An efficient synthesis of 2-cyclopentenones from γ-ketoaldehyde acetals using lithium trimethylsilyldiazomethane. Its application to the synthesis of trichodenone C

Article abstract of DOI:10.1016/S0040-4039(00)01162-X

The reaction of γ-ketoaldehyde acetals with lithium trimethylsilyldiazomethane afforded 2-cyclopentenones via the 1,5-C-H insertion of alkylidene carbene in high to moderate yields. Using this method, the synthesis of trichodenone C was achieved. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01162-X

Tetrahedron Letters 41 (2000) 6859±6863
An ecient synthesis of 2-cyclopentenones from
g-ketoaldehyde acetals using lithium
trimethylsilyldiazomethane. Its application to the
synthesis of trichodenone C
Atsushi Sakai, Toyohiko Aoyama* and Takayuki Shioiri*
Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 19 June 2000; accepted 29 June 2000
Abstract
The reaction of g-ketoaldehyde acetals with lithium trimethylsilyldiazomethane a€orded 2-cyclopentenones
via the 1,5-C±H insertion of alkylidene carbene in high to moderate yields. Using this method, the synthesis
of trichodenone C was achieved. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkylidene carbene; trimethylsilyldiazomethane; C±H insertion; 2-cyclopentenone; trichodenone C.
The intramolecular 1,5-C±H insertion reaction of alkylidene carbenes is a useful method for the
construction of cyclopentene skeletons.1 Alkylidene carbenes have been generated by the base-
induced a-elimination of primary vinyl halides or tri¯ates, by the nucleophilic b-addition to
alkynyliodonium salts and the subsequent reductive cleavage, and by the nitrogen extrusion of
diazoalkenes generated in situ.1 Ohira et al. reported that the reaction of carbonyl compounds
with lithium trimethylsilyldiazomethane in THF, which generated alkylidene carbenes via
diazoalkenes through modi®cation of the Peterson ole®nation, gave the cyclopentene derivatives
in good yields.2 We have also revealed that the alkylidene carbene generated from lithium
trimethylsilyldiazomethane (TMSC(Li)N2) and carbonyl compounds is used for the preparations
of the homologous alkynes, aldehydes, heterocycles, and methylenecyclopropanes.3 Although the
1,5-C±H insertion reaction into oxygen1b and nitrogen4-bearing stereogenic centers have been
used to great e€ect, the insertion into the acetal bearing stereogenic center has not been studied.
Therefore, we thought that it would be possible to extend this type of insertion to the preparation
of 2-cyclopentenones using g-ketoaldehyde acetals with TMSC(Li)N2 (Scheme 1).
At the outset, we examined the e€ect of the acetal moiety in the 1,5-C±H insertion reaction.
Among the acetal functionalities of dimethyl acetal, 1,3-dioxolane, and 1,3-dioxane, the 1,3-dioxane
* Corresponding authors. Tel: +81-52-836-3439; fax: +81-52-834-4172.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01162-X

6860
Scheme 1.
derivatives 1a gave the best result. Thus, TMSC(Li)N2 reacted with 1a in THF to give the ketal-
protected 2-cyclopentenone, and the ketal was easily hydrolyzed with 1N aq. HCl in one pot to
furnish the 2-cyclopentenone 2a in 82% yield (Table 1, entry 1).5 The acyclic g-ketoaldehyde
acetals 1a±f,i were readily prepared from the reaction of the corresponding acyl chlorides and
2-(1,3-dioxan-2-yl)-ethylmagnesium bromide in THF at ^78ꢀC.6 While the competitive reaction
of 1b via the acetal C±H insertion and alkyl C±H insertion gave the cyclopentenone 2b in 82%
yield and the cyclopentene 3b in 7% yield, the acetal C±H insertion versus tertiary alkyl C±H
insertion showed similar reactivities (entries 2, 3).7 The secondary alkyl ketones 1d,e, the more
sterically hindered ketone 1f, and the a,b-epoxy ketone 1g,8 also a€orded the corresponding
2-cyclopentenones 2d±g in high to moderate yields (entries 4±7). When the reaction of the
a,b-unsaturated ketone 1h8 was carried out, TLC analysis showed the complex mixtures, which
were separated by silica gel column chromatography and then HPLC puri®cation, to give the
desired product 2h in 16% yield and the alkyne 3h, the 1,2-rearrangement product via the
alkylidene carbene,3a in 24% yield (entry 8). The aryl ketone 1i gave no desired product. Instead,
the arylalkyne derivative 3i was obtained in 73% yield (entry 9).3a,9
Table 1
Preparation of 2-cyclopentenones from acyclic g-ketoaldehyde acetals
We next investigated the reaction of the cyclic g-ketoaldehyde acetals 1j±n.10 The ®ve-, seven-, and
eight-membered ketones 1j,l,m smoothly a€orded the two-ring fused 2-cyclopentenones 2j,l,m in

6861
Table 2
Preparation of 2-cyclopentenones from cyclic g-ketoaldehyde acetals
high to moderate yields (Table 2, entries 1, 3, 4). However, we were surprised to ®nd that the
cyclohexanone derivative 1k produced complex mixtures under the same reaction conditions. In
fact, the desired 2k was obtained in only 15% yield along with the labile unidenti®ed product
(entry 2). Although the intra3c and intermolecular11 oxonium ylide formation of the electrophilic
alkylidene carbene was reported, the spectral data of the product was not in accord with the one
derived from the oxonium ylide. Further investigation revealed that the reaction of 2-(3-phenyl-
propyl)-cyclohexanone with TMSC(Li)N2 also gave no 2-cyclopentene product and the same type
of unknown products were isolated. Interestingly, when the a-tetralone derived ketone 1n was
employed, 2n was the main product in 57% yield along with a small amount of by-product (entry 5).
These results could be explained by the intramolecular reaction of the a-substituted cycloalkanone
derivatives that is proceeded by another pathway in terms of the di€erences in the conformation.12
Also, the reaction of optically active a-methyl-b-benzyloxyketone 5, which was prepared from
413 and 2-(1,3-dioxan-2-yl)-ethylmagnesium bromide in THF, with TMSC(Li)N2 in THF
followed by acidic hydrolysis, provided 6 in 68% yield with 97.5% ee by chiral HPLC analysis
(Scheme 2).
Scheme 2.

6862
Using this methodology, the synthesis of trichodenone C,14,15 isolated from a strain of
Trichoderma harzianum OUPS-N115 and which exhibited cytotoxicity against cultured P388 cells,
was accomplished. Thus, the Weinreb amide 7 prepared by protection, hydrolysis, and
condensation with diethyl phosphorocyanidate16 from methyl (R)-lactate reacted with 2-(1,3-
dioxan-2-yl)-ethylmagnesium bromide in THF to give the ketone 8 in 84% yield. The reaction of
8 with TMSC(Li)N2 in THF and then acidic hydrolysis gave the desired 2-cyclopentenone 9 in
81% yield with >99% ee by chiral HPLC analysis. Finally, the chlorination of 9 followed by
deprotection of the silyl group with TBAF gave trichodenone C ([ꢀ]2D6.0 ^12.6 (c 1.09, CHCl3)) in
87% yield in two steps (Scheme 3). The synthetic trichodenone C was identical to the natural
trichodenone C based on a comparison of their 1H NMR, 13C NMR, IR, HREIMS, and optical
rotation (natural trichodenone C; [ꢀ]D ^10.8 (c 1.11, CHCl3),14 synthetic trichodenone C; [ꢀ]D
^12.4 (c 0.39, CHCl3)15).
Scheme 3.
In conclusion, the present method using commercially available trimethylsilyldiazomethane
(TMSCHN2) will provide a new preparation of 3-substituted-2-cyclopentenones from g-keto-
aldehyde acetals. Using this method, we achieved the ecient synthesis of trichodenone C in eight
steps.
Acknowledgements
We are grateful to Professor A. Numata (Osaka University of Pharmaceutical Sciences) for the
gift of trichodenone C and spectroscopic data of the natural and synthetic products.
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6863
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