Asymmetric cyclobutane synthesis

The entire field of cyclobutane synthesis via ring enlargement of cyclopropylmethyl compounds is in continuous growth, and the development of asymmetric syntheses will undoubtly gain pace. 

Cyclobutane synthesis allows introduction of substituents on the cyclobutane ring in various patterns (Scheme 8.24) [55], Allyl bromide with boron trichloride and tri-ethylsilane yields the alkyldichloroborane 103, which is converted into pinacol (3-bro-mopropyl)boronate (104) and on to the cyano derivative 105 by standard methods. Transesterification of 105 and reaction with LiCHClj was used to make 100. However, 105 can be deprotonated and monoalkylated efficiently, and transesterification then yields 106. Transesterification with DICHED and asymmetric insertion of the CHCl group furnishes 107, which cyclizes to 108 or 109 with about the same 20 1 di-astereoselection as seen with the unsubstituted intermediate 100. The pattern of substitution shown by 111 was achieved via reaction of pinacol (bromomethyl)boronate (63) with lithioacetonitrile to form 110, which underwent chain extension and substitution in the usual manner. It was necessary to construct 110 in this way because substitution of a (p-haloalkyl)boronic acid is not possible. With R = H or CH3, substituents included Me, Bu, and OBn [55]. 

Strained molecules such as cyclopropanes and cyclobutanes have emerged as important intermediates in organic synthesis. We have already demonstrated here that cyclobutane derivatives can indeed serve as starting materials for the synthesis of natural as well as unnatural products. Unlike cyclopropanes, which can be prepared asymmetrically in a number of ways 175 -182>, the asymmetric synthesis of cyclobutane derivative has received less attention, and, to our best knowledge, very few reports were recorded recently 183). Obviously, the ready availability of chiral cyclobutane derivatives would greatly enhance their usefulness in the enantioselective synthesis of natural products. The overcome of this last hurdle would allow cyclobutane derivatives to play an even more important role in synthetic organic chemistry. 

Photodimerization of cinnamic acids and its derivatives generally proceeds with high efficiency in the crystal (176), but very inefficiently in fluid phases (177). This low efficiency in the latter phases is apparently due to the rapid deactivation of excited monomers in such phases. However, in systems in which pairs of molecules are constrained so that potentially reactive double bonds are close to one another, the reaction may proceed in reasonable yield even in fluid and disordered states. The major practical application has been for production of photoresists, that is, insoluble photoformed polymers used for image-transfer systems (printed circuits, lithography, etc.) (178). Another application, of more interest here, is the use that has been made of mono- and dicinnamates for asymmetric synthesis (179), in studies of molecular association (180), and in the mapping of the geometry of complex molecules in fluid phases (181). In all of these it is tacitly assumed that there is quasi-topochemical control in other words, that the stereochemistry of the cyclobutane dimer is related to the prereaction geometry of the monomers in the same way as for the solid-state processes. 

To allow fast orientation. Table 1 summarizes the most important methods for the synthesis and rearrangement of the cyclopropylmethyl compounds available today. The first column indicates the basic structure(s) to be rearranged, the second details the substituent(s), and the third gives information on the most general methods for the synthesis of the substrates. The fourth column specifies whether cyclobutanes, cyclobutenes and/or cyclobutanones may be obtained, and in the last column the section is given where the corresponding transformation is discussed. Asymmetric versions are indicated with an asterisk ( ). 

Keywords [2+2]photodimerization, absolute asymmetric synthesis, cyclobutane... 

Minami, T., Okada, Y., Nomura, R., Hirota, S., Nagahara, Y., Mid Fukuyama, K. Synthesis and resolution of a new type of chiral bisphosphine ligand, trans-bis-l,2-(diphenylphosphino)cyclobutane. and asymmetric hydrogenation using its rhodium complex, Chem. Lett. 1986, 613-616. 

Chiral crystals generated from non-chiral molecules have served as reactants for the performance of so-called absolute asymmetric synthesis. The chiral environments of such crystals exert asymmetric induction in photochemical, thermal and heterogeneous reactions [41]. Early reports on successful absolute asymmetric synthesis include the y-ray-induced isotactic polymerization of frans-frans-l,3-pentadiene in an all-frans perhydropheny-lene crystal by Farina et al. [42] and the gas-solid asymmetric bromination ofpjp -chmethyl chalcone, yielding the chiral dibromo compound, by Penzien and Schmidt [43]. These studies were followed by the 2n + 2n photodimerization reactions of non-chiral dienes, resulting in the formation of chiral cyclobutanes [44-48]. In recent years more than a dozen such syntheses have been reported. They include unimolecular di- r-methane rearrangements and the Nourish Type II photoreactions [49] of an achiral oxo- [50] and athio-amide [51] into optically active /Mactams, photo-isomerization of alkyl-cobalt complexes [52], asymmetric synthesis of two-component molecular crystals composed from achiral molecules [53] and, more recently, the conversion of non-chiral aldehydes into homochiral alcohols [54,55]. 

Asymmetric [2 + 2] cycloaddition reaction affords a practical means of synthesis of optically active cyclobutanes, which can be used as useful intermediates in organic synthesis [138]. Narasaka reported that asymmetric [2 -i- 2] cycloaddition between acryloyl oxazolidinone derivatives and bis(methylthio)ethylene proceeded with high enantios-electivity when catalyzed by TADDOL-derived titanium complex (Sch. 58) [139]. The cyclobutane product was transformed into carbocyclic oxetanocin analogs or (-n)-grand-isol [140]... 

Some thermally forbidden [2 + 2]-cycloaddition reactions can be promoted by Lewis acids1-6. With chirally modified Lewis acids, the opportunity for application in asymmetric synthesis of chiral cyclobutanes arises (for a detailed description of these methods see Sections D.l. 6.1.3.. D.l. 61.4. and references 7, 28-30). Thus, a chiral titanium reagent, generated in situ from dichloro(diisopropoxy)titanium and a chiral diol 3, derived from tartaric acid, catalyzes the [2 + 2]-cycloaddition reaction of 2-oxazolidinone derivatives of a,/ -unsalurated acids 1 and the ketene thioacetal 2 in the presence of molecular sieves 4 A with up to 96 % yield and 98% ee. Fumaric acid substrates give higher yields and enantiomeric excesses than acrylic acid derivatives8. Michael additions are almost completely suppressed under these reaction... 

As well as [2 + 2], [4 + 4] and [4 + 4 + 4] products, the cyclodimerization of conjugated dienes also yields [4 + 2] cycloadducts47Thus, butadiene gives 4-vinyleyelohexene, ci.v-1,2-divinyl-cyclobutane and 1,5-cyclooctadiene. The influence of the catalyst and reaction conditions on the product distribution has been carefully investigated50- 53. Efforts towards asymmetric induction have concentrated on the stereoselective synthesis of 4-vinylcyclohexene as the sole chiral product. 

Tethering the two reacting species (enone + alkene, carbonyl -t- alkene, arene -I- alkene, or alkene -I- alkene) often helps to facilitate the reaction and control the regiochemistry and the stereochemistry as well. There is still much room for the study of stereoselective cyclobutane and oxetane formation, especially in the area of asymmetric synthesis. 

Thus, traMi-3-alkyl-6-(phthalimido)cyclopentenes were prepared in excellent to modest yields from the corresponding tran -chloroalkene by the palladium coupling reaction [84d]. Inexpensive and efficient Pd-TMG systems, Pd(OAc)2-TMG or PdC -TMG, have been developed for the Heck reaction of an olefin with an aryl halide, in which TMG (1) acts as a ligand [84e]. In the reaction of iodobenzene with butyl acrylate the turnover numbers were up to 1000000. TMG (1) was used as a base for the palladium catalysed asymmetric Wagner-Meerwein shift of nonchiral vinylcyclopropane and cyclobutane derivatives leading to asymmetric synthesis of cyclobutanones, cyclopentenones, y-butyrolactones and 5-valerolactones [85] (Scheme 4.34). Replacement of TMG (1) with an inorganic bases such as lithium or cesium carbonate resulted in little effect. 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf andbis[(/ )-l-phenylethyl]amine as chiral amine, but only moderate enantioselectivities are reached (eq 68). A similar reaction sequence can also be carried out with TMSOTf and HMDS as base, with (—)-8-phenylmenthol as the chiral auxiliary however, the iodotrimethylsilane-HMDS system is more efficient in terms of yield and diastereoselectivity. The combination EtsN/TMSOTf (or some other trialkylsilyl triflates) has been used to accomplish an intramolecular Michael reaction, which was the key step for the synthesis of sesquiterpene (=E)-ricciocarpin A. ... 

The importance of asymmetric synthesis in organic technology was emphasized in Chapter 9. It is also possible to introduce chirality through a photochemical reaction by transferring it from a chiral auxiliary attached to the reacting molecule. If a bimolecular photoreaction is involved, the chiral auxiliary may be attached to any one of the reactants. Examples of such asymmetric induction are cyclobutanes, oxetanes, and cyclohexenes by [4 + 2] photocycloaddition (Pfoertner, 1990). 

Despite the number of reports of the asymmetric synthesis of tertiary a-aryl cyclohexanones, there have only been three reports which describe the asymmetric synthesis of tertiary a-aryl cyclopentanones. The first of these was reported by Shi via asymmetric epoxidation of benzylidene cyclobutanes and epoxide rearrangement in a subsequent step [76]. Backvall used a dynamic kinetic resolution of aUyhc alcohols-aUylic substitution-oxidative cleavage sequence to access 2-phenylcyclopentanone [77]. The first direct catalytic asymmetric synthesis of tertiary a-aryl ketones was recently described by Kingsbury using a series of Sc-catalysed diazoalkane-carbonyl homologations with bis/tris oxazohne ligands [78]. 

Asymmetric [2 + 2] Photocycloadditions. Intramolecular copper-catalyzed [2 + 2] photocycloaddition is a useful methodology for the preparation of bicyclic cyclobutanes and recent studies deal with its asymmetric version albeit with variable success. Diastereoselective reactions are achieved under the control of stereogenic centers incorporated in the dienic precursors. Both CuOTf and the more stable and easy to handle Cu(OTf)2 are suitable catalysts in this context. In the latter case, it is assumed that the copper(I) species is generated from Cu(OTf)2 under the photochemical conditions. A noteworthy example is the application of the CuOTf-catalyzed [2 + 2] photocycloaddition in the stereoselective total synthesis of the tricyclic sesquiterpene kel-soene (eq 128). ... 

Ring and open-chain derivatives of L-erythritol 1,4-dicinnamate have been irradiated yielding products of photochemical asymmetric synthesis, in which intramolecular 2-1-2 cycloaddition occurs to give L-erythritol esters of cyclobutane-1,2-dicarboxylic acid the 2,3-di-O-methyl derivative of l-erythritol gave a high degree of asymmetric induction, whereas the 2,3-0-isopropylidene derivative was much less stereospecific, and gave the opposite cyclobutane enantiomer. ... 

Sarkar N, Nayek A, Ghosh S (2004) Copper(l)-catalyzed intramolecular asymmetric [2+2] photocycloaddition. Synthesis of both enantiomers of cyclobutane derivatives. Org Lett 6 1903-1905... 

Parra, A., Reboredo, S., Aleman, J. (2012). Asymmetric Synthesis of Cyclobutanes by a Formal 2-1-2 Cycloaddition Controlled by Dienamine Catalysis. Angewandte Chemie -International Edition, 51, 9734-9736. 

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