Principles and Applications of Asymmetric Synthesis

432 APPLICATIONS OF ASYMMETRIC REACTIONS

Scheme 7±55. Reagents and conditions: a: (1) THF, ÿ78 C (93%); (2) TBAF, THF, ÿ78 C (80%). b: m-CPBA, CH2Cl2, room temperature (80%). c: H2, Pd/C, ÿ5 C, EtOH (65%). d: CDI, NaH, DMF (81%). e: l-Selectride, THF, ÿ78 C (93%).

Scheme 7±56. Reagents and conditions: a: PhNTf2, KHMDS, THF, ÿ78 C (98%). b: PPTS, acetone, H2O (96%). c: Ph3PbCH2, THF, ÿ78 to 0 C (77%). d: Pd(PPh3)4, K2CO3, CH3CN, 85 C (49%).

The ®nal stage is to introduce the C-13 hydroxyl group via PCC oxidation of 187 and subsequent reduction of the carbonyl group, and this completes the total synthesis of baccatin III (Scheme 7±58). The synthesized compound is identical to a natural sample of baccatin III in all respects, including optical rotation.

434 APPLICATIONS OF ASYMMETRIC REACTIONS

Scheme 7±60. Reagents and conditions: a: 1.2 eq. of MeMgBr, Et2O, 0 to 25 C, 8 hours, then 0.2 eq. of p-TsOH, benzene, 65 C, 3 hours (70%). b: 2.2 eq. of DIBAL±H, CH2Cl2, ÿ78 to 25 C, 12 hours (92%). c: 1.1 eq. of Ac2O, 1.2 eq. of Et3N, 0.2 eq. of DMAP, CH2Cl2, 0 to 25 C, 1 hour (96%). d: 1.5 eq. of 2-chloroacrylonitrile, 130 C, 72 hours (80%). e: 6.0 eq. of KOH, t-BuOH, 70 C. f: For R ˆ TBS, 1.1 eq. of TBSCl, 1.2 eq. of imidazole, CH2Cl2, 25 C, 2 hours (85%); for R ˆ MEM, 1.2 eq. of MEMCl, 1.3 eq. of (i-Pr)2NEt, CH2Cl2, 25 C, 3 hours (95%). g: 2,4,6-Triisopropylbenzenesulfo- nyl)hydrazine.

Scheme 7±61. Reagents and conditions for conversion from 189 and 190 to 191: 1.4 eq. of 190, 1.4 eq. of PhB(OH)2, C6H6, re¯ux, 48 hours. Then 1.4 eq. of 2,2-dimethyl-1,3- propanediol, 25 C, 1 hour (79% based on 77% conversion of 189).

Scheme 7±62. Reagents and conditions: a: 1.3 eq. of TPSCl, 1.35 eq. of imidazole, DMF, 25 C, 12 hours (92%). b: 1.2 eq. of KH, 1.2 eq. of PhCH2Br, 0.04 eq. of (n- Bu)4NI, Et2O, 25 C, 1 hour (88%). c: 3.0 eq. of LiAlH4, Et2O, 25 C, 12 hours (80%). d: 5.0 eq. of 2,2-dimethoxypropane, 0.05 eq. of CSA, CH2Cl2:Et2O (98:2), 25 C, 7 hours (82%). e: 0.05 eq. of TPAP, 1.5 eq. of NMO, CH3CN, 25 C, 2 hours (97%).

Next, a Shapiro coupling brings the A-ring moiety 188 and C-ring moiety 193 together. Compound 188 is treated with BuLi, followed by slow addition of 193. The nucleophilic addition gives compound 194 as the Shapiro coupling product. Clearly, this strategy for constructing the ABC ring system and Danishefsky's strategy of ABC ring system formation are quite similar. The epoxidation of the C-1 and C-14 double bonds introduces an epoxide functional group, which can be converted to a C-1 hydroxyl group with reductive ring-

Scheme 7±63. Reagents and conditions: a: 1.1 eq. of 188, 2.3 eq. of n-BuLi, THF, ÿ78 to 0 C, 1.0 eq. of 193, THF, ÿ78 C, 0.5 hour (82%). b: 0.03 eq. of VO(acac)2, 3.0 eq. of TBHP, C6H6, 4 AÊ MS, 25 C, 14 hours (87%). c: 5.0 eq. of LiAlH4, 25 C, Et2O, 7 hours (76%). d: 3.0 eq. of KH, Et2O:HMPA ˆ 3:1, 1.6 eq. of phosgene (20% in toluene), 25 C, 0.5 hour (86% based on 58% conversion). e: 3.8 eq. of TBAF, THF, 25 C, 14 hours (80%). f: 0.05 eq. of TPAP, 3.0 eq. of NMO, CH3CN:CH2Cl2 ˆ 2:1, 25 C, 2 hours (92%). g: 11 eq. of TiCl3 (DME)1:5, 26 eq. of Zn±Cu, DME, re¯ux, 3.5 hours, then 70 C, then added 198 over 1 hour, 70 C for 0.5 hour.

opening reaction. The thus formed vicinal diol is protected by formation of a cyclic carbonate. The protected C-9 to C-10 primary hydroxyl groups are then deprotected and oxidized to give dialdehyde 198. McMurry cyclization is then carried out in DME at 10 C in the presence of 11 eq. of TiCl3 (DME)1:5 and 26 eq. of Zn±Cu couple. The coupling product, diol 199, is generated with 25% yield. This yield, according to Nicolaou, was the optimal result (Scheme 7±63).

As this synthesis started from an achiral starting material, compound 199 must be resolved to secure enantiomerically pure intermediates for the synthesis of taxol. Treatment of …G†-diol 199 with excess (1S)-…ÿ†-camphanic chloride in methylene chloride in the presence of Et3N forms two diastereomeric monoesters for chromatographic separation. Enantiomerically pure diol 199 can be regenerated from the ester in 90% yield with a speci®c rotation of ‡187 (c ˆ 0:5, CHCl3).

Next comes the adjustment of the C-9 and C-10 functional groups to their ®nal form and the construction of the D ring. The higher reactivity of the allylic C-10 hydroxyl group in 199 makes it possible to selectively carry out the acetylation at the C-10 position. The resulting monoacetate can be oxidized, providing the desired 9-keto±10-acetate 200. Hydroboration at C-5 introduces a hydroxyl group, giving compound 201, which can then be converted to ABCD ring compound 202 via 5-mesylate or 5-tosylate (Scheme 7±64).

436 APPLICATIONS OF ASYMMETRIC REACTIONS

Scheme 7±64. Reagents and conditions: a: 1.5 eq. of Ac2O, 1.5 eq. of DMAP, CH2Cl2, 25 C, 2 hours (95%). b: 0.1 eq. of TPAP, 3.0 eq. of NMO, CH3CN, 25 C, 2 hours (93%). c: 10.0 eq. of BH3 THF, THF, 0 C, 3 hours, then excess H2O2, saturated NaHCO3, 25 C, 1 hour (42% plus 22% of C6 hydroxy isomer).

Scheme 7±65. Reagents and conditions: a: 5.0 eq. of PhLi, THF, ÿ78 C, 10 minutes, then 10 eq. of Ac2O, 5.0 eq. of DMAP, CH2Cl2, 2.5 hours (80%). b: 30 eq. of PCC, 30 eq. of NaOAC, celite, benzene re¯ux, 1 hour (75%). c: Excess NaBH4, MeOH, 25 C, 3 hours.

Phenyl lithium attack on the cyclic carbonate convertes 202 to C-2 benzoate compound 203. PCC oxidation and subsequent NaBH4 reduction then furnishes the ®nal baccatin III for the total synthesis of taxol (Scheme 7±65).

7.5.1.6 Mukaiyama's Synthesis. Mukaiyama's synthesis starts with construction of the B-ring moiety, and aldol reactions are used extensively throughout the entire synthesis process.34 The retro synthesis is outlined in Scheme 7±66.

The procedure begins with the oxidation of commercially available methyl 3- hydroxy-2,2-dimethyl propionate with Swern reagent to give the corresponding aldehyde. This is then converted to dimethyl acetal. Reduction of the ester functional group of this compound with LiAlH4 followed by Swern oxidation gives the desired aldehyde 204. Next, the asymmetric aldol reaction between 204 and ketene silyl acetal 205 is carried out in the presence of chiral diamine and the Lewis acid Sn(OTf )2. The corresponding optically active ester 206 is obtained with good yield and selectivity (anti/syn ˆ 80/20, 87±93% ee for the anti-isomer). See Scheme 7±67.

The secondary hydroxyl group of 206 is now protected with a PMB group. Reduction of the resulting diastereomeric mixture 207 gives the corresponding alcohol 208, which is then separated to give a single stereoisomer. A silyl ether

Scheme 7±71. Reagents and conditions: a: LHMDS, TMSCl, THF, ÿ78 C. b: NBS, THF, 0 C (100%). c: (1) LHMDS, MeI, HMPA, THF, ÿ78 C (100%); (2) 1N HCl, THF, room temperature (r. t.) (83%); (3) (COCl)2, DMSO, Et3N, CH2Cl2, ÿ78 C to r. t. (95%). d: (1) SmI2, THF, ÿ78 C (70%); (2) Ac2O, DMAP, pyridine, r. t. (87%). e: DBU, benzene, 60 C (91%).

oxidation produces aldehyde 216. The ring-closure reaction of the optically active polyoxy unit 216 proceeds smoothly in the presence of excess SmI2, giving the desired aldol product with high yield and good stereoselectivity. Subsequently, treating the acetylated product 217 with DBU generates the desired eight-membered ring enone 218 with high yield (Scheme 7±71). Compound 218 already possesses the B ring of baccatin III and can be used for the introduction of the C-ring moiety.

Michael addition of cuprate reagent, generated in situ from 7 eq. of 2- bromo-5-(triethylsiloxy)pentene, 14 eq. of t-BuLi, and 3.7 eq. of copper cyanide, to the enone 218 gives the eight-membered ring ketone 219 with high yield and perfect diastereoselectivity. Ketoaldehyde 220, a precursor of the BC ring system of taxol, can be obtained in good yield by deprotection of the Michael adduct 219 with 0.5 N HCl and subsequent oxidation with a combination of TPAP and NMO. On treatment with a base, precursor 220 would be expected to generate an enolate anion, which in turn would form the desired bicyclic compound 221. Indeed, when intramolecular aldol reaction of 220 is carried out in the presence of NaOMe at 0 C, the reaction proceeds smoothly, a¨ording a mixture of bicyclic compounds 221 at nearly quantitative yield with good diastereoselectivity (221b/221a ˆ 92/8; see Scheme 7±72).

Diastereoselective reduction of the aldol 221b can be achieved using AlH3 in toluene at ÿ78 C. The corresponding cis-diol is preferentially formed. The diol can be protected with isopropylidene acetal to provide tricyclic compound 222. This can be converted to conformationally rigid C-1 ketone 223 by deprotection of the PMB group and successive oxidation with PDC (Scheme 7±73).

Alkylation of the C-1 carbonyl group of 223 with homoallyllithium reagent in benzene produces the desired bishomoallylic b-alcohol at high yield with perfect diastereoselectivity. Deprotection of the TBS group results in the for-

440 APPLICATIONS OF ASYMMETRIC REACTIONS

Scheme 7±72. Reagents and conditions: a: t-BuLi, CuCN, Et2O, ÿ23 C (99% based on 93% conversion). b: (1) 0.5 N HCl, THF, 0 C (97%); (2) TPAP, NMO, 4 AÊ MS, CH2Cl2, 0 C (92%). c: NaOMe, MeOH, THF, 0 C (98%, 221b/221a ˆ 92/8).

Scheme 7±73. Reagents and conditions: a: (1) AlH3, toluene, ÿ78 C (94%); (2) Me2C(OMe)2, CSA, CH2Cl2, room temperature (r. t.) (100%). b: (1) DDQ, H2O, CH2Cl2, r. t. (97%); (2) PDC, CH2Cl2, r.t. (94% yield based on 96% conversion).

mation of C-1 to C-11 cis-diol 224, and successive treatment with dialkylsilyl dichlorides yields the silylene compounds 225 with almost quantitative yields. Alkylation of these silylene compounds with methyllithium furnishes compounds 226 with the desired C-1 protection. Oxidation of the C-11 secondary alcohol gives the C-11 ketones 227 with good yields. The diketones 228 are obtained via oxygenation of the C-12 positions of 227, and the A-ring moiety is then constructed via intramolecular pinacol coupling in the presence of a lowvalence titanium reagent. Compound 230, which will be used for further functionalization, can be obtained through debenzylation and desilylation of compound 229 (Scheme 7±74).

Regioselective protection of the pentaol 230 with bis-trichloromethyl carbonate and subsequent acetic anhydride treatment a¨ords the C-10 acetoxy C-1, C-2 carbonate compound 231 in good yield. Deprotection of the acetonide function and regioselective silylation of the C-7 hydroxyl group, followed by