Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-Laurencin

An Enantioselective Synthesis of 2-Aryl Cycloalkanones by Sc-Catalyzed Carbon Insertion. Victor L. Rendina , David C. Moebius , and Jason S. Kingsbury...
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J. Am. Chem. Soc. 1997, 119, 7483-7498

7483

Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-Laurencin Jonathan W. Burton, J. Stephen Clark, Sam Derrer, Thomas C. Stork, Justin G. Bendall, and Andrew B. Holmes* Contribution from the Department of Chemistry, UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW U.K. ReceiVed March 21, 1997X

Abstract: The enantioselective synthesis of (+)-laurencin 1 has been achieved in 27 steps from (R)-malic acid 20. The key steps involved methylenation of the lactone 49 followed by intramolecular hydrosilation of the enol ether 14 (Scheme 11) and one carbon homologation of the diol 13 to give the key ethyl substituted cyclic ether 59 (Scheme 13). The lactone 49 was obtained by two efficient routes, namely a Claisen ring expansion (Scheme 3) followed by R-hydroxylation (Scheme 6) and a Yamaguchi lactonization (Scheme 11). Elaboration of the (E)-pentenynyl side chain (Scheme 18) and introduction of bromine (Scheme 19) completed the synthesis of (+)-laurencin 1.

Introduction The eight-membered medium ring ether natural product (+)laurencin 1 is the prototypical member of a growing family of marine natural product cyclic ethers isolated from red algae and those marine organisms which feed on Laurencia species. Laurencin was first isolated from L. glandulifera by Irie and Masamune and co-workers.1,2 Its structure was assigned by chemical degradation, spectroscopic analysis, and X-ray crystallography,3,4 and the absolute configuration was determined by the Prelog atrolactic acid method on a side-chain degradation product. Racemic laurencin was synthesized by Masamune and co-workers in an epic assault reported in the late 1970s.5-7 In recent years we and a number of others have developed new synthetic methodology to prepare medium ring ethers by ring expansion methods. Our own approach has been based on ring expansion reactions of cyclic ketones and vinyl-substituted ketene acetals to produce, respectively, saturated8-12 and unsaturated medium ring lactones13-16 which have been elaborated to 2,n-disubstituted cyclic ethers by Tebbe methylenation X Abstract published in AdVance ACS Abstracts, July 15, 1997. (1) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 1091. (2) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193. (3) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. J. Chem. Soc., Chem. Commun. 1965, 638. (4) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. J. Chem. Soc. (B) 1969, 559. (5) Murai, A.; Murase, H.; Matsue, H.; Masamune, T. Tetrahedron Lett. 1977, 2507. (6) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc. Jpn. 1979, 52, 127. (7) Masamune, T.; Murase, H.; Matsue, H.; Murai, A. Bull. Chem. Soc. Jpn. 1979, 52, 135. (8) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1986, 565. (9) Clark, J. S.; Holmes, A. B. Tetrahedron Lett. 1988, 29, 4333. (10) Carling, R. W.; Curtis, N. R.; Holmes, A. B. Tetrahedron Lett. 1989, 30, 6081. (11) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Soc., Perkin Trans. 1 1992, 83. (12) Carling, R. W.; Clark, J. S.; Holmes, A. B.; Sartor, D. J. Chem. Soc., Perkin Trans. 1 1992, 95. (13) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1986, 325. (14) Curtis, N. R.; Holmes, A. B.; Looney, M. G. Tetrahedron 1991, 47, 7171. (15) Congreve, M. S.; Holmes, A. B.; Hughes, A. B.; Looney, M. G. J. Am. Chem. Soc. 1993, 115, 5815. (16) Fuhry, M. A. M.; Holmes, A. B.; Marshall, D. R. J. Chem. Soc., Perkin Trans. 1 1993, 2743.

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and subsequent functionalization of the enol ether double bond.8-12 Other notable approaches have been reported by Murai,17 Overman,18-21 Palenzuela,22 Nicolaou23 and others,24-26 and these are summarized in a series of recent review articles.27-29 Results and Discussion Synthesis of (+)-Octahydrodeacetyldebromolaurencin 2. Our previous experience with the hydroboration of exocyclic enol ethers derived from saturated eight-membered lactones demonstrated a preference for the cis-2,8-disubstitution pattern,11,12 but we needed unambiguous chemical confirmation of the relative and absolute configuration of the products.

Octahydrodeacetyldebromolaurencin 21,2 offered an excellent opportunity to synthesize a known degradation product of laurencin, confirm the cis-disubstitution pattern, and assign the absolute stereochemistry of the degradation product.9 The Baeyer-Villiger, Tebbe methylenation, hydroboration strategy has been well documented in previous publications.8-12 Scheme 1 summarizes the application of the route to the synthesis of 2. (17) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345. (18) Blumenkopf, T. A.; Bratz, M.; Castan˜eda, A.; Look, G. C.; Overman, L. E.; Rodriguez, D.; Thompson, A. S. J. Am. Chem. Soc. 1990, 112, 4386. (19) Blumenkopf, T. A.; Look, G. C.; Overman, L. E. J. Am. Chem. Soc. 1990, 112, 4399. (20) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248. (21) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958. (22) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett 1996, 983. (23) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589. (24) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 916. (25) Isobe, M.; Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473. (26) Gre´e, D. M.; Martelli, J. T.; Gre´e, R. L. J. Org. Chem. 1995, 60, 2316. (27) Moody, C. J.; Davies, M. J. In Studies in Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science: 1992; Vol. 10, pp 201-239. (28) Elliott, M. C. Contemp. Org. Synth. 1994, 1, 457. (29) Rousseau, G. Tetrahedron 1995, 51, 2777.

© 1997 American Chemical Society

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Scheme 1. Synthesis of Octahydrodeacetyldebromolaurencin

(R)-2-Ethylcycloheptanone 5 was prepared by Enders30,31 alkylation of the azaenolate derived from the SAMP-hydrazone 3. The alkylation product 4 was obtained with a de of 90% [1H NMR, 90 MHz, Eu(fod)3] and was converted into 5 by ozonolysis. The Baeyer-Villiger oxidation was carried out by addition of the ketone 5 to a buffered solution of trifluoroperacetic acid in order to minimize racemization. Tebbe methylenation, followed by hydroboration with the bulky diisoamylborane, afforded only one diastereoisomeric alcohol which was subsequently shown to be the cis-product 8. This was oxidized with PCC, and the resulting aldehyde was treated with pentylmagnesium bromide at 0 °C to afford a 1.5:1 mixture of the alcohols 2 and 9, favoring the required material. Attempts to improve selectivity by chelation control using magnesium bromide or mixed cuprates such as pentylcoppermagnesium iodide or bromide were unsuccessful.32,33 Oxidation of the diastereoisomeric mixture 2 and 9 gave the ketone 10 which was reduced diastereoselectively with L-Selectride in a FelkinAnh sense to afford exclusively the octahydrodeacetyldebromolaurencin 2. This exhibited a specific rotation [R]D21 +19.6 (c 1.52, CHCl3) and was identical in all respects (TLC, 1H NMR, 13C NMR, IR, MS) with an authentic sample [R] 18 +21.6 (c D 1.86, CHCl3).1,2,34 The enantiomeric purity of 2 could not be assayed by the Mosher ester method, but based on the specific rotation it was judged to be of 91% ee. The highly diastereoselective reduction of the side-chain carbonyl group has subsequently been applied by Murai17 and by us in the synthesis of (+)-laurencin 1 itself. The synthesis of (+)-2 based on the well precedented Enders method for preparing (R)-5 independently establishes the absolute configuration of (+)-1. This is an important correlation because although the absolute configuration had previously been determined by X-ray methods, the previous assignment by X-ray of the absolute configuration of (30) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933. (31) Enders, D.; Frey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173. (32) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1986, 27, 4011. (33) Sato, F.; Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.; Kusakabe, M. J. Chem. Soc., Chem. Commun. 1985, 1636. (34) Authentic 2 was kindly supplied by Dr A. Fukuzawa, who degraded natural (+)-laurencin 1 to obtain the sample.

a related molecule, laurenyne,35 had to be revised after its total synthesis by Overman.20 Previous Syntheses of 1. The first enantioselective synthesis of (+)-laurencin was reported by Murai and co-workers and relied on a novel ring expansion reaction of a four-membered ring fused to a tetrahydropyran.17 The resulting lactone was elaborated to the key intermediate 12 (P ) TBS) (see Scheme 2) which serves as a natural focus for the ring synthesis. Overman and colleagues described the second enantioselective synthesis of laurencin using their intramolecular oxacarbenium ion cyclization procedure.21 This was followed by Palenzuela’s formal synthesis involving an intramolecular alkylation of an R-lithiosulfone.22 It is noteworthy that the latter two syntheses demonstrated that ring closure of unconstrained acyclic precursors to eight-membered ring ethers is entirely feasible under certain circumstances.24-26 Retrosynthetic Analysis of 1. The purpose of this paper is to report our own synthesis of (+)-laurencin36 and to demonstrate some interesting aspects of the functionalization of eightmembered lactones. The retrosynthetic analysis of laurencin (Scheme 2) depends on the late introduction of bromine by displacement with inversion of configuration of the corresponding alcohol 11, a process which has precedent from all the earlier reported syntheses. The introduction of the pentenynyl side chain was planned by alkylation of the aldehyde 12. The synthesis of the medium ring 2,8-disubstituted tetrahydro-oxocin 13 relied on elaboration of the corresponding lactone precursor 15 by methylenation and enol ether 14 functionalization. Considerable previous experience encouraged us to prepare the lactone 16 by [3,3]-sigmatropic rearrangement of the vinylsubstituted ketene acetal 17 which was to be generated in situ by selenoxide elimination of the precursor 18. The synthesis therefore relied on a preparation of the triol derivative 19 from (R)-malic acid 20. In the event this strategy was realized. An alternative approach to 15 by an intramolecular ring closure (lactonization) has also been developed. Furthermore, we have (35) Falshaw, C. P.; King, T. J.; Imre, T. J.; Islimyeli, S.; Thomson, R. H. Tetrahedron Lett. 1980, 21, 4951. (36) Burton, J. W.; Clark, J. S.; Bendall, J.; Derrer, S.; Stork, T.; Holmes, A. B. J. Am. Chem. Soc. 1996, 118, 6806.

Synthesis of Medium Ring Ethers. 5 Scheme 2. Retrosynthesis of (+)-Laurencin 1

found two different methods of elaborating the lactone 16 to 2,8-disubstituted oxocane derivatives. Claisen Route to the Lactone 16. The optimum route to the lactone 16 was developed from our racemic synthesis (Scheme 3).13 (R)-Malic acid 20 was esterified37 and selectively reduced38,39 to the diol 21 which was protected as the acetonide 22. Reduction of the ester 22 with DIBAL-H at low temperature to minimize acetonide cleavage, followed by addition of vinylmagnesium chloride to the aldehyde 23 in the presence of thoroughly dried cerium(III) chloride,40 afforded the allylic alcohol 24. Vinylmagnesium bromide will also add to the aldehyde 23, but the reagent becomes less efficient with age, and the most reproducible yields of 24 are obtained with vinylmagnesium chloride. The allylic alcohol 24 was obtained as an approximate 1:1 mixture of diastereoisomers, both of which appeared to undergo the subsequent Claisen rearrangement without difficulty, and the mixture was always carried through the synthesis without separation of the isomers. Acetonide hydrolysis followed by selective silylation of the primary alcohol afforded the TPS ether 19 which was converted with phenylselenoacetaldehyde diethyl acetal41 into the mixture of acetals 25. No attempt was made to separate these isomers, but the spectroscopic evidence from a number of investigations would imply that the major isomers present were 25a, 25b, and 25c (Figure 1). (37) Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933. (38) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389. (39) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron 1992, 48, 4067. (40) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (41) Petrzilka, M. HelV. Chim. Acta 1978, 61, 3075.

J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7485 Oxidation of the selenides 25 to the selenoxides 18, followed by selenoxide elimination in refluxing xylene in the presence of DBU is presumed to have generated the intermediate vinylsubstituted ketene acetal 17 which underwent [3,3]-sigmatropic rearrangement to the lactone 16 in good yield. The fact that high yields were consistently obtained for this rearrangement is indirect evidence that both diastereoisomeric ketene acetals rearranged almost equally well. 1H NMR analysis of a later intermediate, the hydroxy lactone 15 (J5,6 ) 11.0 Hz) indicated that the lactone 16 contained a cis-double bond. Such Claisen ring expansions were first used by Petrzilka41 to prepare a 10membered lactone. We have used this procedure to obtain seven-, eight- and nine-membered lactones, and almost without exception the (Z)-alkene is produced in the smaller rings.13-16 However we have seen occasional exceptions, and a recent example reported by Pearson also yielded a nine-membered lactone with mainly the (E)-double bonded product.42 In the synthesis of the lactone 16 the results are consistent with the involvement of all chair-like transition states (Figure 2) for the 1,3-anti diol-derived precursor TS1, while the 1,3-syn-diol precursor is able to invert one of the rings to a less hindered conformation TS2 to relieve the strain arising from the OTPS substituent. Conversion of the Lactone 16 into a 2,8-Disubstituted Tetrahydrooxocin. Methylenation of the racemic lactone (()16 with the Tebbe reagent43,44 gave the enol ether 26 in good yield (Scheme 4). The conformational rigidity owing to the presence of the endocyclic double bond in 26 meant that it was sufficiently stable to be chromatographed on silica gel in the presence of triethylamine and a suitable solvent. All attempts at hydroborating the enol ether 26 with a variety of organoboranes were uniformly unsuccessful. Either the exocyclic double bond resisted attack, or under more forcing conditions ringopening of the intermediate organoborane occurred together with competing hydroboration of the endocyclic double bond. It was therefore decided to attempt phenylselenoacetalization of the enol ether, according to well established precedent for simple enol ethers.41 The enol ether 26 reacted efficiently with benzeneselenenyl chloride in methanol in the presence of triethylamine to give a 6:1 mixture of methoxy acetals 27a and 27b. The relative stereochemistry of these isomers was not assigned, but precedent would suggest that the major isomer was 27a, because most examples of nucleophilic attack on eightmembered oxacarbenium ions favor the incoming reagent being trans to existing substituents.8-12 In keeping with this observation, reduction of the major methoxy-acetal with alane afforded mainly the cis-phenylselenomethyl derivative 28a plus a trace of the trans-isomer 28b; the harsh reducing conditions resulted in cleavage of the silyl protecting group. These were each converted into the corresponding 3,5-dinitrobenzoates 29a and 29b, respectively. The major product formed crystals suitable for X-ray structure determination, and the structure is shown in Figure 3.45 This is the first crystal structure of a synthetic ∆5,6-2,8disubstituted-tetrahydro-2H-oxocin.26 An examination of the ring conformation of 29a showed that it represents a global minimum characteristic of the ring conformation of the eight(42) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546. (43) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611. (44) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 1980, 102, 3270. (45) Compound 29a, C22H22O7Se, MW 505.39, was obtained as yellow crystals, space group P1h (No. 2), a ) 8.574(1) Å, b ) 11.434(1) Å, c ) 12.702(1) Å, R ) 114.14(1)°, β ) 92.33(1)°, γ ) 103.39(1)°, V ) 1092.6 Å3, Z ) 2, Dcalcd ) 1.54 g cm-3, F(000) ) 516, λ (Cu KR) 1.5418 Å, µ (Cu KR) 27.67 cm-1.

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Scheme 3. Synthesis of the Lactone 16

Scheme 4. Elaboration of the Lactone 16

Figure 1. Diastereoisomeric acetals 25.

Figure 2. Claisen transition states.

membered unsaturated Laurencia metabolites laurencin3,4 1, trans-pinnatifidenyne46 30, and bermudenynol47 31 (Figure 4).

The cis-phenylselenomethyl derivative 28a was protected and then readily transformed by Pummerer rearrangement into the R-acetoxy derivative 32 and then by reduction into the hydroxymethyl derivative 33 (Scheme 5). This sequence therefore established an alternative to hydroboration for the conversion of enol ethers into functionalized eight-membered ring ethers. r-Hydroxylation of the Lactone 16. Before applying a methylenation sequence to the laurencin precursor itself it was necessary to introduce an R-hydroxyl substituent adjacent to the lactone carbonyl group of 16 in anticipation of the need ultimately to replace this substituent by bromine at the end of the synthesis. We were attracted to the possibility of using the (46) Gonza´lez, A. G.; Martı´n, J. D.; Martı´n, V. S.; Norte, M.; Pe´rez, R.; Ruano, J. Z.; Drexler, S. A.; Clardy, J.Tetrahedron 1982, 38, 1009. (47) Cardellina II, J.; Horsley, S. B.; Clardy, J.; Leftow, S. R.; Meinwald, J. Can. J. Chem. 1982, 60, 2675.

Davis oxaziridine reagents to oxidize the lactone enolate diastereoselectively.48 Formation of the potassium enolate derived from the lactone 16, as a solution in THF at -78 °C followed by addition of trans-(()-2-(phenylsulfonyl)-3-phenyloxaziridine 3449,50 gave the hydroxy lactones 15 and 35 as a 1:1 mixture of diastereoisomers in 22% yield (Scheme 6). (48) Davis, F. A.; Chen, B. C. Chem. ReV. 1992, 92, 919.

Synthesis of Medium Ring Ethers. 5

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Scheme 5. Pummerer Rearrangement of 28a

Figure 4. Chem3D representations of the crystal structures of the dinitrobenzoate 29a, laurencin 1, trans-pinnatifidenyne 30, and bermudenynol 31 taken from the Cambridge Crystallographic Database to show the comparison of the oxocane ring conformation (viewed along the 3-C-4-C bond). For clarity, the side chains have been deleted from all the models.

Scheme 6. Enolate Hydroxylation of 16

Figure 3. The X-ray crystal structure of the dinitrobenzoate 29a.

The poor selectivity indicated that the remote CH2OTPS substituent in the enolate derived from 16 provided insufficient conformational bias to favor the required 3(R)-alcohol 15 for the proposed synthesis of (+)-laurencin. It was clear that reagent control would be required to control the diastereoselectivity of attack. Davis48 has advocated the use of the (10camphorsulfonyl)oxaziridines 36 and 37 to perform diastereoselective enolate oxidations. The use of 36 in THF at -78 °C with the potassium enolate derived from 16 afforded only the 3(S)-alcohol 35 in 7% yield. The configuration of the 3(S)alcohol 35 was rigorously established Via 1H NMR 1D gradient NOE measurements51,52 (Figure 5) and Mosher ester analysis53 (see Supporting Information). Irradiation of 8-H (δ 4.82-4.78, m, 1H) led to an enhancement of the signal due to 6-H (δ 5.82, dt, J ) 11.0, 7.7, 1H) but no enhancement of 3-H (δ 4.64(49) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1774. (50) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth. 1988, 66, 203. (51) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am. Chem. Soc. 1994, 116, 6037. (52) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A. J. J. Am. Chem. Soc. 1995, 117, 4199. (53) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.

4.61, m, 1H); irradiation of the signal due to 3-H did not lead to enhancement of 8-H. These experiments indicated that 3-H and 8-H were in a trans-relationship. Molecular modeling (Monte Carlo conformational search54 using the MM2 force field55 in MacroModel version 5.556) provided a unique global minimum conformation for the analogous lactone 35a. This model fitted the NOE data very well and indicated that 8-H and 6-H were in close proximity (3.31 Å apart). Reaction of a THF solution of the potassium enolate derived from the lactone 16 with 1(R)-(-)-(10-camphorsulfonyl)oxaziridine 37 at -78 °C provided the hydroxy lactones 15 and 35 as a 5.3:1 mixture of diastereoisomers (11%). The structure of the 3(R)-alcohol 15 was established Via 1D gradient NOE measurements51,52 which fit well with the results obtained from molecular modeling of the analogous lactone 15a (Figure 6). In particular strong reciprocal NOEs were observed in the 1H NMR spectra between the signals due to 3-H (δ 4.40-4.36, m, 1H) and 8-H (δ 4.62, m, 1H). Performing the above experiments using toluene as the solvent provided the hydroxy lactones in reasonable yield (see Table 1). The desired 3(R)-alcohol 15 could be obtained in an optimum yield of 26% (entry 9) but not as the exclusive product. We have subsequently shown that both 15 and 35 could, in principle, be employed in a synthesis of laurencin, but alternative higher yielding routes to 15 became desirable. The selectivities observed in the above reactions are hard to account for and do not appear to fit the recent model put forward by Bach and Davis57 for oxidation of ketone enolates using the chlorocamphorsulfonyl oxaziridine 38. We relied, in part, on (54) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379. (55) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127. (56) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440. (57) Bach, R. D.; Andre´s, J. L.; Davis, F. A. J. Org. Chem. 1992, 57, 613.

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Figure 5. Chem3D representation of the global minimum conformation (Macromodel, MM2 force field, Monte Carlo conformational search) of 35a (TPS group modeled as TMS group) analogous to the hydroxy lactone 35 and 1D gradient NOE data for 35.

Scheme 8. Synthesis of the Phosphonium Salt 40

Scheme 9. Synthesis of the Aldehyde 41

Figure 6. Chem3D representation of the global minimum conformation (MacroModel, MM2 force field, Monte Carlo conformational search) of 15a (TPS modeled as TMS group) analogous to the hydroxy lactone 15 and 1D gradient NOE data for 15. Table 1. Oxidation of the Enolate Derived from 16 entry

solvent

oxaziridine

base

yield 15 and 35

ratio 15:35

1 2 3 4 5 6 7 8 9

THF THF THF THF THF THF toluene toluene toluene

34 36 37 36 36 36 34 36 37

KHMDS KHMDS KHMDS LiHMDS LDA NaHMDS KHMDS KHMDS KHMDS

22 7 11 trace trace 20 64 65 52

1:1 4.5:95.5 5.3:1 nda nda nda 1:4 1:2 1:1

a

Scheme 10. Synthesis of the seco-Acid 39

Not determined is abbreviated as nd.

the previous model put forward by Davis for ketone enolates in our original incorrect assignment of the structure of 15, although one reported example of a lactone enolate hydroxylation does seem more consistent with our own findings.48 Therefore we conclude that the application of this model to chiral lactone enolates should be exercised with caution. Given that our original hydroxy lactone was compound 35 and not 15, we concluded that we could not have synthesized laurencin; the original paper was therefore withdrawn, and the synthetic sequence was repeated using authentic 15.36 The alternative route to 15 is described below. We note in passing that the major byproduct from the oxaziridine oxidations was the ring opened hydroxy acid, suggesting that the involvement of ketene intermediates may well explain the poor yields of hydroxy lactones isolated. Yamaguchi Lactonization Route to the r-Hydroxy Lactone 15. The recent promising advances in ring closure of secoacids to eight-membered lactones58 suggested the direct lactonization of the hydroxy acid 39. The cis-double bond in 39 (58) Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994, 116, 5511.

implies a Wittig disconnection to provide the phosphonium salt 40 and the aldehyde 41, both available from (R)-malic acid 20 (Scheme 7). The known bromide 4259-61 was treated with molten triphenylphosphine under lithium iodide catalysis to provide the phosphonium salt 40 which could be crystallized by sonication with ether (Scheme 8). The aldehyde 41 was prepared by ethanolysis of the known BOM-protected lactone 4362 and Swern oxidation63 of the resulting primary alcohol (Scheme 9). Wittig reaction of the ylid derived from the phosphonium salt 40 (BuLi, THF, -78 °C to 0 °C) with the aldehyde 41 (59) Mori, K.; Watanabe, H. Tetrahedron Lett. 1984, 25, 6025. (60) Barth, M.; Bellamy, F. D.; Renaut, P.; Samreth, S.; Schuber, F. Tetrahedron 1990, 46, 6731. (61) Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman, R. J. J. Org. Chem. 1986, 51, 5111. (62) Collum, D. B.; McDonald III, J. H.; Still, W. C. J. Am. Chem. Soc. 1980, 102, 2118. (63) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480.

Synthesis of Medium Ring Ethers. 5 provided the alkene 44 (73%) (Scheme 10). The geometry of the alkene 44 was assigned as (Z) according to precedent and was later confirmed by the measurement of a 10.9 Hz coupling between 5-H and 6-H in the lactone 47. A small quantity of the dienes [predominantly the 2(E),4(Z) isomer 45, J2,3 ) 15.3

Hz, J4,5 ) 10.9 Hz] was obtained from the Wittig reaction (the structure of the minor geometrical isomer could not be proved). Standard protecting group manipulations on the alkene 44 provided the lactonization precursor 39 in good overall yield. Corey-Nicolaou64-66 lactonization of the seco-acid 39 gave the required lactone 47 in moderate yield. However, 47 could be prepared in excellent yield using the Yamaguchi lactonization conditions (Scheme 11).67,68 A small quantity of the ninemembered lactone 46 (ratio 47:46, 10:1) was also obtained, owing to silyl group migration from primary to secondary hydroxyl groups before lactonization. The nine-membered lactone 46 was not separated at this stage but was removed by flash chromatography of a later intermediate. Deprotection of the BOM ether from the lactones 46 and 47 with BCl3‚SMe269 afforded the corresponding hydroxy lactones from which 15 could be separated by HPLC for analytical purposes. The hydroxy lactone 15 synthesized Via the seco-acid 39 was identical to the major diastereoisomer formed by Davis oxidation of the potassium enolate of the lactone 16 with the oxaziridine 37 (Table 1, Entry 3). Trimethylsilylation of the hydroxy lactones allowed quantitative separation of the nine-membered lactone 48 by flash chromatography. Methylenation and Intramolecular Hydrosilation Studies. Methylenation of the eight-membered lactone 49 with the Petasis reagent,70,71 which is more convenient to prepare than Tebbe’s reagent,43 gave the enol ether 50 which was converted into the silane 14 (Scheme 11).72 The intramolecular hydrosilation of acyclic enol ethers has been developed by Tamao73 and has subsequently been exploited by us in an approach to the ninemembered cyclic ether obtusenyne.74 The key intramolecular hydrosilation reaction of 14 was carried out with the catalyst bis(1,3-divinyl-1,1,3,3-tetramethyldisiloxane)platinum(0) [Pt(DVS)2].75-77 This reagent has been shown to operate Via a (64) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614. (65) Corey, E. J.; Brunelle, D. J.; Stork, P. J. Tetrahedron Lett. 1976, 38, 3405. (66) Gerlach, H.; Thalmann, A. HelV. Chim. Acta 1974, 57, 2661. (67) Inanaga, J.; Hirata, K.; Hiroko, S.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. (68) Mulzer, J.; Kirstein, H. M.; Buschmann, J.; Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 910. (69) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes, A. B.; Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett 1993, 663. (70) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392. (71) Petasis, N. A.; Lu, S. P.; Bzowej, E. I.; Fu, D. K.; Staszewski, J. P.; Akritopoulou-Zanze, I.; Patane, M. A.; Hu, Y. H. Pure Appl. Chem. 1996, 68, 667. (72) Tamao, K.; Nakagawa, Y.; Arai, H.; Higuchi, N.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 3712. (73) Tamao, K.; Nakagawa, Y.; Ito, Y. Organometallics 1993, 12, 2297. (74) Curtis, N. R.; Holmes, A. B. Tetrahedron Lett. 1992, 33, 675. (75) Karstedt, B. D. (General Electric Co.), U.S. Appl. 226,928, 16 Feb 1972. Chem. Abstr. 1974, 80, P16134j. (76) Karstedt, B. D. (General Electric Co.), Ger. Offen., 2,307,085, 23 Aug 1973. Chem. Abstr. 1974, 80, P16134j. (77) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2, 1694.

J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7489 Scheme 11. Yamaguchi Lactonization and Hydrosilation Studies

mechanism that involves reduction of the ligands on platinum followed by the formation of colloids which then act as the catalyst for the reaction.78,79 The best result obtained in the hydrosilation of 14 involved the portionwise addition of 8 mol % of the catalyst (0.1 M in toluene) to the neat silane 14 under an atmosphere of dry air, followed by oxidation with basic hydrogen peroxide.72,77 This provided the diols 13 and 51 as a 58:42 mixture in 86% yield. However, the reaction was capricious and generally favored the trans-isomer 51. Although control of the stereochemistry of the hydrosilation of 14 is a highly desirable objective, we have been able to use both 13 and 51 in the present route to (+)-laurencin (Vide infra). Larger scale hydrosilation reactions (860 µmol, see Experimental Section) provided the diols in substantially lower yield, which may be due to the development of oxygen deficiency which results in irreversible colloid agglomeration and a consequent loss of catalytic activity.78 Conversion of the diols 51 and 13 into the corresponding p-methoxybenzylidene acetals 52 and 53 allowed assignment of the stereochemistry at 2-C and 3-C. The acetal 52, derived from the trans-diol 51, exhibited a 9.0 Hz coupling constant between 3-H and 2-H in the 1H NMR spectrum, which is consistent with a trans-diaxial relationship between 2-H and 3-H in a six-membered ring, whereas the acetal 53, derived from the cis-diol 13 exhibited a 2.0 Hz coupling constant between 3-H and 2-H. This is consistent with an axial-equatorial coupling in a six-membered ring. Other coupling constants were (78) Lewis, L. N. J. Am. Chem. Soc. 1990, 112, 5998.

7490 J. Am. Chem. Soc., Vol. 119, No. 32, 1997

Burton et al. Scheme 12. Organocuprate Studies

Scheme 13. Organocuprate Studies

Figure 7. Chem3D representations of the ground state conformations (MacroModel, MM2 force field, Monte Carlo conformational search) of 53a and 52a (TPS group modeled as TMS group) analogous to 53 and 52 with predicted coupling constants from Macromodel and coupling constants measured by 500 MHz 1H NMR for 53 and 52.

also in good agreement with those predicted Via computer modeling (Figure 7). Introduction of the Ethyl Side Chain. For the synthesis of (+)-laurencin it was necessary to convert the hydroxymethyl group of 13 into an ethyl substituent. This could be achieved by displacement of a sulfonate ester with an organocuprate. The monotosylate 54 (Scheme 12), formed from the diol 13, showed a large cross-peak between 2-H and 8-H in the 1H NMR NOESY spectrum, lending strength to the structural assignment for the cis-diol 13 given above. However, treatment of 54 with Me2CuCNLi2 afforded the oxetane 55 (85%) and not the required ethyl-substituted oxocane 56 (Scheme 12). Formation of 55 further demonstrates the cis-relationship of 2-H and 3-H. The oxetane 55 failed to react with methyllithium in the presence of BF3‚OEt2 to afford 5680 and therefore it was necessary to protect the 3-hydroxyl group to prevent intramolecular cyclization. Cleavage of the previously formed acetal 53 with DIBALH81 afforded the primary alcohol 57 which was converted into the corresponding tosylate 58 (Scheme 13). Reaction of 58 with (79) Lewis, L. N.; Lewis, N. J. Am. Chem. Soc. 1986, 108, 7228. (80) Elis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106, 3693. (81) Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29, 4085.

Me2CuLi in an ether/benzene solvent system82 provided the required ethyl-substituted oxocane 59 in 19% yield. Reaction of the corresponding triflate 60 under the same conditions provided 59 in an improved 60% yield. If benzene was omitted from these reactions, then no product was observed. This observation can probably be attributed to solvation of the PMB group of 58 and 60 by benzene, which allows reaction to occur. Use of the more reactive Me2CuCNLi2 in the above reactions provided substantial amounts of the alcohol 57 arising Via attack of the organocuprate at sulfur. Removal of the silyl protecting group followed by tetrapropylammonium per-ruthenate(VII) (82) Pougny, J. R. Tetrahedron Lett. 1984, 25, 2363. (83) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.

Synthesis of Medium Ring Ethers. 5 Scheme 14. Epimerization Studies

(TPAP) oxidation83,84 gave the aldehyde 61 in good yield in readiness for introduction of the pentenynyl side chain. In order to make use of the trans-diol 51 in the synthesis of (+)-laurencin it was necessary to epimerize the 2-C stereocenter (Scheme 14). Treatment of the trans-diol 51 under standard tosylation conditions provided the monotosylate 62 (46%) along with starting material (43%). Reaction of the tosylate 62 with Me2CuCNLi2 in ether gave the ethyl-substituted product 63. TPAP oxidation83,84 of 63 afforded the ketone 64 in good yield (85%). Epimerization at 2-C was then accomplished by treatment with potassium carbonate in methanol providing the desired 2-C epimer 65 (71%). This epimerization is precedented from the work of Murai17 and Palenzuela.22 Reduction of the ketone 65 with L-Selectride in THF17 followed by PMB protection afforded the oxocane 59, identical to that previously synthesized, indicating that the reduction had occurred in the expected sense.17,22 Introduction of the Pentenynyl Side Chain. All that remained for the synthesis of (+)-laurencin was the introduction of the unsaturated side chain and replacement of the 3-C oxygen with bromine. The proposed route for introduction of the unsaturated side-chain involved the addition of a pentenynyl anion to the corresponding aldehyde 61. A large number of model studies were conducted in order to realize this plan. For example, reaction of the pentenynyl chloride 6685 with barium metal, formed by the reduction of barium(II) iodide, followed by addition of hexanal yielded the (E)-67 and (Z)-alkenes 68 as a 1:1.5 mixture in 48% overall yield (Scheme 15).86,87 (84) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625. (85) This reagent was prepared from (E)-pent-2-en-4-yn-1-ol; (a) BuLi, TMSCl, THF then HCl (93%); (b) Me2S, N-chlorosuccinimide, CH2Cl2 (80%). (86) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 8955. (87) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6130.

J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7491 Scheme 15. Model Side Chain Studies

This result is in contrast to the work of Yamamoto who demonstrated complete retention of alkene geometry for allylations involving a large number of allylbarium reagents; the reason for the loss of stereochemistry is not clear. The ultimately successful strategy for side-chain introduction involved a samarium(II) iodide Barbier-type reductive coupling reaction.17,88 The reaction was first tested on some model oxocanes. Treatment of the racemic aldehydes 749 or 7511 with the bromide 6989 in the presence of samarium(II) iodide provided the corresponding alcohols 76 and 77 and 78 and 79 as 1:1 mixtures of diastereoisomers in 68% and 71% yield, respectively (Schemes 16 and 17). The structural assignment of all these products is discussed below. Similarly, reaction of 61 with 69 in the presence of samarium(II) iodide provided the alcohols 70 and 71 as a 1:1 mixture of diastereoisomers in 63% yield (Scheme 18). The geometry of the side-chain alkene was confirmed by coupling constant analysis (for 70 J3′,4′ ) 15.9 Hz, for 71 J3′,4′ ) 16.0 Hz). However, a small amount of the (Z)-enyne side chain was also observed in all the unpurified reaction mixtures (for 72 J3′,4′ ) 10.9 Hz), along with the side-chain dimer 73 arising from cross-coupling of the side-chain bromide 69. In all reactions no control of the newly formed stereocenter could be realized, as expected from the synthesis of octahydrodeacetyldebromolaurencin 2.

Octahydrodeacetyldebromolaurencin 2 and the 1′-epimer 9 exhibited two major distinguishing features in the 1H NMR spectrum; in the 1′(R)-alcohol 2 the three hydrogens next to oxygen appeared as a single multiplet [δ 3.42-3.27 (m, 3H, 2 × CHOR, CH1′OH)] and the OH resonance was broad [δ 2.71 (br, 1H, OH)]. For the 1′(S)-alcohol 9 the hydrogens next to (88) Souppe, J.; Namy, J. L.; Kagan, H. B. Tetrahedron Lett. 1982, 23, 3497. (89) This reagent was prepared from (E)-5-trimethylsilylpent-2-en-4-yn1-ol,85 (CH3)2NC(Br)dC(CH3)2, CH2Cl2 (58%); Bendall, J. G.; Payne, A. N.; Screen, T. E. O.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1997, 1067.

7492 J. Am. Chem. Soc., Vol. 119, No. 32, 1997 Scheme 16. Barbier-Type Coupling

Burton et al. Scheme 17. Barbier-Type Coupling

Scheme 18. Side-Chain Introduction oxygen appeared as two separate multiplets [δ 3.60-3.56 (m, 1H, CHOR) and 3.41-3.35 (m, 2H, CHOR, CH1′OH)], and the OH resonance was also broad [δ 2.04-2.03 (br, 1H, OH)].

Each diastereomer of the three pairs synthesized by the samarium(II) iodide mediated reductive coupling fitted the pattern of spectral data observed for octahydrodeacetyldebromolaurencin 2 and its 1′-epimer 9. For one of the pair, the two protons R to the oxocane oxygen and the CH1′OH appeared as an overlapping multiplet (approximately δ 3.55-3.30), and the OH appeared in the range δ 2.80-2.60. For the other, the two protons R to the oxocane oxygen and the CH1′OH appeared as distinct multiplets, and the OH appeared at higher field (approximately δ 2.20-2.00) (see tables). The OH signal was well defined in these cases, suggesting that it may be involved in an intramolecular hydrogen bond with the oxocane oxygen, which fixes the ring conformation and produces chemical shifts indicative of the side-chain alcohol configuration. The structural assignment of all these alcohols was therefore made on the basis of the 1H NMR chemical shift of the OH proton and, to a lesser extent, on the shift of the protons R to oxygen. It was also (90) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (91) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (92) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.

found that the 1′(R)-alcohols were all less polar than the corresponding 1′(S)-alcohols. Following the precedent observed for octahydrodeacetyldebromolaurencin 2, recycling of the 1′(S)-alcohol 71 was achieved by oxidation with the Dess-Martin reagent90-92 to give the corresponding ketone in good yield; this was reduced with L-Selectride to yield the 1′(R)-alcohol 70 as the sole product (as judged by 250 MHz 1H NMR) in accordance with previous experience.9,17 The best procedure required separation of the alcohols 70 and 71 by HPLC, followed by the oxidation/

Synthesis of Medium Ring Ethers. 5 Scheme 19. Completion of the Synthesis

reduction sequence to convert the 1′(S)-alcohol 71 into the 1′(R)-alcohol 70. Introduction of Bromine and Completion of the Synthesis. The free hydroxyl group of 70 was acetylated under standard conditions, and the PMB group was removed on exposure to BCl3‚SMe2 according to the method of Congreve69 to yield the alcohol 80 (Scheme 19). The bromine atom was successfully introduced by treatment of the alcohol 80 with freshly purified carbon tetrabromide and freshly distilled trioctylphosphine in hot toluene.17 This resulted in a very clean reaction to form trimethylsilyl-laurencin 81 in 69% yield. The spectra of 81 were essentially identical to those of the corresponding triisopropylsilyl analog reported by Overman.21 Treatment of TMS-laurencin 81 with a cold solution of TBAF in THF afforded (+)-laurencin 1 {[R]D20 +70 (c 0.05 in CHCl3), lit.1 [R]D27 +70.2 (c 1.00 in CHCl3)} in 98% yield. The synthetic sample was isolated as a white gum, and therefore a melting point could not be obtained. However, in all other respects (1H NMR, 13C NMR, IR, [R]D, MS) the synthetic sample had characteristics in accordance with the data supplied by Professor Murai for a natural and a synthetic sample. Conclusion In summary, this work has demonstrated that medium-ring ether natural products can be obtained from the corresponding lactone precursors by methylenation and subsequent enol-ether functionalization. The Claisen ring expansion route is a convenient method for the preparation of medium-ring lactones, but efficient lactonization of seco-acid precursors is equally effective. Experimental Section For general experimental techniques see Supporting Information. (Z),2(R)-Ethyl-2-[[(benzyloxy)methyl]oxy]-6-[(R)-2,2-dimethyl1,3-dioxolan-4-yl]-hex-4-enoate 44. The phosphonium salt 40 (4.51 g, 9.57 mmol) was freshly prepared from the bromide 4259-61 and was dried in Vacuo (