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Synlett 2014; 25(17): 2467-2470
DOI: 10.1055/s-0034-1379009
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Tenuifolin through Intramolecular Nicholas Reaction

Sinisa Djurdjevic
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, Canada   Fax: +1(519)9737098   Email: jgreen@uwindsor.ca
,
James R. Green*
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, Canada   Fax: +1(519)9737098   Email: jgreen@uwindsor.ca
› Author Affiliations
Further Information

Publication History

Received: 30 June 2014

Accepted after revision: 30 July 2014

Publication Date:
08 September 2014 (online)

 
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Abstract

The synthesis of the Cinnamomum homosesquiterpenoid tenuifolin has been accomplished by way of an intramolecular Nicholas reaction of the [Co2(CO)6] complex of an alkyne-substituted biaryl for construction of the seven-membered ring. The cyclization features the reaction of a nonactivated arene ring with the propargyldicobalt cation to give the dibenzocycloheptyne-Co2(CO)6.


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Key words

alkynes - total synthesis - carbocation - fused-ring systems - electrophilic aromatic substitution - transition metals

The Cinnamomum homosesquiterpenoids are a series of dibenzocycloheptenemethanol derivatives that include tenuifolin (1), subamol (2), reticuol (3), burmanol (4), and several glycosidic subavenosides (Figure [1]). They have been isolated recently from several trees of the genus Cinnamomum, which have been used in folk medicine.[1] The sesquiterpenoid tenuifolin itself has been isolated from the stems of Cinnamomum tenuifolium and Cinnamomum reticulatum, and has been shown to possess weak activity against the prostate tumor cell line LNCaP.[1a] [b] Reticuol has also shown inhibitory activity towards microsome CYP3A4.[1c]

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Figure 1 Cinnamomum debenzocycloheptanoids

Synthetic studies towards members of this group of compounds have been limited. The first total synthesis of tenuifolin was reported recently by Wu and co-workers; this synthesis centered on a PIFA-mediated oxidative biaryl coupling to afford the seven-membered ring of the dibenzocycloheptene.[2] The other members of this class of compounds have not been the subject of published synthetic work.

Our group has developed several protocols for the synthesis of seven-membered-ring systems based on cycloheptynedicobalt complexes,[3] [4] and recently applied this approach to the synthesis of dibenzocycloheptanes and allocolchicines by way of intramolecular Nicholas reaction chemistry (Equation 1).[5–7] These reactions normally involve a very electron-rich arene [R1 = electron-donating group(s)] attacking the propargyldicobalt cation (5 → 6), which is appropriate because the bimolecular reactions of propargyldicobalt cations require a partner with a nucleophilicity greater than that of m-xylene for successful reaction.[8] Conversely, the corresponding approach to tenuifolin or subamol would involve attack of a considerably less electron-rich arene ring site (meta- to methoxy) on the propargyldicobalt cation. Given that (1) this approach would test the reactivity limits of Nicholas reaction based dibenzocycloheptane synthesis, (2) this is a distinct ring-closure approach to the tenuifolins relative to the work of Wu, and (3) there is a paucity of synthetic work in the Cinnamomum dibenzocycloheptanoids in general, we began a programme to investigate the viability of applying the intramolecular Nicholas reaction approach to this group of compounds. Here we describe our synthesis of tenuifolin (1) based on this chemistry.

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Equation 1 Generalized approach to dibenzocycloheptynedicobalt complexes

The intramolecular Nicholas reaction approach relies on the prior construction of an alkyne-substituted biaryl substrate. The initial biaryl formation was accomplished by Suzuki–Miyaura cross-coupling[9] of 4-methoxyphenylboronic acid (7) and 6-bromo-1,3-benzodioxole-5-carboxaldehyde (8); this proceeded smoothly and afforded the intended biaryl 9 in 91% yield (Equation 2). Extension of the aldehyde function in 9 to a propargylic alcohol was then accomplished by the application of Corey–Fuchs chemistry.[10] Subjecting 9 to CBr4 and PPh3 afforded the dibromoalkene 10, which was not purified rigorously but subjected reaction with n-BuLi (2.5 equiv) followed by the addition of paraformaldehyde at low temperature; subsequent workup afforded the intended propargyl alcohol 11 in good yield (86%) over two steps (Scheme [1]).

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Equation 2 Suzuki–Miyaura biaryl formation
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Scheme 1 Preparation of intramolecular Nicholas reaction precursor

Before complexation of the alkyne function with dicobalt octacarbonyl, the alcohol function was converted into the corresponding acetate. Complexation of the propargyl ­acetate then afforded the intended product 12 in 92% yield over the two steps.

When complex 12 was subjected to a cyclization reaction with BF3·OEt2 (3 equiv, 5 × 10–3 M) a reaction proceeded over four hours to give dibenzocycloheptynedicobalt complex 13 (see Equation 3). However, the reaction produced some baseline material on TLC and the maximum yield obtained under these conditions was 61%. In some cases, the addition of DIPEA has been shown to reduce decomposition in intramolecular Nicholas reaction chemistry;[5] in this case, addition of DIPEA (1.5 equiv) to the reaction mixture caused the rate of cyclization to decrease slightly but resulted in an increase in the yield to 73% over a period of six hours (Equation 3). Despite the relatively electron-poor C-ring, this rate of cyclization reaction was roughly in line with other dibenzocycloheptynedicobalt derivatives synthesized previously by our group.[5]

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Equation 3 Intramolecular Nicholas reaction of 12

Reductive decomplexation of dibenzocycloheptynedicobalt complex 13 was accomplished by a two-step procedure involving hydrosilylation mediated by Et3SiH and bis(trimethylsilyl)acetylene, followed by addition of trifluoroacetic acid (TFA) at 0 °C to induce protodesilylation of the intermediate vinylsilane mixture;[5] [11] this produced the intended alkene 14 in 83% yield (Equation 4). Some care was required in the TFA addition step because extended reaction times or higher temperatures resulted in reduced yield, likely due to competing deprotection of the methylenedioxy group.

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Equation 4 Reductive decomplexation of cycloheptynedicobalt complex 13

Conversion of 14 into tenuifolin required considerable experimentation. Hydroboration-oxidation resulted in the smooth formation of ketone 15 (76% yield; Scheme [2]). All attempts to convert 15 into a vinyllithium by way of its tosylhydrazone and subsequent Shapiro reaction[12] resulted in gross decomposition. Wittig reaction on 15 afforded exo-methylene-substituted 16 (70% yield), and epoxidation of the latter with dimethyldioxirane (DMDO)[13] gave 17 (72% yield). This epoxide could be opened by zinc(II) iodide and benzylamine[14] to give tenuifolin 1, but the product was obtained in unacceptably low yield (19%).

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Scheme 2 Conversion of 14 to tenuifolin via epoxide 17

Ultimately, it was found that the most effective route towards tenuifolin involved an initial bromination–dehydrobromination protocol employing Br2 and t-BuOK, respectively, to give brominated dibenzocycloheptene 18 in 86% yield (Scheme [3]). Direct attempts to incorporate the CH2OH function or its acetate by Stille or Suzuki–Miyaura protocols[15] [16] resulted in predominant reduction to 14. Conversely, metal–halogen exchange employing t-BuLi, followed by addition of N,N-dimethylformamide (DMF) gave formylated 19 in 70% yield, along with some 14 (26%).[17] A less efficient, but still synthetically useful alternative proved to be cyclopropanation with dichlorocarbene to afford 20 (93% yield), followed by base-induced (NaOEt, THF–EtOH) ring opening and subsequent acetal hydrolysis[18] to give 19 in 53% yield. Aldehyde 19 was then subjected to reduction with diisobutylaluminum hydride (DIBAL-H) to readily afford tenuifolin (1; 87% yield; Equation 5).

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Scheme 3 Conversion of dibenzocycloheptene 14 into aldehyde derivative 19
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Equation 5 Completion of the tenuifolin synthesis

In summary, we have synthesized tenuifolin in 23% overall yield over 12 steps,[19] with construction of the seven-membered ring by way of intramolecular Nicholas reaction chemistry. This cyclization has been accomplished successfully on the least electron-rich nucleophilic arene partner that has been attempted in benzocycloheptynedicobalt formation to date. This general approach is likely to be amenable to other Cinnamomum dibenzocycloheptanoids, and investigation towards their syntheses is in progress and will be reported in due course.


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Acknowledgment

We are grateful to NSERC (Canada), the Canada Foundation for Innovation (CFI), and the Ontario Innovation Trust (OIT) for support of this research.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information


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Figure 1 Cinnamomum debenzocycloheptanoids
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Equation 1 Generalized approach to dibenzocycloheptynedicobalt complexes
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Equation 2 Suzuki–Miyaura biaryl formation
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Scheme 1 Preparation of intramolecular Nicholas reaction precursor
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Equation 3 Intramolecular Nicholas reaction of 12
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Equation 4 Reductive decomplexation of cycloheptynedicobalt complex 13
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Scheme 2 Conversion of 14 to tenuifolin via epoxide 17
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Scheme 3 Conversion of dibenzocycloheptene 14 into aldehyde derivative 19
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Equation 5 Completion of the tenuifolin synthesis