Highly efficient enantiospecific synthesis of imidazoline-containing amino acids using bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate

Article abstract of DOI:10.1021/ol049439c

A highly efficient enantiospecific synthesis of imidazoline-based amino acids is reported from dipeptides composed of a C-terminal β-ammo-α- amino acid residue using bis(triphenyl) oxodiphosphonium trifluoromethanesulfonate. These imidazolines were easily converted to imidazoles and incorporated into macrolactam analogues of bistratamide H without loss of stereochemical integrity.

Full text of DOI:10.1021/ol049439c

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1681-1683
Highly Efficient Enantiospecific
Synthesis of Imidazoline-Containing
Amino Acids Using
Bis(triphenyl)oxodiphosphonium
Trifluoromethanesulfonate
Shu-Li You and Jeffery W. Kelly*
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, La Jolla, California 92037
jkelly@scripps.edu
Received March 25, 2004
ABSTRACT
A highly efficient enantiospecific synthesis of imidazoline-based amino acids is reported from dipeptides composed of a C-terminal â-amino-
r-amino acid residue using bis(triphenyl) oxodiphosphonium trifluoromethanesulfonate. These imidazolines were easily converted to imidazoles
and incorporated into macrolactam analogues of bistratamide H without loss of stereochemical integrity.
Derivatives of 2-imidazoline and 2-imidazole have attracted
substantial interest due to their interesting biological activi-
ties.1 In addition, these heterocycles are useful synthetic
intermediates2 and function as chiral auxiliaries,3 chiral
catalysts,4 and ligands for asymmetric catalysis.5 The struc-
tures of imidazolines and imidazoles are analogous to those
of oxazolines and oxazoles, or thiazolines, and thiazoles,
respectively. The latter heterocycles are found in numerous
macrolactams isolated from marine sources.6 Developing new
highly enantiospecific methodology for the synthesis of
2-imidazolines and 2-imidazoles will enable the synthesis
and biological evaluation of a new class of macrolactam
natural product analogues containing these heterocycles, as
demonstrated herein. While enantiopure imidazolines have
been prepared from 1,2-diamines,3-5,7 amido alcohols,4e,8 and
other precursors,9 to the best of our knowledge, the enantio-
(1) (a) Li, H.-Y.; Drummond, S.; DeLucca, I.; Boswell, G. A. Tetra-
hedron 1996, 52, 11153. (b) Ueno, M.; Imaizumi, K.; Sugita, T.; Takata,
I.; Takeshita, M. Int. J. Immunopharm. 1995, 17, 597. (c) Rondu, F.;
LeBihan, G.; Wang, X.; Lamouri, A.; Touboul, E.; Dive, G.; Bellahsene,
B.; Renard, P.; Guardiola-Lemaˆıtre, B.; Mane´chez, D.; Pe´nicaud, L.; Ktorza,
A.; Godfroid, J.-J. J. Med. Chem. 1997, 40, 3793. (d) Bousquet, P.; Feldman,
J. Drugs 1999, 58, 799. (e) Schann, S.; Bruban, V.; Pompermayer, K.;
Feldman, J.; Pfeiffer, B.; Renard, P.; Scalbert, E.; Bousquet, P.; Ehrhardt,
J.-D. J. Med. Chem. 2001, 44, 1588. (f) Gust, R.; Keilitz, R.; Schmidt, K.;
von Rauch, M. J. Med. Chem. 2002, 45, 3356.
(3) (a) Jones, R. C. F.; Turner, I.; Howard, K. J. Tetrahedron Lett. 1993,
34, 6329. (b) Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett.
1996, 37, 1707. (c) Langlois; Y.; Dalko, P. I. J. Org. Chem. 1998, 63,
8107.
(2) (a) Jones, R. C. F.; Nichols, J. R. Tetrahedron Lett. 1990, 31, 1771.
(b) Jones, R. C. F.; Smallridge, M. J.; Chapleo, C. B. J. Chem. Soc., Perkin
Trans. 1 1990, 385. (c) Hayashi, T.; Kishi, E.; Soloshonok, V. A.; Uozumi,
Y. Tetrahedron Lett. 1996, 37, 4969. (d) Lin, Y.-R.; Zhou X.-T.; Dai, L.-
X.; Sun, J. J. Org. Chem. 1997, 62, 1799. (e) Hsiao, Y.; Hegedus, L. S. J.
Org. Chem. 1997, 62, 3585. (f) Jun, M. E.; Huang, A. Org. Lett. 2000, 2,
2659.
(4) (a) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. (b) Isobe, T.;
Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun. 2001, 243.
(5) (a) Botteghi, C.; Schionato, A.; Chelucci, G.; Brunner, H.; Ku¨rzinger,
A.; Obermann, U. J. Organomet. Chem. 1989, 370, 17. (b) Morimoto, T.;
Tachibana, K.; Achiwa, K. Synlett 1997, 783. (c) Davinport, A. J.; Davies,
D. L.; Fawcett, J.; Russell, D. R. J. Chem. Soc., Perkin Trans. 1 2001,
1500. (d) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713.
10.1021/ol049439c CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/17/2004

specific synthesis of imidazoline-based amino acids has not
been reported from dipeptides composed of a C-terminal
â-amino-R-amino acid residue or N-acylated â-amino-R-
amino acids. Furthermore, there are very few reports of the
synthesis of imidazole-based amino acids.10
Recently, we reported biomimetic methodology for the
synthesis of thiazolines from N-acylated cysteine sub-
structures using bis(triphenyl) oxodiphosphonium trifluoro-
methanesulfonate (Scheme 1, X ) STrt (trityl), Y ) S).11a
mercially available N-R-Fmoc-N-â-4-methyltrityl-l-diamino-
propionic acid or L-serine methyl (or benzyl) ester.12 To
examine the scope and limitations of imidazoline formation
by the bisphosphonium salt, â-tosylamino-R-acylamino esters
(1a-6a) were subjected to the reaction conditions shown in
Table 1. In general, this reaction afforded imidazoline
Table 1. Bis-phosphonium Salt-Mediated Synthesis of
Imidazolines from â-Tosylamino-R-acylamino Esters
Scheme 1. Heterocycle Formation Mediated by Bis(triphenyl)
Oxodiphosphonium Trifluoromethanesulfonate
entry
substrates, R
products
yield (%)a
ee (%)b
1
1a , Ph
2a , Ph
3a , 4-Me-Ph
4a , 4-MeO-Ph
5a , Bn
1b
2b
3b
4b
5b
6b
96
95
97
95
94
90
97
98
98
97
99
86
2c
Thiazolines are formed by nucleophilic attack of the
cysteine thiol on the phosphonium-activated amide carbonyl
group of the preceding residue, followed by dehydration via
phosphine oxide formation. The reaction proceeds in high
yield with excellent chemo- and enantiospecificity, without
epimerization of the exocyclic stereocenter. Herein, we report
a highly efficient enantiospecific synthesis of imidazoline-
based amino acids using bis(triphenyl) oxodiphosphonium
trifluoromethanesulfonate (Scheme 1, X ) NHTs, Y ) NTs).
The imidazole-based amino acids comprising the macro-
lactam natural product analogues prepared within are ob-
tained by oxidizing the corresponding imidazolines.
3
4
5
6d
6a , 3-CF3-Ph
a Isolated yield. b Determined by chiral HPLC. c R configuration substrate
was used. d Starting material exhibited 96% ee.
products in high yields with excellent retention of stereo-
chemistry at what was the R-carbon. A decreased enantio-
meric excess (86%) was observed only with the 3-CF3-
phenyl-substituted substrate (Table 1, entry 6).
To apply this method to the synthesis of imidazoline-based
amino acids, several R-N-protected dipeptides with tosyl
protected â-amino groups were synthesized and evaluated
as starting materials (7a-13a, Table 2).
The starting materials for imidazoline formation, N-
acylated â-amino-R-amino esters (1a-6a), and fully pro-
tected dipeptides composed of a C-terminal â-amino-R-amino
ester residue (7a-13a), were synthesized either from com-
(6) (a) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Corbett, T. H.;
Valeriote, F. A. J. Am. Chem. Soc. 1990, 112, 8195. (b) Carmeli, S.; Moore,
R. E.; Patterson, G. M. L. Tetrahedron Lett. 1991, 32, 2593. (c) Boyce, R.
J.; Mulqueen, G. C.; Pattenden, G. Tetrahedron 1995, 51, 7321. (d) Ogino,
J.; Moore, R. E.; Patterson, G M. L.; Smith, C. D. J. Nat. Prod. 1996, 59,
581. (e) Admi, V.; Afek, U.; Carmeli, S. J. Nat. Prod. 1996, 59, 396. (f)
Banker, R.; Carmeli, S. J. Nat. Prod. 1998, 61, 1248. (g) Ishida, K.;
Nakagawa, H.; Murakami, M. J. Nat. Prod. 2000, 63, 1315. (h) Rudi, A.;
Chill, L.; Aknin, M.; Kashman, Y. J. Nat. Prod. 2003, 66, 575. (i) Degnan,
B. M.; Hawkins, C. J.; lavin, M. F.; McCaffrey, E. J.; Parry, D. L.; Watters,
D. J. J. Med. Chem. 1989, 32, 1354. (j) Foster, M. P.; Concepcio´n, G. P.;
Caraan, G. B.; Ireland, C. M. J. Org. Chem. 1992, 57, 6671. (k) Perez, L.
J.; Faulkner, D. J. J. Nat. Prod. 2003, 66, 247. (l) For reviews, see:
Davidson, B. S. Chem. ReV. 1993, 93, 1771. Wipf, P. Chem. ReV. 1995,
95, 2115.
(7) (a) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431.
(b) Sutcliffe, O. B.; Bryce, M. R.; Batsanov, A. S. J. Organomet. Chem.
2002, 656, 211.
(8) Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Smyth, M.
P. J. Org. Chem. 2002, 67, 3919.
(9) (a) Hunter, D. H.; Sim, S. K. Can. J. Chem. 1972, 50, 669. (b) Oi,
R.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 999. (c) Molina, P.; D´ıaz,
I.; Ta´rraga, A. Synett 1995, 1031. (d) Hulme, C.; Ma, L.; Romano, J.;
Morrissette, M. Tetrahedron Lett. 1999, 40, 7925. (e) Zhou, X.-T.; Lin Y.-
R.; Dai, L.-X.; Sun, J.; Xia, L.-J.; Tang, M.-H. J. Org. Chem. 1999, 64,
1331. (f) Acharya, A. N.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem.
2001, 66, 8673. (g) Peddibhotla, S.; Tepe, J. J. Synthesis 2003, 1433.
(10) (a) Haberhauer, G.; Rominger, F. Tetrahedron Lett. 2002, 43, 6335.
(b) Haberhauer, G.; Rominger, F. Eur. J. Org. Chem. 2003, 3209.
(11) (a) You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed.
2003, 42, 83. (b) You, S.-L.; Kelly, J. W. Chem. Eur. J. 2004, 10, 71. (c)
You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68, 9506.
Table 2. Bis-phosphonium Salt-Mediated Synthesis of
Imidazoline-Based Amino Acids from Dipeptides
R (configuration),
yield
ee
(%)c
entry
PG
R′
product (%)a
drb
1
2
3
4
5
6
7
7a , Cbz
Bn (L), Me
Bn (D), Me
i-Pr (L), Me
i-Pr (D), Me
i-Pr (L), Bn
i-Pr (D), Bn
i-Pr (L), Bn
7b
71
75
74
81
74
76
88
>99/1
>99/1
99
98
8a , Cbz
8b
9a , Cbz
9b
>99/1 >99.5
>99/1 99
>99/1 >99.5
>99/1 99
>99/1 >99.5
10a , Cbz
11a , Cbz
12a , Cbz
13a , Fmoc
10b
11b
12b
13b
a Isolated yield. b Determined by NMR and chiral HPLC. c Determined
by chiral HPLC.
In all cases, the corresponding imidazolines were obtained
in moderate to very good yields with excellent enantio-
selectivity observed at both chiral centers. Several imid-
1682
Org. Lett., Vol. 6, No. 10, 2004

azoline-based amino acids (8b-13b) revealed two sets of
peaks in their NMR spectra. Since only one set of proton
signals was observed when the sample was heated to 52 °C,
this is likely due to slow epimerization of the nitrogen atom
bearing a tosyl group.12
Scheme 3. Incorporation of Imidazole-Based Amino Acid 16
into a Macrolactam Analogue of Bistratamide H (19)6k
As shown in Scheme 2, the Cbz- and Fmoc-protected
imidazoline-based amino acids 11b and 13b were converted
Scheme 2. Synthesis of Imidazole-Based Protected Amino
Acids
imidazole in 16 was not necessary). After removal of the
Fmoc and allyl protecting groups from compound 18 using
diethylamine and a solid-phase Pd-catalyst, respectively, the
final macrolactamization was accomplished using PyBOP
and DMAP affording 19 in 64% yield.11b-c
In summary, highly efficient enantiospecific syntheses of
imidazolines and imidazoline-based amino acids have been
achieved using bis(triphenyl) oxodiphosphonium trifluoro-
methanesulfonate-mediated cyclodehydrations. These imid-
azolines were easily converted to imidazoles and incorporated
into macrolactam analogues of bistratamide H without loss
of stereochemical integrity.
to imidazoles 14 and 15, using BrCCl3/DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene)13 and activated MnO2,11b,c respectively.
Both the benzyl and tosyl groups were removed from 15 by
hydrogenation affording 16.
To evaluate the suitability of using these heterocyclic
amino acids as building blocks for natural product analogues,
imidazole 16 was incorporated into a macrolactam related
to bistratamide H as shown in Scheme 3.6k Amide 17 (a
known compound11b) was first treated with diethylamine to
liberate the Fmoc group. The resulting free amine of 17 was
coupled with dehydration to the carboxyl group of 16
affording diamide 18 in 93% yield (protection of the
Acknowledgment. We gratefully acknowledge NIH
Grant GM63212 and the Skaggs Institute for Chemical
Biology for generous financial support. We thank Professor
Evan T. Powers for helpful discussions.
Supporting Information Available: Experimental details
and NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) See Supporting Information.
(13) (a) Williams, D. R.; Lowder, P. D.; Gu, Y.; Brooks, D. A.
Tetrahedron Lett. 1997, 38, 331. (b) Downing, S. V.; Aguilar, E.; Meyers,
A. I. J. Org. Chem. 1999, 64, 826.
OL049439C
Org. Lett., Vol. 6, No. 10, 2004
1683