One-pot tethering of organic molecules through non-symmetric malonate derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.05.044

A new method for one-pot chemoselective heterobifunctional cross-linking of organic molecules is described. The method is based on tert-butyldiphenylsilyl malonate and involves two sequential carbodiimide couplings with two different molecules possessing a hydroxy or an amino functionality with one intermediate one-pot fluoride deprotection.

Full text of DOI:10.1016/j.tetlet.2005.05.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4901–4903
One-pot tethering of organic molecules through
non-symmetric malonate derivatives
Daniel Sherman, Rimma Shelkov and Artem Melman*
Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
Received 3 March 2005; revised 4 May 2005; accepted 11 May 2005
Available online 3 June 2005
Abstract—A new method for one-pot chemoselective heterobifunctional cross-linking of organic molecules is described. The method
is based on tert-butyldiphenylsilyl malonate and involves two sequential carbodiimide couplings with two different molecules pos-
sessing a hydroxy or an amino functionality with one intermediate one-pot fluoride deprotection.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Heterobifunctional cross-linking of organic molecules
has found an extensive use in solid phase synthesis,
preparation of prodrugs, targeted delivery of biologi-
cally active compounds and many others applications.1,2
While a variety of different cross-linkers has been pro-
posed, the most commonly used method of permanent
tethering relies on the formation of amide bonds be-
tween amino or carboxylic groups.2 Organic compounds
possessing other functions such as hydroxyls are sub-
stantially less reactive than amines and their acylation
is often complicated, especially if substrates are steri-
cally hindered.3 Elaboration of a methodology that is
capable of efficient covalent tethering of substrates pos-
sessing hydroxy groups (including sterically hindered
ones) in high yields and chemoselectively under mild
reaction conditions is therefore of substantial interest.
Recently we reported a new, highly efficient acylation of
sterically hindered alcohols through the reaction with
carboxylic acids, which can form ketenes upon treat-
ment with carbodiimides.4 Here we report on a new
method for the permanent tethering of two organic units
possessing hydroxy or amino functionalities using the
acylation of these groups through ketene intermediates
produced from malonic acid monoesters.
Homobifunctional cross-linking of two identical mole-
cules possessing hydroxy or amino groups using this
reaction can be done in a straightforward way using a
direct esterification of malonic acid with 2 equiv of an
alcohol and a carbodiimide.5 Acylation through ketene
intermediates can also be applied for much more syn-
thetically important heterobifunctional tethering of
O
O
O
O
O
O
O
AH
CF3COOH for (a)
Et3N.3HF for (b)
PG
PG
H
O
OH
O
A
O
A
A
DCC
1a,b
2a,b
3
4
BH
DCC
(a) PG = t-Bu
(b) PG = Si(Ph)2t-Bu
O
B
Keywords: Bioconjugates; Malonate; Carbodiimide coupling; Silyl esters.
*
Corresponding author. Tel.: +972 2658 5279; fax: +972 2658 5345; e-mail: amelman@chem.ch.huji.ac.il
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.044

4902
D. Sherman et al. / Tetrahedron Letters 46 (2005) 4901–4903
Table 1. Isolated yield of non-symmetrical malonates of type 4 after
three stages
two different units AH and BH using monoprotected
malonic acid derivatives of type 1. Such a procedure
should involve first a carbodiimide-mediated coupling
of substrate AH with a monoprotected malonate of type
1 followed by deprotection of a diester of type 2 and sec-
ond a carbodiimide coupling between the resulting
monoester 3 and substrate BH to afford the desired
non-symmetrical diester of type 4.
Entry Molecule AH
Molecule BH
Isolated
yield, %
a
b
c
Geraniol
Geraniol
tert-BuOH 91
Diacetone-D-glucose 84
Benzhydrol
Geraniol
Geraniol
Adamantol
78
80
74
d
e
(À)-Menthol
4-Hydroxybenzyl
alcohol
Since the removal of a tert-butyl group can be done eas-
ily in the presence of other esters, mono-tert-butyl malo-
nate could be used for implementing this approach6,7
although the conditions of acid-catalyzed deprotection
are too harsh for the majority of polyfunctional sub-
strates. Other protecting groups for malonic acid also
require the use of strongly acidic or basic reagents for
their removal (e.g., methoxybenzyl or 9-fluorenylmethyl
esters) or are difficult to implement in small scale reac-
tions (e.g., catalytic hydrogenation or electrolysis).
f
Adamantol
Mercaptoethanol
Mercaptoethanol
2,3-Isopropylidene
glycerol
68
55
g
h
i
2-Phenyl-2-propanol Diisopropylamine
Octanol 4-aminophenol
56
49 + 26
ones, provided non-symmetrical malonates of type 4 in
good to excellent non-optimized yields.
Silicon-based protecting groups for alcohols have found
extensive use in organic synthesis due to the ease of their
selective removal by fluoride anions.8 In contrast, pro-
tection of a carboxyl group as a silyl ester is much less
common due to their very high reactivity towards nucleo-
philic reagents. However, after the attempted synthesis
of different silyl malonates we found that tert-butyl-
diphenylsilyl malonate can be isolated as a reasonably
stable crystalline solid.9
Reactions with polyfunctional substrates (entries e–g)
demonstrate the chemoselectivity of the method. In all
these entries the acylation selectively proceeded on the
aliphatic hydroxy group and no appreciable amounts
of acylation of thiol or phenol functionalities were
detected. It should be mentioned that these chemoselecti-
vities are completely opposite to conventional carbodi-
imide esterifications.12 Formation of the malonamide
linkage by the current procedure was somewhat slow
and only moderate yields were achieved (entry h). Reac-
tion with 4-aminophenol was the only case where low
chemoselectivity was observed thus providing mainly
products of N-acylation (49%) with a substantial
amount of the O-acylation product (26%).
Like other malonate monoesters, a carbodiimide-medi-
ated coupling of tert-butyldiphenylsilyl malonate with
alcohols and amines proceeded in practically quantita-
tive yields under very mild conditions. The subsequent
removal of the tert-butyldiphenylsilyl ester protecting
group from 2 can be done easily with commercially
available tetra-n-butylammonium fluoride. However,
all commercially available sources of Bu4NF contain
at least 3 equiv of water and attempts to produce dry
Bu4NF result in a highly basic reagent that is prone to
decomposition.10 After searching for alternative fluoride
anion sources, we found that equimolar amounts of
commercially available anhydrous and neutral triethyl-
amine–hydrogen fluoride complex Et3NÆ3HF easily
deprotects silyl malonates of type 2 thus providing mal-
onate monoesters of type 3.
In conclusion, one-pot permanent tethering through
unsymmetric malonate derivatives provide a number
of important advantages versus existing methods includ-
ing the possibility to conjugate sterically hindered hy-
droxy and amino groups, short reaction times,
equimolecular amounts of tethering reagents and the ab-
sence of laborious intermediate purification stages.
Acknowledgements
This research was supported by the Israel Science Foun-
dation (Grant No. 176/02-1).
We found that residual triethylamine–hydrogen fluoride
does not interfere with the subsequent carbodiimide
coupling. This fact made it possible to conduct the sec-
ond carbodiimide-mediated coupling of malonate
monoesters of type 3 with BH in one pot without any
intermediate purification. The final purification of the
resultant non-symmetric malonates of type 4 was
achieved by flash chromatography. No appreciable
amounts of symmetrical malonate diesters such as (AO-
CO)2CH2 or (BOCO)2CH2 were detected in the reaction.
The simplicity of the method is demonstrated by the rep-
resentative procedure that could also be suitable for the
preparation of combinatorial libraries.11
References and notes
1. For a general review of heterobifunctional bioconjugation
methods, see: Bioconjugate Techniques; Hermanson, G. T.,
Ed.; Academic: San Diego, 1996, pp 229–287.
2. For the most recent review on bioconjugation, see: Kluger,
R.; Alagic, A. Bioorg. Chem. 2004, 32, 451–472.
3. (a) For example, see: Macias, F. A.; Aguilar, J. M.;
Molinillo, J. M. G.; Massanet, G. M.; Fronczek, F. R.
Tetrahedron 1994, 50, 5439–5450; (b) Kim, M. H.; Patel,
D. V. Tetrahedron Lett. 1994, 35, 5603–5606; (c) Baldwin,
J. E.; Farthing, C. N.; Russel, A. T.; Schoffield, C. J.;
Spivey, A. C. Tetrahedron Lett. 1996, 37, 3761–3764.
4. Nahmany, M.; Melman, A. Org. Lett. 2001, 3, 3733–3735.
The examples in Table 1 demonstrate the versatility of
this method. Alcohols, including sterically hindered

D. Sherman et al. / Tetrahedron Letters 46 (2005) 4901–4903
4903
5. Shelkov, R.; Nahmany, M.; Melman, A. J. Org. Chem.
2002, 67, 8975–8982.
À18 ꢁC and may be purified by recrystallization from ethyl
acetate–petroleum ether.
6. Bulman, P. C.; Moore, J. P. G.; Mansfield, I.; McKenzie,
M. J.; Bowler, W. B.; Gallagher, J. A. Tetrahedron 2001,
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11. To a solution of geraniol in (1 mL of a 1 M solution in
dichloromethane) was added a solution of tert-butyldi-
phenylsilylmalonate 1a (1 mmol of a 1 M solution in
dichloromethane) and a solution of DCC (1 mmol of a
1 M solution in dichloromethane). The reaction mixture
was stirred for 10 min and a solution of Et3NÆ3HF
complex (1 mmol of a 1 M solution in dichloromethane)
was added. The reaction mixture was stirred for 10 min
and a solution of t-BuOH (1 mmol of a 1 M solution in
dichloromethane) and a solution of DCC (1 mmol of a
1 M solution in dichloromethane) were added. The reac-
tion mixture was stirred for 10 min, filtered and evapo-
rated. The residue was purified by flash chromatography
(0–10% EtOAc–petrol mixture) to give the corresponding
non-symmetric malonate 4a (1.17 g, 91%).
8. Green, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis; Wiley: New York, 1999, pp 113–148.
9. To a solution of malonic acid (3.03 g, 29.1 mmol) and
triethylamine (2.95 g, 29.1 mmol) in CH2Cl2 (20 mL) was
added tert-butylchlorodiphenylsilane (4.0 g, 14.6 mmol)
and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was evaporated and
dissolved in ethyl acetate–petroleum ether 1:1 mixture
(100 mL), washed with cold water (3 · 50 mL), dried over
Na2SO4 and evaporated. The residue was dissolved in
EtOAc (5 mL), diluted with 100 mL of petroleum ether
and kept at À34 ꢁC overnight to crystallize to afford
mono-tert-butyl diphenylsilyl malonate (2.0 g, 5.54 mmol,
38%). This product is a crystalline solid stable for weeks at
12. Shelkov, R.; Nahmany, M.; Melman, A. Org. Biomol.
Chem. 2004, 2, 397–492.