Dimethylaluminum methyltellurate, a new reagent for the cleavage of hindered methyl esters under exceptionally mild conditions by a novel mechanism

Article abstract of DOI:10.1016/j.tetlet.2005.05.003

An efficient and effective new reagent (Me₂AlTeMe)₂ has been developed for the conversion of methyl esters to the corresponding carboxylic acids in toluene solution at 23°C.

Full text of DOI:10.1016/j.tetlet.2005.05.003

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4589–4593
Dimethylaluminum methyltellurate, a new reagent for the
cleavage of hindered methyl esters under exceptionally
mild conditions by a novel mechanism
B. V. Subba Reddy, Leleti Rajender Reddy and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA02138, USA
Received 25 April 2005;revised 2 May 2005;accepted 3 May 2005
Available online 23 May 2005
Abstract—An efficient and effective new reagent (Me2AlTeMe)2 has been developed for the conversion of methyl esters to the
corresponding carboxylic acids in toluene solution at 23 ꢀC.
ꢁ 2005 Published by Elsevier Ltd.
In the course of recent investigations on the total synthe-
sis of the potent proteasome inhibitor salinosporamide A
(1)1 and related structures we encountered great difficulty
in the hydrolysis of the hindered methyl ester function in
a late intermediate (2).2,3 Because of the combination of
strong steric shielding of the COOMe carbonyl in 2 and
the ease of decomposition by retroaldol pathways, the
conversion of methyl ester 2, for example, R = i-Pr, into
the corresponding carboxylic acid failed completely
under a wide variety of acidic and basic conditions.4
In addition, various reagents that might function to
cleave the O–CH3 bond of COOMe in 2 by SN2 displace-
ment (e.g., n-PrSLi or C6H5SLi in DMF or HMPA) also
did not lead to the desired acid. As a result we turned our
attention to the use of novel mixed-function reagents,
that is, combining Lewis acidic and nucleophilic centers,
as a new type of reactant that might activate the COOMe
group by coordination and also effect nucleophilic attack
on the methyl group of the activated species. It was with
the guidance of this idea that we have discovered a very
effective new reagent, dimethylaluminum methyltellurate
(Me2AlTeMe)2.
Dimethylaluminum methyltellurate is readily prepared
by heating tellurium powder (1.2 equiv) and trimethylalu-
minum (1 equiv) in toluene (Aldrich Co.) at reflux under
nitrogen for 6 h and cooling to room temperature.5–7 It
can be obtained as a colorless solid (very air sensitive)
upon evaporation of toluene in vacuo. CAUTION:
Because of their unpleasant odor, organotellurium
reagents should be prepared and used only in a well-ven-
tilated hood;treatment of (Me 2AlTeMe)2 with either
bleach (aq NaOCl) or 1 N hydrochloric acid effects its
destruction and deodorization. The colorless solutions
of (Me2AlTeMe)2 thus obtained (0.8 M) were stable
under a nitrogen atmosphere at room temperature for
at least 1 week. This toluene solution of (Me2AlTeMe)2
was remarkably effective for the required conversion of
RCOOMe to RCOOH even at ambient temperature
(23 ꢀC in our experiments). Table 1 shows eight examples
of such cleavage reactions of hindered methyl esters at
23 ꢀC for reaction times in the range of 6–24 h. In each
case the reactions were clean and gave good yields of
solated pure products. In entry 1, the N-benzyl group
and c-lactam function of methyl N-benzylpyroglutamate
were unaffected and, in addition, no racemization
occurred. Methyl mesitoate, a highly hindered methyl
ester, was readily cleaved (entry 2). The corresponding
benzyl and allyl esters (entries 3 and 4) were also cleaved,
but somewhat more slowly. The intermediates shown in
H
N
H
COOMe
Me
O
R
H
N
O
H
OH
O
OTBS
OH
HO
O
Me
Cl
1
2
*
Corresponding author. Tel.: +1 617 495 4033;fax: +1 617 495
0376;e-mail: corey@chemistry.harvard.edu
0040-4039/$ - see front matter ꢁ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.05.003

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B. V. Subba Reddy et al. / Tetrahedron Letters 46 (2005) 4589–4593
Table 1. (Me2AlTeMe)2 promoted conversion of esters into carboxylic acids in toluene at 23 ꢀC
Entry
1
Ester
Acida
Me2AlTeMe (equiv)
3.2
Time (h)
6
Isolated yield (%)
91
COOMe
COOH
O
O
N
N
H
H
Ph
Ph
COOMe
Me
COOH
Me
Me
Me
Me
Me
2
3
4
1.2
1.2
1.2
6
14
12
91
87
89
Me
Me
COOBn
Me
COOH
Me
Me
Me
O
Me
O
COOH
Me
Me
Me
Me
Me
H
H
COOMe
COOH
N
N
O
H
O
H
Me
OH
Me
OH
5
6
5.2
5.2
12
12
81
83
OTBS
OTBS
HO
HO
H
N
H
N
COOMe
COOH
O
O
Me
OH
Me
OH
H
H
ODMIPS
ODMIPS
HO
HO
H
N
H
N
COOMe
Me
COOH
Me
O
O
H
H
7
8
5.2
5.2
12
24
79
80
ODMIPS
ODMIPS
ODMIPS
ODMIPS
HO
HO
OMe
OH
COOMe
Me
COOH
Me
N
N
O
O
H
H
OTBS
OTBS
Me
OH
Me
OH
a All products were characterized by 1H NMR, IR, and mass spectroscopy.
entries 5–7 for the synthesis of salinosporamide analogs
were likewise cleaved cleanly in good yields. In these cases
it should be noted that the t-butyldimethylsilyl (TBS) and
dimethylisopropylsilyl (DMIPS) protecting groups were
not removed. However, it was necessary to use a larger
excess of the tellurium reagent because of the presence
of reactive OH and NH groups. The example shown in
entry 8 of Table 1 shows that (Me2AlTeMe)2 is capable
of cleaving aromatic methyl ethers as well as methyl esters
under mild conditions. The rate of ArO–Me scission is
somewhat slower than that for RCOOMe. Because of
the observed effectiveness of (Me2AlTeMe)2 in the
demethylation of very hindered esters, we believe that
nucleophilic attack by tellurium on methyl to displace
RCOOAlMe2 best accounts for the cleavage reaction, as
shown.
RCOOMe+(Me2AlTeMe)2 !RCOOAlMe2 +MeTeMe
It is noteworthy that the analogous reagents
5
6
(Me2AlSMe)2 and (Me2AlSeMe)2 were found to be
relatively ineffective for methyl ester cleavage.
Because volatile organotellurium compounds have a
characteristic and unpleasant odor, it was important to
devise an isolation procedure that avoids this problem
and also possible toxicity issues. Fortunately, it was
found that simply by stirring the reaction mixture with
2 N hydrochloric acid for ca. 2 h at 23 ꢀC after dilution
with ethyl acetate the organotellurium coproducts were
converted to odorless water-soluble form. This reaction
process and product isolation are illustrated by the
experimental procedure for the conversion of methyl

B. V. Subba Reddy et al. / Tetrahedron Letters 46 (2005) 4589–4593
4591
Table 2. (Me2AlTeMe)2 promoted conversion of esters into carboxylic acids in toluene at 23 ꢀC
Entry
Ester
Acida
Me2AlTeMe (equiv)
Time (h)
Isolated yield (%)
1
Me Me
H
COOMe
2.2
8
85
Me Me
H
COOMe
Me
Me
AcO
HO
H
H
2
Me Me
H
COOMe
3.2
10
80b
Me Me
H
COOH
Me
Me
Me
Me
AcO
HO
H
H
COOMe
COOMe
COOMe
COOH
Me
H
Me
H
3
4
2.2
3.2
6
8
95
H
H
AcO
AcO
HO
HO
Me
Me
89b
Me
H
Me
H
H
H
OMe
OH
Me
H
Me
H
5
6
7
3.2
2.2
2.2
14
10
8
90
88
85
MeOOC
MeOOC
HOOC
HOOC
Me
Me
Me
H
Me
H
Me
Me
Me
H
Me
H
MeOOC
HOOC
Me
Me
a All products were characterized by 1H NMR, IR, and mass spectroscopy.
b Reaction was carried out at 50 ꢀC.
mesitoate to mesitoic acid (Table 1, entry 2).8 It should
be added that volatile organotellurium coproducts such
as Me2Te (bp 93 ꢀC) can also be removed from the reac-
tion mixture by distillation of solvent and byproducts
under reduced pressure into a cold trap, the contents
of which are then treated with aqueous bleach to destroy
the odor of Te compounds.
and the reaction time. Similar results were obtained with
the steroidal acetoxy methyl ester shown in entries 3 and
4 of Table 2. Methyl podocarpate O-methyl ether, an
extremely hindered methyl ester (Table 2, entry 5)
underwent cleavage of both the ester and ether methoxy
groups to afford podocarpic acid in high yield. Finally,
methyl dehydroabietate (entry 6) and methyl abietate
(entry 7) were converted cleanly to the corresponding
acids. The mildness of the conditions for the successful
demethylation of the very hindered methyl esters shown
in Table 2 provides ample evidence of the potency and
potential of the new demethylating reagent.
Additional examples of dimethylaluminum methyltellu-
rate induced Me–O cleavage with even more hindered
ester substrates are summarized in Table 2. Methyl acet-
yloleanolate undergoes deacetylation followed by some-
what slower demethylation to give either methyl
oleanolate (Table 2, entry 1) or oleanolic acid (Table
2, entry 2), depending on the amount of reagent used
Although the structure of dimethylaluminum methyl
tellurate has not been determined it is likely to be the

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B. V. Subba Reddy et al. / Tetrahedron Letters 46 (2005) 4589–4593
bridged dimeric species 3 on the basis of much analogy9
and especially because the closely related sulfur analog
(Me2AlSMe)2 has been determined to be this type of
S-bridged dimer.10 On the basis of this structure a most
intriguing possibility emerges for the mechanism of the
mild and efficient cleavage of methyl esters by the new
reagent 3. This mechanistic pathway is summarized in
Scheme 1. In this pathway the methyl ester is activated
by coordination of the COOMe carbonyl oxygen to an
aluminum of 3 leading after cleavage of one of the Al–
Te bridge bonds to the putative intermediate 4. Cleavage
of the Me–O bond in 4 could then occur by an unusual
intramolecular backside displacement on methyl by the
distal TeMe subunit, as shown. Because of the number
of bonds in the path between the methyl group being
attacked and the terminal Te nucleophile and the length
of the bonds to Te, a stereoelectronically favorable
colinear O–Me–Te–Me transition state is available from
4.11 This would represent an extremely rare and singular
example of an intramolecular backside nucleophilic dis-
placement reaction in which the nucleophile is linked to
the leaving group. Of course, it is also possible that a
two-step decomposition pathway occurs from 4: termi-
nal MeTe–Al bond dissociation to form MeTeꢀ which
then attacks the methyl ester Me group as an external
nucleophile to produce the ester cleavage product.
Whichever of these two alternatives operates, it is clear
that the mechanistic pathway shown in Scheme 1 pro-
vides a simple explanation of the unique reactivity of
the reagent 3 with hindered carboxylic acid methyl es-
ters. It is also apparent that the process of methyl ester
cleavage outlined in Scheme 1 represents a new para-
digm for ester deprotection.
A similar explanation can be used for the cleavage of
aromatic methyl ethers by 3, except that in this case
the two-step pathway for Me–O bond cleavage from
the complex corresponding to 4 becomes much more
likely for stereoelectronic reasons. Finally, the deacetyl-
ation reactions induced by the reagent 3 (Table 2, entries
1–4) can be explained by attack on the acetate carbonyl
of complex 5 by the distal MeTe group.
Me Me
Me
Me
Al
O
Te
Al
O
Te
Me
Me
Te Me
O
R
Me
Me
RO AlMe2
+
5
H3O+
ROH
MeCOOH
+
References and notes
1. Feling, R. H.;Buchanan, G. O.;Mincer, T. J.;Kauffman,
C. A.;Jensen, P. R.;Fenical, W. Angew. Chem., Int. Ed.
2003, 42, 355–357.
2. Reddy, L. R.;Saravanan, P.;Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 6230–6231.
3. Reddy, L. R.;Fournier, J.-F.;Reddy, B. V. S.;Corey, E. J.
J. Am. Chem. Soc., submitted for publication.
4. For example, none of the carboxylic acid corresponding to
2 could be obtained using sodium, lithium, barium, or
lanthanum hydroxides using a variety of solvents and
temperatures. Aqueous acids and Lewis acidic conditions
(e.g., BCl3, Me3LiI) also failed. For reviews on methyl
ester cleavage, see: (a) Greene, T. W.;Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.;John
Wiley and Sons: New York, 1999;(b) Kocienski, P. J.
Protecting Groups, 3rd ed.;George Thieme: Stuttgart,
New York, 2004;(c) Salomon, C. J.;Mata, E. G.;
Mascaretti, O. A. Tetrahedron 1993, 49, 3691–3734;(d)
Nicolaou, K. C.;Estrada, A. A.;Zak, M.;Lee, S. H.;
Safina, B. S. Angew. Chem., Int. Ed. 2005, 44, 1378–1382;
(e) Olah, G. A.;Narang, S. C.;Salem, G. F.;Gupta, B. G.
B. Synthesis 1981, 142–143;(f) Marchand, P. S. J. Chem.
Soc., Chem. Commun. 1971, 667–668;(g) Bartlett, P. A.;
Johnson, W. S. Tetrahedron Lett. 1970, 4459–4462.
5. For the analogous sulfur reagent, see: (a) Corey, E. J.;
Kozikowski, A. P. Tetrahedron Lett. 1975, 925–928;(b)
Corey, E. J.;Beames, D. J. J. Am. Chem. Soc. 1973, 95,
5829–5830;(c) Hatch, R. P.;Weinreb, S. M. J. Org. Chem.
1977, 42, 3960–3961.
Me
O
Me
Me
Me
Me
Te
R
C
+
Al
Al
O
Me
Te
Me
3
Me Me Me
Al Te
Al
Te
Me
O
Me
Me
R
C
O
Me
4
6. For the corresponding selenium reagent, Me2AlSeMe,
prepared by reaction of selenium with Me3Al, see:
Kozikowski, A. P.;Ames, A. J. Org. Chem. 1978, 43,
2735–2737.
7. At the end of the 6 h reaction time all the gray-white Te
powder had dissolved and only a small amount of an
insoluble colorless solid remained at the bottom of the
flask (possibly due to the presence of impurity in the Te
powder used). The clear supernatant solution of Me2Al-
TeMe was then drawn off by syringe as needed.
Me
Me
O
Al
R
C
Te Me
Me
MeTeMe
+
O
Al
Me
H3O+
RCOOH
8. A solution of methyl mesitoate (1.78 g, 10 mmol) in a
2 mL of toluene was added to a stirred solution of freshly
prepared dimethylaluminum methyltellurolate (3, 15 mL;
12 mmol;0.8 M solution) in toluene. The mixture was
Scheme 1. Possible mechanistic pathway for the facile Me–O bond
cleavage of methyl esters by 3.

B. V. Subba Reddy et al. / Tetrahedron Letters 46 (2005) 4589–4593
4593
stirred at room temperature for 6 h, after which the
reaction was complete as indicated by TLC analysis. The
reaction mixture was treated with 2 N HCl (50 mL) and
ethyl acetate (50 mL) and the resulting mixture was
stirred vigorously at room temperature for 2 h. The
organic phase was separated and the aqueous phase was
twice extracted with ethyl acetate (2 · 30 mL). The
combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo,
purified by column chromatography on silica gel using
ethyl acetate–hexane (1:9) to afford 1.50 g (91.5%) of pure
mesitoic acid as a colorless solid, mp 153–155 ꢀC (lit. mp
154–155 ꢀC).
9. See: (a) Cowley, A. H.;Jones, R. H. Angew. Chem., Int.
Ed. Engl. 1991, 30, 1143–1145;(b) Eisch, J. J. In
Comprehensive Organometallic Chemistry;Wilkinson, G.,
Stone, F. G. A., Eds.;Pergamon: Oxford, UK, 1982;Vol.
1, pp 557–622.
10. Haaland, A.;Stokkeland, O.;Weidlein, J. J. Organomet.
Chem. 1975, 94, 353–360.
11. The large difference between 3 (Me2AlSMe)2 and (Me2Al-
SeMe)2, which at first seems surprising, may be due to the
shorter Al–S and Al–Se bond lengths and different bond
angles, which do not provide the most favorable geometry
for intramolecular nucleophilic attack on the O–CH3
group in complex analogous to 4.