Howard Sard

Cyclohexenol annulation via the alkoxy-accelerated rearrangement of vinylcyclobutanes

Abstract The lithium and potassium salts of 2-vinylcyclobutanols undergo vinylcyclobutane rearrangement at 25–70°, providing an efficient method for the synthesis of 3-cyclohexenol derivatives. 2-Vinylcyclobutanones are prepared from α,β-unsaturated carbonyl compounds by the method of Trost and via [2 + 2]-cycloadditions of olefins and vinylketenes. Addition of hydride or alkyllithium reagents then generates 2-vinylcyclobutanol salts which directly rearrange to afford 3-cyclohexenols. The two methods constitute new [3 + 3]- and [4 + 2]-annulation approaches to 6-membered carbocycles.

A general method for C3 reductive alkylation of indoles

Abstract General indole C 3 reductive alkylation conditions have been developed. The scope of this reaction includes C 2 unsubstituted indoles, aryl and alkyl aldehydes, as well as N–H and N -alkyl indole substrates.

The regiochemical course of [2+2] cycloadditions of dichloroketene with vinyl- and alkynylsilanes

Abstract Alkynylsilanes undergo regioselective [2+2] cycloadditions with dichloroketene in good yield; the regiochemical course of these reactions is in accord with frontier molecular orbital predictions.

Synthesis and pharmacological evaluation of mercapto and thioacetyl analogues of cannabidiol and Δ8-tetrahydrocannabinol

Abstract A series of novel mercapto and thioacetyl derivatives of Δ 8 -tetrahydrocannabinol ( Δ 8 -THC, 5 ), and cannabidiol ( 1 ) were synthesized. Treatment of 10-hydroxy-cannabidiol ( 2 ) with thioacetic acid in the presence of a complex of diisopropylazodicarboxylate and triphenylphosphine in dry THF gave 10-thioacetyl-cannabidiol ( 3 ). Further treatment with LiAlH 4 converted 3 into 10-mercapto-cannabidiol ( 4 ). Using a similar sequence, 11-mercapto- Δ 8 -THC ( 8 ) was synthesized from the metabolite 11-hydroxy- Δ 8 -THC ( 6 ) via the corresponding thioacetyl derivative ( 7 ). Similarly, the 12β-thioacetyl derivative ( 10 ) of Δ 8 -THC was prepared. Although 8 is a derivative of a pharmacologically active cannabinoid ( 6 ), 8 proved to be inactive in 4 different pharmacological evaluations in the mouse. Similarly, 10 and 4 were also inactive. Additionally, 7 was inactive except for the production of hypothermia, but was more than 3-fold less potent than Δ 8 -THC. None of these cannabinoids was able to antagonize the effects of Δ 9 -THC. These data indicate that there are specific structural requirements for the production of cannabimimetic activity, which tends to suggest that activity is determined, in part, via specific molecular interactions such as those observed in receptor-, enzyme-, ion channel-, or other protein-mediated events.