Gold-Catalyzed Double Intramolecular Alkyne

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LETTER

Gold-Catalyzed Double Intramolecular Alkyne Hydroalkoxylation: Synthesis of the Bisbenzannelated Spiroketal Core of Rubromycins Synthesi oftheBisbenzan elatedSpiroketalCoreofRubromZhang, Yuan ycins Jijun Xue,* Zhijun Xin, Zhixiang Xie, Ying Li* State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. of China Fax +86(931)8912582; E-mail: [email protected]; E-mail: [email protected] Received 9 December 2007

Abstract: The synthesis of the bisbenzannelated spiroketal core of natural bioactive rubromycins via a gold-catalyzed double intramolecular hydroalkoxylation was described. A comparative study on the formation of aliphatic and of aromatic spiroketals was also conducted. Key words: alkyne hydroalkoxylation, spiroketal, rubromycin, gold catalysis, coupling

Rubromycins are a class of antibiotics of a wide spectrum of biological activity isolated from the cultures of Streptomyces.1 For example, g-rubromycin (1) is known as a potent inhibitor of DNA polymerase and the reverse transcriptase of HI virus type 1.2 Purpuromycin (2)3 has been considered as a potential topical agent for vaginal infections,4 and heliquinomycin (3)5 can act as an inhibitor of DNA helicase. The basic structure motif of these natural products consists of a 5,6-spiroketal core fused to aromatic naphthoquinone and isocoumarin moiety (Figure 1). As a consequence of their biological activities, together with their unique bisbenzannelated 5,6-spiroketal strucO HO O MeO

CO2Me O

O

1 OH R

O

R2

Using 2-alkynyl phenol 6a as a model substrate, the conditions for the spiroketalization reaction were investigated (Table 1).16,17 To our delight, treatment of 6a with 10 mol% of Ph3PAuCl/AgOTf in CH2Cl2 at room temperature for two days provided the aromatic spiroketal 7a in 62% yield along with small amount of benzofuran 10a as a side product (entry 1).Whereas Ph3PAuCl alone did not induce the sprioketalation but gave 10a as the only prod-

R3

γ-rubromycin (1): R1 = H; R2 = H; R3 = H purpuromycin (2): R1 = H; R2 = H; R3 = OH heliquinomycin (3): R1 = O-cymarose; R2 = OH; R3 = H

Figure 1

The use of gold catalysts in organic synthesis has received much attention in recent years,11 and numerous accounts of gold-catalyzed carbon–heteroatom bond-forming reactions have been reported.12 In particular, Krause has reported a tandem alkyne hydroalkoxylation of alkynyl alcohols to ketals using a dual catalyst system consisting of a gold precatalyst and a Brønsted acid. de Brabander has applied gold-catalyzed twofold additions of two hydroxy groups to internal alkynes for the synthesis of aliphatic spiroketals. Nevertheless, to the best of our knowledge, there is no report on the synthesis of bisbenzannelated spiroketals using gold catalysis so far. Herein, we report the first example of gold-catalyzed double intramolecular hydroalkoxylation of 2-alkynyl phenol that lead to the aromatic spiroketal core of rubromycins. The starting materials of our study were readily prepared from alkyne 513 and various o-iodophenol acetates14 by Sonogashira coupling reaction15 (Scheme 1).

O

OH

ture, many synthetic studies have been made on these compounds.6–10 To date, only the synthesis of racemic aglycone of 37a,b and racemic g-rubromycin (1)7c have been reported. Much attention have been focused on the preparation of the bisbenzannelated spiroketal skeleton. The reported methods were mainly based on acid-catalyzed spiroketalization of bisphenolic ketones,8 halo-etherification of a benzofuran,7a or cycloaddition-type reaction.9

The rubromycin family of nature products

R2

R2

OH HO

OAc

a, b

+ R1

I 4a–g

Scheme 1

72–81% 5

OH

R1 6a–g

Reagents and conditions: a) Pd(Ph3P)2Cl2, CuI, Et3N, DMF, 60 °C, 2 h; b) NaOH, MeOH, r.t., 10 min.

SYNLETT 2008, No. 6, pp 0940–0944xx. 208 Advanced online publication: 11.03.2008 DOI: 10.1055/s-2008-1042910; Art ID: W21307ST © Georg Thieme Verlag Stuttgart · New York

LETTER

Synthesis of the Bisbenzannelated Spiroketal Core of Rubromycins

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Optimization of Reaction Conditions for the Synthesis of Spiroketal from 2-Alkynyl Phenol19

Table 1

HO

HO OH O

O

gold reagent, r.t.

O +

6a

10a

7a

Entry

Catalyst

Solvent

Time (d)

Yield of 7a (%)

Yield of 10a (%)

1

Ph3PAuCl/AgOTf (10 mol%)

CH2Cl2

2

62

28

2


CH2Cl2

5

14

77

3

Ph3PauCl (10 mol%)

CH2Cl2

5

0

95

4

AuCl3a (10 mol%)

CH2Cl2

2

59

30

5

AgOTf (10 mol%)

CH2Cl2

5

38

53

6


THF

5

0

96

7


Et2O

5

13

68

8


MeCN

5

n.r.b

n.r.b

a b

Used as a 0.05 M solution in MeCN. No reaction, a recovery of most of starting material.

uct (entry 3). The yield of 7a was decreased to 14% when using 1 mol% of Ph3PAuCl/AgOTf (entry 2). Gold(III) chloride showed similar catalytic activity in CH2Cl2 as PPh3AuCl/AgOTf (entry 4). To our surprise, AgOTf alone could also trigger the reaction, but gave 7a in poor yield (entry 5). The use of a Brønsted acid as a cocatalyst of PPh3AuCl/AgOTf12d had no obvious effect on the cyclization.18 At the same time, a number of solvents were screened. Among them, CH2Cl2 appeared to the most suitable solvent for the spiroketalization reaction (entries 1 and 4). The reaction in Et2O proceeded slowly and gave 7a in only 13% yield (entry 7). The use of THF as a solvent did not give 7a (entry 6), so was in other strong polar solvent, such as MeCN (entry 8).

With the optimal conditions in hand, we investigated the scope of this spiroketalization reaction using various substrates, and the results are shown in Table 2. In the presence of 10 mol% of Ph3PAuCl/AgOTf, 2-alkynyl phenols 6b–g gave the expected corresponding bisbenzannelated spiroketals 7b–g in moderate to good yields along with the benzofuran side product. Substrates containing an electron-donating group at para position of the phenyl ring A gave 62–68% yields (entries 1, 2, and 3). In contrast, those with electron-withdrawing groups at para position of the phenyl ring A gave lower yields (entries 4 and 5). While 2-alkynyl phenol 6g having o-OMe group proceeded sluggishly, and the spiroketal 7g was afforded in 45% yield (entry 6).

Table 2 Synthesis of Bisbenzannelated Spiroketals20 HO R2

OH A

R1

R2 Ph3PAuCl (10 mol%) AgOTf (10 mol%) CH2Cl2, r.t.

O

O

R1 7b–g

6b–g

Entrya

Substrate

R1

R2

Time (d)

Product

Yield (%)b

1

6b

Me

H

5

7b

64 (26)

2

6c

t-Bu

H

4

7c

68 (30)

3

6d

Ph

H

4

7d

62 (30)

4

6e

COMe

H

7

7e

48 (14)

5

6f

Cl

H

5

7f

50 (41)

6

6g

H

OMe

7

7g

45 (42)

a b

All reactions were performed on a 0.2 mmol scale. Isolated yields; the numbers in parentheses are the yield of benzofurans.

Synlett 2008, No. 6, 940–944

© Thieme Stuttgart · New York

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Y. Zhang et al. Ph3PAuCl (2 mol%) AgOTf (2 mol%) CH2Cl2, r.t., 25 min

OH

O

75%

6h

7h

OH Ph3PAuCl (2 mol%) AgOTf (2 mol%) CH2Cl2, r.t., 30 min

OH

O

Ph3PAuCl (10 mol%) AgOTf (10 mol%) CH2Cl2, r.t., 4 d

OH

OH n

O

7j

OH

6k n = 1 6l n = 2

9

O

84%

6j

O

8

Ph3PAuCl (2 mol%) AgOTf (2 mol%) CH2Cl2, r.t., 30 min

OH

O

+

O

86%, 8/9 = 1.5:1

OH

6i

Scheme 2

O

O

7k 52% 7l 72%

O

n

7k n = 1 7l n = 2

Generation of aliphatic and monobenzannelated spiroketals

O

O

7a

HO AuLn

O

+

OH OH

C

Au– 6a HO H O

H O [Au]

+

B

Scheme 3

OH Au-

A

Proposed mechanism for the formation of 7a

To further explore this gold-catalyzed process, we also examined various 2-alkynylbenzyl alcohols oHOCH2(C6H4)C≡C(CH2)nOH and 2-alkynyl phenols oHO(C6H4)C≡C(CH2)nOH (Scheme 2). Using only 2 mol% of Ph3PAuCl/AgOTf, the cyclization of 6h–j completed within 30 minutes and gave the corresponding aliphatic spiroketals in good to high yields. The present method was more efficient than previous routes.21 For 2alkynyl phenols 6k and 6l, the transformation was rather sluggish, and the corresponding monobenzannelated spiroketals 7k and 7l were obtained in 52% and 72% yields, respectively, after four days. The results showed that aliphatic hydroxyl group has higher nucleophilicity

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than phenolic group toward the gold-complexed triple bond. A proposed mechanism is shown in Scheme 3. The reaction may be initiated by the formation of p-coordinated alkyne–Au complex A via the complexation of the triple bond to the Au catalyst, which enhanced the electrophilicity of the triple bond. The intramolecular addition may also be favored by a complexation of the phenolic hydroxyl group to the gold catalyst to yield an enol vinylgold intermediate B. The enol vinylgold intermediate B then rearranged to the isomeric gold oxocarbenium species C, which then underwent another intramolecular addition of the remaining hydroxyl group leading to the spiroketal 7a and releasing the gold catalyst.

LETTER

Synthesis of the Bisbenzannelated Spiroketal Core of Rubromycins

In conclusion, a novel and efficient method for the construction of the bisbenzannelated 5,6-spiroketal core of rubromycins has been developed, which allows for the synthesis of various substituted 5,6-aromatic spiroketal skeletons under the catalysis of gold reagents. A comparative study on the formatioan of aliphatic and of aromatic spiroketals was also conducted. A tandem cyclization mechanism was proposed. The process would serve as a good complement to the existing methodologies and its mild reaction conditions must be useful in synthesis of nature products with such skeletons. The development of an asymmetric version of this reaction and the extension of this methodology to other functionalized 2-alkynyl phenols are currently under investigation in our laboratory.

Acknowledgment We are grateful for the financial support of the National Natural Science Foundation of China (Grant Nos. 20672050 and 20272020).

References and Notes (1) (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Tetrahedron Lett. 1966, 3525. (b) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Chem. Ber. 1969, 102, 126. (c) Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709. (2) (a) Goldman, M. E.; Salituro, G. S.; Bowen, J. A.; Williamson, J. M.; Zink, L.; Schleif, W. A.; Emini, E. A. Mol. Pharmacol. 1990, 38, 20. (b) Mizushina, Y.; Ueno, T.; Oda, M.; Yamaguchi, T.; Saneyoshi, M.; M, ; Sakaguchi, K. Biochim. Biophys. Acta 2000, 1523, 172. (3) (a) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini, G. C. J. Antibiot. 1974, 27, 161. (b) Bardone, M. R.; Martinelli, E.; Zerilli, L. F.; Cornelli, C. Tetrahedron 1974, 30, 2747. (4) Trani, A.; Dallanoce, C.; Pranzone, G.; Ripamonti, F.; Goldstein, B. P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967. (5) (a) Chino, M.; Nishikawa, K.; Umekia, M.; Hayashi, C.; Yamazaki, T.; Tsuchida, T.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1996, 49, 752. (b) Chino, M.; Nishikawa, K.; Tsuchida, T.; Sawa, R.; Nakamura, H.; Nakamura, K. T.; Muraoka, Y.; Ikeda, D.; Naganawa, H.; Sawa, T.; Takeuchi, T. J. Antibiot. 1997, 50, 143. (6) For a review on the rubromycins, see: Brasholz, M.; Sörgel, S.; Azap, C.; Reissig, H.-U. Eur. J. Org. Chem. 2007, 3801. (7) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4709. (b) Siu, T.; Qin, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4713. (c) Akai, S.; Kakiguchi, K.; Nakamura, Y.; Kuriwaki, I.; Dohi, T.; Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew. Chem. Int. Ed. 2007, 46, 7458. (8) (a) Capecchi, T.; de Koning, C. B.; Michael, J. P. Tetrahedron Lett. 1998, 39, 5429. (b) Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 2681. (c) Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett. 2003, 5, 4425. (d) Tsang, K. Y.; Brimble, M. A. Tetrahedron 2007, 63, 6015. (e) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Tetrahedron Lett. 2006, 47, 5409. (f) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006, 8, 3243. (g) Sörgel, S.; Azap, C.; Reissig, H.-U. Org. Lett. 2006, 8, 4875. (9) (a) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett. 2006, 8, 2365. (b) For a synthesis of bisbenzannelated 6,6spiroketals, see: Zhou, G.; Zheng, D.; Da, S.; Xie, Z.; Li, Y. Tetrahedron Lett. 2006, 47, 3349.

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(10) For syntheses of the isocoumarin subunit, see: (a) Thrash, T. P.; Welton, T. D.; Behar, V. Tetrahedron Lett. 2000, 41, 29. (b) Waters, S. P.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3567. (c) Brasholz, M.; Reissig, H.-U. Synlett 2004, 2736. (d) For syntheses of the naphthalene subunit of rubromycin and related structures, see: Brasholz, M.; Luan, X.; Reissig, H.-U. Synthesis 2005, 3571. (e) Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661. (f) Sörgel, S.; Azap, C.; Reissig, H.-U. Eur. J. Org. Chem. 2006, 4405. (11) For a review of gold-catalyzed reactions, see: (a) Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (12) (a) Liu, Y.; Liu, M.; Guo, S.; Tu, H. Org. Lett. 2006, 8, 3445. (b) Barluenga, J.; Diéguez, A.; Fernández, A.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2006, 45, 2091. (c) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409. (d) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489. (e) Antoniotti, S.; Genin, E.; Michelet, V.; Genêt, J.-P. J. Am. Chem. Soc. 2005, 127, 9976. (f) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907. (g) Li, Y. F.; Zhou, F.; Forsyth, C. J. Angew. Chem. Int. Ed. 2007, 46, 279. (h) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2007, 48, 1439. (13) For a synthesis of alkyne 5, see: Trost, B. M.; Shen, H. C.; Li, D.; Surivet, J. P.; Sylvain, C. J. Am. Chem. Soc. 2004, 126, 11966. (14) For syntheses of o-iodophenols, see: (a) Edgar, K. J.; Falling, S. N. J. Org. Chem. 1990, 55, 5287. (b) Schreiber, F. G.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1 1977, 90. (15) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467. (b) Hiroya, K.; Suzuki, N.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 2000, 4339. (16) On the basis of the protocol described by Uitimoto,17 palladium reagents were tried initially but spiroketal 7a was isolated in very low yields. Treatment of 6a with 5 mol% of PdCl2 in refluxing MeCN for 2 d afforded spiroketal 7a in only 5% yield. Even with 1.0 equiv of PdCl2 or the reaction was performed in sealed tube at 120 °C, the yield of 7a was still as low as 20% and 10%, respectively. Only trace of 7a was isolated by using PdCl2(PhCN)2 and PdCl2(MeCN)2 in Et2O at r.t. (17) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845. (18) We treated 6a with 10 mol% of Ph3PAuCl/AgOTf and 20 mol% of PTSA in CH2Cl2 at r.t. for 2 d provided the aromatic spiroketal 7a in 61% yield. (19) General Procedure for Gold-Catalyzed Spiroketalization Under argon, PPh3AuCl (9.5 mg, 0.02 mmol) and AgOTf (5.2 mg, 0.02 mmol) were added to a stirred solution of 6a (48.0 mg, 0.2 mmol) in CH2Cl2 (4 mL). After the reaction mixture had been stirred at r.t. for 2 d, the solvent was removed and the residue purified by flash chromatography on silica gel (hexane–EtOAc, 8:1 v/v) to give the bisspiroketal 7a (30.0 mg, 62%) as a white solid. (20) Spectral Data for Selected Compounds (Table 2) Compound 7b: white solid; mp 115–117 °C. 1H NMR (300 MHz, CDCl3): d = 7.13–7.07 (m, 2 H), 7.04 (s, 1 H), 6.95– 6.88 (m, 2 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.68 (d, J = 8.1 Hz, 1 H), 3.40 (d, J = 16.5 Hz, 1 H), 3.30–3.18 (m, 2 H), 2.81 (ddd, J = 16.5, 6.0, 2.4 Hz, 1 H), 2.35–2.29 (m, 4 H), 2.17 (td, J = 12.6, 6.3 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 155.8, 152.3, 130.4, 129.1, 128.4, 127.4, 125.4, 125.3, 121.4, 121.1, 117.1, 109.4, 109.0, 41.9, 30.4, 21.9, 20.8. IR: n = 3020 (CH, arom.), 2925 (CH), 1584, 1489 (ArC=C), 1080, 1045 (CO) cm–1. ESI-HRMS: m/z calcd for C17H16O2Na [M + Na]+: 275.1043; found: 275.1046. Compound 7c: pale yellow solid; mp 173–175 °C. 1H NMR (300 MHz, CDCl3): d = 7.26 (s, 1 H), 7.19–7.08 (m, 3 H),

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Y. Zhang et al. 6.91 (td, J = 7.2, 1.2 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 3.44 (d, J = 16.2 Hz, 1 H), 3.31–3.19 (m, 2 H), 2.81 (ddd, J = 16.5, 6.0, 2.4 Hz, 1 H), 2.32 (ddd, J = 13.5, 6.0, 3.0 Hz, 1 H), 2.19 (td, J = 12.3, 6.3 Hz, 1 H), 1.31 (s, 9 H). 13C NMR (75 MHz, CDCl3): d = 155.7, 152.4, 144.1, 129.1, 127.4, 124.9, 124.8, 121.8, 121.4, 121.1, 117.1, 109.1, 109.0, 42.1, 34.3, 31.7, 30.5, 21.9. IR: n = 3021 (CH, arom.), 2962 (CH), 1583, 1492 (ArC=C), 1076, 1046 (CO) cm–1. ESI-HRMS: m/z calcd for C20H23O2 [M + H]+: 295.1693; found: 295.1687. Compound 7d: pale yellow solid; mp 154–155 °C. 1H NMR (300 MHz, CDCl3): d = 7.54 (d, J = 8.2 Hz, 2 H), 7.47–7.37 (m, 4 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 8.1 Hz, 2 H),

Synlett 2008, No. 6, 940–944


6.94 (t, J = 7.5 Hz, 1 H), 6.88–6.81 (m, 2 H), 3.51 (d, J = 16.2 Hz, 1 H), 3.37–3.22 (m, 2 H), 2.84 (ddd, J = 16.5, 6.0, 2.7 Hz, 1 H), 2.36 (ddd, J = 13.5, 6.0, 2.7 Hz, 1 H), 2.22 (td, J = 12.9, 6.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 157.5, 152.2, 141.3, 134.8, 129.1, 128.7, 127.5, 127.2, 126.9, 126.6, 126.0, 123.7, 121.4, 121.2, 117.1, 110.0, 109.4, 41.9, 30.4, 21.9. IR: n = 3032 (CH, arom.), 2925 (CH), 1583, 1480 (ArC=C), 1082, 1046 (CO) cm–1. ESIHRMS: m/z calcd for C22H19O2 [M + H]+: 315.1380; found: 315.1378. (21) (a) Li, X. W.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437. (b) Fugami, K.; Hagiwara, K.; Okeda, T.; Kosugi, M. Chem. Lett. 1998, 81.