A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1992, 70, 35
DOI: 10.15227/orgsyn.070.0035
[2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4a-methyl-, (R)-]
Submitted by G. Revial and M. Pfau1.
Checked by Graham N. Maw and Robert K. Boeckman, Jr..
1. Procedure
A. Imines (1). In a 1000-mL, round-bottomed flask, fitted with a toluene-filled Dean-Stark water separator, 100.0 g (0.825 mol) of (S)-(−)-α-methylbenzylamine (Note 1), 92.5 g (0.825 mol) of 2-methylcyclohexanone (Note 2) and 100 mL of toluene are heated at reflux temperature under a nitrogen atmosphere. After 24 hr, ca. 15 mL of water (ca. 100% theor.) has been removed azeotropically.
B. (R)-(+)-2-Methyl-2-(3-oxobutyl)cyclohexanone (2). The solution of imines 1 is cooled in an ice bath and 72.5 mL (61.0 g, 0.870 mol, ca. 1.05 equiv) of freshly distilled methyl vinyl ketone (Note 3) is added with a syringe, with magnetic stirring, under a nitrogen atmosphere. The flask is then heated at ca. 40°C for 24 hr.
The slightly yellow solution is cooled in an ice bath and 60 mL of glacial acetic acid (ca. 1 mol) and 50 mL of water are added. Hydrolysis is achieved by stirring the heterogeneous mixture at room temperature for 2 hr. The now clear solution is poured into a 2000-mL separatory funnel containing 100 mL of brine and 160 mL of water and is extracted five times with a 50:50 mixture of ether-petroleum ether (35–60°C) (1000-mL total amount). The organic phase is washed efficiently with 20 mL of 10% hydrochloric acid, 20 mL of water, and two 10-mL portions of brine.
The aqueous layer is kept for recovery of the amine (see D below).
The pale yellow organic layer is dried over a small amount of anhydrous magnesium sulfate and filtered. The solvents are removed with a rotary evaporator at ca. 40°C and the crude diketone 2 (ca. 145 g) is used directly for the next step.
C. (R)-(−)-10-Methyl-1(9)-octal-2-one (3). Dry methanol (600 mL) is added to the crude diketone 2 contained in a 2000-mL, round-bottomed flask and a rubber septum is fitted. The solution is stirred at room temperature for 15 min under a slight stream of nitrogen to remove traces of oxygen. A 25 wt. % solution of sodium methoxide in methanol (Note 4) is then introduced dropwise with a syringe, under stirring, until a slightly red color develops (Note 5). At this point, 15 mL (ca. 0.07 mol) of the sodium methoxide solution is added and the mixture is heated at 60°C for 10 hr under a nitrogen atmosphere. The solution is cooled and the now deep red solution is neutralized with glacial acetic acid (ca. 4.5 mL) until the color turns yellow. Methanol is removed with a rotary evaporator until a thick paste (sodium acetate) results; this is dissolved with 200 mL of water. Extraction is effected in a 2000-mL separatory funnel using four portions of a 50:50 mixture (1000 mL total amount) of ether-petroleum ether (35–60°C). The pale orange organic phase is washed twice with 40 mL of water, then twice with 20 mL of brine. The organic layer is dried over a small amount of anhydrous magnesium sulfate and filtered. The solvents are removed with a rotary evaporator at ca. 40°C and the red oily residue of crude octalone 3 is distilled under reduced pressure to afford ca. 110 g of a colorless oil, bp 70°C (2 mm) (Note 6). The oil is purified by recrystallization at a low temperature with an apparatus designed for this purpose.2 The oil is dissolved with stirring in a 1000-mL, round-bottomed flask with 370 mL of pentane under a nitrogen atmosphere. The flask is then cautiously cooled in a Dewar flask containing liquid nitrogen until the solution is solid. The Dewar flask is removed and the temperature is allowed to rise, while magnetic stirring is resumed. When a crystalline mass in suspension appears suddenly (Note 7), an acetone bath adjusted to about −10°C is installed. When only a few crystals remain in suspension, the bath temperature is slowly lowered to −35°C, inducing crystallization. After the mixture has been kept at −35°C for 15 min, magnetic stirring is stopped and efficient filtration is performed through the filter stick. Still at −35°C, the compound is washed with 40 mL of pentane. The solution is stirred vigorously for 5 min and filtered as before. The washing operation is repeated two more times. The flask is warmed to room temperature and the oil is distilled as before, bp 70°C (2 mm), to afford 60–65 g (44–48% overall yield from 2-methylcyclohexanone) of methyloctalone 3 [>99% chemical purity, capillary GLC (Note 6)], [α]D20 −210° (ethanol, c 1.00), optical purity 96% (Note 8).
D. Recovery of (S)-(−)-α-methylbenzylamine. The aqueous layer (see above, B, 3rd paragraph) contained in a 1000-mL flask is cooled in an ice bath under a nitrogen atmosphere. An aqueous 10% sodium hydroxide solution is added with stirring until a pH of 12–14 (Note 9) is reached. The mixture is transferred to a 2000-mL separatory funnel and extracted three times with ether (1000-mL total amount). The organic phase is washed twice with 100 mL of water and twice with 30 mL of brine, then dried over potassium carbonate and filtered. The solution is concentrated at room temperature with a rotary evaporator and distilled under reduced pressure to afford 85–90 g (85–90% yield) of the amine, bp 70°C (15 mm), the specific rotation of which is the same as that of the original starting material.
2. Notes
1. (S)-(−)-α-Methylbenzylamine (95.8% optical purity) and its (R)-(+)-enantiomer (93.4% optical purity) were purchased from Aldrich Chemical Company, Inc. and used without further purification. CAUTION: These amines are toxic. Air must be excluded to prevent formation of carbonates.
2. 2-Methylcyclohexanone was purchased from Aldrich Chemical Company, Inc., and used without further purification.
3. Methyl vinyl ketone, purchased from Aldrich Chemical Company, Inc., is dried over anhydrous potassium carbonate for 0.5 hr. The now slightly-colored oil is filtered and distilled under a nitrogen atmosphere at reduced pressure, bp 55°C (260 mm). The colorless center of the distillate is collected over a few milligrams (ca. 0.05% concentration) of hydroquinone.
4. A 25 wt % solution of sodium methoxide in methanol (4.6 M) was purchased from Aldrich Chemical Company, Inc.
5. Any acetic acid present is thus neutralized (a few drops are usually sufficient). Confirm that a basic pH has been reached by testing a drop of the solution, removed by syringe.
6. Although a TLC test (silica gel Merck 60 F254, ethyl acetate/hexane 20:80 elution, UV and chromic-sulfuric acid visualization) of this oil reveals only one spot (Rf 0.6), capillary GLC (Hewlett-Packard HP-5, 25 m × 0.2 mm × 0.5 μm, 200°C) shows in addition to methyloctalone 3 (retention time, 10.9 min), an 8% impurity (retention time, 11.7 min) which is probably the regioisomer 4.
A chemically pure sample of methyloctalone 3, [α]D20 −190° (ethanol, c 1.00) is obtained by preparative GLC (3 m × ¼", 5% carbowax 20 M on Aeropak 30, 180°C, retention time 12.4 min) of a distillate sample. The impurity has a 13.2-min retention time under these conditions. A good approximation of the reaction ee is calculated as follows, taking into account the optical purity of the starting amine (95.8%) and the [α]D20 −219° (ethanol, c 1.00) value (Note 8) for optically pure methyloctalone 3: ee = 100 × 190 × 100/95.8 × 219 ≅ 91%.
7. If no crystalline mass is formed but instead an emulsion of the two liquid phases appears, the entire solidification must be repeated (liquid nitrogen cooling).
8. Chiral capillary GLC (OV-1701 + trimeb/2), 25 m × 0.3 mm, He, 65 kPa, 130°C: (R)-(−)-3, 58.3 min (98%); (S)-(+)-3, 62.0 min (2%). Optically pure methyloctalone 3 is obtained by recrystallizing a sample of the purified compound several times until a constant [α]D20 −219° (ethanol, c 1.00 or methanol, c 1.10) is observed. As chiral capillary GLC shows only (R)-(−)-3, the [α]D20 −219° (methanol, c 1.1) value from the literature3 is confirmed.
9. If a pH lower than 12 is used, recovery of the amine is poor.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Optically active methyloctalone 3 (or its enantiomer) has been obtained by resolution3,4 and by asymmetric synthesis.5 Both enantiomers are also available commercially. The synthesis described here is by far the most simple and gives the best yield. It is an application of the general method reported for the enantioselective elaboration of quaternary carbon centers through Michael-type alkylation of chiral imines.6 7 8 9 10 11 12 13 14
This general method has the following advantages: very simple procedures, very mild conditions involving moderate reaction temperatures and no acids, bases, catalysts, etc., allowing the use of labile reactants, excellent regio- and enantioselectivities as well as high chemical yields, and creation of useful chiral building blocks with quaternary carbon centers involving functionalized chains, allowing one to devise syntheses of natural compounds of various types (terpenes, steroids, alkaloids, etc.). As both optically active amines are commercially available, targets with either desired absolute configuration can be synthesized. Easy recovery of the auxiliary chiral moiety is possible.
Racemic methyloctalone 3 has been used as a starting material for many transformations as well as for syntheses of racemic natural compounds. In the following examples, the absolute configuration of the methyloctalone that would be required to obtain the natural enantiomer is indicated in parentheses: β-gorgonene15 (S), widdrol16,17 (R), thujopsene16,18 (R), 7-hydroxycostal19,20 (R), β-selinene21,22 (R), costol, costal and costic acid21 (R), norketoagarofuran23,24 (R), β-eudesmol21,22,23,25 (R), taxane model26 (S), polygodial27 (S), warburganal27 (S).
(R)-Methyloctalone 3 itself has been used to synthesize a pasmalinine model,28 a subunit of penitrem D,29 and several biologically active decalin derivatives.30
The following key-intermediates have been prepared by a procedure similar to the one described above, generally with excellent chemical and optical yields :
The use of substituted acrylic acid derivatives shows that besides the high enantioselectivity usually observed, the process is also highly diastereoselective, leading to compounds such as 27-32.
An acetylenic electrophile such as methyl propiolate leads to unsaturated compounds 35 and 36.
Linear β-ketoesters and lactones lead to compounds such as 37-39.
Compounds 40-45 arise from an analogous but intramolecular reaction. A special application of the chiral imine procedure, i.e., the use of an oxaziridine rather than an electrophilic olefin, yielding compound 46, has been reported.
Several of these chiral non racemic compounds were used for the synthesis of bilogically active products. Thus, (R)- and (S)-dimethyloctalones 5 lead respectively to natural and ent-geosmin.31 The (R)-enantiomer is also a precursor for the formal synthesis of isocostic and 3-isocostic acid32 while the (S)-enantiomer would lead to tuberiferine33 and was actually used to synthesize (−)-TMD, a specific inhibitor of the cholesterol biosynthesis.34 (S,S)-Dimethyloctalone 6 (a natural compound) leads to a natural octalin31 and would lead to α-vetispirene35 while the (R,R)-enantiomer would lead to frullanolide.36 Compound 7 (R,R) is a precursor for the formal synthesis of muzigadial27 while the (S,S)-enantiomer would lead to polygodial27 and warburganal.27 (+)-α-Cyperone 8 has been widely used as a starting material for the synthesis of many other sesquiterpenes37 and was in particular converted to ent-allohedycaryol.38 Compound 9 was transformed into a C2-symmetric chiral dione39 while compound 10 was the starting material for the synthesis of (−)-polywood.34 Tricyclic compounds 11 and 12 were used respectively to synthesize a ring C aromatic steroid40 and a key [ABC] steroid intermediate41 while compounds 13 were transformed into isosteres of aphidicolin as potential antiherpes agents.42 Methoxyketone 14 was converted to a precursor of bruceantin43 and compound 15 was used for the preparation of a 14-hydroxymorphinan derivative.44 (R)-Ketoester 16 is a key building block for the synthesis of (+)-cassiol,45 a potent antiulcerogenic agent, tridensone,46 and (−)-19-noraspidospermidine,47 while 17 led to (+)-aspidospermidine.48 Compound 18 was converted to (−)-nitramine.49,14 Lactams 19 show potent inhibition of the recombinant human type-1 steroid 5α-reductase. Compound 20 was used to perform the first synthesis of (+)-petasine and (+)-isopetasine, potent antiinflammatory and spasmolytic agents.50 Ketoester 21 is an intermediate for the formal total synthesis of vallesamidine.51 Ketodiesters 22 or 23 led to the marine antibiotic (−)-malyngolide.52 Aza-heterocycles 24 were used to synthesize substituted isoquinoline derivatives which were evaluated as potential inhibitors of 2,3-oxidosqualene lanosterol cyclase53 while oxo-heterocycles 25 and 26 have been used respectively for the synthesis of the mycotoxin, (−)vertinolide54 and of a subunit of marine polyethers toxins55 as well as to advanced intermediates for the synthesis of the anti-fertility agent, zoapatanol.56 Compounds 32 and 34 lead to precursors of Vinca and Hunteria alkaloids.57 Ethylenic compounds 35 and 36 were used respectively for the total synthesis of both riccardiphenols A and B58 and isocuparene.59 Acyclic compound 39 was converted to a nipecotic acid derivative.60 (R,R)-40 is a common intermediate in the total synthesis of (−)-ajmalicine and (−)-tetrahydroalstonine61,62,63 as well as of (+)-yohimbine,64,62,63 (−)-ochropposinine,63 and (−)-emetine62,63 while (S,S)-40 leads to (−)-(10R)-hydroxydihydroquinine.61,62,63
References and Notes
  1. Unité de Chimie Organique (UA CNRS 476), Ecole Supérieure de Physique et Chimie Industrielles de Paris, 10 rue Vauquelin, 75231 Paris Cedex 05, France.
  2. "Vogel's Textbook of Practical Organic Chemistry", 5th ed.; Longman Inc.: New York, 1989; p. 143.
  3. Toda, F.; Tanaka, K. Tetrahedron Lett. 1988, 29, 551.
  4. Djerassi, C.; Marshall, D. J. Am. Chem. Soc. 1958, 80, 3986; Adams, W. R.; Chapman, O. L.; Sieja, J. B.; Welstead, W. J. Jr. J. Am. Chem. Soc. 1966, 88, 162; Touboul, E.; Brienne, M. J.; Jacques, J. J. Chem. Res. S(Synopsis) 1977, 106; Brugidou, J.; Christol, H.; Sales, R. Bull. Soc. Chim. Fr. 1979, (1–2, Pt. 2) 40; Marshall, J. A.; Flynn, K. E. J. Am. Chem. Soc. 1982, 104, 7430; Johnson, C. R.; Zeller, J. R. J. Am. Chem. Soc. 1982, 104, 4021; Toda, F.; Tanaka, K. Chem. Lett. 1985, 885.
  5. Grattan, T. J.; Whitehurst, J. S. J. Chem. Soc., Chem. Commun. 1988, 43; Tanaka, A.; Kamata, H.; Yamashita, K. Agric. Biol. Chem. 1988, 52, 2043.
  6. Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem. Soc. 1985, 107, 273;
  7. Pfau, M.; Guingant, A.; Revial, G.; d'Angelo, J. PCT Int. Appl. WO 85 04 873, 1985; Chem. Abst. 1986, 105, 190527j;
  8. "Fieser and Fieser's Reagents for Organic Synthesis", Wiley, 1988; Vol. 13, p. 185;
  9. Revial G.; Pfau, M. In "Progress in Terpene Chemistry", Frontières Ed.; Paris: France, 1986; p. 383;
  10. Sevin, A.; Tortajada, J.; Pfau, M. J. Org. Chem. 1986, 51, 2671;
  11. Sevin, A.; Masure, D.; Giessner-Prettre, C.; Pfau, M. Helv. Chim. Acta 1990, 73, 552;
  12. Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1991, 20, 87–170 (see p. 114–115);
  13. d'Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymm. 1992, 3, 459.
  14. d'Angelo, J.; Cavé, C.; Desmaële, D.; Dumas, F. Trends Org. Chem. 1993, 4, 555.
  15. Boeckman, R. K., Jr.; Silver, S. M. J. Org. Chem. 1975, 40, 1755.
  16. Dauben, W. G.; Ashcraft, A. C. J. Am. Chem. Soc. 1963, 85, 3673.
  17. Enzell, C. Tetrahedron Lett. 1962, 185.
  18. Johnson, C. R.; Barbachyn, M. R. J. Am. Chem. Soc. 1982, 104, 4290.
  19. Cuomo, J. J. Agric. Food Chem. 1985, 33, 717.
  20. Wijnberg, J. B. P. A.; Jongedijk, G.; de Groot, A. J. Org. Chem. 1985, 50, 2650.
  21. Marshall, J. A.; Pike, M. T.; Carroll, R. D. J. Org. Chem. 1966, 31, 2933.
  22. Wijnberg, J. B. P. A.; Vader, J.; de Groot, A. J. Org. Chem. 1983, 48, 4380.
  23. Heathcock, C. H.; Kelly, T. R. Tetrahedron 1968, 24, 1801.
  24. Heathcock, C. H.; Kelly, T. R. J. Chem. Soc., Chem. Commun. 1968, 267.
  25. Vig, O. P.; Anand, R. C.; Kumar, B.; Sharma, S. D. J. Indian Chem. Soc. 1968, 45, 1033.
  26. Brown, P. A.; Jenkins, P. R.; Fawcett, J.; Russell, D. R. J. Chem. Soc., Chem. Commun. 1984, 253; Brown, P. A.; Jenkins, P. R. J. Chem. Soc., Perkin Trans. I 1986, 1303.
  27. Jansen, B. J. M.; Sengers, H. H. W. J. M.; Bos, H. J. T.; de Groot, A. J. Org. Chem. 1988, 53, 855; Jansen, B. J. M.; Kreuger, J. A.; de Groot, A. Tetrahedron 1989, 45, 1447.
  28. Smith, III, A. B.; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438.
  29. Smith, III, A. B.; Ohta, M.; Clark, W. M.; Leahy, J. W. Tetrahedron Lett. 1993, 34, 3033.
  30. Michne, W. F.; Schroeder, J. D.; Bailey, T. R.; Neumann, H. C.; Cooke, D.; Young, D. C.; Hughes, J. V.; Kingsley, S. D.; Ryan, K. A.; Putz, H. S.; Shaw, L. J.; Dutko, F. J. J. Med. Chem. 1995, 38, 3197.
  31. Revial, G. Tetrahedron Lett. 1989, 30, 4121, 7275.
  32. Cruz, R.; Martinez, R. M. Aust. J. Chem. 1982, 35, 451.
  33. Grieco, P. A.; Nishizawa, M. J. Chem. Soc., Chem. Commun. 1976, 582.
  34. Jabin, I.; Revial, G.; Melloul, K.; Pfau, M. Tetrahedron: Asymm. 1997, 8, 1101.
  35. Caine, D.; Boucugnani, A. A.; Chao, S. T.; Dawson, J. B.; Ingwalson, P. F. J. Org. Chem. 1976, 41, 1539.
  36. Still, W. C.; Schneider, M. J. J. Am. Chem. Soc. 1977, 99, 948.
  37. Ho, T.-L. "Enantioselective Synthesis, Natural Products from Chiral Terpenes", Wiley-Interscience: New York, 1992; p. 132; Li, Y.; Chen, X.; Shao, S.; Li, T. Synth. Commun. 1993, 23, 2457; Liu, L.; Xiong, Z.; Nan, F.; Li, T.; Li, Y. Bull. Soc. Chim. Belg. 1995, 104, 73.
  38. Zhabinskii, V. N.; Minnaard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 1996, 61, 4022.
  39. Pfau, M.; Jabin, I.; Revial, G; J. Chem. Soc., Perkin Trans. I 1993, 1935.
  40. Volpe, T.; Revial, G.; Pfau, M.; d'Angelo, J. Tetrahedron Lett. 1987, 28, 2367.
  41. d'Angelo, J.; Revial, G.; Volpe, T.; Pfau, M. Tetrahedron Lett. 1988, 29, 4427.
  42. Selwood, D. L.; Challand, S. R.; Champness, J. N.; Gillam, J.; Hibberd, D. K.; Jandu, K. S.; Lowe, D.; Pether, M.; Selway, J.; Trantor, G. E. J. Med. Chem. 1993, 36, 3503.
  43. Chiu, C. K.-F.; Govindan, S. V.; Fuchs, P. L. J. Org. Chem. 1994, 59, 311.
  44. Sdassi, H.; Revial, G.; Pfau, M.; d'Angelo, J. Tetrahedron Lett. 1990, 31, 875.
  45. Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron Lett. 1989 30, 723.
  46. Tori, M.; Kosaka, K.; Asakawa, Y. J. Chem. Soc., Perkin Trans. I 1994, 2039.
  47. d'Angelo, J.; Desmaële, D. Tetrahedron Lett. 1990, 31, 879. Desmaële, D.; d'Angelo, J. Tetrahedron Lett. 1990, 31, 883.
  48. Desmaële, D.; d'Angelo, J. J. Org. Chem. 1994, 59, 2292.
  49. Guingant, A.; Hammami, H. Tetrahedron: Asymm. 1993, 4, 25.
  50. Witschel, M. C.; Bestmann, H. J. Tetrahedron Lett. 1995, 36, 3325.
  51. Heathcock, C. H.; Norman, M.H.; Dickman, D. A. J. Org. Chem. 1990, 55, 798.
  52. Guingant, A. Tetrahedron: Asymm. 1991, 2, 415.
  53. Barth, M. M.; Binet, J. L.; Thomas, D. M.; de Fornel, D. C.; Samreth, S.; Schuber, F. J.; Renaut, P. P. J. Med. Chem. 1996, 39, 2302.
  54. Desmaële, D. Tetahedron 1992, 48, 2925.
  55. Desmaële, D.; Pain, G.; d'Angelo, J. Tetrahedron: Asymm. 1992, 3, 863, 867.
  56. Pain, G.; Desmaële, D.; d'Angelo, J. Tetrahedron Lett. 1994, 35, 3085.
  57. Mekouar, K.; Ambroise, L.; Desmaële, D.; d'Angelo, J. Synlett 1995, 529.
  58. Tori, M.; Hamaguchi, T.; Sagawa, K.; Sono, M.; Asakawa, Y. J. Org. Chem. 1996, 61, 5362.
  59. Sono, M.; Miyake, T.; Kitamura, K.; Hamaguchi, T.; Tori, M. 40th TEAC, Saga 1996.
  60. Felk, A. PhD thesis, University Paris VI, France, 1996.
  61. Hirai, Y.; Terada, T.; Yamazaki, T. J. Am. Chem. Soc. 1988, 110, 958;
  62. Hirai, Y.; Terada, T.; Yamazaki, T.; Momose, T. J. Chem. Soc., Perkin Trans. I 1992, 517;
  63. Hirai, Y.; Momose, T. Stud. Nat. Prod. Chem. 1994, 14, 551.
  64. Hirai, Y.; Terada, T.; Okaji, Y.; Yamazaki, T.; Momose, T. Tetrahedron Lett. 1990, 31, 4755;
  65. Tenius, B. S. M.; de Oliveira, E. R.; Ferraz, H. M. C. Tetrahedron: Asymm. 1993, 4, 633.
  66. Desmaële, D.; d'Angelo, J. Tetrahedron Lett. 1989, 30, 345.
  67. Desmaële, D.; Zouhiri, F.; d'Angelo, J. Tetrahedron: Asymm. 1994, 5, 1645.
  68. Brunner, H.; Kraus, J.; Lautenschlager, H.-J. Monatsh. Chem. 1988, 119, 1161.
  69. Guingant, A.; Hammami, H. Tetrahedron: Asymm. 1991, 2, 411.
  70. Pinheiro, S.; Guingant, A.; Desmaële, D.; d'Angelo, J. Tetrahedron: Asymm. 1992, 3, 1003.
  71. Audia, J. E.; Lawhorn, D. E.; Deeter, J. B.; Tetrahedron Lett. 1993, 34, 7001.
  72. Costa, P. R. R.; Castro, R. N.; Farias, F. M. C.; Antunes, O. A. C.; Bergter, L. Tetrahedron: Asymm. 1993, 4, 1499.
  73. d'Angelo, J.; Revial, G.; Costa, P. R. R.; Castro, R. N.; Antunes, O. A. C. Tetrahedron: Asymm. 1991, 2, 199.
  74. Gaidarova, E. L.; Grishina, G. V. Synlett 1992, 89.
  75. Matsuyama, H.; Ebisawa, Y.; Kobayashi, M.; Kamigata, N. Heterocycles 1989, 29, 449; Matsuyama, H.; Fujii, S.; Kamigata, N. Heterocycles 1991, 32, 1875. Matsuyama, H.; Fujii, S.; Nakamura, Y.; Kikuchi, K.; Ikemoto, I.; Kamigata, N. Bull. Chem. Soc. Jpn. 1993, 66, 1743.
  76. Jabin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M. Tetrahedron: Asymm. 1995, 6, 1795.
  77. Barta, N. S.; Brode, A.; Stille, J. R.; J. Am. Chem. Soc. 1994, 116, 6201.
  78. Ambroise, L.; Desmaële, D.; Mahuteau, J.; d'Angelo, J. Tetrahedron Lett. 1994, 35, 9705.
  79. Cavé, C.; Desmaële, D.; d'Angelo, J.; Riche, C.; Chiaroni, A. J. Org. Chem. 1996, 61, 4361.
  80. Ambroise, L.; Chassagnard, C.; Revial, G.; d'Angelo, J. Tetrahedron: Asymm. 1991, 2, 407.
  81. Felk, A.; Revial, G.; Viossat, B.; Lemoine, P.; Pfau, M. Tetrahedron: Asymm. 1994, 5, 1459;
  82. Hirai, Y.; Terada, T.; Katoh, H.; Sonohara, S.; Momose, T. Heterocycles 1991, 32, 7;
  83. Hirai, Y.; Terada, T.; Yamazaki, T.; Momose, T. J. Chem. Soc., Perkin Trans. I 1992, 509;
  84. Dumas, F.; d'Angelo, J. Tetrahedron: Asymm. 1990, 1, 167.
  85. Dumas, F.; Maine, V.; Cavé, C.; d'Angelo, J.; Chiaroni, A.; Riche, C. Tetrahedron: Asymm. 1994, 5, 339.
  86. d'Angelo, J.; Ferroud, C.; Riche, C.; Chiaroni, A. Tetrahedron Lett. 1989, 30, 6511.
  87. Davis, F. A.; Sheppard, A. C. Tetrahedron Lett. 1988, 29, 4365.

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

silica gel

petroleum ether










costic acid





penitrem D

isocostic and 3-isocostic acid




















2,3-oxidosqualene lanosterol cyclase










ethanol (64-17-5)

potassium carbonate (584-08-7)

hydrochloric acid (7647-01-0)

acetic acid (64-19-7)

ethyl acetate (141-78-6)

methanol (67-56-1)

ether (60-29-7)

sodium acetate (127-09-3)

sodium hydroxide (1310-73-2)

hydroquinone (123-31-9)

oxygen (7782-44-7)

nitrogen (7727-37-9)

sodium methoxide (124-41-4)

toluene (108-88-3)

Pentane (109-66-0)

magnesium sulfate (7487-88-9)

hexane (110-54-3)

methyl vinyl ketone (78-94-4)

2-methylcyclohexanone (583-60-8)


methyl propiolate (922-67-8)

2(3H)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4a-methyl-, (R)- (63975-59-7)

(R)-(+)-2-Methyl-2-(3-oxobutyl)cyclohexanone (91306-30-8)