A Multikilogram-Scale Synthesis
of (R)-Methyl 2-[(1r,4R)-4-(tert-Butoxy­carbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate - A
Doubly Protected Building Block with Three Points of Variation

Gregory Carr; Sam Butterworth; Phil Walker; Folkert Reck; Bolin Geng; Lakshmipathi Pandarinathan

doi:10.1055/s-0031-1289724

PAPER

A Multikilogram-Scale Synthesis of (R)-Methyl 2-[(1r,4R)-4-(tert-Butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate - A Doubly Protected Building Block with Three Points of Variation

Gregory Carr*^a, Sam Butterworth^a, Phil Walker^a, Folkert Reck^b, Bolin Geng^b, Lakshmipathi Pandarinathan^b
^a Astrazeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
^b Infection Innovative Medicines Unit, AstraZeneca R & D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA
Fax: +44(1625)513910; e-Mail: greg.carr@astrazeneca.com;

Abstract

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Abstract

A robust and scalable synthesis of (R)-methyl 2-[(1r,4R)-4-(tert-butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate is reported. This serves as a scaffold for the preparation of trans-substituted aminocyclohexanes. The key synthetic step is the reduction of d-4-hydroxyphenylglycine, or a protected equivalent, to achieve the required regiochemistry across the cyclohexyl ring.

Key words

chirality - diastereoselectivity - hydrogenation - protecting groups - reduction

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References

1a Levin JI, Chen JM, Cole DC, Du MT, and Laakso LM. inventors; US Patent Appl. Publ. US 6225311. ; Chem. Abstr. 2001, 134, 326767

1b Levin JI, Chen JM, and Cole DC. inventors; Patent PCT Int. Appl. WO 2000044709. ; Chem. Abstr. 2000, 133, 150908

2a Semple JE, Brunck TK, Levy OE, and Tamura SY. inventors; Patent PCT Int. Appl. WO 2001027141. ; Chem. Abstr. 2001, 134, 311435

2b Scarborough RM, Marlowe CK, and Zhu B. inventors; US Patent Appl. Publ. US 6211154. ; Chem. Abstr. 2001, 134, 266567

2c Scarborough RM, Marlowe CK, and Zhu B. inventors; US Patent Appl. Publ. US 6022861. ; Chem. Abstr. 2000, 132, 137734

3a Cronin M, Geng B, and Reck F. inventors; Patent PCT Int. Appl. WO 2010055348. ; Chem. Abstr. 2010, 152, 592011

3b Hubschwerlen C, Rueedi G, Surivet J, and Zumbrunn Acklin C. inventors; Patent PCT Int. Appl. WO 2009147616. ; Chem. Abstr. 2009, 152, 37571

3c Hubschwerlen C, Rueedi G, Surivet J, and Zumbrunn Acklin C. inventors; Patent PCT Int. Appl. WO 2008078305. ; Chem. Abstr. 2008, 149, 153099

4 Tullis JS. Laufersweiler MJ. VanRens JC. Natchus MG. Bookland RG. Almstead NG. Pikul S. De B. Hsieh LC. Janusz MJ. Branch TM. Peng SX. Jin YY. Hudlicky T. Oppong K. Bioorg. Med. Chem. Lett. 2001, 11: 1975

5 Parmee ER. He J. Mastracchio A. Edmondson SD. Colwell L. Eiermann G. Feeney WP. Habulihaz B. He H. Kilburn R. Leiting B. Lyons K. Marsilio F. Patel RA. Petrov A. Di Salvo J. Wu JK. Thornberry NA. Weber AE. Bioorg. Med. Chem. Lett. 2004, 14: 43

6 Banfi A. Benedini F. Casanova G. Perego R. Toma L. Synth. Commun. 1989, 19: 1787

7 Hirai Y. Yokota K. Momose T. Heterocycles 1994, 39: 603

8 Hulin B, Parker JC, and Piotrowski DW. inventors; US Patent Appl. Publ. US 20050234065. ; Chem. Abstr. 2005, 143, 406151

9 Slade JS. Vivelo JA. Parker DJ. Bajwa J. Liu H. Girgis M. Parker DT. Repic O. Blacklock T. Org. Process Res. Dev. 2005, 9: 608

10 For alternative preparations of 12, see: Ohta Y. Terada K. Masuda T. Sanda F. Heterocycles 2009, 78: 1477

11 Vaultier M. Knouzi N. Carrie R. Tetrahedron Lett. 1983, 24: 763

12 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis 3rd ed.: Wiley-Interscience; New York: 1999.

13 Turner JJ. Sikkema FD. Filippov DV. van der Marel GA. van Boom JH. Synlett 2001, 1727

14 Bretherick’s Handbook of Reactive Chemical Hazards Vol. 1-2, 7th ed.: Urben P. Elsevier; Amsterdam: 2007.

Supplementary Material

Supporting Information

A Multikilogram-Scale Synthesis of (R)-Methyl 2-[(1r,4R)-4-(tert-Butoxy­carbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate - A Doubly Protected Building Block with Three Points of Variation

A Multikilogram-Scale Synthesis of (R)-Methyl 2-[(1r,4R)-4-(tert-Butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate - A Doubly Protected Building Block with Three Points of Variation