IMDA reactions

Lewis acid catalysis usually substantially improves the stereoselectivity of IMDA reactions, just as it does in intermolecular cases. For example, the thermal cyclization of 4 at 160° C gives a 50 50 mixture of two stereoisomers, but the use of (C2H5)2A1C1 as a catalyst permits the reaction to proceed at room temperature and endo addition is favored by 7 1.125... 

Some examples of IMDA reactions are given in Scheme 6.5. In Entry 1 the dienophilic portion bears a carbonyl substituent and cycloaddition occurs easily. Two stereoisomeric products are formed, but both have the cis ring fusion, which is the stereochemistry expected for an endo TS, with the major diastereomer being formed from the TS with an equatorial isopropyl group. 

Entries 10 and 11 are examples of reactions involving thermal generation of quinodimethanes. In Entry 12 a quinodimethane is generated by photoenolization and used in conjunction with an IMDA reaction to create the carbon skeleton found in the hamigerans, which are marine natural products having antiviral activity. 

Chiral catalysts (see Section 6.1.6) can also achieve enantioselectivity in IMDA reactions. 

Compound 316 contains two suitable ene-diene functions that yielded two diastereomeric tetrahydrobenzo[4]qui-nolizidines in quantitative yield and in a 8 92 ratio in a TiCU-catalyzed intramolecular Diels-Alder (IMDA) reaction (Equation 9) <1998T9529>. 

The IMDA reaction of 58 proved to be unreliable and was reported to suffer from decreased yields (15-20 %) when a fresh bottle of p-dichlorobenzene was used. It was hypothesized that a minor contaminant in commercial p-dichlorobenzene... 

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 actual synthesis (Scheme 10) commenced with the couphng of diene acid 54 and aminophenol 53 to provide diene amide 55. In situ generation of quinone monoimide 52 under oxidative conditions and subsequent intramolecular Diels-Alder (IMDA) reaction furnished an 8 1 mixture of endo/exo... 

In contrast to Nicolaou s model system, the IMDA reaction of quinone 86 to adduct 85 proceeded through an exo transition state geometry. This difference is due to the two additional substitutes attached to the diene side chain of quinone 86. A more detailed analysis (molecular modeling) of the four theoretically possible transition states (Fig. 10) reveals that an enophilic endolexo... 

The significance of this IMDA reaction lies firstly in the use of a tethered (E,Z)-diene - the first case that has been successfully developed - secondly, in the unusually mild and virtually biomimetic conditions (aqueous medium, ambient temperature), and thirdly in the high yield and stereoselectivity. 

In a rather elegant approach towards colombiasin A (36) Flynn et al. [47] would access the tetracyclic carbon skeleton through an enantioselective intermolecular Diels-Alder sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence between double-diene 166 and quinone 167 (Scheme 26). A key element of the proposed approach would be the chiral sulfoxy group in 167 which controls both the regio and facial selectivity of the intermolecular Diels-Alder reaction and eliminates generation of the dienophile for the IMDA reaction. 

Subsequent monosilylation and Wittig reaction furnished unsymmetrical double diene 170. The synthesis of the other Diels-Alder partner started from bromophenol 173 (prepared in three steps from dimethoxytoluene), which was doubly metalated and reacted with (S,S)-menthylp-toluenesulfinate 173. CAN oxidation delivered quinone 171, which underwent a Diels-Alder reaction with double diene 170 to give compound 175 possessing the correct regio- and stereochemistry. Upon heating in toluene the desired elimination occurred followed by IMDA reaction to adduct 176, which was obtained in an excellent yield and enantioselectivity. Both Diels-Alder reactions proceeded through an endo transition state the enantioselectivity of the first cyclization is due to the chiral auxiliary, which favors an endo approach of 170 to the sterically less congested face (top face) (Scheme 27). 

For a recent review on DA reactions, see Nicolaou KC, Snyder SA, Montagnon T, Vassi-likogiannakis GE (2002) Angew Chem Int Ed 41 1668 and references therein. For quinone-hased IMDA reactions also see Layton ME, Morales CA,Shair MD (2002) J Am Chem Soc 124 773... 

Scheme 7 ImidazoUdinone catalysed Type I and Type II IMDA reactions...

The development of intramolecular Diels-Alder (IMDA) reactions for the synthesis of natural products (80CR63) and the facility with which substituted furans can be assembled have been reviewed 840R(32)1, 86CRV795, 87CSR187, 90SL186). Thus, IMDA product from the propargyl sulfone shown in Scheme 43 proceeds via the allene and was converted subsequently into the benzenoid sulfone under base catalysis (92CC735). 

Scheme 21 Preparation of tricyclic [3-lactam 61 using tandem elimination-intramolecular Diels-Alder (IMDA) reaction...

Scheme 22 Preparation of tetracyclic [3-lactam 64 using tandem elimination-IMDA reaction...

Scheme 23 Preparation of tricyclic [1-lactams 67-68 using allenol transposition-IMDA reaction (i) CH3S02C1, Et3N, toluene, sealed tube, 190°C...

Another important application of the iminium catalysis concept has been the development of enantioselective Type I [15, 30] and Type II [15] intramolecular Diels-Alder reactions (IMDA). (For experimental details see Chapter 14.18.3). For these transformations, both catalysts 1 and 3 proved to be highly efficient, as demonstrated by both the short and effective preparation of the marine methabo-lite solanapyrone D via Type I IMDA (Scheme 3.4, top) and the development of an early example of an enantioselective, catalytic Type II IMDA reaction (Scheme 3.4, bottom) [35]. Importantly, cycloadducts incorporating ether and quaternary carbon functionalities could be efficiently produced. 

We examined the IMDA reaction of 62 under Lewis-acid-mediated conditions (Scheme 10). As in the case of the Lewis-acid-mediated IMDA reaction of the substrate 48, no good results were obtained (Table 3, Entries 1-3). Treatment of 62 with 5.0 M LiC104 in Et20 [81] resulted in the formation of a complex mixture (Entries 4, 5). We found that the IMDA reaction of 62 proceeded under thermal conditions as a 0.02 M toluene solution in a sealed tube in the presence of BHT (Entry 6). In contrast to the case of 48, the IMDA reaction of 62 required a longer heating time for completion. Two endo-cycloadducts 63-A and 63-B were isolated in 62% and 21% yields, respectively, after separation on silica gel. Furthermore, an exo-cycloadduct 63-D was isolated in a trace amount of 2%. The stereochemistries of the... 

In summary, we completed the first total synthesis of (-)-mniopetal E (5), a prototype of mniopetals A-D, in its natural form. Our synthesis featured the following aspects (1) the substrate 62 for the IMDA reaction was synthesized in enantiopure form from the known building block 19, and (2) the stereoselective IMDA reaction of 62 under thermal conditions realized practical access to the desired ercdo-cycloadduct 63-A possessing the entire carbon skeleton with the correct stereochemistry. Our total synthesis of 5 as the natural form established the unsettled absolute configuration. 

As the total synthesis of mniopetal E (5) was compleated, we next focused our attention on mniopetal F (6) and kuehneromycin A (7) as synthetic targets. The retrosynthesis of 6 and 7 is shown in Scheme 13. We anticipated that the IMDA reaction of the substrate G would proceed favorably via a chair-like enrfo-transition state F, which would lead to the desired adduct E. In general, a substituent neighboring the dienophile part would dispose of the sterically less-demanding equatorial orientation in the transition state. However, the trialkyl-... 

The synthesis of substrates 88-96 for the IMDA reaction is depicted in Schemes 14 and 15. Treatment of 74 with I2, PPh3, and imidazole [91] provided iodide 75. The substitution of the iodo group in 75 by an anion generated from 2-methylpropionitrile [56-60] provided a hepta-nitrile derivative 76 in 95% yield. Then the secondary hydroxyl group in 76 was protected as an MOM ether to provide 77. Reduction of 77 with DIBALH followed by acidic hydrolysis gave aldehyde 78. The Horner-Emmons reaction of 78 with triethyl 4-phosphonocrotonate in the presence of LiOHH20 and molecular sieves 4A powder [68]... 

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