Dearomatization strategies in the synthesis of complex natural products

Abstract

Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemoselective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This Review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, aromatic scaffolds are converted to three-dimensional molecular architectures.

Figure 1

Classical examples of dearomatization in complex synthesis: a) Myers et al.;^[4] b) Corey et al.;^[5] c) Schultz et al.;^[6] d) Nicolaou et al.;^[8] e) Danishefsky et al.;^[9] f) Corey et al.;^[10] g) Magnus et al.^[11] Abbreviations of reagents and protecting groups are defined at the end of the Review.

Figure 2

Recent work highlighting syntheses of complex natural products using dearomatization strategies (2002–2010).

Scheme 1

Preparation of epoxyquinol synthons by enzymatic dihydroxylation of iodobenzene and elaboration to hexacyclinol (Banwell et al., 2009).^[19]

Scheme 2

Approach to salvileucalin B: Preparation of the pentacyclic framework by Buchner dearomatization (Reisman et al., 2010).^[21]

Scheme 3

Total synthesis of penifulvin A using photoinduced [3+2] cycloaddition (Mulzer et al., 2009).^[23]

Scheme 4

Enantioselective synthesis of (−)-isodomoic acid C by de-aromatizing anionic cyclization (Clayden et al., 2005).^[25]

Scheme 5

Alkylative dearomatization by thionium activation (Procter et al., 2008).^[26]

Scheme 6

Total synthesis of cleroindicin using oxidative dearomatization with Oxone (Carreño/Urbano et al., 2007).^[28]

Scheme 7

Approach to bacchopetiolone employing oxidative spirolactonization/dearomatization (Wood et al., 2006).^[29c]

Scheme 8

Total synthesis of acutumine including late-stage dearomatization (Castle et al., 2009).^[30]

Scheme 9

Total synthesis of (+)-puupehenone involving the regio-selective oxidative dearomatization of a catechol (Quideau et al., 2002).^[31]

Scheme 10

Approach to the cortisatin A framework through tandem oxidative dearomatization/[3+2] cycloaddition (Sorensen et al., 2010).^[32]

Scheme 11

Total synthesis of (+)-rishirilide B by means of the diastereoselective para-oxidative dearomatization of a resorcinol substrate (Pettus et al., 2006).^[36]

Scheme 12

Total synthesis of (+)-biscarvacrol using a tethered chiral auxiliary for ortho-oxidative dearomatization (Quideau et al., 2008).^[37]

Scheme 13

Total synthesis of (−)-mitorubin employing enantioselective ortho-oxidative dearomatization (Porco, Jr. et al., 2006).^[38]

Scheme 14

Formal synthesis of (+)-maritidine employing oxidative dearomatization/C-arylation (Kita et al., 2008).^[41]

Scheme 15

Total synthesis of (−)-platensimycin involving an oxidative para-spiroannulation strategy (Nicolaou et al., 2007).^[42]

Scheme 16

Total synthesis of dalesconol B employing a Friedel–Crafts/oxidative para-cyclization tandem sequence (Snyder et al., 2010).^[44]

Scheme 17

Approach to cortistatin A by means of para-alkylative phenol dearomatization (Danishefsky et al., 2008).^[46]

Scheme 18

Approach to (±)-platensimycin using intramolecular para-alkylative phenol dearomatization (Njardarson et al., 2009).^[47]

Scheme 19

Total synthesis of (±)-clusianone using a MEM sequence (Porco, Jr. et al., 2007).^[48]

Scheme 20

Total synthesis of (±)-garsubellin A by means of para-alkylative dearomatization of a phloroglucinol (Danishefsky et al., 2006).^[50]

Scheme 21

Total syntheses of gambogin involving Claisen rearrangement/dearomatization (Theodorakis et al., 2004; Nicolaou et al., 2005).^{[53, 54]}

Scheme 22

Total synthesis of (−)-longithorone A through oxidation with a hypervalent iodine reagent and Diels–Alder cycloaddition (Shair et al., 2002).^[59]

Scheme 23

Total synthesis of (+)-elisabethin A through oxidative dearomatization/intramolecular Diels–Alder cycloaddition (Mulzer et al., 2003).^[61a]

Scheme 24

Total synthesis of (±)-penicillone A using an ortho-oxidative dearomatization/IMDA cascade (Liao et al., 2007).^[63]

Scheme 25

Total synthesis of (±)-O-debenzoylttashironin through oxidative dearomatization/Diels–Alder cycloaddition (Danishefsky et al., 2006).^[64]

Scheme 26

Approach to maeocrystal V using oxidative ortho-dearomatization/IMDA cycloaddition (Baran et al., 2009).^[65]

Scheme 27

Total synthesis of helisorin with an ortho-oxidative dearomatization and a retro-Diels–Alder/Diels–Alder sequence (Snyder et al., 2009).^[67]

Scheme 28

Total synthesis of (+)-chamaecypanone C by means of enantioselective copper-mediated oxidative dearomatization/[4+2] cycloaddition (Porco, Jr. et al., 2009).^[69]

Scheme 29

Total synthesis of (±)-stenine through dearomatization of a 2-thiomethylfuran (Padwa et al., 2002).^[75]

Scheme 30

Total synthesis of (±)-merrilactone A: catalytic Nazarov cyclization using the dearomatization of a 2-silyloxyfuran (Frontier et al., 2008).^[76]

Scheme 31

Formal synthesis of (±)-morphine highlighted by an IMDA dearomatization of a benzofuran (Stork et al., 2009).^[78]

Scheme 32

Synthetic approach toward (−)-guanacastepene E: oxidative radical annulation by means of furan dearomatization (Trauner et al., 2005).^[80]

Scheme 33

Approach to parvineostemonine employing asymmetric oxyallyl cation [4+3] cycloaddition for pyrrole dearomatization (Hsung et al., 2007).^[82]

Scheme 34

Total synthesis of chartelline C by brominative indole dearomatization/amide trapping (Baran et al., 2006).^[85]

Scheme 35

Total synthesis of (±)-norfluorocurarine using IMDA indolic dearomatization (Vanderwal et al., 2009).^[86]

Scheme 36

Total synthesis of (+)-minfiensine: enantioselective iminium-catalyzed Diels–Alder dearomatization of indoles (MacMillan et al., 2009).^[89]

Scheme 37

Total synthesis of (+)-fendleridine using tandem [4+2]/[3+2] cycloadditions of 1,3,4-oxadiazoles with indole dearomatization (Boger et al., 2010).^[91]

Scheme 38

Total synthesis of (−)-phalarine through indole dearomatization: Pictet–Spengler cyclization and intramolecular carbocation trapping (Danishefsky et al., 2010).^[92c]

Scheme 39

Total synthesis of (+)-cannabisativine using the diastereoselective C2-alkylation of pyridiniums (Comins et al., 2004).^[95]

Scheme 40

Total synthesis of (+)-lepadin B using the diastereoselective alkylation of a pyridinium (Charette et al., 2008).^[97]

Scheme 41

Total synthesis of (±)-hetisine employing the intramolecular 1,3-dipolar cycloaddition of oxidoisoquinolium betaines (Gin et al., 2006).^[100]

Scheme 42

New strategies for arene dearomatization using transition-metal catalysis (Harman,^[102] Y. Yamamoto,^[103] Buchwald^[105] et al., 2008–2010).

Scheme 43

Enantioselective and catalytic oxidative dearomatization methodologies (Kita,^[106] Ishihara,^[107] Quideau,^[108] Birman^[110] et al., 2008–2010).

Scheme 44

Organocatalytic desymmetrization of meso dienones obtained through oxidative dearomatization (Rovis,^[112] Gaunt,^[113] You^[114] et al., 2006–2010).