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Synlett 2005(8): 1281-1285  
DOI: 10.1055/s-2005-868505
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of (+)-Kalafungin and (-)-Nanaomycin D by Asymmetric Dihydroxylation, Oxa-Pictet-Spengler Cyclization, and H2SO4-Mediated Isomerization

Rodney A. Fernandes, Reinhard Brückner*
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany
Fax: +49(761)2036100; e-Mail: reinhard.brueckner@organik.chemie.uni-freiburg.de;
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Publication History

Received 11 March 2005
Publication Date:
03 May 2005 (online)

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Abstract

The pyranonaphthoquinone antibiotics and antitumor agents (+)-kalafungin (1) and (-)-nanaomycin D (3 = ent-1) were synthesized from 1,5-napthalenediol (13) in 11 steps. Stereocontrol was high: 99.5 ee/93% diastereoselectivity for 1, 98.5% ee/94% ­diastereoselectivity for 3. Enantiocontrol was achieved by the asymmetric dihydroxylation of the β,γ-unsaturated ester 9. Dia­stereocontrol was realized in the final step by an almost complete epimerization in H2SO4.

Key words

β,γ-unsaturated carboxylic esters - butyrolactones - epimerization - quinones - pyranonaphthoquinones

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16

Kapferer, T.; Brückner, R. unpublished results.

20

All new compounds gave satisfactory 1H- and 13C NMR spectra and provided correct combustion analyses (±0.4%).

22

Methyl (E)-4-(1,4,5-trimethoxynaphth-2-yl)-3-butenoate (9): NaBr (97.6 mg, 0.948 mmol, 25 mol%), Ph3P (79.6 mg, 0.303 mmol, 8 mol%), Pd2(dba)3CHCl3 (78.5 mg, 0.076 mmol, 2 mol%), and i-Pr2NEt (0.63 mL, 0.49 g, 3.80 mmol) were added sequentially to a solution of allyl acetate 11 (1.200 g, 3.793 mmol) in MeOH (5 mL). The reaction mixture was pressurized with CO (30 atm) in an autoclave and stirred at 50 °C for 6 h before cooling to r.t., quenching with H2O, and extraction with CHCl3 (3 × 20 mL). The combined organic layers were washed twice with H2O, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography using cyclohexane-EtOAc (17:3 → 3:1) as an eluent to give 9 (1.001 g, 83%; 95:5 mixture with the isomeric α,β-unsaturated ester) as a yellow syrup. 1H NMR (500 MHz, CDCl3/TMS): δ = 3.35 (dd, J 2,3 = 7.1 Hz, 4 J 2,4 = 1.5 Hz, 2-H), 3.71 (s, MeO2C), 3.83, 3.93, and 3.96 (3 s, 3 × MeO), 6.40 (dt, J 3,4 = 16.2 Hz, J 3,2 = 7.1 Hz, 3-H), 6.82 (br d, J 6 ′ ,7 ′ = 7.8 Hz, 6¢-H), 6.93 (s, 3¢-H), 6.96 (dt, J 4,3 = 16.2 Hz, 4 J 4,2 = 1.5 Hz, 4-H), 7.38 (dd, J 7 ′ ,6 ′ = J 7 ′ ,8 ′ = 8.1 Hz, 7′-H), 7.68 (dd, J 8 ′ ,7 ′ = 8.4 Hz, 4 J 8 ′ ,6 ′ = 1.1 Hz, 8′-H).

23

The enantioselectivities were determined by HPLC. Column: Chiralcel OD-H No. ODHOCE-AJ071; Daicel Chemical Ind. Ltd.; eluent: n-heptane-EtOH (60:40); flow rate; 0.6 mL/min; UV detector: 233 nm; t R: 12.3 min for 10, 14.7 min for ent-10.

25

This was inferred from the high-field shifts of the italicized resonances in our 1H NMR spectrum (500 MHz, CDCl3; δ3a-H = 4.37, δ5-H = 5.07, and δ11b-H = 5.59 ppm) relative to the values published (ref. [11b] ) for the trans,cis-isomer:
δ3a-H = 4.73, δ5-H = 5.37, and δ11b-H = 5.58 ppm. Ref. [10f] reports a similar shift difference for the analogous signals of cis,cis-20 (δ values in analogous order: δ = 4.27, 4.84, and 5.33 ppm) vs. trans,cis-20 (δ values in analogous order: δ = 4.61, 4.96, and 5.33 ppm). See Figure [2] .

27

CAN oxidation of the C-5 epimer of ent-17. See ref. [11b]

28

The mechanism of the Lewis acid (BBr3)- or Brønsted acid (H2SO4)-mediated epimerization at C-5 of dihydropyranonaphthoquinones 18, 5-epi-1, and their enantiomers has not been investigated. We assume that neither C5-Ar nor C5-O bond cleavage but enone → dienol (as exemplified by formulas 21 and/or 22) tautomerism causes the configurational change. See Figure [3] .

31

[α]D 20 +160.6 (c 0.3, CHCl3); mp 168-170 °C. Ref. [11b] [α]D 24 +160 (c 0.3, CHCl3); mp 171-173 °C.

32

[α]D 20 -159.7 (c 0.35, CHCl3); mp 169-171°C. Ref. [11b] [α]D 24 -163 (c 0.44, CHCl3); mp 171-173 °C.