An Approach to the Synthesis of anti-β^²,³-Amino Acids: Application of β-Trifluoroacetamidoorganozinc Reagents

Abstract

An approach to the synthesis of anti-β^²,³-amino acids is reported. The key steps involve stereoselective lactone alkylation followed by ring opening with iodotrimethylsilane/ethanol to give iodo esters. Formation of the organozinc reagents from these iodo esters, followed by either Pd- or Cu-catalysed reaction with electrophiles gives protected β^²,³-amino acids. The trans stereochemistry in the enolate alkylation is confirmed for the allylated anti-lactone by X-ray crystallography.

amino acids - alkylations - cross-coupling - lactones - zinc

References and Notes

<A NAME="RD13209ST-1">1</A> Seebach D. Beck AK. Bierbaum DJ. Chem. Biodiversity  2004,  1:  1111 

<A NAME="RD13209ST-2">2</A> Lelais G. Seebach D. Biopolymers  2004,  76:  206 

<A NAME="RD13209ST-3">3</A> Liu M. Sibi MP. Tetrahedron  2002,  58:  7991 

<A NAME="RD13209ST-4">4</A> Cardillo G. Tomasini C. Chem. Soc. Rev.  1996,  25:  117 

<A NAME="RD13209ST-5">5</A> Schreiber JV. Frackenpohl J. Moser F. Fleischmann T. Kohler HPE. Seebach D. ChemBioChem  2002,  3:  424 

<A NAME="RD13209ST-6">6</A> Frackenpohl J. Arvidsson PI. Schreiber JV. Seebach D. ChemBioChem  2001,  2:  445 

<A NAME="RD13209ST-7">7</A> Cheng RP. Gellman SH. DeGrado WF. Chem. Rev.  2001,  101:  3219 

<A NAME="RD13209ST-8">8</A> Cole DC. Tetrahedron  1994,  50:  9517 

<A NAME="RD13209ST-9">9</A> Dexter CS. Jackson RFW. Elliott J. J. Org. Chem.  1999,  64:  7579 

<A NAME="RD13209ST-10">10</A> Dexter CS. Hunter C. Jackson RFW. J. Org. Chem.  2000,  65:  7417 

<A NAME="RD13209ST-11">11</A> Jackson RFW. Rilatt I. Murray PJ. Chem. Commun.  2003,  1242 

<A NAME="RD13209ST-12">12</A> Rilatt I. Jackson RFW. J. Org. Chem.  2008,  73:  8694 

<A NAME="RD13209ST-13">13</A> Bartrum HE. Adams H. Caggiano L. Jackson RFW. Tetrahedron  2008,  64:  3701 

<A NAME="RD13209ST-14">14</A> Rilatt I. Caggiano L. Jackson RFW. Synlett  2005,  2701 

<A NAME="RD13209ST-15">15</A> Jefford CW. McNulty J. Helv. Chim. Acta  1994,  77:  2142 

<A NAME="RD13209ST-16">16</A> Jefford CW. Wang JB. Tetrahedron Lett.  1993,  34:  1111 

<A NAME="RD13209ST-17">17</A> Seki M. Shimizu T. Inubushi K. Synthesis  2002,  361 

<A NAME="RD13209ST-18">18</A> Yoda H. Nakagami Y. Takabe K. Tetrahedron: Asymmetry  1994,  5:  169 

<A NAME="RD13209ST-19">19</A> Hanessian S. Schaum R. Tetrahedron Lett.  1997,  38:  163 

<A NAME="RD13209ST-20">20</A> Lapidus M. Sweeney M. J. Med. Chem.  1973,  16:  163 

<A NAME="RD13209ST-21">21</A> Gong B. Lynn DG. J. Org. Chem.  1990,  55:  4763 

<A NAME="RD13209ST-22">22</A>

Procedure for Lactone Alkylation Using a minor modification of conditions already reported for the alkylation of dianions of γ-N-trifluoroacetyl amino acid esters, [¹9] n-BuLi (2.5 M in hexane, 5 mL, 12.5 mmol) was added dropwise to a stirred solution of DIPA (1.9 mL, 13.75 mmol) in THF (5 mL) at 0 ˚C. The resulting solution was stirred for 15 min before being cooled to -78 ˚C for the addition of the lactone 6 (985 mg, 5 mmol) in THF (28 mL). The reaction was stirred at the same temperature for a further hour before the electrophile (5 equiv) was added dropwise with careful monitoring of the internal temperature of the reaction to ensure it did not exceed -78 ˚C. After stirring at -78 ˚C for 18 h, the reaction was quenched with aq citric acid (10%, 30 mL) before being extracted with EtOAc (3 × 50 mL) and the organic fractions combined, washed with brine (2 × 30 mL), dried (MgSO₄) and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography.

<A NAME="RD13209ST-23">23</A>

Crystallographic data (excluding structure factors) for compound 9 has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 733395.

<A NAME="RD13209ST-24">24</A> Chung SJ. Chung S. Lee HS. Kim EJ. Oh KS. Choi HS. Kim KS. Kin YJ. Hahn JH. Kim DH. J. Org. Chem.  2001,  66:  6462 

<A NAME="RD13209ST-25">25</A> Park JI. Tian GR. Kim DH. J. Org. Chem.  2001,  66:  3696 

<A NAME="RD13209ST-26">26</A>

General Procedure for Iodotrimethylsilane Ring Opening
Using conditions originally reported for the analogous N-tosyl-protected lactone, [¹5] [¹6] iodotrimethylsilane (3 equiv) was added dropwise to a solution of the lactone (1 equiv) and EtOH (5 equiv) in dry CH₂Cl₂ under nitrogen at 0 ˚C. The reaction was stirred for 3 h at 0 ˚C and 16 h at r.t. until TLC analysis indicated complete consumption of starting material, at which point aq Na₂S₂O₃ solution (1 M) was added. The organic layer was separated and washed with brine, dried (MgSO₄), and concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography.

<A NAME="RD13209ST-27">27</A> Huo SQ. Org. Lett.  2003,  5:  423 

<A NAME="RD13209ST-28">28</A>

General Procedure for Pd-Catalysed Cross-Coupling
Zinc dust (195 mg, 3 mmol, 6 equiv) was placed in a dry 10 mL round-bottom flask with sidearm, containing a rugby-ball-shaped magnetic stirrer. The flask was flushed with nitrogen, and dry DMF (0.2 mL) was added under nitrogen via syringe followed by catalytic iodine (40 mg, 0.15 mmol, 0.3 equiv). Effervescence was observed and the DMF changed from colourless to yellow and back again. A solution of the appropriate alkyl iodide (0.5 mmol) in DMF (0.3 mL) under nitrogen was transferred to the activated zinc suspension via syringe. The solution was stirred at r.t., and the insertion proceeded with a noticeable exotherm. When the solution had cooled, Pd₂(dba)₃ (11.0 mg, 0.0125 mmol, 2.5 mol%), P(o-tol)₃ (15 mg, 0.05 mmol, 10 mol%) and the aryl iodide (1.3 equiv relative to the alkyl iodide) were added to the flask and the reaction stirred at r.t. overnight.

<A NAME="RD13209ST-29">29</A> Jackson RFW. Rilatt I. Murray PJ. Org. Biomol. Chem.  2004,  2:  110 

<A NAME="RD13209ST-30">30</A> Manolikakes G. Schade MA. Hernandez CM. Mayr H. Knochel P. Org. Lett.  2008,  10:  2765 

<A NAME="RD13209ST-31">31</A> Manolikakes G. Hernandez CM. Schade MA. Metzger A. Knochel P. J. Org. Chem.  2008,  73:  8422 

<A NAME="RD13209ST-32">32</A>

General Procedure for Cu-Catalysed Allylation
The organozinc reagent was formed as described above using zinc (6 equiv) and DMF (0.65 equiv) relative to the alkyl iodide. While the zinc insertion was in progress, CuBr˙DMS (13 mol%) was dried gently under vacuum in a separate flask until it changed from a white to a light green powder. Dry DMF (0.65 equiv) was then added, followed by the allyl chloride (1.3 equiv). Once the zinc insertion reached completion, stirring of the reaction mixture was stopped to allow the zinc powder to settle, and the supernatant was transferred to the solution of allyl chloride and copper catalyst via syringe. After stirring for 18 h at r.t., EtOAc (10 mL) was added and the reaction stirred for a further 15 min. A further aliquot of EtOAc (30 mL) was added and the organic layer separated and washed successively with aq Na₂S₂O₃ solution (1 M, 2 × 30 mL), H₂O (30 mL) and brine (30 mL), dried (MgSO₄), and evaporated under reduced pressure to afford the crude product which was purified by silica gel column chromatography.

<A NAME="RD13209ST-33">33</A> Meyer C. Marek I. Courtemanche G. Normant JF. Tetrahedron Lett.  1993,  34:  6053 

<A NAME="RD13209ST-34">34</A> Meyer C. Marek I. Courtemanche G. Normant JF. Tetrahedron  1994,  50:  11665