthol
Olga Caamaño, Franco Fernández, Xerardo García-Mera ∗ and José E. Rodríguez-Borges
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago. E-15706 Santiago de Compostela,
Spain
Received 20 January 2000; accepted 7 April 2000
Abstract
(+)-8-Phenylneomenthol 2, the structure of which was confirmed by X-ray analysis of its 3,5-dinitrobenzoate,
was efficiently prepared from commercially available (−)-8-phenylmenthol 3 by oxidation with the Sarett reagent,
followed by L-Selectride reduction of the (+)-8-phenylmenthone 6 thus formed. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: terpene alcohols; chiral auxiliaries; phenylneomenthol; Sarett oxidation; L-Selectride.
Since the introduction of (+)-8-phenylmenthol 1 as a chiral auxiliary,1 other stereomeric phenylmen-
thols, among them (+)-8-phenylneomenthol 2,2 have also proved useful in asymmetric synthesis.3
In all previously reported syntheses, the crude product is a mixture of compound 2 with diastereomers
3, 4, and/or 5, and isolation of 2 leads to unavoidable loss of the desired product. For instance, NaBH4
reduction of an equilibrium mixture of 8-phenylmenthone and 8-phenylisomenthone6 yielded a 68:19:13
mixture of 2, 3 and 5, and subsequent preparative HPLC separation followed by Kugelrohr distillation
afforded the desired pure isomer 2 in 47% yield.2 More recent preparations also failed to obtain 2 without
accompanying stereomers.7
We have now found that compound 2 can be rapidly and efficiently obtained in good yield by starting
from the (−)-8-phenylmenthol 3 (now commercially available from Aldrich; see Scheme 1). Oxidation of
∗
Corresponding author. Tel: +00 34 981 56 31 00; fax: +00 34 981 59 49 12; e-mail: qoxgmera@usc.es (X. García-Mera)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00594-3
tetl 16873

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3 in Sarett conditions,8 followed by reduction of the resulting (+)-8-phenylmenthone 6 with L-Selectride
1
in THF9 affords 2, virtually free of diastereomers as shown by H NMR spectra. Both 6 and 2 can
be used for synthetic purposes without further purification (the chromatographic procedures described
below were performed only to obtain analytical samples). The structure of 2 was confirmed via the 3,5-
dinitrobenzoate 7, which was prepared by treatment of the corresponding alcohol with 3,5-dinitrobenzoyl
chloride in presence of Et3N and DMAP.10 Slow recrystallization of the solid thus obtained from Et2O
in the presence of cyclohexane led to crystals of 7 suitable for X-ray diffractometric analysis.11,4,5
Scheme 1. Reagents: (i) CrO3, py, CH2Cl2, 45 min, 0°C; (ii) L-Selectride, THF, 4 h, 0°C; (iii) 3,5-dinitrobenzoyl chloride, Et3N,
DMAP, THF, 5 h, reflux
Acknowledgements
The authors thank the Spanish Ministry of Education and Science (MEC-DGICYT, PB94-0617) and
the Xunta de Galicia (XUGA 20307B94) for financially supporting this work.
References
1. Corey, E. J.; Becker, K. B.; Varma, R. K. J. Am. Chem. Soc. 1972, 94, 8616.
2. Quinkert, G.; Schwalz, H. G.; Dzierzynski, E. M.; Dürner, G.; Bats, J. W. Angew. Chem., Int. Ed. Engl.. 1986, 25, 992.
3. For use of (−)-8-phenylmenthol 3 and (+)-8-phenylisomenthol 4 see Ref. 4 and 5, respectively
4. (a) Oppolzer, W.; Robbiani, C.; Battig, K. Helv. Chim. Acta 1980, 63, 2015. (b) Whitesell, J. K.; Bhattacharya, A.; Aguilar,
D. A.; Henke, K. J. Chem. Soc., Chem. Commun. 1982, 989. (c) Binger, P.; Brinkmann, A.; Richter, W. J. Tetrahedron Lett.
1983, 24, 3599. (d) D’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112. (e) Solladie-Cavallo, A.; Benchegroun,
M. Tetrahedron Asymm. 1991, 2, 1165. (f) Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K.; Hiraga, Y.;
Kojima, S.; Okhata, K. J. Chem. Soc., Perkin-Trans 1 1998, 698. (g) Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.; Rein, T.
J. Org. Chem. 1998, 63, 8284. (h) Kubo, Y.; Yoshioka, M.; Nakajima, S.; Inamura, I. Tetrahedron Lett. 1999, 40, 2335. (i)
Donohoe, T. J.; Guyo, P. M.; Helliwell, M. Tetrahedron Lett. 1999, 40, 435.
5. Whitesell, J. K.; Lin, C.-L.; Buchanan, C. M.; Chen, H.-H.; Minton, M. A. J. Org. Chem. 1986, 51, 551.
6. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 7908.
7. (a) Halterman, R. L.; Vollhardt, P. C. Organometallics 1988, 7, 883. (b) Potin, D.; Dumas, F. Synth. Commun. 1990, 20,
2805.
8. (2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexanone 6: To a solution of pyridine (24.9 g, 311 mmol) in CH2Cl2
(260 mL) at 0°C were added, in small portions CrO3 (15.48 g, 155 mmol), then dropwise a solution of 3 (6 g, 25.8 mmol)
in CH2Cl2 (25 mL). The resulting mixture was stirred for 45 min, filtered on Celite, the solids being washed with Et2O
(4×90 mL). The pooled organic extracts were concentrated to 50 mL, then washed with water (100 mL) and saturated brine
(100 mL), and dried (Na2SO4). Evaporation of the solvents afforded an oil (6.4 g) which upon flash chromatography [silica
23
gel 60 (210 g); hexane:AcOEt, 9:1] gave 6 as a colourless oil (5.7 g, 96%). [α]D −49 (c 1.0, CHCl3). IR (film) νmax: 1709
(CO) cm−1. 1H NMR (300 MHz, CDCl3): 0.97 (d, 3H, J=6 Hz, 5-CH3), 1.41 and 1.47 (2s, 6H, 8-(CH3)2), 1.50–1.89 (m,
5H), 1.91–2.06 (m, 1H, 6-H), 2.22–2.27 (m, 1H, 6-H), 2.61–2.70 (m, 1H, 2-H), 7.13–7.37 (m, 5Harom). 13C NMR (75 MHz,

4125
CDCl3): 22.73, 24.43, 26.91, 29.45, 35.09, 36.69, 39.43 (C-8), 52.76, 59.94, 125.91 (C-40), 126.16 (C-20+C-60), 128.38
(C-30+C-50), 150.31 (C-10), 211.92 (C-1).
9. (1S,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexanol 2: A solution of 6 (8 g, 34.9 mmol) in THF (35 mL) was
added dropwise to a 1.0 M solution of L-Selectride in THF (52 mL, 52 mmol) at 0°C, and the resulting mixture was stirred
for 4 h at 0°C. Aqueous 3 M NaOH (11 mL, 33 mmol) was then added dropwise followed by slow addition of 30% H2O2
(18 mL, 180 mmol). After a further 30 min stirring at room temperature the mixture was extracted with Et2O (4×30 mL),
the combined organic phases being washed with water (2×20 mL) and dried (Na2SO4). The solvents were removed in
vacuo to leave an oil, which was purified by flash chromatography [silica gel 60 (220 g), hexane:AcOEt, 9:1] to afford 2 as
23
a colourless oil (7.21 g, 89%). [α]D +34 (c 1.0, CHCl3). IR (film) νmax: 3464 (OH) cm−1. 1H NMR (300 MHz, CDCl3):
0.84 (d, 3H, J=6 Hz, 5-CH3), 0.88–1.11 (m, 2H), 1.38 and 1.40 (2s, 6H, 8-(CH3)2), 1.43–1.76 (m, 6H), 3.86 (virtual s, 1H,
1eq-H), 7.18 (td, 1H, J=7 Hz, 1 Hz, 40-H), 7.26–7.33 (m, 2H, 30-H+50-H), 7.37–7.40 (m, 2H, 20-H+60-H). 13C NMR (75
MHz, CDCl3): 21.75 (C-3), 22.63 (C-7), 26.26 (C-9), 26.53 (C-5), 28.05 (C-10), 36.06 (C-4), 40.60 (C-8), 44.26 (C-6),
52.71 (C-2), 68.62 (C-1), 125.92 (C-40), 126.59 (C-20+C-60), 128.42 (C-30+C-50), 150.31 (C-10).
10. (10S,20S,50R)-50-Methyl-20-(1-methyl-1-phenylethyl)cyclohexyl 3,5-dinitrobenzoate 7: 3,5-Dinitrobenzoyl chloride (3.22
g; 14 mmol, freshly recrystallized from CCl4) was added at once to a solution of 2 (2.30 g, 10.37 mmol), anhydrous Et3N
(1.98 mL, 14 mmol) and DMAP (20 mg) in anhydrous THF (200 mL) and the mixture was refluxed for 5 h with stirring,
under an argon atmosphere. After cooling, the resulting mixture was concentrated to 20 mL, diluted with CH2Cl2 (80
mL) and washed with saturated NaHCO3 solution (3×100 mL) and saturated brine (100 mL). The organic layer was dried
(Na2SO4), and the solvents were removed in vacuo to leave an oily residue, which was chromatographed [silica gel 60 (100
g), hexane:AcOEt, 9:1] affording 7 as a white solid (3.25 g, 77%). Mp 139–140°C (Et2O-cyclohexane). [α]D23 +114 (c 1.0,
CHCl3). IR (KBr) νmax: 1719 (CO) cm−1. 1H NMR (300 MHz, CDCl3): 0.83–0.86 (d, 3H, J=7 Hz, 50-CH3), 1.02–1.25 (m,
2H), 1.36 and 1.41 (2s, 6H, 80-(CH3)2), 1.58–1.99 (m, 6H), 5.45 (virtual s, 1H, 10eq-H), 6.91 (t, 1H, J=7 Hz, 400-H), 7.11 (t,
2H, J=8 Hz, 300-H+50-H), 7.24 (d, 2H, J=7 Hz, 200-H+600-H), 8.83 (d, 2H, J=2 Hz, 2-H+6-H), 9.18 (t, 1H, J=2 Hz, 4-H).
13C NMR (75 MHz, CDCl3): 22.29 (C-30), 23.26 (C-70), 26.30 (C-50), 27.51 (C-90), 27.88 (C-100), 35.65 (C-40), 40.19
(C-60), 40.34 (C-80), 52.19 (C-20), 74.27 (C-10), 122.47 (C-4), 125.76 (C-400), 126.63 (C-200+C-600), 128.40 (C-300+C-500),
129.52 (C-2+C-6), 134.80 (C-1), 148.40 (C-100), 148.87 (C-3+C-5), 161.71 (C(O)).
11. Results of this analysis will be published elsewhere.