Synthesis of the naturally occurring 3.3.3propellane (plusmn;)-modhephene featuring a photocycloadditionndash;reductive fragmentation diquinane construction

摘要

O Me O R R O Me R H H fragmentation Me Me Me Me O Me H O OMe Me O OMe O Me O Me Me OMOM H modhephene 1 6 4 3 Me radical cyclization A B 5 7 Me Me O 2 alkylation Synthesis of the naturally occurring 3.3.3propellane (plusmn;)-modhephene featuring a photocycloadditionndash;reductive fragmentation diquinane construction Curt A. Dvorak and Viresh H. Rawaldagger; Department of Chemistry, The University of Chicago, Chicago, IL 60637 and Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA Modhephene has been synthesized in 11 steps and 21 overall yield from cyclopentadiene, by a stereoselective route that features a photocycloadditionndash;fragmentation sequence for the construction of the diquinane core.The fascinating realm of the polyquinane sesquiterpenes, recently reviewed,1 has stimulated the development of new methodologies for the construction of fused five-membered rings. Previously we reported a route to di- and tri-quinanes that takes advantage of the connectivity gained when acylnorbornyl derivatives, obtained via the Dielsndash;Alder reaction, are subjected to the Paternondash;B�uchi reaction (Scheme 1).2 This expeditious assembly of a 3.3.0bicyclic array is well suited for the synthesis of many members of the polyquinane class of natural products.We have completed concise, high-yielding syntheses of natural products having linear2d and angular triquinane2b,e frameworks using the photocycloadditionndash;fragmentation sequence.We report here a concise synthesis of naturally occurring propellane, modhephene 1,3 further extending the utility of our general strategy. The propellane skeleton, the three contiguous quaternary centers, and the angular methyl group combine to make modhephene an attractive synthetic challenge, one taken on by several research groups.4 We have examined two routes to modhephene, outlined retrosynthetically in Scheme 2. Appealing at first was a route that took advantage of enone 3, a latestage intermediate in our isocomene synthesis, wherein the methyl group stereochemistry was controlled through a Dielsndash; Alder reaction.2b,e While it was possible to form the third ring by an alkylative cyclization of the terminal iodide derived from 3,5 the resulting enone 2 could not be converted to modhephene. 2h,l An alternate route to the propellane framework of modhephene hinged on formation of the ring containing the angular methyl group, potentially by a radical cyclization.6 The requisite diquinane precursor 6 was expected to be readily available through the photocycloadditionndash;reductive fragmentation sequence.Diquinane 6 was prepared in high overall yield as described in Scheme 3. Norbornene 8, obtained from cyclopentadiene and methyl acrylate (H2O, room temp., 100), was alkylated selectively on the exo face with 4-bromobut-1-ene using LDA in THF with 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin- 2(1H)-one (DMPU). The resulting ester 7 was converted into methyl ketone 9 by a one-pot modification of Coreyrsquo;s procedure,7 affording the Paternondash;B�uchi precursor in 94 yield for the two steps.Irradiation of ketone 9 with Corex-filtered light provided oxetane 10 (89), which possesses the connectivity required for a diquinane. Initially a three step sequence was used to convert oxetane 10 to a diquinane. Treatment of 10 with Pri 2NMgI gave alcohol 11, which on oxidation with pyridinium dichromate (PDC) gave keto alkene 12 in good overall yield.Reductive fragmentation of 12 afforded the expected diquinane, 6, in 80 yield. The hidden diquinane unit was also liberated by a novel, direct fragmentation of the strained oxetane precursor, which shortened the sequence by one step (Scheme 4). Treatment of oxetane 10 with LDBB (2.0 equiv.), the radical anion of 4,4A-ditert- butylbiphenyl, in the presence of Et3Al (2.1 equiv.)8 promoted the simultaneous scission of the oxetane Cndash;O bond and the back-bond of the norbornane skeleton, affording diquinane moiety 13 in 86 yield.9 The resulting allylic alcohol was then oxidized to enone 6 under standard conditions.In preparation for closure of the final propellane ring, a suitable radical precursor was introduced a to the carbonyl group of 6 (Scheme 5). Selenation of the kinetic enolate of 6 afforded the desired phenyl selenide in 61 yield, provided inverse quenching conditions were employed. The bridgehead radical derived from 14 was expected to undergo 5-exo-trig cyclization onto the butenyl side-chain, concurrently setting the angular methyl group stereochemistry.4m Subjection of selenide 14 to standard radical conditions gave an excellent yield of the propellane (95), albeit with a disappointing 2 : 1 ratio of inseparable diastereomers.This ratio was increased to a useful 6 : 1 level (69) by carrying out the cyclization in toluene at 278 deg;C using Et3Bndash;air to initiate the radical chain.10 Scheme 1 Scheme 2 Chem.Commun., 1997 2381O OMe O Me O Me 11 10 12 8 6 O Me H 9 O HO iv iii i, ii v vi HO Me H O Me i ii 6 10 13 Me O Me Me Me Me Me Me Me Me 14 16 15 6 O Me H O Me SePh modhephene 1 iii, iv i ii v The final two carbons were appended as previously described. Introduction of the geminal dimethyl unit to the hindered enone 15 requires a Lewis acid to assist the 1,4-addition of the higher order cuprate.4b,l Wittig olefination of the keto group with triphenylphosphonium methylide4d put in place the final carbon.The major diastereomer from the radical cyclization was separated at this stage by MPLC and then treated with a catalytic amount of TsOH, which isomerized the double bond to the endocyclic position, affording modhephene 1. The minor diastereomer was similarly converted to epimodhephene. The modhephene synthesis described here was accomplished in 11 steps from cyclopentadiene, with an overall yield of 21, the highest to date.The synthesis illustrates the direct fragmentation of the cage-like oxetane 10 to diquinane 13 as well as the stereocontrolled formation of the propellane skeleton. This work was supported financially by the National Institutes of Health (R01-GM-45624) and The University of Chicago. Pfizer and Merck are thanked for additional financial support in the form faculty awards to V. H. R. Footnote and References dagger; Present address: Department of Chemistry, The University of Chicago, 5735 S.Ellis Avenue, Chicago, IL 60637, USA. 1 G. Metha and A. Srikrishna, Chem. Rev., 1997, 97, 671. 2 (a) V. H. Rawal and C. Dufour, J. Am. Chem. Soc., 1994, 116, 2613; (b) V. H. Rawal, C. Dufour and A. Eschbach, J. Chem. Soc., Chem. Commun., 1994, 1797; (c) V. H. Rawal, C. Dufour and S. Iwasa, Tetrahedron Lett., 1995, 36, 19; (d) V. H. Rawal, A. Fabre and S. Iwasa, Tetrahedron Lett., 1995, 36, 6851; (e) V. H. Rawal, A. Eschbach, C. Dufour and S. Iwasa, Pure Appl.Chem., 1996, 37, 675; (f) C. Dufour, S. Iwasa, A. Fabre and V. H. Rawal, Tetrahedron Lett., 1996, 37, 7867. 3 Isolation: L. H. Zalkow, R. N. Harris, III and D. Van Derveer, J. Chem. Soc., Chem. Commun., 1978, 420; F. Bohlmann, C. Zdero, R. Bohlmann, R. M. King and H. Robinson, Phytochemistry, 1980, 19, 579. 4 Syntheses: (a) M. Karpf and A. S. Dreiding, Tetrahedron Lett., 1980, 21, 4569; Helv. Chim. Acta, 1981, 64, 1123; (b) A. B. Smith, III and P. J. Jerris, J. Am. Chem. Soc., 1981, 103, 194; J.Org. Chem., 1982, 47, 1845; (c) H. Schostarez and L. A. Paquette, J. Am. Chem. Soc., 1981, 103, 722; Tetrahedron, 1981, 37, 4431; (d) W. Oppolzer and F. Marazza, Helv. Chim. Acta, 1981, 64, 1575; W. Oppolzer and K. Battig, Helv. Chim. Acta, 1981, 64, 2489; (e) P. A. Wender and G. B. Dreyer, J. Am. Chem. Soc., 1982, 104, 5805; (f) J. Wrobel, K. Takahashi, V. Honkan, G. Lannoye, J. M. Cook and S. H. Bertz, J. Org. Chem., 1983, 48, 139; (g) Y. Tobe, S. Yamashita, T.Yamashita, K. Kakiuchi and Y. Odaira, J. Chem. Soc., Chem. Commun., 1984, 1259; (h) D. Wilkening and B. P. Mundy, Tetrahedron Lett., 1984, 25, 4619; B. P. Mundy, D. Wilkening and K. B. Lipkowitz, J. Org. Chem., 1985, 50, 5727; (i) G. Metha and D. Subrahmanyam, J. Chem. Soc., Chem. Commun., 1985, 768; G. Metha and D. Subrahmanyam, J. Chem. Soc., Perkin Trans. 1, 1991, 395; (j) E. A. Marsh, S. K. Math an J. Flann, Tetrahedron Lett., 1988, 29, 2147; Tetrahedron, 1989, 45, 4950; (k) L.Fitjer, A. Kanschik and M. Majewski, Tetrahedron Lett., 1988, 29, 5525; L. Fitjer, M. Majewski and A. Kanschik, Tetrahedron Lett., 1988, 29, 1263; (l) C. P. Jasperse and D. P. Curran, J. Am. Chem. Soc., 1990, 112, 5601; (m) C. Sha, T. Jean and D. Wang, Tetrahedron Lett., 1990, 31, 3745; (n) G. A. Kraus and J. Shi, J. Org. Chem., 1990, 55, 5423; J. Org. Chem., 1991, 56, 4147; (o) S. C. Suri, Tetrahedron Lett., 1993, 34, 8321; (p) T. Uyehara, T. Murayama, K.Sakai, M. Ueno and T. Sato, Tetrahedron Lett., 1996, 37, 7295; (q) H. Lee, D. Kim and S. Kim, Chem. Commun., 1996, 1539. 5 The details of this alkylation will be reported in a full paper. 6 General reviews on radical chemistry: D. P. Curran, Synthesis, 1988, 417; 489; D. P. Curran, in Comprehesnive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991; vol. 4, pp. 715ndash; 777; pp. 779ndash;899; B. Giese, B. Kopping, T. G�obel, J. Dickhut, G. Thoma, K. J. Kulicke and F.Trach, Org. React., 1996, 48, 301. 7 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1345; J. S. Swenton, D. K. Anderson, D. K. Jackson and L. Narasimhan, J. Org. Chem., 1981, 46, 4825; K. Ishizumi, N. Ohashi and N. Tanno, J. Org. Chem., 1987, 52, 4477. 8 For an extensive investigation of the reductive fragmentation of simple oxetanes, see B. Mudryk and T. Cohen, J. Org. Chem., 1989, 54, 5657; J. Org. Chem., 1991, 56, 5760; For epoxide fragmentations, see: B.Mudryk and T. Cohen, Org. Synth., 1993, 72, 173 and references cited therein. 9 An extensive study has been carried out on the scope of this direct oxetane fragmentation, and the results have been submitted for publication. 10 K. Nozaki, K. Oshima and K. Utimoto, J. Am. Chem. Soc., 1987, 109, 2547; Tetrahedron Lett., 1988, 29, 6125; 6127. Received in Corvallis, OR, USA, 16th June 1997; 7/04260D Scheme 3 Reagents and conditions: i, LDA, THF, DMPU, 4-bromobut- 1-ene; ii, MeS(O)CH2Li, THF; Zn, aq. NaOH, PhCH3 (94 overall); iii, hn, PhH, corex filters (89); iv, Pri 2NMgI (2.6 equiv.) in THF (1.0 m), room temp., 1.5 days (87); v, PDC (2.9 equiv.), DMF, room temp., 1 day (91); vi, LDBB (3 equiv.) in THF (0.1 m), 278 deg;C (80) Scheme 4 Reagents and conditions: i, LDBB, THF, Et3Al, 278 deg;C, 4 h, warm to room temp., 12 h (86); ii PDC, DMF, room temp., 16 h (91) Scheme 5 Reagents and conditions: i, LDA, THF, 278 deg;C to room temp.; PhSeCl, 278 deg;C, inverse quench (61); ii, Bu3SnH, AIBN, PhH, reflux (2 : 1, 95) (6 : 1 at 278 deg;C); iii, Me2CuLiCN, THF, Et2Omiddot;BF3; iv, Ph3PNCH2, THF (85 overall), MPLC separation; v, TsOH (cat.), CH2Cl2, 3 h ( ~ 100) 2382 Chem. Commun., 19