Enantioselective Total Synthesis of (−)‐Doliculide Using Catalytic Asymmetric Hydrogenations

A concise and efficient strategy has been developed to construct a polyketide chain by employing relay asymmetric hydrogenations catalyzed by two chiral spiro iridium catalysts. By using this strategy, an enantioselective total synthesis of (?)‐doliculide has been achieved in 19 steps with 6.9 % overall yield. The route features high enantioselectivity and diastereoselectivity. The catalyst loading can be as low as 0.005 mol‐%. It is convenient to obtain natural polyketides and their analogues by this strategy.     

An Examination of the Scope and Stereochemistry of the Ireland–Claisen Rearrangement of Boron Ketene Acetals

The Ireland–Claisen rearrangement of boron ketene acetals is described. The boron ketene acetal intermediates are formed through a soft enolization that obviates the use of strong bases and the intermediacy of alkali metal enolates. Yields and diastereoselectivities of these rearrangements are very sensitive to the choice of boron reagent, even among those that have been shown to effect quantitative formation of boron ketene acetals from esters. The rearrangement occurs at room temperature for all substrates with generally high levels of stereoselectivity. In contrast to previous reports using boron triflates, the use of a commercially available boron iodide reagent allows for a wider substrate scope that extends to propionates and arylacetates, as well as the previously described α‐oxygenated esters. This work also provides insight into the dynamic nature of boron ketene acetals and the ramifications of this behavior for reactions in which they are intermediates.     

A Concise Total Synthesis of (+)‐Tetrabenazine and (+)‐α‐Dihydrotetrabenazine

Highly concise asymmetric total syntheses of (+)‐tetrabenazine ( 1 ), a drug for the treatment of chorea associated with Huntington’s disease, and of (+)‐α‐dihydrotetrabenazine ( 2 ), an active metabolite of 1 , have been accomplished. Our synthetic route features a trans‐selective enol etherification, followed by an unprecedented cation‐dependent aza‐Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)‐ 2 and eight steps (22 % overall yield) for (+)‐ 1 .     

Synthesis of Substituted Indenes from Isovanillin via Claisen Rearrangement and Ring‐Closing Metathesis

A new synthesis of substituted indenes was studied. Based on Claisen rearrangement, Wittig reaction and ring‐closing metathesis (RCM), a series of substituted indenes was synthesized from isovanillin in good yields.     

Synthesis of (−)‐Morphine: Application of Sequential Claisen/Claisen Rearrangement of an Allylic Vicinal Diol

A detailed exploration of the synthesis of (?)‐morphine based on sequential [3,3]‐sigmatropic rearrangements is described. The sequential Claisen/Claisen rearrangements of an allylic vicinal diol resulted in the stereoselective formation of the two contiguous carbon centers, including a sterically encumbered quaternary carbon, in a single operation. The two ethyl esters generated in this reaction were successfully differentiated during a subsequent Friedel–Crafts‐type cyclization. The (?)‐morphine double bond was introduced at a late stage in our first‐generation synthesis, but was formed at an earlier stage in the second‐generation synthesis, resulting in a more efficient route to the end product.     

The Mechanism of the Claisen Rearrangement: Déjà Vu All Over Again

The great baseball player Yogi Berra, who is quoted in the title, succinctly described what it meant to learn something that others had long ago appreciated. The mechanism by which the enzyme chorismate mutase accelerates the Claisen rearrangement of chorismic acid has for many years perplexed and intrigued chemists and biochemists. Yet classical effects of solvents and catalysts, which were largely ignored by the chemical community, not only provided important clues about the mechanism of the enzyme, but put the Claisen rearrangement in a new perspective. Whereas chorismic acid once seemed exceptional because it rearranged so rapidly under physiological conditions, it is now clear that even allyl vinyl ether rearranges at room temperature in aqueous solution. While the ability of the enzyme to accelerate the rearrangement of chorismate by a factor of 10⁶ was once considered extraordinary, catalysis by trivalent aluminum compounds matches, and in some cases exceeds, those rate enhancements. Therefore, it really should not be surprising to learn that Nature has independently evolved several structurally distinct solutions to the design of enzyme catalysts for the rearrangement of chorismic acid.     

A New Synthesis of Benzofurans from Phenols via Claisen Rearrangement and Ring‐Closing Metathesis

Based on Claisen rearrangement, the double bond isomerization of O‐allyl function together with the formation of O‐vinyl function in one pot, and ring‐closing metathesis (RCM), various phenols were transformed into various benzofurans in good yields.     

Optimization of the Microwave-Assisted Ortho Ester Claisen Rearrangement: Application to Monoterpenols

Two monoterpenols, perillyl alcohol and nerol, have been converted into their γ,δ-unsaturated ester derivatives following a modified process of microwave-assisted ortho ester Claisen rearrangement. The yields obtained (>90%) are better than those previously obtained. The optimized process needs less reaction time (5 min), smaller amount of reagent, and no solvent.     

Regioselectivity of the Claisen rearrangement in meta-allyloxy aryl ketones: an experimental and computational study, and application in the synthesis of (R)-(-)-pestalotheol D

A study of the regioselectivity of the Claisen rearrangement of meta-allyloxy aryl ketones showed that the electron-withdrawing carbonyl group has a major influence and strongly directs rearrangement to the more hindered ortho position. However, when the ketone is part of a ring structure, its electronic effect can be negated by conversion into its triisopropylsilyl enol ether, which dramatically reverses the regiochemistry of the Claisen rearrangement. DFT calculations suggest that the effect is electronic although there is also a steric effect of the bulky silyl group. This strategy for influencing the regiochemical outcome of the Claisen rearrangement was then employed in a short synthesis of the furo[2,3-g]chromene, (-)-pestalotheol D, that confirms the absolute stereochemistry of the natural product.     

Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen Rearrangement for the Synthesis of Chiral Allenes

The asymmetric propargyl Claisen rearrangement provides a convenient entry to chiral allene motifs. Herein, we describe the development of a kinetic resolution and asymmetric rearrangement of racemic propargyl vinyl ethers. This transformation afforded chiral allene products along with the enantiomerically enriched substrate in good yields with excellent diastereo‐ and enantioselectivity. The complete chirality transfer and facially selective rearrangement enabled the simultaneous construction of an axially chiral allenic unit and a quaternary carbon stereocenter.     

The Asymmetric Aza‐Claisen Rearrangement: Development of Widely Applicable Pentaphenylferrocenyl Palladacycle Catalysts

Systematic studies have been performed to develop highly efficient catalysts for the asymmetric aza‐Claisen rearrangement of trihaloacetimidates. Herein, we describe the stepwise development of these catalyst systems involving four different catalyst generations finally resulting in the development of a planar chiral pentaphenylferrocenyl oxazoline palladacycle. This complex is more reactive and has a broader substrate tolerance than all previously known catalyst systems for asymmetric aza‐Claisen rearrangements. Our investigations also reveal that subtle changes can have a big impact on the activity. With the enhanced catalyst activity, the asymmetric aza‐Claisen rearrangement has a very broad scope: the methodology not only allows the formation of highly enantioenriched primary allylic amines, but also secondary and tertiary amines; allylic amines with N‐substituted quaternary stereocenters are conveniently accessible as well. The reaction conditions tolerate many important functional groups, thus providing stereoselective access to valuable functionalized building blocks, for example, for the synthesis of unnatural amino acids. Our results suggest that face‐selective olefin coordination is the enantioselectivity‐determining step, which is almost exclusively controlled by the element of planar chirality.     

Cyclic 1,2‐Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (−)‐Terpestacin

We report a full account of our work towards the total synthesis of (?)‐terpestacin ( 1 ), a sesterterpene originally isolated from fungal strain Arthrinium sp. FA1744. Its promising anti‐HIV and anti‐cancer activity, as well as its novel structure, make terpestacin an attractive synthetic target. A strategy based on the unique reactivity of cyclic 1,2‐diketones (diosphenols) was developed and total synthesis of 1 was achieved in 20 steps, in the longest linear sequence, from commercially available 2‐hydroxy‐3‐methyl‐2‐cyclopenten‐1‐one. The key feature of our synthesis is the double usage of a “Pd AAA‐Claisen” protocol (AAA=asymmetric allylic alkylation), first in the early stages to generate the C1 quaternary center and then in the late stages to install the side chain. In addition, a rather unusual ene‐1,2‐dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. Several possible routes towards the total synthesis have been examined and carefully evaluated. During our exploration many interesting chemoselectivity issues have been addressed, such as a highly selective ring‐closing metathesis and a challenging oxidation of a disubstituted olefin in the presence of three trisubstiuted ones.     

Highly trans‐Selective Arylation of Achmatowicz Rearrangement Products by Reductive γ‐Deoxygenation and Heck–Matsuda Reaction: Asymmetric Total Synthesis of (−)‐Musellarins A–C and Their Analogues

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans‐2,6‐dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two‐step trans arylation of AR products to access 2,6‐trans‐dihydropyranones. This new trans‐arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier‐type and Tsuji–Trost‐type reactions, was finally enabled by an unprecedented, highly regioselective γ‐deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck–Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (?)‐musellarins A–C and 12 analogues in 11–12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three‐to‐six times greater potency than the musellarins as promising new leads.     

Cascade Claisen Rearrangement: Rapid Synthesis of Polysubstituted Salicylaldehydes and Total Syntheses of Hemigossypol and Gossypol

A cascade Claisen rearrangement of a well‐organized maltol propargyl ether for the construction of polysubstituted salicylaldehydes is reported. This reaction features high atom economy (100 %), as well as catalyst‐free and gram‐scale conditions. Based on this novel methodology, the total synthesis of hemigossypol, gossypol, and their analogues has been realized.     

Total Synthesis of (±)-Halomon by a Johnson–Claisen Rearrangement

The total synthesis of the polyhalogenated antitumour agent halomon ( 1 ) was accomplished with two novel transformations as key steps: a Johnson–Claisen rearrangement of a dichlorinated alkene for the preparation of the tertiary chlorinated C3 and a new rearrangement of bromohydrins for the regiospecific introduction of the bromine and chlorine atoms on C6 and C7, respectively.     

Aza‐Belluš‐Claisen Rearrangement‐Enabled Synthesis of Racemic Tapentadol and Its Stereoisomers

A concise synthesis of racemic Tapentadol and its stereoisomers was presented. The key step was a TiCl₄·THF₂‐catalzyed aza‐Belluš‐Claisen rearrangement to create two vicinal tertiary carbon stereogenic centers. The subsequent reduction of amide and hydrogenation of alkene delivered Tapentadol and its stereoisomers. The current approach offers a practical synthetic route to access this class of pharmaceutically significant molecules.