Selective esterifications of primary alcohols in a water-containing solvent

Article abstract of DOI:10.1021/ol3022337

Oxyma and an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (5b), displayed a remarkable effect on selective esterifications of primary alcohols. A wide range of carboxylic acids could be esterified with primary alcohols by using EDCI, NaHCO₃, and Oxyma or Oxyma derivative 5b in 5% H₂O-CH₃CN. Oxyma derivative 5b is particularly useful, since it could be removed after the reaction via a simple basic or an acidic aqueous workup procedure.

Full text of DOI:10.1021/ol3022337

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Selective Esterifications of Primary
Alcohols in a Water-Containing Solvent
Yong Wang, Bilal A. Aleiwi, Qinghui Wang, and Michio Kurosu*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee
Health Science Center, 881 Madison Avenue, Memphis, Tennessee 38163-0001,
United States
mkurosu@uthsc.edu
Received August 13, 2012
ABSTRACT
Oxyma and an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (5b), displayed a remarkable effect on
selective esterifications of primary alcohols. A wide range of carboxylic acids could be esterified with primary alcohols by using EDCI, NaHCO3,
and Oxyma or Oxyma derivative 5b in 5% H2OꢀCH3CN. Oxyma derivative 5b is particularly useful, since it could be removed after the reaction via a
simple basic or an acidic aqueous workup procedure.
In our efforts towards the totalsynthesis of muraymycins
A1 (1) and D1 (2), and their analogs for structureꢀactivity
relationship studies against Gram-positive bacteria includ-
ing M. tuberculosis, it is crucial to develop an efficient
synthesis of the dipeptide 3a and 3b (Figure 1).1 We have
recently reported an efficient synthesis of the ureido-
muraymycidine derivatives (the partial structure high-
lighted in a box in Figure 1).1b In the synthesis of mur-
aymycin A1 selective acetylation of the primary alcohol is
necessary to accomplish an efficient synthesis of the left
half of 1. We have screened reported esterification condi-
tions for 4a to form the monoacetate 3a. Although several
acetylation conditions with the controlled amounts of
reagents and at lowered temperatures provided the mono-
acetate at the primary alcohol, the selectivity of mono- and
diacetate was not satisfactory. For example, acetylation of
4a with Ac2O (5 equiv) and pyridine (10 equiv) in CH2Cl2
at 0 °C gave a mixture of 3a and the diacetate (3/1) in less
than 40% yield. DCC-mediated acetylations under anhy-
drous conditions yielded the diacetate as a major product.
Thus, we commenced optimizing esterification conditions
that protect the primary alcohol of 4a with AcOH to yield
3a exclusively.
In our recent finding of amide-forming reactions with
the ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma for-
merly known as EACNOx)2 derivative (glyceroacetonide-
Oxyma, 5b in Table 1) in water media, it was observed that
the 5b-esters of amino acids (e.g., 9) are stable during
amide-forming reactions in water. Typically, glyceroace-
tonide-Oxymacatalyzed amide-formingreactions could be
achieved with EDCI (1.5 equiv), NaHCO3 (3ꢀ6 equiv) in
water (0.2ꢀ0.3 M) to yield the corresponding peptides in
greater than 90% yield without detectable diastereomers.3
It has been reported that nucleophilicity of the oxygen
atom of alcohols is slightly stronger than that of water.4
Thus, we expected that selective coupling of the oxime-
esters 9 (Table 1) with alcohols could be achieved in water
(2) (a) Khattab, S. N. Bull. Chem. Soc. Jpn. 2010, 83, 1374–1379. (b)
El-Faham, A.; Subiro’s-Funosas, R.; Albericio, F. Chem.;Eur. J. 2010,
19, 3641–3649. (c) Subiro’s-Funosas, R.; Prohens, R.; Barbas, R.;
El-Faham, A.; Albericio, F. Chem.;Eur. J. 2009, 15, 9394–9403. (d)
Thouin, E.; Lubell, W. D. Tetrahedron Lett. 2000, 41, 457–460. (e)
Kaiser, E. T.; Mihara, H.; Laforet, G. A.; Kelly, J. W.; Walters, L.;
Findeis, M. A.; Sasaki, T. Science 1989, 243, 187–192.
(3) Wang, Q.; Wang, Y.; Kurosu, M. Org. Lett. 2012, 14, 3372–3375.
(4) (a) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827–
1836. (b) Pearson, R. G.; Sobel, H.; Songstad, J. J. Am. Chem. Soc. 1968,
90, 319–326.
(1) (a) Kurosu, M.; Li, K. J. Org. Chem. 2008, 73, 9767–9770. (b)
Aleiwi, B. A.; Schneider, C. M.; Kurosu, M. J. Org. Chem. 2012, 77,
3859–3867. (c) Aleiwi, B. A.; Kurosu, M. Tetrahedron Lett. 2012, 53,
3758–3762.
r
10.1021/ol3022337
XXXX American Chemical Society

media in the presence of a weak base. Gratifyingly, acetylation
of 4a with excess AcOH (10 equiv), glyceroacetonide-Oxyma
5b (5 equiv), and NaHCO3 (10 equiv) in water (0.2 M) pro-
vided the monoacetate 3a in 85% yield without the forma-
tion of the diacetate (R2 = OAc in 3a in Figure 1). Herein, we
report the optimization of selective esterifications of primary
alcohols with Oxyma 5a or glyceroacetonide-Oxyma 5b,
EDCI, and NaHCO3 in water-containing solvent systems.
forming reaction in entry 1. In addition, it was realized that
the oxime-ester intermediate 9 has a half-life of approxi-
Table 1. Amide- or Ester-Forming Reactions in Water Media
additive/
solvent
product
yield
(%)d
entry
1a
7 or 8
(10 or 11)
5b
H2O
HCl•H-L-Ala-
OMe (7a)
7a
Boc-Phe-Ala-
OMe (10a)c
10ac
93
25
45
55
2a
3b
4b
5a
H2O
5b
MeOH
MeOH
Boc-Phe-OMe
(11a)c
H2O
5b
11a
50% H2O-
CH3CN
5b
5b
6b
7b
8b
9b
10b
MeOH
MeOH
MeOH
MeOH
iPrOH
tBuOH
11ac
11ac
11ac
11ac
>95
>95
90
85
0
5% H2O-
CH3CN
5a
5% H2O-
CH3CN
5a
Figure 1. Syntheses of muraymycins A1 (1) and D1 (2).
5% H2O-
dioxane
5a
Although an acetylation of 4a to form 3a could be
achieved in water with excess reagents, high-yielding ester-
ifications of alcohols using a limited amount of carboxylic
acids or alcohols are considered to be challenging trans-
formations in aqueous media. Uronium-based reagents
have previously been applied to introduce esters on pri-
mary alcohols under nonaqueous conditions.5 To the best
of our knowledge, no practical esterification reaction has
been developed in water-containing solvent systems. We
have observed that glyceroacetonide-Oxyma 5b is benefi-
cial in high-yielding amide-forming reactions in water with
a wide range of amino acid derivatives.3 The reactivity
difference between Oxyma 5a and 5b in amide-forming
reactions in water is attributed to the fact that the water
solubility of 5bisimproved 2.1 times greater than that of 5a
at pH 8.3 (entries 1 and 2 in Table 1).6 The esterification
reactions of Boc-L-Phe-OH (6, 1 equiv) with alcohols
(2 equiv), 5a or 5b (1.5 equiv), EDCI (1.5 equiv), and
NaHCO3 (6 equiv) were examined in water and water-
containing solvent systems, and these data are summarized
in Table 1. Esterification of 6with MeOH in water furnished
Boc-L-Phe-OMe (11a) in 45% yield in 2 h (entry 3). This
low-yielding reaction in entry 3 was attributed to a slower
reaction rate of the esterification compared to the amide-
5% H2O-
acetone
5a
Boc-Phe-OiPr
(11b)c
5% H2O-
CH3CN
5a
Boc-Phe-OtBu
(11c)c
0
5% H2O-
CH3CN
a 6 (1.0 equiv), 7 (1.5 equiv), additive (1.5 equiv), EDCI (1.5 equiv),
NaHCO3 (6 equiv) in H2O (0.2 M concentrations), 2 h. b 6 (1.0 equiv), 8
(2.0 equiv), additive (1.5 equiv), EDCI (1.5 equiv), NaHCO3 (6 equiv)
(0.2 M concentrations). c de or ee was determined to be >99% via HPLC
analysis. d Isolated yield.
mately 6 h in water at pH 8.3.7 Thus, we examined the effect
of a cosolvent to increase the nucleophilicity of alcohol and
the half-life of 9. The same reaction in H2OꢀCH3CN (1/1)
improved the isolated yield of 11a to 55% after 2 h (entry 4).
Significant improvement in the methyl esterification of 6
was observed when the reaction was performed in 5%
H2OꢀCH3CN (entry 5); the isolated yield of 11a was
greater than 95%. Oxyma 5a could effectively serve as
a coupling additive for an esterification reaction in the
solvent system (5% H2OꢀCH3CN) (entry 6). Thus, further
studies of selective esterifications of primary alcohols were
(5) (a) Twibanire, J. K.; Grindley, T. B. Org. Lett. 2011, 13, 2988–
2991. (b) Twibanire, J. K.; Omran, R. P.; Grindley, T. B. Org. Lett. 2012,
14, 3909–3911.
(6) 6 equiv of NaHCO3 in water (0.2 M) shows pH of 8.3.
(7) The acetate and benzoate of 5b have a half-life of over 12 h.
Org. Lett., Vol. XX, No. XX, XXXX
B

Table 2. Selective Esterifications of Primary Alcohols Using EDCI, Oxyma 5a, and NaHCO3 in 5% H2OꢀCH3CNa
a All reactions were carried out using 5a (1.5 equiv) at rt except where noted. b ee was determined by HPLC (Daicel Chiralcel OD-H column).
c R1ꢀCO2H (1 equiv) and R2ꢀOH (2 equiv) were used. d R1ꢀCO2H (2 equiv) and R2ꢀOH (1 equiv) were used. e Yield was determined via 1H NMR. f The
reaction was carried out at 0 °C. g R1ꢀCO2H (1 equiv) and R2ꢀOH (8 equiv) were used.
performed using Oxyma 5a. Although several solvents such
as 5% H2Oꢀdioxane and 5% H2Oꢀacetone could be
Org. Lett., Vol. XX, No. XX, XXXX
utilized for effective methyl esterification of 6 (entries 7
and 8), the esterifications in 5% H2OꢀCH3CN were
C

27 and 28 in 98% and 99% yields, respectively (entries 11
and 12). Methyl esterification of Boc-L-Thr-OH (17) gave
rise to Boc-L-Thr-OMe (29) in 95% yield (entry 13).
Benzoylation, acetylation, and formylation reactions of
DL-1,2-isopropylideneglycerol (18) provided the corre-
sponding esters 30aꢀc in greater than 95% yields (entries
14ꢀ16). It should be noted that (2,2-dimethyl-1,3-dioxo-
lan-4-yl)methyl formate (30c) was not stable to silica gel;
thus, its yield was determined based on 1H NMR analysis
of the crude product. On the other hand, formylation of
(3,5-bis(benzyloxy)phenyl)methanol (19) afforded 31 in
95% yield after silica gel chromatography (entry 17).
Selective esterifications of diols were also demonstrated,
and selected examples are summarized in Table 2. The
primary alcohol of butane-1,3-diol (20) was selectively
benzoylated to afford 32 in 80% yield. Esterifications of
glycerol (21) with benzoic acid and n-hexanoic acid furn-
ished the corresponding diesters 33a and 33b in 85% and
90% yield, respectively (entries 19 and 20). Benzoylation of
benzyl 2-(acetylamino)-2-deoxy-R-D-glucopyranoside (22)
was achieved selectively at the C6-position to afford the
monobenzoate 34 in 90% yield (entry 21).
Finally, acylations of the diol of a complex muramic acid
derivative 35 were demonstrated as selective esterifications
of primary alcohols (Scheme 1).11 Acetylation and benzoy-
lation of 35 using 5b (1.5 equiv), acid (2 equiv), EDCI
(1.5 equiv), and NaHCO3 (6 equiv) at 0 °C gave rise to the
primary acetate 36a and benzoate 36b in greater than 95%
yield without the formation of diacylated products. In the
reactions summarizedin Scheme 1, it is a significant benefit
to use glyceroacetonide-Oxyma 5b. Although the same
reaction with Oxyma 5a gave an equal conversion yield as
observed in Scheme 1, separation of 5a from the product
was extremely difficult via silica gel chromatography.
On the other hand, 5b could be removed completely via
standard acidic and basic workups.
Scheme 1. Selective Acylations of 35
superior to those in the other solvent systems tested. Under
the optimized conditions [acid (1 equiv), alcohol (2 equiv),
5a or 5b (1.5 equiv), EDCI (1.5 equiv), and NaHCO3
(6 equiv)], isopropanol and tert-butanol did not form the
corresponding esters with 6 even after a prolonged reaction
time.8
In order to understand the scope and limitations of the
selective esterification reactions of primary alcohols with
EDCI, Oxyma 5a, and NaHCO3 in 5% H2OꢀCH3CN,
these conditions were applied to esterifications of a wide
variety of acids with alcohols. Selected examples are
summarized in Table 2. Esterifications of 6 with methanol,
primary alcohols, and phenols furnishedthe corresponding
esters in greater than 90% yield without detectable race-
mization (entries 1ꢀ7). Significantly, an allyl alcohol could
be esterified to provide 23c in 98% yield. It is worth
pointing out that esterifications of carboxylic acid with
allyl alcohols have never been successfully performed using
carbodiimide-mediated reaction conditions (entry 3).9
Unlike 4-(dialkylamino)pyridine-catalyzed DCC-mediated
esterification conditions, the Fmoc-group was not cleaved
during the benzyl esterifications of the Fmoc-protected
amino acids, 12 and 13 (entries 8 and 9).10 Esterifications
of N-sulfonylated R-amino acids using carbodiimide cou-
pling reagents often result in low conversion with signifi-
cant racemization. However, under the conditions in
Table 2, the benzyl esterification of 14 furnished 26 in
98% yield with >99% ee (entry 10). The chiral carboxylic
acids possessing secondary alcohols, 15, 16, and 17, could
be esterified efficiently with the primary alcohols. Benzyl
esterifications of (S)-mandelic acid (15) and 3-hydroxybu-
tanoic acid (16) furnished the corresponding benzyl esters
Inconclusion, wehaveoptimized selectiveesterifications
of primary alcohols using Oxyma 5a or glyceroacetonide-
Oxyma 5b, EDCI, and NaHCO3 in 5% H2OꢀCH3CN.
The selective esterification conditions described here do
not require the strict anhydrous conditions necessary
for ordinal esterification reactions. The coupling additive
5b can be removed easily after the reactions via acidic and
basic workups. The new esterification conditions reported
here should be a valuable asset in organic synthesis and for
selective modifications of polyol molecules.
Acknowledgment. We thank the National Institutes of
Health (NIAID Grant AI AI084411) and University of
Tennessee for generous financial support.
(8) Esterifications of 6 with (þ)-menthol and cholesterol also did not
provide the corresponding esters.
(9) (a) Monagle, J. J. J. Org. Chem. 1962, 27, 3851–3855. (b) Steglich,
€
W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981. (c) Boden, E. P.;
Supporting Information Available. Experimental pro-
cedures and copies of NMRs. This is available free of
charge via the Internet at http://pubs.acs.org.
Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
(10) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43,
5436–5441.
(11) Under the optimized conditions, acetylation of 4a furnished 3a
in greater than 95% yield without the formation of the diacetate
(Figure 1).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX