J. Org. Chem. 1989,54, 279-290 (1M, 3.2 mL, 3.2 mmol). After being stirred at 0 'C for 3 h, the solution was neutralized by addition of Amberlite IR-120 (H'). The resin was removed and washed with MeOH. The combined filtrate and washing were concentrated in vacuo. The residue was chromatographed on silica gel (CHC13/MeOH, 301). The fractions corresponding to Rf 0.25 (EtOH/toluene, 15)were concentrated to give 17 (86 mg, 24%) as a colorless oil. The fractions corresponding to Rf 0.23 were concentrated in vacuo to give 16 (136 mg, 39%) as white crystals, mp 105-106.5 'C. 16: [(Y]"D -32.4' (c 0.96, MeOH); IR umaKBr 3380,2940,2900 cm-'; 'H NMR (400 MHz, CD30D) 6 1.73-1.87 (m, 2 H, H-5, H-59, 2.07-2.17 (m centered at 4 2.11, H-l), 3.51 (dd, 1 H, J = 6.5 and 11.0 Hz, CH20H), 3.63-3.75 (m, 3 H, H-2, H-3, CH20H),4.02 (ddd, 1H, J = 4.9, 4.9, and 7.3 Hz, H-4), 4.72 (9, 2 H, OCH&&), 7.23-7.40 (m, 5 H, OCH2C&,). Anal. Calcd for c&1& C, 65.53; H, 7.61. Found: C, 65.47; H, 7.52. 17: [(Y]"D -12.1' (c 0.92, MeOH); 'H NMR (400 MHz, CD30D) 6 1.20-1.28 (m centered at 6 2.14,l H, H-5), 2.04-2.10 (m centered at 6 2.06, 1 H, H-1), 2.18-2.26 (m centered at d 2.22,l H, H-5'), 3.50-3.66 (m, 3 H, H-3, CH,OH), 3.95 (dd, 1H, J = 5.4 and 5.4 Hz, H-2), 4.16 (dd, J = 6.8 and 12.2 Hz, H-4), 4.64, 4.70 (each d, each 1 H, J = 12.0 Hz, OCH2C6H5), 7.23-7.41 (m, 5 H, OCH,C,&); high-resolution mass spectra, calcd for C13H1804 m / z 238.1203, found (M) 238.1187. (1S,2S ,3S ,4R )-2,3,4-Triacetoxy-1-(acetoxymet hy1)cyclopentane (18). A solution of 16 (117 mg, 0.49 mmol) in EtOH (10 mL) was hydrogenolyzed in the presence of 10% Pd on charcoal (234 mg) under 1atm of hydrogen for 15 h. The catalyst was removed by filtration through a Celite pad, and the filtrate was concentrated in vacuo. The residue was acetylated with acetic anhydride (3 mL) in pyridine (3 mL) for 15 h. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel (AcOEt/hexane, 1:6). The fractions corresponding to Rf 0.72 (AcOEt/hexane, 1:l)were concentrated in vacuo to give 18 (155 mg, quantitative) as a colorless oil: [(Y]"D -46.9' (c 0.72); IR umnWt 2950,1750,1440 cm-'; 'H NMR (90 MHz) 6 1.91-2.01 (m, 3 H, H-1, H-5, H-59, 2.05 (s, 12 H, 4 OCOCH,), 4.05 (d, 2 H, J = 6 Hz, CH,OAc), 4.87-5.30 (m, 3 H, H-2, H-3, H-4). Anal. Calcd for Cl4HZ0O8:C, 53.16; H, 6.37. Found: C, 53.34; H, 6.33. (1R ,2R ,3S,4R)-2,3,4-Triacetoxy-l-(acetoxymethyl)cycl0pentane (19). Compound 17 (68 mg, 0.28 mmol) was hydrogenolyzed in the presence of 10% Pd on charcoal (204 mg) as described in the case of 18. After acetylation of the products and chromatographic purification (AcOEt/hexane, 1:6), 84 mg (95%) of 19 was obtained as a colorless oil. 19: TLC R, 0.72 (AcOEt/hexane, 1:l); [(YIz1D-5.3' (c 0.79); IR vmnWt 2975,1750, 1440,1380 cm-'; 'H NMR (90 MHz) 6 2.09,2.10 (each s, 3 H and 9 H, 4 OCOCH3),2.40-2.81 (m, 3 H, H-1, H-5, H-59, 4.28 (d, 2 H, J = 6 Hz, CH,OAc), 5.20-5.60 (m, 3 H, H-2, H-3, H-4). Anal. Calcd for C14HmO8: C, 53.16; H, 6.37. Found: C, 53.28; H, 6.33.
279
solution was neutralized with Amberlite IR-120 (H'). The resin was removed and washed with MeOH, and the combined filtrate and washing were concentrated in vacuo. The residue was chromatographed on silica gel (CHC13/MeOH, 9:l to 8:1), and the fractions corresponding to Rf 0.41 (CHCl,/MeOH, 2:l) were concentrated in vacuo to give 1 (27 mg, 95%) as a colorless oil: [(Y]16D-40.5' (c 0.84, MeOH); 'H NMR (400 MHz, CD,OD) 6 1.69-1.88 (m, 2 H, H-5, H-5'),2.00-2.08 (m, 1H, H-l), 3.47-3.67 (m, 4 H, H-2, H-3, CH,OH), 3.81 (ddd, 1H, J = 6.4,6.4, and 8.3 Hz, H-4); 13CNMR (100 MHz, CD30D) 6 33.02,44.90,64.50,75.45, 78.53,85.56; high-resolution mass spectrum calcd for C6H1304 m / z 149.0812, found (M + H) 149.0795. (1R ,2R ,3S ,4R) -2,3,4-Trihydroxycyclopentane1-methanol, Pseudo-&D-ribofuranose (2). By the analogous procedure described in the preparation of 1, 19 (59 mg) was deacetylated to give 2 (27 mg, 98%) after silica gel chromatography (CHCl,/MeOH, 2:l) as a colorless oil: TLC R 0.46 (CHC13/ MeOH, 2:l); [(Y]16D+6.6' (c 1.00, MeOH); 'H N h R (400 MHz, CD30D) 6 1.21-1.28 (m, 1 H, H-5), 1.99-2.08 (m, 1 H, H-l), 2.18-2.25 (m, 1 H, H-5'), 3.54 (dd, 1 H, J = 6.3 and 10.7 Hz, CHZOH), 3.63 (dd, 1 H, J = 5.6 and 10.7 Hz, CHZOH), 3.68 (dd, 1 H, J = 4.9 and 5.4 Hz, H-3), 3.85 (dd, 1 H, J = 5.4 and 5.4 Hz, H-2), 3.98 (ddd, 1H, J = 4.4,4.9 and 6.6 Hz, H-4); 13C NMR (100 MHz, CD30D) 6 33.69, 45.98, 65.30, 74.52, 76.64, 79.59; highresolution mass spectrum calcd for C6H1304 m/z 149.0812, found (M + H) 149.0798. (1R ,2R ,3S ,4R )-4-Acetoxy-l-(acetoxymethyl)-2,3-(isopropy1idenedioxy)cyclopentane (20). To a solution of 2 (5 mg, 0.04 mmol) in DMF (0.5 mL) were added 2,2-dimethoxypropane (0.03 mL) and camphorsulfonic acid (2 mg). After being stirred for 6 h, the mixture was neutralized with saturated aqueous NaHC03 and concentrated in vacuo. The residue was acetylated with acetic anhydride (0.5 mL) in pyridine (0.5 mL) for 2 h. After concentration of the mixture, the residue was chromatographed on silica gel (AcOEt/hexane, 1:lO). The fractions corresponding to Rf 0.62 (AcOEt/hexane,23) were concentrated in vacuo to give 20 (7.5 mg, 82%) as a colorless oil: [a]%D-20.1' (c 0.33); E t vmWt 3000,2950,1750,1380 cm-'; 'H NMR (400 M H z ) 6 1.30,1.46 (each s, each 3 H, C(CH3),), 1.59-1.65 (m, 1 H, H-5), 2.05, 2.08 (each s,each 3 H, 20COCH3),2.33-2.40 (m, 1H,H-5'), 2.45-2.52 (m, 1 H, H-1), 4.01-4.09 (m, 2 H, CHzOAc),4.52-4.56 (m, 2 H, H-2, H-3), 5.06-5.08 (m, 1H, H-4). Anal. Calcd for C13HBO6: C, 57.34; H, 7.40. Found: C, 57.42; H, 7.71.
Acknowledgment. We thank Hisao Arita of our university for performing elemental analyses.
Registry No. 1, 118013-55-1;2, 118013-56-2;3, 22529-61-9; 4, 23558-05-6; 5, 117918-35-1;6, 117918-36-2; (Y-7,117918-37-3; (1S,2S,3S,4R)-2,3,4-Trihydroxycyclopentane-l-methanol, @-7,117918-42-0;9,117918-38-4;9', 118013-63-1; 10,117940-39-3; Pseudo-a-L-arabinofuranose (1). A solution of 18 (60 mg, 0.19 lo', 118014-53-2;11,11791839-5; 12,118013-57-3;14,118013-58-4; 15,118013-59-5;16,117918-40-8; 17,118013-60-8; 18,118013-61-9; mmol) in MeOH (5 mL) containing sodium methoxide in MeOH 19, 118013-62-0; 20, 117918-41-9; CH2(COOMe),, 108-59-8. (1 M, 0.57 mL, 0.57 mmol) was stirred at 0 'C for 2.5 h. The
a-Acylamino Radical Cyclizations: Application to the Synthesis of a
Tetracyclic Substructure of Gelsemine Joong-Kwon Choi, Deok-Chan Ha, David J. Hart,* Chih-Shone Lee, Subban Ramesh, a n d Shung Wu Department of Chemistry, The Ohio State University, 120 W. 18th Ave., Columbus, Ohio 43210 Received July 6, 1988 Syntheses of gelsemine substructures 2 and 3 are described. Free-radical precursors 14, 18,35, and 38 were prepared, and their behavior upon treatment with tri-n-butyltin hydride and AIBN was examined. The radical derived from 14 afforded reduction product 15, whereas the radicals derived from 18,35, and 38 gave cyclization products 23, 37, and 39, respectively. Aspects of these free-radical cyclizations as well as the conversion of 23 and 37 to 2 and 3, respectively, are presented. Gelsemine (1) is a n oxindole alkaloid that has eluded synthesis since its structure was reported nearly 30 years 0022-3263/89/1954-0279$01.50/0
This has not, however, been due t o a lack of effort. I n fact, numerous studies t h a t have been reported in t h e 0 1989 American Chemical Society
280
J. Org. Chem., Vol. 54, No. 2, 1989
Choi et al. Scheme I
ax
l
y + o r > -NMe x ~ q + o
.L
:B]. -
-NMe
\
Y
4
5
NMe
Y
0
6
Y
9iMe To S c h e m e IIn
8a
(NMe
7
b
OH&
HO
0
0
9
10 R = CHzCHzOH 11 R = CH=CH2
15
14
e
c"a
Z=R=H
/
12b Z = H R = M e
L 1 3
Z=CH20Me
'(a) PhCHs, A, 7 h; (b) H,, P d / C , EtOH; (c) o-N02CBH4SeCN,n-Bu3P, THF; H20,; (d) NaBH,, MeOH, 0 "C; (e) MeOH, Dowex-50 (H+);
(0 LDA, THF; ClCH,OMe; (9) PhSH, TsOH (cat.), CHzClz; (h) n-Bu3SnH, AIBN, PhH, A.
past few years suggest that this synthetic challenge will eventually be met with a variety of solutions.*~ This paper describes our own progress toward gelsemine within (1)Conroy, H.; Chakrabarti, J. K. Tetrahedron Lett. 1959 (4),6. Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959 (4), 1. (2)Gelsevirine (Wenkert, E. Experientia 1972,28,377) and 21-oxogelsemine (Nikiforov, A. J.; Latzel, J.; Varmuza, K.; Wichtl, M. Monatsh. Chem. 1974,105, 1292) are structurally related to gelsemine. (3)For reviews of literature related to Gelsemium alkaloids, see: Saxton, J. E. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1965;Vol. 8,pp 93-117. Luzio, M. J. Ph.D. Thesis, University of Rochester, 1987. (4)Fleming, I.; Loreto, M. A,; Michael, J. P.; Wallace, I. H. M. Tetrahedron Lett. 1982,23,2053. Clarke, C.; Fleming, I.; Fortunak, J. M. D.; Gallagher, P. T.; Honan, M. C.; Mann, A.; Nubling, C. 0.;Raithby, P. R.; Wolff, J. J. Tetrahedron 1988,44,3991. (5)Jones, K.; Thompson, M.; Wright, C. J . Chem. Soc., Chem. Commun. 1986,115. ( 6 ) Stork, G.; Krafft, M. E.; Biller, S. A. Tetrahedron Lett. 1987,28, 1035. Stork, G.; Nakatani, K. Tetrahedron Lett. 1988,29,2283. (7)Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987,52, 4130. Earley, W. G.; Jacobsen, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988.29.3781. Earlev, W. G.: Oh, T.: Overman, L. E. Tetrahedron Lett. 1988,29,3785. (8)Vijn, R. J.; Hiemstra, H.; Kok, J. J.; Knotter, M.; Speckamp, W. N. Tetrahedron 1987,43,5019.Hiemstra, H.; Vijn, R. J.; Speckamp, W. N. J . Org. Chem. 1988,53,3884. (9)(a) Guthrie, R. D. Ph.D. Thesis, University of Rochester, 1963; Diss.Abstr. 1963,24,1834.(b) Tahk, R. C. Ph.D. Thesis, University of Rochester, 1966;Diss.Abstr. 1966,27B,118. (c) Landeryon, V.A. Ph.D. Thesis, University of Rochester, 1965;Diss.Abstr. 1965,26,2477. (d) Lovett, E. G. Ph.D. Thesis, University of Rochester, 1967;Diss.Abstr. 1967,27,110-B.
the context of syntheses of the tricyclic and tetracyclic substructures 2 and 3.1°
I
1
COzEI
T O M e
3
Our approach to gelsemine follows a retrosynthetic analysis (Scheme I) that is closely related to that recently presented by Hiemstra and Speckamp.6 We projected that (10)Taken in part from the following: Ha, D.-C. Ph. D. Thesis, Ohio State University, 1987. Lee, C.4. Ph.D. Thesis, Ohio State University, 1988.
J. Org. Chem., Vol. 54, No. 2,1989 281
a-Acylamino Radical Cyclizations Scheme 111"
0'
19
18
a f - l3 X = C H 2
T O M e
To* -NMe
COiEt
*
2o
I
C02E1
I
R
I
tl-NMe
y
I
C02Et
T O M e
-17
5TMe
22
I
COzEt
24 R = CHpOH 25 R = CHO 2 R = CH=CHp
(a) NaIO4,0 8 0 4 (cat.); (b) Ph3P=CHC02Et; (c) PhSH, TsOH; (d) n-Bu3SnH, AIBN (cat.), P h H ; (e) BBr,; (f) DMSO,(COCl),; Et3N; ( 9 ) Ph,P=CH,.
gelsemine might be prepared from hypothetical intermediate 4,where X,Y,and Z were suitable for introduction of the oxindole, tetrahydropyran, and vinyl moieties, respectively. We have previously shown that a-acylamino radical cyclizations are of some use in the construction of carbon-carbon bonds adjacent to nitrogen, and thus we imagined that 4 might be prepared through cyclization of a radical of type 5."J2 An interesting conformational issue arises, however, when this projected cyclization ( 5 4) is considered. One would expect radical 5 to be in conformational equilibrium with radical 6. In fact, one would expect 6,a conformation from which cyclization cannot take place, to be more stable than 5 . Thus, the success of the proposed construction of the incipient c5+6 bond of gelsemine would depend on a sensitive balance of cyclization rates (5 4),conformational equilibria (5 6), and rates of other radical processes (5 or 6 noncyclized products). We felt this was an interesting issue which might be of general value as organic chemists continue to increase their use of radical cyclizations in synthesis de: sign.13 Synthesis of Compound 2: Preparation and At-
-
-
-
=
(11)Hart,D.J.; Tsai, Y.-M. J.Am. Chem. SOC.1982,104,1430. Choi, J.-K.; Hart, D. J. Tetrahedron 1985,41,3959. (12)For other studies using a-acylamino radical cyclizations, see: Bach, M. D.; Hoornaert, C. Tetrahedron Lett. 1981,22,2693.Kametani, T.;Honda, T. Heterocycles 1982,19,1861.Kano, S.;Yuasa, Y.; Shibuya, S. Heterocycles 1988,27,253. (13)For an excellent introduction to the use of free-radical reactions in organic synthesis, see: Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Baldwin, J. E., Ed.; Pergamon Press: New York, 1986. Also see: Ramaiah, M. Tetrahedron 1987,43, 3541. Curran, D.P. Synthesis 1988,417.Curran, D.P. Synthesis 1988, 489.
tempted Cyclization of Perhydroisoindoles 14 and 18. Our initial studies, which ignored the need for a functional handle to introduce the oxindole and tetrahydropyran moieties, focused on the synthesis of radical cyclization precursor 14 using the reaction sequence outlined in Scheme 11. A Diels-Alder reaction between N-methylmaleimide (7)and the known dienol 8 gave hexahydroisoindole 9 in 97% yield.14 A catalytic hydrogenation followed by application of the Grieco dehydration sequence to 10 afforded imide 11 (84% overall).15 Reduction of imide 11 with sodium borohydride in methanol followed by hydroxy-methoxy exchange gave lactam 12b in 88% yield.16 The stereochemical assignment at C5 of lactam 12b was based on the appearance of the C5 methine as a singlet at 6 4.16, an indication of a 90° H4a-C4a-C5-H6 dihedral angle. The regiochemical course of this reduction is remarkable, but is explained by the popular antiperiplanar effect. In this case, antiperiplanar alignment of the HOMO of the incoming nucleophile and the C4-C4a u* orbital appears to be imp0rtant.l' Hiemstra and Speck(14)Martin, s.F.;Tu,C Y . ; Chou, T.4. J.Am. Chem. SOC.1980,102, 5274. Howden, M. E.H.; Maercker, A.; Burdon, J.; Roberts, J. D. J.Am. Chem. SOC.1966,88,1732. (15)Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976,30, 3760. (16)Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975,31,1437. Chamberlin, A. R.; Chung, J. Y. L. Tetrahedron Lett. 1982,23, 2619. Hart, D.J.; Yang, T.-K. J. Chem. Soc., Chem. Commun. 1983,135. (17)Kayser, M. M.; Wipff, G. Can. J. Chem. 1982,60,1192.Kayser, M. M.;Salvador, J.; Morand, P.; Krishnamurty, H. G. Can. J. Chem. 1982,60, 1199. Kayser, M. M.; Salvador, J.; Morand, P. Can. J. Chem. 1983,61,439. Anh, N. T.;Eisentein, 0. Nouu. J. Chim. 1977,I , 61. Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. J.Am. Chem. SOC.1981,103,2438.
282 J. Org. Chem., Vol. 54, No. 2, 1989
Choi et al. Scheme IVo
27
26
28 0
h OMe
L N M e E102C
R'l
0
(
35
kNMe
0
31 R1 = CHzCH2, R2 = H 32 R, = CH=CH*, R2 = CH20Me
i
J
c
e
