Addition-cyclization, diastereoselective

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Reductive coupling of acrylates 521 and imines in the presence of iridium provides azetidin-2-ones bearing aromatic, alkenyl, and alkynyl side chains, with high diastereoselection (Equation 213) <2002OL2537>. The reaction has been proposed to occur through a reductive Mannich addition-cyclization mechanism. 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

Keck and Wagner used a diastereoselective thiyl radical addition/cyclization sequence to generate the key compound 157 for a total synthesis of ewMycoricine 158 (Scheme 2.28). In this sequence, photogenerated PhS undergo exclusive addition at the p-site of the C = C triple bond in the starting alkyne 156 to produce the resonance-stabilized vinyl radical 159 (interestingly, with BusSn, ... 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

The reaction of enantiopure cycUc nitrone 69 with alk5mylzinc reagents led to a tandem addition/cyclization process affording 2,3-dihydroisoxazole derivatives 72 in high yields and with complete diastereoselectivity <05EJO2694>. 

We further explored the steric effect of this Michael addition-cyclization reaction sequence. A series of secondary amines 13a-f were prepared and subjected to the Michael addition and acid-induced cyclization (Scheme 6) [12]. The results are summarized in Table 2. In general, we found that the secondary amines were less reactive in this Michael addition-cyclization reaction sequence. The p-toluene acetylenic sulfoxide la was not reactive enough and only the stronger electron-withdrawing o-nitrophenyl acetylenic sulfoxide 1 b achieved the transformation. In contrast to the primary amine approach, the secondary amine approach resulted in a reversed diastereoselectivity bias with compounds 14 as the major isolated products (except 13e). In general, a lower reaction temperature and increase in the steric hindrance of the secondary amine improved the diastereoselectivity. Exceptionally good diastereoselectivity was observed for the cyclization of 13 f (Scheme 6) (Table 2)... 

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

The radical addition cyclization which occurs on 350 nm irradiation of mixed acetonitrile solutions of A, A -dimethylaniline and menthyloxyfuranone (41) is reported to be diastereoselective and is initiated by photoinduced electron transfer from the amine to the semiconductors Ti02, Sn02, ZnS or SiC. The major and minor adducts are proposed to be formed by the route outlined in Scheme 3 and are accompanied by products derived from the radical produced on partial reduction of (41). 

A chiral menthol auxiliary has been utilized by Hoffmann and coworkers for the radical addition/cyclization reaction of N,N-dimethylaniline 242 with 5R)-menthyloxyfuran-2(5H)-one 245 using photochemical electron transfer (PET). The reaction led to 246 and 247 with 44% yield and 3.3 1 diastereoselectivity [77, 78] (Scheme 5.52). A modified menthol auxiliary was utilized for the asymmetric synthesis of a chiral precursor to the natural terpenoid (+)-triptocallol by Yang and coworkers [79]. The reaction was performed under oxidative radical conditions mediated by l.Oequiv of Yb(OTf)3 and 2.2equiv of Mn(0Ac)3-2H20 Mn(OAc)3. Reasonable yields of 55-72% and a diastereoselectivity of 24.2 1-2.8 1 were... 

P-Lactams have been of great synthetic interest because of their use as antibiotic agents, protease inhibitors, and chlolesterol absorption inhibitors [34]. Morken et al. [35] disclosed an efficient iridium-catalyzed diastereoselective synthesis of trans-P-lactams 83 from acrylates 82 and imines 81 through a reductive Man-nich addition/cyclization (Table 9.1). The yields ranged from 58 to 80% and the diastereoselectivity exceeded 20 1. 

The stereoselective vinylogous Michael addition-cyclization cascade of alkylidene malononitriles and 3-alkylideneoxindoles was effectively catalyzed by rosin-derived thiourea 36 to give spirocyclic oxindoles with excellent stereoselectivity (Scheme 35) [61]. Although simple thiourea 20 (see Scheme 16) provided low stereoselectivity (dr = 3 1, 29% ee), introduction of the rosin unit into the thiourea core significantly improved the diastereoselectivity to >20 1 the pyrrolidine structure was essential for high enantioselectivity. The effect of the chirality of the rosin component on the absolute stereocontrol was negligible and, thus, the major proposed role of this structural unit was to increase the steric hindrance of the catalyst. One of the salient features of this protocol is the... 

A photochemically sensitized radical tandem addition cyclization reaction was carried out with aniline derivatives such as 122 (Scheme 29.20) [81]. Thus, tetrahydroquinoline derivatives such as 123a,b are obtained in with diastereoselectivities around 90%. The reaction is highly efficient... 

In 2012, Hu and coworkers developed a three-component, tandem 1,4-conjugated addition-cyclization reaction of diazoacetophenones 107 with anilines 108 and p,y-unsaturated a-ketoesters 109 (Scheme 2.28). This reaction performed well over a broad range of substrates to give the multisubstituted pyrrolidine products 110 in moderate to high yields (up to 84%) with high diastereoselectivities [43]. 

Zhang, X., Ji, J., Zhu, Y., Jing, C., Li, M., Hu, W. (2012). A highly diastereoselective three-component tandem 1,4-conjugated addition-cyclization reaction to multisubstituted pyrrolidines. Organic Biomolecular Chemistry, 10, 2133—2138. 

Evans [211] and Akiba [212] reported in 1996 and 1997, respectively, that some pentacoordinated phosphorane-stabilized carbanions could undergo olefination with aldehydes, which we suggest be called the Evans-Akiba reaction. Similar to the HWE and Homer-Wittig reactions, this reaction has been proposed by Akiba et al. to proceed through diastereoselective carbonyl addition, cyclization, and elimination to yield an alkene (Scheme 45) [213-216]. It is noteworthy that the phosphoms atom is hexacoordinated in the four-center transition state. 

Another class of configurationally stable a-mctallo amines is derived from the N-tert-butoxy-carbonyl-protected piperidines 32 and 3516, l7. Addition of the lithiated piperidines to aldehydes leads to mixtures of the anti- and. yin-diastereoiners. Although the diastereoselectivity is low, the diastereomers can be readily separated by chromatography since the. vyn-isomer is often in a cyclized form 34. The stereochemistry of the products obtained from piperidines 32 are consistent with an equatorial a-lithiation followed by addition to the aldehyde with retention of configuration. However, with piperidine 35 selective axial lithiation is observed. 

Aluminum oxide catalyzed addition of ethyl nitroacetate to racemic 2,3-cpoxy aldehydes 7 affords substituted 4,5-dihydroisoxazole 2-oxides through a regio- and stereospecific tandem nitroaldol cyclization process. High diastereoselectivities are observed in the reaction of cis-epoxyaldehydes to yield the ethyl, vi7 -4.5-dihydro-4-hydroxy-5-( I -hydroxyalkyl)-3-isoxazole-carboxylate 2-oxides, with tram configuration at the ring positions, whereas reactions of trans-and 3,3-disubstituted 2,3-epoxyaldehydes proceed with lower selectivities28. 

The addition of a-(acylamino) esters to 3-aryl-2-propenoates, with sodium ethoxide in ethanol or sodium hydride in benzene as base, is a frequently ultilized procedure9-" A The initial Michael adducts cyclize to 3-aryl-5-oxo-2-pyrrolidinecarboxylic acids with modest to high trans diastereoselectivities 10°. 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

---