Synthetic Studies toward Haouamine B: Construction of Indenotetrahydropyridone Skeleton

Abstract

Synthetic studies on haouamine B are described. The characteristic indenotetrahydropyridone skeleton was constructed by intramolecular Friedel-Crafts alkylation of mesyloxy β-lactam derivative and intramolecular McMurry coupling as key processes.

Key words

Friedel-Crafts reaction - β-lactam - McMurry coupling - natural products

References and Notes

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• 11 The stereochemistry was tentatively assigned as described based on the general reactivity of 4-substituted azetidine 2,3-dione. For a typical example, see: Kant J. Schwartz WS. Fairchild C. Gao Q. Huang S. Long BH. Kadow JF. Langley DR. Farina V. Vyas D. Tetrahedron Lett.  1996,  37:  6495 
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1

Current address: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

8

The relative stereochemistry was determined after derivatization to β-lactam 18. The absolute stereochemistry was tentatively assigned according to the Qin’s proposed transition state (ref. 7).

10

The ee was determined by HPLC (Daicel CHIRALCEL
OD-H, flow rate: 0.50 mL/min, hexane-i-PrOH = 80:20, t _R = 10.0, 13.1 min).

12

We found that the hydroxyl group should be activated as a mesylate for the smooth and high-yielding process. The O-methylated substrate has a low reactivity, and degradation of the starting material was observed. On the contrary, The O-triflated substrate was found to be unstable.

13

Procedure for the Intramolecular Friedel-Crafts Alkylation: A 30-mL round-bottomed flask equipped with a magnetic stirrer bar and an inlet adapter with three-way stopcock was charged with tertiary alcohol 21 (740 mg, 1.62 mmol). The flask was evacuated and backfilled with argon gas. To the flask was added anhyd CH₂Cl₂ (6.0 mL), and the resulting solution was cooled to 0 ˚C. To the solution were added Et₃N (0.70 mL, 5.0 mmol) and methanesulfonyl chloride (0.25 mL, 3.2 mmol) at 0 ˚C, respectively. The reaction mixture was then warmed to r.t. and stirred for 8 h, after which time TLC (hexanes-EtOAc, 1:1) indicated complete consumption of the starting alcohol. The reaction was quenched with sat. aq NH₄Cl, and the mixture was extracted with CH₂Cl₂ (3 ×). The combined organic extracts were washed with brine, dried over MgSO₄, and filtered. The filtrate was concentrated under reduced pressure to give a crude mesylate (1.1 g), which was used for the next reaction.
A 30-mL round-bottomed flask equipped with a magnetic stirrer bar and an inlet adapter with three-way stopcock was charged with the crude mesylate (1.1 g). The flask was evacuated and backfilled with argon gas. To the flask was added anhyd MeCN (20 mL), and the resulting solution was cooled to -40 ˚C. To the solution was added TfOH (0.70 mL, 7.9 mmol) at -40 ˚C. The reaction mixture was warmed to r.t. and stirred for 3 h, after which time TLC (hexanes-EtOAc, 3:2) indicated complete consumption of the starting mesylate. After cooling to 0 ˚C, the reaction mixture was treated with sat. aq NaHCO₃, and the mixture was extracted with EtOAc (3 ×). The combined organic extracts were concentrated under reduced pressure to give the crude material, which was purified by column chromatography on silica gel to provide the title compound 23 (495 mg, 1.19 mmol, 74% over 2 steps) as a pale yellow amorphous solid; [α]_D ^²³ -67.8 (c = 1.15, CHCl₃). IR (neat): 2939, 2835, 1747, 1601, 1489, 1456, 1339, 1151, 1078, 1047, 910, 733, 698 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.20-7.37 (m, 6 H), 6.88-6.95 (m, 2 H), 6.76-6.81 (m, 1 H), 6.31-6.35 (m, 2 H), 4.66 (d, 1 H, J = 15.2 Hz), 4.23 (d, 1 H, J = 15.2 Hz), 4.02 (d, 1 H, J = 6.4 Hz), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.63 (s, 3 H), 2.99 (dd, 1 H, J = 17.6, 6.4 Hz), 2.87 (d, 1 H, J = 17.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.8, 161.9, 159.5, 158.3, 144.9, 139.0, 136.0, 129.2, 128.7, 128.1, 127.6, 120.8, 119.1, 112.5, 112.4, 102.0, 98.1, 75.4, 65.3, 55.7, 55.5, 55.1, 43.7, 32.8. HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₂₆H₂₅NO₄Na: 438.1681; found: 438.1674.

15

Procedure for the Intramolecular McMurry Coupling Reaction: A 10-mL test tube equipped with a magnetic stirrer bar and an inlet adapter with three-way stopcock was charged with Zn/Cu (6.2 mg, 95 µmol). The flask was flame-dried and backfilled with argon gas. To the flask was added degassed anyhd 1,2-dimethoxyethane (0.18 mL), and the resulting suspension was cooled to 0 ˚C. To the suspension was added TiCl₄ (4.0 µL, 36 µmol), and the mixture was heated at 90 ˚C for 1.5 h. After the flask was cooled to 0 ˚C, substrate 6 (2.0 mg, 3.5 µmol) in 1,2-dimethoxyethane (50 µL) was added to the flask. The reaction mixture was warmed to r.t. over 30 min and then heated at 90 ˚C for 2 h, after which time TLC (hexanes-EtOAc, 1:1) indicated complete consumption of the starting material. After cooling to r.t., the mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the crude material, which was purified by preparative TLC providing the title compound 5 (0.42 mg, 0.78 µmol, 22%) as a colorless film. IR (neat): 3302, 2934, 1674, 1599, 1470, 1337, 1290, 1207, 1150, 754 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.45 (d, 1 H, J = 8.8 Hz), 7.21-7.26 (m, 1 H), 6.91 (d, 1 H, J = 2.4 Hz), 6.78-6.86 (m, 3 H), 6.75 (dd, 1 H, J = 8.8, 3.2 Hz), 6.66 (s, 1 H), 6.48 (d, 1 H, J = 2.0 Hz), 6.36 (d, 1 H, J = 2.0 Hz), 5.66 (s, 1 H), 4.14-4.21 (m, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.59 (s, 3 H), 3.33 (dd, 1 H, J = 16.0, 7.6 Hz), 3.08-3.16 (m, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 163.4, 161.7, 159.8, 158.8, 157.2, 145.1, 143.9, 141.1, 138.9, 134.0, 133.0, 129.3, 122.3, 119.1, 117.2, 115.0, 114.4, 112.9, 112.0, 101.2, 98.3, 77.2, 64.6, 55.6, 55.5, 55.2, 55.1, 41.2. HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₂₈H₂₆ ⁷⁹BrNO₅Na: 558.0892; found: 558.0873.

16

Reduction of the amide is reported using a similar compound by Weinreb (ref. 3d).

17

Chemical shifts of ^¹H NMR and ^¹³C NMR of 5 were in excellent agreement with those of the analogous compound reported by Weinreb (ref. 3d).