Abstract
Guanacastepene A, the leading member of a structurally diverse family of diterpene natural products, was isolated from the extracts of an unidentified fungus. The discovery of its potent antibiotic activity as well as its previously unreported tricyclic architecture render guanacastepene A an attractive and formidable target for total synthesis. Specifically, guanacastepene A’s synthetic challenges include 2 ring-junction quaternary methyl groups and a novel 5-7-6 tricyclic carbon skeleton possessing a dense array of oxygen and unsaturated functionalities. In this account, we will discuss our motivation and efforts toward the total synthesis of guanacastepene A as well as highlight the contributions from the synthetic community toward this pursuit.
1 Introduction
1.1 Biological Activity
1.2 Isolation and Characterization
2 An Overview of Synthetic Strategies
2.1 Hydroazulene Core
2.2 Hydroazulene to Tricycle
2.3 Tricycle Closure by a Formal C10-C11 Connection
2.4 Tricycle Closure between C1-C2
2.5 A-Ring to Tricycle
2.6 C-Ring to Tricycle
3 Our Strategy
3.1 Initial Planning
3.2 Retrosynthesis
3.3 Synthesis of the Guanacastane Tricycle
3.4 Elaboration of the Tricycle
3.5 Investigation of the Aldol Reaction
3.6 A More Convergent Synthetic Approach
4 Current Investigation
5 Conclusion
Key words
guanacastepene - diterpene - total synthesis
References and Notes
1 Brady SF.
Singh MP.
Janso JE.
Clardy J.
J. Am. Chem. Soc.
2000,
122:
2116
2 Henkel T.
Brunne RM.
Müller H.
Reichel F.
Angew. Chem. Int. Ed.
1999,
38:
643
3 Singh MP.
Janso JE.
Luckman SW.
Brady SF.
Clardy J.
Greenstein M.
Maiese WM.
J. Antibiot.
2000,
53:
256
4 Tan DS.
Dudley GB.
Danishefsky SJ.
Angew. Chem. Int. Ed.
2002,
41:
2185
5 Brady SF.
Bondi SM.
Clardy J.
J. Am. Chem. Soc.
2001,
123:
9900
6 Mischne M.
Curr. Org. Synth.
2005,
2:
261
7a Mandal M.
Yun H.
Dudley GB.
Lin S.
Tan DS.
Danishefsky SJ.
J. Org. Chem.
2005,
70:
10619
7b Yun H.
Danishefsky SJ.
Tetrahedron Lett.
2005,
46:
3879
7c Mandal M.
Danishefsky SJ.
Tetrahedron Lett.
2004,
45:
3831
7d Mandal M.
Danishefsky SJ.
Tetrahedron Lett.
2004,
45:
3827
7e Dudley GB.
Danishefsky SJ.
Sukenick G.
Tetrahedron Lett.
2002,
43:
5605
7f Lin S.
Dudley GB.
Tan DS.
Danishefsky SJ.
Angew. Chem. Int. Ed.
2002,
41:
2188
7g Tan DS.
Dudley GB.
Danishefsky SJ.
Angew. Chem. Int. Ed.
2002,
41:
2185
7h Dudley GB.
Tan DS.
Kim G.
Tanski JM.
Danishefsky SJ.
Tetrahedron Lett.
2001,
42:
6789
7i Dudley GB.
Danishefsky SJ.
Org. Lett.
2001,
3:
2399
8a Shi B.
Hawryluk NA.
Snider BB.
J. Org. Chem.
2003,
68:
1030
8b Snider BB.
Shi B.
Tetrahedron Lett.
2001,
42:
9123
8c Snider BB.
Hawryluk NA.
Org. Lett.
2001,
3:
569
9a Boyer F.-D.
Hanna I.
Ricard L.
Org. Lett.
2004,
6:
1817
9b Boyer F.-D.
Hanna I.
Tetrahedron Lett.
2002,
43:
7469
10a Mehta G.
Pallavi K.
Umarye JD.
Chem. Commun.
2005,
4456
10b Mehta G.
Umarye JD.
Srinivas K.
Tetrahedron Lett.
2003,
44:
4233
10c Mehta G.
Umarye JD.
Srinivas K.
Tetrahedron Lett.
2002,
43:
6975
10d Mehta G.
Umarye JD.
Org. Lett.
2002,
4:
1063
11a Magnus P.
Ollivier C.
Tetrahedron Lett.
2002,
43:
9605
11b Magnus P.
Waring MJ.
Ollivier C.
Lynch V.
Tetrahedron Lett.
2001,
42:
4947
12a Evans DA.
Andrews GC.
Acc. Chem. Res.
1974,
7:
147
12b Zhou ZS.
Flohr A.
Hilvert D.
J. Org. Chem.
1999,
64:
8334
13 Nakazaki A.
Sharma U.
Tius MA.
Org. Lett.
2002,
4:
3363
14 Chiu P.
Li S.
Org. Lett.
2004,
6:
613
15 Srikrishna A.
Dethe DH.
Org. Lett.
2004,
6:
165
16 Quinkert G.
Müller T.
Königer A.
Schultheis O.
Sickenberger B.
Dürner G.
Tetrahedron Lett.
1992,
33:
3469
17 Shipe WD.
Sorensen EJ.
Org. Lett.
2002,
4:
2063
18a Hughes CC.
Miller AK.
Trauner D.
Org. Lett.
2005,
7:
3425
18b Hughes CC.
Kennedy-Smith JJ.
Trauner D.
Org. Lett.
2003,
5:
4113
19 Wright DL.
Whitehead CR.
Sessions EH.
Ghiviriga I.
Frey DA.
J. Am. Chem. Soc.
1999,
121:
1535
20 Mihelcic J.
Moeller KD.
J. Am. Chem. Soc.
2004,
126:
9106
21a Du X.
Chu HV.
Kwon O.
Tetrahedron Lett.
2004,
45:
8843
21b Du X.
Chu HV.
Kwon O.
Org. Lett.
2003,
5:
1923
22 Li C.-C.
Liang S.
Zhang X.-H.
Xie Z.-X.
Chen J.-H.
Wu Y.-D.
Yang Z.
Org. Lett.
2005,
7:
3709
23 Brummond KM.
Gao D.
Org. Lett.
2003,
5:
3491
24a Nguyen TM.
Seifert RJ.
Mowrey DR.
Lee D.
Org. Lett.
2002,
4:
3959
24b Nguyen TM.
Lee D.
Tetrahedron Lett.
2002,
43:
4033
25 Meyers AG.
Hammond M.
Wu Y.
Xiang J.-N.
Harrington PM.
Kuo EY.
J. Am. Chem. Soc.
1996,
118:
10006
26 Burke SD.
Buchanan JL.
Rovin JD.
Tetrahedron Lett.
1991,
32:
3961
27 Sivik MR.
Stanton KJ.
Paquette LA.
Org. Synth.
1995,
72:
57
28a Erman WF.
J. Am. Chem. Soc.
1967,
89:
3828
28b Erman WF.
J. Am. Chem. Soc.
1967,
89:
779
29 A slight loss of optical purity (13%) was noted in the photorearrangement, presumably due to a process involving fragmentation of the diradical to an intermediate ketene.
30a Kulkarni YS.
Niwa M.
Ron E.
Snider BB.
J. Org. Chem.
1987,
52:
1568
30b Erman WF.
Wenkert E.
Jeffs PW.
J. Org. Chem.
1968,
34:
2196
31 Murthy AR.
Sundar NS.
Rao GSRS.
Tetrahedron
1982,
38:
2831
32a Black TH.
Aldrichimica Acta
1983,
16:
3
32b Cushman M.
Cheng L.
J. Org. Chem.
1978,
43:
286
33 Hareau GP.-J.
Koiwa M.
Hikichi S.
Sato F.
J. Am. Chem. Soc.
1999,
121:
3640 ; and references cited therein
34 Lipshutz BH.
Wood RH.
Tirado R.
Org. Synth.
1999,
76:
252
35a Zakarian A.
Batch A.
Holton RA.
J. Am. Chem. Soc.
2003,
125:
7822
35b Zhu L.
Weymeyer RM.
Rieke RD.
J. Org. Chem.
1991,
56:
1445
36a Kim M.
Park S.
Maifeld SV.
Lee D.
J. Am. Chem. Soc.
2004,
126:
10242
36b Hansen E.
Lee D.
J. Am. Chem. Soc.
2004,
126:
15074
36c Maifeld SV.
Miller RL.
J. Am. Chem. Soc.
2004,
126:
12228
36d Miller RL.
Maifeld SV.
Lee D.
Org. Lett.
2004,
6:
2773
