HETEROCYCLES

Communication | Special issue | Vol. 82, No. 1, 2010, pp. 319-323
Received, 1st July, 2010, Accepted, 27th July, 2010, Published online, 29th July, 2010.
DOI: 10.3987/COM-10-S(E)91

■ Enantioselective Synthesis of the C(2)-C(11) Cyclopropylfuran Segment of Pinnatin A

Masayoshi Tsubuki,* Terunobu Abekura, Kazunori Takahashi, and Toshio Honda*

Research Centre of Medicinal Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Synthesis of the C(2)-C(11) segment, cyclopropylfuran derivative, of pinnatin A was accomplished by Suzuki cross-coupling between chiral cyclopropylboronic acid and bromofuran as a key step. Addition of silver (I) oxide was found to promote the Suzuki cross-coupling reactions.

Pinnatin A 1 is a unique gersolane-type furanoditerpene isolated from a Caribbean gorgonian, Pseudopterogorgia bipinnata.1 The compound shows significant differential antitumor activity in the National Cancer Institute’s 60-cell-line tumor panel. Pinnatin A has a highly functionalized polycyclic α,γ-disubstituted α,β-unsaturated γ-lactone and consists of bicyclo[11.1.0]carbon skeleton joined in a trans fashion. With its unusual structural features and specific cytotoxic properties, pinnatin A is a challenging target. No total synthesis of pinnatin A has been reported to date. Recently, we have achieved a diastereoselective construction of syn- and anti-isopropenyl alcohol moieties at the C(1) and C(2) positions of 2,5-bridged furanocycles based on the [2,3] Wittig rearrangement of cyclic furfuryl ethers as a key step.2 Thus we intended to study the synthesis of pinnatin A using this strategy. We report here the stereoselective synthesis of the C(2)-C(11) segment 2, cyclopropylfuran part, of pinnatin A 1.

We first investigated Suzuki cross-coupling between furanboronic ester 43 and cyclopropyl iodide 54 under Charette’s conditions5a (eq. 1). Pd(OAc)2-catalyzed cross-coupling reaction with K2CO3 and Bu4NBr gave the adduct 6 in only 6% yield. The addition of CsF instead of K2CO3 afforded trisubstituted cyclopropane 6 in 25% yield. Poor yields and lower reactivities in this Suzuki cross-coupling could be due to the steric effect of geminal substitution in 5, since the coupling reaction of 2-alkyl-1-iodocyclopropanes with arylboronic acids gave good yields.5

We next carried out Suzuki cross-coupling reaction between bromofuran 76 and cyclopropylboronic acid derivatives 8-117 under Falck’s and Deng’s conditions8 (Table 1). Moderate to good yields of the cross-coupling products 6 and 12 were obtained using a combination of Ag2O-K2CO3. Increasing amounts of K2CO3 (5.0 eq) gave better coupling yields with both 6 and 12 (entries 1, 3 vs 2, 4). Boronic acids 8 and 9 were preferable to boronates 10 and 11 (entries 3, 4 vs 5, 6).

With the optimized condition in hand, we embarked on the synthesis of chiral cyclopropylfuran 2 as follows. Scheme 2 shows a preparation of cyclopropyl iodide 15 from the known alkyne 13.9 Alkyne 13 was subjected to Organ’s carbometalation conditions10 to provide vinyl iodide 14 in one-pot sequence. Cyclopropanation of vinyl iodide 14 under Shi’s conditions11 resulted in the formation of cyclopropane 15 in a single diastereomer. The absolute configuration of cyclopropyl iodide 15 was determined by the MTPA esters of the corresponding cyclopropanol 16.

Suzuki cross-coupling of cyclopropylboronic acid 17, prepared from 15 by lithium/halogen exchange followed by treatment with B(i-PrO)3, with bromofuran 7 under the optimized condition gave the desired product 18 in 77% (2 steps). Acetal group of 18 was switched from cyclohexylidene to p-methoxy- benzylidene by acid hydrolysis followed by acetalization of the corresponding diol with p-methoxy- benzaldehyde to give 19. Reduction of furoate 19 with LiAlH4 followed by etherification of the furfuryl alcohol with TBDPSCl afforded silyl ether 20. Regioselective cleavage of p-methoxybenzylidene acetal 20 with DIBAL gave an inseparable mixture (ratio: 2.5 : 1) of alcohols, which were oxidized with Dess-Martin periodinane to afford the desired aldehyde 2112 together with ketone 22.

In conclusion, we have succeeded in the enantioselective synthesis of cyclopropylfuran derivative 21, the C(2)-C(11) segment of pinnatin A employing the silver (I) oxide promoted Suzuki cross-coupling as a key step. Further studies on the synthesis of pinnatin A are in due course.

ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Open Research Center Project.

References

1. A. D. Rodriguez, J.-G. Shi, and S. D. Huang, J. Org. Chem., 1998, 63, 4425. CrossRef
2. M. Tsubuki, K. Takahashi, and T. Honda, J. Org. Chem., 2003, 68, 10183. CrossRef
3. Furanboronic ester 4 was prepared by Pd-catalyzed borylation of bromofuran 7 with diboron under Miyaura’s conditions (T. Ishiyama, M. Murata, and N. Miyaura, J. Org. Chem., 1995, 60, 7508). CrossRef
4. Cyclopropyl iodide 5 was prepared by cyclopropanation of the corresponding (E)-vinyl iodide in 96%. (E)-Vinyl iodide: M. Kunishima, K. Hioki, K. Kono, A. Kato, and S. Tani, J. Org. Chem., 1997, 62, 7542. CrossRef
5. (a) A. B. Charette and A. Giroux, J. Org. Chem., 1996, 61, 8718; CrossRef (b) D. J. Wallace and C.-Y. Chen, Tetrahedron Lett., 2002, 43, 6987. CrossRef
6. (a) D. W. Knight and D. J. Rustidge, J. Chem. Soc., Perkin Trans. 1, 1981, 679; CrossRef (b) R. Grigg, J. A. Knight, and M. V. Sargent, J. Chem. Soc., 1966, 976.
7. Cyclopropylboronic acid 8 was prepared by hydrolysis of the known boronate 10 (K. Takai, S. Toshikawa, A. Inoue, R. Kokumai, and M. Hirano, J. Organomet. Chem., 2007, 692, 520). Cyclopropyl iodide 5 was converted cyclopropylboronic acid 9 by lithium/halogen exchange followed by treatment with B(i-PrO)3. Esterfication of 9 with pinacol gave 11. CrossRef
8. (a) G. Zou, K. Reddy, and J. R. Falck, Tetrahedron Lett., 2001, 42, 7213; CrossRef (b) H. Chen and M.-Z. Deng, J. Org. Chem., 2000, 65, 4444. CrossRef
9. D. A. Evans and J. D. Burch, Org. Lett., 2001, 4, 503. CrossRef
10. M. G. Organ and S. Bratvanov, Tetrahedron Lett., 2000, 41, 6945. CrossRef
11. Z. Yang, J. C. Lorenz, and Y. Shi, Tetrahedron Lett,. 1998, 39, 8621. CrossRef
12. 21: a colorless oil. [α]D22 -24.1 (c 0.64, CHCl3); IR (thin film) cm-1: 1110, 1740; 1H-NMR (CDCl3 270 MHz) δ: 0.91 (1H, dd, J = 5.1 and 5.9 Hz, 3’-CHH), 0.96 (3H, s, 2’-CCH3), 1.02 (9H, s, SiC(CH3)3), 1.08 (1H, dd, J = 5.1 and 9.2 Hz, 3’-CHH), 1.75 (3H, s, ArCH3), 2.11 (1H, dd, J = 5.9 and 9.2 Hz, 1’-CH), 3.29 (1H, d, J = 2.1 Hz, 1’’-CH), 3.80 (3H, s, OCH3), 4.54 (2H, s, ArCH2O), 4.59 (2H, s, CH2OSi), 5.82 (1H, s, ArH), 6.89 and 7.29 (each 2H, each d, J = 8.6 Hz, CH3OC6H4) 7.28-7.64 (6H, m, ArH), 7.62-7.72 (4H, m, ArH), 9.69 (1H, d, J = 2.1 Hz, CHO); 13C-NMR (CDCl3 67.8 MHz) δ: 9.7, 14.1, 16.1, 17.3, 19.3, 23.1, 26.7, 55.2, 56.6, 71.5, 87.3, 110.5, 113.9, 117.9, 127.6, 129.3, 129.5, 129.5, 133.7, 135.6, 147.8, 151.5, 159.5, 202.0; MS (EI): 582 (M+); HRMS (EI): calcd for C36H42O5Si: 582.2801. Found; 582.2800.