Total synthesis of modhephene

Modhephene 24 is the most synthetically investigated natural product containing the characteristic [3.3.3]propellane moiety. Its polycyclic scaffold consists exclusively of carbon atoms and contains a single double bond, which is the only unsaturated part of the molecule. However, these structural features are synthetically challenging. There are nineteen total syntheses of modhephene published up to date, which cover all possible cationic, nucleophilic, radical and photochemical approaches.²⁴

Scheme 2. Total synthesis of modhephene 24 by Dreiding.²⁵

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For the first time modhephene 24 was synthesized by the group of Dreiding in 1980 (Scheme 2).²⁵ Starting from the unsaturated bicyclic ketone 25, a Michael addition of cyanide was performed, followed by a Wittig reaction and subsequent hydrogenation of the obtained olefin furnished nitrile 26 as a mixture of diastereomers in good yield.

After basic hydrolysis of 26 the obtained carboxylic acid was converted to the corresponding acid chloride and directly subjected to AlCl3 catalyzed reaction with bis(trimethylsilyl)acetylene 27. Following basic desilylation provided ynone 28 in 90%

yield. The next step enabled formation of the desired [3.3.3]propellane motif via thermic annulation of α-alkynone. By heating 28 at 620 °C, an alkylidene carbene is formed in situ which after abstraction of the tertiary hydrogen atom cyclizes to 31 along with the side products 30, 29 in a ratio 2:1:1 albeit in impressive 95% combined yield. The obtained mixture of regioisomers 29, 30 and 31 was not separated at this stage, but after two additional steps. Subsequent 1,2-addition of MeLi and Jones oxidation gave pure intermediate 32 30% yield over two steps. Following copper-mediated Michael addition furnished gem-dimethyl 33. Finally, the carbonyl moiety was olefinated giving 34 and the resulting exocyclic double bond was shifted providing modhephene 24.

Similar approaches were independently used in total synthesis of modhephene 24 by other research groups.^26,27,28

Alternatively, the group of Smith III developed an effective strategy towards modhephene 24 utilizing a spectacular carbocationic rearrangement (Scheme 3).²⁹ This synthesis commences with building block 35 which was subjected to irradiation in the presence of 1,2-dichlorethen 36 thus assembling the propellane scaffold 37 already

Scheme 3. Total synthesis of modhephene 24 by Smith III.²⁹

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in the first step. Next the ketone moiety was protected as an acetal and Birch conditions were used to install the cyclobutene ring. Following deprotection under acidic conditions, led to the highly strained β,γ-unsaturated ketone 38. Hereupon Cargill reaction was performed during which a 1,2-shift of the olefin occurred to 39 followed by the pinacol rearrangement which furnished the modhephene-like intermediate 40 in excellent 93% yield. The following MeLi addition and Jones oxidation enabled successful allylic transposition. Subsequent 1,4-addition using Me2CuLi provided compound 41. The final olefination/double bond shift sequence was performed in analogy with the synthesis of Dreiding et al.²⁵ to give modhephene 24 in 43% yield over two steps.

Another impressive example of a modhephene synthesis in terms of cationic rearrangement was demonstrated by Fitjer (Scheme 4).³⁰ The synthesis started with an olefination of acetone with cyclobutane phosphor ylide 42, followed by [2+2]-ketene cycloaddition furnishing spirocyclic ketone 43 in an efficient manner. Both chlorine atoms were removed by using zinc in acetic acid and after one more Wittig olefination with 42 tricyclic intermediate 44 was obtained. Subsequent epoxidation of the tetrasubstituted double bond with mCPBA worked in excellent 91% yield. Upon exposure to Lewis acid the obtained epoxide reacted in a semipinacol rearrangement with moderate yield, which was followed by α-methylation to give a mixture of diastereomeric ketones 45.

Scheme 4. Total synthesis of modhephene 24 by Fitjer.³⁰

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Additional deprotonation with LDA and quenching with aquatic sodium sulfate enriched desired diastereomer and after addition of methyl lithium intermediate 46 was isolated.

After nine steps the stage was set for the key cationic cascade rearrangement. Heating the 46 to 70 °C in benzene with pTsOH resulted in formation of the desired modhephene 24 and triquinane 47 in excellent combined yield. This is a remarkable example for the application of cationic cascade reactions in the synthesis of complex natural products containing propellane fragments.

Other total syntheses of modhephene utilizing a carbocationic rearrangement key step were reported by Mundy³¹ and Tobe.³²

The group of Cook developed a very simple but rather practical approach towards the total synthesis of modhephene 24 (Scheme 5).³³ The desired [3.3.3]propellane motif was assembled using Weiss reaction already in the first step. First double Knoevenagel condensation of 1,2-diketone 48 with dimethyl 3-oxoglutarate 49, followed by the double Michael addition of a second equivalent of 49 installed the propellane moiety, which after ester decarboxylation provided diketone 50. One ketone moiety was selectively converted to the corresponding enol phosphonate which was reduced under hydrogen atmosphere in the presence of Pt on charcoal in 75% yield over two steps. Subsequent classic Regitz diazo-transfer gave the diazo compound which, upon addition of copper sulfate and formation of corresponding copper carbenoid, was converted to cyclopropane 51. Next, the less sterically hindered α-position of ketone 51 was methylated twice with good yields and the tertiary alpha position was deprotonated with tBuLi. Trapping of the formed enolate with carbon dioxide followed

Scheme 5. Total synthesis of modhephene 24 by Cook.³³

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by esterification using diazomethane resulted in the formation of compound 52 in moderate yield.

Reaction with Me2CuLi resulted in the addition of methyl group on γ-position with accompanied opening of cyclopropane ring. Obtained derivative was further smoothly methylated yielding 53 with all methyl groups in place. Upon heating of 53 in the presence of lithium iodide and collidine, the ester moiety was efficiently removed and final reduction/alcohol elimination furnished modhephene 24.

Almost in a decade two other syntheses of modhephene followed, which featured anionic cyclization as key step for the propellane formation.^34,35

In 1982 group of Wender pioneered the application of the meta-photocycoaddition in the synthesis of complex natural products, thus synthesizing modhephene 24 in a very short and concise manner (Scheme 6).³⁶

Scheme 6. Total synthesis of modhephene 24 by Wender.³⁶

The synthesis started with very simple building blocks - arene 54 and vinyl acetate 55 which were irradiated with UV-light for 35 hours using the Vycor filter. In this manner, tetracyclic compound 56 could be obtained in 21% yield, but with the already build up propellane skeleton and right oxidation states on carbon framework for further functionalization. With this in hand, in next steps the alcohol moiety was deprotected and oxidized with BaMnO4 in high yields. Obtained ketone 57 was extensively methylated, albeit in low yield (apart from 68% of double methylated product). Addition of copper reagent resulted in methylation with concomitant opening of the cyclopropane ring, whereupon the in situ generated enolate was trapped giving

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phosphoramide 59 in 76% yield. After two additional selective reductions modhephene 24 was synthetized over 7 steps in 8.2% overall yield.

Another remarkable example of application of photochemistry in total synthesis of modhephene belongs to the oxa-di-π-methane rearrangement. The synthesis started with Grignard 1,2-addition to bicyclic enone 60 followed by the acid mediated water elimination thus providing a complex and very sensitive mixture of olefins in a combined yield of 86% containing diene 61 as a major component. This mixture was immediately subjected to Diels-Alder reaction with α-chloroacrylonitrile leading to the formation of two products 62 and 63 in a 43% yield. After subsequent hydrolysis, the ketones 64 and 65 were obtained, which could be separated using silica gel column chromatography. Next the ketone 64 was irradiated with a 450W Hanovia medium-pressure lamp in acetone to give propellane 66 by pivotal oxa-di-π-methane rearrangement in 50% yield. The less substituted α-position of 66 was methylated twice furnishing intermediate 67 with 55% yield. The cyclopropane ring of 67 was opened under Birch conditions, and the ketone moiety was reinstalled using PCC oxidation.

Subsequent introduction of the last methyl group yielded derivative 68.

Scheme 7. Total synthesis of modhephene 24 by Mehta.³⁷

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Final reduction with lithium aluminium hydride and treatment with phosphoryl chloride completed the synthesis of modhephene 24.

The similar key oxa-di-π-methane rearrangement was also used by the group of Uyehara for the synthesis of modhephene in 1996.³⁸

Another method which also proved to be very suitable for the assembly of propellane units is a radical cyclization cascade reaction. For example, such an approach was developed by the group of Lee (Scheme 8).³⁹ The synthesis began with the ketoester 69 which was deprotonated with two equivalents of LDA in the presence of HMPA.

After addition of 4-bromobutene 70 the first alkylation product was obtained in 87%

yield. Repetition of this procedure with another electrophile 71 furnished the intermediate 72 in moderate yield. Subsequent treatment with KOH in MeOH under elevated temperature led to the saponification of the ester moiety and carbon dioxide extrusion.

Scheme 8. Total synthesis of modhephene 24 by Lee.³⁹

The obtained ketone was condensed with N-amino aziridine 73 providing the hydrazone 74. Next, the key radical cyclization cascade was performed utilizing classic conditions and therefore allowing the smooth formation of 75 in 74% yield. The remaining exocyclic double bond from the alkyne part was ozonolyzed to the corresponding ketone, which in turn was deprotonated, reacted with PhSeBr and after following selenoxide elimination converted to enone 76. Compound 76 was already

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used in several total syntheses of modhephene 24, thereby Lee successfully accomplished the formal synthesis.

A different approach to modhephene was developed by Pattenden and coworkers, who started the synthesis with cyclooctanone derivative 77 (Scheme 9).⁴⁰ The intermolecular McMurry coupling of ketone 77 with acetone followed by TBS-deprotection and Swern oxidation provided intermediate 78. Next, Peterson olefination was used to introduce ester side chain. Subsequent basic hydrolysis yielded corresponding carboxylic acid which was transformed into the thioester 79 using Steglich coupling conditions. Heating of 79 and tributyltin hydride in the presence of azobisisobutyronitrile triggered the radical cyclization cascade thus enabling smooth formation of tricyclic propellane 80. Two step Regitz protocol was used for the synthesis of diazo-compound 81. The reflux of 81 with CuSO4 resulted in a C-H insertion of the corresponding carbenoid, leading to the literature-known tetracyclic derivative 82 and thus finishing the formal synthesis of modhephene 24.

Scheme 9. Formal total synthesis of modhephene 24 by Pattenden.⁴⁰

Apart from the approaches mentioned above there are syntheses by Curran⁴¹, Sha⁴² and Rawal⁴³ which used the radical cyclization as a key step.