Hetero diastereoselective

Simple 1-hetero-substituted allyllithium derivatives, such as 1-alkoxy-94"96, 1-alkyl-thio-50,97, 1-phenylselenyl-54,98 show insufficient regio- and simple diastereoselectivity in their reaction with aldehydes. The rcgiosclectivity is greatly enhanced in favor of the a-products by in... 

Allylic titanates having an electrofugal leaving group, e.g., trimethylsilyl68 75 - 77, at the 3-position are powerful reagents for the highly stereoselective synthesis of 1-hetero-substituted 3-alkadienes. For the carbonyl addition of the appropriate titanated allyl sulfides ( ) or carbamates ( and ), reliable y-selectivity and anti diastereoselectivity are reported. The... 

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). 

A successful case study for asymmetric nitrogen oxidation was reported for a series of (hetero)aromatic tertiary amines. High diastereoselectivity was observed for the enzyme-mediated oxidation of S-(—)-nicotine by isolated CHMOAdneto to give the corresponding ds-N-oxide [215]. The stereoselectivity of this biooxidation was complementary to the product obtained by flavin M O (FM O) from human li ver (trows-selective [216]) as well as unspecific oxidations by FMOs from porcine and guinea pig liver. 

Scheme 2.168. Diastereoselective domino Knoevenagel/hetero-Diels-Alder reactior with chiral aliphatic aldehydes.

A regio- and diastereoselective Pd-catalyzed domino silastannylation/allyl addition of allenes 6/1-236 containing a carbonyl moiety with Bu3Sn-SiMe3 6/1-237 is described by Kang and coworkers [117]. The reaction allows the synthesis of hetero-and carbocyclic compounds with a ring size of five and six. It can be assumed that... 

A diastereoselective intramolecular hetero-Diels-Alder reaction of optically active 428 gave unstable 1,3,4,8,9,9a-hexahydropyrido[2,l-f][l,3]oxazin-l-one 429 (X = 0), and l,3,4,8,9,9a-hexahydropyrido[l,2-(z]pyrazin-l-one 429 (X = NTs) (Equation 80) <2003JA4970, 2004T10277>. In the case of pyrido[l,2- ]pyrazine, the reaction was carried out in the presence of 2,6-di- /-butyl-4-methylphenol. 

A general hetero-Diels-Alder cycloaddition of fulvenes with azadienes to furnish tetrahydro-[l]pyrindines has been described by Hong and coworkers (Scheme 6.241 see also Scheme 6.92) [424]. A solution of the azadiene and fulvene (1.2 equivalents) precursors in chlorobenzene was heated under open-vessel microwave irradiation for 30 min at 125 °C to provide the target compounds in excellent yields and with exclusive regio- and diastereoselectivity. Performing the reactions under conventional conditions or under microwave irradiation in different solvents provided significantly reduced yields. 

In Scheme 14 the effect of pressure on Diels-Alder reactions with acyclic heterodienophiles or heterodienes is presented. The application of high pressure leads also in these reactions to an enhancement of rates and improvement of yields. The hetero-Diels-Alder reaction (entry 3) is a good example of the interplay between pressure and temperature. At high pressure the rate of reaction as well as the diastereoselectivity are increased. The pressure-induced acceleration allows the temperature of reaction to be lowered, which leads to a further increase of diastereoselectivity. 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

The hetero-Diels-Alder reaction between a,p-unsaturatcd ketoesters and nucleophilic alkenes has been described in two concurrent and independent reports (220, 222). As with acylphosphonates, these proved to be excellent substrates for catalyst 269c. The reaction proceeds efficiently in THF at low temperatures providing the cycloadduct in >99% ee at -78°C. Indeed, the impressive selectivity exhibited under these conditions allows the reaction to be conducted at a convenient temperature of 0°C, using the hydrated catalyst 266c in the presence of molecular sieves, Eq. 181. Observed diastereoselectivities... 

Another example, in which the piperidine cycle is generated de novo, exploits a hetero Diels-Alder cycloaddition of 1 -/r-tolylsulfinyl-1,3-penta-diene 91 with benzylnitrosoformate, that generates an oxazine 92 with complete regioselectivity and 7i-facial diastereoselectivity.69 Osmilation of the double bond inserts stereoselectively two hydroxyl groups on the oxazine skeleton, protection and catalytic hydrogenation finally afforded the enantiomerically pure imino sugars 94 (Fig. 38). 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

Furthermore, Akiyama and coworkers applied phosphoric acid (/ )-3m (10 mol%, R = 9-anthryl) to the asymmetric inverse-electron-demand hetero-Diels-Alder reaction of A-2-hydroxyphenyl-protected aldimines 8 with vinyl ethers 99 (Scheme 38) [61], Tetrahydroquinolines 100 were obtained in good yields (59-95%), excellent yyn-diastereoselectivities (24 1-99 1), and high enantioselec-tivities (87-97% ee). 

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

Scheme 6.74 Typical N-Boc-protected syn-P-nitroamines obtained from the enantio- and diastereoselective aza-Henry (nitro-Mannich) reaction between N-Boc-protected (hetero) aromatic aldimines and nitroalkanes in the presence of biflinctional thiourea catalyst 12.

The precursor to (5) was made diastereoselectively by Fessner and coworkers [44]. When the intermediate ketose 1-phosphate was immediately submitted to hydrogenation conditions, l,5,6-trideoxy-l,5-imino-D-galactitol (1,6-dideoxygalactonojirimycin, 10) was obtained in fair yield [42]. The latter derivative was also obtained by a hetero Diels-Alder cycloaddition of a benzyloxycarbonyl nitroso dienophile to ( , )-sorbaldehyde dimethylacetal [45]. 

ZnCl2 was also used for a hetero-Diels-Alder reaction of 192 with Danishefsky diene. The dihydropyranone was obtained in 61% yield and good diastereoselectivity (Equation 59) <1998T14573>. 

The hetero-Diels-Alder reaction of homochiral camphor-derived thiabutadienes has given, for the first time, optically active bornene ring-fused dihydrothiopyrans with high diastereoselectivity (Scheme 53) <2000H(53)1685>. The exo endo- t2X o varied with the nature of substituent, varying from 91 9 (X = CH2, R = R = H) to 1 99 (X = CO,... 

A novel one-pot synthesis of various fused lactones has been achieved via a domino sequence of Knoevenagel/ hetero-Diels-Alder/elimination reactions of N- and 0-prenyl aryl aldehyde derivatives with Meldrum s acid in the presence of D- or L-proline with high diastereoselectivity (Scheme 68) <2005MI1353>. 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

A very interesting application of the above methodology is the synthesis of hetero-cycles60. Thus, substituted tetrahydrofurans 121-123 are obtained easily with perfect diastereoselectivities (equation 57)60a. 

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