A Method To Accomplish a 1,4-Addition Reaction of Bulky Nucleophiles to Enones and Subsequent Formation of Reactive Enolates

William, Anthony D.; Kobayashi, Yuichi

doi:10.1021/ol010071i

Cited by 40 publications

(18 citation statements)

References 30 publications

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“…The formal total synthesis20 of Δ 9 ‐THC ( 1 ) was completed by the reaction of trans ‐ 2 c with methyl magnesium chloride, to afford hydroxy phenol 12 . This compound has previously been converted into 1 in two steps (Scheme ) 3i,j…”

Section: Methodsmentioning

confidence: 99%

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ⁹‐THC

Pearson¹,

Kanizaj²,

Willis³

et al. 2010

Chemistry A European J

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Cannabinoids are tricyclic terpenoid compounds containing a benzopyran moiety. Of the 60 or so known plant-derived cannabinoids, the most well known is (À)-D 9 -tetrahydrocannabinol (D 9 -THC; 1), a natural product isolated from Cannabis sativa L. (Indian hemp) and the key psychoactive constituent of marijuana.[1] It exhibits a range of activities including antiemetic, analgesic, and antiglaucoma effects [2] and has been the focus of many synthetic studies. [3,4] In recent times, synthetic interest in these structures has been reinvigorated by the identification of the cannabinoid receptors CB1 and CB2 and their selective binding of THC analogues.[5] Existing synthetic approaches are dominated by strategies involving the construction of ring B through the union of suitably functionalized ring A and ring C building blocks. [3,4] These previous studies have identified two main issues associated with the synthesis of D 9-THC: the stereoselective formation of the trans ring junction and the unwanted, facile isomerization of its thermodynamically more stable D 8 -isomer.[3a] Herein, we present a short diastereoselective synthesis of D 9 -THC (1) by a trans-selective intramolecular Diels-Alder (IMDA) [6] reaction of an appropriately functionalized, benzo-tethered, ester-linked 1,3,9-decatriene 3 as the key step (Scheme 1). The synthesis is noteworthy for three reasons: 1) it differs from previous approaches in that rings B and C are assembled in one step with concomitant installation of the required D 9-alkene (Scheme 2, 3!2), 2) it represents the first total synthesis application of Yamamotos highly sterically hindered aluminum tris(2,6-diphenylphenoxide) (ATPH) catalyst, [7] and 3) the synthetic work is driven by an understanding of the stereoselectivity of the key IMDA reaction, which in turn is provided through computational analysis. Despite the presence of the cyclohexene ring in many naturally occurring cannabinoids, there are only three published synthetic approaches to cannabinoids employing Diels-Alder reactions: 1) Korte, Dlugosch, and Claussens approach to trans-cannabidiol through an intermolecular cycloaddition, [8] 2) Evans synthesis of D 9-tetrahydrocannabinol through an enantioselective intermolecular cycloaddition, [9] and 3) Inoues approach to the cis isomer of D 9 -tetrahydrocannabinol through an IMDA reaction. [10] The IMDA precursors 3 a-3 d, differing only in the nature of the C12 phenol substituent, were synthesized from olivetol (4) through the short sequence depicted in Scheme 2. [11] Protection of the two phenol groups in 4 as methoxymethyl [3d] or ethoxyethyl ethers followed by C6-formylation of the olivetol ring by directed ortho-lithiation and trapping with DMF afforded aldehydes 5 a (EE) and 5 b (MOM), [12] respectively. Selective deprotection [12] of one acetal group of 5 a and 5 b afforded monophenols 6 a and 6 b. Methyl ether 6 c was obtained from 6 b through alkylation of the free -THC. P = protecting/stereodirecting group.

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Section: Methodsmentioning

confidence: 99%

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ⁹‐THC

Pearson¹,

Kanizaj²,

Willis³

et al. 2010

Chemistry A European J

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“…The authors aimed to use α-iodocyclohexenones and a variety of resorcinols and unveil the arylation of these cyclohexenones (Scheme 12). 47 They observed that 1,4-addition of bulky diaryl cuprates to enones was only successful in the presence of BF 3 OEt 2 . The stereochemistry of α-iodocyclohexenone 52 facilitated the exclusive formation of trans-configured arylated products.…”

Section: α-Iodocyclohexenonesmentioning

confidence: 99%

“…69 was finally treated with methylmagnesium chloride and cyclised using ZnBr 2 to obtain (−)-trans-Δ 9 -THC (7). 47,48 Minuti and co-workers applied late stage hyperbaric Diels-Alder reactions giving rise to a variety of Δ 8 -THC derivatives. 64 The authors performed this reaction with six benzylidene acetone dienophiles (70) and two diene coupling partners (71a, 71b) promoted by mildly Lewis acidic conditions.…”

Section: Concerted Approachesmentioning

confidence: 99%

“…(−)-trans-Δ 9 -THC (7) was formed using an esterification, ring-closing metathesis, deprotection using MeMgI and a final Lewis acidbased cyclisation with ZnBr 2 . 47,48,59 Previously, the S N 2 arylation of α-iodocyclohexanone was demonstrated by Kobayashi, in the preparation of (−)-trans-Δ 9 -THC and -CBD. Alternatively, Zhou and co-workers later found that α-iodocyclohexanones are effective candidates in Suzuki-Miyaura cross-coupling reactions (Scheme 18).…”

Section: Scheme 16mentioning

confidence: 99%

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Synthetic pathways to tetrahydrocannabinol (THC): an overview

Bloemendal

Hest

Rutjes³

2020

Org. Biomol. Chem.

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“…Alternatively, enantiopure tetrahydrocannabinols can be synthesised using various chiral pool approaches in a limited number of synthetic steps [15][16][17][18][19][20][21][22][23][24]. To the best of our knowledge, the application of flow chemistry for the stereoselective synthesis of THC has not yet been reported (Scheme 1b).…”

Section: Introductionmentioning

confidence: 99%

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

et al. 2021

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Continuous flow chemistry holds great potential for the production of biologically relevant molecules. Herein, we present an approach for the continuous synthesis of cannabidiol and tetrahydrocannabinol in a one-flow system. The designed route consists of a reaction cascade involving Friedel-Crafts alkylation, subsequent ring opening and cyclisation in up to 45% yield. The reactions were successfully performed using both hetero- and homogeneous Lewis acids in continuous flow and provide yields that are similar to comparable batch processes. Graphical abstract

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A Method To Accomplish a 1,4-Addition Reaction of Bulky Nucleophiles to Enones and Subsequent Formation of Reactive Enolates

Cited by 40 publications

References 30 publications

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ⁹‐THC

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ⁹‐THC

Synthetic pathways to tetrahydrocannabinol (THC): an overview

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

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A Method To Accomplish a 1,4-Addition Reaction of Bulky Nucleophiles to Enones and Subsequent Formation of Reactive Enolates

Cited by 40 publications

References 30 publications

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ9‐THC

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ9‐THC

Synthetic pathways to tetrahydrocannabinol (THC): an overview

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

Contact Info

Product

Resources

About

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ⁹‐THC

Experimental and Computational Studies into an ATPH‐Promoted exo‐Selective IMDA Reaction: A Short Total Synthesis of Δ⁹‐THC