Proposal 2 - Biosci. Biotechnol. Biochem., 72 (7),...

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Unformatted text preview: Biosci. Biotechnol. Biochem., 72 (7), 1921–1928, 2008 Enantioselective Synthesis and Stereochemical Revision of Communiols A–C, Antibacterial 2,4-Disubstituted Tetrahydrofurans from the Coprophilous Fungus Podospora communis Masaru E NOMOTO and Shigefumi K UWAHARAy Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan Received March 17, 2008; Accepted April 10, 2008; Online Publication, July 7, 2008 [doi:10.1271/bbb.80173] The enantioselective synthesis of the originally proposed structure of communiol C, an antibacterial 2,4disubstituted tetrahydrofuran natural product from the coprophilous fungus Podospora communis, and its epimer via the Sharpless asymmetric dihydroxylation as the source of chirality led us to propose that the genuine stereochemistry of communiol C should be 3R, 5R, and 6S. The synthesis of the (3R,5R,6S)-isomer of communiol C and its good accordance with natural communiol C in every respect enabled us to confirm the newly proposed (3R,5R,6S)-stereochemistry for communiol C. The stereochemistries of structurally-related natural products (communiols A and B) of the same microbial origin were also revised through their total synthesis. Key words: communiol; antibacterial; enantioselective synthesis; asymmetric dihydroxylation; stereochemical revision In the course of screening for bioactive natural products from coprophilous (dung-colonizing) fungi, Gloer and coworkers isolated three novel tetrahydrofuranyl carboxylic acids from the culture broth of Podospora communis as substances exhibiting significant antibacterial activity against Bacillus subtilis and Staphylococcus aureus, and named them communiols A, B, and C (Fig. 1).1) They also isolated five new structurally-related compounds (communiols D–H), apparently of the same biosynthetic origin, from the culture broth of P. communis.1,2) The structures of communiols A–C were proposed to be (5R,7S,8S)-1, (5R,7S,8S)-2 and (3S,5S,6S)-3, respectively, based mainly on NMR analyses including Mosher’s MTPA methodology.3) The 2,4disubstituted tetrahydrofuran substructure incorporated in communiols A–C is relatively rare as a structural unit OH HO2C 8 5 7 OH OH communiol A (5R,7S,8S )-1 HO2C OH HO2C 3 5 6 OH communiol C (3S,5S,6S )-3 OH communiol B (5R,7S,8S )-2 Fig. 1. Structures of Communiols A–C Proposed by Gloer et al. of natural products,1) displaying a clear difference in substitution pattern from 2,5-disubstituted tetrahydrofurans which are frequently found in annonaceous acetogenins or ionophores.4,5) The structural uniqueness of communiols A–C coupled with their interesting biological activity prompted our efforts to synthesize communiols A–C, which recently culminated in our new proposal on the stereochemistries of communiols A–C and the confirmation of the newly proposed stereochemistries by total synthesis,6) as well as the enantioselective synthesis of communiols D–F and H with revised stereochemistries.7,8) Herein, we describe the full details of our synthetic studies on communiols A–C, which led to the revision of their stereochemistries.6) Results and Discussion Our retrosynthetic analysis of the originally proposed structure of communiol C [(3S,5S,6S)-3)], chosen as our first synthetic target due to its structural simplicity, is shown in Scheme 1. Bearing in mind that the 5,6-threo y To whom correspondence should be addressed. Fax: +81-22-717-8783; E-mail: skuwahar@biochem.tohoku.ac.jp Abbreviations: DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD, diethyl azodicarboxylate; DIBAL, diisobutylaluminum hydride; DMAP, 4-(dimethylamino)pyridine; LDA, lithium diisopropylamide; MTPA, -methoxy- -(trifluoromethyl)phenylacetate; PNB, p-nitrobenzoate; TBAF, tetrabutylammonium fluoride; TBDPSCl, tert-butyldiphenylsilyl chloride; TBSCl, tert-butyldimethylsilyl chloride 1922 M. ENOMOTO and S. KUWAHARA oxidative cleavage reduction O OH HO2C 3 5 OH 6 OH (3S,5S,6S )-3 allylation Sharpless AD reaction CO2R2 OR1 A O OH OR1 B C Scheme 1. Retrosynthetic Analysis of (3S,5S,6S)-3. EtO2C AD-mix-α EtO2C OH 4 5 OH + O OH a) TrCl b) TBSCl O TsOH (94%, 2 steps) OH c) TBDPSCl OR2 8: 9: 10: R2 R2 R2 = Tr = TBS (96%) = TBDPS (quant) OR1 6: =H = MTPA 7: (93.5% ee) R1 R1 Scheme 2. Preparation of Protected Lactone Intermediates 8–10. stereochemistry of (3S,5S,6S)-3 would readily be installed using the Sharpless asymmetric dihydroxylation (AD) reaction,9,10) we planned to synthesize the target molecule from lactone intermediate A, which possesses an allyl substituent with the desired stereochemistry at the C3 position, via reduction of the lactone ring to the tetrahydrofuran ring followed by oxidative cleavage of the double bond. The lactone (A) with 3,5-trans relative stereochemistry could be prepared by applying the welldocumented trans-selective alkylation of -substituted -lactones to B,11,12) which in turn should be derivable from olefinic ester C by the Sharpless AD reaction and subsequent lactonization. Our synthesis of (3S,5S,6S)-3 began with the exposure of known olefinic ester 413,14) to the AD reaction conditions using AD-mix- as the chiral catalyst to give a mixture of dihydroxy ester 5 and monohydroxy lactone 6 (Scheme 2).9,10) Treatment of the mixture with p-toluenesulfonic acid cleanly transformed 5 into 6, whose 1 H-NMR spectrum was in good agreement with that reported for an authentic sample of 6 previously prepared from L-glutamic acid.15) The absolute stereochemistry of 6 was confirmed by comparing its specific rotation (½ Š22 D +40.3 (c 2.25, CH2 Cl2 )) with the literature value (½ Š22 D +46.0 (c 2.0, CH2 Cl2 )),15) and the enantiomeric excess (ee) of 6 was determined to be 93.5% by converting the alcohol into the corresponding (R)- and (S)-MTPA esters (7) and analyzing their 1 HNMR spectra.7) Prior to the introduction of an allyl substituent to the lactone, the protection of the hydroxyl group of 6 was attempted by treating 6 with trityl chloride (TrCl) and DBU in dichloromethane at room temperature,16) in the hope that the very bulky protective group (trityl) of product 8 would effectively hamper the approach of the allylating agent from the bottom face of the lactone ring and thereby help enhance the transselectivity in the allylation step (B ! A, Scheme 1). Unexpectedly, however, the protection did not proceed at all, resulting in the recovery of 6, although the tritylation conditions (TrCl, DBU, CH2 Cl2 ) have been known to effectively protect a variety of secondary alcohols. Other reaction conditions (TrCl, Et3 N, DMAP, CH2 Cl2 , room temperature to 40  C; and TrCl, DBU, DMAP, DMF, 100  C) brought about the formation of complex mixtures. On the other hand, silylation of the hydroxyl group using TBSCl or TBDPSCl as silylating agents gave the corresponding TBS- or TBDPS-protected products (9 or 10, respectively) in almost quantitative yields. Quite fortunately, the TBDPS-protected lactone (10) was obtained as a crystalline solid, which suggested the possibility that lactone 10 might be enantiomerically enriched by recrystallization from an appropriate solvent (vide infra). The good crystallinity of 10 coupled with the bulkier nature of TBDPS as compared to TBS led us to select 10 as the substrate for the next allylation step. Allylation of the lithium enolate of 10 prepared by treating TBDPS-protected lactone 10 with LDA gave a 8.3:1 mixture of 11a and its C3-epimer in 90% yield favoring the desired 3,5-trans-isomer 11a, while the corresponding prenylation with prenyl bromide exhibited a slightly better trans-selectivity of 10:1 (74% combined yield) (Scheme 3).11,12) When the allylation and prenylation were conducted using the TBS-ether (9) (see Scheme 2), the trans/cis ratio was 2.3:1 for the allylation and 4.2:1 for the prenylation. After careful purification of 11a by silica gel column chromatography, the trans-allylation product isolated in 64% yield was reduced with DIBAL to give lactol 12 as a 3:1 anomeric mixture, which was further reduced with triethylsilane in the presence of BF3 OEt2 to afford tetrahydrofuran derivative 13.17,18) The prenylation product (11b) was also converted into tetrahydrofuran derivative 14 by the same two-step sequence of reactions. Oxidative cleavage of the double bond of 13 was performed using RuCl3 and NaIO4 ,19) and the resulting carboxylic acid intermediate was deprotected with aqueous HF to afford (3S,5S,6S)-3, the structure proposed by Gloer for communiol C, while the prenylated derivative 14 gave a complex mixture when subjected to the same oxidative cleavage conditions (RuCl3 /NaIO4 ). Unexpectedly, direct comparison of the 1 H-NMR spectrum of (3S,5S,6S)-3 with that of natural communiol C revealed several clear differences, especially in the chemical shifts for 5-H, 6-H, and 9-H2 . In . Synthesis of Communiols A–C O a) LDA allyl bromide 10 OH b) LDA prenyl bromide R 3 5 OTBDPS R 11a: R = H (90%) 11b: R = Me (74%) HO 11a OH DIBAL 12 R Et3SiH BF3·OEt2 OTBDPS (86%, 2 steps) 1) RuCl3 NaIO4 OH 9 2) aq HF OTBDPS (42%, 2 steps) 13: R = allyl 1923 0 OH 3 5 HO2C 6 OH (3S,5S,6S )-3 OH OTBDPS 14 Scheme 3. Synthesis of (3S,5S,6S)-3. the synthetic sample, the signals for 5-H, 6-H, and 9-H2 appeared at  3.85, 3.34, and 4.06/3.49, respectively, while the corresponding signals for natural communiol C were observed at  3.90, 3.68, and 4.09/3.41. In their report on the structural determination of communiols A–D, Gloer et al. determined the trans-relative stereochemistry between the C3 and C5-substituents of communiol C by observing several clear diagnostic NOESY correlations, and assigned the absolute configuration at the C6 chiral center to be S by analogy with the S-absolute configuration of communiol A (1), which in turn was established unambiguously by the modified Mosher method.1,3) On the other hand, the threo-relative stereochemistry between C5 and C6 was proposed based only on Born’s empirical rule, which has been employed to determine the relative stereochemistry between the C2 and C10 stereogenic centers of 2-(10 -hydroxyalkyl)tetrahydrofurans including those bearing an additional C5-alkyl substituent (Fig. 2).20–22) According to the rule, the 10 -C signal is observed at ca. 74 ppm in 13 C-NMR when the C2/C1 -relative stereochemistry is threo, while that of the corresponding erythro-isomer appears at ca. 72 ppm. The observed chemical shift (73.7 ppm) for the C6 carbon of natural communiol C led Gloer et al. to propose its 5,6-relative stereochemistry to be threo as shown in Fig. 1. To the best of our knowledge, however, Born’s rule has never been applied to the determination of the C2/C10 -relative stereochemistry of 2,4-disubstituted tetrahydrofurans like communiol C. This led us to presume that the genuine 5,6-relative stereochemistry of communiol C might not be threo, but erythro, judging from the fact that the 3,5-trans-stereochemistry was determined by the well-established NOESY methodology.1) According to our presumption that the genuine 5,6-relative stereochemistry of cmmuniol C might be erythro, we set about the synthesis of (3S,5S,6R)-3 possessing 3,5-trans-5,6-erythro stereochemistry from intermediate 13 used in the synthesis of (3S,5S,6S)-3 (Scheme 4). Deprotection of the TBDPS-ether gave alcohol 14, which was then exposed to the Mitsunobu inversion conditions to afford PNB-ester 15 with inversion of the absolute configuration at the C6 position.23,24) Oxidative cleavage of the double bond of 15 gave a carboxylic acid intermediate, the PNB-ester group of which was deprotected by alkaline hydrolysis to furnish (3S,5S,6R)-3. As expected, the 1 H-NMR spectrum of (3S,5S,6R)-3 was exactly the same as that of natural communiol C, which enabled us to establish the relative stereochemistry of communiol C as 3,5-trans and 5,6-erythro. Comparison of the specific rotation of (3S,5S,6R)-3 (½ Š22 D +3.6 (c 0.24, CH2 Cl2 )) with that of natural communiol C (½ ŠD À3:4 (c 0.142, CH2 Cl2 )) as well as the newly established relative stereochemistry of communiol C led us to conclude that the genuine structure of communiol C should be revised to (3R,5R,6S)-3, the enantiomer of (3S,5S,6R)-3 depicted in Scheme 4. Based on our new proposal for the stereochemistry of communiol C, we embarked on the synthesis of (3R,5R,6S)-3 (Scheme 5). By following the same two- 13 CO2H (66%) 14 R1 4 5 DEAD Ph3P OH TBAF OH O2N R1 OH 2 1' R2 OH C2/C1'-threo δ C for 1'-C = ca. 74 ppm R1 = H or alkyl R2 = alkyl OH R2 OH C2/C1'-erythro δ C for 1'-C = ca. 72 ppm R1 = H or alkyl R2 = alkyl Fig. 2. Born’s Rule for the Assignment of Relative Stereochemistry. OH R OPNB 15: R = allyl (59%) 1) RuCl3 NaIO4 2) aq K2CO3 (36%, 2 steps) OH HO2C OH (3S,5S,6R )-3 [α]22D +3.6 (lit.1) [α]D –3.4) Scheme 4. Synthesis of (3S,5S,6R)-3. 1924 M. ENOMOTO and S. KUWAHARA 1) AD-mix-β EtO2C 2) TsOH (89%, 2 steps) 4 O OH 16 OH (96% ee) then recryst. (75%) OH O3, MeOH then Me2S (85%) OHC 21 OH LDA, allyl bromide 17 OTBDPS (100% ee) then purification (85%) 1) Ph3P=CHCO2Et OPNB OH O TBDPSCl 20 2) aq. LiOH, THF (78%, 2 steps) H2, Pd/C HO2C (96%) (5S,7R,8S )-2 OH OH HO2C (5S,7R,8S )-1 OH O 1) DIBAL OH 18 OH 2) Et3SiH R BF3·OEt2 OTBDPS OTBDPS (84%, 19: R = allyl 2 steps) OH 1) TBAF 2) DEAD, Ph3P CO2H R OPNB 20: R = allyl O2N (68%, 2 steps) 1) RuCl3, NaIO4 2) aq K2CO3 (60%, 2 steps) OH HO2C (3R,5R,6S )-3 OH Scheme 5. Synthesis of (3R,5R,6S)-3. step sequence of reactions as employed for the preparation of 6 except that AD-mix- , instead of AD-mix- , was used in the asymmetric dihydroxylation step,9,10) olefinic ester 4 was converted into hydroxy lactone 16, whose enantiomeric excess was determined to be 96% by the same MTPA method as used for 6. Protection of its hydroxyl group as a TBDPS ether gave rise to 17 as a white crystalline solid. Fortunately, and expectedly as well, a single recrystallization of the solid from hexane/ EtOAc yielded enantiomerically pure 17 as colorless prisms (mp 62.5–63.0  C), whose optical integrity was checked by deprotecting the TBDPS group with TBAF into the corresponding alcohol (i.e., 16) and analyzing the alcoholic product by the MTPA method.7) Lactone 17 was transformed in 3 steps, via allylated intermediate 18, into tetrahydrofuran derivative 19, the TBDPS protecting group of which was then removed with TBAF to give an alcoholic intermediate. The inversion of the absolute configuration of the hydroxyl-bearing chiral center of the alcohol by the Mitsunobu reaction afforded 20, which was then converted into (3R,5R,6S)-3 via oxidative cleavage followed by hydrolysis. The 1 Hand 13 C-NMR spectra of the synthetic product were identical with those of natural communiol C, and its specific rotation (½ Š22 D À2:7 (c 1.16, CH2 Cl2 )) was in fairly good agreement with that of natural communiol C Scheme 6. Synthesis of (5S,7R,8S)-1 and (5S,7R,8S)-2. (½ ŠD À3:4 (c 0.142, CH2 Cl2 )). Based on these results, we concluded that the genuine structure of communiol C is (3R,5R,6S)-3 as depicted in Scheme 5. The same conclusion was reported by Murga and coworkers based on their synthesis of (3S,5S,6R)-3 just after our preliminary communication.25) Assuming that the structurally-related tetrahydrofuran derivatives (communiols A and B) of the same microbial origin should have the same stereochemical arrangement as communiol C, we supposed that the correct structures of communiols A and B would be (5S,7R,8S)-1 and (5S,7R,8S)-2, respectively, and set about their synthesis from 20, the synthetic intermediate for (3R,5R,6S)-3 (Scheme 6). Exposure of 20 to ozonolysis conditions gave aldehyde intermediate 21, the chain elongation of which by the Wittig reaction afforded (5S,7R,8S)-2 after hydrolysis of the PNB ester group. Finally, catalytic hydrogenation of (5S,7R,8S)-2 afforded (5S,7R,8S)-1. The 1 H- and 13 C-NMR spectra of (5S,7R,8S)-1 and (5S,7R,8S)-2 were exactly the same as those of natural communiols A and B, respectively, which confirmed the 5,7-trans-7,8-erythro stereochemistry of natural communiols A and B, as expected. To confirm the absolute stereochemistry of communiols A and B, we next compared the specific rotations of synthetic and natural communiols A and B. Curiously, the specific rotations of (5S,7R,8S)-1 (½ Š22 D +1.4 (c 1.17, CH2 Cl2 )) and (5S,7R,8S)-2 (½ Š22 D +4.7 (c 1.00, CH2 Cl2 )) were inconsistent with reported data for communiols A and B, ½ ŠD À1:6 (c 0.25, CH2 Cl2 ) and ½ ŠD À95 (c 0.075, CH2 Cl2 ), respectively. Similar discrepancies were also reported by Murga et al.;25) they attributed the discrepancies to concentration-dependency in specific rotation of chiral carboxylic acids. We believe that such big differences in optical rotation might be brought about also by the presence of small quantities of impurities in the synthetic and/or natural samples of communiols A and B; a recent report on the synthesis of communiol A by Trost and Zhang mentioned concentration- and impurity-dependency in the specific rotation of communiol A.26) Despite this ambiguity, the complete agreement in 1 H- and 13 C-NMR data between (5S,7R,8S)-1 Synthesis of Communiols A–C OH HO2C OH communiol A (5S,7R,8S )-1 OH HO2C OH HO2C OH communiol C (3R,5R,6S )-3 OH communiol B (5S,7R,8S )-2 Fig. 3. Revised Stereochemistries for Communiols A–C. and natural communiol A, and between (5S,7R,8S)-2 and natural communiol B, together with the unambiguous determination of the absolute configuration of the C8 hydroxy-bearing stereogenic center as S by the wellestablished modified Mosher’s MTPA method3) strongly supported that the genuine structures of communiols A and B should be (5S,7R,8S)-1 and (5S,7R,8S)-2, respectively. In conclusion, the enantioselective synthesis of the originally proposed structure of communiol C, (3S,5S,6S)-3, was accomplished in 8 steps from known olefinic ester 4 using the Sharpless asymmetric dihydroxylation as the source of chirality. Clear differences in 1 H-NMR between (3S,5S,6S)-3 and natural communiol C as well as good agreement of natural communiol C with the synthetic C6-epimer of (3S,5S,6S)-3 in every respect except for the sign of specific rotation led us to propose that the genuine stereochemistry of communiol C should be 3R, 5R, and 6S. The synthesis of (3R,5R,6S)-3 and its good accordance with natural communiol C in every respect confirmed the new proposal for the stereochemistry of communiol C (Fig. 3). Based on this stereochemical revision for communiol C, (5S,7R,8S)-1 and (5S,7R,8S)-2 were also synthesized as the most probable candidates for the genuine structures of communiols A and B, respectively. The 1 H- and 13 C-NMR of the synthetic products were identical with those of the corresponding natural products, which, coupled with the unambiguous determination of the (8S)-absolute stereochemistry by Gloer et al., strongly supported the genuine structures of communiols A and B should be (5S,7R,8S)-1 and (5S,7R,8S)-2, respectively (Fig. 3), although some ambiguities in their optical rotations have yet to be settled. Experimental IR spectra were recorded as films by a Jasco IR Report-100 spectrometer. 1 H NMR spectra (300, 500 or 600 MHz) and 13 C NMR spectra (125 or 150 MHz) were recorded with TMS as an internal standard in CDCl3 by a Varian Gemini 2000 spectrometer, a Varian UNITY plus-500 spectrometer or a Varian UNITY plus-600 1925 spectrometer. Optical rotation values were measured with a Horiba Septa-300 polarimeter, and mass spectra were obtained with a Jeol JMS-700 spectrometer. Merck silica gel 60 (70–230 mesh) was used for silica gel column chromatography. (2S,4R,5R)-2-Allyl-5-(tert-butyldiphenylsilyloxy)-4heptanolide (18). To a stirred solution of LDA, prepared by treating a solution of diisopropylamine (1.26 ml, 9.02 mmol) and hexamethylphosphoramide (1.50 ml, 8.63 mmol) in THF (30 ml) with butyllithium (1.6 M in hexane, 5.39 ml, 8.63 mmol) at À15  C, was added dropwise a solution of 17 (3.00 g, 7.84 mmol) in THF (30 ml) at À78  C. After 25 min, a solution of allyl bromide (0.747 ml, 8.63 mmol) in THF (10 ml) was added, and the resulting mixture was stirred for 15 min at À78  C. After the addition of sat. NH4 Cl aq. (ca. 20 ml), the mixture was extracted with ether. The extract was successively washed with water and brine, dried (MgSO4 ), and concentrated in vacuo. The residue was repeatedly chromatographed over SiO2 (hexane/EtOAc, 30:1) to give 2.82 g (85%) of 18 as a colorless oil: ½ ŠD 22 À10:9 (c 1.00, CHCl3 ); IR max cmÀ1 : 3080 (w), 3050 (w), 1770 (s), 1110 (s), 705 (s); 1 H-NMR (300 MHz)  0.70 (3H, t, J ¼ 7:5 Hz), 1.04 (9H, s), 1.39 (1H, ddq, J ¼ 13:8, 5.4, 7.5 Hz), 1.59–1.74 (1H, m), 1.94 (1H, dt, J ¼ 13:2, 8.1 Hz), 2.16–2.33 (2H, m), 2.51–2.61 (1H, m), 2.78–2.89 (1H, m), 3.63 (1H, ddd, J ¼ 7:8, 5.1, 3.3 Hz), 4.48 (1H, ddd, J ¼ 8:1, 3.9, 3.3 Hz), 5.10 (1H, br d, J ¼ 11:1 Hz), 5.11 (1H, dm, J ¼ 15:9 Hz), 5.67– 5.81 (1H, m), 7.35–7.48 (6H, m), 7.65–7.72 (4H, m); 13 C-NMR (150 MHz)  9.6, 19.5, 25.7, 27.0, 28.9, 35.5, 39.1, 76.6, 78.4, 117.7, 127.5 (2C), 127.7 (2C), 129.7, 129.9, 133.1, 133.9, 134.5, 135.81 (2C), 135.83 (2C), 179.1; HRMS (FAB) m=z calcd for C26 H35 O3 Si ([M + H]þ ) 423.2355, found 423.2358. (2R,4S)-4-Allyl-2-[(R)-1-(tert-butyldiphenylsilyloxy)propyl]tetrahydrofuran (19). To a stirred solution of 18 (0.603 g, 1.43 mmol) in CH2 Cl2 (6 ml) was added dropwise DIBAL (0.94 M in hexane, 1.67 ml, 1.57 mmol) at À75  C. After 20 min, the reaction was quenched with a saturated aqueous solution of Rochelle’s salt, and the mixture was gradually warmed to room temperature over 1 h. The mixture was extracted with EtOAc, and the extract was washed with brine, dried (MgSO4 ), and concentrated in vacuo to give 0.627 g of an oil containing (2R/S,3S,5R)-3-allyl-5-[(R)-1-(tert-butyldiphenylsilyloxy)propyl]tetrahydrofuran-2-ol, which was then dissolved in CH2 Cl2 (6.0 ml). To the solution was added dropwise Et3 SiH (0.251 ml, 1.57 mmol) at À78  C, and the mixture was stirred for 5 min. BF3 OEt2 (0.198 ml, 1.57 mmol) was then added, and the mixture was gradually warmed to À5  C while being stirred overnight. The reaction was quenched with a suspension of NaHCO3 in MeOH, and the mixture was diluted with water and extracted with EtOAc. The extract was washed with brine, dried (MgSO4 ), and concentrated in . 1926 M. ENOMOTO and S. KUWAHARA vacuo. The residue was chromatographed over SiO2 (hexane/EtOAc, 10:1) to give 0.490 g (84%) of 19 as a colorless oil: ½ ŠD 22 +18.0 (c 1.00, CHCl3 ); IR max cmÀ1 : 3080 (w), 3050 (w), 1430 (m), 1110 (s), 700 (s); 1 H-NMR (300 MHz)  0.75 (3H, t, J ¼ 7:5 Hz), 1.04 (9H, s), 1.28–1.42 (1H, m), 1.47–1.63 (2H, m), 1.97 (1H, ddd, J ¼ 12:3, 7.8, 6.3 Hz), 2.07 (2H, t, J ¼ 7:2 Hz), 2.14–2.30 (1H, m), 3.33 (1H, dd, J ¼ 8:4, 6.3 Hz), 3.59 (1H, dt, J ¼ 5:5, 5.1 Hz), 3.83 (1H, dd, J ¼ 6:3, 8.4 Hz), 4.00 (1H, ddd, J ¼ 7:8, 6.6, 5.1 Hz), 4.98 (1H, dm, J ¼ 10:2 Hz), 5.01 (1H, dm, J ¼ 17:1 Hz), 7.33–7.46 (6H, m), 7.68–7.75 (4H, m); 13 C-NMR (150 MHz)  10.0, 19.5, 25.5, 27.1, 32.7, 37.5, 38.8, 73.0, 76.6, 79.9, 115.7, 127.32 (2C), 127.35 (2C), 129.3, 129.4, 134.2, 134.7, 135.96, 135.98, 137.0; HRMS (FAB) m=z calcd for C26 H36 O2 SiNa ([M + Na]þ ) 431.2382, found 431.2390. (S)-1-[(2R,4S)-4-Allyltetrahydrofuran-2-yl]propyl pnitrobenzoate (20). To a stirred solution of 19 (0.941 g, 2.30 mmol) in THF (2 ml) was added TBAF (1 M in THF, 11.5 ml, 11.5 mmol) at room temperature. After 3 d, the reaction was quenched with water, and the mixture was extracted with EtOAc. The extract was successively washed with water and brine, dried (MgSO4 ), and concentrated in vacuo. The residue was chromatographed over SiO2 (hexane/ethyl acetate, 10:1) to give 0.386 g (99%) of (S)-1-[(2R,4S)-4-allyltetrahydrofuran-2-yl]-1-propanol as a colorless oil: ½ ŠD 22 À1:59 (c 1.00, CHCl3 ) ; IR max cmÀ1 : 3460 (m), 3070 (w), 1640 (m); 1 H-NMR (300 MHz)  1.00 (3H, t, J ¼ 7:4 Hz), 1.34–1.57 (2H, m), 1.66 (1H, ddd, J ¼ 12:9, 7.5, 5.7 Hz), 2.13 (2H, t, J ¼ 6:5 Hz), 2.25–2.38 (1H, m), 2.38 (1H, d, J ¼ 4:2 Hz, OH), 3.27–3.36 (1H, m), 3.45 (1H, dd, J ¼ 8:4, 6.3 Hz), 3.82 (1H, q, J ¼ 6:9 Hz), 3.95 (1H, dd, J ¼ 8:4, 6.3 Hz), 5.02 (1H, dm, J ¼ 10:2 Hz), 5.05 (1H, dm, J ¼ 17:1 Hz), 5.77 (1H, ddd, J ¼ 17:1, 10.2, 6.5 Hz); 13 C-NMR (150 MHz)  10.1, 26.5, 33.8, 37.4, 38.9, 72.9, 75.4, 81.4, 116.0, 136.6; HRMS (EI) m=z calcd for C10 H18 O2 (Mþ ) 170.1306, found 170.1313. To a stirred solution of the alcohol (0.117 g, 0.684 mmol) in THF (4 ml) was successively added Ph3 P (0.718 g, 2.74 mmol), p-nitrobenzoic acid (0.457 g, 2.74 mmol), and DEAD (0.499 ml, 2.74 mmol) at 0  C, and the mixture was stirred for 2 d at room temperature. The reaction was quenched with sat. NaHCO3 aq., and the mixture was extracted with EtOAc. The extract was washed with brine, dried (MgSO4 ), and concentrated in vacuo. The residue was chromatographed over SiO2 (hexane/ EtOAc/CHCl3 , 20:1:2) to give 0.150 g (69%) of 20 as a colorless oil: ½ ŠD 22 À1:88 (c 1.00, CHCl3 ); IR max cmÀ1 : 3070 (w), 1720 (s), 1515 (s), 1270 (s); 1 H-NMR (300 MHz)  0.98 (3H, t, J ¼ 7:4 Hz), 1.66–1.84 (3H, m), 2.00 (1H, ddd, J ¼ 12:6, 7.8, 6.3 Hz), 2.14 (2H, t, J ¼ 7:0 Hz), 2.26–2.40 (1H, m), 3.43 (1H, dd, J ¼ 8:4, 6.6 Hz), 3.95 (1H, dd, J ¼ 8:4, 6.6 Hz), 4.16 (1H, ddd, J ¼ 7:5, 6.3, 5.1 Hz), 5.02 (1H, dm, J ¼ 10:2 Hz), 5.05 (1H, dm, J ¼ 17:1 Hz), 5.19 (1H, ddd, J ¼ 7:8, 5.1, 4.8 Hz), 5.76 (1H, ddt, J ¼ 17:1, 10.2, 7.0 Hz), 8.20– 8.25 (2H, m), 8.28–8.33 (2H, m); 13 C-NMR (150 MHz)  9.8, 23.8, 33.1, 37.1, 38.4, 73.4, 78.1, 79.0, 116.2, 123.5, 130.7, 135.8, 136.4, 150.5, 164.3; HRMS (FAB) m=z calcd for C17 H22 O5 N ([M + H]þ ) 320.1498, found 320.1498. {(3R,5R)-5-[(S)-1-Hydroxypropyl]tetrahydrofuran-3yl}acetic acid [(3R,5R,6S)-3]. To a stirred solution of 20 (70.0 mg, 0.219 mmol) in H2 O/CH3 CN/CCl4 (3:2:2, 2.8 ml) was successively added NaIO4 (0.192 mg, 0.899 mmol) and a catalytic amount of RuCl3 (H2 O)n at 0  C. After 2.5 h, the reaction was quenched with 2propanol, and the mixture was extracted with CH2 Cl2 . The extract was washed with brine, dried (MgSO4 ), and concentrated in vacuo. The residue was chromatographed over SiO2 (CHCl3 /MeOH, 75:1) to give 52.0 mg (70%) of {(3R,5R)-5-[(S)-1-( p-nitrobenzoyloxy)propyl]tetrahydrofuran-3-yl}acetic acid as a colorless crystalline solid (mp 100.0–100.2  C): ½ ŠD 22 À5:14 (c 2.60, CHCl3 ); IR max cmÀ1 : $3000 (br m), 1720 (vs), 1600 (w), 1510 (s), 1275 (s), 1100 (s); 1 H-NMR (300 MHz)  0.98 (3H, s, J ¼ 7:5 Hz), 1.68–1.86 (3H, m), 2.18 (1H, ddd, J ¼ 12:9, 7.8, 6.3 Hz), 2.47 (2H, d, J ¼ 7:5 Hz), 2.61–2.76 (1H, m), 3.46 (1H, dd, J ¼ 8:7, 6.6 Hz), 4.04 (1H, dd, J ¼ 8:7, 6.6 Hz), 4.21 (1H, ddd, J ¼ 7:8, 6.3, 5.1 Hz), 5.22 (1H, dt, J ¼ 7:8, 4.8 Hz), 8.21–8.26 (2H, m), 8.28–8.33 (2H, m); 13 C-NMR (150 MHz)  9.8, 23.9, 33.0, 35.1, 36.9, 73.2, 77.8, 78.9, 123.5, 130.7, 135.6, 150.5, 164.3, 178.1; HRMS (FAB) m=z calcd for C16 H20 O7 N ([M + H]þ ) 338.1240, found 338.1243. To a stirred solution of the carboxylic acid (48.3 mg, 0.143 mmol) in THF (1 ml) was added 1 M K2 CO3 aq. (1 ml) at room temperature. After 3 d, the mixture was acidified with 2 M HCl aq., and extracted with EtOAc. The extract was washed with brine, dried (MgSO4 ), and concentrated in vacuo. The residue was chromatographed over SiO2 [CHCl3 /MeOH (50:1) containing a trace amount of AcOH] to give 23.0 mg (86%) of [(3R,5R,6S)3 as a colorless oil: ½ ŠD 22 À2:7 (c 1.16, CH2 Cl2 ); IR max cmÀ1 : 3350 (m), $3000 (m), 1710 (s), 1460 (w), 1410 (m), 1235 (m), 1080 (m), 975 (m), 760 (m); 1 H-NMR (300 MHz)  0.99 (3H, t, J ¼ 7:4 Hz), 1.38– 1.50 (2H, m), 1.56 (1H, ddd, J ¼ 12:6, 7.7, 6.0 Hz), 2.15 (1H, ddd, J ¼ 12:6, 8.5, 7.4 Hz), 2.42 (1H, dd, J ¼ 16:1, 8.0 Hz), 2.48 (1H, dd, J ¼ 16:1, 6.9 Hz), 2.58–2.73 (1H, m), 3.44 (1H, dd, J ¼ 8:8, 6.6 Hz), 3.72 (1H, ddd, J ¼ 8:0, 5.2, 3.6 Hz), 3.95 (1H, dt, J ¼ 3:6, 7.5 Hz), 4.12 (1H, dd, J ¼ 8:5, 6.6 Hz); 13 C-NMR (125 MHz)  10.3, 25.6, 30.7, 35.5, 37.3, 73.3, 73.7, 81.3, 177.4; HRMS (FAB) m=z calcd for C9 H17 O4 ([M + H]þ ) 189.1127, found 189.1128. 1 H- and 13 C-NMR data for (3S,5S,6S)-3, the originally proposed structure for communiol C. 1 H-NMR (500 MHz)  1.00 (3H, t, J ¼ 7:6 Hz), 1.37–1.54 (2H, m), 1.70 (1H, ddd, J ¼ 12:7, 7.3, 5.9 Hz), 1.94 (1H, ddd, Synthesis of Communiols A–C J ¼ 12:7, 7.8, 7.3 Hz), 2.46 (2H, d, J ¼ 7:3 Hz), 2.68 (1H, sep, J ¼ 6:8 Hz), 3.32–3.37 (1H, m), 3.49 (1H, dd, J ¼ 8:3, 6.3 Hz), 3.85 (1H, q, J ¼ 6:8 Hz), 4.06 (1H, dd, J ¼ 8:3, 6.8 Hz); 13 C-NMR (125 MHz)  10.1, 26.5, 33.9, 35.6, 37.2, 72.8, 75.2, 81.3, 177.1. (S)-1-[(2R,4R)-4-(2-Oxoethyl)tetrahydrofuran-2-yl]propyl p-nitrobenzoate (21). Ozone was bubbled into a stirred solution of 20 (0.200 g, 0.626 mmol) in MeOH (2 ml) at À78  C until the disappearance of 20 was observed by TLC monitoring. Me2 S (0.4 ml) was then added, and the mixture was gradually warmed to room temperature and then concentrated in vacuo. The residue was chromatographed over SiO2 (hexane/EtOAc, 2:1) to give 0.171 g (85%) of 21 as a colorless oil: ½ ŠD 22 À3:8 (c 0.510, CHCl3 ); IR max cmÀ1 : 2725 (w), 1720 (vs), 1605 (m), 1525 (s), 1275 (s); 1 H-NMR (300 MHz)  0.98 (3H, t, J ¼ 7:5 Hz), 1.63–1.88 (3H, m), 2.18 (1H, ddd, J ¼ 12:9, 7.8, 6.3 Hz), 2.60 (2H, d, J ¼ 6:8 Hz), 2.65–2.80 (1H, m), 3.39 (1H, dd, J ¼ 8:7, 6.6 Hz), 4.05 (1H, dd, J ¼ 8:7, 6.6 Hz), 4.17 (1H, ddd, J ¼ 7:5, 6.3, 4.8 Hz), 5.22 (1H, dt, J ¼ 7:8, 3.9 Hz), 8.20–8.26 (2H, m), 8.28–8.34 (2H, m), 9.79 (1H, s); 13 C-NMR (125 MHz)  9.8, 23.9, 32.9, 33.2, 47.1, 73.3, 77.9, 78.9, 123.6, 130.7, 135.7, 150.5, 164.3, 200.6; HRMS (FAB) m=z calcd for C16 H20 O6 N ([M + H]þ ) 322.1290, found 322.1293. 4-{(3S,5R)-5-[(S)-1-(p-Nitrobenzoyloxy)propyl]tetrahydrofuran-3-yl}-2-butenoic acid [(5S,7R,8S)-2]. A mixture of 21 (0.170 g, 0.530 mmol) and Ph3 P=CHCO2 Et (0.203 g, 0.583 mmol) in CH2 Cl2 (2.5 ml) was stirred for 9 h at room temperature. The mixture was diluted with water and extracted with EtOAc. The extract was washed with brine, dried (MgSO4 ), and concentrated in vacuo. The residue was chromatographed over SiO2 (hexane/EtOAc, 10:1) to give 0.170 g (82%) of ethyl 4-{(3S,5R)-5-[(S)-1-( p-nitrobenzoyloxy)propyl]tetrahydrofuran-3-yl}-2-butenoate as a colorless oil: ½ ŠD 22 À1:9 (c 0.810, CHCl3 ); IR max cmÀ1 : 1720 (vs), 1650 (m), 1605 (w), 1530 (s), 1280 (s); 1 H-NMR (300 MHz)  0.98 (3H, t, J ¼ 7:4 Hz), 1.29 (3H, t, J ¼ 7:1 Hz), 1.67– 1.86 (3H, m), 2.05 (1H, ddd, J ¼ 12:9, 7.8, 6.3 Hz), 2.29 (1H, br t, J ¼ 7:0 Hz), 2.34–2.46 (1H, m), 3.44 (1H, dd, J ¼ 8:7, 6.3 Hz), 3.97 (1H, dd, J ¼ 8:7, 6.3 Hz), 4.15– 4.24 (1H, m), 4.18 (2H, q, J ¼ 7:1 Hz), 5.20 (1H, dt, J ¼ 8:1, 4.8 Hz), 5.85 (1H, dt, J ¼ 15:6, 1.4 Hz), 6.89 (1H, dt, J ¼ 15:6, 7.0 Hz), 8.19–8.25 (2H, m), 8.28–8.34 (2H, m); 13 C-NMR (125 MHz)  9.8, 14.2, 23.9, 33.1, 35.4, 37.8, 60.4, 73.3, 77.9, 79.0, 122.8, 123.6, 130.7, 135.7, 146.3, 150.5, 164.3, 166.3; HRMS (FAB) m=z calcd for C20 H26 O7 N ([M + H]þ ) 392.1709, found 392.1709. The ethyl ester (0.143 g, 0.364 mmol) was dissolved in THF (2.5 ml) and mixed with 1 M LiOH aq. (2 ml), and the mixture was stirred at room temperature for 20 h. The mixture was acidified with 2 M HCl aq. and extracted with EtOAc. The extract was washed with brine, dried (MgSO4 ), and concentrated in vacuo. 1927 The residue was chromatographed over SiO2 [CHCl3 / MeOH (70:1) containing a trace amount of AcOH] to give 0.074 g (95%) of (5S,7R,8S)-2 as a colorless oil: ½ ŠD 22 +4.7 (c 1.00, CH2 Cl2 ); IR max cmÀ1 : 3400 (m), $3000 (m, broad), 1700 (s), 1655 (m), 1250 (m), 1085 (w), 980 (m), 885 (w), 760 (m); 1 H-NMR (300 MHz)  0.99 (3H, t, J ¼ 7:4 Hz), 1.38–1.49 (2H, m), 1.52 (1H, ddd, J ¼ 12:6, 7.4, 5.2 Hz), 2.09 (1H, dt, J ¼ 12:6, 7.8 Hz), 2.32 (2H, br t, J ¼ 7:1 Hz), 2.32–2.46 (1H, m), 3.42 (1H, dd, J ¼ 8:5, 6.6 Hz), 3.71 (1H, ddd, J ¼ 7:7, 5.5, 3.6 Hz), 3.93 (1H, dt, J ¼ 3:6, 7.7 Hz), 4.05 (1H, dd, J ¼ 8:5, 6.6 Hz), 5.87 (1H, br d, J ¼ 15:7 Hz), 7.01 (1H, dt, J ¼ 15:7, 7.1 Hz); 13 C-NMR (150 MHz)  10.3, 25.7, 30.5, 35.7, 38.2, 73.2, 73.6, 81.4, 122.0, 149.3, 170.7; HRMS (FAB) m=z calcd for C11 H19 O4 ([M + H]þ ) 215.1283, found 215.1286. 4-{(3S,5R)-5-[(S)-1-Hydroxypropyl]tetrahydrofuran3-yl}butanoic acid [(5S,7R,8S)-1]. A mixture of (5S,7R,8S)-2 (0.025 g, 0.117 mmol) and 10% Pd-C (2.5 mg) in ethanol (0.25 ml) was stirred at room temperature for 1.5 h under hydrogen at atmospheric pressure. The mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc. The combined filtrates were concentrated in vacuo, and the residue was chromatographed over SiO2 [CHCl3 /MeOH (70:1) containing a trace amount of AcOH] to give 0.024 g (96%) of (5S,7R,8S)-1 as a colorless oil: ½ ŠD 22 +1.4 (c 1.17, CH2 Cl2 ); IR max cmÀ1 : 3400 (m), $3000 (m, broad), 1710 (s), 1460 (m), 1260 (m), 1070 (m), 975 (w); 1 H-NMR (300 MHz)  0.97 (3H, t, J ¼ 7:4 Hz), 1.37–1.51 (5H, m), 1.56–1.73 (2H, m), 2.06 (1H, ddd, J ¼ 12:4, 8.8, 6.9 Hz), 2.12–2.27 (1H, m), 2.36 (2H, t, J ¼ 7:4 Hz), 3.35 (1H, dd, J ¼ 8:2, 7.7 Hz), 3.69 (1H, ddd, J ¼ 7:7, 5.5, 3.3 Hz), 3.91 (1H, ddd, J ¼ 7:7, 6.7, 3.6 Hz), 4.04 (1H, dd, J ¼ 8:2, 6.6 Hz); 13 C-NMR (150 MHz)  10.4, 23.5, 25.7, 30.9, 32.5, 34.0, 39.3, 73.69, 73.74, 81.5, 178.7; HRMS (FAB) m=z calcd for C11 H21 O4 ([M + H]þ ) 271.1440, found 271.1442. Acknowledgments We are grateful to Prof. Gloer (University of Iowa) for providing the copies of the NMR spectra of communiols A–C. 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