Synthetic studies toward biselides. Part 1: synthesis of the core carbon framework of biselides A, B, and E using Stille coupling

Tetrahedron Letters 53 (2012) 1390–1392

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Synthetic studies toward biselides. Part 1: synthesis of the core carbon framework of biselides A, B, and E using Stille coupling Yohsuke Satoh  , Dai Kawamura, Masashi Yamaura, Yoichi Ikeda, Yumi Ochiai, Ichiro Hayakawa, Hideo Kigoshi ⇑ Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan

a r t i c l e

i n f o

Article history: Received 7 December 2011 Revised 23 December 2011 Accepted 5 January 2012 Available online 13 January 2012

a b s t r a c t Biselides A and B are cytotoxic marine polyketides. We have achieved synthesis of the C-1–C-15 segment of biselides A and B by using Stille coupling and regioselective oxidative cleavage as key steps. Furthermore, we constructed the a,b-unsaturated lactone part of biselide E by using a similar strategy. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Biselides Polyketides Stille coupling Regioselective oxidative cleavage

Introduction 19

Biselides A–E (1–5)1 are polyketides isolated from the Okinawan ascidian Didemnidae sp. and their structures were determined to be C-20 oxygenated analogues of haterumalides2 in our group (Fig. 1). Haterumalide NA (6) and biselides A (1) and B (2) showed stronger cytotoxicity than did the anticancer drug cisplatin against human breast cancer and human nonsmall cell lung cancer.1b On the other hand, haterumalide NA (6) showed strong toxicity against brine shrimp (LD50 of 0.6 lg/mL), while biselide A (1) exhibited no toxicity against this animal even at 50 lg/mL. These results suggested that haterumalides and biselides could become lead compounds of novel-type anticancer drugs without severe side effects. The unique structures and potent biological activities of haterumalides and biselides have made them attractive synthetic targets, and a number of research groups have published synthetic studies of these compounds.3 However, total synthesis of biselides has never been reported. In 2008, we achieved the total synthesis of haterumalide NA (6) by using B-alkyl Suzuki–Miyaura coupling and Nozaki–Hiyama–Kishi coupling as key steps.4 The next year, we reported the total synthesis of haterumalide B (7) and artificial analogues of haterumalides, and the structure–cytotoxicity relationships of haterumalides, which revealed that the combination of lactone and side chain parts is important for the strong cytotoxicity of haterumalides.5 We planned a synthesis of ⇑ Corresponding author. Tel./fax: +81 29 853 4313.  

E-mail address: [email protected] (H. Kigoshi). Research fellow of the Japan Society for the Promotion of Science (JSPS).

0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2012.01.020

8

Cl

O

4

3

20

R1

13

OH

O

1

R1

R2

biselide A (1)

OAc

OH

biselide B (2)

OAc

biselide C (3)

OH

O

15 21

OAc 5

R2

9

O

O CO2 H

Cl

O

O OH OH

OH

biselide D (4)

H

H N

haterumalide NA (6)

H

OH

haterumalide B (7)

H

SO 3H

O O

O biselide E (5)

O

Figure 1. Structures of biselides and haterumalides.

biselides as part of a series of structure–cytotoxicity relationships studies of haterumalides. Thus, we describe herein the synthetic studies of biselides by using Stille coupling as a key step. The outline of our previous synthesis of the intermediate of haterumalides is shown in Figure 2. In that synthesis, the Z-olefin part at C-4 to C-5 of aldehyde 11 was constructed by using the Z-selective Horner–Wadsworth–Emmons reaction.6 However, in the synthesis of biselides, aldehyde 13 (20-hydroxy analogue of 11) cannot be obtained by using the Z-selective Horner– Wadsworth–Emmons reaction because it is predicted that the oxygen functional group at the b-position in the corresponding

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Y. Satoh et al. / Tetrahedron Letters 53 (2012) 1390–1392 Z-selective Horner–Wadsworth–Emmons reaction O OP 2 9

O

Cl

O O

CHO

CO 2Et

O

8

Z

ODMPM

CO2Et

O O

4 20

1 ODMPM

THF, –78 °C

ODMPM

CHO

5

15 O

OH CO2-i-Pr

DIBAL CH 2Cl2, –78 °C

O ODMPM

CN 4

3

OTBDPS 21 Scheme 2. Study of the introduction of a C1 unit at the C-3 position.

O

O

O

5

O

Cl

O

O

Cl

12 synthetic intermediate of haterumalides

O

Cl

OTBDPS 20

20

11

ODMPM

3

OTBDPS

Bu3SnCN Pd(PPh3 )4 CuI benzene, 75 °C 88%

O

LHMDS i-PrOAc

O

CHO

18 O

Cl

O

DMF, rt

20

10

Cl

ODMPM

I

O

CO Pd(PPh3) 4 Et 3SiH i-Pr 2NEt

O O

O

Cl

O

O

Cl

NaH, THF, – 78 °C

ODMPM

O

Cl

15 O

OH ODMPM

CHO

1 ODMPM CO2-i-Pr

Z 20

20

OR

OR

14 synthetic intermediate of biselides (C-1–C-15 segment of biselides A and B)

13 *DMPM: 3,4-dimethoxybenzyl

Figure 2. Outline of the previous synthesis of the intermediate of haterumaralides and the synthetic plan for the intermediate of biselides.

O

Cl

O

5

O

Cl 15 O

O

a, b

ODMPM

15 common intermediate for haterumalides and biselides

4 20 CO Et 2

O

16 O

Cl

O

c

ODMPM

I

5

OH

Cl

O

O

hyde 20 could not be obtained. Next, we examined the introduction of a nitrile group by using Stille coupling.9 Thus, the Pd catalysed coupling reaction between vinyl iodide 18 and tributyltin cyanide afforded the desired nitrile 21 in an 88% yield. However, reduction of the nitrile group in 21 by using DIBAL did not give the desired aldehyde 20. Under this condition, conjugate reduction of the C-4 to C-5 double bond occurred. We next tried to synthesize aldehyde 20 via the introduction of a vinyl group (two-carbon unit) at C-3 in vinyl iodide 18 followed by oxidative cleavage (Scheme 3). The Stille coupling reaction9 with vinyl iodide 18 and tributyl(vinyl)tin gave terminal olefin 22. The regioselective dihydroxylation of the terminal olefin in 22 was then investigated. Dihydroxylation of 22 with OsO4 in aqueous acetone gave the desired diol 23 (30%) and the undesired diol 24 (20%). Oxidative cleavage of diol 23 with NaIO4 afforded aldehyde 20, which was converted into b-hydroxy ester 2510 as a C-1–C-15 segment of biselides A (1) and B (2) by aldol reaction (1:1 ratio of hydroxy group at C-3). The b-hydroxy ester 25 is an

O

O d or e 5

NOE 3.5%

Z

ODMPM

I

I

ODMPM

20

OH

OR 17

O

Cl

O

Cl

O

O

O

18 R = TBDPS 19 R = TBS

ODMPM

I

Scheme 1. Synthesis of vinyl iodides 18 and 19. Reagents and conditions: (a) Dess– Martin periodinane, CH2Cl2, rt; (b) Ph3P@C(I)CO2Et, benzene, 60 °C, 96% in 2 steps; (c) DIBAL, CH2Cl2, 78 °C, Z (desired): 68%, E (undesired): 21%; (d) TBDPSCl, imidazole, DMF, rt, 90% (for 18); (e) TBSCl, imidazole, DMF, rt, quant. (for 19).

O a

3

OTBDPS 18

O

Cl

O

O

O

phosphonate is eliminated under the conditions of the Z-selective Horner–Wadsworth–Emmons reaction. In this work, we examined the synthesis of aldehyde 13 by using Stille coupling as a key step. Synthesis of aldehyde 13 started from alcohol 15,4,5 which was employed in our total synthesis of haterumalides (Scheme 1). Thus, the primary hydroxy group of 15 was oxidized by using Dess–Martin periodinane to afford an aldehyde, which was converted into iodo olefin 16 as a mixture of geometrical isomers at the C-4 to C-5 double bond (Z:E = 3:1).7 Reduction of the ethyl ester group of 16 gave allylic alcohol 17, and the geometrical isomers were separated by silica gel chromatography. The geometry of the C-4 to C-5 double bond in 17 was determined by NOE experiments. Allylic alcohol 17 was converted into vinyl iodides 18 and 19 as precursors of the Pd-catalysed coupling reaction. We next attempted to introduce a one-carbon unit at C-3 in vinyl iodide 18 by using a Pd-catalysed coupling reaction (Scheme 2). First, we tried the Pd-catalysed formylation of vinyl iodide 18 with carbon monooxide and triethylsilane.8 However, the desired alde-

b

OTBDPS 22 O

Cl

ODMPM

OH OH ODMPM

O

+

ODMPM HO HO

OTBDPS 23 (desired)

OTBDPS 24 (undesired)

c O

Cl

O

Cl

O

O

O 3

CHO

ODMPM

OTBDPS 20

15 O

OH

d

1 ODMPM CO2-i-Pr 20

OTBDPS 25 C-1–C-15 segment of biselides A and B

Scheme 3. Synthesis of the C-1–C-15 segment of biselides A and B. Reagents and conditions: (a) tributyl(vinyl)tin, Pd(PPh3)4, CuI, DMF, rt; (b) OsO4, NMO, acetone– H2O (5:1), rt, 23: 30% in 2 steps, 24: 20% in 2 steps; (c) NaIO4, dioxane–H2O (2:1), rt; (d) i-PrOAc, LHMDS, THF, 78 °C, 50% in 2 steps.

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Y. Satoh et al. / Tetrahedron Letters 53 (2012) 1390–1392

O

Cl

O

Cl

O

O

O ODMPM

I 20

O a

ODMPM

OTBS 19

TBSO

20 CO2 Et

26 O

Cl

O 15 O

b ODMPM Z 20

O

Chemistry, Japan (Meiji Seika Award in Synthetic Organic Chemistry, Japan) and the Suntory Institute for Bioorganic Research (SUNBOR GRANT) for financial support.

O 27

Scheme 4. Construction of the a,b-unsaturated lactone part of biselide E. Reagents and conditions: (a) (Z)-3-(tributylstannyl)propenoic acid ethyl ester, Pd(PPh3)4, CuI, DMF, rt, 80%; (b) HF
py, THF–py, rt, quant.

important synthetic intermediate, from which biselides would be synthesized by the same strategy from compound 12 to haterumalides NA and B.4,5 We next investigated the synthesis of biselide E (5) from vinyl iodide 19 (Scheme 4). The Stille coupling reaction between vinyl iodide 19 and (Z)-3-(tributylstannyl)propenoic acid ethyl ester11 afforded the a,b-unsaturated ester 26. Cleavage of the TBS ether group in a,b-unsaturated ester 26 by HF
py and a spontaneous lactonization gave a,b-unsaturated lactone 27.12 This compound 27 is a building block of biselide E (5). In conclusion, we have achieved synthesis of the C-1–C-15 segment 25 of biselides A and B by using Stille coupling and regioselective oxidative cleavage as key steps. Furthermore, we constructed the a,b-unsaturated lactone part of biselide E by using a similar strategy. Efforts toward the completion of the total synthesis of biselides A (1), B (2) and E (5) are currently underway by our group. In the following paper, we report on the synthetic studies of aldehyde 20 by using allylic oxidation as a key step.13 Acknowledgements This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; by a grant from the Uehara Memorial Foundation (H.K.); and by a grant from the University of Tsukuba, Strategic Initiatives (A), Center for Creation of Functional Materials (CCFM). I.H. thanks The Society of Synthetic Organic

References and notes 1. (a) Teruya, T.; Shimogawa, H.; Suenaga, K.; Kigoshi, H. Chem. Lett. 2004, 33, 1184–1185; (b) Teruya, T.; Suenaga, K.; Maruyama, S.; Kurotaki, M.; Kigoshi, H. Tetrahedron 2005, 61, 6561–6567. 2. (a) Ueda, K.; Hu, Y. Tetrahedron Lett. 1999, 40, 6305–6308; (b) Takada, N.; Sato, H.; Suenaga, K.; Arimoto, H.; Yamada, K.; Ueda, K.; Uemura, D. Tetrahedron Lett. 1999, 40, 6309–6312. 3. Review: (a) Kigoshi, H.; Hayakawa, I. Chem Rec. 2007, 7, 254–264. Total synthesis of haterumalides derivatives; (b) Kigoshi, H.; Kita, M.; Ogawa, S.; Itoh, M.; Uemura, D. Org. Lett. 2003, 5, 957–960; (c) Gu, Y.; Snider, B. B. Org. Lett. 2003, 5, 4385–4388; (d) Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005, 127, 6950– 6951; (e) Roulland, E. Angew. Chem., Int. Ed. 2008, 47, 3762–3765; (f) Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2008, 130, 12228–12229; Synthetic studies of biselide E: (g) Salit, A.-F.; Barbazanges, M.; Miege, F.; Larraufie, M.-H.; Meyer, C.; Cossy, J. Synlett 2008, 2583–2586. 4. Hayakawa, I.; Ueda, M.; Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Kigoshi, H. Org. Lett. 2008, 10, 1859–1862. 5. Ueda, M.; Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Hayakawa, I.; Kigoshi, H. J. Org. Chem. 2009, 74, 3370–3377. 6. Ando, K. J. Org. Chem. 1998, 63, 8411–8416. 7. Chenault, J.; Dupin, J.-F. E. Synthesis 1987, 498–499. 8. Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452–461. 9. Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813–817. 10. Chemical data for compound 25: 1H NMR (400 MHz) d 7.70–7.65 (m, 4H), 7.47– 7.36 (m, 6H), 6.91 (d, J = 1.7 Hz, 1H), 6.87 (dd, J = 8.2, 1.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.44 (t, J = 7.0 Hz, 1H), 5.42 (t, J = 7.5 Hz, 1H), 5.06 (m, 1H), 5.03 (septet, J = 6.2 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 11.7 Hz, 1H), 4.37 (q, J = 6.3 Hz, 1H), 4.35 (d, J = 13.0 Hz, 1H), 4.20 (d, J = 13.0 Hz, 1H), 4.17–4.10 (m, 2H), 4.09 (ddd, J = 8.3, 6.3, 1.8 Hz, 1H), 3.98–3.95 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.39 (m, 1H), 3.05–2.90 (m, 2H), 2.76–2.70 (m, 1H), 2.50–2.42 (m, 2H), 2.40–2.30 (m, 1H), 2.21 (dd, J = 13.4, 5.4 Hz, 1H), 1.81–1.70 (m, 2H), 1.57 (ddd, J = 13.4, 10.0, 4.3 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.06 (s, 9H); 13C NMR (100 MHz) d 171.4, 149.0, 148.6, 138.1 (0.5C), 138.1 (0.5C), 135.6 (4C), 135.1 (0.5C), 135.1 (0.5C), 133.0 (0.5C), 133.0 (0.5C), 130.9, 129.8, 129.8, 128.3 (0.5C), 127.8 (0.5C), 127.7 (2C), 127.7 (2C), 125.9 (0.5C), 125.8 (0.5C), 123.1 (0.5C), 123.0 (0.5C), 120.0, 111.0, 110.9, 108.5, 82.4, 79.1, 77.4 (0.5C), 77.4 (0.5C), 74.1 (0.5C), 74.1 (0.5C), 71.3, 68.0, 67.0, 66.6 (0.5C), 66.6 (0.5C), 65.8 (0.5C), 65.8 (0.5C), 55.9, 55.8, 41.3, 38.2, 36.2, 33.9 (0.5C), 33.9 (0.5C), 27.0, 26.8 (3C), 25.6, 21.8 (2C), 19.1; HRMS (ESI) m/z 887.3930, calcd for C48H6535ClNaO10Si [M+Na]+ 887.3933. 11. Leusink, A. J.; Budding, H. A.; Marsman, J. W. J. Organomet. Chem. 1967, 9, 285– 294. 12. Chemical data for compound 27: 1H NMR (270 MHz) d 7.40 (d, J = 9.6 Hz, 1H), 6.89–6.79 (m, 3H), 5.97 (d, J = 9.6 Hz, 1H), 5.72 (br t, J = 7.0 Hz, 1H), 5.46 (t, J = 7.0 Hz, 1H), 4.84 (s, 2H), 4.54 (d, J = 11.6 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.34 (q, J = 6.2 Hz, 1H), 4.15–4.03 (m, 3H), 3.98–3.91 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.08 (t, J = 7.0 Hz, 2H), 2.55–2.30 (m, 2H), 2.19 (dd, J = 13.2, 5.4 Hz, 1H), 1.88–1.50 (m, 3H), 1.41 (s, 3H), 1.35 (s, 3H); 13C NMR (67.8 MHz) d 164.3, 149.2, 148.8, 139.0, 136.9, 131.3, 131.1, 127.1, 121.4, 120.3, 119.7, 111.2, 111.1, 108.9, 82.7, 79.5, 77.6, 74.6, 71.8, 71.4, 67.3, 56.3, 56.2, 38.6, 36.7, 34.1, 27.7, 27.3, 26.0; HRMS (ESI) m/z 571.2062, calcd. for C29H3735ClNaO8 [M+Na]+ 571.2069. 13. Satoh, Y.; Yamada, T.; Onozaki, Y.; Kawamura, D.; Hayakawa, I.; Kigoshi, H. Tetrahedron Lett 2012, 53, 1393–1396.