Abstract
The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.
Highlights
We celebrated in a paper [1] the long-lasting presence on stage of the Pictet-Spengler (P-S) cyclization as one of the most direct, efficient, and variable synthetic method for the construction of important privileged pharmacophores, such as tetrahydroisoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic architectures embodying them
(2013–2014) Three renieramycin type anticancer alkaloids, jorunnamycins A and C, and jorumycin, were synthesized by a new convergent approach, which couples for a highly regio- and stereo-selective Pictet-Spengler reaction (P-S) cyclization tryptamine 87a and tetrahydroisoquinoline 88 to provide the intermediate 89a as a single isomer (Scheme 25, up) [97]
Other Pictet-Spengler Reactions in Cascade Sequences: Update (2011–2015) MolecuPles-S20c2y0,c2l5iz, 4a1t4ion attends in different manners to cascade reactions, providing framework4s0 otfh8a2t are mostly cSecnhteemreed5o1.nDTeHsigIQn aonrdTpHraBctCicemionttihfse.construction of THBC-fused bispirooxindoles. 41.-3b.3e.Ifn(noOz2rty0eth1lrt-h-1et)eratnTPradahischesitnyeepmttdr-rSaebopmvliieisnonolguqgesculoleuyifrnlacRotreilettiPeanrd-aceSthicdcoyoyendurcsriplvoiilzna-ia5ntCtiHgvioa-eonissnfcs1adac8droo3yelnolieScn[lte3uhmq,2dyu-ielcelad]cnmqacrusieencisanae:cdsoUtiel1oipn8snde1eaqcsatouen1ne8d(dn26cia0tetir1sohy1nril–naos2cu0t(ehSg1teca5hhl)mdethemehecehyfad5on2eri)sms[m13a80l2i]n[.4tvoo+gkie2vd]e cPy-cSlocaydcldizitaiotinonofabtteennzdysl ainzideiff1e8r4enatndmNan-pnreorstetcotecdaisncdadoeler1e8a5ct(iSocnhse,mpero5v3i)d[i1n8g0]f.rameworks that are mAosmtlyetcheondteorleodgyon(iTnHclIuQdionrgTHP-BSCrmeaocttiifosn. ) was applied in the stereodivergent synthesis of
Summary
We celebrated in a paper [1] the long-lasting presence on stage of the Pictet-Spengler (P-S) cyclization as one of the most direct, efficient, and variable synthetic method for the construction of important privileged pharmacophores, such as tetrahydroisoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic architectures embodying them. In a type B building example, the four diastereomers (1R,3R; 1S,3S; 1R,3S; 1S,3R) of the 1,3substituted THBC 59 were synthesized by a non-stereoselective P-S reaction to give the corresponding hydantoin derivatives 60a–d (four diastereomers for each substituent R) by tMreolaectumlees n20t20w, 2i5t,h41e4thyl-, butyl-, tert-butyl-, and allyl-isocyanate. (2012) The key intermediate 81, containing the THBC ring of mitragynine, paynantheine, and speciogynine (Scheme 22), was constructed via an enantioselective thiourea-catalyzed P-S cyclization involving the tryptamine derivative and the aldehyde [89]. (2013–2014) Three renieramycin type anticancer alkaloids, jorunnamycins A and C, and jorumycin, were synthesized by a new convergent approach, which couples for a highly regio- and stereo-selective P-S cyclization tryptamine 87a and tetrahydroisoquinoline 88 to provide the intermediate 89a as a single isomer (Scheme 25, up) [97]. IInntthheesseeccoonnddcecenntuturyryononstsatgaeg,et,htehPe-PS-cSycyliczlaitziaotniomnaminatianintasinits pitescpuelicaurlicahramchealmeoenleicoqnuicalqituya, lbituyt, tbourtetmoarienmaatitnheatlitmheelliigmhetlnigehetdns etoedjositnotjhoeinfotrhceesfowrcieths iwn-itfhasihni-ofnasahliloiens,aslluiecsh, assuctheassutphpeosrutpopf osrotliodf psholaisdesp,hthaesepsu, stheopf nueswh ocfatnaelywstcsa, atanldysmtsa, iannlydtmheaimnlpyutlhse oimf npeuwlsheaobfitnse, wsuchhabasitsth, esuccahscasdethseqcuaescnacdese asneqdutehnecmesualtnidcotmhepomnuelntitcroemacptioonnesn(tMreCaRctsi)o.ns (MCRs)
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