Synthesis of Natural Fragrant Molecules cis-3-Methyl-4-decanolide

Novel iodine catalyzed diastereoselective synthesis of trans-2,6-disubstituted tetrahydro-2H-pyrans: synthesis of C1–C13 fragment of bistramide-A. J...
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J. Org. Chem. 2002, 67, 3802-3810

Synthesis of Natural Fragrant Molecules cis-3-Methyl-4-decanolide and Aerangis Lactone. General Enantioselective Routes to β,γ-cis-Disubstituted γ-Lactones and γ,δ-cis-Disubstituted δ-Lactones Yikang Wu,* Xin Shen, Chao-Jun Tang, Zhi-Long Chen,† Qi Hu, and Wei Shi‡ State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China [email protected] Received January 21, 2002

General enantioselective routes to 3,4-cis-dialkyl substituted γ-lactones and 4,5-cis-dialkyl substituted δ-lactones using TiCl4-mediated Evans asymmetric aldolization as the key step are reported. The syntheses are exemplified with two natural fragrant molecules, cis-3-methyl-4-decanolide (1) and aerangis lactone (2). The (R,R) steroegenic centers were established using (S)-phenylalaninederived 2-oxazolidinone or thiazolidinethione as chiral auxiliary, whereas the (S,S) ones were constructed with auxiliary prepared from (R)-phenylglycine. NaBH4/CaCl2/THF in the presence of a small amount of EtOH was introduced as a new effective method for reductive cleavage of chiral oxazolidinone auxiliaries. Previously unknown, tricky concentration effects were observed during the monotosylation of diol 7 and BOM protection of Evans aldol 23. Introduction In the orchid family, many natural species emit timedependent, fascinating scents. Using a special trapping technique, Kaiser identified1 that cis-3-methyl-4-decanolide (1) and aerangis lactone (2) are odoriferous components of the Aerangis species (native to Kenya and Tanzania). Compound 1 (of undetermined absolute stereochemistry) also exists2 in the volatile components of the juices of blood oranges as well as blond oranges and has been used3 as an active ingredient of oral bactericides in dentifrices. The mixture of cis- and trans-2 is a perfume and flavoring component that can enhance the ylang-ylang, alpine herb, and creamery notes of various perfume and flavoring compounds.4

The first synthesis of 1 (as a mixture of diastereomers) was conducted in 1979 by Shono5 using the electroreduction of the methyl ester of 3-hydroxy-2-[1-(phenylthio)† Present address: Deptartment of Chemical Defense Medicine, Second Military Medical University, Shanghai 200433, China. ‡ Undergraduate trainee from Department of Medicinal Chemistry, College of Pharmacy, Fudan University. (1) (a) Kaiser, R. The scent of orchids: Olfactory and chemical investigations; Elsevier: Amsterdam, 1993. (b) Kaiser, R. In Perfumes: Art, Science and Technology; Mu¨ller, P. M., Lamparsky, D., Eds.; Elsevier Applied Science: London, 1991; Chapter 7. (2) Na¨f, R.; Velluz, A.; Meyer, A. P. J. Essent. Oil Res. 1996, 8, 587595. (3) Tsuneda, Fumihiko Jpn. Kokai Tokkyo Koho JP 09169624 A2 30 Jun 1997 Heisei; Chem. Abstr. 1997, 127:99565. (4) Kaiser, Roman (Givaudan-Roure (International) S. A., Switz.). Eur. Pat. Appl. EP 513627 A1 19; Chem. Abstr. 1993, 118:66625. (5) Shono, T.; Matsumura, Y.; Kashimura, S.; Hatanaka, K. J. Am. Chem. Soc. 1979, 101, 4752-4753.

ethyl]nonanoic acid. The diastereoselective synthesis6 of 1 appeared in the literature 10 years later. (R,R)-1 was first synthesized by Larcheveˆque7 in 1989 with conjugate addition of methyl Grignard reagent to a chiral substrate derived from R-alkoxyoctanal as key step. Later, in 1999, Kitahara8 reported another synthesis of both enantiomers with (1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-3-one ((1S,5R)39) or its enantiomer ((1R,5S)-39) as starting material. While the stereochemistry of the target molecules was indeed secured when using such an advanced chiral starting material, their route was relatively lengthy and required such inconvenient reagents as DIBAL, LiHBEt3, and BuLi. Compound 2 was initially prepared in the form of a mixture of cis- and trans-isomers through BayerVilliger oxidation of corresponding cyclopentanone.4 Synthesis of enantiopure 2 was first claimed10 by Kitahara in 1999 without disclosing any information. Herein, we wish to detail11 efficient and economic routes to these fragrant target molecules that do not involve the abovementioned expensive/air-sensitive reagents at all and thus have better prospects for large-scale preparation. Results and Discussion The two stereogenic centers in both 1 and 2 fall into the types that are easily accessible through Evans12 (6) Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1989, 1521-1527. (7) Larcheveˆque, M.; Tamagnan, G.; Petit, Y. J. Chem. Soc., Chem. Commun. 1989, 31-33. (8) (a) Masuzawa, Y.; Tamogami, S.; Kitahara, T. Nat. Prod. Lett. 1999, 13, 239-249 and references therein. (b) Kitahara, T.; Masuzawa, Y. (Hasegawa Koryo Co. Ldt., Japan) Jpn. Kokai Tokkyo Koho JP 200086647 A2; Chem. Abstr. 2000, 132:222392. (9) Commercially available from Aldrich (catalogue for year 2000/ 2001) at $40.0(US)/500 mg (for (1S,5R)-3) and $50.9(US)/1 g (for (1R,5S) -3), respectively. (10) See ref 3 in ref 8a above. (11) Wu, Y.-K.; Shen, X.; Tang, C.-J.; Chen, Z.-L. Synthesis of (R,R)-1 and (R,R)-2 was communicated recently. Helv. Chim. Acta 2001, 84, 3428-3432.

10.1021/jo025540o CCC: $22.00 © 2002 American Chemical Society Published on Web 04/30/2002

Synthesis of Natural Fragrant Molecules

J. Org. Chem., Vol. 67, No. 11, 2002 3803

asymmetric aldolization. The main factors that discourage broader application (especially on large scales) of this extremely useful and highly reliable methodology used to be involvement of stoichiometric amounts of Bu2BOTf (which is quite expensive and highly sensitive to both air and moisture) in the “standard”12a procedure and the relative difficulty in obtaining the chiral auxiliary 2-oxazolidinones (rather expensive13 from commercial sources and involved either tedious procedures or expensive reagents to prepare from corresponding amino acids). However, over the past few years there were an increasing number of cases14 in the literature showing that the inexpensive but less commonly employed TiCl4 variant12b could replace the original Bu2BOTf procedure in many cases, if a proper base of adequate amount is employed. The auxiliary availability problem was also eliminated recently by a highly practical procedure15 developed by us. Thus, a route to these targets using Evans’ methdology would be not only expeditious but also practical. Besides, such a route would provide a general enantioselective access to a large class of cis-dialkyl-substitued lactones of various utilities (vide infra) in everyday life. On the basis of this reasoning, we started the syntheses described below. As shown in Scheme 1, the desired 1,2-syn stereochemistry was easily attained by a TiCl4-mediated aldol condensation of the known N-propionyloxazolidinone16 (which now can be prepared17 from (S)-4-benzyl-2-oxazo-

lidinone15 auxiliary and acid halide without involving such strong bases as butyllithium) with n-heptaldehyde, with N,N′-tetramethylethylenediamine (TMEDA) as base. The resulting alcohol 6a (ca. 75% yield based on the chiral auxiliary) was readily reduced in THF with aqueous18 NaBH4 in ca. 80% yield. We also tested Ca(BH4)2 formed in situ from NaBH4 and CaCl2 in THF (a reagent system that to our knowledge has not been used for reductive removal of chiral oxazolidinone auxilaries) containing EtOH and got the diol in 74.8% yield. It should be noted that this reducing system19 was successfully utilized in the reduction of amino acids to corresponding amino alcohols but has never been used for reductive cleavage of chiral auxiliaries.20 Selective tosylation of the primary hydroxyl group in diol (R,R)-7, to our surprise, was very difficult. In the beginning, we thought the most likely encountered problem in this step would be the formation of the corresponding ditosylate. Therefore, we started with Martinelli’s21 Bu2SnO procedure in order to suppress the seemingly unavoidable overtosylation. The first result was totally to our surprise. The reaction was very sluggish (with much starting 7 remained unconsumed, even after prolonged reaction), and definitely no trace of the ditosylate was formed. More forcing conditions (more p-TsCl, higher reaction temperature, or higher concentrations, etc.) could lead to faster consumption of the starting diol, but they did not result in more desired product. Instead, the reaction mixture became tarred. Repeating the reaction in the absence of Bu2SnO gave the same results, indicating that Bu2SnO did not have any effects at all. Thus, contrary to what we foresaw in the beginning, the real difficulty here turned out to be how to speed up the reaction instead of prevention of overreaction. In efforts to seek solutions to the slow reaction problem, we noticed through literature study that tosylation of simple alcohols in fact was not always facile and highyielding as broadly believed. It appears that the alcohols with a long, unfunctionalized aliphatic chain are relatively “resistant”22 to tosylation compared with those23 with short chains, suggesting that the elusive difficulty we encountered is not unique to our substrate. Then, by accident we found that, contrary to the common sense of chemical kinetics, a run at a slightly lower reactant concentration appeared to lead to a faster reaction and a somewhat higher yield of (R,R)-8 than at a higher concentration. This seemingly abnormal phenomenon urged us to further examine the effects of lowering concentration. The results were very gratifying. By reducing the starting diol concentration from 1-0.5 M

(12) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1990, 113, 1047-1049. (13) (S)-4-Benzyl-2-oxazolidinone and (R)-4-phenyl-2-oxazolidinone, e.g., are available from Aldrich (catalogue for year 2000/2001) at 25 g/US$ 220.50 and 5 g/US$ 174.50, respectively. (14) See, for example: (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883-7884. (b) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc. 1998, 120, 59215942. (c) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653-5660. (d) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775-777. (e) Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000, 2, 53-56. (f) Sulikowski, G. A.; Lee, W.-M.; Jin, B.-H.; Wu, B. Org. Lett. 2000, 2, 1439-1442. (15) Wu, Y.-K.; Shen, X. Tetrahedron: Asymmetry 2000, 11, 43594363. (16) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77-91. (b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453.

(17) Cf. e.g., Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 22712273. (18) Duan, M.-S.; Paquette, L. A. Tetrahedron Lett. 2000, 41, 37873792. (19) Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson, R. J. Synth. Commun. 1995, 25, 561-568. (20) It appears that this reagents/solvent combination may serve as a complement to the existing procedures for the reductive removal of chiral auxiliaries, as it could cleave the auxiliary in some substrates that were resistant to NaBH4 while some functionalities that are incompatible with the more powerful LiBH4 still survived. (21) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450. (22) (a) Bradshaw, J. S. J. Org. Chem. 1990, 55, 3129-3137. (b) Kabalka, G. W.; Varma, M.; Varma, R. S. J. Org. Chem. 1986, 51, 23862388. (23) (a) Pilli, R. A.; Andrade, C. K. Z. Synth. Commun. 1994, 24, 233-241. (b) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org. Chem. 1990, 55, 6260-6268.

Scheme 1a

a Conditions: (a) TiCl /TMEDA/CH Cl , 80.7% for 6a or 56.5% 4 2 2 for 6b; (b) aq NaBH4/THF, 79.4% from 6a or NaBH4/EtOH, 85% from 6b; (c) p-TsCl/NEt3/DMAP/CH2Cl2, 84.3% (96.6% based on consumed starting diol); (d) NaCN/DMSO, 89.6%; (e) (i) 2 N NaOH/ EtOH/reflux, (ii) dilute H2SO4/THF, 84.1% (from crude 9).

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J. Org. Chem., Vol. 67, No. 11, 2002 Scheme 2a

a Conditions: (a) TiCl /TMEDA/CH Cl , 79.3%; (b) aq NaBH / 4 2 2 4 THF, 79.7%; (c) p-TsCl/NEt3/DMAP/CH2Cl2, 79.9%; (d) NaCN/ DMSO, 89%; (e) (i) 2 N NaOH/EtOH/reflux, (ii) dilute H2SO4/THF, 82.9% (from the crude 9).

to ca. 0.1 M (with the reactants ratios unchanged) the conversion of 7 to 8 was unmistakably sped up and raised the yield of the desired monotosylate from around 50% to 84%. To the best of our knowledge, such an abnormal concentration effect has not been reported before, at least not for the tosylation of alcohols. Although it is not clear yet whether this abnormal concentration effect stems from hydrogen bonding of the hydroxyl groups or aggregation of the side chain (or both), the knowledge gained here may be of general guiding significance in the tosylation of alcohols with long aliphatic chains. The monotosylate (R,R)-8 was treated with sodium cyanide in DMSO in the presence of a catalytic amount of NaI to give corresponding nitrile (R,R)-9 in ca. 90% yield. The crude 9 could also be used directly in the subsequent base-catalyzed hydrolysis followed by lactonization under acidic conditions to afford the desired target molecule (R,R)-1 in 84% yield (over two steps). The overall yield based on the chiral auxiliary was around 40.7% (cf. lit.8 8%). We also briefly examined the parallel reactions using a thiazolidinethione14d (which up to now is much less exploited in asymmetric aldolization with only a limited number of examples in the literature) instead of the 2-oxazolidinone auxiliary. Thus, aldol condensation of 4b with 5 under the same conditions led to 6b in ca. 57% yield, somewhat lower than in the 2-oxazolidinone auxiliary case. However, this shortcoming is partially compensated in the next step by the much more facile reductive cleavage of 6b than that of 6a. The relatively complex technique of aqeuous18 NaBH4 in THF was no longer necessary. In EtOH, the thiazolidinethione auxiliary was cleanly cleaved by NaBH4 to give diol (R,R)-7 in 85%. (S,S)-1 was synthesized via the same route (Scheme 2), except (R)-4-phenyl-2-oxazolidinone was utilized as the chiral auxiliary because it was less expensive than (R)-4-benzyl-2-oxazolidinone. The yields were also comparable to those in the synthesis of (R,R)-1. Due to similar polarity/chromatographic behavior, the diol (S,S)-7 was always contaminated with traces of 4-phenyl-2oxazolidinone auxiliary, and thus, it was rather difficult to acquire reliable spectroscopic data. However, the impurity could be easily removed at the tosylate stage.

Wu et al. Scheme 3a

a Conditions: (a) TiCl /TMEDA/CH Cl , 74.5%; (b) aq NaBH / 4 2 2 4 THF, 75.1%; (c) quinolinium chlorochromate.

The remaining steps from the diol on were the same as those employed in the synthesis of (R,R)-1. The stereogenic centers in the six-membered lactone (R,R)-2 were also established using the TiCl4-mediated aldolization (Scheme 3) as described above for the fivemembered lactones. In the beginning, we attempted to seek a route without evoking any protection step during the carbon chain elongation (Scheme 2). Thus, the aldol 14 was directly reduced with NaBH4 in high yield to give diol24 (R,R)-13, which was treated with quinolinium chlorochromate with the hope that the primary hydroxyl would be selectively oxidized in the presence of the secondary one, as reported25 by Singh. The resultant aldehyde might be possible to react with a stabilized ylide to fulfill the chain extension without recourse to any protecting group for the secondary hydroxyl. Unfortunately, this route did not work out. The oxidation was rather sluggish at low temperatures (well below 0 °C), presumably due to the relatively large steric crowding around the primary hydroxyl group compared with those β-unsubstituted ones in Singh’s25 substrates. At higher temperatures, practically no selectivity was observed at all. We also examined a few TEMPO-based selective oxidation protocols, including NaClO/TEMPO,26 PhI(OAc)2/TEMPO,27 and trichloroisocyanuric acid/TEMPO,28 but none of them gave acceptable results. The failure of the selective oxidation forced us to adopt a longer route. We first attempted to mask the hydroxyl group in 14 as a Piv ester (pivaloate), because this would reduce the cost of the synthesis compared with siliconcontaining protecting groups (Scheme 4). Although (to our knowledge) conversion of Evans aldols into corresponding pivaloates has not been reported before, the reaction proceeded well, leading to the desired product in 95.9% yield. The subsequent reduction was a disappointment. It was expected that the steric bulk associated with the Piv (24) For racemic 13, see: Pelter, A.; Bugden, G.; Rosser, R. Tetrahedron Lett. 1985, 26, 5097-5100. (25) (a) Singh, J.; Kalsi, P. S.; Jawanda, G. S.; Chhabra, B. R. Chem. Ind. (London) 1986, 751-752. (b) Singh, J.; Kad, G. L.; Vig, S.; Sharma, M.; Chhabra, B. R. Ind. J. Chem. B. 1997, 36, 272-274. (26) Siedlecka, R.; Skarzewski, J.; Mlochowski, J. Tetrahedron Lett. 1990, 31, 2177-2180. (27) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974-6977. (28) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041-3043.

Synthesis of Natural Fragrant Molecules

J. Org. Chem., Vol. 67, No. 11, 2002 3805 Scheme 4a

a Conditions: (a) PivCl/NEt /DMAP/CH Cl , 95.9%; (b) NaBH /CaCl /THF/EtOH, 28.5%; (c) TBSOTf/2,6-lutidine/CH Cl , 94.1%; (d) 3 2 2 4 2 2 2 LiBH4/ether/H2O, 69%; (e) IBX/DMSO; (f) (i) Ph3PdCHCO2Et/THF, 93.3% (from 20), (ii) H2/Pd-C/MeOH, 95.6%; (g) dilute H2SO4/THF/ reflux, 66.8%.

group would increase the difficulty in the removal of the chiral auxiliary with the NaBH4 protocol, while the more powerful LiBH4 would not only cut off the auxiliary but also reduce the Piv ester. Therefore, we chose the aforementioned Ca(BH4)2 procedure, which in our hands did not reduce esters in similar reductive cleavages. However, in the present case, the desired alcohol 18 was obtained only in 28.5% yield, along with some diol (R,R)13, presumably caused by either hydrolysis or alkoxyl exchange. The remaining material was apparently lost due to reductive cleavage of the oxazolidinone, a major side reaction29 that sometimes may seriously interfere the removal of the chiral auxiliary. The low yield of reductive cleavage of 17 persuaded us to adopt the more conventional protection protocol, to mask the hydroxyl as a tBuMe2Si (TBS) ether. To achieve excellent yields, using TBSOTf instead of TBSCl was essential. Subsequent reductive removal of the chiral auxiliary in 19 with LiBH4 in aqueous ether30 gave the expected alcohol 20 in 69% yield. An IBX31 (o-iodoxybenzoic acid) oxidation, which was more convenient than Swern oxidation due to much simpler operation and remarkably superior to PCC since chromatographic purification was not needed, afforded the intermediate aldehyde 21. The crude aldehyde after simple workup could be directly used in the next step. Thus, treatment with Ph3PdCHCO2Et gave an intermediate R,β-unsaturated ester as a mixture of the cis- and trans-isomers in 93.3% yield. The carbon-carbon double bond was then saturated by atmospheric catalytic hydrogenation over 10% Pd-C (95.6% yield). Finally, the TBS protecting group in 22 was removed in refluxing THF containing H2SO4 with a concurrent lactonization to afford (R,R)-2 in 66.8% yield. The attempted synthesis of (S,S)-2 started with an aldolization reaction between 10 and 12 (Scheme 5). To explore alternative approaches to the six-membered lactones, we attempted extending the carbon chain by (29) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-875. (b) Davies, S. G.; Doisneau, G. J.-M.; Prodger, J. C.; Sanganee, H. J. Tetrahedron Lett. 1994, 35, 2369-2372. (30) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307-312. (31) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022.

Scheme 5a

a Conditions: (a) TiCl /TMEDA/CH Cl , 81.5%; (b) NaBH / 4 2 2 4 CaCl2/THF/EtOH, 72.5%; (c) p-TsCl/NEt3/DMAP/CH2Cl2, 85.8%.

Scheme 6a

a Conditions: (a) EtO CCH CO H/DCC/CH Cl , 100%; (b) NaH/ 2 2 2 2 2 toluene/reflux, 85.5% of 27; (c) NaI/DMSO, 91.7%; (d) NaH/toluene.

substitution instead of the oxidation-Wittig reactionreduction sequence employed above. Thus, the aldol 23 was directly reduced into diol (S,S)-13 with the NaBH4/ CaCl2/THF/EtOH system in 81.5% yield. Conversion of this diol into monotosylate 24 was also fulfilled using the same technique for preparing (R,R)-8 without any complications. To construct the lactone ring, we had to make a C-C σ bond and an O-C ester bond (Scheme 6). One attractive choice was to use the methodology introduced by Suginome32 et al., exploiting the intramolecular alky-

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Wu et al. Scheme 7a

Figure 1. The possible transition state for the intramolecular cyclization of iodoalkyl malonates.

lation of a malonate enolate. Having noticed that Welzel33 et al. disclosed earlier that similar attempts did not lead to the anticipated five-membered lactones at all and that the Suginome’s lactones appeared to be the only successful examples by this approach up to now, we felt that the intramolecular alkylation deserved further exploration. The EtO2CCH2CO2H required for this endeavor was prepared according to a known34 procedure. Condensation of 24 with the mono acid promoted by N,N′-dicyclohexyldicarbodiimide (DCC) proceeded smoothly, giving 25 in quantitative yield. At this stage, we thought it would be interesting to see if the tosylate could also undergo the intramolecular alkylation as the Suginome’s iodides. Therefore, we treated 25 with EtONa, which should be a strong enough base to deprotonate the acidic methylene group in the malonate. Unfortunately, only alkoxyl exchange occurred (recovering 24), with no cyclization product detected at all. Use of NaH as base did not result in cyclization either. Instead, 27 was isolated in 85.5% yield.32 Under the given circumstances, it appeared that conversion of tosylate 25 to iodide 28 would be the only choice to achieve the anticipated intramolecular alkylation. Therefore, we treated 25 with NaI in DMSO and subjected the resulting 28 to the Suginome’s conditions35 for the cyclization. The outcome of the reaction was totally to our surprise. At ambient temperature, there was substantially no reaction at all. At elevated temperatures, extensive side reactions occurred. The main difference between 28 and Suginome’s compound is a methyl group at C-2. A careful inspection of molecular model shows that when X is changed from H to a methyl, the energy of the transition state would be remarkably increased, because the methyl group could only adopt an axial position (Figure 1). This analysis suggests that the intramolecular cyclization is rather sensitive to the substitution pattern, with the cis-disubstitution in a 1,2-arrangement being the least favorable situation, due to the unavoidable appearance of an axial substituent in the transition state. Such an insight is not attainable from Suginome’s results and therefore may be useful in evaluating the feasibility of similar cyclization plans. Finally, (S,S)-2 was obtained using the sequence shown in Scheme 7. The hydroxyl group in 23 was first masked (32) Kobayashi, K.; Minakawa, H.; Sakurai, H.; Kujime, S.; Suginome, H. J. Chem. Soc., Perkin Trans. 1 1993, 3007-3010. (33) Adams, E.; Heigemann, M.; Duddeck, H.; Welzel, P. Tetrahedron 1990, 46, 5975-5992. (34) (a) Mandai, T.; Imaji, M.; Takada, H.; Kawata, M.; Nokami, J.; Tsuji, J. J. Org. Chem. 1989, 54, 5395-5397. (b)To¨ke, L.; Hell, Z.; Szabo´, G.; To´th, G.; Bihari, M.; Rockenbauer, M. Tetrahedron 1993, 49, 5133-5146. (35) Unlike hydrolysis of esters, conversion of tosylate to the corresponding alcohol is not normally an easily realizable task. Therefore, this unexpected yet clean reaction perhaps could be useful in protective group chemistry.

a Conditions: (a) BnOCH Cl/iPrNEt /CH Cl , 92.6%; (b) NaBH / 2 2 2 2 4 CaCl2/THF/EtOH, 83.1%; (c) (i) IBX/DMSO; (ii) Ph3PdCHCO2Et/ THF, 87.8% (from 30); (d) (i) H2/Pd-C/MeOH; (ii) dilute H2SO4, 65.4% (from 31).

as a BOM ether with BnOCH2Cl. It is interesting to note that this reaction was also concentration dependent. At higher concentrations (∼0.5 M for 23), the reaction appeared to be halted after a short initial stage, giving only ca. 30% yield of 29. Dilution of the reaction system with solvent to ca. 0.1 M raised the yield of 29 to 92.6%. The auxiliary was reductively cleaved with NaBH4/CaCl2/ THF/EtOH in 83.1% yield. The resulting alcohol was then oxidized with IBX and treated with Ph3PdCHCO2Et to give 31, which was directly subjected to hydrogenation at atmospheric pressure in the presence of a catalytic amount of 10% Pd-C, followed by acid-catalyzed BOM removal and concurrent cyclization to give the desired enantiomer of lactone 2.

It deserves to be mentioned here that the syntheses described above also illustrate efficient and flexible general routes to enantiopure cis-dialkyl-substituted lactones 32, a class of compounds of marked significance as flavoring agents,36 perfume ingredients,37 insect propellant,38 bactericides,39 additives for food and drugs,40 etc. Judging from the starting materials, reagents, and reaction conditions involved, the approach disclosed here should be able to serve as an advantageous complement to these existing41-48 ones. Although up to now chiral odorants, flavoring agents, and the like are employed only (36) (a) Boidron, J. N.; Chatonnet, P.; Pons, M. Connaiss. Vigne Vin 1988, 22, 275-94; Chem. Abstr. 1989, 110, 230120. (b) Ebata, T.; Kawakami, H.; Matsushita, H. (Nippon Tobacco Sangyo, Japan). Jpn. Kokai Tokkyo Koho JP 05086045 A2 6 Apr 1993 Heisei; Chem. Abstr. 1993, 119, 225799. (c) Maga, J. Food Rev. Int. 1996, 12, 105-130; Chem. Abstr. 1996, 124, 287296. (d) Chatonnet, P.; Boidron, J. N.; Pons, M. Connaiss. Vigne Vin 1989, 23, 223-250; Chem. Abstr. 1991, 114, 80026. (e) Williams, A. A.; Lewis, M. J.; May, H. V. J. Sci. Food Agric. 1983, 34, 311-319; Chem. Abstr. 1983, 98, 214087. (f) Van Straten, S.; Jonk, G.; Van Gemert, L. Flavor Foods Beverages: Chem. Technol; Charalambous, G., Inglett, G. E., Eds.; Academic: New York, N. Y. (English) 1978; [Proc. Conf.] 381-390. Chem. Abstr. 1979, 91, 106546. (37) (a) Zaslona, A. (Firmenich S. A., Switz.). Patentschrift (Switz.) CH 685390 A 30 Jun 1995; Chem. Abstr. 1996, 124, 29588. (b) Kaiser, R. (Givaudan-Roure (International) S. A., Switz.). Eur. Pat. Appl. EP 513627 A1 19 Nov 1992; Chem. Abstr. 1993, 118, 66625. (38) Shiono, Y.; Tsukasa, H. (Sumitomo Chemical Co., Ltd.; Toyotama Perfumery Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho JP 63048203 A2 29 Feb 1988 Showa; Chem. Abstr. 1988, 110, 168109. (39) Tsuneda, F. (Lion Corp., Japan). Jpn. Kokai Tokkyo Koho JP 09169624 A2 30 Jun 1997 Heisei; Chem. Abstr. 1997, 127, 99565. (40) Yamaguchi, M.; Inanaga, J.(Yoshitomi Pharmaceutical Industries, Ltd., Japan). Jpn. Kokai Tokkyo Koho JP 63068578 A2 28 Mar 1988 Showa; Chem. Abstr. 1989, 110, 154131.

Synthesis of Natural Fragrant Molecules

as mixtures of enantiomers, it is not impossible that in the future they may follow the steps of development of chiral drugs, gradually entering an enantiomer era. In fact, even back in the 1980s it was already known49 that the odor properties might be different for different enantiomers. Since then, there has been a growing interest50 in the chirality-odor relationship. Development of efficient practical routes to enantiomerically pure, fragrant molecules would undoubtedly facilitate the studies on this aspect.

Experimental Section General Methods. 1H NMR spectra were taken on spectrometers working at 300 MHz for observing 1H with Me4Si as internal standard and CDCl3 as solvent. Column chromatography was performed on silica gel (230-400 mesh). The diethyl ether for chromatography was of A. R. grade and used as received (containing ca. 0.1% water). (2S)-4-Benzyl-3-((2S,3R)-3-hydroxy-2-methylnonanoyl)oxazolidin-2-one (6a). Under an atmosphere of N2 (balloon) with cooling (ice-water bath) and stirring, TiCl4 (0.7 mL, 7.25 mmol) was added (via a syringe) dropwise to a solution of 4a (1.166 g, 5.0 mmol) in dry CH2Cl2 (25 mL). A yellow precipitate formed soon. After stirring for 5 min, dry TMEDA (2.0 mL, 13.25 mmol) was introduced dropwise via a syringe. The resulting dark red mixture was stirred for another 1 h before n-heptanal 5 (1.5 mL, ca. 11.16 mmol) was added. Stirring was continued at 0 °C for 12 h. Diethyl ether (25 mL) and water (20 mL) were added. The resulting mixture was stirred until the color faded. The precipitates were filtered off (washed with diethyl ether) through Florisil with suction and the filtrate/washings were washed with brine and dried over Na2SO4. After removal of the solvent, the residue was chromatographed (eluting with 1:1 hexanes/ether) to afford 6a as a pale yellow oil (1.410 g, 80.7%): [R]19D +39.0 (c 1.17, CHCl3); (41) (a) Marino, J. P.; Fernandez de la Pradilla, R. Tetrahedron Lett. 1985, 26, 5381-5384. (b) Kosugi, H.; Tagami, K.; Takahashi, A.; Kanna, H.; Uda, H. J. Chem. Soc., Perkin Trans. 1 1989, 935-943. (c) Ferreira, J. T.; Marques, J. A.; Mario, J. P. Tetrahedron: Asymmetry 1994, 5, 641-648. (42) (a) Yamamoto, Y.; Nishii, S.; Ibuka, T. J. Chem. Soc., Chem. Commun. 1987, 464-466. (b) ref 7. (43) (a) Chevtchouk, T.; Ollivier, J.; Salau¨n, J. Tetrahedron: Asymmetry 1997, 7, 1011-1014. (b) Hedenstro¨m, E.; Ho¨gberg, H.-E.; Wassgren, A.-B. Tetrahedron 1992, 48, 3139-3146. (c) Yamaguchi, M.; Hirao, I. Chem. Lett. 1985, 337-338. (44) (a) ref 21a. (b) Brandange, S.; Leijonmarck, H. Tetrahedron Lett. 1992, 33, 3025-3028. (45) (a) Ebata, T.; Matsumoto, K.; Yoshikoshi, H.; Koseki, K.; Kawakami, H.; Okano, K.; Matsushita, H. Heterocycles 1993, 36, 10171026. (b) Suzuki, Y.; Mori, W.; Ishizone, H.; Naito, K.; Honda, T. Tetrahedron Lett. 1992, 33, 4931-4932. (c) ref 8. (46) (a) Ebata, T.; Matsumoto, K.; Yoshikoshi, H.; Koseki, K.; Kawakami, H.; Okano, K.; Matsushita, H. Heterocycles 1993, 36, 10171026. (b) Suzuki, Y.; Mori, W.; Ishizone, H.; Naito, K.; Honda, T. Tetrahedron Lett. 1992, 33, 4931-4932. (47) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997, 38, 3531-3534. (48) Benedetti, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E.; Vicario, M. Tetrahedron: Asymmetry 2001, 12, 505-511. (49) Ohloff, G.; Vial, C.; Wolf, H. R.; Job, K.; Jegou, E.; Polonsky, J.; Lederer, E. Helv. Chim. Acta 1980, 63, 1932-1946. (50) See e.g. (a) Escher, S.; Giersch, W.; Niclass, Y.; Bernardinelli, G.; Ohloff, G. Helv. Chim. Acta 1990, 73, 1935-1947. (b) Ohloff, G. Helv. Chim. Acta 1992, 75, 1341-1415. (c) Buchbauer, G.; Lebada, P.; Wiesinger, L.; Weiss-Greiler, P.; Wolschann, P. Chirality 1997, 9, 380385. (d) Chastrette, M.; Rallet, E. Flavour Fragrance J. 1998, 13, 5-18; Chem. Abstr 129, 39036. (e) Padrayuttawat, A.; Yoshizawa, T.; Tamura, H.; Tokunaga, T. Food Sci. Technol. Int. (Tokyo) 1997, 3, 402-408; Chem. Abstr. 128, 179608. (f) Bader, S.; Colonna, S. Cosmet. News 1997, 20, 346-347.; Chem. Abstr. 128, 145137. (g) Spreitzer, H.; Piringer, I.; Holzer, W.; Widhalm, M. Helv. Chim. Acta 1998, 81, 2292-2299. (h) Bajgrowicz, J. A.; Frater, G. Enantiomer 2000, 5, 225-234. (i) Ohloff, G.; Maurer, B.; Winter, B.; Giersch, W. Helv. Chim. Acta 1983, 66, 192-217. (j) Pickenhagen, W. In Flavor Chemistry, Trends and Developments; Teranishi, R., Buttery, R. G., Shahidi, F., Eds.; ACS Symposium Series No. 388. Am. Chem. Soc.: Washington, DC, 1989; p.152; Chem. Abstr. 110, 229193.

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H NMR δ 7.40-7.28 (m, 5H), 4.73 (m, 1H), 4.30-4.15 (m, 2H), 3.95 (m, 1H), 3.76 (m, 1H), 3.25 (dd, J ) 3.3, 13.3 Hz, 1H), 2.89 (br s, 1H, OH), 2.79 (dd, J ) 9.4, 13.3 Hz, 1H), 1.60-1.15 (m, 10H), 1.26 (d, J ) 7.1 Hz, 3H), 0.88 (t, J ) 6.5 Hz, 3H); IR (film) 3523, 1783, 1699, 1456, 1387, 1211 cm-1; MS m/z 347 (M+, 0.8), 330 (3), 329 (3), 262 (2), 244 (25), 233 (24), 205 (14), 178 (25), 153 (14), 142 (30), 134 (20), 117 (27), 91 (36), 56 (100); HRMS calcd for C20H29NO4 347.2097, found 347.2122. (2S)-4-Benzyl-3-((2S,3R)-3-hydroxy-2-methylnonanoyl)thiazolidine-2-thione (6b). Under N2 (balloon) with cooling (ice-water bath) and stirring, TiCl4 (0.7 mL, 7.25 mmol) was added (via a syringe) dropwise to a solution of amide 4b (1.33 g, 5.0 mmol) in dry CH2Cl2 (20 mL). A yellow precipitate formed soon. After stirring for 10 min, dry TMEDA (2.0 mL, 13.25 mmol) was introduced dropwise via a syringe. The resulting dark red mixture was stirred for another 30 min before the ice-water bath was replaced by a dry ice/acetone one (-75 °C). n-Heptanal 5 (1.5 mL, ca. 11.16 mmol) was added. Stirring was continued at -75 °C for 2 h, then at 0 °C for 8 h before the reaction was quenched by addition of water. The precipitates were filtered off (washed with diethyl ether) and the filtrate/washings was washed with brine, dried over Na2SO4. After removal of the solvent, the residue was chromatographed (eluting with 6:1 hexanes/EtOAc) to afford 6b as a pale yellow oil (1.07 g, 56.5%): 1H NMR δ 7.40-7.22 (m, 5H), 5.36 (m, 1H), 4.50 (dq, J ) 3.0, 6.9 Hz, 1H), 3.94 (m, 1H), 3.41 (dd, J ) 6.4, 11.3 Hz, 1H), 3.23 (dd, J ) 3.8, 13.2 Hz, 1H), 2.29 (d, J ) 11.5 Hz, 1H), 2.64 (OH, 1H), 1.40-1.20 (m, 10H), 1.26 (d, J ) 8.6 Hz, 3H), 0.89 (t, J ) 6.7 HZ, 3H); IR (film) 3400, 1695, 1604, 1585, 1496, 1455, 1342, 1262 cm-1; MS m/z 379 (M+, 1.2), 378 (2.0), 346 (12.3), 332 (17.9), 276 (9.5), 224 (40), 210 (57), 191 (100), 118 (52), 81 (99); [R]19D +186 (c 1.24, CHCl3); HRMS calcd for C20H29NO2S2 379.1640, found 379.1666. (2R,3R)-2-Methylnonane-1,3-diol51 ((R,R)-7). Method A (Reduction of 6a). A freshly prepared solution of NaBH4 (540 mg, 14.2 mmol) in cold water (4 mL) was added dropwise to a solution of 6a (1.23 g, 3.5 mmol) in THF (10 mL) with concurrent gas (H2) evolution. The mixture was then stirred at room temperature until TLC showed full consumption of the starting material. Excess hydride was carefully destroyed by dropwise addition of 1 N HCl with cooling (ice-water bath). The mixture was concentrated on a rotary evaporator and the residue was partitioned between water and diethyl ether. The ethereal phase was washed with brine and dried over Na2SO4. Column chromatography (eluting with 3:1 ether/hexanes) gave the diol (R,R)-7 as a colorless oil (490 mg, 79.4%): 1H NMR δ 3.84 (br m, 1H), 3.73 (br t, J ) 4.7 Hz, 2H), 2.20 (br s, 1H), 2.09 (br s, 1H), 1.80 (m, 1H), 1.57-1.40 (m, 3H), 1.401.20 (m, 7H), 0.93 (d, J ) 5.8 Hz, 3H), 0.90 (t, J ) 6.6 Hz, 3H); IR (film) 3351 cm-1; MS m/z 157 (M+ - 17, 4.3), 139 (1.2), 126 (0.7), 115 (32), 97 (100), 89 (34), 71 (34), 55 (91); [R]19D +4.3 (c 1.18, CHCl3). Method B (Reduction of 6b). NaBH4 (400 mg, 10.5 mmol) was added to a stirred solution of 6b (1.0 g, 2.6 mmol) in EtOH (99.5%, 25 mL). After stirring at room temperature for 1 h, when TLC showed full consumption of the starting material, the excess hydride was carefully destroyed by dropwise addition of 1 N HCl with cooling (ice-water bath). Solvents were removed by rotary evaporation, and the residue was extracted with diethyl ether (3 × 25 mL), washed with 1 N NaOH, water, and brine in turn, dried over Na2SO4, and chromatographed (eluting with 3:1 ether/hexanes) to give the diol (R,R)-7 as a colorless oil (390 mg, 85%). (2R,3R)-3-Hydroxy-2-methylnonanyl Tosylate ((R,R)8). A solution of diol (R,R)-7 (409 mg, 2.3 mmol), Et3N (0.67 mL, 5.6 mmol), p-TsCl (658 mg, 3.45 mmol), and a catalytic (51) Racemic diol 7 has been known, see: (a) Marshall, J. A.; Wang, X. J. J. Org. Chem. 1992, 57, 1242-1252. (b) Kobayashi, S.; Hachiya, I.; Yasuda, M. Tetrahedron Lett. 1996, 37, 5569-5572. (c) Kalve, I.; Svarcs, E.; Timotheus, H.; Kaerd, A. Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 1982, 605-608; Chem. Abstr. 1983, 98, 23028. (d) Chong, J.; Cyr, D. R.; Mar, Eduardo K. Tetrahedron Lett. 1987, 28, 50095012.

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amount of DMAP (20 mg) in dry CH2Cl2 (23 mL) was stirred at ambient temperature for 24 h. The reaction mixture was then diluted with diethyl ether (50 mL), washed with water and brine, and dried over Na2SO4. The drying agent was filtered off, and solvents were removed on a rotary evaporator to give an oily residue, which was subjected to column chromatography (eluting with 1:4 EtOAc/hexanes) to yield the monotosylate (R,R)-8 as a colorless oil (650 mg, 84.3%, along with 52 mg of unreacted diol): [R]19D +1.55 (c 3.89, CHCl3); 1 H NMR δ 7.81 (d, J ) 8.2 Hz, 2H), 7.36 (d, J ) 8.2 Hz, 2H), 4.09 (dd, J ) 8.0, 9.6 Hz, 1H), 3.90 (dd, J ) 6.1, 9.6 Hz, 1H), 3.70 (m, 1H), 2.46 (s, 3H), 1.91 (m, 1H), 1.55-1.20 (m, 10H), 0.91 (t, J ) 6.0 Hz, 3H), 0.89 (d, J ) 7.5 Hz, 3H); IR (film) 3554, 1599, 1466, 1359, 1189 cm-1; MS m/z 287 (M+ - 41, 3.4), 243 (1.1), 216 (3.2), 173 (100), 155 (17.5), 139 (6.7), 115 (8.1), 97 (15), 91 (40). (3R,4R)-4-Hydroxy-3-methyldecanenitrile ((R,R)-9). NaCN (980 mg, 10 mol equiv) was added to a solution of the tosylate (R,R)-8 (560 mg, 1.7 mmol) in DMSO (5.0 mL) containing a catalytic amount of NaI (26 mg). The mixture was stirred at 60 °C overnight before being diluted with water and extracted with diethyl ether (3 × 50 mL). The combined ethereal phases were washed with brine and dried over Na2SO4. The drying agent was filtered off, and solvents were removed on a rotary evaporator to give the nitrile (R,R)-9 as a colorless oil (280 mg, 89.6%): 1H NMR δ 3.63 (m, 1H), 2.49 (dd, J ) 6.9, 16.8 Hz, 1H), 2.31 (dd, J ) 7.7, 16.7 Hz, 1H), 1.96 (m, 1H), 1.65 (br d, J ) 4.7 Hz, OH), 1.50-1.20 (m, 10H), 1.04 (d, J ) 6.6 Hz, 3H), 0.89 (t, J ) 6.8 Hz, 3H); IR (film) 3457, 2251 cm-1; MS m/z 166 (M+ - 17, 5.9), 115 (13), 97 (73), 69 (77), 55 (100); [R]19D +9.4 (c 0.72, CHCl3); HRMS calcd for C11H21NO 186.1623, found 186.1631. (4R,5R)-5-Hexyl-4-methyldihydrofuran-2-one ((R,R)-1). The crude nitrile (R,R)-9 (130 mg, 0.71 mmol) from the above step (without chromatographic purification) was directly dissolved in EtOH (5.0 mL) and treated with 2 N NaOH (1 mL) at reflux for 8 h. Solvents were removed on a rotary evaporator. To the residue were added THF (10 mL) and (with cooling on ice-water bath) aqueous H2SO4 (0.73 M, ca. 2 mL) until pH ) 1-2. The mixture was stirred at ambient temperature (10 °C) overnight before being diluted with diethyl ether, washed with aqueous NaHCO3, water, and brine, and dried over Na2SO4. After removal of the drying agent and solvents, column chromatography of the residue on silica gel (eluting with 1:4 EtOAc/hexanes) gave (R,R)-1 as a fragrant colorless oil (110 mg, 84.1% over two steps): [R]12D +56.7 (c 2.47, CHCl3) (lit.8 [R]22D +59.8 (c 0.40, CHCl3)); 1H NMR δ 4.42 (m, 1H), 2.63 (dd, J ) 7.8, 16.8 Hz, 1H), 2.56 (m, 1H), 2.16 (dd, J ) 3.7, 16.8 Hz, 1H), 1.70-1.20 (m, 10H), 0.98 (d, J ) 7.1 Hz, 3H), 0.86 (t, J ) 6.8 Hz, 3H); IR (film) 1779 cm-1; MS m/z 142 (M+ - 42, 14), 105 (10), 92 (28), 91 (40), 86 (23), 83 (15), 69 (28), 57 (100). (2R)-4-Phenyl-3-((2R,3S)-3-hydroxy-2-methylnonanoyl)oxazolidin-2-one (11). The procedure was the same as that for preparing 6a, except with 10 in place of 4a: yield 79.3%; [R]14D -70.6 (c 0.89, CHCl3); 1H NMR δ 7.40-7.20 (m, 5H), 5.46 (dd, J ) 4.0, 8.7 Hz, 1H), 4.72 (t, J ) 8.8 Hz, 1H), 4.27 (dd, J ) 4.0, 8.9 Hz, 1H), 3.94 (m, 1H), 3.82 (m, 1H), 2.77 (br s, 1H), 1.65-1.20 (m, 10H), 1.17 (d, J ) 7.1 Hz, 3H), 0.89 (br t, J ) 6.8 Hz, 3H); IR (film) 3533, 1783, 1698 cm-1; MS m/z 334 (M + 1), 316 (49), 219 (47), 164 (62), 120 (49), 104 (100); HRMS calcd for C19H26NO3 (M - 17) 316.1913, found 316.1921. (2S,3S)-3-Hydroxy-2-methylnonanyl Tosylate ((S,S)-8). The reduction of 11 (79.7% yield) followed the same procedure for that of 6a, and tosylation of (S,S)-7 used the same procedure as that for preparing (R,R)-8: yield 79.9%; [R]13D ) -2.0 (c 3.75, CHCl3); 1H NMR δ 7.81 (d, J ) 8.1 Hz, 2H), 7.36 (d, J ) 8.1 Hz, 2H), 4.09 (dd, J ) 7.7, 9.6 Hz, 1H), 3.90 (dd, J ) 6.0, 9.6 Hz, 1H), 3.70 (m, 1H), 2.46 (s, 3H), 1.90 (m, 1H), 1.55-1.20 (m, 10H), 0.89 (t, J ) 6.0 Hz, 3H), 0.86 (d, J ) 6.9 Hz, 3H); IR (film) 3351, 1598, 1494, 1357, 1176 cm-1; MS m/z 287 (M+ - 41, 4.3), 243 (1.5), 216 (3.6), 173 (100), 155 (22.6), 139 (18.3), 115 (7.9), 97 (17.4), 91 (43.7).

Wu et al. (3S,4S)-4-Hydroxy-3-methyldecanenitrile ((S,S)-9). The procedure was the same as that for preparing (R,R)-9: yield 89.0%; [R]26D -8.79 (c 1.03, CHCl3); 1H NMR δ 3.66 (m, 1H), 2.49 (dd, J ) 6.9, 16.8 Hz, 1H), 2.31 (dd, J ) 7.4, 16.8 Hz, 1H), 1.95 (m, 1H), 1.69 (br d, J ) 4.9 Hz, 1H, OH), 1.50-1.20 (m, 10H), 1.03 (d, J ) 6.9 Hz, 3H), 0.88 (t, J ) 6.7 Hz, 3H); IR (film) 3352, 2249 cm-1; MS m/z 184 (M + 1, 7), 166 (61), 115 (9), 97 (58), 69 (65), 55 (100); HRMS calcd for C11H21NO 183.1623, found 183.1593. (4S,5S)-5-Hexyl-4-methyldihydrofuran-2-one ((S,S)-1). The procedure was the same as that for preparing (R,R)-1: yield 82.9% (from (S,S)-9); [R]26D -56.1 (c 3.56, CHCl3) (lit.8 [R]23D -57.6 (c 1.06, CHCl3)); 1H NMR δ 4.45 (br quintet, J ≈ 4.8 Hz, 1H), 2.70 (dd, J ) 7.8, 17.0 Hz, 1H), 2.60 (m, 1H), 2.20 (dd, J ) 3.7, 17 Hz, 1H), 1.75-1.20 (m, 10H), 1.02 (d, J ) 6.9 Hz, 3H), 0.90 (t, J ) 6.6 Hz, 3H); IR (film) 1774 cm-1; MS m/z 185 (M + 1, 2), 142 (6), 124 (7), 115 (9), 99 (100). (2S)-4-Benzyl-3-((2S,3R)-3-hydroxy-2-methyloctanoyl)oxazolidin-2-one (14). The procedure was the same as that for preparing 6a: yield 74.5%; [R]14D +51.6 (c 1.8, CHCl3); 1H NMR δ 7.40-7.20 (m, 5H), 4.72 (m, 1H), 4.28-4.18 (m, 2H), 3.96 (m, 1H), 3.78 (dq, J ) 1.9, 7.1 Hz, 1H), 3.27 (dd, J ) 3.3, 13.5 Hz, 1H), 2.85 (br s, 1H, OH), 2.80 (dd, J ) 9.3, 13.5 Hz, 1H), 1.60-1.20 (m, 8H), 1.27 (d, J ) 7.1 Hz, 3H), 0.90 (t, J ) 6.5 Hz, 3H); IR (film) 3523, 1782 cm-1; MS m/z 333 (M+, 0.9), 316 (3), 289 (0.5), 262 (1), 244 (14), 233 (17), 200 (6), 178 (16), 157 (3), 142 (23), 134 (11.5), 117 (17), 91 (48), 57 (100); HRMS calcd for C19H25NO3 (M+ - H2O) 315.1834, found 315.1833. (2S)-4-Benzyl-3-[(2S,3R)-3-(tert-butylcarbonyloxy)-2methyloctanoyl]oxazolidin-2-one (17). To a solution of 14 (666 mg, 2.0 mmol) in dry CH2Cl2 (10 mL) were added a catalytic amount of 4-(dimethylamino)pyridine (DMAP, ca. 20 mg), NEt3 (1.0 mL, 7.0 mmol), and, with cooling (ice-water bath), pivaloyl chloride (0.5 mL, 4.0 mmol). The mixture was stirred at ambient temperature (ca. 8 °C) for 48 h before being diluted with ether, washed with water and brine, and dried over anhydrous Na2SO4. The oily residue after removal of drying agent and solvents was chromatographed (eluting with 1:8 EtOAc/hexanes) to give 17 as a colorless oil (800 mg, 95.9 yield): [R]14D +40.1 (c 4.78, CHCl3); 1H NMR δ 7.40-7.18 (m, 5H), 5.24 (m, 1H), 4.67 (t, J ) 10.3 Hz, 0.6H), 4.51 (m, 0.4H), 4.40 (dd, J ) 4.2, 11.0 Hz, 0.6H), 4.30 (t, J ) 8.8 Hz, 0.4H), 4.15 (dd, J ) 2.2, 8.8 Hz, 0.4H), 3.95 (dq, J ) 3.3, 7.1 Hz, 0.4H), 3.82-3.60 (lump, 0.6H), 3.25-3.16 (m, 1H), 3.06 (dd, J ) 14, 6.3 Hz, 0.6H), 2.77 (dd, J ) 13, 9.8 Hz, 0.4H), 2.58-2.48 (lump, 0.6H), 1.78-1.10 (m, including several s, 17H altogether), 1.02 (d, J ) 7.4 Hz, 3H), 0.89 (t, J ) 7.0 Hz, 3H); IR (film) 1776, 1703 cm-1; MS m/z 417 (M+, 1.6), 316 (21.3), 315 (23.5), 244 (26.2), 241 (14.7), 218 (24.6), 200 (43.7), 178 (14.5), 139 (77.4), 117 (28.0), 91 (27.5), 85 (42.4), 57 (100); HRMS calcd for C24H35NO5 417.2515, found 417.2502. (2R,3R)-3-(tert-Butylcarbonyloxy)-2-methyloctan-1ol (18). To a solution of 17 (660 mg, 1.58 mmol) in a 1:2 (v/v) mixture of THF and EtOH (10 mL) containing CaCl2 (10 mmol) was added NaBH4 (308 mg, 6.32 mmol). The mixture was stirred at ambient temperature (1-4 °C) overnight. When TLC showed the disappearance of the starting 17, the excess hydride was destroyed with dilute HCl and the reaction mixture was extracted with ether three times. The combined ethereal phases were washed with water and brine and then dried over anhydrous Na2SO4. The oily residue after removal of drying agent and solvents was chromatographed (eluting with 1:5 EtOAc/hexanes) to afford 18 as a colorless oil (110 mg, 28.5% yield): [R]14D +16.7 (c 1.07, CHCl3); 1H NMR δ 5.09 (m, 1H), 3.44 (m, 1H), 2.96 (m, 1H), 1.88 (m, 1H), 1.72 (m, 1H), 1.55-1.20 (m, 8H), 1.22 (s, 9H), 0.89 (t, J ) 6.4 Hz, 3H), 0.82 (d, J ) 6.9 Hz, 3H); IR (film) 3445, 1735 cm-1; MS m/z 227 (M+ - 17, 79.8), 177 (3.9), 159 (1.9), 143 (40.7), 125 (61.3), 103 (34.3), 85 (43.0), 57 (100); HRMS calcd for C14H27O2 (M+ - 17) 227.2011, found 227.2040. (2S)-4-Benzyl-3-[(2S,3R)-3-(tert-butyldimethylsilanyloxy)-2-methyloctanoyl]oxazolidin-2-one (19). With cooling (ice-water bath) and stirring, TBSOTf (1.7 mL, ca. 7.4 mmol) was added to a mixture of 14 (950 mg, 2.8 mmol) and 2,6lutidine (1.4 mL, 12 mmol) in dry CH2Cl2 (30 mL). The bath

Synthesis of Natural Fragrant Molecules was removed and the mixture was stirred at ambient temperature until the starting 14 was fully consumed, as shown by TLC. The mixture was diluted with diethyl ether, washed with water and brine, and dried over Na2SO4. After removal of the drying agent and solvents, column chromatography of the residue (eluting with 1:8 diethyl ether/hexanes) gave 19 as a colorless oil, which solidified on standing for a long time (1.18 g, 94.1%): mp 61-62 °C; [R]14D +52.8 (c 1.3, CHCl3);1H NMR δ 7.39-7.19 (m, 5H), 4.61 (m, 1H), 4.20-4.14 (m, 2H), 4.00 (q, J ) 5.4 Hz, 1H), 3.87 (m, 1H), 3.31 (dd, J ) 13, 3.2 Hz, 1H), 2.78 (dd, J ) 13, 9.7 Hz, 1H), 1.60-1.20 (m, 8H), 0.91-0.80 (m, 4 × CH3), 0.05 (s, 3H), 0.00 (s, 3H); IR (film) 1765, 1702 cm-1; MS m/z 448 (M+, 4), 432 (9), 390 (71), 316 (29), 290 (100), 250 (10), 213 (20), 199 (11), 139 (18), 117 (12), 91 (24). Anal. Calcd for C25H41NO4Si: C, 67.07; H, 9.23; N, 3.13. Found: C, 67.02; H, 9.27; N, 2.99. 3-(tert-Butyldimethylsilanyloxy)-2-methyloctan-1-ol (20). With cooling (ice-water bather) and stirring, LiBH4 (2 M, in THF, ca. 0.6 mL) was added dropwise via a syringe into a solution of 19 (520 mg, 1.2 mmol) in dry diethyl ether (20 mL). The bath then was allowed to warm gradually to ambient temperature and the stirring was continued overnight. Excess hydride was destroyed (with cooling on a ice-water bath) by dropwise addition of 1 N NaOH. The phases were separated. The aqueous phase was further extracted with diethyl ether. The organic phases were combined, washed with water and brine, and dried over Na2SO4. After removal of the drying agent and solvents, column chromatography of the residue (eluting with 1:5 diethyl ether/hexanes) gave 20 as a colorless oil (220 mg, 69%): [R]14D +4.2 (c 2.2, CHCl3);1H NMR δ 3.803.66 (m, 2H), 3.52 (m, 1H), 2.64 (dd, J ) 6.6, 3.6 Hz, 1H, OH), 1.97 (m, 1H), 1.80-1.20 (m, 8H), 0.90 (s, 9H), 0.82, (d, J ) 6.9 Hz, 3H), 0.11 (s, 3H), 0.08 (s, 3H); IR (film) 3357 cm-1; MS m/z 275 (M, 3), 259 (7), 257 (6), 217 (39), 215 (34), 203 (8), 175 (26), 159 (7), 133 (15), 119 (20), 105 (24), 83 (29), 75 (100); HRMS calcd for C11H25O2Si (M+ - tBu) 217.1624, found 217.1616. (4R,5R)-5-(tert-Butyldimethylsilanyloxy)-4-methyldecanoic Acid Ethyl Ester (22). To a solution of 20 (388 mg, 1.4 mmol) in DMSO (10 mL) stirred at ambient temperature was added IBX (588 mg, 2.1 mmol). Stirring was continued until TLC showed disappearance of 20 (ca. 8 h). Water (ca. 10 mL) was added. The white precipitates (o-iodobenzoic acid) were filtered off with suction (washing with diethyl ether). The two phases of the filtrate/washings were separated. The aqueous layer was further extracted with diethyl ether. The combined organic phases were washed with water and brine and dried over Na2SO4. After removal of the drying agent and solvents, the crude aldehyde was directly dissolved in THF (10 mL) and treated with Ph3PdCHCO2Et (740 mg, 2.1 mmol) at reflux until TLC showed disappearance of the aldehyde (ca. 5 h). Column chromatography (eluting with 1:25 diethyl ether/ hexanes) gave the Wittig product as a colorless oil (452 mg, a mixture of cis/trans-isomers, 93.3%), which was dissolved in MeOH (5 mL) containing 10% Pd/C (10 mg) and stirred under hydrogen gas (1 atm) at ambient temperature until completion of the reaction. The catalyst was filtered off, and the filtrate/ washings were concentrated and chromatographed (eluting with 1:25 diethyl ether/hexanes) to give 22 as a colorless oil (201 mg, 95.6%): [R]14D +13.9 (c 1.0, CHCl3); 1H NMR δ 4.13 (q, J ) 7.1 Hz, 2H), 3.53 (dt, J ) 3.3, 6.0 Hz, 1H), 2.30 (m, 2H), 1.80 (m, 1H), 1.60-1.20 (m, 9H), 1.26 (t, J ) 7.1 Hz, 3H), 0.89 (s and t, J ) 5.8 Hz, 12 H altogether), 0.84 (d, J ) 6.6 Hz, 3H), 0.04 (s, 6H); IR (film) 1740, 1736 cm-1; MS m/z 329 (M - 15, 21), 299 (18), 287 (100), 273 (14), 255 (9), 241 (53), 215 (65), 213 (48), 73 (54); HRMS calcd for C15H31O3Si (M+ t Bu) 287.2042, found 287.2070. (5R,6R)-5-Methyl-6-pentyltetrahydropyran-2-one11 ((R,R)-2). To a solution of 22 (358 mg, 1.04 mmol) in THF (10 mL) was added 0.73 M H2SO4 (1.0 mL). The mixture was then heated to reflux until the starting material disappeared on TLC. After cooling to ambient temperature, the reaction mixture was diluted with diethyl ether, washed with aqueous NaHCO3, water, and brine, and dried over Na2SO4. After removal of the drying agent and solvents, column chromatog-

J. Org. Chem., Vol. 67, No. 11, 2002 3809 raphy of the residue (eluting with 1:4 EtOAc/hexanes) gave (R,R)-211 as a colorless oil with a pleasant fragrance (128 mg, 66.8%). (2R)-3-((2R,3S)-3-Hydroxy-2-methyloctanoyl)-4-phenyloxazolidin-2-one (23). The procedure was the same as that for preparing 6a, except using 10 and 12 in place of 4a and 5, respectively: yield 81.5%; mp 86-87 °C; [R]14D -77.5 (c 0.93, CHCl3); 1H NMR δ 7.45-7.22 (m, 5H), 5.47 (dd, J ) 8.7, 4.0 Hz, 1H), 4.72 (t, J ) 8.9 Hz, 1H), 4.26 (dd, J ) 4.0, 8.9 Hz, 1H), 3.94 (m, 1H), 3.81 (dd, J ) 7.1, 2.5 Hz, 1H), 2.77 (br s, 1H), 1.62-1.20 (m, 8H), 1.17 (d, J ) 7.1 Hz, 3H), 0.90 (t, J ) 6.5 Hz, 3H); IR 3537, 1785, 1756 cm-1; MS m/z 302 (M - 17, 50), 148 (6), 219 (54), 164 (60), 120 (48), 104 (100); Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.49; H, 7.90; N, 4.18. (2S,3S)-2-Methyloctane-1,3-diol24 ((S,S)-13). The procedure was the same as that for reduction of 17 (to 18) with NaBH4/THF/EtOH/CaCl2: yield 72.5%; [R]14D -6.0 (c 3.28, CHCl3); 1H NMR δ 3.84 (br m, 1H), 3.73 (br m, 2H), 2.28 (br m, 1H), 2.18 (br m, 1H), 1.78 (m, 1H), 1.60-1.40 (m, 3H), 1.401.20 (m, 5H), 0.93 (d, J ) 7.1 Hz, 3H), 0.90 (t, J ) 6.7 Hz, 3H); IR (film) 3354 cm-1; MS m/z 159 (M+ - 1, 9), 81 (52), 69 (100), 55 (28). (2S,3S)-3-Hydroxy-2-methyloctanyl Tosylate (24). The procedure was the same as that for preparing (R,R)-8: yield 85.8%; [R]14D -38.8 (c 0.76, CHCl3); 1H NMR δ 7.81 (d, J ) 8.0 Hz, 2H), 7.36 (d, J ) 8.0 Hz, 2H), 4.08 (dd, J ) 8.0, 9.6 Hz, 1H), 3.90 (dd, J ) 6.0, 9.6 Hz, 1H), 3.70 (m, 1H), 2.46 (s, 3H), 1.90 (m, 1H), 1.52-1.20 (m, 8H), 0.90 (t, J ) 6.3 Hz, 3H), 0.85 (d, J ) 6.9 Hz, 3H); IR (film) 3551, 1598, 1493, 1356, 1176 cm-1; MS m/z 315 (M+ + 1, 9), 297 (7), 173 (100), 125 (98), 91 (57). (2S,3S)-3-(2-Ethoxycarbonylacetoxy)-2-methyloctanyl Tosylate (25). 1,3-Dicyclohexylcarbodiimide (DCC; 500 mg, 1.66 mmol) was added to a solution of 24 (260 mg, 0.83 mmol) and EtO2CCH2CO2H (219 mg, 1.66 mmol) in dry CH2Cl2 (10 mL) stirred at 0 °C. The stirring was then continued at ambient temperature (14-19 °C) until TLC showed the disappearance of 24. Solids were filtered off (washing the filter cake with ether) and the filtrate was concentrated to give a crude mixture, which on column chromatography (eluting with 1:4 EtOAc/hexanes) gave 25 as a colorless oil (209 mg, 91.7% yield): [R]13D 0.0 (c 1.84, CHCl3); 1H NMR δ 7.81 (d, J ) 8.2 Hz, 2H), 7.36 (d, J ) 8.2 Hz, 2H), 4.96 (m, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 3.93 (m, 2H), 3.30 (s, 2H), 2.46 (s, 3H), 2.08 (m, 1H), 1.60-1.40 (m, 2H), 1.32-1.18 (m, 6H), 1.27 (t, J ) 7.1 Hz, 3H), 0.94 (d, J ) 7.1 Hz, 3H), 0.88 (t, J ) 6.9 Hz, 3H); MS m/z 429 (M+ + 1, 2.4), 297 (8), 257 (15), 172 (21), 155 (41), 133 (58), 125 (76), 115 (100); IR (film) 1736, 1365, 1189 cm-1; MS m/z 429(M+ + 1, 2), 297 (8), 125 (76), 115 (100), 91 (57). (2R,3S)-2-Methyl-3-ethoxycarbonylacetoxyiodooctane (28). A mixture of 25 (254 mg, 0.59 mmol) and NaI (445 mg, 3.0 mmol) in acetone (5 mL) was stirred at refluxing temperature for 3 h, when TLC showed the disappearance of the starting material. Acetone was removed by rotary evaporation. The residue was mixed with water (10 mL) and extracted with ether (4 × 20 mL). The combined extracts were washed with brine, dried over Na2SO4, and chromatographed (1:10 EtOAc/ hexanes) to give iodide 28 as a colorless oil (209 mg, 91.7% yield): [R]9D -2.3 (c 1.15, CHCl3); 1H NMR δ 5.10 (m, 1H), 4.21 (q, J ) 7.1 Hz, 2H), 3.37 (s, 2H), 3.26 (dd, J ) 5.5, 9.9 Hz, 1H), 3.04 (dd, J ) 7.7, 9.9, 1H), 1.95 (m, 1H), 1.70-1.20 (m, 8H), 1.29 (t, J ) 7.1 Hz, 3H), 1.06 (d, J ) 6.6 Hz, 3H), 0.89 (t, J ) 6.9 Hz, 3H); MS m/z 384 (M+, 0.38), 257 (88), 143 (93), 43 (100); IR (film) 1736, 1327, 1151 cm-1; HRMS calcd for C14H25O4 (M+ - 127) 257.1753, found 257.1754. (2R)-3-((2R,3S)-3-Benzyloxymethoxy-2-methyloctanoyl)4-phenyloxazolidin-2-one (29). To a solution of 23 (400 mg, 1.25 mmol) in dry CH2Cl2 (12 mL) stirred under argon were added BnOCH2Cl (0.80 mL, 3.75 mmol) and iPrNEt2 (1.0 mL, 5.75 mmol). The mixture was stirred at 25 °C for 48 h before being diluted with ether (50 mL), washed with water and brine, and dried over Na2SO4. After removal of the solvent, the residual material was chromatographed (1:7 EtOAc/ hexanes) to give 29 as a colorless oil, which solidified on

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standing (510 mg, 92.6% yield): mp 58-59 °C; [R]14D +65.5° (c 1.46, CHCl3); 1H NMR δ 7.40-7.25 (m, 8H), 7.20-7.15 (m, 2H), 5.04 (dd, J ) 2.9, 8.3 Hz, 1 H), 4.78 (s, 2H), 4.56 (d, J ) 11.8 Hz, 1H), 4.56 (d, J ) 11.8 Hz, 1H), 4.37 (t, J ) 8.4 Hz, 1H), 4.09 (dd, J ) 3.1, 8.8 Hz, 1H), 4.00-3.93 (m, 2H), 1.631.23 (m, 8H), 1.13 (d, J ) 7.1 Hz, 3H), 0.89 (t, J ) 6.6 Hz, 3H); MS m/z 410 (M+ - 29, 1.4), 392 (3.5), 332 (63.4), 302 (100), 246 (3.6), 91 (19.5); IR (film) 1779, 1705, 1197 cm-1; HRMS calcd for C19H26O4 (M+ - 107) 332.1862, found 332.1861. (2S,3S)-3-(Benzyloxymethoxy)-2-methyloctan-1-ol (30). Using the same procedure for converting 17 to 18, compound 29 (200 mg, 0.456 mmol) gave 30 as a colorless oil (106 mg, 83.1% yield): [R]14D +46.3° (c 0.76, CHCl3); 1H NMR δ 7.25 (m, 5H), 4.83 (d, J ) 6.8 Hz, 1H), 4.78 (d, J ) 7.0 Hz, 1H), 4.70 (d, J ) 11.8 Hz, 1H), 4.61 (d, J ) 11.8 Hz, 1H), 3.803.75 (m, 1H), 3.67 (ddd, J ) 4.5, 8.8, 11.0 Hz, 1H), 3.54 (ddd, J ) 5.3, 7.1, 11.0 Hz, 1H), 2.64 (dd, J ) 4.9, 7.3 Hz, 1H), 2.051.90 (m, 1H), 1.63-1.20 (m, 8H), 0.89 (t, J ) 6.6 Hz, 3H), 0.85 (d, J ) 7.1 Hz, 3H); IR (film) 3436 cm-1; MS m/z 263 (M+ 17, 1.7), 173 (5.9), 143 (5.5), 108 (7.6), 91 (100). HRMS calcd for C10H21O2 (M+ - 107): 173.1542, found 173.1540. (5S,6S)-5-Methyl-6-pentyltetrahydropyran-2-one ((S,S)2). IBX (660 mg, 2.36 mmol) was added to a solution of 30 (330 mg, 1.18 mmol) in DMSO (7.5 mL) stirred at 25 °C. The stirring was continued at the same temperature until TLC showed complete consumption of 30. Water (25 mL) was added. The white precipitates were filtered off (washed with ether). The filtrate/washings were extracted with ether (4 × 25 mL), and the combined organic layers were washed with aq NaHCO3 and brine and dried over Na2SO4. To the residue (crude aldehyde), after removal of the solvent, were added dry THF (15 mL) and Ph3PdCHCO2Et (520 mg, 1.50 mmol). The mixture was heated to reflux with stirring until TLC showed disappearance of the starting aldehyde. The solvent was removed by rotary evaporation, and the residue was chromatographed (1:15 EtOAc/hexanes) to afford the Wittig prod-

Wu et al. uct as a colorless oil (389 mg, 87.8% yield over two steps). This oil was then dissolved in methanol (6.0 mL) and hydrogenated at ambient temperature (25-35 °C) at atmospheric pressure in the presence of 10% Pd on charcoal (80 mg). The catalyst was filtered off with the aid of Florisil (washed with ether), and the filtrate/washings were concentrated to dryness on a rotary evaporator. THF (5.0 mL) and 2 N H2SO4 (1.0 mL) were introduced. The solution was stirred at the ambient temperature overnight. The reaction mixture was evaporated to dryness by rotary evaporation. To the residue was added saturated aq NaHCO3 (ca. 25 mL) before being extracted with ether (4 × 25 mL). The combined extracts were washed with water and brine, dried over Na2SO4, and chromatographed (1:4 EtOAc/hexanes) to give (S,S)-2 as a fragrant liquid (144 mg, 65.4% over two steps): [R]14D -63.5° (c 1.28, CHCl3); 1H NMR δ 4.32-4.26 (m, 1H), 2.54 (bt, J ) 7.3 Hz, 2H), 2.30-1.95 (m, 2H), 1.78-1.20 (m, 8H), 0.97 (d, J ) 6.9 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H); MS m/e 185 (M+ + 1, 100), 167 (M+ - 17, 58), 149 (16), 41 (7); IR (film) 1735 cm-1.

Acknowledgment. This work was supported by the National Natural Science Foundation of China (20025207, 29832020), the Major State Basic Research Development Program (G2000077502), the Chinese Academy of Sciences (CAS “Knowledge Innovation” Project), and the Life Science Special Fund of CAS Supported by the Ministry of Finance (Stz 98-3-03). Supporting Information Available: 1H NMR spectra of compounds 6a, 6b, 7, (R,R)-8, (R,R)-9, (R,R)-1, 11, 14, 17, 18, 19, 20, 22, 23, 24, 25, 28, 29, and 30. This material is available free of charge via the Internet at http://pubs. acs.org. JO025540O