540 (B) From Loganin Aglucone 6-Acetate (5). To an ice-cold
solution of 105 mg of optically active aglucone 5, 408 mg of 2,3,4,6tetra-O-acetyl-~-~-glucose,~~ and 500 mg of Drierite in 3 ml of 1,2dichloroethane was added dropwise 0.10 ml of boron trifluoride
etherate. The mixture was stirred at 0" for 2 hr and at room temperature for 36 hr.. After neutralization with pyridine, the mixture was poured into water and the product (550 mg) was isolated with ethyl acetate. The viscous oil was fractionated by thick layer chromatography to give 165 mg of a glucoside mixture. Further purification by tlc yielded 50 mg of an oil, [ c Y ] ~ ~ -60" D (c 1.05, CHCl3), which crystallized on standing. The solid was recrystallized twice from ethanol to give 40 mg (17%) of fine white needles: mp 139-140" ( l i t 2 mp 140-141 "); [ctIz5D -79.1 (c 0.35, CHC13) (lit.z[ c Y ] ~ ~-79.6' D ( c 0.39, CHCl,)} ; ir (CHC13) 1740 (CO, broad),
1710 (CO), 1645 (C=C), 1255, 1085, 1070, and 1045 cm-1; uv (C2HjOH) 233 nm ( E 10,600); nmr (CDCI,) 6 7.31 (s, 1, -CH=), 3.70 (s, 3, OCH,), 3.02 (m, 1, H-4a), 2.09 (s, 3, CH,CO), 2.03 (s, 6, CHKO), 2.00 (s, 3, CH3CO), 1.81 (s, 3, CHICO), and 1.02 (d, 3, J = 7 Hz, CHJ; mass spectrum nr/e (re1 intensity) 600 (M+, O.l), 5.69 (O.l), 540 (0.3), 331 (70), 271 (5), 253 (4), 193 (35), 169 (loo), 109 (40). A 1 : 1 mixture of this material and authentic loganin pentaacetate exhibited mmp 139-140". Anal. Calcd for C2?H36015:C, 54.00; H, 6.04. Found: C, 53.90; H, 6.00.
Acknowledgment. We express our gratitude to the staff of the Physical Chemistry Department of Hoffmann-La Roche Inc. for their assistance in this work.
Total Synthesis of Loganin G. Buchi," John A. Carlson,' J. E. Powell, Jr.,2 and L.-F. Tietze Contribution from the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Received July 27, 1972 Abstract: A synthesis of loganin, a monoterpene glucoside occupying a central position in the biosynthesis of secoiridoids and alkaloids, is described. The photochemical cycloaddition of 2-formylmalonaldehydic acid methyl ester to the tetrahydropyranyl ether of 3-cyclopentenol is the key step in the synthesis, allowing the construction of the tetrahydrocoumalate unit typical of iridoids in a single operation. Methanolysis followed by oxidation with chromium trioxide afforded the crystalline ketoacetal 7. The methyl group was introduced regioselectivekjGia the n-butylthiomethylene ketone and the resulting product 12 epimerized to the more stable epimer 13. Reduction of the carbonyl group and treatment of the corresponding mesylate with tetraethylammonium acetate followed by hydrolysis with aqueous acetic acid-perchloric acid gave loganol 5-acetate (21). Glucosidation of (23) yielded optically active loganin pentaacetate which racemic 21 using 2,3,4,6-tetra-0-acetyl-P-~-glucopyranose had previously been converted to loganin.
T
he glucoside loganin, first isolated from Strychnos nux v ~ m i c a is , ~ a widely distributed product of secondary plant metabolism4 and a key intermediate in the biosynthesis of Corynanthe, Aspidosperma, Iboga, Ipecacuanha, and structurally simpler monoterpene alkaloid^.^ Its detailed structure was established by chemical and confirmed by X-ray analysis of the m e t h o ~ y b r o m i d e . ~In this paper we present details on the total synthesis of loganin ( l ) , l o which represents the first synthesis of an iridoid glucoside. (1) National Institutes of Health Predoctoral Fellow 1966-1969. (2) National Institutes of Health Predoctoral Fellow 1967-1969. (3) W. R. Dunstan and F. W. Short, Pharm. J . Trans., 14, 1025 (1884). (4) An up-to-date list of its occurrence in nature is presented in the accompanying paper: J. J. Partridge, N. I d , J =7Hz). Formation of a-C-Methyl Ketone 13 by Base Treatment of Ketone 12. The epimeric mixture of ketones containing mainly 12 (350 mg, 1.46 mmol) was dissolved in 50 ml of methanolic 0.13 N sodium methoxide and allowed to stand for 18 hr at 0" under argon. After neutralization with glacial acetic acid, the reaction solution was poured into water and extracted withether. The ether extract was washed with saturated sodium bicarbonate solution, water, and saturated salt solution, dried (MgSOJ, and concentrated iiz cuciio to give 348 mg of a pale yellow oil which was chromatographed on 30 g of silica gel ( 2 : l silica gel PF-254-silica gel 0.050.2 mm, Merck). Elution with 9:1 benzene-ether provided 315 mg (90%) of pure a-C-methyl ketone 13 as a colorless gum. This material crystallized readily but even after repeated recrystallization from ether always exhibited mp 90-110". Two sublimations of 275 mg (70", 0.01 mm) produced 270 mg of material, mp 75-90". The sublimed solid when recrystallized from hexane showed mp 90-105'. However. when the melt recrystallized and the melting point was determined a second time, the material exhibited mp 90--92"(this phenomenon could he duplicated). The sublimed material exhibited spectral characteristics identical with those of the degradation product 13 prepared from loganin: ir (CHCI,) 1740, 1700, 1630 cm-*; u v max (95% ethanol) 235 nm ( 6 10.500); nmr (CDCla)6 7.46 (1 H , d. J = 1.5 Hz), 4.96 (1 H, d,
Journal of the American Chemical Society
1 95.2 1 January
J = 2.5 Hz), 3.72 (3 H, s), 3.52 (3 H, s), 3.18 (1 H , m), 2.58 (2 H, d, J = 6 Hz), 2.3-1.9 (2 H , m), 1.14 (3 H, d, J = 6.5 Hz); mass spectrum m/e 240 (M+). Anal. Calcd for C12H160j: C, 59.99; H , 6.71. Found: C, 59.88; H, 6.34. Preparation of 1-0,6-0-Diacetylloganol 15.22 A mixture of loganin pentaacetatez2(1.2 g, 2.0 mmol), acetic anhydride (14 ml), acetic acid (6 ml), and sulfuric acid (0.4 ml) was heated at 100" for 30 min under nitrogen. After cooling, water was added carefully (very exothermic reaction) to hydrolyze excess anhydride. The dark reaction mixture was then diluted with more water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate solution, water, and saturated salt solution, dried (MgSOd), and concentrated i/r caciia to leave 1.01 g of a dark semisolid mass which was chromatographed on 70 g of silica gel (4: 1 silica gel PF-254-silica gel 0.05-0.2 mm, Merck). Development with 2:l benzene-ethyl acetate eluted first 285 mg (48%) of the diacetate 15 as a yellow oil and the 510 mg of pure glucose pentaacetate. The diacetate was distilled in a kugelrohr apparatus to provide 276 mg (46%) of diacetate 15 as a yellow gum: 135" (bath) (0.02 mm); ir (CHCI,) 1750, 1730, 1705, 1640 cm-l; nmr (CDC13)67.52(1H,d,J= 1 . 5 H z ) , 6 . 2 5 ( 1 H , d , J = 3Hz).5.32 ( l H , t , J = 4 H z ) , 3 , 8 2 ( 3 H , s ) , 3 , 2 2 ( 1 H , q : J = 7.5Hz).2.65-1.6 (10 H , m, two sharp singlets at 2.16 and 2.10), 1.10 ( 3 H , d, J = 6.5 Hz). Conversion of Diacetate 15 to Hydroxyacetal 16.23 A solution of diacetate 15 (273 mg, 0.79 mmol) in methanol (30 ml) containing 0.5 ml of boron trifluoride etherate was stirred under argon at room temperature for 3 days. Then 10 ml of saturated sodium bicarbonate solution was added and the mixture concentrated irr cocuo. The aqueous residue was diluted with water and extracted with ether. The ether extract was washed with water and saturated salt solution, dried (MgSO?), and concentrated iiz cuciio to leave 162 mg of a yellow oil. This material was distilled in a kugelrohr apparatus to provide 144 mg (76%) of a colorless gum which appeared as two incompletely resolved spots on tlc (silica gel; 2 : l benzene-ethyl acetate): 125" (bath) (0.02 mm); ir (CHC13) 3600, 1705, 1635 cm-l; nmr (CDCI3) 6 7.58 (1 H , d. J = 1.5 Hz), 5.04 and 4.75 (1 H , two doublets in ratio 15:85, J = 3 and 4 Hz, respectively), 4.20 (1 H, t, J = 4 Hz), 3.80 (3 H, s), 3.58 and 3.52 ( 3 H , t w o s i n g l e t s i n r a t i o 8 5 : 1 5 ) , 3 . 1 ( 1 H,m),2.75(1 H.sh2.6-1.5 (4 H, m), 1.14 (3 H , d, J = 6.5 Hz). The coupling constants for the acetal protons indicate a mixture containing 85% of the epimer with an a-methoxy group and 15 % of the epimer with the 0-methoxy group. Oxidation of Natural Hydroxyacetal 16 to Ketoacetal 13.23 A solution of natural hydroxyacetal 16 (140 mg, 0.58 mmol) in methylene chloride (2 ml) was added in one portion t o a mixture of bipyridinechromium(V1) oxide (1.5 g, 5.8 mmol) in methylene chloride (20 ml). After stirring 15 min, the black reaction mixture was filtered through a plug of silica gel with the aid of ethyl acetate. The filtrate was concentrated if7 cacuo, leaving 125 mg of a n offwhite solid, mp 112-117', which on recrystallization from ether provided 105 mg (75%) of analytically pure ketoacetal 13: mp 118-120"; [ a ] z 5 J ~-141" (c 0.45, 95% ethanol); uv max (95% ethanol) 234 nm (e 11,300)[lit.7mp 118-118.5"; [cU]22D -146"(0.33, CHC1,); uv max (95% ethanol) 235 nm (log e 4.06)]; ir (CHCI,) 1740, 1700, 1630 cm-*; nmr (CDCI,) 6 7.46 (1 H, d, J = 1.5 Hz), 4.96 (1 H, d, J = 2.5 Hz), 3.72 (3 H , s ) , 3.52 (3 H. s), 3.18 (1 H, m), 2 . 5 8 ( 2 H , d , J = 6 H z ) , 2 . 3 - 1 . 9 ( 2 H , m ) , l . l 4 ( 3 H , d , J = 6.5Hz); mass spectrum m/e 240 (M"). Anal. Calcd for C12H160j: C, 59.99; H, 6.71. Found: C, 60.28; H , 6.60. Attempted Epimerization of Natural Ketone 13. A solution of natural ketone 13 (56 mg; 0.23 mmol) in methanol (25 ml) containing a small amount of sodium methoxide was stirred overnight at room temperature under argon. After neutralization with acetic acid and concentration in cacuo, the residue was partitcned between water and ether. The organic layer was washed with saturated sodium bicarbonate solution. water, and saturated salt solution, dried (MgS04), and concentrated in cacuo, leaving 50 mg (95%) of an off-white solid, mp 90-112". This material on tlc (silica gel; 3 : l hexane-ethyl acetate) showed the ketone 13 (Rr 0.25) as the principal component and lesser amounts of a more polar material (Rf 0.18). The major component obtained pure by preparative tlc exhibited mp 117-120" and spectral characteristics identical with those of the ketone 13 before base treatment. This observation agrees with that of Battersby.7 The minor impurity obtained pure by preparative tlc was tentatively formulated as the
24, 1973
545 addition product of methanol t o the enol-ester double bond from its spectral data: no uv max above 210 nm; ir (CHC11) 1740 cm-l. Deuterium Incorporation into Natural Ketone 13. A solution of sodium methoxide (0.01 mmol) in methanol-0-d was added to a solution of natural ketone 13 (16 mg, 0.066 mmol) in methanol-0-d (2 ml). The solution was stirred at room temperature for 24 hr under argon. Then an additional 0.01 mmol of sodium methoxide in methanol-0-d was added and stirring was continued for 24 hr. The solution was neutralized with glacial acetic acid and concentrated in uucuo. The residue was partitioned between ether and water, and the organic phase was washed with saturated sodium bicarbonate solution, water, and saturated salt solution. Drying (MgS04) and concentration in DUCUO left 15 mg of a white solid, mp 112-118", which appeared homogeneous o n tlc (silica gel; 3 : l hexane-ethyl acetate). Two recrystallizations from ether gave 10 mg of small white crystals, mp 119-119.5". The mass spectrum of this material confirmed the incorporation of three deuterium atoms, exhibiting major ions at m/e 243 (M+)212, 168, 124, 86. 85, 56,45,44,40, 34,29 [79 % d j , 19 % d2,2 % d, species]. Alcohol 17 from Sodium Borohydride Reduction of Ketone 13. Sodium borohydride (39 mg, 1.0 mmol) was added t o a chilled (0") solution of ketone 13 (240 mg, 1.0 mmol) in methanol (15 ml). After stirring for 30 min at O " , the reaction mixture was neutralized with glacial acetic acid, poured into aqueous sodium bicarbonate and extracted with ether. The ether extract was washed with water and saturated salt solution, dried ( MgS04),and concentrated in C N C L ~ Oto leave 242 mg of a yellow oil which was chromatographed on 12 g of silica gel (0.05-0.2 mm, Merck). Elution with 1 :1 benzene-ether provided 235 mg which was distilled in a kugelrohr apparatus to give 212 nig (88%) of alcohol 17 as a colorless gum: 120" (bath) (0.02 mm); ir (CHCI,) 3660, 3600, 1700, 1630 cm-l; uv max ( 9 5 z ethanol) 237 nm ( E 11,900); nmr (CDCI,) 6 7.42 (1 H, d, J = 1 Hz), 4.74 (1 H, d, J = 5 Hz), 3.8-3.4 (1 H, m),3.72 (3 H, s), 3.52 (3 H , s), 3.1 (1 H, sharp singlet which exchanges with D~O),2.95-2.3(2H,m),1.9-1.25(3H.m),1.12(3H,d.J= 7Hz); mass spectrum m / e 242 (M+). A d . Calcd for Cl2HI8O3: C , 59.49; H, 7.49. Found: C , 59.38; H , 7.56. Acetate 19 from 17. Methanesulfonyl chloride (85 pl, 1.09 mmol) was added dropwise t o an ice-water cooled solution of alcohol 17 (170 mg, 0.70 mmol) in dry pyridine (1 ml). Stirring was continued at 0" under argon for 1.5 hr. The reaction mixture was diluted with ether and filtered, and the filtrate concentrated it2 cucuo. The residue was extracted with ether and filtered through a plug of silica gel. Concentration of the filtrate in cucuo left 232 mg of a colorless gum which appeared homogeneous on tlc (silica gel, 1 : 1 benzene-ether) and exhibited ir (CHCI,) absorptions expected for the mesylate 18: 1700, 1635. 1440, 1360, 1340, 1290, 1175,1085,955 cm-'. The crude mesylate (232 mg, 0.70 mmol) was dissolved in acetone along with tetraethylammonium acetate (1.4 g, 7.4 mmol). This mixture was refluxed for 23 hr, cooled. and concentrated iii cacuo. The residue was partitioned between ether and water. The ether extract was washed with saturated sodium bicarbonate solution, water, and saturated salt solution, dried (MgSO,), and coilcentrated i!r cacuo to leave 195 mg of a pale yellow oil. This material was chromatographed on 18 g of silica gel ( I : 1 silica gel PF-254-silica gel 0.05-0.2 mm, Merck). Elution with 6 : l benzene-ether first gave 16 mg (10%) of a colorless gum which appears to be olefin 20 from its spectral characteristics: ir (CHCI,) 1700, 1635 cm-l;
nmr(CDCI3) 67.49 (1 H, d , J = 1.5 Hz), 5.9 (1 H, d, J = 6 Hz), 5.6 (1 H , d, J = 6 Hz), 4.58 (1 H , d, J = 6 Hz), 3.75 (3 H , s ) , 3.54 (3 H, s), 2.8 (1 H, m), 2.3-1.7 (2 H, m), 1.12 (3 H , d, J = 7 Hz). Further elution with the same solvent system produced 162 mg (82%) of a n oil which was distilled in a kugelrohr apparatus to provide 160 mg (81 %) of acetate 19 as a colorless oil, 115" (bath) (0.01 mm), which crystallized. Recrystallization of 135 mg from petroleum ether provided 126 mg of white crystals: mp 62.563.5"; ir (CHCI,) 1730, 1700, 1630 cm-'; uv max (95% ethanol) 236 nm ( t 11,100); nmr (CDCI,) 6 7.40 (1 H, d, J = 1.5 Hz), 5.18 (1 H, m), 4.65 (1 H , d, J = 4 Hz), 3.70 (3 H, s), 3.50 (3 H , s), 3.1 (1 H, m), 2.5-1.5 (7 H , m with sharp s at 2.05), 1.05 (3 H , d, J = 6.5 Hz); mass spectrum m/e 284 (Mf). Anal. Calcd for C14H2006: C, 59.14; H, 7.09. Found: C, 59.20; H, 7.42. Methyl 6a-Acetoxy-7cu-methyI-l-hydroxy-1,4acr,5,6,7,7aa-hexahydrocycIopenta[c]pyran-4-carboxylate (21). A mixture of 260 mg (0.92 mmol) of the acetal 19, 40 ml of acetic acid, 20 ml of water, and 6 ml of 70% perchloric acid were heated at 50" under nitrogen for 3 hr. After cooling, 200 ml of cold saturated brine was added and the mixture was extracted with ether. The extract was washed (saturated NaHCO, solution and saturated brine), dried (Na2S04),and evaporated to a yellow gum: which was purified by column chromatography (1 : 1 mixture of silica gel PF-254-silica gel 0.05-0.2 mm, Merck) using benzene-ether 1 :1. The first fraction gave 125 mg (51 %) of the hemiacetal 21 as a light yellow gum: uv max ( 9 5 z ethanol) 237 nm ( e 9700); uv max (95% ethanolNaOH) 274 nm ( e 10,800);ir (CHC13) 3400, 1740, 1710, 1640 cm-1; nmr (CDCI,) 6 7.40 (d, 1 H , J = 1 Hz), 5.20 (m, 1 H), 5.00 (d, -1 H , J = 7 Hz). 3.73 (s, 3 H), 3.73 (s, 1 H, exchangeable with D20), 2.10(s, 3 H ) , 1 . 0 7 ( d , 3 H , J = 7 H z ) , 1 - 3 . 5 ( m , 5 H ) . Anal. Calcd for Cl3H1806: C, 57.77; H, 6.71. Found: C, 57.75; H, 6.76. ( -)-Methyl 6a-Acetoxy-7a-methy1-la-(2,3,4,6-tetraacetyl-~-~glucopyranosyIoxy)-4aa,5,6,7,7aa-hexahydr oc yclopenta[c]pyran4 carboxylate (22). T o a solution of 62 mg (0.23 mmol) of the hemiacetal 21 and 174 mg (0.5 mmol) of 2,3,4,6-tetraacetyl-P-~glucopyranose (23) in 5 ml of dry 1,2-dichloroethane was added under nitrogen at 0" boron trifluoride etherate (0.5 ml), freshly distilled from CaH?. The mixture was stirred at room temperature for 4 hr, during which time 260 mg (0.75 mmol) of 2,3,4,6-tetraacetyl-P-D-glucopyranose (23)was added. The mixture was diluted with 50 ml of chloroform, neutralized with saturated NaHCOj solution, and extracted with chloroform. The extract was washed (water and saturated brine), dried (Na2S0,), and evaporated to 602 mg of a white foam, which was fractionated by thick layer chromatography (silica gel PF-254 in ethyl acetate-benzene 1 : 1). The second zone with Rf 0.40 was collected (96 mg) and purified further by repeated thick layer chromatography (aluminum oxide PF-254, Type E in chloroform-ether 1 :1 (five times)). The first main zone was eluted giving 6 mg of an oil, which crystallized from ethanol giving 2.0 mg (1.4%) of the glucoside 22 as white needles: sample mp 137-139"; mixed with authentic sample, mp 137-139"; [cY]22D -77" (C 0.1, CHCI,) [lit.' [cU]z2D-79.6" (C 0.39, CHCIJ]; ir (CHCls) 1765, 1645, 1090, 1070. 1040 cm-l. The ir was identical with that of loganin pentaacetate derived from natural sources.
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Acknowledgment. Financial support from the Na, tional Institutes of Health and Hoffmann-La RocheInc., is gratefully acknowledged.
Buchi, Carlson, Powell, Tietze / Total Synthesis of Loganin
