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. 2006 Oct 11;128(40):13095-101.
doi: 10.1021/ja0650504.

Enantioselective total synthesis of guanacastepene N using an uncommon 7-endo Heck cyclization as a pivotal step

Shin Iimura  1 , Larry E Overman, Ralph Paulini, Armen Zakarian
Affiliations

Enantioselective total synthesis of guanacastepene N using an uncommon 7-endo Heck cyclization as a pivotal step

Shin Iimura et al. J Am Chem Soc. .

Abstract

A convergent, enantioselective total synthesis of (+)-guanacastepene N was developed that features a 7-endo Heck cyclization as the key step. In the course of this synthesis, short syntheses of the enantiomerically pure cyclopentenone and cyclohexene building blocks 5 and 6, which constitute A and C ring fragments of guanacastepene N, were developed. These fragments were linked by a challenging conjugate addition reaction that also generated the C11 quaternary carbon stereocenter. Regioselective 7-endo Heck cyclization gave rise to a tricyclic intermediate, which was elaborated to complete the first total synthesis of guanacastepene N and the second enantioselective total synthesis of a guanacastepene natural product.

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Figures

Figure 1
Figure 1
Structures of selected members of the guanacastepene family of natural products and epimer 2.
Figure 2
Figure 2
Eclipsed insertion topographies for cyclizations of the alkenylpalladium intermediate derived from triflate 7.
Scheme 1
Scheme 1
Synthetic Strategy for Preparing (+)-Guanacastepene N.
Scheme 2
Scheme 2
Synthesis of Enantioenriched Cyclohexene 6.a a(a) LDA, THF, −78 °C, 30 min, then DMPU, TBSCl, −78 °C → rt, 30 min. (b) toluene, 80 °C, 10 h. (c) DIBAL-H, toluene, −78 °C → rt, 1 h. (d) I2, Ph3P, imidazole, CH2Cl2, 0 °C → rt, 5 h, 69% (overall), 80% ee. LDA = lithium diisopropylamide; DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; TBSCl = tert-butyldimethylsilyl chloride; DIBAL-H = diisobutylaluminum hydride; rt = room temperature.
Scheme 3
Scheme 3
Preparation of Enantioenriched Cyclopentenone 5.a a(a) menthol, p-TsOH, benzene, 80 °C, 9 h, 76%. (b) LDA, THF, −78 °C, 20 min, then Et2Zn, 2-iodopropane, DMPU, −78 °C → rt, 20 h, 71%, 1.5:1 mixture of diastereomers, separated by HPLC. (c) MeLi, THF, −78 → 0 °C, 3 h; aqueous NaHSO4, 79%, 88% ee. THF = tetrahydrofuran, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
Scheme 4
Scheme 4
Stereoselective Conjugate Addition of Alkyl Iodide 6 to Enone 5 and Introduction of the Exomethylene Group.a a Optimized conditions: i) 6, t-BuLi (1 equiv), Et2O–pentane, −78 °C, 30 min; (ii) CuCN (1 equiv), −78 → −30 °C; (iii) Me3SiBr (1 equiv), THF, −78 °C, then add 5 (0.7 equiv), −78 °C, 6 h; (iv) 16, 2,6-lutidine, DMF, 0 °C, 1 h; (v) MeI, Et2O, rt, 12 h; (vi) K2CO3, CH2Cl2/MeOH/H2O (4:1:3), rt, 3 h, 53–58% overall from 5.
Scheme 5
Scheme 5
Elaboration of Intermediate 18 to Heck Cyclization Precursor 23.a (a) m-CPBA, CH2Cl2, 0 °C, 3 h. (b) NaBH4, CeCl3·7 H2O, MeOH, −78 °C, 1 h. (c) TBSCl, imidazole, CH2Cl2, rt, 30 min. (d) LiEt3BH, THF, 0 °C, 2 h. (e) NMO, TPAP, CH2Cl2, rt, 1 h, 83% overall (5 steps). (f) LiN(SiMe3)2, THF, −78 → −30 °C, 10 min, then DMPU, benzyl cyanoformate, −78 → −45 °C, 10 min. (g) KN(SiMe3)2, THF, −78 °C, 20 min, then Tf2O, −78 °C, 10 min. (h) HF, CH3CN/MeOH/H2O (8:2:1), 0 °C, 3 h. (i) NMO, TPAP, CH2Cl2, rt, 4 h, 47–53% overall (4 steps). DMF = N,N-dimethylformamide; TBSCl = tert-butyldimethylsilyl chloride; NMO = N-methylmorpholine-N-oxide; TPAP = tetra-n-propylammonium perruthenate; DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
Scheme 6
Scheme 6
7-Endo Heck Cyclization and Completion of the Total Synthesis of (+)-Guanacastepene N (1) and (+)-5-epi-Guanacastepene N (2).a a(a) Pd2(dba)3·CHCl3 (12 mol %), dppb (24 mol %), KOAc, DMA, 80 °C, 12 h, 75%. (b) TESOTf, Et3N, CH2Cl2, −78 °C, 4 h. (c) DMDO, CH2Cl2/acetone, −78 °C, 10 h (dr = 9:1). (d) Ac2O, Et3N, DMAP, rt, 3 h, 67% (3 steps). (e) Et3SiH, Pd(OAc)2, Et3N, CH2Cl2, rt, 2 h, 77%. (f) NBS, benzoyl peroxide, CCl4, reflux, 1.5 h, 64% (dr = 20:1). (g) See Table 1. dba = dibenzylideneacetone; dppb = bis(diphenylphosphino)butane; DMA = N,N-dimethylacetamide; TESOTf = triethylsilyltriflate; DMDO = dimethyldioxirane; DMAP = 4-N,N-dimethylaminopyridine; NBS = N-bromosuccinimide.
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