Microbial and Enzymatic Processes for the Production of Biologically and Chemically Useful Compounds [New Synthetic Methods (69)]

In recent years, the most significant development in the field of synthetic organic chemistry has been the application of biological systems to chemical reactions. Reactions catalyzed by enzymes and enzyme systems display far greater specificities than more conventional organic reactions. Biological and/or enzymatic syntheses and transformations, that is, “microbial transformations,” have great potential. Some of these reactions have already been shown to have useful applications in the fields of synthetic organic chemistry and biotechnology. This article reviews the current status of the rapidly developing field of microbial transformation, the methodology, available technological procedures, and fields of application being described especially in relation to conventional organic synthesis methods.     

Microbial Asymmetric Catalysis—Enantioselective Reduction of Ketones [New Synthetic Methods (45)]

Microbial asymmetric reduction of ketones is a method widely used for the preparation of chiral alcohols. The present progress report deals with the basic concepts that govern enantioselectivity of enzymes and intact cells. Strategies to control the stereochemical course of microbial reductions of carbonyl compounds and the relationship of substrate structure to enantioselectivity are considered.     

New Reductive Transformations of Unsaturated Cyclic Hydrocarbons [New Synthetic Methods (66)]

The successive reduction of fully conjugated cyclic hydrocarbons leads to singly and multiply charged ions with unusual bonding. The charge distribution in these ions can be determined spectroscopically, and the information so obtained is then used in kinetically controlled trapping reactions for the regioselective introduction of electrophilic groups. When non-benzenoid substrates are used, syntheses become possible which can either not be carried out or can only be carried out with great difficulty in other ways. Examples of new preparative applications are cycloannelation and bridging reactions as well as polymerization reactions. The ion pair structure of the intermediate and the type of electrophile used are of paramount importance in controlling the mechanism of these reductive transformations.     

Gene Synthesis [New Synthetic Methods (77)]

Oligonucleotide synthesis, until a few years ago the rather exotic preserve of a few experts, has become an integral part of the arsenal of molecular-biological techniques. The last decade, in particular, has seen unbelievably rapid development in this area. DNA synthesis has been automated and can now produce genes greater than 1000 base pairs in length. Tailor-made synthetic genes also permit the synthesis of altered or even novel proteins (de novo protein design) by gene-technological methods. Together with modern methods of gene isolation, sequencing, and expression, gene synthesis has played a major part in the enormous advances achieved in gene technology.     

Reduction and Hydrogenation with the System Hydrocarbon/Carbon [New Synthetic Methods (70)]

For the synthesis of organic compounds, reduction is an indispensible reaction type which is also widely used on an industrial scale. In industrial processes hydrogen is usually used as reducing agent, since strong reducing agents like alkali metals and hydrides can only be used to a limited extent for safety and economic reasons. Very economical reducing agents that are convenient to handle and have high potential application are hydrocarbons in presence of carbon. Hydrocarbon/carbon systems can be readily used instead of molecular hydrogen and expensive metal catalysts for the hydrogenation of compounds containing, for example, CC-, CO-, or NO-double bonds. Furthermore, these systems can be used for carrying out reductions which hitherto required strong reducing agents such as zinc, tin, alkali metals and hydrides. Especially suitable as economic sources of hydrogen are refinery products such as vacuum gas oil, fuel oil S or vacuum residue oil. Hydrocarbons are dehydrogenated to unsaturated systems and finally to carbon.     

Enzymes as Catalysts in Synthetic Organic Chemistry [New Synthetic Methods (53)]

Enzymes have great potential as catalysts for use in synthetic organic chemistry. Applications of enzymes in synthesis have so far been limited to a relatively small number of largescale hydrolytic processes used in industry, and to a large number of small-scale syntheses of materials used in analytical procedures and in research. Changes in the technology for production of enzymes (in part attributable to improved methods from classical microbiology, and in part to the promise of genetic engineering) and for their stabilization and manipulation now make these catalysts practical for wider use in large-scale synthetic organic chemistry. This paper reviews the status of the rapidly developing field of enzyme-catalyzed organic synthesis, and outlines both present opportunities and probable future developments in this field.     

Carbene Complexes in Organic Synthesis [New Synthetic Methods (47)]

Transition metals are finding increasing use in organic synthesis on the borderline between “organic” and “inorganic” chemistry. Advantage is taken thereby of the fact that metal-induced CC bond formation often takes place with remarkable selectivity. The rapid development that has taken place in this area of chemistry is clearly demonstrated by the carbene complexes, examples of which are now known for almost all transition elements, and which have transformed from organometallic curiosities into synthetically useful reagents in less than two decades since the first studies of E. O. Fischer. They are not only suitable as carbene-transfer agents but also undergo interesting cycloadditions with other ligands in the co-ligand sphere. Their manipulation requires techniques no more complicated than those for Grignard reactions. Thus, carbene complexes can also be used in the synthesis of natural products such as vitamins or antibiotics.     

Directed Homogeneous Hydrogenation [New Synthetic Methods (65)]

Stereochemical control is a major concern in the application of homogeneous catalysis to organic chemistry. In this context, the directed hydrogenation of olefins employing cationic rhodium or iridium catalysts has considerable potential, for very high selectivity can be attained under mild reaction conditions. The only requirement is a polar functional group in proximity to the double-bond which remains bound to the metal during the catalytic cycle and thereby controls the Stereochemical course of hydrogen delivery through the constraints of chelation. The substituent is most frequently a hydroxy group OH but can also be an ester, amide or carbamate group; other groups remain to be scrutinized. In cyclic compounds, directed hydrogenation can lead to face-selectivity, and the polar substituent may be in the β-, γ-, or δ-position to the double-bond. Acyclic stereoselection ensues with β- or γ-substituents in appropriate compounds, and the configuration of reduced product is predictable on the basis of simple rules. The application of optically active rhodium complexes leads to useful kinetic resolution procedures.     

New Approaches to the Use of Amino Acids as Chiral Building Blocks in Organic Synthesis [New Synthetic Methods (85)]

α-Amino acids protected at nitrogen in quite different ways can be transformed without racemization into the corresponding α-amino aldehydes. Provided one chooses the right protecting groups (e.g., two benzyl residues on nitrogen) it is possible for the first time to carry out Grignard-like, aldol, and Me₃SiCN additions, and hetero-Diels–Alder reactions with a high degree of nonchelation control. If the reactions of classical carbanions turn out to be nonselective, transmetalation, for example into organotitanium reagents, constitutes an important tool in controlling stereoselectivity. Diastereoselectivity can be reversed by specific variation of the protecting group and reagent. “Protecting-group tuning”, “metal tuning”, and “ligand tuning” are very useful in reactions of α-amino aldimines as well. The α-amino aldehydes can also be converted by Wittig reactions into electron-poor γ-amino olefins, which in turn undergo stereoselective cuprate, Michael, and cycloadditions.     

Selective Reactions Using Organoaluminum Reagents [New Synthetic Methods (54)]

In addition to their high oxyphilicity, organoaluminum compounds are endowed with ambiphilic character. These properties can be successfully utilized in developing new synthetic reactions with unique selectivities. Especially noteworthy are the organoaluminum-promoted Beckmann rearrangement of oxime sulfonates, new syntheses of polyamino macrocycles via reductive cleavage of aminals and amidines by diisobutylaluminum hydride, the diastereoselective cleavage of chiral acetals by organoaluminum compounds leading to optically active secondary alcohols, allylic alcohols, and β-substituted carbonyl compounds, and biomimetic terpene syntheses. These and other examples, which illustrate the characteristics of organoaluminum chemistry, are used to demonstrate the distinct advantages of organoaluminum reagents in selective organic synthesis.     

The Stereoselectivity of Intermolecular Free Radical Reactions [New Synthetic Methods (78)]

The regio- and chemoselectivities of free radical reactions are often high and largely predictable; systematic studies have now shown that the stereoselectivity of free radical reactions can also be directed. Examples involving five- and six-membered cyclic radicals will be used to show how steric and stereoelectronic effects influence the diastereoselectivity of reactions of cyclic radicals with olefins. The temperature, the solvent, and the nature of the radical scavenger used also play a role, so that, if the correct reaction conditions are used, the stereoselectivity of reactions for cyclic reactants can be very high. Lower stereoselectivities are often observed for reactions between acyclic radicals and acyclic alkenes. However, preliminary experiments have indicated that under certain conditions such systems can also react in a stereoselective manner.     

Cobalt-Mediated [2 + 2 + 2]-Cycloadditions: A Maturing Synthetic Strategy [New Synthetic Methods (43)]

Dicarbonyl (η⁵-cyclopentadienyl)cobalt functions as a matrix on which a variety of unsaturated organic substrates undergo mutual bond formation. In this way α,ω-diynes cocyclize with monoalkynes to give annelated benzenes, while o-diethynylbenzenes furnish biphenylenes, and α,ω-enynes lead to the formation of complexed bi-and tricyclic dienes. Nitriles cocyclize with two alkynyl groups to give pyridines and other heterocycles, isocyanates allow access to annelated 2-pyridones, and incorporation of carbon monoxide provides complexed cyclopentadienones. In many cases remarkable chemo-, regio-, and stereoselectivity are observed, partially facilitated by use of the trimethylsilyl substituent as a controlling group. The scope and level of maturity of the method are demonstrated by the synthesis of a series of hitherto inaccessible, novel, and theoretically interesting molecules, and by its utilization in several unique approaches to a variety of natural products, e.g. protoberberines, steroids, vitamin B₆, and camptothecin.     

Cyclobutanones and Cyclobutenones in Nature and in Synthesis [New Synthetic Methods(71)]

The chemical reactivity of cyclobutanones and cyclobutenones is considerably different from that of cyclic ketones with larger rings; this is due to their ring strain of ca. 25 kcal/mol. Detailed knowledge regarding the influence of this ring strain on regio-, chemo- and stereoselective transformations of four-membered ring ketones is of particular importance. While several reactions, such as the Baeyer–Villiger reaction, the Beckmann and Favorskii rearrangements and cine-substitution often proceed in a manner specific to four-membered rings, other reactions such as the facile ring-opening by nucleophiles, the rearrangement to tropolones, the thermal [2+2]-cycloreversion, the isomerization to vinylketenes and the photochemical formation of oxacarbenes are rather specific to cyclobutanones and cyclobutenones. The remarkable selectivity and the excellent yields of such transformations, which are favored or caused by ring strain as the inherent driving force, offer the synthetic chemist fascinating possibilities for the development of new strategies for the synthesis of natural products and biologically active compounds.     

Organic Synthesis at High Temperatures. Gas-Phase Flow Thermolysis [New Synthetic Methods (57)]

The preference for carrying out synthetic organic reactions at the lowest possible temperature is due to the expectation that the selectivity often increases with decreasing temperature, as is confirmed by many examples and also theoretically justified. Selectivity, however, is not the only problem at high temperatures; further factors include the frequently limited thermal stability of the functional groups and structural elements not directly involved in the transformation. In spite of these limitations, the advantages of high temperatures and the greatly improved knowledge of the mechanisms of dynamic gas-phase processes accumulated in recent years can be exploited in directed organic synthesis. In this review the synthetic potential of gas-phase flow thermolysis will be described from the viewpoint of the synthetic chemist with the aid of typical examples of application.     

Cyclizations via Palladium-Catalyzed Allylic Alkylations [New Synthetic Methods (79)]

The history of ring systems in organic chemistry parallels their synthetic accessibility. Transition-metal-catalyzed cyclizations offer a new opportunity to create carbo- and heterocyclic compounds with great facility. Among these methods, allylic alkylations catalyzed by palladium have proven unusually productive because of the extraordinary chemo-, regio-, and diastereoselectivity and the continuing possibility for the development of enantioselectivity. The rules for ring closure differ from those for non-transition-metal-catalyzed reactions. A major benefit is the ability to generate medium (eight-, nine-, ten-, and eleven-membered) and large rings in preference to normal (five-, six- and seven-membered) rings. With the appropriate substrate, efficient macrocyclizations are possible under conditions of normal concentrations. A second major benefit derives from the complementary stereochemistry of the metalcatalyzed substitution (net retention of configuration) compared to non-metal-catalyzed reactions (inversion of configuration). Further, the requirement for the substrate to conform to the transition-metal template may impose a stereochemical preference in the intermediate that ultimately translates into the thermodynamically less stable organic product regardless of the stereochemistry of the starting material. While more work has focused on carbocyclic synthesis, the possibilities for heterocyclic synthesis are just beginning to be tapped. In addition to forming heterocycles by C? C bond formation, use of a heteroatom as a nucleophile has already proven effective for oxygen and nitrogen, with other nucleophiles awaiting investigation. New dimensions for cyclization via allylic alkylation arise by generating the requisite π-allylpalladium intermediates by methods other than palladium(0)-initiated allylic ionizations. In addition, metals other than palladium will clearly expand the possibilities, but as yet remain untapped.     

Carbohydrates as Chiral Auxiliaries in Stereoselective Synthesis. New Synthetic Methods (90)

Carbohydrates are inexpensive natural products in which numerous functional groups and stereogenic centers are combined in one molecule. By directed regio-and stereoselective formation of derivatives they can be converted into efficient chiral auxiliaries for controlling asymmetric syntheses. Stereoelectronic effects and pre-orientation of the reactive and shielding groups through formation of complexes can often be used for effective diastereofacial differentiation. In aldol reactions and alkylations on carbohydrate ester enolates intramolecular complexation promotes simultaneous elimination with formation of ketene. The steric, stereoelectronic, and coordinating properties of carbohydrate templates can also be used selectively to attain high levels of asymmetric induction in processes such as Diels–Alder reactions, hetero-Diels–Alder reactions, [2 + 2] cycloadditions, cyclopropanations, and Michael additions. It was possible with bicyclic, strongly stereodifferentiating carbohydrate auxiliaries to achieve a diastereoselective synthesis of carboxylic acid derivatives branched in the β position by a new 1,4-addition of alkylaluminum halides to α,β-unsaturated N-acylurethanes, in which methylaluminum halides and higher alkyl- or arylaluminum compounds behave mechanistically in a strikingly different manners. As complex ligands in chiral reagents and promoters, carbohydrates allow highly stereoselective reductions and aldol reactions that lead, amongst others, to chiral alcohols and β-hydroxy-α-amino acids in excellent enantiomeric excesses. Glycosylamines offer the possibility of versatile stereoselective applications: in the presence of Lewis acids the corresponding aldimines permit high-yielding syntheses of enantiomerically pure α-amino acids by Strecker and Ugi reactions, controlled by steric and stereoelectronic effects and by complex formation. They can be used with equal efficiency for asymmetric syntheses of chiral homoallylamines and for asymmetric Mannich syntheses of β-amino acids and chiral heterocycles, for example alkaloids.     

Mercury(II)- and Palladium(II)-Catalyzed [3,3]-Sigmatropic Rearrangements [New Synthetic Methods (46)]

Mercury(II) and palladium(II) salts have found broad applications as catalysts for [3,3]-sigmatropic rearrangements leading to formation of C? O, C? N, C? S, and C? C σ bonds. Increases in reaction rate are often very large (10¹⁰ – 10¹⁴ at 1 M catalyst concentration) and allow many previously difficult transformations to be conducted at or near room temperature, often with attendant increases in stereoselectivity and decreases in by-product formation. The mechanism of these catalyzed transformations is briefly discussed, and evidence is summarized to suggest that many follow a cyclization-induced rearrangement mechanism.     

Indirect Electroorganic Syntheses—A Modern Chapter of Organic Electrochemistry [New Synthetic Methods (59)]

The electrochemical formation and regeneration of redox agents for organic syntheses (indirect electrolysis) widens the potential of electrochemistry, as higher or totally different selectivities can often be obtained while at the same time the energy input can be lowered significantly. Higher current densities can also be obtained by preventing otherwise often encountered electrode inhibition. New types of redox catalysts can be formed in-situ and can be regenerated after reaction with the substrates. This principle is of increasing importance also for the application of already known redox agents with regard to environmental protection, since large amounts of a product can be generated in a closed circuit using only relatively small amounts of the redox reagent. Consequently the operation of such a process can be greatly simplified, and the release of ecologically objectionable spent reagents into the environment can be prevented. The broad spectrum of redox catalysts currently in use includes, inter alia, metal salts in very low or high oxidation states, halogens in various oxidation states, and, in particular, a wide variety of transition-metal complexes. A great deal of progress has recently been made in the application of organic electron transfer agents, since compounds have been found that are sufficiently stable in both the reduced as well as the oxidized state.     

Synthesis of Glycopeptides,Partial Structures of Biological Recognition Components [New Synthetic Methods (67)]

Glycopeptides are partial structures of the connecting regions of glycoproteins and, like these, always contain glycosidic bonds between the carbohydrate and peptide parts. Glycoproteins are not only widely distributed but are also decisive factors in post-translational biological selectivity, especially in biological recognition. Targeted syntheses of glycopeptides require stereoselective formation of the glycosidic bonds between the carbohydrate and the peptide parts and protective group methods that enable selective deblocking of only one functional group in these polyfunctional molecules. These heavy demands have been met by the well-established use of benzylic protective groups, which can be removed by hydrogenolysis, combined with the use of base-labile 2-phosphonioethoxycarbonyl (Peoc) or 9-fluorenylmethoxycarbonyl (Fmoc) protective groups or of bromoethyl esters, which can be removed under neutral conditions. The acidolysis of tert-butyloxycarbonyl (Boc) groups and of tert-butyl esters has also been successfully used, although, under acidic conditions, anomerization or rupture of the glycosidic bonds may occur, especially when nucleophiles are present. The stable, two-stage 2-(pyridyl)ethoxycarbonyl (Pyoc) protective groups allow a more reliable synthesis of complex glycopeptides since they can be removed, after modifications, under mild conditions. Particularly suitable for the synthesis of sensitive glycopeptides are the stable allyl protective groups. They can be removed from the complex glycopeptides in a highly selective and effective manner by means of noble-metal catalysts under practically neutral conditions. These methods have been employed to synthesize glycopeptides corresponding to partial structures of interesting glycoproteins. Deprotected glyopeptides representing tumor-associated antigen structures can be coupled to bovine serum albumin, which serves as a biological carrier molecule, without the necessity of using an artificial coupling component (spacer).     

Chelation or Non-Chelation Control in Addition Reactions of Chiral α- and β- Alkoxy Carbonyl Compounds [New Synthetic Methods (44)]

The addition of C-nucleophiles such as Grignard reagents or enolates to chiral α- or β-alkoxy aldehydes or ketones creates a new center of chirality and is therefore diastereogenic. In order to control stereoselectivity, two strategies have been developed: (1) Use of Lewisacidic reagents which form intermediate chelates, these being attacked stereoselectively from the less hindered side (chelation control); (2) use of reagents incapable of chelation, stereoselective attack being governed by electronic and/or steric factors (non-chelation control). Generally, the two methods lead to the opposite sense of diastereoselectivity. It is possible to predict the outcome by careful choice of organometallic reagents containing elements such as Li, Mg, B, Si, Sn, Cu, Zn, or Ti. For corrigendum see DOI: 10.1002/anie.198407461