Acylnitrilium ion initiated spiroannulations in heterocycle synthesis: an application directed toward the total synthesis of theLycopodiumalkaloid (±)-serratine

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1995 Acylnitrilium ion initiated spiroannulations in heterocycle synthesis: an application directed toward the total synthesis of the Lycopodiumalkaloid ( ? )-serratine Gregory Luedtke and Tom Livinghouse*9t Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 5971 7, USA A concise synthesis of a prospective tricyclic intermediate en route to the Lycopodium alkaloid ( k )-serratine is described which involves the consecutive utilization of an acylnitrilium ion initiated spiroannulation and intramolecular Michael addition. Alkaloids belonging to the Lycopodium family have remained 0 an enduring challenge for efficient chemical synthesis. Although a number of these alkaloids possess intriguing pharmacology, the ongoing interest in total synthesis would appear to be stimulated at least as much by the structural complexity of these substances and the attendant strategic imperatives for skeletal construction.Despite the continuing activity in this area, relatively little progress has been reported with regard to the 7 synthesis of the irregular alkaloids belonging to the serratinane isubgroup. With the exception of (?)-serratinine 1 and the corresponding 8-deoxy derivative, each of which have been synthesized once previously, no completed syntheses of alkaloids in this category have appeared. 0-TBDMS -OH 0 4 5 Scheme tH4-oH0 1 2 We have previously shown that cyclizations initiated by acylnitrilium ions can provide access to a wide variety of heterocyclic system^.^ In addition, we have demonstrated that this heteroannulation method can facilitate unusually efficient syntheses of the erythrinane skeleton5 as well as the Orchidaceae alkaloid dendrobine.6 Our interest in ( k )-serratine 2 'was stimulated by the possibility that the essential tricyclic core of this Lycopodium alkaloid could be derived from a simple arene nucleus uia sequential utilization of an acyl- nitrilium ion initiated spiroannulation and intramolecular 1,4-addition (Scheme 1).In this communication we report the successful implementation of this strategy. The key isonitrile 4a that was employed in this investigation was prepared by sequential formylation/dehydration (i, EtOCHO; ii, POC1,-Et,N, THF, 0 "C) of 3-4-(tert-butyl- dimethylsiloxy)-2-methoxyphenylpropanamine 3.Acylation of 3 with the acyl chlorides 8a-f (CH2C1,, room temp.) was found to proceed in close analogy with previous examples 4-6 to provide the intermediate a-ketoimidoyl chlorides 9a-f in ca. quantitative yield (NMR). Exposure of 9a-f to AgBF, (1.5 equiv.) in ClCH,CH,Cl-CH!,Cl, (1 :1) at -70 "C resulted, without exception, in the immediate precipitation of AgCl signalling the generation of the corresponding transient -f Fellow of the Alexander von Humboldt Foundation 1993-1995. acylnitrilium ions. In contrast to most previously reported example^,^-^ cation interception by the pendant carbon centred nucleophile did not occur rapidly at -78 "C.Optimally, pre- formed solutions of the reactive intermediates were subse-quently warmed to -20 "C and maintained at this temperature for 20 h to induce spirocyclization. By way of this procedure the spirocyclohexa-2,5-diene-1,3'-(3',4',5',6'-tetrahydropyridin)-ones 6a-could be obtained on a preparative scale in 80- 84 purified yield. It is of interest that cyclization of 9funder an analogous set of reaction conditions resulted in only a modest yield (55) of the desired spirocyclic intermediate 6f. Presumably, the enhanced propensity of the P-ketosulfonyl moiety of 9fto enolize was responsible for the degradation of spirocyclization efficiency in this instance. In this connection, the successful conversion of 9b-f to 6b-f constitutes the first reasonably comprehensive series of acylnitrilium ion cycliz- ations involving substrates that possess readily enolizable sites a-to the carbonyl function.The predisposition of the spirocyclic intermediates 6b-e to undergo intramolecular 1,4-addition was subsequently exam- ined. Several attempts to convert 6c into the corresponding tricycle 10a uia free-radical intermediates under reductive conditions (Bu,SnH)' led only to the production of 6b albeit in excellent ( > 90) yield. By way of contrast, base-mediated cyclization of 6d and 6e gave more encouraging results. In an initial experiment, exposure of 6d to NaH (1.1 equiv.) in DMF O "C(10 min)+25 "C (8 h) followed by protonolysis (AcOH, 1.1 equiv.) afforded the unstable a-phenylthioketone 10b in good yield.We suspected that the observed instability of 10b 2370 J. CHEM. SOC. PERKIN TRANS. I 1995 r 1 8a-f 9a-f a R =But bR=Me 6a (82) c R = CHC12 d R = CH2SPh 6r (80) e R = CH2SMe 6d (83) f R=CH2SOZPh 6e (84) 6f (55) 0 i, EtOCHO, 25 OC; ii, POC1,-Et,N, THF, 0 "C; iii, CH,Cl, or CDCl,, 25 "C; iv, AgBF, (1.5 equiv.), CICH,CH,Cl-CH,Cl,, -78 "C--20 "C might be a consequence of initial tautomerization involving the sensitive g-keto imine moiety. Accordingly, this bifunctional array was derivatized by alkylative protection in situ. To this end, cyclization of 6d (NaH-DMF, 0 "C-+25 "C) followed by enolate interception SEM-Cl (1.1 equiv.), -60 "C-25 "C furnished the tricyclic imine 7d in 96 purified yield.Cyclization of 6ein a similar manner provided 7e in 98 yield.$ Although 6f could be induced to undergo an analogous cyclization, 6b proved resistant toward base-mediated intra- molecular Michael addition. i 10a -+ 6c >go 6b '0 OSEM 10a R=H 7d R=Ph lob R=SPh 7e R=Me Reagents and conditions: i, Bu3SnH, PhH, reflux; ii, NaH (1.1 equiv.), DMF, 0 "C+25 "C; iii, NaH (1.1 equiv.), DMF, 0 "C-+25 "C; iv, SEM-CI (1.1 equiv.), -60 "C+25 "C At least three features of the preceding cyclizations are worthy of comment. These studies have shown that a variety of functionally varied a-keto imidoyl chlorides can serve as effective precursors to synthetically viable acylnitrilium ions; intramolecular capture of the enolates derived from 6d and 6e by the least substituted (and most electrophilic) cyclohexa- dienone P-carbon is completely selective; and the in situ enolate trapping protocol gives rise to the functionally well differentiated intermediates 7d and 7e.Studies directed toward the stereodefined annulation of the serratinane D ring and the completion of the synthesis of (f)-serratine 2 are underway. Progress in these areas will be disclosed in due course. $The tricyclic imines 7d and 7e were found to undergo slow decomposition at room temperature but could be stored indefinitely in a benzene matrix under argon at -20 "C. Experimental 2-Methoxy-2'-methylsulfanylacetylspiro cyclohexa-2,s-diene-1,3'-(3',4',5',6'-tetrahydropyridin) -4-one 6e An oven-dried NMR tube fitted with a rubber septum was purged with Ar and then charged with compound 4a (0.305 g, 1.O mmol), methylsulfanylacetyl chloride (1 37 mg, I.1 mmol) and CDCl, (1.0 cm3). The coupling reaction, monitored by NMR, was found to be complete after 3 h. After the volatile components had been removed under reduced pressure from the imidoyl chloride, the crude material was diluted with CH,Cl, (4.5 cm3), and l72-dich1oroethane (4.5 cm3) and cooled to -78 "C. The solution was then added dropwise via a cannula to a stirred solution of AgBF, (0.50 mol dm-, in 1,2-dichloro- ethane; 3.0 cm3, 1.5 mmol, 1.5 equiv.) and CH,Cl, (3.0 cm3) maintained at -70 "C. After the addition, the reaction mixture was stirred for 1 h at -70 "C and then maintained at -20 "C for 20 h whereupon it was quenched with 10aqueous KHCO, (30 cm3).The resulting white-grey slurry was subsequently filtered through a pad of Celite. The organic layer was separated and the aqueous layer was extracted with CH,Cl, (4 x 20 cm3). The combined organic layer and extracts were washed with brine (65 cm3), dried (Na,SO,) and concentrated under reduced pressure. Chromatography of the residue on Florisil(50 ethyl acetate-CH,Cl, for elution) provided 6e as a viscous oil (0.235 g, 84); aH(CDC1,) 6.59 (d, J 9.9, 1 H, CHSH), 6.23 (dd, J9.9, 1.6, 1 H, CH=CH), 5.63 (d, J 1.2, 1 H, CH,OC=CH), 4.15-4.07 (m, 1 H, HCHN=C), 3.95-3.84 (m, 1 H, HCHNX), 3.67(s,3 H,0CH3),3.62(d,J13.2, 1 H,O=CCHHSCH,), 3.47 (d, J 13.2, 1 H, MCHH-SCH,), 2.14 (m, 1 H, HCHCH,), 1.97 (s, 3 H, SCH,) and 1.86-1.73 (m, 3 H, HCHSH,); G,(CDCl,) 191.7 (C), 187.3 (C), 177.8 (C), 161.7 (C), 144.6 (CH), 128.3 (CH), 101.7 (CH), 55.9 (CH,), 50.0 (CH,), 45.4 (C), 36.7 (CH,), 33.7 (CH,), 18.0 (CH,) and 15.6 (CH,); v,,,(film)/cm-' 3365, 2958, 2930, 2857, 1693, 1658, 1637, 1592, 1539,1504,1464,1392,1362,1324,1286,1260,1224,1179,1105, 1017,980,945,841 and 798; m/z (EI) 279,191,164, 137,77 and 61 Found (HRMS): M+, 279.0929.Calc. for C,,H,,NO,S: M -t , 279.09291. 10-Methoxy-6-methylsulfanyl-5- (2'-trimethylsilylethoxy)-methoxy -2,3,5,6,6a,7-hexahydro-lH-indeno 1,7a-b pyridin-8- one 7e To a slurry of NaH (12 mg, 0.5 mmol, 1.1 equiv.) in DMF (3.0 cm3) at 0 "C was added dropwise over 10 min a solution of 6e (127 mg, 0.45 mmol) in DMF (6.0 cm3).The resulting mixture was allowed to warm to 25 "C over several hours. After 12 h the mixture was cooled to -60 "C and SEM-Cl(84 mg, 88 pl, 0.5 mmol, I. 1 equiv.) was added to it over 1 min. The reaction mixture was allowed to warm to 25 "C over 2 h whereupon it was poured into water (20 cm3) and extracted with ethyl acetate (4 x 10 cm3). The combined extracts were dried (MgSO,) and evaporated under reduced pressure after which the residue was purified by chromatography on Florisil (50 ethyl acetate- CH,CI, for elution) to provide 7e as a viscous oil (0.180 g, 98). This compound was found to deteriorate over a short amount of time if not stored at -20 "C in a matrix of benzene. Silica gel and alumina were found to be incompatible with this compound: d,(CDCI,) 5.45 (d, J 5.9, 1 H, OCHH-0), 5.33 (s, 1 H, CH,OC=CH), 5.04 (d, J 5.9, 1 H, OCHHO), 3.78- 3.67 (m, 3 H,OCHHCH,), 3.63 (s, 3 H, OCH,), 3.58 (m, 1 H, OCHHCH,), 3.03 (d, J 5.5, 1 H, CHCH,), 2.84 (d, J 17.7, 1 H, CHCHH),2.58(dd,J17.7,6.3Hz, 1 H,CHCHH),2.46(s,3 H, SCH,), 2.13-1.86 (m, 3 H, HCH), 1.58-1.40 (m, 1 H, HCH), 0.92-0.79 m, 2 H, CH,Si(CH,), and -0.03 (s, 9 H, 3 CH,); G,(CDCl,) 195.1 (C), 178.7(C),166.8 (C),150.9(C),131.6 (C), 101.5 (CH), 93.5 (CH,), 47.4 (CH), 47.3 (C),33.3 (CH,), 28.1 (CH,), 20.0 (CH,), 18.2 (CH,), 15.4 (CH,) and -1.4 (CH,); J.CHEM. SOC. PERKIN TRANS. I 1995 v,,,(film)/cm 2949, 1660, 1603, 1506, 1438, 1416, 1346, 1249, 1217, 1148, 1100, 1039, 1007, 948, 859, 836 and 758; m/z (EI) 409, 366, 336, 308, 231, 117, 73, 57 and 43 Found (HRMS): M', 409.1743.Calc. for C,oH,,NO,SSi: M', 409.17431. 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