Mistunobu reaction 重点参考 光延反应

Easy Access to 9-Epimers of Cinchona Alkaloids: One-Pot Inversion by Mitsunobu Esterification–Saponification

Łukasz Sidorowicz, Jacek Skarżewski*

Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, PolandFax +48(71)32840; E-mail: jacek.skarzewski@pwr,wroc.plReceived 22 November 2010; revised 10 January 2011

Abstract: Cinchona alkaloids were efficiently converted into their9-epi diastereomers. The applied one-pot procedure was based onthe Mitsunobu esterification with 4-nitrobenzoic acid followed byin situ saponification of the ester. This method requires only onecolumn chromatography, easily separating the epi-isomer from thenative alkaloid and the Mitsunobu byproducts. The procedure giveshigher yields and is operationally simpler than the previously usedstereoselective hydrolysis of the corresponding sulfonic acid esters.Key words: cinchona alkaloids, Mitsunobu reaction, inversion, al-cohols, chiral pool

Easily available cinchona alkaloids, namely quinine(QN), quinidine (QD), cinchonine (CN), and cinchonidine(CD), (Figure1) enjoy much interest as privileged cata-lysts, effective in numerous mechanistically different,enantioselective transformations.1 Their additional advan-tage comes from the fact that they constitute near enantio-mers. Often, the formation of the opposite stereoisomer ofthe product can be achieved using such pseudoenantio-meric catalysts.

3SR4S4SR

6'

3S8SN

N

6'

S8R9R11S9SOH

HO

N

N

R = OMe, quinine (QN)R = OMe, quinidine (QD)R = H, cinchonidine (CD)

R = H, cinchonine (CN)

Figure 1Their stereodifferentiating properties are mainly deter-mined by configurations at the C8/C9 stereogenic cen-ters.1 Thus for the native, 8,9-unlike isomers, e.g. (8S,9R)-QN, the anti-closed conformation dominates, locatingboth the quinuclidine nitrogen atom and 9-hydroxy groupfar away from each other. In contrast, 9-epi-alkaloids(8,9-like isomers) form preferential conformations withboth functionalities located closely, forming an intramo-lecular hydrogen bond that is absent in the native alka-loids.2 Essentially, the unnatural alkaloids of 9-epi-configuration are available by the tartaric acid catalyzed

SYNTHESIS 2011, No. 5, pp0708–0710Advanced online publication:31.01.2011

DOI: 10.1055/s-0030-1259483; Art ID:T22410SS© Georg Thieme Verlag Stuttgart · New York

hydrolysis of tosylates or mesylates of the nativeepimers.3 However, in spite of recent improvements3b inthe original Suszko method,3a the whole procedure is rath-er tedious, requiring two separate chromatographic purifi-cations.

For our ongoing project on the synthesis of various chal-cogen derivatives of cinchona alkaloids4 we often neededgram amounts of the 9-epi-alkaloids. In order to simplifytheir preparation we decided to examine a classical meth-od for the inversion of chiral secondary alcohols, i.e. theMitsunobu esterification and subsequent ester hydroly-sis.5 In spite of the high reputation of this well-establishedapproach, there were also numerous reports on the esteri-fication/hydrolysis sequence resulting in the retention ofconfiguration. It especially happened for sterically hin-dered secondary alcohols, where the oxophosphonium ac-tivation of carboxylic acid prevails over that of the alcoholand the alcohol acts as a nucleophile (Scheme1).6

COOEtPhP+NN+Ph3•3•PNN–EtOOCEtOOCCOOEt2 R2OHR1COOHHCOOEtOR2Ph3P+HNN+Ph3PNNEtOOCHOR2EtOOCCOOEtR1COOHR2OH1R1COO–+PhCOO–OR2R3P+OR2nucleophilePh3POCOR1PhOSN23PO+–R1OR2OR2+Ph3P+OCOR1inversion productnucleophileSNAcOPh3PO+R1OR2retention productScheme 1The simplified mechanism of the Mitsunobu esterifica-tion, for details, see ref. 6

The database screening revealed that the application of theMitsunobu method to the inversion of cinchona alkaloidshas not been reported as yet. On the other hand, theMitsunobu reaction has already been used with these alka-loids for the preparation of azides/primary amines (HNpK3a 4.72, Ph3P, DIAD, followed by in situ reduction withPh3P; 45–65% yield)7 and thioacetates (AcSH pKP, DEAD; 44–59% yield).4c Both reactions workeda 3.33,Phwell, giving selectively the S3N2-type products in fair to

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Table 1

9-Epimerization of Cinchona Alkaloids709

Inversion of Cinchona Alkaloids by Mesyl Ester Hydrolysis and Mitsunobu Esterification/Saponificationa

epi-Alkaloid (Rf)b

epi-Alkaloid, this work Yield (%)

[a]D20 (EtOH)+39.2 (c 0.90)+96.5 (c 0.60)+113.8 (c 0.53)+55.1 (c 0.54)

epi-Alkaloid, two stepsTotal yield (%)74,4c 713b68,4c 683b488b66,4c 388a,b

[a]D20 (EtOH)+39.5 (c 0.96)4c+96.9 (c 1.12)4c+114.5 (c 1.07)9+55.6 (c 0.80)4c

Alkaloid (Rf)b

QN (0.204)QD (0.186)CN (0.168)CD (0.159)

a

epi-QN (0.575)epi-QD (0.584)epi-CN (0.602)epi-CD (0.611)

85794562

Reaction conditions: PNBA (1.1 equiv), DEAD (1.2 equiv), Ph3P (1.3 equiv), then LiOH (5 equiv). For the details, see the experimental sec-tion.b

Eluent: CHCl3–MeOH–Et3N, 40:1:4.

good yields regardless whether the substrate was used ineither native or epi configuration. However, it should benoted that the nucleophiles that have been used weremuch stronger than the carboxylate (carboxylic acid an-ion) needed for esterification.

RRN(8S)N(9R)1. PNBA, DEAD Ph3P, THF(9S)(8S)OH2. LiOH, HOHN2ONCD, R = HQN, R = OMeepiepi-CD, R = H-QN, R = OMeRROH1. PNBA, DEAD PhN3P, THFOH(9S)(8R)2. LiOH, HN2O(9R)(8R)NNCN, R = HQD, R = OMeepiepi-CN, R = H-QD, R = OMeScheme 2

We decided to examine the standard esterification of thenative alkaloids with 4-nitrobenzoic acid (PNBA pK3.44). The first experiment performed with quinine (QN)a[PNBA (1.1 equiv), DEAD (1.2 equiv), Ph0 °C] gave the crude product containing 72% of the 3P (1.3 equiv),epi-ester, 3% of the ester of native configuration, and 9-epi-quinine (10%), along with native quinine (9%). The sam-ple composition was evaluated by integration of the low-field 1H NMR resonances originating from the respective2¢-quinoline hydrogen atoms. The inverted quinine esterwas isolated, fully characterized, and compared with theseparately synthesized 4-nitrobenzoic acid ester of nativequinine. Both compounds were prone to hydrolysis whichexplains the presence of epi-quinine and quinine in thecrude product. Taking into account the steric hindrancearound the 9-hydroxy group we considered this outcomeas quite satisfactory. In turn, all four alkaloids were ester-ified in the same manner and subsequently the obtainedmixtures were treated in situ with aqueous 1 M lithium hy-droxide solution. The reaction products were easily puri-

fied by column chromatography resulting in samples ofanalytical purity (Scheme2). It is noteworthy that the na-tive and epi alkaloids markedly differ in their R1), thus they are easily separated by chromatogra-f values(Tablephy on silica gel. Our present results are compared(Table1) with the highest reported yields of the literatureprocedures (the preparation and inversions of mesylates intwo separate steps, both requiring chromatography).While quinine and quinidine were inverted in high yield,improved against the previous method, both cinchonineand cinchonidine gave yields similar to the former two-step method. Nevertheless, it is noteworthy that thepresent one-pot inversion procedure requires only onecolumn chromatography, easily separating the epi-isomerfrom the native one and the Mitsunobu byproducts.

In order to further examine the applied reaction conditionswe tested the influence of solvents, acids, and amounts ofthe reagents. Thus, attempting to improve the yield of cin-chonine inversion, instead of tetrahydrofuran we used py-ridine, toluene, or N,N-dimethylformamide getting 40, 22,and 15% of epi-cinchonine, respectively. For all four al-kaloids the experiments using 3,5-dinitrobenzoic acid orchloroacetic acid with diethyl azodicarboxylate (1.2equiv) and triphenylphosphine (1.3 equiv) in tetrahydro-furan at 0 °C for 72 hours did not improve our previous re-sults. Improved yields were also not observed withdoubled amount of PNBA/DEAD/Phat 0 °C for 24 hours.

3P in tetrahydrofuranIn summary, the developed one-pot procedure for theMitsunobu PNBA esterification followed by ester sapon-ification can be recommended as an operationally simpleand quick procedure for the inversion of configuration atthe 9-stereogenic centers of cinchona alkaloids.

All solvents were purified and dried by standard methods. The start-ing cinchona alkaloids were commercially available and were usedafter drying by azeotropic distillation with toluene. Melting pointswere determined using a Boetius hot-stage apparatus and are uncor-rected. IR spectra were recorded on a Perkin Elmer 1600 FTIR spec-trophotometer. 1H and 13C NMR spectra were measured on a BrukerCPX (1H, 300 MHz) spectrometer using TMS as internal standard.Optical rotations at 578 nm were measured using an Optical Activ-ity Ltd. Model AA-5 automatic polarimeter. HRMS were recordedon a Waters LCT Premier XE (TOF/ESI) apparatus. Silica gel (60–120 mesh) was used for chromatographic separation. Separations of

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Downloaded by: Nanjing University of Technology. Copyrighted material.710Ł. Sidorowicz, J. Skarżewskiproducts by chromatography were performed on silica gel 60 (230–400 mesh) purchased from Merck. TLC was performed using silicagel 60 precoated plates (Merck).

9-epi-Quinine 4-Nitrobenzoic Acid Ester

A stirred suspension of quinine (1.0 mmol, 324.4 mg), Phmmol, 262.3 mg), and PNBA (1.1 mmol, 183.8 mg) in anhyd THF3P (1.3(10 mL) was placed in an ice-water bath for 10 min. Then DEAD(1.1 mmol, 171 mL) was added dropwise via syringe. After the ad-dition of DEAD, the homogenic mixture was stirred at 0 °C for 20min, then at r.t. overnight. The solvent was removed in vacuo andthe crude product was isolated by column chromatography (EtOAc)giving after vacuum drying an oil (353 mg, 74%); Rf = 0.118(EtOAc).

[a]D20 –79.9 (c 0.8, CH2Cl2).

IR: 2938, 1723, 1621, 1526, 1268, 1102, 718 cm–1.

1

H NMR (300 MHz, CDCl3): d=0.81–0.86 (m, 1 H), 1.42–1.51 (m,1 H), 1.52–1.61 (m, 2 H), 1.62–1.69 (m, 1 H), 2.25–2.32 (m, 1 H),2.71–2.83 (m, 2 H), 3.21 (dd, J=14.01, 10.2 Hz, 1 H), 3.29–3.41(m, 1 H), 3.59 (q, J=9.3 Hz, 1 H), 3.99 (s, 3 H), 4.95–5.05 (m, 2H), 5.75–5.87 (m, 1 H), 6.72 (d, J=10.2 Hz, 1 H), 7.38 (dd, J=9.3,2.7 Hz, 1 H), 7.50 (d, J=4.5 Hz, 1 H), 7. (d, J=2.7 Hz, 1 H),8.02 (d, J=9.3 Hz, 1 H), 8.14–8.24 (m, 4 H), 8.77 (d, J=4.5 Hz, 1H).

13C NMR (75.5 MHz, CDCl3): d=1.2, 158.3, 150.6, 147.6,145.0, 141.6, 141.0, 135.5, 132.0, 131.0, 127.8, 123.5, 122.0, 120.5,114.6, 101.6, 72.5, 59.3, 56.1, 55.7, 41.4, 39.6, 28.0, 27.3, 25.3.HRMS: m/z [M + H]+ calcd for C474.2041.

27H28N3O5: 474.2029; found:Quinine 4-Nitrobenzoic Acid Ester

PNBA (167 mg, 1 mmol) and SOClround-bottom flask were refluxed for 3 h and excess SOCl2 (2.0 mL) placed in a 2-neck2 was re-moved in vacuo. After drying for 2 h in vacuo CHadded. The round-bottom flask was secured with drying tube2Cl2 (5.0 mL) was(CaCl2), cooled in an ice bath, Et3N (210 mL, 1.5 mmol), and thenquinine (1.0 mmol, 342 mg) in CHwise. The mixture was stirred 15 min at 0 °C, then overnight at r.t.2Cl2 (5.0 mL) were added drop-The resulting mixture was washed with H2O (2 ×) and brine (1 ×),and dried (Naproduct was isolated by column chromatography (silica gel, EtOAc)2SO4). The solvent was evaporated in vacuo and theyielding the ester (298 mg, 63%); mp 151–153 °C (CHClR3–hexane);f = 0.091 (EtOAc).[a]D20 +150.0 (c 0.5, CH2Cl2).

IR: 2941, 1727, 1621, 1527, 1268, 1100, 718 cm–1.

1H NMR (300 MHz, CDCl3): d=1.50–1.70 (m, 3 H), 1.85–2.05 (m,2 H), 2.25–2.35 (m, 1 H), 2.60–2.75 (m, 2 H), 3.05–3.20 (m, 2 H),3.55 (q, J=2.1 Hz, 1 H), 3.98 (s, 3 H), 5.00–5.10 (m, 2 H), 5.80–5.92 (m, 1 H), 6.75 (d, J=7.20 Hz, 1 H), 7.38 (dd J=9.3, 2.7 Hz,1 H), 7.42 (d, J=4.5 Hz, 1 H), 7.50 (d, J=2.7 Hz, 1 H), 8.02 (d,J=9.3 Hz, 1 H), 8.20–8.33 (m, 4 H), 8.74 (d, J=4.5 Hz, 1 H).13C NMR (75.5 MHz, CDCl3): d=163.9, 158.1, 150.8, 147.5,144.9, 143.0, 141.6, 135.1, 132.0, 130.8, 127.0, 123.8, 121.9, 118.8,114.8, 101.4, 75.4, 59.4, 56.7, 55.7, 42.6, 39.6, 28.0, 27.6, 24.6.HRMS: m/z [M + H]+ calcd for C474.2041.

27H28N3O5: 474.2029; found:Inversion of Cinchona Alkaloids; General Procedure

To a stirred suspension of the alkaloid (1 mmol), Ph3P (1.3 mmol)and PNBA (1.1 mmol) in THF (10 mL) placed in an ice-water bathwas added DEAD (1.1 mmol) dropwise via syringe. The mixture

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was stirred at 0 °C for 20 min, at r.t. for 3 h, and then again cooledto 0 °C. 1 M LiOH in H2O (5.0 mL) and MeOH (1.0 mL) were add-ed and the mixture was stirred at r.t. overnight. Organic solventswere evaporated in vacuo and the residue was quenched with H(5 mL) and CH (15 mL). The organic phase was separated,2Owashed with brine, and dried (K2Cl22CO3). The solvent was removed invacuo and the product was purified by column chromatography [sil-ica gel, 1. CHCldiethyl hydrazine-1,2-dicarboxylate), then 2. CHCl3–t-BuOMe, 3:1 (to remove Ph3PO and most of the40:1:4 (to isolate the corresponding epi-alkaloid)].

3–MeOH–Et3N,When the above procedure was scaled up to 1 g of the alkaloid (ca.3 mmol), all the reagents but THF solvent (15 mL) were used intriplicate amounts.

Acknowledgment

We are grateful to the Polish Ministry of Science and Higher Edu-cation for financial support; Grant No. N204 161036. Ł.S. thanksfor a fellowship co-financed by European Union within EuropeanSocial Fund.

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