Double annulation

The syntheses of stemodin and stemodinone, structural relatives of aphidicolin, were accomplished using the A/B double annulation and B/C spiro annulation processes developed for the assembly of aphidicolin. 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

The total synthesis described in the following account was a product of the last motivation. Our group had developed a synthetic methodology, a suite of reactions that we called double annulation, and we sought to apply it to the synthesis of a naturally-occurring compound. 

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

Ill. N. Naz, T. H. Al-Tel, Y. Al-Abed, and W. Voelter, Palladium-cobalt-mediated double annulation process a new strategy to chiral and poly substituted bis-cyclopentanoids on carbohydrate precursors, J. Org. Chem., 61 (1996) 3250-3255. 

Eaton and his co-workers found it possible to prepare the tetracyclo[6.6.0.02,6. O10,14]tetradecanes 494 and 495 through implementation of the double annulation sequence illustrated in Scheme 72.46, 60, 41S Twofold addition of the 3-lithiopropyl... 

The same authors then proceeded to synthesise the corresponding azolium salt based on the l,r-binaphthyl scaffold (see Figure 5.23) [79]. The same failure to synthesise either the free carbene or transition metal carbene complexes from it was estabUshed experimentally. Electronic destabilisation by a double annulation effect from the two phenyl (naphthyl) rings on the seven-membered azolium ring systan is indeed the most likely explanation. 

The naturally occurring clerodane diterpenoid ( )-sacacarin has been synthesized by R.B. Grossman and co-workers in only 10 steps using a double annulation of a tethered diacid and 3-butyn-2-one. " The second ring of sacacarin was prepared by an intramoiecuiar Dieckmann condensation of an ester and a methyl ketone in excellent yield. The resulting end was then immediately converted to the corresponding ethyl enol ether using ethanol and an acid catalyst. 

Grossman, R. B., Rasne, R. M. Short Total Syntheses of Both the Putative and Actual Structures of the Clerodane Diterpenoid ( )-Sacacarin by Double Annulation. Org. Lett. 2001, 3, 4027 030. 

The nucleus of the gilvocarcins, benzo[(/]naphtho[l,2-6]pyran-6-ones, has been derived in one step by the double annulation of a styryl sulfone with a phthalide <05JOC9017>. 

Apparent attempts to effect a double annulation using a diiodobiphenyl have been reported to produce a single alkyne insertion product, in which the second iodo group has been replaced by a methyl group from added methyl... 

A convenient synthesis of highly functionalized dihydropyrido[2,3-tfjpyrimidines via a double [5 + l]-annulations stoategy was developed. The double annulation route starts from easily available a-alkenoyl-a-carbamoyl ketene-(5,S)-acetals. 2-Amino-3-carbamoyl-5,6-dihydro-4-pyridones was firstly created in excellent yield by a formal [5C + IN] annulation reaction of ketene-(iS. 5)-acetals with ammonia. In the second step, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3/f)-ones (when R = aryl) and 7,8-dihydropyrido[2,3-d]pyrimidines (when R = H), were prepared in good yields by reacting 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones with excessive Vilsmeier reagent (DMF/POCI3) via a second [5 + 1] annulation step. 

Kumar, K. (2012) Stereoselective cascade double-annulations provide diversely ring-fused tetracyclic benzopyrones. Org. Lett, 14, 5924-5927. 

Finally, the same group carried out a mono and a double annulation of arynes to synthesize fluoren-2-ones 60 and polycyclic aromatic systems 62 respectively [40]. These methods involve the in situ formation of highly reactive arynes by reaction of 2-(trimethylsilyl)aryl triflates 58 and CsF. In the presence of Pd(dba)2 (dba = dibenzylideneacetone), a crosscoupling and cyclization with a 2-halobenzaldehyde occur in the former case and C—H activation and cyclization occur in the latter case (Scheme 8.13). 

Scheme 13.18 Stereoselective domino double annulation to ring-fused benzopyrenes.

Carbopalladation of Arynes by Arylpalladium Complexes Pd-Catalyzed Annulation Reactions of Arynes. Whereas the Pd-catalyzed annulation of alkynes by aiyl halides has proven to be an effective method for the construction of a wide variety of hetero- and carbocycles similar carbopalladation of arynes were unprecedented until Larock and Zhang reported the synthesis of flu-oren-9-ones 115 through the annulation of arynes by o-haloarenecarboxaldehydes (Scheme 12.57) [100]. Larock s group has also developed a Pd-catalyzed annulation of arynes by 2-halobiaryls, affording polycyclic aromatic and hetCToaromatic compounds such as 116 from simple starting materials. Larock and Cheng have independently reported the related double annulation of arynes by simple aryl halides as an efficient route to functionalized triphenylenes (Scheme 12.57) [101]. 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

Corey, E. J. Balanson, R. D. Simple synthesis of ( )-cedrene and ( )-cedrol using a synchronous double annulation process Tetrahedron Lett. 1973, 14, 3153-3156. 

SCHEME 22.32 Double annulation of 1,2-diboryl reagents with dibromobis(2-bromoethenyl)arenes. 

SCHEME 22.38 Double annulation of 9-stannafluorenes with tetrabromides. 

The cyclization of o-alkynyl allyl ethers 31 can be promoted not only by plat-inum(II) catalysts [4] but also palladium(O) catalysts (Scheme 27.13) [17]. Penta-cyclic compound 35 were synthesized from bis(allyloxy)bis(alkynyl)benzenes 33 via palladium-catalyzed double annulations to the benzodifuran 34, ring-closing metathesis, and oxidation (Scheme 27.14) [18]. 

In studies toward the synthesis of the antibacterial natural product pleuromutilin (Scheme 25.66), Procter et al. reported a cascade double annulation process using Sml2 to generate an initial ketyl radical from 137. After a subsequent cyclization, the resulting new ketyl radical was reduced to form the organosamarium (III) intermediate 138, which in turn promoted a diastereoselective intramolecular aldol reaction to give 139. ° ... 

Fries, J.L., Jeffrey, C.S., and Sorensen, E.J. (2009) A hypervalent iodine-induced double annulation enables a concise synthesis of the pentacydic core structure of the cortistatins. Oig. Lett., 11, 5394-5397. 

---