IMDA precursor

Corey s retrosynthetic concept (Scheme 9) is based on two key transformations a cationic cyclization and an intramolecular Diels-Alder (IMDA) reaction. Thus, cationic cychzation of diene 50 would give a precursor 49 for epf-pseudo-pteroxazole (48), which could be converted into 49 via nitration and oxazole formation. Compound 50 would be obtained by deamination of compound 51 and subsequent Wittig chain elongation. A stereocontroUed IMDA reaction of quinone imide 52 would dehver the decaline core of 51. IMDA precursor 52 should be accessible by amide couphng of diene acid 54 and aminophenol 53 followed by oxidative generation of the quinone imide 52 [28]. 

The next attempt was Martin s formal synthesis of racemic dendrobine (82) (158, 159,183). Again, IMDA was used as the key step. Martin et al. replaced the usually lengthy linear synthesis of the IMDA precursor by a more convenient, convergent synthesis. After testing the feasibility of their key step, the intramolecular addition of a dieneamide to an unactivated trisubstituted olefin, with model compounds, the authors started with the synthesis of the diene unit (Scheme 26). 

Perhaps the greatest drawback with this tethering approach is the relatively poor yield in the formation of the triene IMDA precursor 1, although the reaction was not optimized. Fortin and co-workers have reported an improved procedure for the efficient formation of unsymmetrical di-ferf-butylsilyl acetals using Bu2Si(Cl)OTf, which is readily prepared from the corresponding chlorosilane [7]. Successive incorporation of the die-nophile and diene is possible by exploiting the different reactivity of silyl trifiates and chlorides towards nucleophilic substitution (Scheme 10-3). 

In the cases of dimethylsilyl IMDA precursors, the exolendo selectivity was poor. However, this ratio could be readily and quite dramatically influenced by varying the alkyl substituents on the silicon template [12]. Thus with dienol 24, tether formation with dimethylvinylsilyl chloride and subsequent IMDA reaction afforded a 4 1 mixture of exolendo products (Scheme 10-7). The ratio could be further improved to 10 1 by using a diphenylsilyl tether, and when bulky Bu groups were used, a single stereoisomer, resulting from exo addition, was observed. This example once more illustrates the potential for tuning the stereoselectivity of the reaction by varying the steric interactions with the tether. 

A boron-tethered (C-B-O) intramolecular Diels-Alder (IMDA) approach has been used to prepare cyclic alkenyl boronic esters 140 (Scheme 19). Thus, reaction of 2equiv of the dienyl alcohol 138 with 137 in THF, in the presence of molecular sieves, provides the corresponding IMDA precursors 139. The IMDS reaction was then accomplished at 190 °C in a toluene solution, with 5 mol% of 2,6-di-fer7-butyl-4-methylphenol as a free radical inhibitor. Transformation of the carbon-boron bond in 140, using standard organoborane reactions, can then afford a variety of functionalized cyclohexene derivatives <1999JA450>. 

Hence, use of the N-acyl derivative BXII as the IMDA precursor was indicated. 

As shown in Fig. 2.26, the other IMDA precursor 2.2.32 also underwent Wessely oxidative dearomatization to create a pair of separable 2 1 products 2.2.37 and 2.2.38 with 92 % total yield. Unfortunately, the precursors could not be transformed into IMDA products under the same conditions. It was speculated that the steric hindrance of the bromine atom blocked the activity of the reaction. 

SCHEME 16 Synthetic steps toward the IMDA precursor. 

SCHEME 19 Synthetic steps toward the more substituted IMDA precursor. 

A related IMDA key step, however with exo geometry, was apphed in Mulzer s synthesis of ehsabethin A (22) [32]. According to the retrosynthetic plan (Scheme 14) the elisabethane carbon skeleton would be assembled via an IMDA cychzation of quinone 86 which would be generated by oxidation of the corresponding hydroquinoid precursor. Selective hydrogenation, base-catalyzed... 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

The use of silyl acetals as tethering groups in the IMDA reaction is often hampered by the relatively poor yields observed in the formation of unsymmetrical systems. However, the preparation of the triene precursors can be facilitated if only one of the r-systems is linked through a silyl ether connection, while its reacting partner is attached directly to the silicon tether [9]. 

In Shea s approach to the polyhalogenated cyclohexane 87, derived from a red marine alga, Plocamium sp., a Type II IMDA reaction utilizing a disposable (allyl)silyl tether was used as a key step [29nj. The triene cyclization precursor 88 was readily prepared and underwent Diels-Alder reaction in 74% yield with the expected, complete regiocon-trol affording exclusively bicycle 89. The rigid, bicyclic framework of the cycloadduct... 

One of the early examples of a furan IMDA reaction involved a multistep route to a precursor alkyne that gave a mixture of two diastereomeric cycloadducts as an entry to a functionalized gibbane <82TL329i>. The protocol was extended to a relatively short route to gibberelins, for example ( )GA5, and made use of an alkyne-furan IMDA reaction. The IMDA reaction, when carried out in benzene at 80°C proceeded slowly and gave a low yield of a 3 1 mixture in which the required... 

Although arynes are recognized as highly reactive dienophiles there are relatively few reports of IMDA reactions where those reactive intermediates are tethered to a furan. A three or four atom tether linking the aryne precursor to the furan leads to efficient reactions <86AJC635>. The use of a... 

The copper(II) catalyst has been applied to the intramolecular Diels-Alder reaction.The precursor (8.71) imdergoes an intramolecular Diels-Alder reaction (IMDA reaction) which proceeds with remarkable selectivity to give the product (8.72), which was subsequently converted into the marine toxin (—)-... 

With this first round of simplifications complete, the majority of the cyclic bulk appended to the central core of the target molecules has been successfully excised. Of course, what still remains within 15 is the challenging [4.3.1] bicyclic system endowed with the anti-Bredt bridgehead C—C double bond. While this latter motif does seem formidable, if it is viewed within the context of the smaller six-membered ring in which it resides, then a possible course of retrosynthetic action should immediately be suggested in the form of an intramolecular Diels—Alder reaction (IMDA). Accordingly, application of this transform to 15 would lead directly to a precursor such as 17. Although the power of the Diels—Alder reaction to create complicated polycyclic architectures is rarely paralleled,"... 

There are two types of IMDA reactions Type-I and Type-II. Type-I reactions are those in which the diene is attached to the dienophile by a tether from its terminus while in Type-II reactions, the tether is attached to an internal diene position (Figure 4.18). In general, both Type-1 and Type-11 IMDA reactions only occur if the tether contains three or more atoms. This is due to the high level of strain involved in the transition states of reactions of precursors with one or two atoms in the connecting chains. 

Model compound 2.1.1 was designed to test key reactions, which may be applied to the total synthesis, such as intramolecular Diels-Alder reaction, Wessely oxidative dearomatization reaction, and Pinhey arylation. The synthetic strategy of model research is shown in Fig. 2.16 compound 2.1.1 could be constructed from the precursor 2.1.2 after IMDA. Compound 2.1.2 could be prepared from compound 2.1.3 through esterification. Compound 2.1.3 could be obtained from 2.1.4 by reduction. Compound 2.1.4 was designed to be obtained by Pinhey arylation between 1,3-keto ester compounds 2.1.5 and organic lead compound 2.1.6. The advantage of this model system is that it contains three key reactions in total synthesis design, which can effectively supply the synthetic information for the total synthesis. 

With intramolecular oxa-Michael precursor 3.47, constructing the six-seven bicyclic structure directly through the oxygen Michael addition reaction was carried out under the alkaline condition. However, only the starting materials were recovered. Thus, MOM group was first removed to obtain the free phenol 3.50 under sulfuric acid. After Wessely oxidative dearomatization, we got a pair of diastereomeric isomers 3.51 with the ratio 3 1, which was considered as the Diels-Alder precursor. The expected IMDA reaction did not happen in a sealed tube. No desired 3.52 or IMDA product 3.53 was separated. Starting materials were partially recycled, but most of the precursors were decomposed (Fig. 3.23). 

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