Cyclization Diels-Alder, intramolecular

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

An intramolecular Diels-Alder cyclization produces excellent yields of 2-aminoquinoline-3-carboxylate esters (57). Equally fine yields of the requited carbodiimides have been reported, making this an attractive route to an unusual substitution type. 

A similar intramolecular Diels-Alder strategy was employed in an efficient synthesis to an appropriately functionalized hydrindanone nucleus (212). After functionalization, Diels-Alder cyclization, and appropriate functional group manipulation, this hydrindanone was converted into ( )-cortisone. The overall process afforded ( )-cortisone in a total of 18 chemical steps in approximately 3% yield. 

A first milestone was the development of a novel intramolecular Diels-Alder cyclization of terphenyl monomers 38 and 41, containing both 4-phenylbuta-dienyl and styryl functions. The formation of the [4-1-2] cyclization adducts 39 and 42 is followed by a simple aromatization of the cyclohexene moieties [59]. In this way, the phenylated, two-dimensional arylene structures, 40 and 43,... 

The possible importance of side reactions such as Friedel Craft alkylation, inter or intramolecular Diels Alder cyclization or re-addition of HC1 in this context have also been emphasised (43). 

Intramolecular Diels-Alder cyclizations of (E)- -nitro-1,7.9-decatrienes under thermal conditions and Lewis acid conditions lead to the formation of decalin ring systems with excellent endo selectivity (Eq. 8.21). This strategy is used for preparing of the AB ring system of norzoanthamine.33... 

Scheme 6.246 Intramolecular Diels—Alder cyclization of biodihydroxylated benzoic acid derivatives.

As reported previously in CHEC-II(1996) <1996CHEC-II(7)229>, intramolecular Diels-Alder cyclization is useful for the preparation of the partially reduced pyrrolopyridazine 79 (Equation 33) <1998JOC6329, 2000JOC9120>. 

On irradiation, the aldehyde 1 underwent photoenolization to give the quinone methide 9. Intramolecular Diels-Alder cyclization then proceeded with high diastereocontrol to give 2 as a mixture of epimeric esters. 

The marine alkaloid (-)-norzoanthamine 3 suppresses bone loss in ovariectomized mice, and so is of interest as a lead to antiosteoporotic drugs. A substantial challenge in the assembly of 3 is the stereocontrolled construction of the C ring, with its three all-carbon quaternary centers. In the synthesis of 3 by Masaaki Mayashita of Hokkaido University (Science 2004,305,495), the and C rings were built and two of the three needed quaternary centers were set by the intramolecular Diels-Alder cyclization of 1 to 2. 

Functional group manipulation then gave 1, setting the stage for the intramolecular Diels-Alder cyclization. 

Sordaricin 2 is the aglycone of sordarin 3, the parent of a family of clinically-effective antifungal agents. Lewis N. Manderof the Australian National University has published (./. Org. Chern. 2005, 70, 1654) a full account of their enantioconvergent (see below) synthesis of 2, based on the intramolecular Diels-Alder cyclization of the triene 1. For a complementary total synthesis by Narasaka of sordaricin 2, see Org. Chem. Highlights 2005, April 4. 

It is interesting that on heating 1 or the cycloadduct above 150 "C, the predominant product (3-4 1) from the cycloaddition is the undesired regioisomer 16. So, even though the transition state in the intramolecular Diels-Alder cyclization is product-like, the more stable transition state for the cyclization of 1 in fact leads to the thermodynamically less stable regioisomer 2. 

Further reactions that are highly suited to the synthesis of cyclohexane derivatives, such as cycloaddition processes, 1,3-dipolar additions, and Diels-Alder cyclizations, have been used extensively. In the latter set, carbohydrate-based dienes or dienophiles have been employed and, in addition, intramolecular processes have provided highly suitable means of synthesizing complex polycyclic systems. 

Diels-Alder cyclization of IfiAO-undecatrienals.5 These unsaturated aldehydes undergo intramolecular Diels-Alder cyclization, particularly under Lewis acid catalysis. The reaction is highly endo-selective. Silyl-protected alcohol groups at C4 and Q can be present, and t-butyldimethylsilyl ethers show a strong axial preference. 

Starting from substituted 2-azetidinones, a family of tribactams (II, Fig. 7) has been reported to be prepared by using two main steps an intramolecular metathesis reaction and a Diels-Alder cyclization [258],... 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

The prochiral triene 16 (Figure 5) is a suitable precursor for the bicyclic core structure 17, and can be obtained in ten steps starting from dimethyl malonate. The intramolecular Diels-Alder cyclization to 17 proceeds with Me2AlCl catalysis in very good yield under mild conditions [12, 18],... 

Fig. 5. Total synthesis by Nicolaou intramolecular Diels-Alder cyclization and introduction of the C-7 side chain. TBDPS = tert-butyldiphenylsilyl, PMB = p-methoxybenzyl.

The authors elaborated an innovative synthesis of the Taxane core based on an intramolecular Diels-Alder reaction as the key step. The TBDMS-protected cylohexenone-derived alcohol was converted into the corresponding nitrile intermediate in five steps by known synthetic manipulations (Scheme 43), mainly based on transmetallation protocols. The diene handle for the Diels-Alder reaction was then introduced following a simple but highly efficient four-step procedure. The dienophile for the cycloaddition, the terminal acetylene moiety, was incorporated via lithiation chemistry to furnish the substrate for the intramolecular Diels-Alder cyclization (Scheme 43). 

Products from such reactions have been employed in the synthesis of terpenes via intramolecular Diels-Alder cyclizations (94-96). If the bulk of the carbonyl reagent is increased by inclusion of a large adjacent protecting group, much improved regioselectivity toward terminal attack is acheived (97,98). A complementary approach has been adopted by Oppolzer who... 

Intramolecular imino Diels-Alder cyclization is a useful method in alkaloid synthesis. The reaction is highly stereoselective but gives results opposite to those usually found in closely analogous all-carbon systems. Thus, the diene (284) on pyrolysis gives the single trans cycloadduct (286). The reaction is rationalized by assuming initial formation of the... 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

The scope of the 2-azadiene intramolecular Diels-Alder cyclization, employed for the synthesis of the daphniphyllum alkaloids, has been further investigated by Heathcock et al.[76j. The protocol involves Moffatt-Swem oxidation of the 1,5-diol to the dialdehyde, and treatment of the crude methylene chloride solution with ammonia followed by solvent exchange from methylene chloride to a buffered acetic add solution. The cydopentyl ring, quaternary carbon and tertiary carbon centers in... 

Dodecatrienals undergo intramolecular Diels-Alder cyclization in the presence of ethylaluminum dichloride or the milder Lewis acid diethylaluminum chloride at — 78 to -23°. -Example ... 

Equally intriguing is an intramolecular Diels-Alder cyclization after hexaketide formation. The domain in LovB that catalyzes the cyclization has not been discovered. 

A separate study of the alkylations of 1 has been reported by Oppolzer and co-workers. The group has employed LDA, LiTMP, and n-C4Hs,Li to metalate 1. The resulting anion condenses with a variety of electrophiles (primary alkyl bromides, iodides, tosylates, disulfides, and acyl derivatives) to afford the corresponding monosubstituted derivatives in 30-95% yield. If the alkyl group contains a double bond in the 4- or 5-position, polycyclic compounds are prepared by thermal extrusion of SO2 followed by intramolecular Diels-Alder cyclization. 

Conjugated polyeneyne 136 is a model precursor for the intramolecular Diels-Alder cyclization in a biomimetic pathway to the esperamycins (Scheme 5-7). This model compound is synthesized via 133-135 by regiocontrolled sequential coupling of three different alkynes using two kinds of appropriate Pd catalyst [66]. 

Williams, D. R., Brugel, T. A. Intramolecular Diels-Alder Cyclizations of (E)-1-Nitro-1,7,9-decatrienes Synthesis of the AB Ring System of Norzoanthamine. Org. Lett. 2000, 2,1023-1026. 

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