Stereo Selective Synthesis and Absolute Configuration Determination of (2E,4S)-4-(t-butoxycarbonylamino)-5-[(3S)-2'-oxo-3'-pyrrolidinyl]-2-pentenoic Acid Ethyl Ester†

doi:10.7503/cjcu20130465

Abstract

Abstract:

(2E,4S)-4-(t-Butoxycarbonylamino)-5-[(3S)-2'-oxo-3'-pyrrolidinyl]-2-pentenoic acid ethyl ester(1) is a key intermediate widely used in drug candidate synthesis, such as the human rhinovious 3C protease inhibitor AG7088 and its related substances which are currently being developed for treatment of common cold, severe acute respiratory syndromes(SARS) and hand, foot, mouth disease(HFMD). Based on existing synthetic routes using L-glutamic acid as starting material, the optical purities of each intermediate product was rigorously examined, and the effects of reaction conditions on the optical purities of the products were studied in details. Meanwhile, racemic samples of each product were prepared from D,L-glutamic acids using the same procedures and used for comparison in high performance liquid chromatography(HPLC) analyses. Thus, new factors that could influence the optical purities of the final products were discovered, and methods for solving the problems were provided. The molecular structure of intermediate product (2S)-2-(t-butoxycarbonylamino)-3-[(3S)-2'-oxo-3'-pyrrolidinyl]propanol(5) was determined by the X-ray diffraction method, which provides direct evidence for the absolute configuration of these products.

Key words: AG7088, Optical purity, Chiral HPLC, X-Ray diffraction

CLC Number:

O621.3

TrendMD:

ZHANG Yongpo, ZHANG Yang, SUN Huailin. Stereo Selective Synthesis and Absolute Configuration Determination of (2E,4S)-4-(t-butoxycarbonylamino)-5-[(3S)-2'-oxo-3'-pyrrolidinyl]-2-pentenoic Acid Ethyl Ester^†[J]. Chem. J. Chinese Universities, 2014, 35(2): 292.

Figures/Tables 6

References 21

[1]	Tian Q., Nayyar N. K., Babu S., Chen L., Tao J., Lee S., Tibbetts A., Moran T., Liou J., Guo M., Tetrahedron Lett., 2001, 42, 6807—6809
[2]	Dragovich P. S., Prins T. J., Zhou R., Webber S. E., Marakovits J. T., Fuhrman S. A., Patick A. K., Matthews D. A., Lee C. A., Ford C. E., J. Med. Chem., 1999, 42, 1213—1224
[3]	Dragovich P. S., Prins T. J., Zhou R., Brown E. L., Maldonado F. C., Fuhrman S. A., Zalman L. S., Tuntland T., Lee C. A., Patick A. K., Matthews D. A., Hendrickson T. F., Kosa M. B., Liu B., Batugo M. R., Gleeson J. P. R., Sakata S. K., Chen L., Guzman M. C., Meador J. W., Ferre R. A., Worland S. T., J. Med. Chem., 2002, 45, 1607—1623
[4]	Dragovich P. S., Prins T. J., Zhou R., Johnson T. O., Hua Y., Luu H. T., Sakata S. K., Brown E. L., Maldonado F. C., Tuntland T., Lee C. A., Fuhrman S. A., Zalman L. S., Patick A. K., Matthews D. A., Wu E. Y., Guo M., Borer B. C., Nayyar N. K., Moran T., Chen L., Rejto P. A., Rose P. W., Guzman M. C., Dovalsantos E. Z., Lee S., McGee K., Mohajeri M., Liese A., Tao J., Kosa M. B., Liu B., Batugo M. R., Gleeson J. P. R., Wu Z. P., Liu J., Meador J. W., Ferre R. A., J. Med. Chem., 2003, 46, 4572—4585
[5]	Yang H., Xie W., Xue X., Yang K., Ma J., Liang W., Zhao Q., Zhou Z., Pei D., Ziebuhr J., Hilgenfeld R., Yuen K., Wong L., Gao G., Chen S., Chen Z., Ma D., Bartlam M., Rao Z., PLoS Biology, 2005, 3, 1742—1752
[6]	Ghosh A. K., Xi K., Grum-Tokars V., Xu X., Ratia K., Fu W., Houser K. V., Baker S. C., Johnson M. E., Mesecar A. D., Bioorg. Med. Chem. Lett., 2007, 17, 5876—5880
[7]	Shie J. J., Fang J. M., Kuo T. H., Kuo C. J., Liang P. H., Huang H. J., Wu Y. T., Jan J. T., Cheng Y. S., Wong C. H., Bioorg. Med. Chem., 2005, 13, 5240—5252
[8]	Mou K., Xu B., Ma C., Yang X., Zou X., Lü Y., Xu P., Bioorg. Med. Chem. Lett., 2008, 18, 2198—2202
[9]	Kuo C. J., Shie J. J., Fang J. M., Yen G. R., Hsu J. T., Liu H. G., Tseng S. N., Chang S. C., Lee C. Y., Shih S. R., Liang P. H., Bioorg. Med. Chem., 2008, 16, 7388—7398
[10]	Ghosh A. K., Xi K., Ratia K., Santarsiero B. D., Fu W., Harcourt B. H., Rota P. A., Baker S. C., Johnson M. E., Mesecar A. D., J. Med. Chem., 2005, 48, 6767—6771
[11]	Johnson T.O., Hua Y., Luu H. T., Brown E. L., Chan F., Chu S. S., Dragovich P. S., Eastman B. W., Ferre R. A., Fuhrman S. A., Hendrickson T. F., Maldonado F. C., Matthews D. A., Meador J. W., Patick A. K., Reich S. H., Skalitzky D. J., Worland S. T., Yang M., Zalman L. S., J. Med. Chem., 2002, 45, 2016—2023
[12]	Lin D., Qian W., Hilgenfeld R., Jiang H., Chen K., Liu H., Sci. China Chem., 2012, 55, 1101—1107
[13]	Hanessian S., Margarita R., Tetrahedron Lett., 1998, 39, 5887—5890
[14]	McCarthy T. J., Nuzzo R. G., Whitesides G. M., J. Am. Chem. Soc., 1981, 103, 3396—3403
[15]	Kokotos G., Padron J. M., Martin T., Gibbons W. A., Martin V. S., J. Org. Chem., 1998, 63, 3741—3744
[16]	Wu Y.C., Bernadat G., Masson G. R., Couturier C. D., Schlama T., Zhu J., J. Org. Chem., 2009, 74, 2046—2052
[17]	Arda A., G. Soengas R., Nieto M. I., Jiménez C., Rodriguez J., Org. Lett., 2008, 10, 2175—2178
[18]	Padrón J. M., Kokotos G., Martín T., Markidis T., Gibbons W. A., Martín V. S., Tetrahedron: Asymmetry, 1998, 9, 3381—3394
[19]	Gu Z.Q., Hesson D. P., Tetrahedron: Asymmetry, 1995, 6, 2101—2104
[20]	Chen L., Lee S., Renner M., Tian Q., Nayyar N., Org. Proc. Res. Dev., 2006, 10, 163—164
[21]	Zhou D. J., Toyooka N., Chem. J. Chinese Universities, 2012, 33(3), 511—515
	(周德军, 丰岗尚树.高等学校化学学报,2012, 33(3), 511—515)

Empirical formula	C₁₂H₂₂N₂O₄	F(000)	560
Formula weight	258.32	θ range	5.82°—72.56°
Temperature/K	113(2)	Limiting indices	-9≤h≤9, -10≤k≤9, -26≤l≤25
Wavelength/nm	0.154187	Reflections collected/unique	16207/2747[R(int)=0.0432]
Crystal system	Orthorhombic	Completeness to θ=72.56(%)	98.9
Space group	P2₁2₁2₁	Absorption correction	Semi-empirical from equivalents
a/nm	0.80190(10)	Max. and min. transmission	0.8768 and 0.8523
b/nm	0.81220(10)	Refinement method	Full-matrix least-squares on F²
c/nm	2.1735(3)	Data/restraints/parameters	2747/0/179
α/(°)	90	Goodness-of-fit on F²	1.089
β/(°)	90	Final R indices[I>2σ(I)]	R₁=0.0293, wR₂=0.0769
γ/(°)	90	R indices(all data)	R₁=0.0303, wR₂=0.0779
Volume/nm³, Z	1.4156(3), 4	Absolute structure parameter	0.19(15)
Calculated density/(g·cm^-3)	1.212	Extinction coefficient	0.0057(8)
Absorption coefficient/mm^-1	0.750	Largest diff. peak and hole/(e·nm^-3)	154 and -192

Empirical formula	C₁₂H₂₂N₂O₄	F(000)	560
Formula weight	258.32	θ range	5.82°—72.56°
Temperature/K	113(2)	Limiting indices	-9≤h≤9, -10≤k≤9, -26≤l≤25
Wavelength/nm	0.154187	Reflections collected/unique	16207/2747[R(int)=0.0432]
Crystal system	Orthorhombic	Completeness to θ=72.56(%)	98.9
Space group	P2₁2₁2₁	Absorption correction	Semi-empirical from equivalents
a/nm	0.80190(10)	Max. and min. transmission	0.8768 and 0.8523
b/nm	0.81220(10)	Refinement method	Full-matrix least-squares on F²
c/nm	2.1735(3)	Data/restraints/parameters	2747/0/179
α/(°)	90	Goodness-of-fit on F²	1.089
β/(°)	90	Final R indices[I>2σ(I)]	R₁=0.0293, wR₂=0.0769
γ/(°)	90	R indices(all data)	R₁=0.0303, wR₂=0.0779
Volume/nm³, Z	1.4156(3), 4	Absolute structure parameter	0.19(15)
Calculated density/(g·cm^-3)	1.212	Extinction coefficient	0.0057(8)
Absorption coefficient/mm^-1	0.750	Largest diff. peak and hole/(e·nm^-3)	154 and -192

O1—C1	0.12349(15)	O4—C8	0.13519(13)	N2—C8	0.13423(14)
O2—C7	0.14192(16)	O4—C9	0.14592(13)	N2—C6	0.14547(14)
O2—H2A	0.085(2)	N1—C1	0.13377(16)	N2—H2B	0.0898(16)
O3—C8	0.12269(13)	N1—C4	0.14600(16)	C1—C2	0.15205(17)
C1—N1—C4	11.358(11)	C1—C2—C3	10.300(10)	N2—C6—C5	11.042(9)
C8—N2—C6	12.351(9)	C5—C2—C3	11.559(10)	C7—C6—C5	11.038(9)
O1—C1—N1	12.492(12)	C2—C3—C4	10.419(10)	O2—C7—C6	11.350(11)
O1—C1—C2	12.610(11)	N1—C4—C3	10.244(10)	O3—C8—N2	12.589(10)
N1—C1—C2	10.896(10)	C2—C5—C6	11.257(9)	O3—C8—O4	12.498(10)
C1—C2—C5	11.315(10)	N2—C6—C7	10.907(10)	N2—C8—O4	10.913(9)

O1—C1	0.12349(15)	O4—C8	0.13519(13)	N2—C8	0.13423(14)
O2—C7	0.14192(16)	O4—C9	0.14592(13)	N2—C6	0.14547(14)
O2—H2A	0.085(2)	N1—C1	0.13377(16)	N2—H2B	0.0898(16)
O3—C8	0.12269(13)	N1—C4	0.14600(16)	C1—C2	0.15205(17)
C1—N1—C4	11.358(11)	C1—C2—C3	10.300(10)	N2—C6—C5	11.042(9)
C8—N2—C6	12.351(9)	C5—C2—C3	11.559(10)	C7—C6—C5	11.038(9)
O1—C1—N1	12.492(12)	C2—C3—C4	10.419(10)	O2—C7—C6	11.350(11)
O1—C1—C2	12.610(11)	N1—C4—C3	10.244(10)	O3—C8—N2	12.589(10)
N1—C1—C2	10.896(10)	C2—C5—C6	11.257(9)	O3—C8—O4	12.498(10)
C1—C2—C5	11.315(10)	N2—C6—C7	10.907(10)	N2—C8—O4	10.913(9)