“…To our pleasant surprise we found that bromoketone 4d , contrary to the literature, can be subjected to a substitution reaction with amine 5 providing us with the so far unknown, but much sought-after, even mistakenly claimed 9 product ( 6a ), if one has the patience to allow the reaction to proceed at ambient temperature in toluene. The amine component ( 5 ) was already known and could easily be prepared .…”
Section: Resultsmentioning
confidence: 82%
“…As a second approach, ring D of the tetracyclic skeleton was formed by an intramolecular Dieckmann condensation of a diester, obtained in a modified Reformatsky reaction of a properly substituted derivative of 4c , followed by elimination of water . Neither of these methods, however, could be further elaborated to achieve (+)-lysergic acid. 2 Synthesis of 4-Bromo-Uhle's Ketone ( 4 g ) from 3 a a Reagents and conditions: (a) (1) powdered KOH + Piv-Cl, CH 2 Cl 2 + THF, (2) SOCl 2 , (3) AlCl 3 + ClCH 2 COCl, CH 2 Cl 2 (43%, overall); (b) ref (85%); (c) HO(CH 2 ) 2 OH, p -TSA, benzene, reflux, 6 h (81%); (d) MeNH 2 , CHCl 3 , 10−15 °C, 3−4 h (88%); (e) aq HCl (1 M), acetone, rt, 3 h (97%). …”
Section: Resultsmentioning
confidence: 99%
“… a Reagents and conditions: (a) (1) powdered KOH + Piv-Cl, CH 2 Cl 2 + THF, (2) SOCl 2 , (3) AlCl 3 + ClCH 2 COCl, CH 2 Cl 2 (43%, overall); (b) ref (85%); (c) HO(CH 2 ) 2 OH, p -TSA, benzene, reflux, 6 h (81%); (d) MeNH 2 , CHCl 3 , 10−15 °C, 3−4 h (88%); (e) aq HCl (1 M), acetone, rt, 3 h (97%). …”
The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Schöllkopf's method into the mixture of esters 2e and 2f. Upon hydrolysis the latter mixture afforded (+)-2a. The peptide part of alpha-ergocryptine (1) was prepared according to the Sandoz method; the stereoefficiency, however, has been significantly improved by applying a new resolution method and recycling the undesired enantiomer. Coupling the peptide part with lysergic acid afforded 1. Having synthetic (+)-7 in hand, we can claim the total synthesis of all the alkaloids which were prepared earlier from (+)-7 that had been obtained through degradation of natural lysergic acid.
“…To our pleasant surprise we found that bromoketone 4d , contrary to the literature, can be subjected to a substitution reaction with amine 5 providing us with the so far unknown, but much sought-after, even mistakenly claimed 9 product ( 6a ), if one has the patience to allow the reaction to proceed at ambient temperature in toluene. The amine component ( 5 ) was already known and could easily be prepared .…”
Section: Resultsmentioning
confidence: 82%
“…As a second approach, ring D of the tetracyclic skeleton was formed by an intramolecular Dieckmann condensation of a diester, obtained in a modified Reformatsky reaction of a properly substituted derivative of 4c , followed by elimination of water . Neither of these methods, however, could be further elaborated to achieve (+)-lysergic acid. 2 Synthesis of 4-Bromo-Uhle's Ketone ( 4 g ) from 3 a a Reagents and conditions: (a) (1) powdered KOH + Piv-Cl, CH 2 Cl 2 + THF, (2) SOCl 2 , (3) AlCl 3 + ClCH 2 COCl, CH 2 Cl 2 (43%, overall); (b) ref (85%); (c) HO(CH 2 ) 2 OH, p -TSA, benzene, reflux, 6 h (81%); (d) MeNH 2 , CHCl 3 , 10−15 °C, 3−4 h (88%); (e) aq HCl (1 M), acetone, rt, 3 h (97%). …”
Section: Resultsmentioning
confidence: 99%
“… a Reagents and conditions: (a) (1) powdered KOH + Piv-Cl, CH 2 Cl 2 + THF, (2) SOCl 2 , (3) AlCl 3 + ClCH 2 COCl, CH 2 Cl 2 (43%, overall); (b) ref (85%); (c) HO(CH 2 ) 2 OH, p -TSA, benzene, reflux, 6 h (81%); (d) MeNH 2 , CHCl 3 , 10−15 °C, 3−4 h (88%); (e) aq HCl (1 M), acetone, rt, 3 h (97%). …”
The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Schöllkopf's method into the mixture of esters 2e and 2f. Upon hydrolysis the latter mixture afforded (+)-2a. The peptide part of alpha-ergocryptine (1) was prepared according to the Sandoz method; the stereoefficiency, however, has been significantly improved by applying a new resolution method and recycling the undesired enantiomer. Coupling the peptide part with lysergic acid afforded 1. Having synthetic (+)-7 in hand, we can claim the total synthesis of all the alkaloids which were prepared earlier from (+)-7 that had been obtained through degradation of natural lysergic acid.
“…Considering the limitations of the previous approach and always using a Stobbe reaction as a key step, Szántay and co-workers attempted to construct the ring D of ergoline by employing an amide as a tethered nucleophile instead of a tertiary amine (Scheme 15). 32 In this case, N-pivaloyl-Uhle's ketone 55, obtained in three steps from indole-3-propanoic acid according to the method of Goto (Scheme 8), 21 was chosen as the starting material and treated with bromine in 1,4-dioxane/CCl 4 to yield 4-bromo-Uhle's ketone. According to observations by Bowman and co-workers, 33 direct bromine-amine exchange is possible only with a weak base, e.g.…”
Section: Short Review Synthesismentioning
confidence: 99%
“…Scheme 15 1999 Szántay and co-workers 32 attempts toward the synthesis of the tetracyclic ergoline core A third approach that Szántay and co-workers reported for the construction of the tetracyclic ergoline skeleton, always starting from N-pivaloyl-Uhle's ketone 55, employed an intramolecular Dieckmann condensation of diester 91 (Scheme 16). 34 In this case, the ketone of 55 was protected with ethylene glycol, and then the azide was reduced with H 2 in the presence of Pd/C to afford amine hydrochloride 88.…”
Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook
The Stobbe condensation is a strong base (e.g., NaOEt) promoted condensation between a ketone (or aldehyde) and a dialkyl ester of diacid (e.g., succinate) in an alcoholic solution to form a half ester of the substituted itaconate. It has been reported that the Stobbe condensation involving a ketone usually gives a higher yield and purer substituted itaconate, if potassium
t
‐butoxide or sodium hydride is used in a short reaction period rather than sodium ethoxide. The driving force for the Stobbe condensation is assumed to be the formation of a γ‐lactone. This reaction has wide application in organic synthesis especially for the preparation of estrone derivatives.
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