A Versatile and Stereoselective Synthesis of Functionalized Cyclobutenes

Frébault, Frédéric; Luparia, Marco; Oliveira, Maria Teresa; Goddard, Richard; Maulide, Nuno

doi:10.1002/anie.201000911

Cited by 77 publications

(26 citation statements)

References 65 publications

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“…This was resolved by decreasing the reaction temperature from 50°C to 10°C, however, a conversion decrease of 2.3% per hour was still observed. Despite this, the continuous flow setup achieved a productivity of 144 mg/h (~3.5 g/day) over an 8-h run, significantly higher than previously reported batch reactions (14-21 mg/ h, 336-504 mg/day) [41]. Photochemically induced cyclisation reactions have been applied to the synthesis of a range of natural product derivatives.…”

Section: Laboratory Scale (< 100 G/day)mentioning

confidence: 86%

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Scalability of photochemical reactions in continuous flow mode

2021

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Continuous flow photochemistry as a field has witnessed an increasing popularity over the last decade in both academia and industry. Key drivers for this development are safety, practicality as well as the ability to rapidly access complex chemical structures. Continuous flow reactors, whether home-built or from commercial suppliers, additionally allow for creating valuable target compounds in a reproducible and automatable manner. Recent years have furthermore seen the advent of new energy efficient LED lamps that in combination with innovative reactor designs provide a powerful means to increasing both the practicality and productivity of modern photochemical flow reactors. In this review article we wish to highlight key achievements pertaining to the scalability of such continuous photochemical processes. Graphical abstract

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Section: Laboratory Scale (< 100 G/day)mentioning

confidence: 86%

“…One such example is the photo-electrocyclization of 2-pyrone derivatives which was first reported by Corey in 1964 [37]. The resulting cyclobutene lactone product 8 is a synthetically versatile chemical building block due to its high ring strain [38][39][40][41]. Recently, the Kappe group investigated the applicability of…”

Section: Laboratory Scale (< 100 G/day)mentioning

confidence: 99%

Scalability of photochemical reactions in continuous flow mode

2021

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“…4 They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereo-defined 1,3-dienes and ligands for catalytic asymmetric synthesis. 5 Even though direct synthesis of suitably functionalized cyclobutane precursors from readily available starting materials has been the subject of a burgeoning area of research, 6 there is considerable room for improvement with respect to diversity of functional groups on the ring and stereoselectivity associated with the ring formation. In this regard, a class of compounds with enormous potential for diversification are the chiral 3-substituted cyclobutenes (Figure 1, B), which allow further modification of the small ring through a myriad of ways involving the double bond, 7 the G group, 8 or through activation of the ring C-H bonds.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives

2019

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Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available precursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis and eventually manufacture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural products and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereo-defined 1,3-dienes and ligands for catalytic asymmetric synthesis. The simplest approach to make cyclobutenes is through an enantioselective [2+2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here we disclose a broadly applicable enantioselective [2+2]cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earthabundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for synthesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including a key role of a cationic Co(I)-intermediate, ligand and counter ion effects on the reactions, can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.

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“…Given the fact that boron-containing functional groups can be readily transformed into many other functional groups, [27] the introduction of ab oryl group using B 2 pin 2 was explored (Scheme7b). To our surprise, Pd-catalyzedr eaction of 1a with B 2 pin 2 in THF afforded silacyclobutene 8,b earing ah ighly strained four-membered ring, [28] as the major product (71 % yield), together with 16 %y ield of alkenylboron compound 9. The insertion of the pending olefin into the vinyl-Pd bond (cf.…”

Section: Resultsmentioning

confidence: 99%

An Efficient Approach to Regio‐ and Stereodefined Fully‐Substituted Alkenylsilanes by Pd‐Catalyzed Allenic C(sp³)−H Oxidation

Zhu

Bäckvall

2019

Chemistry A European J

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A highly efficient palladium‐catalyzed functionalization of allenylsilanes to give regio‐ and stereodefined fully‐substituted alkenylsilanes has been developed. This oxidative coupling reaction showed good functional group compatibility with exclusive regio‐ and stereoselectivity. The pending olefin on the silyl group was shown to be an indispensable element for the initial allenic C(sp3)−H bond cleavage, and performs as the directing group to control the overall selectivity. The addition of substoichiometric amounts of Et3N was found to increase the reaction rate leading to a higher reaction yield. The reaction can be easily scaled up and applied for the late‐stage functionalization of natural products and pharmaceutical compounds, including amino acids and steroid derivatives. The newly introduced functional groups include aryl, alkynyl, and boryl groups. The highly strained four‐membered ring, silacyclobutene was obtained when B2pin2 was employed as the coupling partner. Mechanistic studies, including kinetic isotope effects, showed that the allenic C(sp3)−H bond cleavage is the rate‐limiting step.

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A Versatile and Stereoselective Synthesis of Functionalized Cyclobutenes

Cited by 77 publications

References 65 publications

Scalability of photochemical reactions in continuous flow mode

Scalability of photochemical reactions in continuous flow mode

Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives

An Efficient Approach to Regio‐ and Stereodefined Fully‐Substituted Alkenylsilanes by Pd‐Catalyzed Allenic C(sp³)−H Oxidation

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A Versatile and Stereoselective Synthesis of Functionalized Cyclobutenes

Cited by 77 publications

References 65 publications

Scalability of photochemical reactions in continuous flow mode

Scalability of photochemical reactions in continuous flow mode

Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives

An Efficient Approach to Regio‐ and Stereodefined Fully‐Substituted Alkenylsilanes by Pd‐Catalyzed Allenic C(sp3)−H Oxidation

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An Efficient Approach to Regio‐ and Stereodefined Fully‐Substituted Alkenylsilanes by Pd‐Catalyzed Allenic C(sp³)−H Oxidation