Cobalt-mediated cyclization

P-citronellene 605 f 612 (/Q-citronellic acid 232, 235 (/ )-citronellol 360 Claisen rearrangement 17, 87, 90, 137 f., 140, 142, 194 -, Johnson ortho ester variant see Johnson ortho ester Claisen rearrangement cobalt-mediated cyclization... 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

A completely stereoselective, one-step assembly of a strained protoilindane framework can be achieved by cobalt-mediated cyclization of an appropriate acyclic enediyne precursor, which leads to a total synthesis of illudol (l) 1. 

In a similar manner, these researchers have also synthesized [48] a C-8 side-chain analog 60 of domoic acid using a cobalt-mediated cyclization-elimination sequence on the iodide 59 (Scheme 22). They extended this methodology to an enantiospecific total synthesis of acromelic acid A 64, a potent neurotoxin obtained from poisonous mushrooms [46]. The cornerstone of their synthetic strategy was a cobalt-mediated radical cyclization of the substrate 61 which was prepared from the epoxy alcohol in optically pure form. Treatment of 61 with cobalt(I) afforded 62, which was converted to the natural product 64 via pyridone 63 using routine functional group manipulation (Scheme 23). 

Siebert also used the cobalt-mediated cyclization of alkynes to synthesize the first tetraborylated and hexaborylated benzene compounds (48-50 Scheme 10). The boronate ester (49) which formed initially was converted into the intriguing base-free hexafunctional triorganoborane (50) with trimethylaluminum." ... 

This synthetic methodology was used to prepare (+)-estrone in 5 steps and 12.5% yield from 2-methylcyclopentenone where the benzocyclobutene was prepared by a cobalt-mediated cyclization of 1,5-diynes and acetylenes. The reaction type was also used in an alkaloid synthesis. 

A recent synthesis of this building block has been published by Eastham et al. in 2006 (48). Their key step is a Dotz benzannulation reaction and is shown in Scheme 2.10. The bromohydrin 66 was formed from dihydrofuran (50). Cobalt-mediated cyclization, followed by ozonolysis with reductive work-up yielded 68 after hydrazine formation. Reductive removal of the hydrazine function, followed by chromium-carbonyl formation gave the Dotz reaction precursor 69. This reacted with an alkyne in the Dotz reaction, and was then oxidized and hydrogenated 70). Pyrolysis gave the protected alcohol and the remaining free alcohol was protected as a triflate (—> 71). Reductive removal of the triflate and deprotection of the silyl ether yielded the desired 33 in 1.2% overall yield. 

Another cobalt-mediated cyclization reaction is the Pauson Khand reaction (PKR). In a [2 -H 2 - - 1] fashion, the reaction of TMSA with alkenes delivers regioselectively silylated cyclopen-tenones. Following the trend typically observed in the PKR, the bulky TMS-group is always positioned a to the carbonyl group (eqs 37 and 38)7 ... 

Under the conditions of the cobalt-mediated carbonylative A-oxide-promoted cocyclization (Pauson-Khand reaction) at room temperature, compound 547 provides exocyclic 1,3-diene 548 as the major product (>98%) together with only traces of the corresponding carbonylative product 549. Owing to the relative instability of the diene, it is more efficient to perform a one-pot cobalt cyclization/Diels-Alder process after A-oxide-promoted cyclization of the cobalt complexes. Compound 550 is obtained as a single diastereomer in 39% overall yield if MTAD is used as a dienophile (Scheme 90) <2003JOC2975>. 

Malacria and co-workers76 were the first to report the transition metal-catalyzed intramolecular cycloisomerization of allenynes in 1996. The cobalt-mediated process was presumed to proceed via a 7r-allyl intermediate (111, Scheme 22) following C-H activation. Alkyne insertion and reductive elimination give cross-conjugated triene 112 cobalt-catalyzed olefin isomerization of the Alder-ene product is presumed to be the mechanism by which 113 is formed. While exploring the cobalt(i)-catalyzed synthesis of steroidal skeletons, Malacria and co-workers77 observed the formation of Alder-ene product 115 from cis-114 (Equation (74)) in contrast, trans-114 underwent [2 + 2 + 2]-cyclization under identical conditions to form 116 (Equation (75)). 

Some of the most striking examples for an intramolecular Pauson-Khand reaction involving a tetrasubstituted double bond are the cobalt-mediated cyc-lizations of bicyclopropylidene derivatives 234 leading to the interesting spirocyclopropanated tricyclic products 235. The successful cyclizations even of the trimethylsilyl-substituted enynes 234 demonstrate the unique reactivity of the strained double bond in the bicyclopropylidene moiety of these molecules (Scheme 55) [145]. 

Cyclizing ca-chloro Reissert compound 136 gives rise to tricyclic lactam 137 (72JHC541). In a study of the cobalt-mediated reaction of pyridones with alkynes, in the case of the N-hexynyl compound, C-H activation with... 

Previous work in Baldwin s group based around cobalt(I)-mediated cyclization had led to syntheses of (-)-a-kainic acid 2, (+)-allokainic acid 3,34 and acromelic acid A 5.35 A cobaloxime-mediated cyclization of 27 gave the separable pyrrolidines 28 and 29, suitable for conversion to (-)-a-kainic acid 2 and (+)-allokainic acid 3, respectively.34 In this instance, the required stereoisomer 28 for the preparation of (-)-a-kainic acid 2 predominated in a ratio of 28 29,1.7 1 (Scheme 6). Both 28 and 29 were carried through to the respective kainoids 2 and 3. In this case, asymmetry was introduced at a very early stage in the synthesis via a Sharpless asymmetric epoxidation. 

Reaction of aryl Grignard compounds, obtained in situ by iodine-magnesium exchange, with C0CI2, presumably generates aryl radicals. In the presence of a double bond or aromatic ring an intramolecular radical cyclization may take place. This reaction was used for the synthesis of spiro-indolines.244 Oshima has applied cobalt-mediated tandem radical cyclization-cross-coupling reaction for the synthesis of benzyl-substituted heterocycles (Scheme 80).245... 

In previous works this group had observed a competition between the PKR and a [2 + 2 + 2] cyclization in the second reaction step of three triple bonds. Thus, when reacting linear triynes 174 under catalytic, high CO pressure, cobalt mediated PKR conditions, they obtained mixtures of products 175 coming from two [2 + 2 + 1] cycloadditions, and 176 from a [2 + 2 + 1]/ [2 + 2 + 2] tandem reaction. When the triple bonds were ether linked, the latter was the favored reaction, while with substrates lacking oxygen atoms, the iterative PKRs was the major pathway (Scheme 51) [166]. When the reaction was performed intramolecularly between a diyne and an alkyne, the only reaction products were the result of a [2 + 2 + 1 ]/[2 + 2 + 2] tandem cycloaddition [167,168]. 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

Pauson-Khand Cycloaddition. Pauson Khand cycloaddition (see Pauson-Khand Reaction) is a cobalt-mediated method to prepare cyclopentenone from the cyclization of an alkyne with an alkene and CO (equation 14). This method is widely used to produce cychc ketones. Originally, stoichiometric amounts of Co2(CO)g were used in these reactions with the cobalt carbonyl being the CO source. However, it was shown that a strict temperature profile and high-purity reagents allowed the use of catalytic amounts of Co2(CO)g for reactions with 1 atm of CO. Currently, there is intense interest in developing catalytic cobalt starting materials for use in Pauson-Khand reactions. 

In 1993, Paolesse, et al. described the synthesis of the first weso-phenyl substituted corroles. These were obtained from the mono-phenyl substituted dideoxy-biladiene-ac 2.145, a species obtained, in turn, from the acid-catalyzed condensation of the monoformyl pyrrole 2.143 and the diacid dipyrrylmethane derivative 2.144. Once the hydrobromide salt of this phenyl-substituted dideoxybiladiene-ac 2.145 was in hand, cobalt(II)-mediated cyclization afforded the mono-7nejo-phenyl-cobalt(III) cor-role 2.146 in 40% yield (Scheme 2.1.38). As in the case of the me o-unsubstituted corroles, addition of PPh3 proved necessary for the isolation of the product. 

The resulting heterocycles in the complex may be further reduced or desilylated (either in the complex or after demetallation). Further synthetic potential exists in the use of the primary products, obtained by cobalt-mediated cycloadditions, as synthons in organic chemistry. For example, indole derivatives have been co-cyclized at the j/ -Cp-cobalt catalyst to give 4a,9a-dihydro-9//-carbazoles or, after oxidation, precursors for strychnine [50]. Remarkably, the cycloaddition of acrolein in the presence of a small amount of methyl acetate occurs at the carbonyl, rather than at the C=C double bond, to give vinylpyran selectively (eq. (19)) [48]. 

For several examples of cobalt-mediated intramolecular cyclizations of nitriles to pyri-... 

In studies directed towards forskolin, Pattenden et al. have observed dichotomous reactivity in stannane- and cobalt-mediated radical cyclization. In one instance, it was shown that the radical cyclization of the bromoacetal 24 initiated by BuySn" (BusSnH, AIBN) led to predominantly (95%) the equatorial-oriented side-chain isomer 25a, whereas use of catalytic vitamin B12 (MeOH, LiC104, -1.9 V, 24 h) produced (70%) almost entirely the corresponding axial epimer 25b (Scheme 9) [13j. 

Scheme 9. Dichotomous reactivity in stannane and cobalt-mediated radical cyclization...

Scheme 15. Mechanism of cobalt-mediated intramolecular radical cyclization...

Pattenden and coworkers have developed a cascade cobalt group transfer reaction by effecting consecutive cobalt-mediated radical cyclizations in a controlled... 

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