Vinyl ether, Chiral

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

The inverse electron-demand Diels-Alder reaction is also accelerated by Lewis acids, but the successful application of chiral Lewis acids to this kind of Diels-Alder reaction is very rare. Marko and coworkers applied Kobayashi s catalyst system (Yb(OTf)3-BINOL-amine) to the Diels-Alder reaction of 3-methoxycarbonyl-2-py-rone with vinyl ether or sulfide [58] (Scheme 1.72, Table 1.29). A bulky ether or... 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

Other substrates were tested the results are summarized in Table 5.2. Vinyl ethers (2b-2d) also worked well to afford the corresponding tetrahydroquinoline derivatives (3a-3e) in good to high yields with good to excellent diastereo- and en-antioselectivity (entries 1-10). Use of 10 mol% of the chiral catalyst also gave the adducts in high yields and selectivity (entries 2 and 6). As for additives, 2,6-di-t-bu-... 

The above described reaction has been extended to the application of the AlMe-BINOL catalyst to reactions of acyclic nitrones. A series chiral AlMe-3,3 -diaryl-BINOL complexes llb-f was investigated as catalysts for the 1,3-dipolar cycloaddition reaction between the cyclic nitrone 14a and ethyl vinyl ether 8a [34], Surprisingly, these catalysts were not sufficiently selective for the reactions of cyclic nitrones with ethyl vinyl ether. Use of the tetramethoxy-substituted derivative llg as the catalyst for the reaction significantly improved the results (Scheme 6.14). In the presence of 10 mol% llg the reaction proceeded in a mixture of CH2CI2 and petroleum ether to give the product 15a in 79% isolated yield. The diastereoselectiv-ity was the same as in the acyclic case giving an excellent ratio of exo-15a and endo-15a of >95 <5, and exo-15a was obtained with up to 82% ee. 

Sinnlarly, f-i- -casuralme, a pentahydroxy pyrrolizidine alkaloid, is prepared by a tandem [4-i-3 /[3-i-3 cycloadchdon involving nitroalkene, chiral vinyl ether, and vinyl silane This process creates five of the six stereocenters present in this potent glycosidase inhibitor fScheme 8 35 ... 

Keywords acrylates, acrylamides, fumarates, a, -unsaturated ketones, vinyl ethers, vinyl sulphoxides, chiral dienophiles, chiral dienes, chiral catalysts polymer-supported chiral Lewis acids... 

In another context, Davies et al. have developed the Rh2(-S -DOSP)4-catalysed decomposition of vinyldiazocarbonyl derivatives in the presence of vinyl ethers.The corresponding chiral cyclopentenecarboxylates were formed in high enantioselectivities of up to 99% ee with the full control of the relative stereochemistry at up to three contiguous stereogenic centres, as depicted in Scheme 10.9. 

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

Asymmetric tandem cycloaddition of a chiral carbohydrate nitroalkene with ethyl vinyl ether in the presence of electron-withdrawing alkenes produces a facile assembly of bicyclic systems, which can further be selectively cleaved to give homologated carbohydrates (Eq. 8.110).176... 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

The total syntheses of the potent glycosidase inhibitors (+)-castanospermine, (+)-6-epicas-tanosperimine, (+)-australine, and (+)-3-epiaustraline have been reported. These four natural products are derived from a single common intermediate, the nitroso acetal (as shown in Scheme 8.43), which is created in the key step by the asymmetric tandem [4+2]/[3+2] cycloaddition between silaketal nitroolefin and chiral vinyl ether.182 The strategy of the synthesis is outlined in Scheme 8.43. Scheme 8.44 presents a total synthesis of (+)-castanosperimine and (+)-6-epi-castanosperimine from the common intermediate prepared by tandem [4+2]/[3+2] cycloaddition. 

Nitrone 1,3-DC reactions are still the most general approach to isoxazolidines. The stereocontrol is usually achieved by the use of chiral nitrones and/or dipolarophiles, but new interesting achievements on Lewis acid catalyzed cycloadditions are also frequently reported. Tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanatedionate) europium(III) [Eu(fod)3] selectively activated the Z-isomer of C-alkoxycarbonyl nitrone 75 existing as an E,Z-equilibrium mixture by forming the (Z)-75-Eu(fod)3 complex. (Z)-75-Eu(fod)3 reacted with electron-rich dipolarophiles such as vinyl ethers to give the trans-adducts with excellent diastereoselectivity <06T12227>. 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

The asymmetric synthesis of six-membered cyclic nitronates with the use of dipolarophiles containing auxiliaries was studied in more detail. Chiral vinyl ethers are most commonly used for this purpose. This process is schematically shown in Scheme 3.182. 

Mukai et al.85 reported an asymmetric 1,3-dipolar cycloaddition of chromium(0)-complexed benzaldehyde derivatives. As shown in Scheme 5 52, heating chiral nitrone 171a, derived from Cr(CO)3-complexed benzaldehyde, with electron-rich olefins such as styrene (173a) or ethyl vinyl ether (173b) generates the corresponding chiral a.v-3,5-disubstitutcd isoxazolidine adduct 174 or... 

Various substituted unsaturated acylphosphonates participate in highly dias-tereoselective and enantioselective cycloadditions with vinyl ethers, Eqs. 177 and 178. It is intriguing to note that catalysts [(.V,.Y)-f-Bu-box]Cu (OTf)2 (269c) and [(.V,.S )-Ph-box]Cu (OTf>2 (269d) possessing the same sense of chirality afford opposite antipodes of the cycloadduct in comparable selectivities. Cyclopentadiene was found to react with acylphosphonates to give a mixture of the normal Diels-Alder adduct and the inverse electron demand hetero-Diels-Alder adduct (35 65), Eq. 179. This result may be contrasted with crotonylimide, which furnishes the normal demand Diels-Alder adduct exclusively. 

When comparing these results with those previously obtained using carbohydrate-based vinyl ethers as chiral dienophiles, this improved facial diastereoselectivity to heterodienes under similar conditions is noteworthy.81 The efficient chiral transfer in the second example might mostly be attributed to the specific architecture of the l,2 5,6-di-0-isopropylidene-a-D-glucofuranose moiety.Those findings open the way to develop well-defined spiro-carbohydrate templates towards improved auxiliaries for chirality transfer in a wide range of syntheses. 

Mark6 and colleagues178 studied the Eu(hfc)3 catalyzed inverse electron demand Diels-Alder reactions between (—)-pantolactone derived chiral a-pyrones 279 and vinyl ethers and thio ethers 280. This auxiliary proved superior to other auxiliaries in these reactions. The reactions generally proceeded with high yields, affording the endo adducts 281 with de values generally above 95%. The de proved independent of the chirality or achirality of the Lewis acid employed, as (+)-Eu(hfc)3, (—)-Eu(hfc)3 and Eu(fod)3 all afforded the same diastereomer with >95% de (equation 78, Table 13). 

The asymmetric tandem cycloaddition of the chiral carbohydrate nitroalkene (35) with ethyl vinyl ether involves the initial formation of the nitronate (36) which reacts exclusively with electron-withdrawing alkenes by 3 -I- 2-cycloaddition to yield chiral bicycles (37) and (38) (Scheme 12). ... 

Inspired by the previous results, Leighton et al. reported the enantioselective [3 + 2] acylhydrazone-enol ether cycloaddition reaction by employing the same pseudoephedrine-based chiral silane. The pyrazohdine product was obtained in 61% yield with 6 1 dr and 77% ee in 24 h. The use of tert-butyl vinyl ether led to an improvement in both diastereoselectivity and enantioselectivity as shown in Scheme 34 [108]. 

In 2008, Yamamoto et al. disclosed an asymmetric 1,3-dipolar cycloaddition of diarylnitrones 156 with ethyl vinyl ether (157) (Scheme 66). Under the influence of the bulky chiral A-triflyl phosphoramide (5)-4s (5 mol%, R = 2,6- Prj-4-Ad-C Hj), the enrfo-products 158 were formed as the major diastereomers in good yields and enantioselectivities (66 to >99%, 7 1-32 1 endolexo, 70-93% ee(endo)) [86]. High asymmetric induction was achieved only with electron-deficient aryl groups on the nitrones. 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

---