Pantolactone auxiliary

A double diastereotopic differentiation strategy on a phosphonoacetate template has been described. The approach utilizes Rh2(OAc)4-catalysed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate (328).The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is an effective method to access bicyclic P-chiral phos-phonates (329) (Scheme 87). ... 

Mark6 and co-workers also have explored the use of chiral derivatives of 2-pyrones to induce asymmetry. Chiral pyrones 66-69 were studied in their reactions with ethyl vinyl ether. As the data in Table 9 indicate, the pantolactone auxiliary is the most useful of those studied. Most intriguing is the fact that catalysis with either antipode of the europium Lewis acid, or even an achiral europium Lewis acid, yields the same stereochemically impressive results. 

The [3+4] annulation approach to the hydroazulenes is achieved with high asymmetric induction (greater than 90% de) by using (/ )-pantolactone as a chiral auxiliary (Table 7). The nature of the catalyst has a considerable effect on the level of asymmetric induction. A sterically crowded catalyst, such as rhodium pivalate, results in much lower diastereoselectivity than rhodium(II) acetate or rho-dium(II) hexanoate. Consequently, even though the enantiomers of rhodium(II) mandelate exhibit double stereodifferentiation with the (/ )-pantolactone auxiliary (entries 5,6), both catalysts are bulky and result iinferior asynunetric induction compared to that obtained with an uncrowded achiral catalyst (entries 1-3). 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

The cyclic a-hydroxylactone, pantolactone, has been used extensively as a chiral auxiliary in D-A reactions.84 Reactions involving TiCl4 and SnCl4 occur through chelated TSs.85... 

Entry 6 uses a chiral auxiliary derived from pyroglutamic acid. Entry 7 is an example of the use of pantolactone as a chiral auxiliary to form a prostaglandin precursor. 

Brimble and coworkers176 studied the asymmetric Diels-Alder reactions of cyclopentadiene with chiral naphthoquinones 272 bearing different chiral auxiliaries. The highest endo and facial selectivities were obtained using zinc dichloride as the Lewis acid catalyst and (—)-pantolactone as the chiral auxiliary. Thus, the reaction between cyclopentadiene and 272 afforded a 98 2 mixture of 273 and 274 (equation 76). The chiral auxiliary was removed easily by lithium borohydride reduction. 

Hansen and colleagues177 used (+)-pantolactone as a chiral auxiliary to achieve asymmetric induction in the first step toward their synthesis of d.v-perhydroisoq uinol inc 278. The titanium tetrachloride catalyzed reaction between 1,3-cyclohexadiene (275) and chiral acrylate 276 proceeded with high diastereofacial selectivity to give 277 (94% de) in 75% yield (equation 77). 

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 inter- or intramolecular cyclopropanation of achiral alkenes with enantiome-rically pure diazoacetic esters [1016,1363,1364] or amides [1365,1366] does not usually proceed with high diastereoselectivity. A chiral auxiliary which occasionally gives good results is pantolactone (3-hydroxy-4,4-dimethyltetrahydro-2-furanone) [1016,1367,1368]. 

I 74 Rhodium (ll)-Stabilized Carbenoids Containing Both Donor and Acceptor Substituents Tab. 14.2 Asymmetric cyclopropanation using (R)-pantolactone as the chiral auxiliary. 

The asymmetric [3 + 4] cycloaddition is readily achieved using chiral auxiliaries or catalysts [16]. The efficiency of the chiral auxiliary approach is illustrated in the [3-1-4] cycloaddition with cyclopentadiene. The vinyldiazoacetate 6, with (T)-pantolactone as the chiral auxiliary, generated the bicyclo[3.2.1]octadiene 75 in 87% yield and 76% dia-stereomeric excess (Eq. 10) [82]. Alternatively, the chiral rhodium prolinate Rh2(S-DOSP)4-catalyzed reaction of 4 generated the bicyclo[3.2.1]octadiene 76 in 77% yield and with 93% enantiomeric excess (Eq. 11) [83]. 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

At Tokyo College of Pharmacy [284], esters of 2-(trifluoromethyl)propenoic acid were used to synthesise 16,16,16-trifluororetinal (Eq. 101). Intermolecular Lewis acid-catalysed Diels-Alder reaction with a pantolactone chiral auxiliary allowed the diastereoselective construction of the core cyclohexenone portion with the quaternary centre set in the desired absolute configuration. 

Stereosectivity is a broad term. The stereoselectivity in cyclopropanation which has been discussed in the above subsection, in fact, can also be referred to as diastereoselectivity. In this section, for convenience, the description of diastereoselectivity will be reserved for selectivity in cyclopropanation of diazo compounds or alkenes that are bound to a chiral auxiliary. Chiral diazoesters or chiral Ar-(diazoacetyl)oxazolidinone have been applied in metal catalysed cyclopropanation. However, these chiral diazo precursors and styrene yield cyclopropane products whose diastereomeric excess are less than 15% (equation 129)183,184. The use of several a-hydroxy esters as chiral auxiliaries for asymmetric inter-molecular cyclopropanation with rhodium(II)-stabilized vinylcarbenoids have been reported by Davies and coworkers. With (R)-pantolactone as the chiral auxiliary, cyclopropanation of diazoester 144 with a range of alkenes provided c yield with diastereomeric excess at levels of 90% (equation 130)1... 

The diastereoselectivity of the tropanes 1062 obtained from vinyldiazomethanes 1061 containing (/ )-pantolactone as the chiral auxiliary and various pyrroles (Equation 251) was roughly parallel to the results observed with the (5)-lactate auxiliary and ranged from 37% to 78% de <1997JOG1095>. 

In the hydroxyamination reactions performed with cyclohexene, low diastereoselectivity was induced by both ( + )-2-hydroxyheptahelicene ( )-A and ( —)-dihydroquinine (—)-B. Excellent diastereoselectivity was obtained in the reactions performed on (E)-, 2-diphenylethylene, especially by using the auxiliaries ( + )-A and (—)-B. The new stereogenic centers were formed with the same (S,S) configuration using either (—)-B or ( —)-pantolactone ( )-H, but unsatisfactory diastereoselectivity was achieved with the latter auxiliary. 

Use as a Chiral Auxiliary. (5)-Ethyl lactate has been used as a chiral auxiliary in a variety of simple Diels-Alder reactions. As the fumaric acid diester, the de employing cyclopentadiene can almost be completely reversed by addition of Titanium(IV) Chloride (eq 8). In general, superior de values are achieved using (R)-Pantolactone in this context, and also for base-mediated addition to ketenes. ... 

Diels-Alder Reactions. (i )-Pantolactone is one of the most effective chiral auxiliaries for preparative scale Diels-Alder additions of simple enoate esters in the presence of Lewis acids (eq 1). ... 

Prompted by the X-ray studies of the acryloyl lactate-TiCU complex (380a), commercially available pantolactone was chosen as an auxiliary aiming to facilitate entropically the formation of a seven-mem-bered titanium chelate (385). Indeed, using 0.1-0.75 mol equiv. of TiCU the acrylate and crotonate of (/ )-pantolactone (384) underwent smooth addition of cyclopentadiene, butadiene and isoprene to give adducts (386) and (387) in ratios of >93 <7 (Scheme 94, Table 24, entries a-d). Opposite product ratios were obtained using dienophiles (388) derived from (S)-pantolactone (entiy e) or (390) derived from the more readily available A -methyl-2-hydroxysuccinimide (entries f, g). The major products were purified by crystallization and saponified without epimerization (LiOH, THF/water, r.t.) to furnish the corresponding carboxylic acids. 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

Enantioselective carbenoid cyclopropanation of achiral alkenes can be achieved with a chiral diazocarbonyl compound and/or chiral catalyst. In general, very low levels of asymmetric induction are obtained, when a combination of an achiral copper or rhodium catalyst and a chiral diazoacetic ester (e.g. menthyl or bornyl ester ) or a chiral diazoacetamide ° (see Section 1.2.1.2.4.2.6.3.3., Table 14, entry 3) is applied. A notable exception is provided by the cyclopropanation of styrene with [(3/ )-4,4-dimethyl-2-oxotetrahydro-3-furyl] ( )-2-diazo-4-phenylbut-3-enoate to give 5 with several rhodium(II) carboxylate catalysts, asymmetric induction gave de values of 69-97%. ° Ester residues derived from a-hydroxy esters other than ( —)-(7 )-pantolactone are not as equally well suited as chiral auxiliaries for example, catalysis by the corresponding rhodium(II) (S )-lactate provides (lS, 2S )-5 with a de value of 67%. 

Diels-Alder reactions with Oppolzer s chiral sultam Diels-Alder reactions with pantolactone as chiral auxiliary Chiral auxiliaries attached to the diene Improved Oxazolidinones SuperQuats Asymmetric Michael (Conjugate) Additions... 

Diels-Alder reactions with pantolactone as chiral auxiliary... 

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