9796
J. Am. Chem. Soc. 1996, 118, 9796-9797
apparent after several days or less at rt (room temperature),
depending on crystal quality. Simple amines reacted rapidly
with 1 and 2 under aprotic conditions. With zwitterionic amino
acids, the best results were achieved by stirring a suspension
of 1 or 2 in a solution of the amino acid in NaOH-H2O while
maintaining pH in the range of 10-10.5. This method afforded
crystalline N-Bts and N-Ths derivatives in 92-97% yield with
alanine, valine, phenylalanine, proline, and phenylglycine (Phg).8
The N-Ths derivatives formed significantly faster (2 h at 0 °C
for Ths-Phg vs 10 h at 10 °C for Bts-Phg), probably because
ThsCl has greater water solubility compared to BtsCl. Under
similar conditions, but using 3.1 equiv of ThsCl, both amino
groups of lysine were protected (NR,Nꢀ-bis-Ths-Lys, 89%).
Serine reacted selectively using 1.5 equiv of ThsCl (74% N-Ths-
Ser isolated),9 but similar treatment with BtsCl afforded a
mixture. The standard method produced the mono-Bts deriva-
tive of tryptophan (>95% yield) without affecting the indole
nitrogen. Tyrosine gave the bis-sulfonylation product using 3.1
equiv of ThsCl at pH 10 (90%), but O-sulfonylation could be
prevented by temporary O-silylation. Thus, heating with bis-
(trimethylsilyl)acetamide (2.1 equiv, CH3CN) followed by
reaction with BtsCl in pyridine afforded N-Bts-Tyr in 72% yield.
Modified nonaqueous conditions were also used to prepare Bts-
Phg from Phg + Me3SiCl/Et3N (THF, reflux) followed by BtsCl/
Et3N to give Bts-Phg in 87% yield. Useful bis-N-sulfonylation
of arginine was not achieved under a variety of conditions,
however.
Heteroarene-2-sulfonyl Chlorides (BtsCl; ThsCl):
Reagents for Nitrogen Protection and >99%
Racemization-Free Phenylglycine Activation with
SOCl2
Edwin Vedejs,* Shouzhong Lin, Artis Klapars, and
Jiabing Wang
Chemistry Department, UniVersity of Wisconsin
Madison, Wisconsin 53706
ReceiVed May 6, 1996
Acid chlorides derived from N-acylamino acids undergo facile
cyclization to the easily racemized oxazolinones.1 Nitrogen
protection using alkoxycarbonyl groups improves amino acid
chloride stability and the N-(fluorenylmethoxy)carbonyl (FMOC)
derivatives can be stored in crystalline form.1b However, they
can still cyclize to oxazolinones, especially if tertiary amines
are present.2 The corresponding acid fluorides may offer a better
combination of reactivity and stability for use in peptide
synthesis.3,4 For applications that demand the reactivity of an
acid chloride, the risk of oxazolinone formation can be avoided
by using an arenesulfonyl group to protect nitrogen,5,6 but
arenesulfonamide cleavage in the amino acid series has been
difficult. We report a solution to this problem using the
heteroarenesulfonyl chlorides benzothiazole-2-sulfonylchloride
(1, BtsCl, “betsyl” chloride) or 5-methyl-1,3,4-thiadiazole-2-
sulfonyl chloride (2, ThsCl, “thisyl” chloride).
Removal of the N-Bts or N-Ths groups was accomplished at
rt by treatment with Zn/HOAc-EtOH or Al-Hg/ether-H2O.
Slow addition of excess 50% H3PO2 to a ca. 1 M DMF solution
of the substrate also worked, although removal of the DMF was
tedious. No cleavage was observed in THF at rt, but good
results were obtained by slow addition of 50% H3PO2 to the
substrate in refluxing THF (for example, NR-Bts-Trp to Trp;
90% isolated). Other reducing agents (Na2S2O4 or NaHSO3)
removed the Bts group of N-Bts-Phg in refluxing EtOH-H2O.
The most convenient Zn, Al-Hg, or H3PO2 conditions did not
cleave p-toluenesulfonamides in control experiments, indicating
that the electron-withdrawing heterocycle activates the sulfone
for reduction.10 Deprotection of N-Bts-Phg with Zn/HOAc-
EtOH at rt (14 h) produced Phg, in quantitative yield, 99.9%
ee by chiral stationary phase (CSP) HPLC assay after conversion
to the 3,5-dinitrobenzamide (DNB). Deprotection by the drop-
wise addition of excess 50% aqueous H3PO2 at 50 °C over 2 h
gave Phg with 99.5% ee (93% yield). Benzothiazole (3) was
formed as the byproduct of reductive cleavage and was easily
separated by organic extraction. Deprotection of N-Ths-Phg
also proceeded smoothly (>99.8% ee using Zn-HOAc/EtOH,
Zn-HCl/THF, Al-Hg/THF-H2O, >90% yield). The Bts
group of Bts-Phg easily survived conditions that cleave BOC
(CF3CO2H, 2 days at rt) or FMOC (Et2NH, DMF, 21 h, rt).
Slow cleavage did occur in CF3CO2H/C6H5SH (ca. 25%, 2 days
rt), and Cbz hydrogenolysis conditions (H2, Pd/C, EtOAc)
resulted in partial Bts cleavage and catalyst poisoning. Depro-
tection with NaOH was effective for N-Bts-Pro (2.5 M NaOH:
rt, 12 h, >99.8% ee by CSP HPLC after conversion to DNB-
Pro-OMe; neutral byproduct 2-hydroxybenzothiazole, 4), but
harsher conditions were needed for N-Bts-Phg (1 M NaOH:
90-100 °C, 24 h; 14% ee). Finally, NR-Bts-Trp-Met-Asp-Phe-
NH2 (protected cholecystokinin C-terminal tetrapeptide) was
cleaved using slow addition of 50% H3PO2 in DMF at rt.11
Commercially available 2-mercaptobenzothiazole or 2-mer-
capto-5-methyl-1,3,4-thiadiazole were treated with excess chlo-
rine in HOAc-H2O.7 The resulting crystalline 1 or 2 were
stable for months in the freezer, but evolution of SO2 was
(1) (a) For reviews, see: Kemp, D. S. In The Peptides; Gross, E.,
Meienhofer, J., Eds.; Academic Press, Inc.: New York, 1979; Vol. 1, p
315. Beyermann, M.; Granitza, D.; Bienert, M.; Carpino, L. A. In
Peptides: Chemistry and Biology; Marshall, G. R., Ed.; ESCOM: Leiden,
The Netherlands, 1988; p 101, 189. Bodanszky, M. Principles of Peptide
Synthesis, 2nd ed.; Springer-Verlag: Berlin, 1993. (b) Carpino, L. A.; Cohen,
B. J.; Stephens, K. E., Jr.; Sadat-Aalaee, S. Y.; Tien, J.-H.; Langridge, D.
C. J. Org. Chem. 1986, 51, 3732. Frerot, E.; Coste, J.; Pantaloni, A.; Dufour,
M.-N.; Jouin, P. Tetrahedron 1991, 47, 259. Benoiton, N. L.; Lee, Y. C.;
Steinaur, R.; Chen, F. M. F. Int. J. Pept. Protein Res. 1992, 40, 559. Spencer,
J. R.; Antonenko, V. V.; DeLaet, N. G. J.; Goodman, M. Int. J. Pept. Protein
Res. 1992, 40, 282. Akaji, K.; Kuriyama, N.; Kiso, Y. Tetrahedron Lett.
1994, 35, 3315.
(2) Carpino, L. A.; Chao, H. G.; Beyerman, M.; Bienert, M. J. Org.
Chem. 1991, 56, 2635. Sivanandaiah, K. M.; Suresh Babu, V. V.;
Shankaramma, S. C. Int. J. Pept. Protein Res. 1994, 44, 24.
(3) (a) Carpino, L. A.; Mansour, E.-S. M. E.; Sadat-Aalaee, D. J. Org.
Chem. 1991, 56, 2611. (b) Carpino, L. A.; El-Faham, A. J. Am. Chem.
Soc. 1995, 117, 5401. (c) Wenschuh, H.; Beyermann, M.; Krause, E.; Brudel,
M.; Winter, R.; Schumann, M.; Carpino, L. A.; Bienert, M. J. Org. Chem.
1994, 59, 3275. Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms,
R. H. J. Am. Chem. Soc. 1990, 112, 9651. (d) Carpino, L. A.; Mansour,
E.-S. M. E.; El-Faham, A. J. Org. Chem. 1993, 58, 4162.
(4) (a) Kearns, J.; Kayser, M. M. Tetrahedron Lett. 1994, 35, 2845. (b)
Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 6595. (c) Weisz, I.;
Roboz, J.; Bekesi, J. G. Tetrahedron Lett. 1996, 37, 563.
(5) (a) Fischer, E. Chem. Ber. 1915, 48, 93. (b) Cleavage of N-(toluene-
sulfonyl)amino protecting groups: Maurer, P. J.; Takahata, H.; Rapoport,
H. J. Am. Chem. Soc. 1984, 106, 1095. Hamada, T.; Nishida, A.; Yonemitsu,
O. J. Am. Chem. Soc. 1986, 108, 140. Art, J. F.; Kestemont, J. P.;
Soumillion, J. Ph. Tetrahedron Lett. 1991, 32, 1425. Roemmele, R.;
Rapoport, H. J. Org. Chem. 1988, 53, 2367. (c) Vedejs, E.; Lin, S. J. Org.
Chem. 1994, 59, 1602.
(6) (a) Carpino, L. A.; Shroff, H.; Triolo, S. A.; Mansour, E.-S. M. E.;
Wenschuh, H.; Albericio, F. Tetrahedron Lett. 1993, 34, 7829. Arzeno, H.
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(8) (R)-Phenylglycine (0.483 g, 3.20 mmol) was dissolved in 0.25 M
aqueous NaOH (11 mL, 2.8 mmol) at 10 °C. Solid 1 (1.10 g, 4.72 mmol)
was added, and the suspension was stirred for 10 h at 10 °C while the pH
was monitored and 1.3 M NaOH was added to maintain pH 10-10.5 (1.09
g, 97%), mp 162-165.5 °C (dec) after acidification and recrystallization.
(9) Product is water soluble; good yield requires evaporation of water.
(10) Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1990, 31, 7105.
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S0002-7863(96)01485-0 CCC: $12.00 © 1996 American Chemical Society