Astruc D. - Modern arene chemistry (2002)(en)

8.5 Synthesis of Specific Arenes 283

Whereas the torsion angle across the central arene CbC bond is small (< 6 ) for 5,11-dialkyl substitution, it increases with diaryl substitution and terminal Cr(CO)3 coordination to > 30 for 5,11-diphenylchrysene-6,12-dione, obtained from 98a upon careful ether cleavage and oxidation.

Another route to chrysenes was based on the benzannulation of bis(chromium carbenes) of 1,6-methano[10]annulenes [75b].

A series of other polycyclic hydrocarbons has been synthesized in moderate to good yields by benzannulation of tricyclic diarylcarbene complexes [36b].

8.5.5

Fused Heterocycles

Benzannulated five-membered heterocycles have been synthesized starting from furyl-, thienyl-, and pyrrolylcarbene complexes. With the exception of thiophene (for example, the transformation of 101 into 102), the corresponding 2- and 3-heteroarylcarbene complexes have been prepared and subjected to the benzannulation reaction (Scheme 38) [35a, 82].

Scheme 38. Benzannulation of furyl-, thienyl-, and pyrrolylcarbene complexes.

2848 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

While both 2- and 3-furylcarbene complexes 99 and 103 gave [b]-annulated benzofurans (100 and 104), only the 2-pyrrolyl carbene complex 105 a orded the aromatic indole skeleton (106). In contrast, annulation of the 2,5-dimethylated 3-pyrrolylcarbene complex 107 occurred at the 4-position to give isoindole quinone 108 after oxidative work-up [82g].

A complementary access to extended indole and carbazole systems is based on the thermal intramolecular benzannulation of ortho-alkynylanilinocarbene complexes or on a photoinduced benzannulation of phenylpyrrolylcarbene complexes. The first example involves an intramolecular access to the carbazole skeleton. Refluxing a solution of ortho-alkynylphenyl amino carbene complex 109 in acetonitrile gave a 63 % yield of benzocarbazole 110. Less strongly coordinating solvents (TBME, THF, or di-n-butyl ether) or other substituents less bulky than 2,4,6-trimethylphenyl (for example, phenyl or 4-methylphenyl) led to a considerably reduced yield (Scheme 39) [83].

Scheme 39. Fused carbazoles by intramolecular benzannulation.

Benzoindole 114 has been synthesized by a remarkable sequence, in which the benzannulation precursor 113 is pre-assembled starting from two di erent chromium carbenes. It is formed in a [3þ2] cycloaddition, in which the acylamino carbene complex 111 acts as the dipolar component and the alkynylcarbene complex 112 serves as the dipolarophile. The resulting 3-pyrrolylcarbene complex 113 undergoes a photoinduced intramolecular benzannulation to give the benzoindole 114 [84a]. This strategy complements an approach towards carbazoles [84b]. Isoindolines and 1,2,3,4-tetrahydroisoquinolines are accessible from the reaction of pentacarbonyl (a-methoxyethylidene) chromium with p,o-dialkynes bearing a nitrogen atom in the carbon ether [84c].

Pyrazolyl- [85], dihydropyridyl- [86], and pyrrolizinylcarbene complexes [87] have also been subjected to the benzannulation to give the respective oxygenated benzo-N- heterocycles. Finally, a,b,g,d-dienyl carbene complexes containing a heterocycle at the internal double bond have been utilized to prepare 2,3-dihydro-1,2-benzisoxazoles and indazoles by intramolecular benzannulation [60h].

8.6 Synthesis of Biologically Active Compounds 285

Scheme 40. Tandem cycloaddition/photobenzannulation approach to benzoindoles.

8.6

Synthesis of Biologically Active Compounds

Due to its versatility with respect to the scope and substitution pattern, both in terms of the chromium carbene and the alkyne, the benzannulation reaction has been recognized as a valuable methodology for the synthesis of complex biologically active compounds.

8.6.1

Vitamins

Soon after its discovery, the benzannulation reaction was applied to an organometallic synthetic approach to vitamins of the K and E series in order to test its scope [88]. The route leading to vitamin K1(20) has been optimized; its key step, the benzannulation involving chromium phenylcarbene 1 and enyne 116 finally gave a 92 % yield of a 2 : 1 regioisomeric mixture (both regioisomers ultimately a ord the identical naphthoquinone (vitamin K) upon oxidation) of the Cr(CO)3-coordinated hydroquinone monomethyl ether after chromatographic work-up. Since this method avoids the acidic conditions typically required for the attachment of the allylic terpenoid side chain to the arene nucleus, no undesired (E )/(Z )- equilibration in the alkene part occurs, which is known to hamper the biological activity of vitamin K [88b]. The related synthesis of vitamin E is outlined in Scheme 41. Starting from (E )-2-butenylcarbene complex 115 and enyne 116, it a orded a 36 % non-optimized yield of hydroquinone complex 117 as a mixture of two regioisomers. Demetalation under CO atmosphere, ether cleavage, and ZnCl2-promoted cyclization a orded vitamin E 119 in an overall yield of 20 %.

286 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

Scheme 41. Total synthesis of vitamin E involving a benzannulation.

8.6.2

Antibiotics

There are several classes of antibiotics that contain adjacent quinone and hydroquinone moieties. Since both functionalities are directly accessible by chromium carbene benzannulation, this organometallic methodology o ers an attractive strategy towards targets of this type. Special attention has been payed to antitumor agents having naphthoquinone and anthraquinone skeletons, such as anthracyclins, which contain a sugar moiety attached to the anthracyclinone [79, 89]. Depending on whether quinone ring C or hydroquinone ring D is to be constructed by benzannulation, there is a choice of complementary key steps combining the appropriate chromium carbene and alkyne precursors, as illustrated for daunomycinone 120 in Scheme 42 [89c, 90].

The route for the assembly of the C ring of 11-deoxydaunomycinone 124 is shown in Scheme 43 and corresponds to path C in Scheme 42. Reacting tetracarbonyl carbene complex 121 (available in quantitative yield by heating the corresponding pentacarbonyl carbene complex in boiling tert-butyl methyl ether) with the propargylic A-ring synthon 122 forms ring C in the tricarbonylchromium complex 123. Subsequent demetalation, C1- homologation of the ketone to the carboxylic acid, and Friedel–Crafts-type cyclization leads to ring B, and final functionalization of ring A completes the total synthesis of 11deoxydaunomycinone 124.

8.6 Synthesis of Biologically Active Compounds 287

Scheme 42. Synthetic strategies towards the anthracyclinone daunomycinone.

Scheme 43. A chromium carbene route to 11-deoxydaunomycinone.

288 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

Scheme 44. Total synthesis of fredericamycin A.

Apart from anthraquinone antibiotics, the benzannulation approach has also been applied to naphthoquinone antibiotics, as demonstrated for the antitumor agent fredericamycin A 128 [91]. This hexacyclic compound has a significant degree of complexity, including a series of functional groups and a stereogenic spirocenter. Its total synthesis relied on a regiospecific intermolecular benzannulation to form ring B as the final key step (Scheme 44) [91c, 92]. This involved assembly of the relatively simple chromium carbene 126 and the densely functionalized bulky alkyne 125 to give the desired regioisomer 127 in 35 % yield after oxidative demetalation. The final C/D-spirocyclization completed the total synthesis of fredericamycin A.

8.6 Synthesis of Biologically Active Compounds 289

8.6.3

Steroids

A less common ‘‘two-alkyne’’ benzannulation approach (a formal [2þ2þ1þ1] cycloaddition involving two alkyne, one carbon, and one carbonyl synthon [15a]) has been exploited in a tandem Diels–Alder benzannulation sequence leading to the tetracyclic steroid skeleton (Scheme 46) [93]. The triynylcarbene complex precursors 129a and 129b were first subjected to an intermolecular Diels–Alder reaction with the Danishefsky diene, which occurred at the activated CcC bond adjacent to the metal carbene fragment and generated the D-ring in the diynylarylcarbene complex 130 (87 % yield for the Diels–Alder reaction giving the chromium complex 130a and 82 % for that giving the tungsten complex 130b). The remaining rings A– C were constructed by a two-alkyne benzannulation a ording ring B attached to a central sixmembered and a terminal five-membered ring in a meta connectivity. Whereas the cyclization of the chromium carbene complex 130a was accompanied by competing formation of lactone 131a, the tungsten analogue 130b selectively a orded the desired steroid skeleton 132b in 51–78 % yield depending on the solvent used [93]. The influence of the metal is determined by the sequence of carbene carbonylation and insertion of the second alkyne into the metal–carbene bond; the more reactive chromium carbonyl bond has been suggested to favor both ketene formation prior to alkyne insertion and a final carbonylation to give lactone 131a.

Scheme 45. The ‘‘two-alkyne’’ benzannulation sequence as applied to steroids.

290 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

The benzannulation approach has also been used to generate a steroid D ring bearing both a tunable donor (ferrocenyl substituent) and an acceptor site (benzoquinone functionality), which allows for modification of the electron-transfer properties [94].

Another application aimed at the synthesis of novel steroidal systems, for example heterosteroids such as oxasteroids [95].

8.6.4

Alkaloids

Some selected alkaloids are readily accessible via the corresponding chromium carbenes. A versatile synthesis of indolocarbazoles 133 and 134, bioactive natural products with interesting protein kinase C inhibiting properties, is based on photobenzannulation. Depending on the nature of the C1-synthon, dioxy and oxyamino derivatives have been synthesized in good to very good yields (Scheme 46) [96].

Scheme 46. Synthetic approach towards bioactive indolocarbazoles.

The benzannulation allows a facile incorporation of a hydrogen-bonding functionality, which complements the pharmacophore in naturally occurring indolocarbazoles. Orthogonally protected indolocarbazole nitrogen atoms allow a concise and selective glycoside formation en route to synthetic indolocarbazoles as natural product analogues.

A model compound from a second group of alkaloids related to colchicine (allocolchicinoid 137) has been synthesized by benzannulation of racemic benzocycloheptenyl carbene complex 135 with 1-pentyne; the annulation product 136 was obtained in 48 % yield after oxidative demetalation (Scheme 47) [97].

8.7 Summary and Outlook 291

Scheme 47. Formation of the allocolchicinoid C ring by benzannulation.

8.7

Summary and Outlook

The chromium-templated benzannulation of Fischer carbene complexes with alkynes provides a flexible synthetic tool for a wide range of both natural and theoretically interesting compounds. The key features of this [3þ2þ1] cycloaddition are the regioselective and (in the presence of a chiral auxiliary) diastereoselective, mild, one-pot assembly of the alkyne, the carbene ligand, and one carbonyl ligand, as assisted by the template e ect of the transition metal, to give densely functionalized Cr(CO)3-labeled arenes. Beyond the traditional strategy for preparing arene tricarbonylchromium complexes by Cr(CO)3-transfer onto a preassembled arene, the benzannulation allows a regioselective complexation of polycyclic hydrocarbons under mild conditions. The regioselectivity is virtually complete with terminal alkynes, and can be accomplished for internal alkynes by the intramolecular version of the reaction. The resulting hydroquinone tricarbonylchromium complexes are valuable building blocks possessing a plane of chirality; they can be demetalated to give either densely substituted arenes or, after oxidative work-up, the corresponding quinones. Moreover, the tricarbonylchromium fragment can be exploited in further arene functionalization by stereocontrolled nucleophilic addition or substitution. Finally, the Cr(CO)3 fragment per se incorporated into polycyclic arenes by benzannulation provides a label that can be shifted

2928 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

along the aromatic p-face in a haptotropic metal migration, and may thus serve as a movable functional group.

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