Total Synthesis of (-)-Chokol A by an Asymmetric Domino Michael Addition-Dieckmann Cyclization [1]

Abstract

A convergent and asymmetric total synthesis of (-)-chokol A was accomplished in six steps starting from the α,β-unsaturated ester (E)-9 in an overall yield of 27% with an enantiomeric excess of 95%. The key step of this synthesis is the asymmetric tandem conjugate addition-Dieckmann cyclization of the higher-order cuprate 8 derived from vinyl bromide 7 with the α,β-unsaturated ester (E)-9.

antifungal agents - asymmetric synthesis - Michael addition - tandem reaction - total synthesis

References and Notes

1a Stereoselective Synthesis of Steroids and Related Compounds, IX. For part VIII, see: Groth U. Kalogerakis A. Richter N. Synlett  2006,  905 

1b Lanthanides in Organic Synthesis, part VI. For part V, see: Groth U. Kesenheimer C. Neidhöfer J. Synlett  2006,  12:  1859 

2 Koshino H. Yoshihara T. Togiya S. Terada S. Tsukada S. Okuno M. Noguchi A. Sakamura S. Ichihara A. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu  1989,  31:  244 

3 Yoshihara T. Togiya S. Koshino H. Sakamura S. Shimanuki T. Sato T. Tajimi A. Tetrahedron Lett.  1985,  26:  5551 

4 Sakamura S. In Biologically Active Natural Products - Potential Use in Agriculture   Culter HG. ACS Symposium Series, Vol. 380, Oxford University Press; New York: 1988. 

5a Oppolzer W. Cunningham AF. Tetrahedron Lett.  1986,  27:  5467 

5b Lawler DM. Simpkins NS. Tetrahedron Lett.  1988,  29:  1207 

5c Tanimori S. Ueda T. Nakayama M. Biosci. Biotechnol. Biochem.  1994,  58:  1174 

5d Groth U. Halfbrodt W. Köhler T. Kreye P. Liebigs Ann. Chem.  1994,  9:  885 

5e Deloux L. Srebnik M. Tetrahedron Lett.  1996,  37:  2735 

6a Mash EA. J. Org. Chem.  1987,  52:  4142 

6b Suzuki T. Sato E. Matsuda Y. Tada H. Koizumi S. Unno K. Kametami T. J. Chem. Soc., Chem. Commun.  1988,  1531 

6c Suzuki T. Tada H. Unno K. J. Chem. Soc., Perkins Trans. 1  1992,  2017 

6d Urban E. Knühl G. Helmchen G. Tetrahedron  1995,  51:  13031 

6e For the enantio-selective synthesis of (-)-chokol G, see: Kanada RM. Tanaguchi T. Ogasawara K. Chem. Commun.  1998,  1755 

7 Groth U. Halfbrodt W. Kalogerakis A. Köhler T. Kreye P. Synlett  2004,  291 

For recent reviews on domino reactions, see:

8a Tietze LF. J. Heterocycl. Chem.  1990,  27:  47 

8b Tietze LF. Beifuss U. Angew. Chem., Int. Ed. Engl.  1993,  32:  131 ; Angew. Chem. 1993, 105, 137

8c Tietze LF. Bachmann J. Wichmann J. Burkhardt O. Synthesis  1994,  1185 

8d Tietze LF. Chem. Ind. (London, U.K.)  1995,  453 

8e Tietze LF. Chem. Rev.  1996,  96:  115 

8f Tietze LF. Modi A. Med. Res. Rev.  2000,  20:  304 

8g Tietze LF. Haunert F. Domino Reactions in Organic Synthesis. An Approach to Efficiency, Elegance, Ecological Benefit, Economic Advantage and Preservation of our Resources in Chemical Transformations, In Stimulating Concepts in Chemistry   Shibasaki M. Stoddart JF. Vögtle F. Wiley-VCH; Weinheim: 2000.  p.39-64  

8h Tietze LF. Rackelmann N. Pure Appl. Chem.  2004,  76:  1967 

8i Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 

9 For the synthesis of 2-bromo-5-hydroxypent-2-ene 7, see also: Lawler DM. Simpkins NS. Tetrahedron Lett.  1988,  29:  1207 

10 Gewald K. Jänsch HJ. J. Prakt. Chem.  1973,  4:  779 

11

(1 S ,2 S ,1′ R ,2′ S ,5′ R )-2-[1-(3-Benzyloxypropyl)vinyl]-5-oxocyclopentanecarboxylic Acid [5′-Methyl-2′-(1-methyl-1-phenylethyl)]cyclohexyl Ester ( 10a) To a solution of 2.55 g (10.0 mmol) 2-bromopentenylbenzyl ether (7) in 20 mL of abs. Et₂O 10.0 mL (20.0 mmol, 2 M solution in Et₂O) of t-BuLi was slowly added at -90 °C and stirred then at this temperature for 90 min. The resulting organolithium compound was then added at -80 °C via canula to a suspension of 0.45 g (5.0 mmol) copper(I) cyanide in 10 mL Et₂O and stirred then for 2 h until the temperature reached -30 °C and the suspension turned into a bright-green solution. After cooling the solution again to
-80 °C 0.64 mL (5.0 mmol) BF₃·OEt₂ were added by syringe and stirred for 15 min, whereupon the solution was cooled to -115 °C by an EtOH-dry ice bath. After reaching this temperature a degassed solution of 0.37 g (1.0 mmol) of the chiral ester 9 in 10 mL Et₂O was added (very) slowly to the solution of the higher order cuprate 8 and the resulting reaction solution was then stirred for 12 h under warming to r.t. For the work-up 30 mL of a sat. NH₄Cl solution were added to the black suspension, stirred for 2-3 min and then filtered over Celite^®. After phase separation the aqueous phase was extracted 3 times with 25 mL portions of Et₂O. The combined organic phases were dried over MgSO₄ and concentrated with a rotary evaporator at 30 °C/13 mbar. The resulting residue was then purified via column chromatography over 200 g silica gel with PE-Et₂O = 2:1 as eluent, which gave 0.48 g (0.93 mmol, 93% yield) of the compound 10a (Figure [2] ). The diastereomeric excess was determined to be >95% by ¹³C NMR spectroscopy. R _f = 0.35 (PE-Et₂O = 2:1). ¹H NMR (200 MHz, CDCl₃): δ = 0.85 (d, 3 H, -CH₃, J = 6.3 Hz), 1.18 (s, 3 H, -CH₃), 1.26 (s, 3 H, -CH₃), 1.34-2.39 (m, 18 H, H2-H4, H1′-H6′ and H2′′-H3′′), 2.86-2.88 (m, 1 H, H1), 3.5 (t, 2 H, H4′′, J = 6.2 Hz), 4.52 (s, 2 H, -CH₂Ph), 4.76-4.83 (m, 2 H, C=CH₂), 7.06-7.50 (m, 10 H, 2 × Ph). ¹³C NMR (50.3 MHz, CDCl₃): δ = 21.71 (C5′-CH₃), 26.29 [C2′-C(CH₃)₂Ph], 26.56 (C3′), 26.83 [C2′-C(CH₃)₂Ph], 26.90 (C3′′), 27.96 (C5′), 30.96 (C3), 31.25 (C2′), 34.48 (C4′), 38.09 (C4), 39.81 [C2′-C(CH₃)₂Ph], 41.22 (C2), 45.13 (C6′), 49.90 (C2′), 60.35 (C1), 69.66 (C4′′), 72.91 (OCH₂Ph), 76.27 (C1′), 109.38 (C1′′=CH₂), 124.90 (C_para,Ph), 125.42 (C_ortho,Ph), 127.48 (C_para,Bn), 127.55 (C_ortho,Bn), 127.92 (C_meta,Ph), 128.30 (C_meta,Bn), 138.42 (C1_Bn), 148.38 (C1′′), 151.21 (C1_Ph), 167.49 (-CO₂R), 210.23 (C5). MS (EI, 70eV): m/z (%) = 516.4 (0.1) [M⁺], 302.2 (52.0) [M⁺ - C₁₆H₂₂], 119.1 (50.0) [Ph-C(CH₃)₂ ⁺], 91.1 (100.0) [C₇H₇ ⁺]. IR (film): 3020, 3005 (C=CH₂), 1745 (C=O), 1710 (-CO₂R), 1640 (C=C) cm^-1. [a]_D ²⁰ +4.21 (c 1.13, CHCl₃). Anal. Calcd for C₃₄H₄₄O₄: C, 79.03; H, 8.58. Found: C, 78.90; H, 8.71.

12a Parish EJ. Mody NV. Hedin PA. Miles DH. J. Org. Chem.  1974,  39:  1592 

12b Huang B.-S. Parish EJ. Miles DH. J. Org. Chem.  1974,  39:  2647 

12c For a review article about this topic, see: Krapcho AP. Synthesis  1982,  805 

13 Alcarez C. Groth U. Angew. Chem., Int. Ed. Engl.  1997,  36:  2480