Tetr&dmnletters.Vol.34.No.34.PP.5393-5396.

1993 oo40-4039/93
S6.00+ .oO
Printedin GreatBritain PagamonPressLbl

An Efficient Procedure for the Demethylation of Aryl-Methyl

Ethers in Optically Pure Unusual Amino Acids

Guigett LI, Dine& potel and Victor J. Hruby*

Abstract: An efficbt pnxedmz was developedfor the removalof methylgroupsfromarylmahyl ether&without

racemization.in derivative8of unusual amino acids that are.of significat importancein the design of highly
selective peptideand proteinligands with specific confcsmaMW and topographicalfeatures.Deme&yMionof
amnaticaminoecidscanrtsultinm~iabhfnaarssInneepa~,~mcntwmildpmccdunwhich
have been developedmpraa~ts a facii lad pr&csl methodfor deme&yletionof Tyr (OMe)derivatives,including
novel sidaain ringor c-3 modsed analog&

Ethers are among the most used protective groups in synthetic organic chemistry.t Methylation of a
hydroxyl moiety is regarded as one of the most effective protection methodologies, due to its very high stability
under numerous reaction conditions. However, it is this fact that makes it difficult to cleave the methoxyl group
under many normal milder conditions? especially when them exists an active hydrogen in the optically pure
substrates. Some reagents developed for the &methylation of aromatic methyl ethers include Lewis acids,
mixed mineral acids, oxidants, mducdants as well as silica & aluminum compounds.3a-e Very few methods are
suitable for demethylatlon for aromatic amino acids for considering the so!ubility of amino acids and
racemization problems encotmtemd with the active hydrogens in the a positions.
We have successfully developed novel methodologies utilizhrg methylated phenolic hydroxy moieties
which were used as the protecting group (directly from Aldrich) in the total procedure for the synthesis of four
optically pure isomers of D- and L-O-Methyl-p-Methyl Tyrosine,4D- and L-U-Methyl-2’.&Dimethyltyrosine
and a series of their precursors.5 Obviously, the efficient/selective demethylation of the P-methyl tyrosine
derivatives became crucial with respect to maintenance of optical purity in order to obtain the unusual Boc-
amino acids for incorporation into polypeptide hormones. The complex of 48% hydrobromic acid and acetic
acid6 (v/v=S/l, refhnt for 4 hm) has heen tried in our laboratories msulting in successful demethylation but with
some observed racemization (about 30%) in optically pure special amino acids. It is for this mason we did not
try other HX-HOAc (X= Cl, I) reagents, even though they have been used for the demethylation of 3.5 di-iodo-
p-methoxyl-phenoxy-N-acetyl-L-phenylalanlne ethyl ester (reflex 4-18 hrs).7 Hem we report a successful
procedure in an acetic acid free aqueous phase for the demethylation of five O-methyl-P-methyltyrosine
derivatives (Figure 1) with the corresponding results listed in Table 1. The reactions are demonstrated by the
demethylation of (2R,3R)-2-Amino-3-(4’methoxy-2’-methylphenyl) butanoic acid la. A possible concerted
bond formation and demethylation of a protonated substrate could be attributed to the mild demethylation
conditions employed in the sealed reaction system (pigure 2).

5393
5394

RO

OH OH

la, lb 2a, 2b

“NoH "%OH “woH

3 3 3 3 3

3a, 3b Sa, 5b

Figure 1. Methyl tyrosine derivatives examined in the demethylation study described

(a. R=CH3 b, R=H)

Table 1. Results of dimethylation of the methyl tyrosine derivatives examined

ltmltant &OCH3 of 6H’s of b (ppm) configurations kX]Dzs of b

chirality (96) * a @pm) a (d) P (m) (CH30W

I
la 90.2 >99 3.62 3.54 3.15 (2R, 3R)# +30.4 (c=2.3)

2a 82.0 B99 3.62 3.54 3.15 (2S, 3s) -31.0 (c=l.5)

3a 90.7 B99 3.59 3.60 3.51 (2R, 3s) +21.0 (c=3.0)

LL 4a

5a
96.0

95.8
>99

>99

* > 99% indicates no I nor isomer observed

3.59

3.60
3.60

3.51

#I the X-ray structureh I been determined for the key precurso@

3.51

3.01
(2s. 3R)

(2R. 3R)
-22.4 (c-3.0)

i40.8 (~1.3)

A representative procedure is illustrated by the synthesis of (2R,3R)-2-Amino-3-(2’-methyl-4’-

hydroxylphenyl) butanoic acid lb. Into a l-neck 250 ml round bottomed flask with a stirbar was placed sodium
iodide (2.298, 15.3 mmol, l.leqv) and hydrobromic acid (48%, 156 ml ). To the stirring solution was added
(2R.3R)-2-Amino-3-(4’-methoxyl-2’-methylphenyl) butanoic acid la (3. log, 13.9 mmol) in one portion. The
flask was sealed tightly with a septum fastened by rubber rings, before being immersed into a 90-94‘C water
bath. The reaction mixture was stirred at this temperature for 2 hours. The flask was removed from the water
bath and cooled down to room temperature before being opened, (while the flask was still hot a syringe needle
 5395

was inserted through the septum to equilibrate the pmssun on the inside of the flask prior to being opened).
The resulting mixtuxe was evapomtai irr vucw to yield a crude yellow solid which was evaluated by Ht-NMR.
Thecrwlelnnductwarurad~yasit~to~thcNa-Bocderivative.
A small scale demethylation nactian was pe&rmed in o&er to determine the yields of the free amino
acids, utilizing ion-exchange cagey to obtain the fr#, acids. lln? crude product (from 0.39g la) was
puri&d by Amberlite IR-12U-plus exchange resin (2Jg) to yield 0.33g lb (90.2%). (Table 1)

exeessHBr(48%).Nal(l.leq),
OH

Figum 2. Demethylation utilizing acetic acid free aqueous phase

and mild sealed reaction conditions

HI-NMR (25OMHz) was used to monitor the ma&on process and evaluate the resulting chin&y. The
disappearance of the methoxyl group signal from substrate a (as the bromide salt - sampled from the conthming
reaction) or the upfield shift of hydrogen signals on the aromatic ring as the naction proceeded, indicated the
progress of the demethylation reaction. The chemical shifts of the a and p hydrogens of the diastemomeric
isomers of the bromi& salts being ~s~ly diffemnh makes them ~nvenient for the ~~~nadon of the
resulting chin&y.
53%

In summary, the ncwiy estabIisb@dtr&od provides a cuttveaient and efficient demtthylatiou fw

aromatic methyl ethers of optically pure special amino acids. The application of this method to tlte
demethylation of mothoxy and polymetboxy moieties in other tymeine derivatives will be exploited in the near
future.
~~1~B~ Suppon has bermpzovkitd by tJ. S. Public !kmic!e Giant NS 19972 and CA 57723,
and NIDAGrant DA 06284.

References and Notes

1. Greene, T.W. and Wuts, P.G.M.Proucrtvc Groups in Organic &thesis, 2nd ed John Wiley, New
Yo& 1991,p14-17.
2. Node, M.; Hcai, H and Ikjita, E. .F.Chem.Sot. Perkin I, #76,2237-22&l.
3. (a) Hwu, J.R. and Tsay, S-C. J. Org. Churn..l990,55,5987-5991 and refctmces cited therein, (b)
Aihsra, K.; IQuchi, T. andHirobe, M. Ckm. Pham. Bull. E&88,36(2), 83’7-840,(c) Review articles
conce~g et& cleavage se8 Tiecco, M. Sy*s&, 19I#), 749-759and several reviews cited the&.
4. Nicolas.3%Dharanipmda,R.; Toth, G.; Hruby. V.I. Tetmhcpbo~Len. 19139,30(49). 6845-48.
5. (a) Li, 0.; Jam&ski, M.A. and Hruby, VJ. Tmzhedron Z&t, 1993,34(16), 256144, (b) Li. G.;
Russell, KC.; Jarosinski,M.A. and Hmby, V.J. Temhed~odm., 1993,34(16), 2565-68, (c) Li, G,;
Boteju, L.B.; Pat& D. and H&y, V.J. in Peptides, Pmt. 13thAm&an Peptide Symp., R.S. Hodges
and J.A. Smith,eds., BSCOMSci. Fubl., Leiden, 1993, accepted.
6. Doxsee, KM.; Stewart,K.D.; Canary, J.W. and* D.J. J.Am. Chem.Sot. l987,109,3098-3107.
7. Chalmers,J.R.; Dickson,G.T.; Elks, J. andHems, B.A. f. Chmt. Sot. 1949,3424.

(Receivedin USA 11 May 1993;accepted 22 June 1993)