Shengming Ma

Allenes in Catalytic Asymmetric Synthesis and Natural Product Syntheses

Allenes are the simplest class of cumulenes, with two contiguous C=C bonds, and show unique physical and chemical properties. These features make allenes particularly attractive in modern organic chemistry. In this Review, attention is paid to the advances made in catalytic asymmetric synthesis and natural product syntheses based on well-established reactions of allenes, such as propargylation, addition, cycloaddition, cycloisomerization, cyclization, etc., with or without catalysts. Their versatile reactivity, substituent-loading ability, axial to center chirality transfer, and controllable selectivity allow access to target molecules by unique and efficient approaches. The main topics in this Review are presented with selected examples from 2003 to 2011.

Electrophilic Addition and Cyclization Reactions of Allenes

Modern organic synthesis depends on the development of highly selective methods for the efficient construction of potentially useful target molecules. A primary goal in our laboratory is the discovery of new reactions that convert readily available starting materials to complex products with complete control of regio- and stereoselectivity. Allenes are one underused moiety in organic synthesis, because these groups are often thought to be highly reactive. However, many compounds containing the allene group, including natural products and pharmaceuticals, are fairly stable. The chemistry of allenes has been shown to have significant potential in organic synthesis. Electrophilic additions to allenes have often been considered to be synthetically less attractive due to the lack of efficient control of the regio- and stereoselectivity. However, this Account describes electrophilic reactions of allenes with defined regio- and stereoselectivity developed in our laboratory. Many substituted allenes are readily available from propargylic alcohols. Our work has involved an exploration of the reactions of these allenes with many different electrophiles: the E- or Z-halo- or seleno-hydroxylations of allenyl sulfoxides, sulfones, phosphine oxides, carboxylates, sulfides or selenides, butenolides, and arenes, and the halo- or selenolactonization reactions of allenoic acids and allenoates. These reactions have produced a host of new compounds such as stereodefined allylic alcohols, ethers, amides, thiiranes, and lactones. In all these reactions, water acts as a reactant and plays an important role in determining the reaction pathway and the stereoselectivity. The differing electronic properties of the two C=C bonds in these allenes determine the regioselectivity of these reactions. Through mechanistic studies of chirality transfer, isolation and reactivity of cyclic intermediates, (18)O-labeling, and substituent effects, we discovered that the E-stereoselectivity of some reactions results from the neighboring group participation of functional groups forming cyclic intermediates. We rationalize Z-stereoselectivity under other conditions by soft Lewis acid-base interactions and steric effects. These electrophilic reactions of allenes are efficient and useful methods for the synthesis of stereodefined alkenes and lactones, useful functionalities for synthesis.

Highly Selective Mild Stepwise Allylation of N-Methoxybenzamides with Allenes

An efficient Rh(III)-catalyzed stepwise ortho allylation of N-methoxybenzamides 1 with polysubstituted allenes is reported. This C-H functionalization involving allenes is conducted under very mild conditions (-20 °C or room temperature) and compatible with ambient air and moisture, and it can be applied to terminal or internal allenes with different synthetically attractive functional groups. Highly efficient axial chirality transfer has been realized, yielding optically active lactones.

Palladium-Catalyzed Cyclization Reactions of Allenes in the Presence of Unsaturated Carbon–Carbon Bonds

Modern synthetic chemists have looked for rapid and efficient ways to construct complex molecules while minimizing synthetic manipulation and maximizing atom-economy. Over the last few decades, researchers have made considerable progress toward these goals by taking full advantage of transition metal catalysis and the diverse reactivities of allenes, functional groups which include two cumulative carbon-carbon double bonds. This Account describes our efforts toward the development of Pd-catalyzed cyclization reactions of allenes in the presence of compounds that contain unsaturated carbon-carbon bonds such as alkenyl halides, simple alkenes, allenes, electron-deficient alkynes, or propargylic carbonates. First, we discuss the coupling-cyclization reactions of allenes bearing a nucleophilic functionality in the presence of alkenyl halides, simple alkenes, functionalized and nonfunctionalized allenes, or electron-deficient alkynes. These processes generally involve a Pd(II)-catalyzed sequence: cyclic nucleopalladation, insertion or nucleopalladation, and β-elimination, reductive elimination, cyclic allylation or protonation. We then focus on Pd(0)-catalyzed cyclization reactions of allenes in the presence of propargylic carbonates. In these transformations, oxidative addition of propargylic carbonates with Pd(0) affords allenylpalladium(II) species, which then react with allenes via insertion or nucleopalladation. These transformations provide easy access to a variety of synthetically versatile monocyclic, dumbbell-type bicyclic, and fused multicyclic compounds. We have also prepared a series of highly enantioenriched products using an axial-to-central chirality transfer strategy. A range of allenes are now readily available, including optically active ones with central and/or axial chirality. Expansion of these reactions to include other types of functionalized allenes, such as allenyl thiols, allenyl hydroxyl amines, and other structures with differing steric and electronic character, could allow access to cyclic skeletons that previously were difficult to prepare. We anticipate that other studies will continue to explore this promising area of synthetic organic chemistry.

Enantioselective halocyclization reactions for the synthesis of chiral cyclic compounds.

Nowadays it is relatively easy to develop a transition-metalcatalyzed enantioselective reaction owing to the wide availability of chiral ligands able to smoothly coordinate with metals to afford a variety of chiral catalysts. Although diastereoselective electrophilic cyclizations with chiral electrophilic selenium reagents have been realized with excellent diastereoselectivities in many cases, the enantioselective cyclization of nonchiral unsaturated substrates with nonchiral electrophiles is challenging, as it is difficult to install the required chirality. Thus, in addition to the metal-mediated approach, conceptually new chiral reagents have to be developed that can interact with electrophiles to induce asymmetry before the background racemic reaction occurs. In this Highlight, we comment on recent advances in this area. In 1992, Taguchi and co-workers reported a desymmetrizing enantioselective iodolactonization reaction of 2-allyl-2hydroxy-4-pentenoic acid (2) with I2 in the presence of 1 equivalent of a titanium complex generated from (Me,Ph)taddol (1) and Ti(OiPr)4 to afford the corresponding g-lactone cis-3 with 65 % ee (Scheme 1). Interestingly, the iodocarbocyclization of dibenzyl 2-(4-pentenyl)malonate (5) with I2, CuO, and the chiral titanium taddolate 4 (1.0 equiv) produced 6 in 96% yield with 85 % ee. When 2,6-dimethoxypyridine (DMP) was used instead of CuO as the base, the reaction could even be carried out in CH2Cl2/THF (4:1) with a catalytic amount of the chiral titanium taddolate 4 (20– 30 mol%) to give 8, which upon heating afforded bicyclic lactones 9 with 96–99% ee! The high enantioselectivity of this reaction may be attributed to the strong coordination between the chiral titanium taddolate 4 and the malonate moiety in the substrates. Later, Kang and co-workers developed a catalytic enantioselective iodoetherification to form tetrahydrofurans 12 with up to 90 % ee by using the combination of the chiral salen–Co complex 10 a (0.3 equiv) and N-chlorosuccinimide (NCS; 0.75 equiv; Scheme 2). With the salen–Cr complex 10b, 7 mol % of the catalyst was enough for enantioselective iodocyclization with up to 93 % ee. It is thought that NCS first reacts with the iodide anion to release ICl slowly, which is crucial for minimization of the background reaction, and that the intermediate 13 generated from ICl and the salen–metal catalyst 10 determines the enantioselectivity. When 10 a was used as the catalyst, I2 was added first, and then the substrate was added over 8 h with a syringe pump; when 10b was used as the catalyst, the substrate was added first, and then the I2 was added in one portion. [5b]

Enantioselective Double Manipulation of Tetrahydroisoquinolines with Terminal Alkynes and Aldehydes under Copper(I) Catalysis

Tetrahydroisoquinoline alkaloids with a C1 stereogenic center are a common unit in many natural and non-natural compounds of biological importance. Herein we describe a novel Cu(I) -catalyzed highly chemo- and enantioselective synthesis of chiral tetrahydroisoquinoline-alkaloid derivatives from readily available unsubstituted tetrahydroisoquinolines, aldehydes, and terminal alkynes in the presence of the ligand (R,R)-N-pinap. This synthetic operation installs two substituents in the 1- and 2-positions.

Room-Temperature Synthesis of Trisubstituted Allenylsilanes via Regioselective C–H Functionalization

A Rh(III)-catalyzed o-C-H bond functionalization-based allenylation reaction of allenylsilanes 2 with N-methoxybenzamides 1 affords poly-substituted allenylsilanes with a wide range of attractive functional groups in moderate to excellent yields under very mild conditions (20 °C, compatible with ambient air and moisture). Those products may be transformed to different products with attractive structural features. Careful mechanistic studies suggest the reaction proceeds via o-rhodation, regioselective insertion, and β-H elimination.

Catalytic Asymmetric Synthesis of Optically Active Allenes from Terminal Alkynes

CuBr and ZnI(2) have been developed as catalysts or subcatalysts for the efficient asymmetric synthesis of axially chiral allenols with up to 97% ee from readily available propargylic alcohols, aliphatic or aromatic aldehyde, pyrrolidine, and commerically available ligands. The alcohol unit in the terminal alkynes plays a very important role for ensuring high enantioselectivity via coordination.

An efficient synthesis of carbazoles from PtCl2-catalyzed cyclization of 1-(indol-2-yl)-2,3-allenols

The PtCl(2)-catalyzed reaction of 1-(indol-2-yl)-2,3-allenols occurred smoothly to form carbazoles by connecting the 3-carbon atom of indole with the 4-carbon atom of the allenol moiety, referring to the carbon atom connected to the hydroxyl group.

Conquering three-carbon axial chirality of allenes

While one-carbon central chirality of organic molecules has been recognized and extensively studied for more than a century, far less attention has been paid to three-carbon axial chirality of allenes, although they exist in nature with interesting biological activity and have been demonstrated with great synthetic potentials. However, remarkable progress has been made in this field in recent years, giving rise to axially chiral allenes with a wide range of functionalities with practical enantioselectivity. This review provides a concise account of enantioselective syntheses of axially chiral allenes with a selection of published protocols.