Forskolin synthesis

Inspired by Nature, hydroxocobalamine 247 (X=OH) itself or modified vitamin B12 derivatives (review [331]) were probed as catalysts for radical cyclizations. This methodology is mediated by light and electrochemical or chemical reduction to close the catalytic cycle. It was applied to total syntheses of forskolin 280 by Pattenden [325] (Fig. 67, entry 13) as well as of jasmonate 284 and prostaglandin precursors 287 by Scheffold (entry 14) [326, 327], Starting materials were bromoacetaldehyde cyclohexenyl or cyclopentenyl acetals 278, 281, or 285, which cyclized in the presence of 247 to annulated butyrolactols 279, 283, or 287. In the forskolin synthesis the cyclized radical was reduced directly, while a radical addition ensued in the presence of acetoxyacrylonitrile 282 or ynone 286 in... 

The hydroxydiene A could be obtained by enantioselective CBS reduction of dienone B in 90% ee, which led to an enantioselective synthesis of the natural occurring form of forskolin. 

The tricyclic substance 18A and 18B are both potential synthetic intermediates for synthesis of the biologically active diterpene forskolin. These intermediates can be prepared from the monocyclic precursors shown. Indicate the nature of the reactions involved in these transformations. 

An enantioselective synthesis of the Ziegler intermediate 107 of forskolin (108) has been achieved using an intramolecular allenic Diels-Alder reaction (Scheme 19.20) [24], Treatment of propargyl ether 104 with potassium tert-butoxide in tert-butanol affords 106, presumably through the intermediate allene 105. Compound 106 was obtained as a single stereoisomer. 

One of the best-characterized effectors and second messenger systems is the cAMP cascade that can be either activated or inhibited by neurotransmit-ter/neuropeptide receptors, including those implicated in anxiety/stress such as CRE Receptors that activate cAMP synthesis couple with the stimulatory G protein, Gsa, and those that inhibit this second messenger couple with the inhibitory G protein, Gia, and these either stimulate or inhibit adenylyl cyclase, the effector enzyme responsible for synthesis of cAMP (Duman and Nestler 1999). There are at least nine different forms of adenylyl cyclase that have been identified by molecular cloning, each with a unique distribution in the brain. The different types of adenylyl cyclase are activated by Gsa as well as the diterpene forskolin, but are differentially regulated by Gia, the Py subunits, Ca, and by phosphorylation. This provides for fine control of adenylyl cyclase enzyme activity and regulation by other effector pathways. 

Several effects of forskolin on B-lymphocytes, the cells of the immune system responsible for the production of immunoglobulins, have further been reported. This diterpene was found to inhibit cellular proliferation of B cells stimulated either by antibodies to surface immunoglobulins (anti-mu), and an antibody to CD20 antigen or 12-O-tetradecanoyl phorbol 13-acetate [219]. There was also a clear inhibition of G1 entry and DNA synthesis, and forskolin maintained its inhibitory effect even when added later after anti-mu stimulation. Additionally, no differences were found in the inhibitory effect of forskolin on neoplastic B cells, as compared to the responses of normal cells. Growth inhibition associated with an accumulation of cells in G1 was later found when cells of the B-lymphoid precursor cell line Reh were incubated with forskolin [220]. In that study, a delay of cells in G2/M prior to G1 arrest was observed, suggesting that important restriction points located in the G1 and G2 phases of the cell cycle may be controlled by forskolin (due to cAMP levels elevation). In a subsequent study [221], it was found that the arrest of Reh cells was accompanied by rapid dephosphorylation of retinoblastoma protein, which was suggested to be a prerequisite for the forskolin mediated arrest of these cells in Gl. 

Despite this A3 AR desensitisation, the adenylyl cyclase activity is not reduced, but almost a twofold increase is detected in the presence or in the absence of forskolin. This effect seems not to be mediated by e new receptor synthesis, but is probably due to an increased coupling efficiency between Gs and adenylyl cyclase. The sensitization of adenylyl cyclase activity is evidence that acute and chronic treatment of adenosine receptors might lead to opposite effects (Palmer et al. 1997). 

Encouraged by this calculation, the racemic ester 46 was prepared readily in 5 steps from a-ionone in 65% overall yield via a known sequence used in the synthesis of forskolin [Scheme 9].14 The subsequent intramolecular Diels-Alder reaction of 13 in refluxing n-decane gave the tricyclic lactone 47 in 65% yield.52... 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

Calvo D, Port M et al (1996) Total synthesis of forskolin - part III studies related to an asymmetric synthesis. Tetrahedron Lett 37 1023-1024... 

Nagashima S, Kanematsu K (1990) A synthesis of an optically active forskolin intermediate via allenyl ether intramolecular cycloaddition strategy. Tetrahedron Asymmetry 1 743-749... 

Oplinger, f. A. Paquette, L. A. Synthesis ofthe forskolin skeleton via anionic oxy-Cope rearrangement. Tetrahedron Lett. 1987, 28, 5441-5444. 

A few key steps in the synthesis of optically active forskolin were achieved using allylation of aldehydes by a tin route (equation 205)208. 

In chicken granulosa cells, TMB-8, a putative antagonist of intracellular calcium mobilization, inhibited progesterone synthesis in calcium free medium and also inhibited LH stimulated 45Ca release from digitonin permeabilized cells [31]. The latter occurred in two phases after 1-2 min followed by a slower phase after 5 min. Forskolin and 8-Br-cyclic AMP stimulated only the slow phase of calcium mobilization. These studies indicate that LH may initially stimulate calcium mobilization in granulosa cells via a cyclic AMP-independent pathway followed by a slower cyclic AMP-dependent pathway. 

Bld-HrTH administration to B. discoidalis in vivo or to isolated fat body fails to stimulate either fat body cAMP levels or adenylate cyclase activity and supports the previous findings (25). Nevertheless, for B. discoidalis, fat body phosphorylase activity is elevated and trehalose levels increase both in vivo and in vitro, and calcium is essential in vitro in addition to Bld-HrTH. No stimulation of trehalose synthesis is noted with agents that elevate adenylate cyclase, such as forskolin, or by inhibitors of phosphodiesterase such as theophylline or isobutylmethylxanthine (IBMX). Additions of cAMP, dibutyryl cAMP or 8-bromo-cAMP are not stimulatory to trehalose synthesis either in vivo or in vitro. This same result was observed for P. americana in that neither cAMP nor dbcAMP stimulated trehalose production by fat body in vitro, and xanthine inhibitors of phosphodiesterase that should cause accumulation of intracellular cAMP were inhibitory, except for isobutylmethylxanthine (IBMX) which was stimulatory for unknown reasons (26). We have not observed a stimulatory effect by IBMX with B. discoidalis fat body in vitro. 

The reagent has been used by Magnus in studies directed towards a synthesis of bachrachotoxin (71). A cir-decalin was oxidized selectively at the 7-position without the acetal or triple bond moieties present being affected (equation 37). The reagent has also found use in an approach to forskolin ° cyclohexadienone (72) was prepared by exclusive oxidation at the 7-position of (73 equation 38). 

---