Diastereoselectivity cycloadditions

There is no doubt that the field of asymmetric induction occupies a very important place in modem synthetic methodology. Elegant protocols designed to cany out dipolar cycloadditions have been developed and important advances in the theoretical description of these processes have taken place as a consequence (vide infra) Diastereoselective cycloadditions have been carried out between optically active nitrile oxides, nitrones,azomethine ylides and achiral dipolarophiles, and between optically active dipolarophiles and achiral nitrile oxides and achiral nitrones. The products have b n put to good use, either by translating the cycloaddition diastereoselectivity to the construction of useful optically active acyclic intermediates, or in Ae total synthesis of natural products (vide infra) ... 

The configurational matrix reveals that the absolute configuration at C(14) in D, due to an auxiliary s help is responsible for the diastereoselective generation of the stereogenic center C(13) in the Michael adduct AD, whilst the [4+2]-cycloaddition diastereoselectively takes care of stereogenic centers C(8) and C(9). 

Dramatic rate accelerations of [4 + 2]cycloadditions were observed in an inert, extremely polar solvent, namely in5 M solutions oflithium perchlorate in diethyl ether(s 532 g LiC104 per litre ). Diels-Alder additions requiring several days, 10—20 kbar of pressure, and/ or elevated temperatures in apolar solvents are achieved in high yields in some hours at ambient pressure and temperature in this solvent (P.A. Grieco, 1990). Also several other reactions, e.g, allylic rearrangements and Michael additions, can be drastically accelerated by this magic solvent. The diastereoselectivities of the reactions in apolar solvents and in LiClO EtjO are often different or even complementary and become thus steerable. 

Methacrylates have also found use in diastereoselective -ene reactions. Although not a cycloaddition reaction, this reaction is mechanistically related to the Diels-Alder reaction (37). 

The validity of the model was demonstrated by reacting 35 under the same reaction conditions as expected, only one diastereoisomer 41 was formed, the structure of which was confirmed by X-ray analysis. When the vinylation was carried out on the isothiazolinone 42 followed by oxidation to 40, the dimeric compound 43 was obtained, showing that the endo-anti transition state is the preferred one. To confirm the result, the vinyl derivative 42 was oxidized and the intermediate 40 trapped in situ with N-phenylmaleimide. The reaction appeared to be completely diastereoselective and a single diastereomer endo-anti 44 was obtained. In addition, calculations modelling the reactivity of the dienes indicated that the stereochemistry of the cycloaddition may be altered by variation of the reaction solvent. 

Using dioxolane as a substituent in the 1,3-dipolar cycloaddition of diazomethane with olefinic double bonds, it was found that the bulky dioxolane ring plays a major role in the diastereoselection [OOJOC388]. 

Danishefsky et al. were probably the first to observe that lanthanide complexes can catalyze the cycloaddition reaction of aldehydes with activated dienes [24]. The reaction of benzaldehyde la with activated conjugated dienes such as 2d was found to be catalyzed by Eu(hfc)3 16 giving up to 58% ee (Scheme 4.16). The ee of the cycloaddition products for other substrates was in the range 20-40% with 1 mol% loading of 16. Catalyst 16 has also been used for diastereoselective cycloaddition reactions using chiral 0-menthoxy-activated dienes derived from (-)-menthol, giving up to 84% de [24b,c] it has also been used for the synthesis of optically pure saccharides. 

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

Danishefsky s diene 154 DBFOX 232 dendrimers 229 DPT calculations 308 diacetone glucose derived-titanium(IV) 178 diastereoselectivity 216 diazo compounds 242 diazoalkane cycloadditions 278 diazoalkanes 213, 231 (R,R)-4,6-dibenzofurandiyl-2,2 -bis(4-phenylox-azoline) 250... 

There has been some investigation of auxiliary-controlled cycloadditions of azir-ines. Thus, camphor-derived azirine esters undergo cycloaddition with dienes, with poor diastereoselectivity [70]. The same azirines were also observed to react unselectively with phenylmagnesium bromide. Better selectivities were obtained when Lewis acids were used in the corresponding cycloaddition reactions of 8-phe-nylmenthyl esters of azirine 2-carboxylates (Scheme 4.48) [71]. The same report also describes the use of asymmetric Lewis acids in similar cycloadditions, but mediocre ees were observed. 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

The enantiomerically pure, doubly activated a, /j-olefinic sulfoxides 46-5095 98 undergo highly diastereoselective Diels-Alder cycloadditions with cyclopentadiene, and pyridyl vinylic sulfoxide 5199 reacts diastereoselectively with furan. It is noteworthy that olefins singly-activated by only a sulfinyl group are not effective partners in Diels-Alder cycloadditions, as we have found after many attempts and as has been reported recently98. 

Racemic pyrone sulfoxide 52 undergoes a diastereoselective inverse-electron-demand 2 + 4-cycloaddition with 1,1-dimethoxyethylene to afford adduct 53 in > 95% yield (equation 49)100 this is the first example of an asymmetric Diels-Alder cycloaddition using a sulfinyldiene as an electron-deficient enophile101. 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

Another example of a [2s+2sh-1c+1co] cycloaddition reaction was observed by Barluenga et al. in the sequential coupling reaction of a Fischer carbene complex, a ketone enolate and allylmagnesium bromide [120]. This reaction produces cyclopentanol derivatives in a [2S+2SH-1C] cycloaddition process when -substituted lithium enolates are used (see Sect. 3.1). However, the analogous reaction with /J-unsubstituted lithium enolates leads to the diastereoselective synthesis of 1,3,3,5-tetrasubstituted cyclohexane- 1,4-diols. The ring skeleton of these compounds combines the carbene ligand, the enolate framework, two carbons of the allyl unit and a carbonyl ligand. Overall, the process can be considered as a for-... 

The cycloaddition between norbornadiene (23 in Scheme 1.12) and maleic anhydride was the first example of a /mmo-Diels-Alder reaction [55]. Other venerable examples are reported in Scheme 1.12 [56]. Under thermal conditions, the reaction is generally poorly diastereoselective and occurs in low yield, and therefore several research groups have studied the utility of transition metal catalysts [57]. Tautens and coworkers [57c] investigated the cycloaddition of norbornadiene and some of its monosubstituted derivatives with electron-deficient dienophiles in the presence of nickel-cyclo-octadiene Ni(COD)2 and PPhs. Some results are illustrated in Tables 1.4 and 1.5. 

The cycloadditions of the C-2 vinyl glicals with maleic anhydride are an interesting example of facial stereocontrol. The allylic methoxy group in dienes 55a and 55b exerts an nnh -stereodirecting effect as shown by the stereochemistry of the endo-cycloadducts 56 and 57 obtained as the sole products from 55a and 55b, respectively, and by the fact that 55c produces [51] a mixture of the diastereoisomers 56c and 57c (Scheme 2.22). When linear acetylenic dienophiles were used, the degree of facial diastereoselectivity decreased, which indicates its dependence on steric effects. 

Trienone 124 underwent intramolecular cycloaddition affording hydrobenzo-suberone 125. Thermal reaction was poorly diastereoselective (62 38 cis trans stereoisomers). When the cycloaddition was carried out in the presence of LiBF4, trienone 124 was converted into cA-adduct 125 quantitatively and stereo selectively [118] (Equation 2.35). 

A sequence of two thermal intramolecular cycloadditions has been used to develop a short synthetic approach to tetrahydrothiopyrans [122], The multiple process includes an m m-hetero- and an intramolecular-carbon Diels-Alder reaction. An intramolecular /zctcro-Diels-Alder reaction of divinyl-thioketone 134 afforded a 9 1 mixture of cycloadducts 135 and 136 which then underwent a second intramolecular cycloaddition which syn o H-2)-exo-diastereoselectively led to hexacyclic tetrahydrothiopyrans 137 and 138, respectively (Scheme 2.51). 

Tetraene 141 has been converted into various complex polycondensed adducts by reacting with a variety of dienophiles such as maleic anhydride, N-phenylmaleimide, N-phenyltriazolinedione,p-benzoquinone and tetracyano-ethylene carried out under thermal conditions. All cycloadditions occurred facial-diastereoselectively from an outside attack and provided monocycloadducts which had an exceptionally close relationship between diene and dieno-phile and then underwent intramolecular cycloaddition [125]. The reaction between 141 and p-benzoquinone is illustrated in Scheme 2.53. 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

It is believed that clay minerals promote organic reactions via an acid catalysis [2a]. They are often activated by doping with transition metals to enrich the number of Lewis-acid sites by cationic exchange [4]. Alternative radical pathways have also been proposed [5] in agreement with the observation that clay-catalyzed Diels-Alder reactions are accelerated in the presence of radical sources [6], Montmorillonite K-10 doped with Fe(III) efficiently catalyzes the Diels-Alder reaction of cyclopentadiene (1) with methyl vinyl ketone at room temperature [7] (Table 4.1). In water the diastereoselectivity is higher than in organic media in the absence of clay the cycloaddition proceeds at a much slower rate. 

Oxazoborolidinone 8 is an example of catalyst supported on silica gel. It is prepared by immobilizing the N-tosyl-0-allyl-(S)-tyrosine with mercaptopropyl silica and treatment with BF3 and has been used to catalyze the Diels-Alder reaction of methacrolein with cyclopentadiene [17] (Equation 4.2). The cycloaddition occurs with good diastereoselectivity but with low enantioselec-tivity. 

---