method for deprotection: complete oxidation of the dithiane
ring into disulfone with hydrogen peroxide catalyzed by
ammonium molybdate, followed by base-catalyzed elimina-
tion. In view of our results, we envisioned that a controlled
electrochemical oxidation could prove a more delicate
technique for amino acid deprotection. In this study we
synthesized the Dim esters of t-BOC-protected phenylalanine
(4), valine, (5), and leucine (6) via the DCC/4-pyrrolidi-
Scheme 1
It is well-known that cation radicals in acetonitrile are
generally superacids. For example, Arnold reported the pKa
of the toluene cation radical to be -12.4 It is therefore
plausible that the proton at position 2 of the dithiane ring is
eliminated, prompting the departure of the carboxylate. We
did not identify the final product of the dithiane ring
degradation, although it is known from the literature that
the end products of anodic oxidations of various substituted
dithianes are 1,2-dithiolane 1-oxides.5
We also considered the possibility of an intramolecular
elimination of carboxylic acid from the cation radical, similar
to pyrolysis of acetates. To this end we carried out ab initio
computations at the MP2/6-31G(d) level of theory. For
computational simplicity we utilized the Dim ester of formic
acid. After full geometry optimization of the starting cation
radical, we located the transition state and found the ZPE-
corrected barrier to be only 22.7 kcal/mol (Figure 2). Thus,
nopyridine mediated esterification with 2-(hydroxymethyl)-
1,3-dithiane.7,8 Electrolytic deprotection was carried out in
a 85% acetonitrile-15% 50 mM aqueous sodium acetate
solution. We utilized a divided electrolytic cell with two 5
cm2 platinum electrodes at a constant current of 3 mA.9 The
reaction progress was monitored by reversed-phase (C18)
HPLC using the same 85:15 acetonitrile-50 mM aqueous
sodium acetate buffer. The proton NMR of the reaction
mixture at 100% conversion showed complete deprotection
of the C terminus, leaving the t-BOC-protected N-terminus
intact. The isolated yields were also determined (Table 1).
Table 1
yield, %
ester
esterification
deprotectiona
4, R ) CH2Ph
5, R ) CH(CH3)2
6, R ) CH2CH(CH3)2
90
84
98
74
65
67
a Isolated yields.
Although 100% deprotection was achieved in 3 h, ex-
tended (e.g., overnight) electrolysis did not cause any
overoxidation of the deprotected amino acids, conceivably
Figure 2.
(6) Kunz, H.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1983, 22,
62. Waldmann, H.; Kunz, H. J. Org. Chem. 1988, 53, 4172.
(7) General procedure for esterification with DCC/4-aminopyridines:
Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46, 4475-4478.
(8) A note about the stability of Dim esters: Kunz and Waldmann6
reported that in acidic media the Dim esters were stable enough to allow
selective deprotection of the t-BOC-protected N-termini. We also tested
the stability of Dim esters under basic conditions. For example, an ethereal
solution of 3 was shaken vigorously with 10% KOH. The layers were
separated. The organic layer contained pure starting material. The aqueous
layer was acidified with HCl and extracted with ether. No benzoic acid
was detected, attesting to the stability of Dim esters to bases.
(9) For example: 82.6 mg of t-BOC-Phe-O-Dim (4) was dissolved in
20 mL of 85:15 acetonitrile-50 mM aqueous NaOAc. This solution was
added to the cathode chamber of the divided cell; the anode chamber was
filled solely with the acetonitrile buffer solution. A current of 3 mA was
maintained for 3 h. HPLC monitoring showed that all starting material
disappeared at this point. Solvent was removed, and the residue was worked
up with 20 mL of 10% KOH/10 mL of ether. The aqueous layer was
separated, acidified with hydrochloric acid, extracted with 2 × 15 mL of
ether, and dried over Na2SO4. Ether was removed to give 41 mg (74%) of
faintly yellow oil. Both NMR and HPLC confirmed pure N-t-BOC-Phe-
OH.
it is conceivable that the reaction proceeds via this elimina-
tion mechanism.
We then proceeded to the primary goal of this projectsto
develop electrochemically removable protection for amino
acids.
Kunz and Waldmann,6 who originally introduced the Dim
ester protecting group, utilized quite a drastic wet chemistry
(3) Electrolysis conditions: 5 cm2 Pt cathode and anode, 20 °C,
acetonitrile, 9 mM Dim ester, 0.1 M LiClO4, under constant current (3 mA)
conditions. Workup included evaporation of the solvent, addition of 10%
aqueous KOH, ether extraction of organic side products, and acidification
with hydrochloric acid followed by ethereal extraction of the acid.
(4) Nicholas, A. M. d. P.; Arnold, D. R. Can. J. Chem. 1982, 60, 2165.
(5) Glass, R. S.; Petsom, A.; Wilson, G. S. J. Org. Chem. 1986, 51,
4337.
800
Org. Lett., Vol. 2, No. 6, 2000