Diels-Alder reaction camphor derivatives

For acrylates, or type I reagents, applied in asymmetric Diels-Alder reactions, several chiral auxiliaries such as menthol derivatives, camphor derivatives,16,3 and oxazolidinones4 are available. Carbohydrate compounds have also been reported as chiral auxiliaries in a recent publication, although the stereoselectivity was not good.5 Here are examples in which asymmetric Diels-... 

Camphor sultam derivatives have proved to be effective chiral auxiliaries in many different types of asymmetric reactions. As shown in Scheme 5-44, chiral camphor sulfam can be applied in the synthesis of (—)-pulo upone precursor 151 using an intramolecular Diels-Alder reaction. A Wittig reaction of 148 with 147 connects the chiral auxiliary to the substrate, and subsequent intramolecular Diels-Alder reaction via transition state 150 affords product 151. Compound 151 already has the stereochemistry of (—)-pulo upone 153.72... 

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,... 

It was clear that 1 would be derived from a Diels-Alder adduct. There has been a great deal of work in recent years around the development of enantioselective catalysts for the Diels-Alder reaction, but the catalysts that have been developed to date only work with activated dienophile-diene combinations. For less reactive dienes, it is still necessary to use chiral auxiliary control. One of the more effective of those was the known camphor-derived tertiary alcohol, so that was used in this project. Diels-Alder cycloaddition of the diene 4 with the enantiomerically-pure enone 5 led to the adduct 6 with high diastereocontrol. Oxidative cleavage led to the acid 7, which was carried on to the bis-enone I. 

The reagent has one handicap only (+)-pulegone is readily available. Consequently, Oppolzer and coworkers2 have examined a number of chiral alcohols, derived from various monoterpenes, in which the hydroxyl group is similarly shielded. The endo, e/.r-diphenylmethylisoboraeol (2), obtained from ( + )-camphor, and the enantiomer, obtained from ( —)-camphor, are almost as effective as 1 as chiral adjuncts in this Diels-Alder reaction. 

Chiral metal alkoxides M(OR)4 have been developed as asymmetric variants of ordinary Lewis acids, such as A1C13 and ZrCU, and are used as catalysts for selective carbon-carbon bond formation. Thus, starting from bidentate l,l -bi-2-naphthol derivatives (BINOL) and SnCU, a series of chiral tin(iv) aryloxides 221 (Figure 7) was prepared and successfully applied to the enantioselective Diels-Alder reaction <2006TL873>. Similar silocanes obtained from menthone- or camphor-derived 2,2 -biphenols have been obtained and their configuration was analyzed by NOE differential spectroscopy (NOEDS) <1997JOC7156>. 

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

By using chiral auxiliary groups derived from phenylmenthol or camphor, Lewis acid catalyzed Diels-Alder reactions gave an easy access to enantiomerically pure carbamate alcohols38,39. For example, the enantiomerically pure cycloadduct from cyclohexadiene and chiral IV-sulfinyl carbamate could be transformed into the bicyelic carbamate with complete transfer of chirality. 

Zwanenburg and coworkers have examined the diastereoselectivity of chiral sulfme systems in Diels-Alder reactions. In one case, a-chlorosulHne (195) derived from camphor reacts with 2,3-dimethy(butadiene via attack on the sulfme conformer indicated in equation (103) to afford adduct (196) as a single diastereomer. 

Diastereoselective acylnitroso Diels-Alder reactions were performed using enantiopure hydroxamic acids derived from camphor and a-amino acids as chiral auxiliaries (Equation 90) <1997JOC3806, 1998T10537, 2003TL4571>. 

This is a Diels-Alder reaction in which 25 as the dienophile and 26 as the diene form a new cyclohexene ring. In terms of the electron demand this is a normal Diels-Alder reaction with an electron-rich diene 26 and an electron-poor dienophile 25. The use of a chiral camphor-derived auxiliary means that only one diastereomer is obtained in 70 % yield. The reaction proceeds via the endo transition state 38 with the auxiliary blocking one side of the dienophile. 

Optically pure sultams have been used by Oppolzer as chiral auxiliaries in various asymmetric transformations, including Diels-Alder reaction, aldoliza-tion, conjugate addition, his-hydroxylation, and catalytic hydrogenation [42,43]. In the literature, the most commonly used chiral sultam is derived from camphor (Oppolzer s sultam). The ready access to 80 and other chiral sultams from the Diels-Alder cycloadducts could further expand the scope of their use as chiral auxiliaries in asymmetric synthesis. 

Asymmetric Diels-Alder reaction, ene reaction, hydrogenation, halogenaflon by means of dwal olelin, such as camphor derivative 1 or 2. 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Among the Lewis acids studied in asymmetric hetero Diels-Alder reactions of carbonyl compounds rare earth cations proved to be mild and efficient catalysts. This is demonstrated by the results observed in reactions of camphor sultam (63) derivatives with achiral 1-methoxy-l,3-butadiene. 

Lee and co-workers reported camphor sulfonyl hydrazines 54 as organocatalysts in enantioselective Diels-Alder reactions of cyclopentadiene and a,[L-unsaturated aldehydes, Scheme 3.21 [34], On the other hand, a similar Diels-Alder cycloaddition reactions with camphor-derived sulfonylhydrazines and HC10 in MeNO were also developed by Langlois, et al. [35]. 

Synthesis of Chiral Auxiliaries. Their availability and crystalline nature has made camphor derivatives the precursors of choice for the design and synthesis of chiral auxiliaries. 10-Camphorsulfonyl chloride is the starting material for the synthesis of chiral auxiliaries (9)-(12) (eq 2). Sulfonamides (9) and (10) have been used as chiral auxiliaries in a number of reactions, e.g. the Lewis acid-catalyzed Diels-Alder reaction, the [3 + 2] cycloaddition of a nitrile oxide to an acrylate, and the stereoselective conjugate addition reaction of organocopper reagents to ci ,)3-unsaturated esters. ... 

Scheme 6.1 Camphor-derived sulfonylhydrazine-catalysed Diels-Alder reactions.

Products with up to 99% enantiomeric excess have been obtained during the TiCl2(OR)2-mediated Diels-Alder reaction between camphor derivatives such as (70) and cyclopentadiene. The results are explained by assuming the conformation shown in structure (70), where attack on the lower -face of the double bond is clearly less hindered than that from the upper rc-face, which is shielded by the t-butyl group. 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

With the aim of increasing secondary-amine-catalyst turnover, Ogilive and coworkers disclosed the novel class of camphor-derived five-membered cyclic hydrazines 5 to enhance their nucleophilicity by means of the a-heteroatom effect [7]. With the use of this catalyst, aqueous Diels-Alder reactions proceeded efficiently... 

Denmark advanced a strategy that involves tandem cycloaddition sequences with nitronates for the asymmetric synthesis of alkaloids [73, 74). A camphor-derived auxiliary permits the preparation of chiral enol ethers (cf. 68) as the reacting partners. A noteworthy example of the complex structures that could be generated by use of 68 is illustrated in Scheme 18.15. A hetero-Diels-Alder reaction between 68 and nitronate 67 generated 69 as a 96 4 mixture of endo/exo diastereomers. The adduct then participated in an intramolecular dipolar cycloaddition at elevated temperatures to yield cycloadduct 70 as a single diastereomer (90%). The tricyclic target 72 was obtained in 88 % yield after reductive removal of the chiral auxiliary and lactam formation [74]. 

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