Pergamon Trrrahedron Leuers. Vol. 36, No. 45. pp X263-8266, 1995 Elsevier Science Ltd

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0040.4039(95)01773-9

Stereoselective Synthesis of A’-Oxonene and Its Novel Ring Contraction to A*-Oxocene

Kenshu Fujiwara, Misa Tsunashima, Daisuke Awakura, and Akio Murai*

Division of Chemistry, Graduate School of Sctence, Hokkaido University, Sapporo 060, Japan

Abstrocr: The stereoselcctive syntheses of I-3.bromo-r-2. c-9-dicthyl- and r-2, c-9-diethyl3-3-hydroxy- A”-oxonenes have been achieved by the oxldattve acctalization of 2, 9-diethyl-A*‘-oxonadiene and subsequent reduction. Furthermore, the novel ring contraction of r-2, c-9-diethyl-l-3.hydroxy-A’-oxonene to irons-2.(l-bromopropyl).R-ethyl-A4-oxocene has been discovered.

The specific structures and bioactivities as well as their biosynthesis’ of the 9- and &membered cyclic bromo ethers from Laurencia, such as laurencin,* laurallene,3 obtusenynes,4 and isolaurallene,5 have attracted

much attention, and these compounds are now important targets for total synthesis. 6 As part of our studies on

the total synthesis of the above natural products, we describe here the stereoselective synthesis of 9-membered cyclic bromo ethers from the related enol ethers through oxidative acetalization, followed by reduction, and our attempts to apply the method to an g-membered ring system. The novel stereospecific transformation of r-2, c-9-diethyl-t-3-hydroxy-A5-oxonene 8 to rran.s-2-( l-bromopropyl)-A4-oxocene 16, which is a common structure in laurenan compounds, tg is also described.

First, nonconjugated cyclic dienol ethers 2 and 1 I were synthesized from lactones 1 and 10, respectively, by a slightly modified previously reported method7 (Scheme 1): 1 and 10 were separately treated with KHMDSsV9 at -78 ‘C for 1 h in the presence of HMPA (2 eq), and the resultant dienolates were allowed to

react with PhNTf2 at -78 “C for 1 h, to afford dienol triflates, which were stable only at low temperature and could not be isolated.’ The solutions of the triflates were immediately treated with Et2CuMgBr (6 eq) in THF at -40 “C for 8-16 h in the presence of Me$ (12 eq) to give 2 (in 82% yield from 1) and 11 (in 80% yield from 10). respectively. 10 Although 2 was fairly stable, enabling purification by flash silica gel column chromatography, 11 was extremely unstable to water and required careful handling in purification by Florisil chromatography.

Next, we examined oxidative acetalizations of 2 and 11 (Scheme 1). In the reactions with NBS (1 eq) in MeOH at -40 “C, 2 and 11 gave soon the desired 3 and 12 in high yields, respectively. The regioselectivity would be probably due to the higher electron density of enol ether over A5 double bond.

11 In the case of

mCPBA, hydroxyl acetals 4 and 13 were provided mainly but in moderate yields from 2 and 11, respectively, because side reactions and decomposition of the products occurred under these conditions. 11 The stereochemistry of 3, 4, 12, 13 was assigned as shown in Scheme 1 by the large NOE enhancements between the protons indicated by arrows. Despite the similar reaction profile and the same substrate, the stereochemistry of 12 was different from 13. This difference was presumably due to the conformational change of the oxonium cation intermediate, which was induced by the change in bulkiness of C3 substituent. The following attack of MeOH would occur at the other side of C2 in each case. In the case of ‘)-membered series, such change in bulkiness

8264

Scheme 1

35% CH, 3 NOE 4% 8 - NoE Jz3 = 8.2 Hz

Me

pJ+? c 40$y$!3<,~,o*

, 1' 11 NOE Rezgents and conditions: a) KHMDS (2 eqy, HMPA (2 eq), THF, -78 ‘C, 1 h, then PhNTfz (2 e@ -78 "C. 1 h, then Et,CuMgBr (6 eq), MezS (12 eq), -78 ‘C. 10 min, then -40 ‘C, 8- 16 h; b) NBS (1 eq), MeQH, -40 "C, within 15 min; c) mCPBA (l-l.4 eq) with gradual additon, NaHC03 (2 eq), MeOH, O’C; d) TMSCI (2.6 eq), imidazole (excess), DMF, 0 “C, 15 min; e) SnC& (1 .S eq), Et$iH (6 eq). CH$&, -78 ‘C, 10 min.

at C3 would have no effect on stereoselectivity. Then, the cyclic acetals were subjected to Lewis acid catalyzing reduction

12 conditions (Scheme 1).

When 3 was treated with Et?SiH in the presence of SnCI, in C$Cl, at -78 ‘C for 10 min, the desired A5-oxonene 613 was mainly produced in 68% yield together with a 1:l mixture of diastereomers of acyclic methyl ethers 7 in 18% yield. The TMS ether 5 provided from 4 in 90% yield also gave cyclic ether 8 13 . In 49% yield along with 9 in 13 % yield. In the cases of both 6 and 8, other stereoisomers were not detected. On the other hand, g-membered cyclic acetals (12 and 13) afforded only acyclic products (14 and 15) under the same conditions as for the g-membered series. The different selectivity between 8- and 9- membered systems

was probably due to the lower dissociation ability of the Lewis acid coordinated methoxyl group in the strained g-membered system than that in the strain-less g-membered system. Since the coordination of Lewis acid to the methoxyl group and ring oxygen is supposed to be at equilibrium in each case, the difference in coordination ability of the methoxyl groups of 8- and 9 membered acetals would have no effect on the

selectivity. The &-relationships between ethyl substituents on C2 and C9 of 4 and 8 were assigned by the

clear N0E.s between H2 and H9 according to Holmes’ observations. Id Because of the large NOE between H2

and H3, the lack of NOE between H2 and H3, and large J values (8.2 and 9.5 Hz) between H2 and H3, the relationships of CZ-ethyl and C3-substituent of 6 and 8 were determined as Iruns. I4 From the fact that the

8265

J2m3 = 2.7 Hz

J1..2 6.6 Hz 8.2 Hz

3 2.43-2.48 2.53-2.62

‘H-NMR spectra were measured at 400 MHz in CD&. 9r E-pretaureatin

reduction of 3 and 5 disclosed the same stereoselection at C2 as the preceding acetalization of 2, the same oxonium cation intermediate might rule the stereoselection in these reactions.

Next, we examined the bromination of the hydoxyl group of 8 (Scheme 2). When 3-hydroxy-A5-oxonene 8 was refluxed with the complex of 1, 2-bis(diphenylphosphino)ethane and bromine rrans-2-(1-bromopropyl)-A4-oxocene 16 13

I5 in CH2C!12 for 1 h, was surprisingly obtained as a single stereoisomer in 50% yield

along with an inseparable 2:3 mixture of C3-retained 6 and C3-inverted 1713 in a combined 50% yield. The stereochemistry of 17 was determined by NOE experiments and small J value (2.7Hz) between H2 and H3 13’14 (Scheme 2). The g-membered cyclic structure of 16 was determined by HMBC spectrum. The trans-relationship between C2 and C8 substituents was assigned by the existence of NOE between Hl’ and H8 and lack of NOE between H2 and H8.14 At present, we can only speculate on the stereochemistry of Cl’ of 16 and the origin of the stereoselection. Based on the fact of production of 6 while there was no other stereoisomer

of 16, it seems likely that the bridged oxonium cation 18 16 would involve synchronously with dissociation of hydroxyl group and react with bromide anion to give 16 via path A and to give 6 via path B. Therefore, Cl’ of 16 might have B-Br, which was also supported by the similarity of ‘H-NMR data of 16 with those of E-prelaureatin 191e (Table). Product 17 appears to be provided from the active phosphonium intermediate of 8 by S,2 reaction with bromide anion, These findings suggest the possibility of an alternate biosynthetic pathway to oxocenes .

Thus, we provided a new synthetic route to r-3-substituted-r-2, c-9-diethyl-A5-oxonenes and discovered its novel ring contraction to rrans-2-( 1 -bromopropyl)-A4-oxocene. Further studies toward the total synthesis of oxocene and oxonene natural products are currently under way in our laboratories.

References and Notes 1. (a) Fukuzawa, A.; Masamune. T. Terrahedron Len. 1981, 22, 4081. (b) Fukuzawa, A.; Aye, M.; Murai,

A.: Chem. Left. 1990, 1579. (c) Fukuzawa, A.; Aye, M.; Murai, A. Tetrahedron Lett. 1990, 34,4895. (d) Fukuzawa, A.; Takasugi, Y.: Murai, A.; Nakamura, M.; Tamura, M. Terruhedron Len. 1992,33,2017. (e)

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Ishihara, J.; Kanoh, N.; Murai, A. Terrahedron Lett. 1995,36,737. (f) Kikuchi, H.; Suzuki, T.; Kwsawa, E.; Suzuki, M. Bull. Chem. Sot. Jpn. 1991, 64, 1763. (g) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Len. 1991,32,5597.

2. Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Len. 1965, 1091. 3. Fukuzawa. A.; Kurosawa, K. Tetrahedron Lett. 1979, 1091. 4. (a) King, T. J.; Imre, S.; Oztunc, A.; Thomson, R. H. Tetrahedron Len. 1979, 1453. (b) Howard, B. M.;

Schulte, G. R.; Fenical, W.; Solheim, B.; Clardy, J. Tetrahedron 1980, 36, 1747. (c) Gopichand, Y.; Shumitz, F. J.; Shelly, J.; Rahman, A.; van der Helm, D. J. Org. Chem. 1981, 46, 5192. (d) Norte, M.; Gontilez, A. G.; Cataldo, F.; Rodriguez, M. L.; Brito, I. Terrahedron 1991,47,9411.

5. Kurata, K.; Furusaki, A.; Suehiro, K.; Katayama, C.; Suzuki, T. Chem. Lett. 1982, 1031. 6. Total synthesis of laurencin: (a) Murai, A; Murase, H.; Matsue, H.; Masamune, T. Tetrahedron Lett.

1977,2507. (b) Tsushima, K.; Murai, A. Tetrahedron Letr. 1992, 33,4345. (c) Robinson, R. A.; Clark, J. S.; Holmes, A. B. J. Am. Chem. Sot. 1993, 115, 10400. (d) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. 1. Am. Chem. Sot. 1995, 117, 5958. Total synthesis of other oxocene natural products: (-)-laurenyne: (e) Overman, L. E.; Thompson, A. S. J. Am. Chem. Sot. 1988, 110, 2248. Total synthesis of oxonene natural product has not been reported.

7. (a) Tsushima, K.; Araki, K.; Murai, A. Chem. Left. 1989, 1313. (b) Tsushima, K.; Murai, A. Chem. Lerf. 1990,761.

8. LiHMDS and NaHMDS were not effective. It was necessary to use KHMDS (0.5 M solution in toluene, Aldrich Inc.) as soon as possible after opening.

9. Honma, T.; Hirade, T.; Murai, A. unpublished results. 10. In the presence of excess HMPA more than 2 eq, g-membered cyclic dienol triflate derived from 10 did

not react with Et$uMgBr, whereas 9-membered dienol triflate derived from 1 reacted. 11. Nakamura, A.; Tani, N.; Murai, A. unpublished results. 12. (a) Mori, A.; Ishihara, K.; Yamamoto, H. Terrohedron Lert. 1986, 27, 987. (b) Kotsuki, H.; Ushio, Y.;

Kadota, I.; Ochi, M. J. Org. Chem. 1989,54,5 153. 13. 6: ‘H-NMR (4OOMHz. CDCl,) 60.86 (3H, t, J=7SHz), 0.92 (3H, t, J=7.5Hz), 1.45 (lH, quint-d, J=7.5,

13.9Hz), 1.53-1.62 (lH, m), 1.62-1.73 (lH, m), 1.76 (IH, dqd, J=4.2, 7.3, 14.6), 1.83 (lH, dqd, J=3.7, 7.5, 14.6Hz), 1.94 (lH, brqd, J=5.1, 13.OHz), 2.41 (lH, brtd, J=4.6, 14.3Hz), 2.51 (lH, dtd, J=4.6, 10.0, 13.2Hz), 3.31 (lH, ddd, J=3.5, 9.2, 14.3Hz), 3.42 (lH, tt, J=4.8,7.7Hz), 3.54 (lH, td, J=3.9,9.5Hz), 4.17 (lH, td, J=3.8,9.5Hz), 5.64-5.77 (2H, m). 8: ‘H-NMR (4OOMHz. CDCl,) 60.87 (3H, t, J=7.5), 0.95 (3H, t, J=7.5Hz), 1.46 (lH, quint-d, J=7.3, 13.7Hz), 1.50-1.77 (5H, m), 1.96 (lH, dtd. J=4.1,6.1, 13.2Hz), 2.22 (IH, td, J=5.8, 13.6Hz). 2.49 (lH, dtd, J=4.2, 10.1, 13.2Hz), 2.84 (lH, ddd, J=2.9, 10.1, 13.2Hz), 3.18 (lH, td, J=4.4, 8.2Hz), 3.41 (IH, brtt, J=4.6,7.9Hz), 3.76-3.83 (lH, m), 5.62 (lH, dt, J=6.4, 10.2Hz), 5.70 (lH, dt, J=6.8, 10.2Hz). 16: ‘H-NMR (4OOMHz. CDC$) 60.92 (3H, t, J=7.5Hz, H2”), 1.08 (3H, t, J=7.5Hz, H3’), 1.42-1.56 (3H, m, H7a, HI”), 1.62-1.70 (lH, m, H7b), 1.73-1.90 (lH, m, H2’a), 2.15-2.26 (3H, m, H6, H2’b), 2.53-2.62 (2H, m, H3), 3.72 (lH, ddd, J=4.0, 8.2, lO.OHz, H2), 3.82 (IH, dddd, J=1.8, 4.8, 6.7, 11.7Hz, H8), 4.00 (IH, brddd, J=2.9, 8.2, 9.OHz, Hl’), 5.68(1H, brtd, J=7.9, 10.4Hz, H4), 5.91 (lH, td, J=7.5, 10.6Hz, H5); 13C-NMR (lOOMHz, CDC13, ‘3CDCI, as 77 ppm) 69.6 (CH3, H2”). 11.9 (CH3, H3’), 25.7 (CH,, H6), 29.7 (CH,, H3), 29.8 (CH,, H2’). 30.1 (CH,, HI”), 34.8 (CHp H7), 60.8 (CH, Hl’), 75.1 (CH, H8), 78.4 (CH, H2), 127.1 (CH, H4), 132.7 (CH, H5). 17: ‘H-NMR (4OOMHz, CDClJ) Xl.83 (3H, t, J=7.5Hz), 0.87 (3H, t, J=7.5Hz), 1.47 (lH, quint-d, J=7.5, 13.7Hz) 1.55-1.81 (5H, m), 1.81-1.91 (lH, m), 2.53 (lH, brtd, J=5.5, 12.8Hz), 2.66 (lH, brdtd, J=3.8, 10.6, 13.5Hz), 3.22 (lH, ddd, J=2.7, 6.2, 8.OHz), 3.31-3.41 (2H, m), 4.20 (lH, ddd, J=2.7, 5.1, 11.2Hz), 5.40 (lH, brdt, J=5.9, 10.6Hz), 5.69 (lH, brdt, J=6.4, 10.6Hz). Although 17 was obtained as a 3:2 mixture with 6, ‘H-NMR data of 17 was given clearly after subtracting the data of 6 from the mixture.

14. (a) Curtis, N. R.; Holmes, A. B. Tetrahedron Len. 1992,33, 675. (b) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Sot., Perkin Trans. 11992, 83. and cf. ref 6c.

15. Schmidt, S. P.; Brooks, D. W. Tetrahedron Lerr. 1987,28,767. 16. Ring enlargements via bridged oxonium cation have been reported: (a)Nakata, T.; Schmid, G.; Vranesic,

B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y. J. Am. Chem. Sot. 1978, 100, 2933.(b) Bartrett, P. A.; Ting, P. C. J. Org. Chem. 1986,51, 2230.

(Received in Japan 7 August 1995; revised 13 September 1995; accepted 14 September 1995)