The new synthesis of sesquiterpenoids 10-bromo-a-chamigrene

Qing Cui, Lin Kang, Hai Shen Yang, Xiao Hua Xu *

State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China

Received 20 October 2008

Abstract

The new synthesis of 10-bromo-a-chamigrene was achieved as follows; 6-methyl-5-heptene-2-one was transformed into

corresponding thioacetals, and then successively treated with Cp2Ti(P(OEt)3)2. The intermediate reacted with mono-ketal of

cyclohexane-1,4-dione, and gave the carbonyl coupling product. It was then transformed into the key intermediate g-bisabolene via

deketalization, Grignard reaction, dehydration and then furnished the target molecule by polyene cyclization, with total yield 2%.

All structures were confirmed by 1H NMR and 13C NMR. The final compound was confirmed by 1H NMR, 13C NMR and MS.

# 2009 Xiao Hua Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: 10-Bromo-a-chamigrene; Halogenated sesquiterpenoids; Carbonyl coupling; Synthesis

Halogenated sesquiterpenoids is the secondary metabolites of the red algae of the genus Laurencia. They usually

have novel skeletons and exhibit many important biological and pharmacological activities [1–4].

10-Bromo-a-chamigrene (Fig. 1), one of halogenated sesquiterpenoids was isolated firstly from L. Pacifica Kylin,

the most abundant California Laurencia [5]. Our group found that the EtOAc extract of Laurencia majuscule from the

South China sea could inhibit sclerotinia sclerotiorum, tomato gray mold and cucumber fusarium wilt, especially for

sclerotinia sclerotiorum (72% inhibition at 100 ppm). We isolated and confirmed four chamigrene-type halogenated

sesquiterpenoids from the EtOAc extract [6], one of them was 10-bromo-a-chamigrene.

In continuation of our on-going program on the studies of antibacterial activity of this kind of sesquiterpenoids, we

report herein a new approach (Scheme 1) for the total synthesis of 10-bromo-a-chamigrene as illustrated.

1,4-Dioxaspiro[4,5]decan-8-one 2 was synthesized in 71% yield by reaction of cyclohexane-1,4-dione 1 and

ethane-1, 2-diol catalyzed by triethyl orthoformate and p-toluenesulfonic acid (TsOH) at room temperature for 3 days

[7]. Then treatment of 6-methylhept-5-en-2-one 3 and thiophenol with trimethylchlorosilane (TMSCl) in chloroform

(CHCl3) under nitrogen yielded compound 4 in 63% yield [8]. The carbonyl coupling of compound 2 and compound 4

was achieved subsequently in tetrahydrofuran (THF) by the action of magnesium powder-bis (cyclopentadienyl)

titanium dichloride (Cp2TiCl2)-triethyl phosphate-4A molecular sieve to give the desired compound 5 in 54% yield

[9–10]. Ketone 6 was obtained via deketalization in hydrochloric acid–water–acetone solution in 87% yield.

Whereafter, adding dropwise ether solution of ketone 6 to methylmagnesium iodide solution in diethyl ether at�5 8Cand stirring the reaction mixture at room temperature for 3 h then refluxing 30 min under nitrogen, alcohol 7 was

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Chinese Chemical Letters 20 (2009) 554–556

* Corresponding author.

E-mail address: xiaohuaxu@nankai.edu.cn (X.H. Xu).

1001-8417/$ – see front matter # 2009 Xiao Hua Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2009.01.029

prepared in 73% yield. After that, the key intermediate of g-bisabolene 8 [11] was gained by treatment of compound 7

in pyridine solution with phosphorus oxychloride under nitrogen in 88% yield. The conversion of compound 5 to g-

bisabolene 8 was similar with the Vig’s method [12]. In the end the target molecule 9 was furnished by polyene

cyclization with TBCO in 10% yield [13]. The overall yield for the entire six-step synthesis is 2%. Altogether, this

synthetic process should be able to be use to prepare 10-bromo-a-chamigrene needed for investigating antibacterial

activity. The target compound was characterized by 1H NMR and 13C NMR and MS data [14], and the intermediates

were characterized by 1H NMR and 13C NMR. The synthetic 10-bromo-a-chamigrene has identical spectral data with

those of natural products.

Acknowledgment

We thank the National Natural Science Foundation of China (No. 20421202) for financial support.

References

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Q. Cui et al. / Chinese Chemical Letters 20 (2009) 554–556 555

Fig. 1. The structure of 10-bromo-a-chamigrene.

Scheme 1. Reagents and conditions: (a) (CH2OH)2, (CH3CH2O)3CH, TsOH/CH2Cl2, 0 8C, 15 min, to rt, 3 days; (b) PhSH, TMSCl/CHCl3, rt, 1 h;

(c) Cp2Ti(P(OEt)3)2/THF, rt, 4 h; (d) HCl/acetone, H2O, rt, 6 h; (e) Mg, CH3I/ether, 0 8C to reflux; (f) POCl3/Py, 0 8C, 2 h; (g) TBCO/CH3NO2, 0 8Cto rt.

[6] Undisclosed information.

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[10] Spectral data of compound 5: 1H NMR (CDCl3-TMS, 400 MHz, dppm): 1.68, (s, 6H, (CH3)2C CH), 5.12 (m, 1H, CH C), 2.05 (m, 2H,

CH2CH ), 2.05 (t, 2H, CH2C(CH3) ), 1.60 (S, 3H,CH3C(CH2) ), 2.29 (t, 4H, (CH2)2C ), 1.27 (t, 4H, (CH2CO)2), 3.96 (s, 4H, (CH2O)2).13C NMR (CDCl3-TMS, 400 MHz, dppm): 17.83, 27.38, 25.98, 18.47, 34.56, 26.93, 27.21, 36.23, 35.96, 64.47, 109.29, 124.58, 126.26,

130.33, 131.72.

[11] Spectral data of g-bisabolene 8: 1H NMR (CDCl3-TMS, 400 MHz, dppm): 1.67, 1.60 (s, 3H, (CH3)2C CH), 1.67 (S, 3H, CH3C(CH2) ), 5.37

(m, 1H, CH C(CH3)2), 5.13 (t, 1H, CH C(CH2)CH3), 2.73 (d, 2H, CH2C CH2CH3), 2.07 (m, 2H, CH2CH C(CH3)2), 2.03 (t, 2H,

CH2C(CH3) ), 2.03 (t, 4H, (CH2)2C ), 1.99 (t, 2H, CH2C(CH3) CH), 1.69 (d, 3H, CH3C CH), 1.66 (s, 3H, CH3C CH) 1.69 (s, 3H,

CH3C(CH2) C), 1.60 (d, 3H, CH3C(CH2) CH). 13C NMR (CDCl3-TMS 400 MHz, dppm): 17.82, 23.64, 25.95, 26.71, 26.99, 27.10, 27.55,

29.53, 29.92, 31.78, 32.02, 34.67, 34.40, 121.07, 124.716, 126.12, 128.61, 131.64, 134.44.

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[14] Spectral data of 10-bromo-a-chamigrene: 1H NMR (CDCl3-TMS, 400 MHz, dppm): 1.68, (s, 3H, CH3C(C) CH), 1.60 (t, 3H, CH3C(CH2) ),

1.66, (d, 6H, (CH3)2CHBr), 2.79 (m, 2H, CH2CHBr), 2.31 (t, 2H, CH2(C)CH ), 2.07 (t, 2H, CH2C ), 2.02 (t, 2H, CH2CH2), 5.84 (t, 1H,

CH C (CH3)), 4.29 (d, 1H, CH C (CH3)), 3.39 (m, 1H, CHBr). 13C NMR (CDCl3-TMS, 400 MHz, dppm): 12.40, 19.87, 21.23, 25.97, 28.32,

28.41, 31.09, 35.56, 44.04, 58.84, 66.54, 124.09, 125.86, 129.10, 130.24. C15H23Br, m/z 283, 285 (M + 1+), 203 (42), 135 (22), 119 (33), 109

(100), 95 (65).

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