Enantioselective approach to the asymmetric synthesis of (6R)-hydroxymethyl-5,6-dihydro-2H-pyran-2-one. A formal synthesis of (R)-argentilactone and total synthesis of (R)-goniothalamin
Abstract:The asymmetric synthesis of the (6R)-hydroxymethyl-5,6-dihydro-2H-pyran-2-one, a key intermediate in the formal synthesis of (R)-argentilactone, and the total synthesis of (R)-goniothalamin are described. Our aproach involved the Lemieux-Johnson oxidative cleavage, enantioselective Keck allylation, ring-closing metathesis and Wittig olefination.
“…Due to its diverse pharmacological properties, GTN gained huge interest from researchers because several successful approaches have been adopted for its synthesis [ 50 – 54 ]. The absolute configuration in the pyran-2-one moiety has generally been secured from chiral starting material, asymmetric allylboration of aldehydes with β -allyldiisopinocampehylborane [ 50 , 55 , 56 ], or through asymmetric reduction using enzymes or microorganisms [ 51 , 53 , 54 , 57 – 61 ]. De Fátima and Pilli [ 51 ] reported the syntheses of GTN via catalytic asymmetric allylation of α-benzyloxyacetaldehyde, followed by ring-closing metathesis and Wittig olefination, and via catalytic asymmetric allylation of trans-cinnamaldehyde, followed by ring-closing metathesis [ 62 ].…”
Section: Synthesis Of Goniothalaminmentioning
confidence: 99%
“…The absolute configuration in the pyran-2-one moiety has generally been secured from chiral starting material, asymmetric allylboration of aldehydes with β -allyldiisopinocampehylborane [ 50 , 55 , 56 ], or through asymmetric reduction using enzymes or microorganisms [ 51 , 53 , 54 , 57 – 61 ]. De Fátima and Pilli [ 51 ] reported the syntheses of GTN via catalytic asymmetric allylation of α-benzyloxyacetaldehyde, followed by ring-closing metathesis and Wittig olefination, and via catalytic asymmetric allylation of trans-cinnamaldehyde, followed by ring-closing metathesis [ 62 ]. Gruttadauria et al [ 54 ] along with coworkers reported that the high-yielding three-step synthesis of GTN involves an enzymatic kinetic resolution in the presence of vinyl acrylate followed by ring-closing metathesis [ 54 ].…”
The treatment of most cancers is still inadequate, despite tremendous steady progress in drug discovery and effective prevention. Nature is an attractive source of new therapeutics. Several medicinal plants and their biomarkers have been widely used for the treatment of cancer with less known scientific basis of their functioning. Although a wide array of plant derived active metabolites play a role in the prevention and treatment of cancer, more extensive scientific evaluation of their mechanisms is still required. Styryl-lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess antiproliferative activity against cancer cells. A large body of evidence suggests that this activity is associated with the induction of apoptosis in target cells. In an effort to promote further research on the genus Goniothalamus, this review offers a broad analysis of the current knowledge on Goniothalamin (GTN) or 5, 6, dihydro-6-styryl-2-pyronone (C13H12O2), a natural occurring styryl-lactone. Therefore, it includes (i) the source of GTN and other metabolites; (ii) isolation, purification, and (iii) the molecular mechanisms of actions of GTN, especially the anticancer properties, and summarizes the role of GTN which is crucial for drug design, development, and application in future for well-being of humans.
“…Due to its diverse pharmacological properties, GTN gained huge interest from researchers because several successful approaches have been adopted for its synthesis [ 50 – 54 ]. The absolute configuration in the pyran-2-one moiety has generally been secured from chiral starting material, asymmetric allylboration of aldehydes with β -allyldiisopinocampehylborane [ 50 , 55 , 56 ], or through asymmetric reduction using enzymes or microorganisms [ 51 , 53 , 54 , 57 – 61 ]. De Fátima and Pilli [ 51 ] reported the syntheses of GTN via catalytic asymmetric allylation of α-benzyloxyacetaldehyde, followed by ring-closing metathesis and Wittig olefination, and via catalytic asymmetric allylation of trans-cinnamaldehyde, followed by ring-closing metathesis [ 62 ].…”
Section: Synthesis Of Goniothalaminmentioning
confidence: 99%
“…The absolute configuration in the pyran-2-one moiety has generally been secured from chiral starting material, asymmetric allylboration of aldehydes with β -allyldiisopinocampehylborane [ 50 , 55 , 56 ], or through asymmetric reduction using enzymes or microorganisms [ 51 , 53 , 54 , 57 – 61 ]. De Fátima and Pilli [ 51 ] reported the syntheses of GTN via catalytic asymmetric allylation of α-benzyloxyacetaldehyde, followed by ring-closing metathesis and Wittig olefination, and via catalytic asymmetric allylation of trans-cinnamaldehyde, followed by ring-closing metathesis [ 62 ]. Gruttadauria et al [ 54 ] along with coworkers reported that the high-yielding three-step synthesis of GTN involves an enzymatic kinetic resolution in the presence of vinyl acrylate followed by ring-closing metathesis [ 54 ].…”
The treatment of most cancers is still inadequate, despite tremendous steady progress in drug discovery and effective prevention. Nature is an attractive source of new therapeutics. Several medicinal plants and their biomarkers have been widely used for the treatment of cancer with less known scientific basis of their functioning. Although a wide array of plant derived active metabolites play a role in the prevention and treatment of cancer, more extensive scientific evaluation of their mechanisms is still required. Styryl-lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess antiproliferative activity against cancer cells. A large body of evidence suggests that this activity is associated with the induction of apoptosis in target cells. In an effort to promote further research on the genus Goniothalamus, this review offers a broad analysis of the current knowledge on Goniothalamin (GTN) or 5, 6, dihydro-6-styryl-2-pyronone (C13H12O2), a natural occurring styryl-lactone. Therefore, it includes (i) the source of GTN and other metabolites; (ii) isolation, purification, and (iii) the molecular mechanisms of actions of GTN, especially the anticancer properties, and summarizes the role of GTN which is crucial for drug design, development, and application in future for well-being of humans.
“…Subsequent RCM of 2 using the catalyst 5 produced the polycyclic ether 4 in a high yield. This methodology was applied to the total synthesis of gambierol. 13c,d Recent reports on the total synthesis of heterocyclic natural products using RCM are summarized in Table . 13c,d,− 3 4 5 6 …”
Section: 1 Ring-closing Metathesis For Total Synthesismentioning
“…Several batch strategies have been proposed for the asymmetric synthesis of goniothalamin ( 1 ). , For example, Singh and co-workers employed an auxiliary-controlled asymmetric aldol reaction for the construction of an enantiopure homoallylic alcohol intermediate . Asymmetric allylboration was described by Brown and co-workers, achieving homoallylic alcohol intermediate ( 12 ) in 92–97% enantiomeric excess (ee) .…”
An integrated batch and continuous
flow process has been developed
for the gram-scale synthesis of goniothalamin. The synthetic route
hinges upon a telescoped continuous flow Grignard addition followed
by an acylation reaction capable of delivering a racemic goniothalamin
precursor (
16
) (20.9 g prepared over 3 h), with a productivity
of 7 g·h
–1
. An asymmetric Brown allylation
protocol was also evaluated under continuous flow conditions. This
approach employing (−)-Ipc
2
B(allyl) provided an
(
S
)-goniothalamin intermediate in 98% yield and 91.5%
enantiomeric excess (ee) with a productivity of 1.8 g·h
–1
. For the final step, a ring-closing metathesis reaction was explored
under several conditions in both batch and flow regimes. In a batch
operation, the Grubbs second-generation was shown to be effective
and highly selective for the desired ring closure product over those
arising from other modes of reactivity, and the reaction was complete
in 1.5 h. In a flow operation, reactivity and selectivity were attenuated
relative to the batch mode; however, after further optimization, the
residence time could be reduced to 16 min with good selectivity and
good yield of the target product. A tube-in-tube reactor was investigated
for in-situ ethylene removal to favor ring-closing over cross-metathesis,
in this context. These results provide further evidence of the utility
of flow chemistry for organometallic processing and reaction telescoping.
Using the developed integrated batch and flow methods, a total of
7.75 g of goniothalamin (
1
) was synthesized.
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