Synthesis 2018; 50(01): 64-83
DOI: 10.1055/s-0036-1590948
feature
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

Solange Da Silva Pinto
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK   Email: steve.davies@chem.ox.ac.uk
,
Stephen G. Davies*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK   Email: steve.davies@chem.ox.ac.uk
,
Ai M. Fletcher
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK   Email: steve.davies@chem.ox.ac.uk
,
Paul M. Roberts
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK   Email: steve.davies@chem.ox.ac.uk
,
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK   Email: steve.davies@chem.ox.ac.uk
› Author Affiliations
Further Information

Publication History

Received: 04 September 2017

Accepted after revision: 10 October 2017

Publication Date:
12 December 2017 (eFirst)

Abstract

Epoxidation of racemic trans-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl3CCO2H then m-CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans-2-(N-benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity (>95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1RS,2SR,3SR,4SR)-2-(N-benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF4 as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N–H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans-2-(N-benzylamino)cyclohex-3-en-1-ol (>99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3 (>98% ee in each case) from 1,3-cyclohexadiene.

Supporting Information

 
  • References

  • 1 Kubler K. Arch. Pharm. 1908; 246: 620
  • 2 Abe F. Yamauchi T. Honda K. Hayashi N. Chem. Pharm. Bull. 2000; 48: 1090

    • For recent examples, see:
    • 3a Pandey G. Tiwari KN. Puranik VG. Org. Lett. 2008; 10: 3611
    • 3b Kurbanoglu IN. Besoluk S. Zengin M. ARKIVOC 2010; (x): 77
    • 3c Ahmad S. Thomas LH. Sutherland A. Org. Biomol. Chem. 2011; 9: 2801
    • 3d Katakam R. Anugula R. Macha L. Batchu VR. Tetrahedron Lett. 2017; 58: 559

      For reviews, see:
    • 4a Kurosawa W. Roberts PM. Davies SG. Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem. Jpn.) 2010; 68: 1295
    • 4b Davies SG. Fletcher AM. Thomson JE. Org. Biomol. Chem. 2014; 12: 4544
  • 5 Aciro C. Claridge TD. W. Davies SG. Roberts PM. Russell AJ. Thomson JE. Org. Biomol. Chem. 2008; 6: 3751
  • 6 Aciro C. Davies SG. Roberts PM. Russell AJ. Smith AD. Thomson JE. Org. Biomol. Chem. 2008; 6: 3762
  • 7 Knapp S. Sebastian MJ. Ramanathan H. J. Org. Chem. 1983; 48: 4786
  • 8 Claridge TD. W. Davies SG. Polywka ME. C. Roberts PM. Russell AJ. Savory ED. Smith AD. Org. Lett. 2008; 10: 5433
  • 9 Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1572458–1572467.
  • 10 Due to the volatility of epoxide 14, the conversion was judged by determining the ratio of unreacted dibenzylamine to ring-opened product (±)-16.
  • 11 The diastereoisomeric purity of (±)-16 was assigned from the known diastereoisomeric purity of the precursor (±)-15, i.e., >180:1 dr.
  • 12 Recrystallization of (1R,2S,3S,4S)-17 yielded single crystals of suitable quality for analysis by X-ray diffraction.
  • 13 Parker RE. Isaacs NS. Chem. Rev. 1959; 59: 737
  • 14 Addy JK. Parker RE. J. Chem. Soc. 1963; 915
  • 15 Fürst, A.; Plattner, P. A. 12th International Congress on Pure & Applied Chemistry, New York, 1951, 409.
  • 16 Bond CW. Cresswell AJ. Davies SG. Fletcher AM. Kurosawa W. Lee JA. Roberts PM. Russell AJ. Smith AD. Thomson JE. J. Org. Chem. 2009; 74: 6735
  • 17 Davies SG. Fletcher AM. Kurosawa W. Lee JA. Poce G. Roberts PM. Thomson JE. Williamson DM. J. Org. Chem. 2010; 75: 7745
  • 18 Bagal SK. Davies SG. Fletcher AM. Lee JA. Roberts PM. Scott PM. Thomson JE. Tetrahedron Lett. 2011; 52: 2216
  • 19 Brennan MB. Claridge TD. W. Compton RG. Davies SG. Fletcher AM. Henstridge MC. Hewings DS. Kurosawa W. Lee JA. Roberts PM. Schoonen AK. Thomson JE. J. Org. Chem. 2012; 77: 7241
  • 20 Cresswell AJ. Davies SG. Lee JA. Morris MJ. Roberts PM. Thomson JE. J. Org. Chem. 2012; 77: 7262
  • 21 Chini M. Crotti P. Flippin LA. Gardelli C. Giovani E. Macchia F. Pineschi M. J. Org. Chem. 1993; 58: 1221
  • 22 Crotti P. Di Bussolo V. Favero L. Macchia F. Pineschi M. Eur. J. Org. Chem. 1998; 1675
  • 23 A sample of analytically pure (±)-26 was subsequently prepared via ring-opening of epoxide (±)-24 upon treatment with 40% aq HBF4 (see the experimental section for details); recrystallisation of this sample yielded single crystals of suitable quality for analysis by X-ray diffraction.
  • 24 Brennan MB. Davies SG. Fletcher AM. Lee JA. Roberts PM. Russell AJ. Thomson JE. Aust. J. Chem. 2015; 68: 610
  • 25 Brennan MB. Csatayová K. Davies SG. Fletcher AM. Green WD. Lee JA. Roberts PM. Russell AJ. Thomson JE. J. Org. Chem. 2015; 80: 6609
  • 26 Knapp S. Sebastian MJ. Ramanathan H. Bharadwaj P. Potenza JA. Tetrahedron 1986; 42: 3405
  • 27 The enantiomeric excesses of (1R,2R)-15, (1S,2S)-15, (1R,2S,3R,4R)-26, (1R,2S,3S,4R)-38 and (1R,2S,3R,4S)-40 were determined by chiral HPLC analyses (with comparison to the corresponding authentic racemic standards), for which the authors would like to thank Professor Darren J. Dixon and Mr Sam R. Ellis. Samples of (±)-26, (±)-38 and (±)-40 were prepared via analogous routes to those described for enantiopure material (see the experimental section and Supporting Information for details).
  • 28 Chemoselective N-benzylation of (1R,2S,3S,4S)-20 (treatment with BnBr/iPr2NEt/DMAP) gave a sample of enantiopure (1R,2S,3S,4S)-25. The enantiomeric excess of (1R,2S,3S,4S)-25 was determined by chiral HPLC analysis (and comparison with the corresponding authentic racemic standard), for which the authors would like to thank Professor Darren J. Dixon and Mr Sam R. Ellis.
  • 29 The enantiomeric excesses of dihydroconduramines A-2 (32), B-2 (36), C-3 (39) and F-3 (41) were assigned from the known enantiomeric excesses of the corresponding precursors (1R,2S,3S,4S)-20, (1R,2S,3R,4R)-26, (1R,2S,3S,4R)-38 and (1R,2S,3R,4S)-40, respectively.
  • 30 Compared to the use of Cl3CCO2H to effect the ring-opening of (±)-24, which gave a 4:96 mixture of (±)-25 and (±)-26, respectively.
  • 31 Winstein S. Hess HV. Buckles RE. J. Am. Chem. Soc. 1942; 64: 2157
  • 32 Roberts JD. Young WG. Winstein S. J. Am. Chem. Soc. 1942; 64: 2796
  • 33 Recrystallisation of (±)-38 and (±)-40 yielded single crystals of suitable quality for analysis by X-ray diffraction.
  • 34 Pangborn AB. Giardello MA. Grubbs RH. Rosen RK. Timmers FJ. Organometallics 1996; 15: 1518
  • 35 Swern D. Org. React. 1953; 7: 392
  • 36 Betteridge PW. Carruthers JR. Cooper RI. Prout CK. Watkin DJ. J. Appl. Crystallogr. 2003; 36: 1487
  • 37 Other signals associated with the aromatic rings within 21 and 22 (which could not be unambiguously assigned to their respective diastereoisomer) were observed: 1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H, ArMe), 2.48 (s, 3 H, ArMe), 7.22–7.88 (m, 28 H, Ar, Ph). 13C NMR (100 MHz, CDCl3): δ = 127.1, 127.2, 127.5, 127.7, 128.4, 129.0, 129.3, 129.8, 129.9, 133.6, 133.7, 139.2, 129.3, 144.8, 145.1 (Ar, Ph).
  • 38 The signal associated with N(CH2Ph)2 was very broad and of low intensity; the approximate peak position (to the nearest integer) is shown in italics and marked with an asterisk.
  • 39 This signal was partly obscured by the signal associated with the toluene-d 8 solvent; other signals in these regions could not be discerned.