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

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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• 26a

  Ref. [24d] reports a dihydropyran annulation using HCl (gaseous) and benzaldehyde; cis,cis:trans,cis ratios were 94:6 after 5 min at -5 °C and 16:84 after 2 h at r.t.

• 26b

  Ref. [24g] describes a related dihydropyran generation using HCl and butanal at 25 °C; cis,cis:trans,cis ratios were 84:16 after 3 h and 22:78 after 8 h.

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• H₂SO₄-mediated epimerizations of lactone-free dihydropyranonaphthoquinones:
• 30a

  0:100 trans-23:cis-23 → 67:33 (ref. [10b] );

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• 30c

  60:40 trans-24:cis-24 → 80:20 (ref. [24e] ).

• 30d

  Related isomerization of the more highly substituted dihydropyranonaphthoquinone 25 (Figure [4] ): see ref. [11b]

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Kapferer, T.; Brückner, R. unpublished results.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; δ_3a-H = 4.37, δ_5-H = 5.07, and δ_11b-H = 5.59 ppm) relative to the values published (ref. [11b] ) for the trans,cis-isomer:
δ_3a-H = 4.73, δ_5-H = 5.37, and δ_11b-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.