Studies Towards the Synthesis of Salvinorin A

Lingham, Anthony R.; Hügel, Helmut; Rook, Trevor J.

doi:10.1071/ch05338

Cited by 27 publications

(15 citation statements)

References 35 publications

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“…The first studies toward the total synthesis of 2a were reported by Lingham et al 90 The proposed synthetic route dissected 2a into cyclohexanone 147 and lactone 148 ( Figure 12). It was envisioned that Michael addition followed by olefin metathesis and hydrogenation would afford 2a.…”

Section: Total Synthesis Effortsmentioning

confidence: 99%

Salvinorin A Analogs as Probes in Opioid Pharmacology

2008

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Recently, the biosynthetic route of 2a was studied using the incorporation of [1-13 C]glucose, [CH 3-13 C]methionine, and [1-13 C;3,4-2 H 2 ]-1-deoxy-D-xylulose into its structure. 58 Neoclerodane 2a, like other terpenoids, results from the assembly of isopentenylpyrophosphate and dimethylallyl pyrophosphate to form geranylgeranyl pyrophosphate (31) (Figure 4). 59 Cyclization of 31 affords the labdanyl cation (32), which after several methyl shifts yields clerodane pyrophosphate (33). Further oxidation, acetylation, and methylation of 33 constructs 2a. Despite low incorporation, feeding experiments with [1-13 C;3,4-2 H 2 ]-1-deoxy-D-xylulose (DOX) yielded a pattern of incorporation consistent with the deoxyxylulose phosphate pathway. 58 Furthermore, enrichment of the C-23 methoxy group suggests the participation of an S-adenosyl-L-methionine dependent type III O-methyltransferase. However, the enzymes responsible for the oxygenation of 33 remain uncharacterized. 3. Structure-Activity Relationships of Salvinorin A Analogs Over the last 150 years, opioid receptor ligands have remained an active area in central nervous system (CNS) drug discovery. Opioid agonists are used clinically for the management of cancer pain, chronic pain, and cough and to treat diaherra. 28 Opioid antagonists, such as naloxone and naltrexone, are used to treat opioid overdose, narcotic addiction, and alcohol dependence. 60 Preclinical studies suggest that opioid agonists may have utility in treating stimulant

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Section: Total Synthesis Effortsmentioning

confidence: 99%

Salvinorin A Analogs as Probes in Opioid Pharmacology

2008

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“…Synthesis of 12 by Scheerer et al50 Reagents and conditions : (a) propyne, n -BuLi, Et 2 O, −78 °C; (b) ( R )-β-Methyl-CBS catalyst, BH 3 •Me 2 S, −30 °C; (c):(1) KH, H 2 N(CH 2 ) 3 NH 2 , 0 °C; (2) Me 3 Al, Cp- 2 ZrCl 2 , I 2 , −45 °C; (3) TESCl, imidazole; (d) Ni-( R )-BINAP(OTf) 2 , 2,6-lutidine, BF 3 •OEt 2 , HC(OMe) 3 ; (e) HO 2 CCH 2 CO 2 Et, i -PrMgCl, 65 °C ; (f) LiHMDS ; ClPO(OEt) 2 ; (g) Fe(acac) 3 , MeMgCl, −20 °C; (h):(1) DIBAL-H, −78 °C; (2) MnO 2 ; (3) Sn(OTf) 2 , N -ethylpiperidine, chiral auxiliary, −78 °C; (i): (1) TBSOTf, 2,6-lutidine; (2) K 2 CO 3 , CH 3 OH; (3) OsO 4 , NMO, NaIO 4 ; (4) Zn(OTf) 2 , (−)- N -Methyl-ephedrine, Et 3 N, 4-phenyl-1-butyne; (j):(1) BOMCl, NaHMDS, −78 °C; (2) Lindlar catalyst, H 2 ; (3) K 2 OsO 4 , NMO, citric acid, 50 °C, Pb(OAc) 4 , K 2 CO 3 ; (k) 27 , n -BuLi, MgBr•OEt 2 , CH 2 Cl 2 , −78 to 0 °C; (l): (1) TBSOTf, 2,6-lutidine; (2) PPTS, CH 3 OH; (3) LiOH, i -PrOH, H 2 O; (m):(1) MNBA, DMAP, [0.0015 M]; (2) TBAF; (3) Dess-Martin periodinane; (n) TBAF, −78 to 5 °C; (o): (1) NaH, Comins reagent; (2) Pd(OAc) 2 , dppf, Et 3 SiH; (3) L-selectride, t -BuOH, −78 to −55 °C; (p) LiBF 4 , acetonitrile/H 2 O; (q) NaClO 2 , TMSCHN 2 ; (r) K 2 CO 3 , CH 3 OH; (s) Ac 2 O, pyridine, DMAP.…”

Section: Figuresmentioning

confidence: 99%

Chemical methods for the synthesis and modification of neoclerodane diterpenes

Lozama

Prisinzano

2009

Bioorganic & Medicinal Chemistry Letters

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Diterpenes are a structural class of molecules that are derived from four isoprene subunits and are widespread throughout nature. A number of neoclerodane diterpenes have been found to have biological activity but a limited number of chemical investigations have been conducted. Recently, the neoclerodane diterpene, salvinorin A (12) has been investigated due to its unique pharmacological profile. This review will discuss the chemical methods used to chemically modify and synthesize 12. Keywords diterpene; neoclerodane; salvinorin A; Salvia divinorumTerpenes are a wide variety of 10-carbon skeletons formed from the coupling of two isoprene subunits.1 They are ubiquitous in nature as they are used as biosynthetic building blocks in many living organisms including plants and animals.1 There are many different types of terpenes and they are classified by their structure.1 Diterpenes are one class that possess a core 20-carbon skeleton and are found in many different plant families and some animals. 1 They are biosynthesized by two different pathways, the mevalonic acid pathway (MVA) or the deoxyxylulose phosphate pathway (DOXP). 2-5 Diterpenes are of interest as many have been found to have biological activity. Some biologically active diterpenes include taxol (1), cafestol (2) and kahweol (3) (Figure 1). Diterpenes 1-3, isolated from Taxus brevifolia 6 and Coffea arabica respectively, 7,8 all display anticancer properties.One type of structural class of diterpenes are clerodanes which are found in many different plant families and contain four contiguous stereocenters contained in a cis or trans decalin (4). 9,10 Various clerodane diterpenes have been isolated and displayed biological activity. These include columbin (5), isolated from the roots of Calumbae radix ,11 which has cancer chemo-preventive properties 12 and clerocidin (6), isolated from Oidiodendron truncatum ,13 which has shown antibiotic activity. 13 Terpentecin (7), a microbial clerodane diterpene from © 2009 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Despite their biological properties, few synthetic works have been published on neoclerodane diterpenes. 9,20-22 One neoclerodane diterpene that has been investigated recently is salvinorin A (12). Neoclerodane 12 is isolated from the leaves of Salvia divinorum, and has shown to have hallucinogenic effects. [23][24][25][26] However, 12 is unlike classical hallucinogens, as it does not interact with the 5-HT 2A receptor. 25,27 Rather, 12 is a selective κ opioid agonist. 28 This was the first report of a neoclerodane d...

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“…All structural derivatization studies reported to date have involved systematic modification of salvinorin A extracted directly from the leaves of S. divinorum. Several total synthesis efforts have been reported (Lingham et al, 2006;Scheerer et al, 2007;Burns and Forsyth, 2008;Nozawa et al, 2008;Bergman et al, 2009;Hagiwara et al, 2009); however, their time and resource investment, compared with the relative ease in isolation from natural sources, render their application thus far suboptimal for use in SAR development. Binding affinities and functional activities of analogs at MOP, DOP, and KOP receptors are described in Table 1.…”

Section: A Structure-activity Relationships Of Analogsmentioning

confidence: 99%