J. Org. Chem. 1991,56,95-102 (d), 111.8 (s), 54.1 (q), 50.77 (t), 46.6 (t). Anal. Calcd for C15H1106Br:C, 49.07; H, 3.02; Br, 21.76. Found: C, 49.35; H, 3.14; Br, 22.27. 2,2-Dimethyl-6-[ (2-bromo-bhydroxy-l,4-dioxonaphth-3yl)methyl]-1,3-dioxen-4-one (21). Method A. In a 250-mL 3-necked round-bottom flask, naphthoquinone 1 (1.0 g, 4 mmol) was dissolved in THF (75 mL), placed under nitrogen, and cooled to -78 "C. The diene 4 (2.6 g, 12 mmol) was added via syringe, and the reaction mixture was allowed to stir for 12 h. To effect desilylation, 6 N HCl(10 mL) was added at -78 OC and stirred for 2 h while allowing the solution to warm to room temperature. The solvent was removed under reduced pressure, and the residue was diluted with dichloromethane (125 mL). The solution was washed with water (3 X 50 mL) and dried over MgSO,. The solvent was removed under reduced pressure. Flash chromatography (hexane-acetone, 51) afforded 21 (1.2 g, 77%) Method B. In a 250-mL round-bottom flask were placed T H F (50 mL) and diisopropylamine (1.7 mL, 12 mmol) under nitrogen. The solution was cooled to -78 OC, and maintained at that temperature throughout the reaction. Added dropwise to this solution was 4.75 mL of n-butyllithium (12 mmol). The solution was allowed to stir for 10 min. 2,2,6-Trimethyl-l,3-dioxen-4-one (1.6 mL, 12 mmol) was added via syringe, and the solution was allowed to stir for 1h. Naphthoquinone 1 (1.0 g, 4 mmol) dissolved in THF (40 mL) was added slowly through a dropping funnel. The reaction mixture was allowed to stir for 4 h and was treated with 6 N HCl (15 mL) at -78 "C followed by stirring for 2 h while allowing the solution to warm to room temperature. The reaction was subjected to the same procedure as described in method A, affording 21 (1.0 g, 68%): mp 115 "C; 'H NMR 11.77 (1H, s), 7.74-7.38 (3 H, m), 5.30 (1 H, s), 3.86 (2 H, s), 1.69 (6 H, s); IR 1710, 1690, 1640, 1580 cm-'; *%NMR 185.3, 176.4, 171.5,165.2, 158.1,144.0, 141.9, 137.2, 135.0, 125.2, 121.7, 114.3, 98.2,92.5,47.8, 19.1. Anal. Calcd for Cl7Hl3O6Br: C, 51.93; H, 3.33; Br, 20.32. Found: C, 51.45; H, 3.54; Br, 20.01. 2-Bromo-5-hydroxy-3-[2-hydroxy-l-(methoxycarbonyl)-lpropenyl]-1,4-naphthoquinone(25). In a 250-mL 3-necked round-bottom flask were placed T H F (30 mL) and NaH (0.6 g, 10 mmol) under nitrogen. The solution was cooled to -78 OC and maintained at that temperature throughout the reaction. Methyl acetoacetate (1.1mL, 10 mmol) was added via syringe, and resulting solution was allowed to stir for 10 min. Added dropwise
95
to this solution was 4.2 mL of n-butyllithium (11 mmol), and the mixture was allowed to stir for 10 min. Naphthoquinone 1 (2.0 g, 8 mmol) dissolved in THF (50 mL) was added via a dropping funnel, and the reaction mixture was allowed to stir for 30 min. The solution was permitted to warm to room temperature and stirred for an additional 15 min. The mixture was cooled to -78 "C and 6 N HCl (7 mL) was added and stirred for 5 min. The reaction mixture was allowed to warm to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (125 mL), washed with water (2 X 50 mL), and dried over MgSO,. Flash chromatography (hexane-ethyl acetate, 101) afforded 25 (2.6 g, 88%): mp 134-135 "C; IR 1678, 1656, 1636 cm-'; 'H NMR 13.06 (1 H, s), 11.93 (1 H, s), 7.76-7.27 (3 H, m), 3.72 (3 H, s), 1.93 (3 H, s); 13C NMR 186.5 (s), 175.3 (s), 170.1 (s), 162.1 (s), 145.7 (s), 143.7 (s), 140.1 (s), 136.6 (d), 129.0 (s), 125.1 (d), 120.8 (d), 118.5 (s), 98.3 (s), 52.2 (q), 20.1 (q). Anal. Calcd for ClSHl,06Br: C, 49.07; H, 3.02; Br, 21.76. Found: C, 48.91; H, 3.15; Br, 21.65.
Acknowledgment. We are grateful to the National Science Foundation for a Grant (CHE-8418897) (A.K.) used t o purchase the CAD-4 X-ray diffractometer system. Registry No. 1,69008-03-3;2, 52431-65-9;3, 130573-42-1;4, 130573-43-2;5,605-89-0;6,6566-25-2;7,77189-69-6;8,77197-58-1; 10, 2065-37-4; 11, 110362-29-3;12, 130573-44-3;13, 117-10-2;15, 74590-73-1; 16, 52431-74-0; 17, 52431-73-9; 18, 130573-45-4; 19, 130573-46-5;20, 130573-47-6;21, 130573-48-7;25, 130573-49-8; MeCOCH2C02Me, 105-45-3; Cl2SiMez, 75-78-5; MeCH/ dbdCHCOzMe, 18707-60-3;1,6-diacet~xynaphthalene, 59335-81-8; 2-bromo-6-acetoxy-l,4-naphthoquinone, 130573-50-1; 1,7-diacetoxynaphthalene, 51850-49-8; 3-bromo-6-acetoxy-l,4naphthoquinone, 130573-51-2; 2-ethyl-l-hydroxynaphthalene, 30159-69-4;2-ethyl-1,4-naphoquinone, 5409-32-5; l,4-diacetoxy2-methylnaphthalene, 573-20-6;2-brom0-3-methyl-1,I-naphthoquinone, 3129-39-3; l-hydroxynaphthalene, 90-15-3; 2,2,6-trimethyl-1,3-dioxen-4-one, 5394-63-8. Supplementary Material Available: Tables of final atomic fractional coordinates, anisotropic displacement parameters, and selected bond distances and angles and an ORTEP diagram for 12 (4 pages); observed and calculated structure factors (9 pages). Ordering information is given on any current masthead page.
Radical Cyclization of N-(Cyclohex-2-enyl)-cu,a-dichloroacetamides. Stereoselective Syntheses of (f)-Mesembranol and (&)-Elwesine Hiroyuki Ishibashi,* Taru Su So, Kyoko Okochi, Tatsunori Sato, Nobuyuki Nakamura, Hiroshi Nakatani, and Masazumi Ikeda* Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan Received March 28, 1990 (Revised Manuscript Received July 17, 1990) Stereoselective syntheses of the Sceletium alkaloid (*)-mesembranol (2) and the Amaryllidaceae alkaloid radical cyclization (*)-elwesine (3)have been achieved. A key step in the syntheses involves the B~~SnH-mediated of the dichloroacetamides 34 and 46, which provides the cis-3a-aryloctahydroindolones36 and 47, respectively. The amides 34 and 46 were prepared in a highly stereocontrolled manner from the corresponding l-arylcyclohexenes 29 and 41 along the lines: 29 30a 31 32 33 34 and 41 42a 44a 45a 46. Transformation of 36 into (h)-mesembranol was readily accomplished by reduction with diborane and subsequent removal of the O-benzyl protecting group by hydrogenolysis over Pd/C. On the other hand, debenzylation of 36 with Raney Ni afforded a mixture of the 6a- and 66-alcohols 39a and 39b, which was then reduced by alane to give a separable mixture of (*)-mesembranol and (*)-6-epimesembranol (40). Reduction of 47 with diborane followed by catalytic hydrogenolysis over Pd/C afforded the amino alcohol 50, which has already been converted into (*)-elwesine by Pictet-Spengler cyclization.
- ----
Sceletium alkaloids such as mesembrine (1) a n d mesembranol (2), which possess a cis-3a-arylhydroindole
- - - -
nucleus as the basic structural element, have remained attractive target molecules for total synthesis.' This may
0022-3263/91/1956-0095$02.50/00 1991 American Chemical Society
Ishibashi et al.
96 J. Org. Chem., Vol. 56,No. 1, 1991 Scheme I1
Scheme I
aNiCI
H
__t Bu3SnH
-
5 .OQH
Bnd'
NHR
- DA' 8
Me 15
_ Bu3SnH .c
bo
HMe
RMe
18
17
BnO
7 Bn
-
19
8
20
CH,Ph
reflect not only the potential central nervous system activity of mesembrine2 but also the close structural relationship with the more complex Amaryllidaceae alkaloids elwesine (3)and pretazettine (4h3
21
OMe
1
3
2
chloroacetamides 9 give only a minute amount of the ybutyro lactams 11, whereas the cyclization of the monochloro-substituted carbamoylmethyl radicals 13 from dichloroacetamides 12 proceeded smoothly to give the achloro lactams 14 in good yields. The chloro lactams 14 can readily be converted into the dechlorinated lactams 11 if desired, by treatment with an additional equivalent of Bu3SnH.
4
Our interest in this area was stimulated by the prospect of designing a stereoselectiveentry to this class of alkaloids according to the strategy outlined in retrosynthetic format depicted in Scheme I. The key feature of our approach is based upon a tributyltin hydride (Bu3SnH) mediated radical cyclization of the a,a-dichloroacetamides 6 to give the cis-3a-aryloctahydroindolones5.4 The synthesis of the amides 6 having a relative stereochemistry characteristic of the six-membered ring in 2 or 3 was envisaged to arise from the amino alcohols 7,which in turn were prepared from the cyclohexenes 8 via a stereoselective epoxidation followed by ring opening with the appropriate amines. We now wish to report an application of this methodology to the total synthesis of (&)-mesembranol(2) and the formal total synthesis of (&)-elwesine (3).5
Synthesis of (&)-Mesembranol(2) Our previous studies6 on the Bu3SnH-mediated radical cyclization of N-allyl-a-chloroacetamides have revealed that the carbamoylmethyl radicals 10 derived from a(1) For a review of the chemistry of the Sceletium alkaloids, see: Jeffs, P. W. In The Alkaloids; Rodrigo, R. G. A., Ed., Academic Press: New York, 1981; Vol. 19, pp 1-80. (2) Ohishi, A.; Kugita, H. Japan. Patent 1971,7143,539 [Chem.Abstr. 1972, 76, 59443~). (3) For a review of the Amaryllidaceae alkaloids, see: Martin, S. F. In The Alkaloids: Brossi, A,, Ed.; Academic Press: New York, 1987; Vol. 30, pp 251-376. (4) For other approaches to octahydroindolesvia a radical process, see: (a) Nagashima, H.; Ara, K.; Wakamatsu, H.; Itoh, K. J. Chem. Soc., Chem. Commun. 1985,518. (b) Jolly, R. S.;Livinghouse, T. J. Am. Chem. SOC. 1988, 110, 7536. (c) Stork, G.: Mah, R. Heterocycles 1989,28, 723. (5) For a preliminary account of a portion of this work, see: Ishibashi, H.; So, T. S.;Sato. T.; Kuroda, K.; Ikeda, M. J. Chem. Soc., Chem. Commun. 1989,762. (6) Sato, T.; Wade, Y.; Nishimoto, M.; Ishibashi, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1, 1989, 879.
9
10
11
t
^.
A
A
A
12
13
14
Bu,SnH
With this information in hand, we began our investigations by examining the cyclization of N-(cyclohex-2-enl-y1)-N-methyl-a,cu-dichloroacetamide (15). Thus, a mixture of Bu3SnH (1equiv) and a catalytic amount of azobis(isobutyronitri1e) (AIBN) in toluene was added to a boiling solution of 15 (6.5 X M) in toluene over a period of 1 h, and the mixture was refluxed for a further hour. At this stage, the chloro lactam 16 might be formed. Further BuBSnH (1.1 equiv) and AIBN in toluene were then added before the solution was heated again under reflux for 2 h. Evaporation of the solvent followed by chromatography on silica gel afforded the dechlorinated cis-bicyclic lactam 17 in 92% yield. Next, the phenyl-substituted compound 21,which was prepared from l-phenylcyclohexene oxide (18)in 3 steps (Scheme 11), was treated with Bu,SnH (2.1 equiv) and AIBN to give the cis-3a-phenylhydroindolone 22 and an unexpected product 23 in 43 and 6% yields, respectively, along with the reduction product 24 (28%). The 'H NMR spectrum of the rearranged product 23 exhibited a singlet at 6 6.03 due to the olefinic proton at C3. The protons at C4 and C7a appeared as a doublet (J = 4.7 Hz) at 6 4.25 and a doublet of doublets (J = 11.5, 6.3 Hz) at 6 3.78, respectively.
J. Org. Chem., Vol. 56, No. 1, 1991 97
Synthesis of (*I-Mesembranol and (*)-Elwesine
Scheme IV
Scheme I11
28
29
36
37
OME
30b
30a
+
dNkl
BnO
Me 33
--
35
34
Bn CH,Ph Ar
3,4dknethoxyphenyl
Formation of 22 and 23 can be explained in terms of the common intermediate 26 generated by a cyclization of the carbamoylmethyl radical 25. The attack of BuaSnH on the radical center of 26 would afford the normal product 22 via a reductive dechlorination. On the other hand, when the radical center of 26 attacks the angular phenyl group intramolecularly,a new radical (27) might result. This step is then followed by elimination of the chlorine atom, with concomitant 172-arylmigration, to lead to 23. 21
dN
