Improved synthesis of C8–C20 segment of pectenotoxin-2

Tetrahedron Letters 52 (2011) 5589–5592

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Improved synthesis of C8–C20 segment of pectenotoxin-2 Kenshu Fujiwara ⇑, Yuki Suzuki, Nao Koseki, Shun-ichi Murata, Akio Murai, Hidetoshi Kawai  , Takanori Suzuki Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan

a r t i c l e

i n f o

Article history: Received 12 July 2011 Revised 3 August 2011 Accepted 8 August 2011 Available online 24 August 2011

a b s t r a c t The C8–C20 segment of pectenotoxin-2 was efficiently synthesized in 16% overall yield in 22 steps from L-malic acid via an improved route. Ó 2011 Elsevier Ltd. All rights reserved.

Keywords: Pectenotoxin-2 Natural product synthesis Polyether macrolide

Pectenotoxin-2 (1, Fig. 1) was first isolated from Japanese scallop Patinopecten yessoensis and the dinoflagellate Dinophysis fortii and characterized as a causative toxin of diarrhetic shellfish poisoning by Yasumoto.1 Further, pectenotoxin-2 possesses a specific 34-membered macrolactone framework with a non-anomeric [6,5]-spirocyclic acetal (AB-ring),2 a bicyclic acetal (D-ring), three oxolanes (C-, E-, and F-rings), and a six-membered cyclic hemiacetal (G-ring).1 The macrolide also exhibits strong cytotoxicity against cancer cells due to actin-depolymerization.3,4 Its unusual structural and biological properties have prompted us to initiate a program directed toward the total synthesis of 1.5 Since the absolute stereochemistry of pectenotoxin-6, a congener with a carboxy group instead of the methyl group at C18 of 1, was determined in 1997,1b several research groups have reported their extensive efforts toward achieving the total synthesis of the pectenotoxin family of natural compounds.6 In 2002, the Evans group achieved the first total synthesis of pectenotoxins-4 and -8, which are the C18-hydroxymethyl-congeners of 1 having an anomeric[6,5]-spirocyclic acetal or a [6,6]-spirocyclic acetal, respectively, as the AB-ring.7,8 During the course of our program, we achieved the synthesis of the left half of 1 (2),5c C21–C30 segment 3,5d and C8–C20 segment 45d (Scheme 1). However, the output of 4 (0.3% overall yield in 31 steps from L-malic acid) was insufficient for further investigations, and therefore, the synthetic route was reconsidered. In this study, we describe an efficient synthesis of a new C8–C20 segment of 1 (5; 16% overall yield in 22 steps from L-malic acid). ⇑ Corresponding author. E-mail address: [email protected] (K. Fujiwara). Present address: Department of Chemistry, Faculty of Science Division I, Tokyo University of Science, Tokyo 162-8601, Japan.  

0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.08.051

Me O

O HO OH

Me

G

O

40

F O

O

1

H

33

A

O

7

OH Me

Me

C O

B 8

30

31

O

H Me

Me

O

O D

21

O E

18

Me 43

20

Pectenotoxin-2 (PTX2; 1) Figure 1.

O TBSO Me G 40

H

Me

O

OMe O

1

F O

H

OTBS 7CHO

OPMB

Me Me

OTMS C 15 O 16 Me TMSO

11

PMBO

20

31

2

30

R

OTBS

Me

SO2Ph PTX2 (1)

TBSO 4: R= TBDPSO

8

10

Ph

MeO H CHO 21 E

5: R=

3

O 8

O

10

Scheme 1.

The retrosynthesis of C8–C20 segment 5 is outlined in Scheme 2. Phenyl sulfone 5, of which the benzylidene acetal was used for the protection of the oxygen atoms at C8 and C10, was newly designed for the C8–C20 segment. For obtaining high efficiency in the synthesis of 5, we employed a convergent synthetic route and reduced the

5590

K. Fujiwara et al. / Tetrahedron Letters 52 (2011) 5589–5592

Ph O

O Me

8

PMBO

8

11

PMBO

14

15

OTBS O 16

20

6

O P(OMe)2

OHC 16

16

18

+

OTMS Me

HO

OTMS Me

20

7

8

O 20

9

O

OH

O

8

P h TBSO

14

O

O Me

11

PMBO 10

O

8

Ph

14 11

HO 11

O

O

10 100%

8

Me

12

O

Me

OH

HO

O L-Malic Acid

THF, 25 °C

OH

Ph

OMe

CSA

14

O

O

CH 2Cl2, 25 °C 1 5 OH

96% (2 steps) (COCl)2, DMSO CH2Cl2, –7 8 °C then E t3N

Me

OMe N H ·HCl

Ph O

NaClO2, NaH 2PO4 2-methyl-2-butene

O

12 EDCI, DMAP CH 2Cl 2, 2 5 °C 79% (3 steps)

OH O 17

Ph O

O H

t -Bu OH 0 → 2 4 °C

Scheme 3.

HO

O

NaH, PMBBr B u4NI, THF 0 → 24 °C

PMBO

Me OH

O

O 16

O HO

Ph O

NOEs

Ph

7

DMPI NaHCO3 O CH 2Cl2 24 °C 92%

HO

O PMBO

OTBDPS

O CH 3

11

2) K2CO3 MeOH, – 15 °C 9 1% (2 steps)

H 22

12O O 1'

H

OMe Ph

DMPI NaHCO 3

O

Me OTMS CH 2Cl2 24 °C

O PMBO

OH O P(OMe)2

CHO

O PMBO

Me OTMS

24

23 Ph

O Me

19

2) DDQ CH2Cl2-pH 7 buffer (10 :1) 0 °C 48%

O

TBSO

Ph

100%

1) TBDPSCl, imidazole DMF, 24 °C 77%

1) TMSOTf 2,6-lutidine CH 2Cl2, – 40 °C

Ph O H OH

O

21

OMe OH

Bu4NF Ph TBSO THF 25 °C O O O Me P MB O 100 %

0 → 24 °C 9 5%

13

number of protection/deprotection steps. The benzylidene acetal and the phenyl sulfonyl groups of 5 were used in its original form from the starting materials 12 and 9, respectively. The assembly of 5 from C8–C15 segment 7 and C16–C20 segment 8 was undertaken according to our previous synthesis:5d the C-ring would be constructed by the 5-exo cyclization of epoxide 6, which would be formed through the Horner–Wadsworth–Emmons reaction between 7 and 8, stereoselective reduction of the ketone at C14, and diastereoselective epoxidation at C15–C16. For the synthesis of phosphonate 7, we planned a simple route starting from 12 and 13,9 which relied on a process including the construction of 11 by a coupling reaction of 12 with an anion from 13 followed by stereoselective reduction, selective formation of 10 via stereocontrolled epoxidation at C12–C13 of 11, and the installation of a phosphonate group. Aldehyde 8 would be prepared from epoxide 9 via regioselective reductive cleavage followed by oxidation. Amide 12 was synthesized from L-malic acid, which was first converted to 15 by reduction with borane followed by acetalization with benzaldehyde dimethyl acetal (96% over two steps) (Scheme 3).10 Further, 15 was subjected to a three-step process involving Swern oxidation,11 Pinnick oxidation,12 and condensation with N,O-dimethylhydroxylamine to produce 12 (79% yield over three steps). The synthesis of phosphonate 7 from amide 12 and bromoalkene 139 is illustrated in Scheme 4. After 13 was lithiated with t-BuLi, the resulting alkenyllithium was reacted with 12 to afford enone 18 (87%),13 which was diastereoselectively reduced with

O

11 Me –78 → – 30 °C (11:C11-epimer = 16:1) 94% (isolated 11)

20

14

Scheme 2.

BH 3·SMe2 B(OMe)3

O 18

SO2Ph

OMe + N Me Br

TBHP, VO (acac)2 CH 2Cl2

Zn( BH4)2, E t2O 11

LiA lH4 THF – 15 °C

Me

TBS O

O

then 1 2 87%

TBSO 11

O

13

Ph

Ph

Ph

SO2Ph

18

SO2Ph

t-BuL i THF – 78 °C

OTMS Me

OTMS PMBO Me

SO2Ph O

8

14

O

15

20

Ph O

O

OTMS C 15 O 16 Me TMSO 5

O

Ph

OTBS

O Me P(OMe)2 B uLi, THF – 78 °C

OTMS Me

then 24

25

87% (2 steps)

Scheme 4.

Zn(BH4)2 to produce 11 (94%) and a small amount of its C11-epimer (6%).14 The absolute configuration at C11 of 11 was determined by modified Mosher’s method.15 Further, the epoxidation of 11 under Oshima’s conditions16 led to 19 as a single diastereomer in 95% yield. The hydroxy group of 19 was protected with 4-methoxybenzyl bromide (PMBBr) (100%), and the resulting 20 was desilylated with Bu4NF to give 10 (100%). When 10 was treated with LiAlH4 at 15 °C, the epoxide was regioselectively cleaved, and diol 21 was produced quantitatively. In order to confirm the stereochemistry at C12, diol 21 was first converted to acetal 22 by sequential protection with tert-butyldiphenylsilyl chloride (TBDPSCl) (77%) and oxidative acetalization (48%).17 Acetal 22 was then analyzed by NMR spectroscopy, and the observed NOE correlations among H11, H1’, and CH3 at C11 indicated that these protons were located at the same side of the 1,3-dioxolane ring of 22; this clearly establishes the R-configuration at C12 based on the S-configuration at C11. Diol 21 was subsequently transformed to trimethylsilyl (TMS) ether 23 through a full-protection/partial-deprotection process (91% over two steps). Dess–Martin oxidation18 of 23 followed by a reaction with an anion of dimethyl methylphosphonate produced alcohol 25 (87% over two steps), which was oxidized to furnish phosphonate 7 (92%). The synthesis of C16–C20 segment 8 was started from 3-butyn1-ol (26) (Scheme 5). The tosylation of 26 (100%) followed by the substitution with lithium thiophenolate produced 28 (100%), which was then reacted with methyl chloroformate under basic conditions to give 29 (89%). The stereoselective conversion of 29 into 31 was conducted according to the Kobayashi–Mukaiyama procedure:19 Z-selective addition of thiophenol to 29 afforded 30 (89%), which was then reacted with MeMgBr in the presence of CuI to yield 31 with retention of stereochemistry (98%). Ester 31 was reduced to 32 with diisobutylaluminum hydride (DIBAH) (100%). Because the direct transformation of 32 into 9 under

K. Fujiwara et al. / Tetrahedron Letters 52 (2011) 5589–5592

CH 2Cl2 23 °C 100%

HO 26

Bu Li, THF – 78 °C

PhSH BuLi

TsCl pyridine

THF 2 4 °C 100%

TsO 27

then MeOCOCl 89%

PhS 28

OMe OMe Me

DIBAH O CH 2Cl2 0 °C 100%

MeMgBr CuI

O

OMe SPh

P hSH PhSNa

PhS

MeOH 2 3 °C (Z:E ~ 8 :1) Z: 89%

THF – 78 °C 98 %

PhS 31

OH

30

(NH ) Mo7O24• 4H 2O Me H O4 ,6EtOH, –1 5 °C 2 2

(+)-DET Ti(O i-Pr )4 TBHP

OH Me

CH 2Cl2 –40 °C 90%

100% PhS

PhO2S

32

O

PhS 29

LiAlH 4 9 THF ( 93%ee) 25 °C 99%

33

8

1 ) TMSOTf 2,6-l utidine CH 2Cl2, – 40 °C

OH OTMS Me

DMPI NaHCO3 CH 2Cl2 25 °C 97%

OH OH Me

2 ) K2CO3 MeOH, – 15 °C 72% (2 steps)

PhO2S

PhO2S

35

34

Scheme 5.

Katsuki–Sharpless asymmetric epoxidation conditions20 resulted in a low yield due to the sluggish oxidation of the phenylthio group, a two-step oxidation/epoxidation was applied to 32. The oxidation of 32 with H2O2 in the presence of (NH4)6Mo7O244H2O selectively produced 33 (100%),21 and 33 was subjected to Katsuki–Sharpless asymmetric epoxidation20 using (+)-diethyl tartrate (DET) to furnish 9 successfully (90%, 93%ee).22 The epoxide of 9 was regioselectively cleaved with LiAlH4 (99%), and the resulting diol 34 was converted to TMS ether 35 via a stepwise protection/ deprotection process (77% over two steps). Finally, the Dess–

5591

Martin oxidation18 of 35 produced aldehyde 8 corresponding to the C16–C20 segment of 1 (97%). The assembly of 5 was started from the Horner–Wadsworth– Emmons reaction between 7 and 8, which selectively yielded 36 (91%) (Scheme 6). The reduction of 36 with DIBAH below 100 °C stereoselectively produced 37 as an inseparable mixture with its C14-epimer (99% yield, 37:C14-epimer = 9.4:1). After intensively investigating the optimum conditions for the stereoselective epoxidation of the olefin at C15–C16 of 37 or its derivatives, we found that the epoxidation of 37 with mCPBA in the presence of NaHCO3 in CH2Cl2 at 0 °C gave relatively good results—epoxide 38 was furnished as a major component in 68% isolated yield (the NMR ratio of 38 to its C15,16-epimer in the crude mixture was 3.7:1). Alcohol 38 was protected with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) to afford 6 (81%). The treatment of 6 with 10-camphorsulfonic acid (CSA) promoted the removal of the TMS groups and the simultaneous 5-exo cyclization to produce 39 (76%), which was then transformed to 523 with TMSOTf (100%). The configuration at C15 of 5 was proved to be R by the presence of an NOE enhancement between H15 and the CH3 group at 12R-stereocenter. The determination of the R-configuration at C16 relied on the application of modified Mosher’s method to 39.15 Further, the R-configuration at C18 was confirmed by the presence of the NOE correlation between H19 and the proton at 16R-stereocenter of cyclic carbonate 40, derived from 39. In conclusion, the C8–C20 segment (5) of pectenotoxin-2 (1) was efficiently synthesized in 16% overall yield in 22 steps from L-malic acid via an improved route. Further efforts toward the total synthesis of PTX2 are currently underway in our laboratory. Acknowledgments We thank Dr. Eri Fukushi (GC–MS & NMR Laboratory, Graduate School of Agriculture, Hokkaido University) for the measurements of mass spectra. This work was supported by the Grants-in-Aid for Scientific Research from MEXT, Japan. References and notes

Ph NaH PhH-THF ( 1:3) O O 0 °C 7

O

OTMS PMBO Me

then 8 91%

36

Ph O

15

38

mCPBA NaHCO 3

OTMS Me

Ph O

CSA

O

14

O

OTBS

O Me

OH

CH2Cl2, 0 °C 76%

O PMBO

18

HO 39

O PMBO

16

Ph SO 2Ph Me

O

O

O H 3C PMBO

O

CH2Cl2, 0 °C 100%

SO2Ph

18

O 40

Me

99%

NOE

TBSO H H O Me H 19

TMSOTf 2,6-lutidine

OH

16

triphosgene, pyridine 0 → 23 °C Ph

O

CH2Cl2, 0 °C

CH2Cl2 – 20 °C 6

PhO 2S

OTMS OTMS Me Me PMBO (38:C15,1 6-epimer = 3.7:1) PhO2S 68% (isolated 38) 3 7 PhO 2S 16

OTMS PMBO Me

TBSOTf 2,6-lutidine 8 1%

(37:C14-epimer = 9.4:1) 99% (37+C14-epimer) Ph

OH O

O

DIBAH, CH2Cl2 – 104 °C

OTMS Me

NOE

TBSO H O 15 TMSO

12

5 Scheme 6.

OTMS Me S O2Ph

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7. 8.

9. 10.

11. 12.

13. 14. 15. 16.

K. Fujiwara et al. / Tetrahedron Letters 52 (2011) 5589–5592

P. M. Org. Lett. 2008, 10, 4179; (o) Helmboldt, H.; Aho, J. E.; Pihko, P. M. Org. Lett. 2008, 10, 4183; (p) Carley, S.; Brimble, M. A. Org. Lett. 2009, 11, 563; (q) Heapy, A. M.; Brimble, M. A. Tetrahedron 2010, 66, 5424; (r) Joyasawal, S.; Lotesta, S. D.; Akhmedov, N. G.; Williams, L. J. Org. Lett. 2010, 12, 988; (s) Vassilikogiannakis, G.; Alexopoulou, I.; Tofi, M.; Montagnon, T. Chem. Commun. 2011, 47, 259; (t) Aho, J. E.; Piisola, A.; Krishnan, K. S.; Pihko, P. M. Eur. J. Org. Chem. 2011, 1682; (u) Canterbury, D. P.; Micalizio, G. C. Org. Lett. 2011, 13, 2384; A review, see: (v) Halim, R.; Brimble, M. A. Org. Biomol. Chem. 2006, 4, 4048. Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998, 63, 2475. (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569; (b) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4573. Cho, C.-G.; Kim, W.-S.; Smith, A. B., III Org. Lett. 2005, 7, 3569. (a) Pawlak, J.; Nakanishi, K.; Iwashita, T.; Borowski, E. J. Org. Chem. 1987, 52, 2896; (b) Flögel, O.; Ghislaine, M.; Amombo, O.; Reißig, H.-U.; Zahn, G.; Brüdgam, I.; Hartl, H. Chem. Eur. J. 2003, 9, 1405. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480. (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175; (b) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825; (c) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. Nakata, T.; Oishi, T. Tetrahedron Lett. 1980, 21, 1641. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (a) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron Lett. 1979, 20, 4733; (b) Tomioka, H.; Suzuki, T.; Nozaki, H.; Oshima, K. Tetrahedron Lett. 1982, 23, 3387.

17. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 889. 18. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. 19. Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1974, 3, 705. 20. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. 21. Williams, D. R.; Ihle, D. C.; Plummer, S. V. Org. Lett. 2001, 3, 1383. 22. The enantiomeric purity of 9 was determined by HPLC analysis using a chiral column (CHIRALPAK IA, Daicel Chemical Industries, 4.6 mm  25 cm, hexane/ EtOH = 2:1, flow rate = 1 ml/min). 1 23. Selected spectral data of 5: a colourless oil; ½a24 D +32.0 (c 0.165, CHCl3); H NMR (C6D6, 400 MHz, 7.15 ppm for C6HD5) d 0.002 (6H, s) 0.08 (9H, s), 0.24 (9H, s), 0.92 (9H, s), 1.18 (3H, s), 1.31 (1H, br d, J = 13.5 Hz), 1.44 (3H, s), 1.70– 1.82 (3H, m), 2.06–2.15 (3H, m), 2.28 (1H, br dq, J = 4.8, 12.6 Hz), 3.25–3.40 (2H, m), 3.31 (3H, s), 3.58 (1H, br ddd, J = 2.3, 11.3, 12.6 Hz), 3.66 (1H, br s), 4.02 (1H, br dd, J = 4.8, 11.3 Hz), 4.09 (1H, dd, J = 1.8, 5.6 Hz), 4.14–4.19 (1H, m), 4.22–4.29 (1H, m), 4.36 (1H, br d, J = 10.9 Hz), 4.69 (1H, d, J = 11.5 Hz), 4.86 (1H, d, J = 11.5 Hz), 5.49 (1H, s), 6.79 (2H, d, J = 8.7 Hz), 6.88–6.98 (3H, m), 7.11–7.16 (1H, m), 7.23–7.30 (4H, m), 7.75 (2H, br d, J = 7.8 Hz), 7.85–7.89 (2H, m); 13C NMR (C6D6, 100 MHz, 128.0 ppm for C6D6) d 4.7 (CH3), 4.2 (CH3), 1.1 (CH3  3), 2.6 (CH3  3), 17.9 (C), 22.5 (CH3), 25.9 (CH3  3), 27.4 (CH2), 27.9 (CH3), 36.3 (CH2), 44.6 (CH2), 47.4 (CH2), 52.7 (CH2), 54.7 (CH3), 66.6 (CH2), 69.7 (CH), 72.3 (CH), 73.4 (CH2), 74.8 (C), 78.6 (CH), 83.5 (C), 85.9 (CH), 88.8 (CH), 102.0 (CH), 114.0 (CH  2), 126.6 (CH  2), 128.3 (CH  4), 128.7 (CH), 129.2 (CH  2), 130.4 (CH  2), 130.8 (C), 133.0 (CH), 140.1 (C), 140.8 (C), 159.8 (C); IR (film) mmax 3066, 3035, 2955, 2896, 2857, 1612, 1586, 1514, 1463, 1447, 1369, 1305, 1249, 1211, 1173, 1098, 1038, 938, 838, 776, 751, 697, 689, 650 cm1; HR-FDMS calcd for C48H76O10Si3S [M+]: 928.4467, found: 928.4467.