Synthesis of a Chiral Auxiliary Family from Levoglucosenone and Evaluation in the Diels–Alder Reaction

Julian Klepp; Christopher J. Sumby; Ben W. Greatrex

doi:10.1055/s-0037-1610148

Synlett, Table of Contents

Synlett 2018; 29(11): 1441-1446
DOI: 10.1055/s-0037-1610148

letter

Synthesis of a Chiral Auxiliary Family from Levoglucosenone and Evaluation in the Diels–Alder Reaction

Julian Klepp

^aSchool of Science and Technology, University of New England, Armidale, New South Wales, 2351, Australia Email: ben.greatrex@une.edu.au

,

Christopher J. Sumby

^bDepartment of Chemistry, School of Physical Sciences, University of Adelaide, North Terrace, Adelaide, South Australia, 5005, Australia

,

Ben W. Greatrex *

^aSchool of Science and Technology, University of New England, Armidale, New South Wales, 2351, Australia Email: ben.greatrex@une.edu.au

› Author Affiliations

Abstract

All articles of this category

Abstract

A new family of chiral auxiliaries has been developed based on the lignocellulosic biomass pyrolysis product levoglucosenone. A promising single stereoisomer with an alcohol and π-stacking phenyl substituents was prepared in excellent yield in two steps from dihydrolevoglucosenone without chromatography on >50 g scale. Acrylate esters prepared from the auxiliaries underwent diastereoselective Lewis acid promoted Diels–Alder reactions with cyclopentadiene (endo/exo 98:2, endo d.r. up to 98:2), dimethylbutadiene (d.r. 93:7), and isoprene (d.r. > 98:2)

Key words

chiral auxiliary - chiral pool - levoglucosenone - Diels–Alder reaction - diastereoselectivity

Full Text

References

References and Notes

For reviews of asymmetric synthesis using auxiliaries, see:

1a Christmann M. Bräse S. Asymmetric Synthesis: The Essentials . Wiley-VCH; Weinheim: 2008. Vol. 1
1b Seyden-Penne J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis . Wiley-Interscience; New York: 1995
1c Ager D. Handbook of Chiral Chemicals . CRC Press; Boca Raton, FL: 2005
1d Roos G. Key Chiral Auxiliary Applications . Academic Press; Oxford: 2014

2 Corey EJ. Ensley HE. J. Am. Chem. Soc. 1975; 97: 6908

3a Jones GB. Chapman BJ. Synthesis 1995; 475
3b Whitesell JK. Liu CL. Buchannan CM. Chen HH. Minton MA. J. Org. Chem. 1986; 51: 551

4a Oppolzer W. Angew. Chem., Int. Ed. Engl. 1984; 23: 876
4b Comins DL. Goehring RR. Joseph SP. O'Connor S. J. Org. Chem. 1990; 55: 2574

5a Davies SG. Lee JA. Roberts PM. Thomson JE. Yin J. Tetrahedron 2011; 67: 6382
5b Whitesell JK. Chem. Rev. 1992; 92: 953

6 Muñiz K. Lesato A. Nieger M. Chem. Eur. J. 2003; 9: 5581
7 Donohoe TJ. Guyo PM. Helliwell M. Tetrahedron Lett. 1999; 40: 435

8a Little RD. Moeller KD. J. Org. Chem. 1983; 48: 4487
8b Selvakumar S. Sakamoto R. Maruoka K. Chem. Eur. J. 2016; 22: 6552

9 Kozikowski AP. Zhao L. Zhang A. Wang CZ. Flippen-Anderson J. Johnson KM. ChemMedChem 2006; 1: 58
10 Buschmann H. Scharl H.-D. Synthesis 1988; 827

11a Esser P. Buschmann H. Meyer-Stork M. Scharf HD. Angew. Chem., Int. Ed. Engl. 1992; 31: 1190
11b Mezrhab B. Dumas F. d'Angelo J. Riche C. J. Org. Chem. 1994; 59: 500
11c Chu Y.-Y. Yu C.-S. Chen C.-J. Yang K.-S. Lain J.-C. Lin C.-H. Chen K. J. Org. Chem. 1999; 64: 6993
11d Al Hazmi AM. Sheikh NS. Bataille CJ. Al-Hadedi AA. Watkin SV. Luker TJ. Camp NP. Brown RC. Org. Lett. 2014; 16: 5104
11e Gelat F. Richard V. Berger O. Montchamp J.-L. Org. Lett. 2015; 17: 1819
11f Sarakinos G. Corey EJ. Org. Lett. 1999; 1: 1741

12 Kunz H. Rück K. Angew. Chem. Int. Ed. 1993; 32: 336
13 Lawrence CH. Raverty WD. Duncan AJ. WO 2011000030, 2011

14a Sarotti AM. Joullié MM. Spanevello RA. Suárez AG. Org. Lett. 2006; 8: 5561
14b Sarotti AM. Spanevello RA. Suárez AG. Org. Lett. 2006; 8: 1487
14c Sarotti AM. Fernández I. Spanevello RA. Sierra MA. Suárez AG. Org. Lett. 2008; 10: 3389
14d Sarotti AM. Spanevello RA. Duhayon C. Tuchagues J.-P. Suárez AG. Tetrahedron 2007; 63: 241
14e Sarotti AM. Spanevello RA. Suárez AG. Tetrahedron Lett. 2005; 46: 6987
14f Sarotti AM. Spanevello RA. Suárez AG. Tetrahedron 2009; 65: 3502

15 Zanardi MM. Suárez AG. Tetrahedron Lett. 2009; 50: 999
16 Ledingham ET. Stockton KP. Greatrex BW. Aust. J. Chem. 2017; 70: 1146
17 Experimental Procedure for the Synthesis of the Auxiliary 19a and Diels–Alder Reactions: (1S,5R)-3,3-Dibenzyl-6,8-dioxabicyclo[3.2.1]octan-4-one (14a) ¹⁶ To a stirred solution of ketone 8 (30.0 g, 1.0 equiv, 234 mmol) and BnBr (88.2 g, 59.7 mL, 2.2 equiv, 515.1 mmol) in dry THF (250 mL) cooled using a water/ice bath was added t-BuOK (21.3 g, 2.2 equiv, 171.7 mmol) portion wise, such that the temperature of the reaction did not exceed 30 °C. The mixture was stirred until complete by TLC (3 h), then 1 M HCl (250 mL) and EtOAc (600 mL) were added. The organic phase was separated and washed with sat. NaHCO₃ (300 mL) then brine (300 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. If spontaneous crystallization did not occur, residual benzyl bromide was removed using a high-vacuum pump with gentle warming of the mixture. The residue was then dissolved in MeOH (400 mL) and allowed to crystallize for 24 h over which time some solvent evaporated to give a final volume of ca. 100 mL. The crystals were collected by vacuum filtration and washed with cold MeOH to give 14a as colorless crystals (50.4 g, 70%). Evaporation of the mother liquor and flash chromatography (EtOAc/hexanes = 1:4) afforded an additional portion of 14a (13.2 g, 18%). ¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.22 (m, 6 H, Ar-H), 7.12–7.07 (m, 4 H, Ar-H), 5.04 (s, 1 H, 5-H), 4.53 (br dd, J = 6.0, 5.5 Hz, 1 H, 1-H), 3.53 (dd, J = 6.9, 5.5 Hz, 1 H, 7-Hα), 3.27 (d, J = 13.3 Hz, 1 H, 9-H), 3.26 (d, J = 13.3 Hz, 1 H, 9-H), 3.10 (d, J = 7.20 Hz, 1 H, 7-Hβ), 2.75 (d, J = 13.3 Hz, 1 H, 9-H), 2.58 (d, J = 13.3 Hz, 1 H, 9-H), 2.39 (dd, J = 14.7, 6.0 Hz, 1 H, 2-H), 1.75 (d, J = 14.7 Hz, 1 H, 2-H). (1S,4S,5R)-3,3-Dibenzyl-6,8-dioxabicyclo[3.2.1]-octan-4-ol (7a) The ketone 14a (60.0 g, 1.0 equiv, 195 mmol) was dissolved in CH₂Cl₂ (100 mL), MeOH (180 mL) was added and the solution cooled to –15 °C. Finely powdered NaBH₄ (6.0 g, 0.8 equiv, 156 mmol) was then added at a rate such that the temperature of the reaction did not exceed 0 °C. After stirring for 2 h, the reaction was allowed to warm to ambient temperature and the reaction monitored by TLC. When no starting material remained, the reaction mixture was concentrated under reduced pressure and 1.0 M HCl (100 mL) was added. The aqueous phase was extracted with CH₂Cl₂ (3 × 100 mL) ensuring that no product remained in the aqueous layer by TLC, then the organic layers were combined, dried with MgSO₄, filtered, and concentrated under reduced pressure. The residue was recrystallized using an EtOAc/hexanes (1:4) mixture by slow evaporation to give 7a as colorless crystals (56.9 g, 94%); mp 126–127 °C (from (i-Pr)₂O); [α]_D ²⁵–43 (c 1.1, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 7.36–7.33 (m, 2 H, Ar-H), 7.30–7.26 (m, 6 H, Ar-H), 7.08–7.07 (m, 2 H, Ar-H), 5.34 (d, J = 2.0 Hz, 1 H, 5-H), 4.43–4.41 (ddd, J = 5.4, 2.8, 2.8, 1 H, 1-H), 4.29 (d, J = 7.5 Hz, 1 H, 7-Hβ), 3.82 (dd, J = 7.5, 5.4 Hz, 1 H, 7-Hα), 3.71 (dd, J = 10.0, 2.1 Hz, 1 H, 4-H), 3.17 (d, J = 13.9 Hz, 1 H, 9-H), 3.02 (d, J = 13.9 Hz, 1 H, 9-H), 2.88 (d, J = 13.4 Hz, 1 H, 9-H), 2.38 (d, J = 13.5 Hz, 1 H, 9-H), 1.87–1.84 (m, 1 H, OH), 1.74 (app. br d, J = 2.9 Hz, 2 H, 2-H). ¹³C NMR (126 MHz, CDCl₃): δ = 138.2, 137.7, 131.9, 131.6, 128.40, 128.38, 126.74, 126.67, 103.0, 73.7, 71.6, 68.1, 44.4, 41.4, 39.4, 31.1. FT-IR (neat): 3514, 2969, 1365, 1229, 897, 701 cm^–1. MS (ESI): m/z = 332.9 [M + Na]⁺; ESI-HRMS: m/z calcd for [M + Na]⁺: C₂₀H₂₂O₃Na: 333.1467; found: 333.1473. General Procedure for the Diels–Alder Reactions of Acrylates with Cyclopentadiene The acrylic ester 19a (1.0 equiv) was dissolved in dry CH₂Cl₂ (0.2 M final concentration) under N₂ and then cooled to the temperature indicated in Table 1. The Lewis acid was added under N₂ and stirred for 20 min at the indicated temperature, then freshly distilled cyclopentadiene (5 mmol) was added dropwise, and the reaction was stirred at the temperature indicated in Table 1 for the appropriate time. After 18 h, if the reaction was incomplete a further portion of cyclopentadiene (5 mmol) was added. The reactions without Lewis acid were concentrated after completion. The reactions where Lewis acids were used were quenched by the addition of water and 1 M HCl, then extracted with CH₂Cl₂(3×). The combined organic extracts were dried over MgSO₄, filtered, and then concentrated under reduced pressure. For all reactions, the residues were absorbed onto a pad of silica (10 g/g ester), and the remaining cyclopentadiene and its corresponding dimer were washed from the silica using hexanes. Then the product was eluted with EtOAc. (1S,4S,5R)-3,3-Dibenzyl-6,8-dioxabicyclo[3.2.1]octan-4-yl (1R,4R)-bicyclo[2.2.1]hept-5-ene-2-carboxylate ((R)-22a) Following the general procedure, acrylate ester 19a (1.0 g, 1.0 equiv, 2.8 mmol) was treated with cyclopentadiene (1.81 mg, 10 equiv, 28.0 mmol) catalyzed by 1.8 M EtAlCl₂ in toluene (1.50 mL, 1.0 equiv, 2.8 mmol). The product was recrystallized by slow evaporation from dry MeOH to afford (R)-22a as colorless crystals (1.05 g, 89%); mp 96–98 °C; [α]_D ²⁵ –23 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 7.37–7.34 (m, 2 H, Ar-H), 7.30–7.26 (m, 4 H, Ar-H), 7.22–7.20 (m, 2 H, Ar-H), 6.97–6.95 (m, 2 H, Ar-H), 6.33 (dd, J = 5.7, 3.1 Hz, 1 H, 15-H), 6.11 (dd, J = 5.7, 2.8 Hz, 1 H, 16-H), 5.35 (d, J = 1.9 Hz, 1 H, 5-H), 4.91 (d, J = 1.9 Hz, 1 H, 4-H), 4.40 (ddd, J = 5.5, 5.2, 3.1 Hz, 1 H, 1-H), 4.34 (d, J = 7.5 Hz, 1 H, 7-Hβ), 3.81 (dd, J = 7.5, 5.2 Hz, 1 H, 7-Hβ), 3.46 (d, J = 14.5 Hz, 1 H, 18-H), 3.37 (br s, 1 H, 11-H), 3.15–3.11 (m, 1 H, 12-H), 3.12–3.08 (d, J = 14.5 Hz, 1 H, 18-H), 2.98 (br s, 1 H, 14-H), 2.60 (d, J = 14.0 Hz, 1 H, 18-H), 2.48 (d, J = 14.0 Hz, 1 H, 18-H), 1.98 (ddd, J = 11.8, 9.3, 3.7 Hz, 1 H, 13-H), 1.76 (app. d, J = 2.9 Hz, 2 H, 2-H), 1.57–1.50 (m, 2 H, 13-H, 17-H), 1.35 (d, J = 8.3 Hz, 1 H, 17-H). ¹³C NMR (126 MHz, CDCl₃): δ = 174.2, 138.7, 138.2, 136.7, 132.1, 132.0, 131.6, 128.31, 128.29, 126.8, 126.6, 100.1, 73.3, 72.7, 68.0, 50.2, 46.2, 43.8, 42.7, 40.48, 40.45, 30.9, 29.9, 29.2. FT-IR (neat): 2958, 1746, 1356, 1231, 899, 708 cm^–1. MS (ESI): m/z = 453.1 [M + Na]⁺. ESI-HRMS: m/z calcd for [M + Na]⁺ C₂₈H₃₀O₄Na: 453.2042; found: 453.2042

18a Corey EJ. Loh TP. Roper TD. Azimioara MD. Noe MC. J. Am. Chem. Soc. 1992; 114: 8290
18b Maddaluno JF. Gresh N. Giessner-Prettre C. J. Org. Chem. 1994; 59: 793
18c Loncharich RJ. Schwartz TR. Houk K. J. Am. Chem. Soc. 1987; 109: 14
18d Barba C. Carmona D. Garcia JI. Lamata MP. Mayoral JA. Salvatella L. Viguri F. J. Org. Chem. 2006; 71: 9831

19 Dumas F. Mezrhab B. d'Angelo J. Riche C. Chiaroni A. J. Org. Chem. 1996; 61: 2293
20 Whitesell JK. Lawrence RM. Chen HH. J. Org. Chem. 1986; 51: 4779
21 Hirai H. Komiyama M. J. Polym. Sci. A 1974; 12: 2701

22a Funel JA. Abele S. Angew. Chem. Int. Ed. 2013; 52: 3822
22b Kelly MG. Childers WE. Harrison BL. Zhang G. Bravo BA. Schecter LE. WO 2004111035, 2004

Supplementary Material

Supporting Information