Tetrahedron 63 (2007) 8046–8053 Olefination of ketenes for the enantioselective synthesis of allenes via an ylide route Chuan-Ying Li,a Ben-Hu Zhu,b Long-Wu Ye,a Qing Jing,a Xiu-Li Sun,a Yong Tanga,* and Qi Shenb,* aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China bSchool of Chemistry and Chemical Engineering, Suzhou University, Suzhou 215123, China Received 5 February 2007; revised 14 May 2007; accepted 15 May 2007 Available online 18 May 2007 Abstract—Pseudo-C2-symmetric chiral phosphorus ylide is designed and synthesized for the enantioselective preparation of allenic esters, amides, ketone, and nitrile. Up to 92% ee is achieved. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction phosphorus ylide bearing 10-phenylsulfonylisoborneol re- acted with methylketene to give penta-2,3-dienoic ester In recent years, optically active allenes have been used as with excellent diastereoselectivity.7e versatile chiral building blocks in organic synthesis due to their high reactivity and the unique ability that they can In a previous study on ylide chemistry in organic synthesis,8 transfer the axial chirality to final products efficiently.1 In we were interested in developing asymmetric ylide-medi- addition, allenes are important subunits in a variety of natu- ated synthesis of optically active allenes and communicated ral products and biologically active compounds.2 Thus, the that newly designed chiral phosphorus ylides could react development of synthetic methodology for enantiomerically with ketenes to afford enantiomerically enriched allenic es- enriched allenes is of great interest and several strategies ters.9 Recently, we modified the chiral ylides and found that have been developed. One of the most commonly used the enantioselectivities were further improved in some cases. approaches is substitution or isomerization of chiral propar- We also extended this method to the synthesis of chiral al- gylic derivatives.3 Asymmetric catalysis4 and kinetic resolu- lenic ketones, amides, nitrile, and 4-monosubstituted allenic tion5 also provide accesses to optically active allenes. esters. In this paper, we wish to report the synthesis and the Phosphorus ylides are good reagents for the synthesis of modification of the phosphorus ylides, the scope, and limita- allenes by olefination of ketenes,6 but only a few examples tion in detail. were reported for its asymmetric version.7 The first example was described by Bestmann in 1964,7a in which a stabilized phosphorus ylide containing a chiral alcohol was docu- 2. Results and discussion mented to react with acyl chloride to afford optically active allenes. Later on, they reported a reaction of racemic phos- 2.1. Design and synthesis of phosphorus salts phorus ylides with enantiomerically enriched acyl chloride and found that the resulting chiral allenes were obtained In a previous study, we demonstrated that chiral telluronium with up to 31% ee.7b Pure ketenes were first used as sub- salts 1 could react smoothly with a,b-unsaturated ketones, strates by Musierowicz and his co-workers in the enantio- esters, and imines to afford optically active vinylcyclopro- selective synthesis of allenes. They found that the reaction pane derivatives with high diastereoselectivities and enan- between chiral phosphinate ester and ketenes afforded tioselectivities.8c,f It is envisioned that phosphonium salt 2 allenes with 23% ee.7c Tanaka et al. described that optically with a similar structure is a potential reagent for the enantio- active 4,4-disubstituted allenic esters could be prepared with selective synthesis of allenes (Fig. 1). One attractive advan- binol-derived HWE reagents in 21–71% yields with 23–89% tage of salt 2 is its high flexibility since substituents R1,R2, ee’s.7d Melo and his co-workers documented that a and R3 are readily variable. Another advantage is that the chiral phosphine oxide produced in the reaction is possible * Corresponding authors. E-mail: [email protected] to be recovered and reused. 0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2007.05.053 C.-Y. Li et al. / Tetrahedron 63 (2007) 8046–8053 8047 1 Br R with methanesulfonyl chloride, followed by reaction with R2 + dilithium phenylphosphate 7a to afford 6a and 6b, respec- Te CH2CH=CHR P 3 tively. Phosphines 6a and 6b reacted with the corresponding BPh R 4 R1 bromides to give the desired phosphonium salts 2a, 2b, and 1 2 2c, respectively. Figure 1. Design of phosphorus salt. 2.2. Effects of reaction conditions on the asymmetric olefination Phosphorus salts 2a–2c are readily prepared from the corre- Initially, the reaction of phosphonium salt 2b with phenyl sponding diketones. As shown in Scheme 1, hexane-2,5- ethyl ketene 9a was chosen as a model reaction to optimize dione 3a was reduced by baker’s yeast to the corresponding the reaction conditions. As shown in Table 1, the cation of diol 4a in 60% yield with excellent de and ee.10a And 1,4- the base influenced both the yield and the selectivity diphenylbutane-1,4-dione could be easily reduced by strongly. The base bearing K+ furnished the desired products proline-derived chiral borane10b or by asymmetric hydro- in moderate yields with moderate ee’s (entries 4 and 6). Al- genation10c in gram scale to give the desired diol 4b in though n-BuLi, LiHMDS, and LiTMP gave the allenes with high yield with excellent selectivity. Diols 4a and 4b reacted good enantioselectivities (entries 1, 2, and 5), the yields were O OH OMs 1 condition a or b or c 1 MsCl, Et N 1 R R 3 R1 R R1 R1 CH2Cl2 O OH OMs 3a, R1 = Me 4a, R1 = Me, condition a, 60%, >99% de 5a, R1 = Me, 97% 3b, R1 = Ph 4b, R1 = Ph, condition b, 98%, 99% de, 98% ee 5b, R1 = Ph, 72% condition c, 95%, 90% de, 99% ee R1 R1 PhPLi , 7a BrCH COOR2 O Ph 2 Ph P 2 P THF Et O, 25 °C, 15 h 2 Br 2 R O R1 R1 6a, R1 = Me, 70% 2a, R1 = Me, R2 = Et, 91% 6b, R1 = Ph, 54% 2b, R1 = Ph, R2 = Et, 95% 2c, R1 = Ph, R2 = t-Bu, 94% Scheme 1. Synthesis of phosphonium salts 2a–2c. Condition a: baker’s yeast. Condition b: (2S)-2-(Diphenylhydroxymethyl) pyrrolidine, B(OMe)3,BH3$SMe2, THF. Condition c: RuCl2(R3P)2[(S,S)-DPEN], i-PrOH, t-BuOK, H2. Table 1. Effects of reaction conditions on the asymmetric olefination of ketenes Ph Ph Ph Ph • O O O Ph H Et P Br solvent Et 9a + base P • EtO rt EtO additive EtOOC Ph Ph Ph -78 °C 10a 2b 8b Entry Base Additive Solvent (v/v) Yielda (%) eeb (%) 1 n-BuLi None THF 60 80 2 LiHMDS None THF 67 80 3 NaHMDS None THF 80 81 4 KHMDS None THF 47 70 5 LiTMP None THF 63 79 6 t-BuOK None THF 42 59 7 NaH None THF 73 80 8 NaH NaBr (0 equiv) THF 69 64 9 NaH NaBr (1 equiv) THF 73 80 10 NaH NaBr (2 equiv) THF 56 80 11 NaH LiBr (1 equiv) THF 67 80 12 NaH LiBr (2 equiv) THF 42 81 13 NaH Et3N$HCl (2 equiv) THF 14 70 14 NaH None DME/THF (5/1) 56 64 15 NaH None Ether 26 70 16 NaH None n-Butyl ether 46 39 17 NaH None CH2Cl2 67 56 18 NaH None ClCH2CH2Cl/CH2Cl2 (10/7) 67 52 19 NaH None Toluene 65 50 20 NaH None Hexane 37 60 a Isolated yield. b Determined by chiral HPLC. 8048 C.-Y. Li et al. / Tetrahedron 63 (2007) 8046–8053 only moderate. In our screened conditions, NaHMDS was Table 3. Asymmetric synthesis of allenes 10 from phosphonium salt 2ba Ph H R3 the optimal (entry 3). Ph i, NaHMDS, 25 °C, THF O • P Br R3 R2OOC R4 ‘Salt effects’ were observed in this reaction. Et N$HCl dete- R2O 10 3 Ph ii, • O , -78 °C R2 = Et 2b riorated both the yield and the selectivity greatly (entry 13). R4 9 Addition of NaBr improved the enantioselectivities (entries 8–10). LiBr could also increase the ee but decreased the Entry Ketene 9 (R3/R4) Allene 10 Yieldb (%) eec (%) yield (entries 11 and 12). Solvent effect was also examined. It was found that the reaction proceeded well in toluene and 1 9a (Et/Ph) 10a 80 81 2 9b (Me/Ph) 10b 61 45 dichloromethane (entries 17 and 19). The best result was 3 9c (n-Pr/Ph) 10c 78 80 achieved in THF (entry 7). 4 9d (n-Bu/Ph) 10d 70 64 5 9e (i-Pr/Ph) 10e 76 71 2.3. Effects of phosphonium salts 6 9f (i-Bu/Ph) 10f 71 85 7d 9g (Allyl/Ph) 10g 46 61 8d 9h (3-Butenyl/Ph) 10h 59 65 Having established the optimal reaction conditions, the 9d 9i (Bn/Ph) 10i 51 52 effects of various phosphonium salts were examined. As 10 9j (Et/o-Me–C6H4) 10j 53 25 shown in Table 2, 2a gave the desired allene in moderate 11 9k (Et/p-MeO–C6H4) 10k 78 91 yields and ee’s (entries 1 and 4). Replacement of methyl 12 9l (Et/p-Cl–C6H4) 10l 75 85 a group in 2a with phenyl group improved both the yield Reactions were carried out in THF at À78 C under N2 with 0.2 mmol of and enantioselectivity (entry 1 vs 2 and entry 4 vs 5). salt 2b (0.2 M in THF, 1.0 mL), 0.2 mmol of NaHMDS, and 0.2 mmol of ketene 9.