Asymmetric Ortholithiation of Amides by Conformationally Mediated Chiral Memory: An Enantioselective Route to Naphtho- and Benzofuranones

Abstract

An enantiomerically pure sulfinyl group ortho to an aromatic amide imposes absolute stereochemistry on the conformation of its Ar-CO axis. Sulfoxide-lithium exchange followed by addition to an aldehyde relays the chirality of the amide axis to the new hydroxyl-bearing stereogenic centre with good stereochemical fidelity. Lactonisation of the hydroxyamide gives naphthofuranones and benzofuranones, including the fungal metabolite isoochracein, but with substrate-dependent stereoselectivity.

chiral memory - amide - sulfoxide - directed metallation - benzofuranone

References

<A NAME="RD09905ST-1A">1a</A> Gschwend HW. Rodriguez HR. Org. React.  1979,  26:  1 

<A NAME="RD09905ST-1B">1b</A> Snieckus V. Chem. Rev.  1990,  90:  879 

<A NAME="RD09905ST-1C">1c</A> Clayden J. Organolithiums: Selectivity for Synthesis   Pergamon; Oxford: 2002. 

<A NAME="RD09905ST-1D">1d</A> Clayden J. In Chemistry of Organolithium Compounds   Rappoport Z. Marek I. Wiley; Chichester: 2004.  p.495-646  

<A NAME="RD09905ST-2">2</A> This is true only for uncomplexed aromatic rings: in the ferrocene and arenechromiumtricarbonyl series, chiral ortho-directing groups are a highly effective way of introducing planar chirality; for a discussion, see: Clayden J. In Organolithiums in Enantioselective Synthesis   Hodgson DM. Springer; New York: 2003.  p.251-286  

<A NAME="RD09905ST-3">3</A> Pollet P. Turck A. Plé N. Quéguiner G. J. Org. Chem.  1999,  64:  4512 ; and references therein

<A NAME="RD09905ST-4">4</A> Beak P. Tse A. Hawkins J. Chen C.-W. Mills S. Tetrahedron  1983,  39:  1983 

<A NAME="RD09905ST-5">5</A> Meyers AI. Hanagan MA. Trefonas LM. Baker RJ. Tetrahedron  1983,  39:  1991 

<A NAME="RD09905ST-6">6</A> Pratt SA. Goble MP. Mulvaney MJ. Wuts PGM. Tetrahedron Lett.  2000,  41:  3559 

<A NAME="RD09905ST-7">7</A> Takahashi H. Tsubuki T. Higashiyama K. Chem. Pharm. Bull.  1991,  39:  260 

<A NAME="RD09905ST-8">8</A> Quesnelle C. Iihama T. Aubert T. Perrier H. Snieckus V. Tetrahedron Lett.  1992,  33:  2625 ; and ref. 3

<A NAME="RD09905ST-9">9</A> Ahmed A. Bragg RA. Clayden J. Lai LW. McCarthy C. Pink JH. Westlund N. Yasin SA. Tetrahedron  1998,  54:  13277 

<A NAME="RD09905ST-10A">10a</A> Bowles P. Clayden J. Helliwell M. McCarthy C. Tomkinson M. Westlund N. J. Chem. Soc., Perkin Trans. 1  1997,  2607 

<A NAME="RD09905ST-10B">10b</A> Bowles P. Clayden J. Tomkinson M. Tetrahedron Lett.  1995,  36:  9219 

1-Silylethyl groups:

<A NAME="RD09905ST-11A">11a</A> Clayden J. Pink JH. Yasin SA. Tetrahedron Lett.  1998,  39:  105 

<A NAME="RD09905ST-11B">11b</A> Clayden J. Johnson P. Pink JH. Helliwell M. J. Org. Chem.  2000,  65:  7033 

Proline-derived imidazolidines:

<A NAME="RD09905ST-11C">11c</A> Clayden J. Lai LW. Angew. Chem. Int. Ed.  1999,  38:  2556 

Ephedrine-derived oxazolidines:

<A NAME="RD09905ST-11D">11d</A> Clayden J. Lai LW. Tetrahedron Lett.  2001,  42:  3163 

<A NAME="RD09905ST-11E">11e</A> Clayden J. Lai LW. Helliwell M. Tetrahedron: Asymmetry  2001,  12:  695 

<A NAME="RD09905ST-11F">11f</A> Clayden J. Lai LW. Helliwell M. Tetrahedron  2004,  60:  4399 

<A NAME="RD09905ST-11G">11g</A> Clayden J. Lund A. Vallverdú L. Helliwell M. Nature (London)  2004,  431:  966 

Sulfinyl groups:

<A NAME="RD09905ST-11H">11h</A> Clayden J. Mitjans D. Youssef LH. J. Am. Chem. Soc.  2002,  124:  5266 

<A NAME="RD09905ST-11I">11i</A> Clayden J. Kubinski PM. Sammiceli F. Helliwell M. Diorazio L. Tetrahedron  2004,  60:  4387 

See ref. 7h. For further examples of sulfoxide displacement by sulfoxide-metal exchange, see:

<A NAME="RD09905ST-12A">12a</A> Clayden J. Organolithiums: Selectivity for Synthesis   Pergamon; Oxford: 2002.  Chap. 3.3.3. p.142 

<A NAME="RD09905ST-12B">12b</A> Capozzi MMM. Cardellicchio C. Naso F. Eur. J. Org. Chem.  2004,  1855 ; and references therein

<A NAME="RD09905ST-12C">12c</A> Satoh T. Horiguchi K. Tetrahedron Lett.  1995,  36:  8235 

<A NAME="RD09905ST-12D">12d</A> Carpintero M. Nietro I. Fernández-Mayorales A. J. Org. Chem.  2001,  66:  1768 

<A NAME="RD09905ST-12E">12e</A> Milne JE. Jarowicki K. Kocienski PJ. Alonso J. Chem. Commun.  2002,  426 

<A NAME="RD09905ST-13">13</A> Andersen KK. Tetrahedron Lett.  1962,  93 

<A NAME="RD09905ST-14A">14a</A> Beak P. Brown RA. J. Org. Chem.  1977,  42:  1823 

<A NAME="RD09905ST-14B">14b</A> Beak P. Brown RA. J. Org. Chem.  1982,  47:  34 

<A NAME="RD09905ST-14C">14c</A>

As is usual with tertiary amides at the more sterically encumbered end of the scale, the addition of TMEDA to these lithiations was found to be unnecessary.

<A NAME="RD09905ST-15">15</A> A convenient synthesis of (-)-menthyl sulfinate on a 100 g scale has been described, see: Solladié G. Hutt J. Girardin A. Synlett  1987,  173 

<A NAME="RD09905ST-16">16</A> A similar loss of absolute stereochemistry for this reason plagues the analogous synthesis of ferrocenyl p-tolyl sulfoxide. See: Riant O. Argouarch G. Guillaneux D. Samuel O. Kagan HB. J. Org. Chem.  1998,  63:  3511 ; and references therein

<A NAME="RD09905ST-17">17</A>

See ref. 7h. The level of conformational selectivity has recently been determined in related compounds to be of the order of 200:1 (Clayden, J.; Helliwell, M.; Mitjans, D.; Regan, A. C. manuscript in preparation).

<A NAME="RD09905ST-18">18</A>In our earlier work on the addition of racemic organolithiums to aldehydes (ref. 10), we reported somewhat lower diastereoselectivities, although those reactions were carried out at -78 °C. Repeating some of the earlier racemic reactions at -90 °C confirmed that it is simply the temperature, and not the enantiomeric purity of the organolithiums, which improves the diastereoselectivity. Racemic ortholithiated amides are heterochiral dimers (at least in the solid state: see

<A NAME="RD09905ST-18">18</A> Clayden J. Davies RP. Hendy MA. Snaith R. Wheatley AEH. Angew. Chem. Int. Ed.  2001,  40:  1238 ), and some differences in reactivity between organolithiums of different ee are therefore to be expected

<A NAME="RD09905ST-19">19</A>

The major diastereoisomer was identified by comparison with known compounds whose structure had been confirmed by X-ray crystallography (ref. 10). Absolute stereochemistry was deduced from the preferred orientation of amides adjacent to enantiomerically pure sulfoxides and from the absolute stereochemistry of comparable atropisomeric amides obtained by quenching with simple, ‘non-prochiral’ electrophiles (see ref. 7h).

<A NAME="RD09905ST-20">20</A>

An alternative explanation, that the sulfoxide by-product of the reaction, tert-butyl tolyl sulfoxide, which may be generated in enantiomerically pure form, could mediate the asymmetric formation of the new centre, seems unlikely, given this dependence on amide structure.

Attempts to extend this application of chiral memory to the control of stereogenic centres formed by lateral lithiation were hampered by the remarkably fast racemisation of laterally lithiated amides. See:

<A NAME="RD09905ST-21A">21a</A> Clayden J. Helliwell M. Pink JH. Westlund N. J. Am. Chem. Soc.  2001,  123:  12449 

<A NAME="RD09905ST-21B">21b</A> Clayden J. Pink JH. Westlund N. Frampton CS. J. Chem. Soc., Perkin Trans. 1  2002,  901 

<A NAME="RD09905ST-21C">21c</A> See also: Clayden J. Stimson CC. Keenan M. Wheatley AEH. Chem. Commun.  2004,  228 

<A NAME="RD09905ST-22A">22a</A> Fuji K. Kawabata T. Chem.-Eur. J.  1998,  4:  373 

<A NAME="RD09905ST-22B">22b</A> Kawabata T. Chen J. Suzuki H. Nagae Y. Kinoshita T. Chancharunee S. Fuji K. Org. Lett.  2000,  2:  3883 

<A NAME="RD09905ST-22C">22c</A> Kawabata T. Kawakami S. Majumdar S. J. Am. Chem. Soc.  2003,  125:  13012 

<A NAME="RD09905ST-22D">22d</A> Kawabata T. Fuji K. Top. Stereochem.  2003,  23:  175 

<A NAME="RD09905ST-22E">22e</A> Kawabata T. Öztürk O. Chen J. Fuji K. Chem. Commun.  2003,  162 

<A NAME="RD09905ST-23">23</A> Seebach D. Sting AR. Hoffmann M. Angew. Chem., Int. Ed. Engl.  1996,  35:  2709 

<A NAME="RD09905ST-24">24</A>

Ortholithiation, addition to aldehydes, and lactonisation under acid conditions is an established way of making benzofuranones from aromatic amides: see ref. 1b and references therein, and ref. 27.

It is of course possible that chiral memory effects operate during the cyclisation, and we cannot rule out retentive cyclisation via a benzylic carbocation. Our confidence in the absolute stereochemistry of the products is based upon the fact that simple 3-alkylbenzofuranones with reported optical rotations are laevorotatory if S and dextrorotatory if R. See: ref. 5 and:

<A NAME="RD09905ST-25A">25a</A> Watanabe M. Hashimoto N. Araki S. Butsugan Y. J. Org. Chem.  1992,  57:  742 

<A NAME="RD09905ST-25B">25b</A> Ramachandran PV. Chen G.-M. Brown HC. Tetrahedron Lett.  1996,  37:  2205 

<A NAME="RD09905ST-25C">25c</A> Kawasaki T. Kimachi T. Tetrahedron  1999,  55:  6847 .In a previous publication (ref. 7h) we got this wrong: we claimed, erroneously, the opposite dependence of optical activity on stereochemistry (though in mitigation we suggest that the experimental section of ref. 25b invites misinterpretation!), and the proposed cationic mechanism for the lactonisation reported in ref. 7h is consequently probably wrong

<A NAME="RD09905ST-26">26</A> (-)-Isoochracein is a fungal metabolite isolated from Hypoxylon spp. See: Anderson JR. Edwards RL. Whalley AJS. J. Chem. Soc., Perkin Trans. 1  1983,  2185 

<A NAME="RD09905ST-27">27</A> Anstiss M. Clayden J. Grube A. Youssef LH. Synlett  2002,  290