Amino alcohols in organocatalysed acylation and deacylation: The effect of dialkylamino substituents on the rate

Article abstract of DOI:10.1002/adsc.200600491

In alcohols and esters, a neighbouring dialkylamino group can enhance the reactivity towards acylation and deacylation, respectively, that is, such amino alcohols can act as transacylation catalysts like DMAP. This effect is dependent on the number of (carbon) spacer atoms, flexibility of the molecule and the presence and position of further heteroatoms. Based on this effect, the site selective acylation and deacylation of desmycosin, a macrocycle antibiotic possessing an amino sugar moiety, is described.

Full text of DOI:10.1002/adsc.200600491

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DOI: 10.1002/adsc.200600491
Amino Alcohols in Organocatalysed Acylation and Deacylation:
The Effect of Dialkylamino Substituents on the Rate
Ludger A. Wessjohanna,* and Mingzhao Zhua
a
Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
Fax : (+49)-345-5582-1309; e-mail: wessjohann@ipb-halle.de
Received: September 27, 2006; Revised: September 19, 2007; Published online: November 23, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: In alcohols and esters, a neighbouring dial- atoms. Based on this effect, the site selective acyla-
kylamino group can enhance the reactivity towards tion and deacylation of desmycosin, a macrocycle an-
acylation and deacylation, respectively, that is, such tibiotic possessing an amino sugar moiety, is de-
amino alcohols can act as transacylation catalysts scribed.
like DMAP. This effect is dependent on the number
of (carbon) spacer atoms, flexibility of the molecule Keywords: amino alcohols; amino sugars; desmyco-
and the presence and position of further hetero- sin; organocatalysis; acylation; transesterification
Introduction
Amino alcohols are very common structures in nature
and as ligands for catalysis, especially for the asym-
metric addition of organozinc reagents to ketones and
aldehydes.[1] However, they can also serve as catalysts
in their own right, that is, without any metal ion. The
basis for this claim lies in singular observations of the
reactivity of hydroxy groups neighbouring tertiary
amino groups (commonly in the b-position). It has
been suggested that amino alcohols may be employed
as serine protease mimics,[2] with the aim to achieve
non-enzyme-catalysed transesterification. Selected
amino alcohols were tested as candidates, exhibiting
similar effects as the well studied DMAP and its re-
Scheme 1.
cently developed derivatives.[3,4] In a noteworthy ex-
ample, Sammakia et al.[4d] incorporated electron-with-
drawing groups in proximity to the hydroxy group of monium) group, intermediate 2 has an increased sus-
(chiral) amino alcohols to increase their acyl transfer ceptibilty to hydrolysis or alcoholysis, to finally gener-
ability. These amino alcohols have been applied to ate an acid or ester 4, respectively. The uncatalysed
catalyse the kinetic resolution of a-acetoxy-N-acylox- conversion from 1 to 4 may also occur (indicated by
azolidinethiones and a-amino acid derivatives.[4e,f]
the dashed arrow) as a background reaction, but is
A general catalytic cycle of an amino alcohol cata- comparably slow.
lyst 3 is shown in Scheme 1. The hydroxy group of 3
Although it has been widely accepted for the first
is activated by forming a hydrogen bond with the ni- catalytic step that the hydroxy group of 3 attacks the
trogen which acts as a general base, imitating the acyl donor 1 directly, an alternative mechanism was
function of a histidine imidazole in serine proteases.[5] proposed by H. M. R. Hoffmann et al.[6] in the acyla-
With enhanced nucleophility, the hydroxy group, a tion of two b-dialkylamino alcohols, Quincorineꢀ and
mimic of the serine hydroxy group, is transacylated Quincoridineꢀ. They suggested that initially the terti-
with substrate 1 to readily form the amino ester 2. ary amino group attacks the activated acyl donor,
Due to the neighbouring effect of the amino (or am- forming an ammonium cation intermediate. The acyl
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Figure 1. Acylation of amino alcohols influenced by spatial effects (188C, in CDCl3; control: 1:1 mixture of 2-propanol/tri-
ethylamine).
group is subsequently transferred to the neighbouring and 9a are both g-amino alcohols, the latter reacts
hydroxy group. A similar mechanism was proposed very slowly due to the fact that the rather rigid ring
by Waddell et al. in their acylation of quinine deriva- system restricts a proper positioning or movement of
tives.[7] This N!O acyl transfer mechanism is – in the amino group relative to the hydroxy group. Mean-
principle – known from the intermolecular acylation while, the conversion rate of the control reaction is
catalysis found with DMAP which utilises an sp2-hy- undetectable within the given time, indicating that
bridised nitrogen activated by a conjugated dimethyl- there is no noteworthy intermolecular base-catalysed
amino group.
transfer or that it proceeds very slowly.
Even though several amino alcohols have been ap-
To explore the steric effect of the amino substitu-
plied in acyl transfer reactions in some specialised ent, the acylations of diethylamino alcohol 5a and di-
cases, no systematic structure-activity relationship benzylamino alcohol 10a with butyric anhydride were
studies have been performed to pave the way for the compared (Figure 2). The acylation speed of 10a was
development of more general organocatalysts of this impeded significantly by the bulkier dibenzyl substitu-
type. Herein we present a series of detailed kinetic tion, but was still faster than the control reaction,
studies of the influence of structural and electronic which finally became visible in this prolonged experi-
factors on the acylation and deacylation rates of ment (NB! The scale of Figure 2 vs. Figure 1 is days
amino alcohols.
vs. minutes, respectively).
In an attempt to find out whether the presence of
an additional heteroatom can enhance the activity of
the amino alcohols, three cyclohexane trans-b-amino
alcohols 11a–13a were synthesised.[8] Their acylation
Results and Discussion
First, the influence of the carbon tether between the rate with butyric anhydride is shown in Figure 3. In-
amino and hydroxy group on the acylation rate was terestingly, the reactivity of 12a and 13a was inhibited
probed, and the importance of the spatial arrange- by the extra oxygen and nitrogen atoms due to elec-
ment of these crucial functions, based on the flexibili- tronic effects and, in contrast to intuitive expectations,
ty of the carbon skeleton. Four acyclic diethylamino the more basic piperazinyl derivative were the least
alcohols 5a–8a with increasing carbon spacers and active one in this series.
one cyclic g-amino alcohol 9a were chosen as sub-
As depicted in Scheme 1, the alcoholysis (or hy-
strates. Butyric anhydride was used as the acyl donor drolysis) of amino ester/amide intermediates 2 is also
1
and the reaction progress was monitored by H NMR accelerated by neighbouring amino groups, a necessa-
in CDCl3. A control reaction of unconnected amine ry requirement for a useful catalytic cycle. In the as-
and alcohol (a mixture of 2-propanol, triethylamine, sumption that the amino group might aid the deproto-
and butyric anhydride) was also executed. As depict- nation of the incoming final nucleophile (alcohol or
ed in Figure 1, the reaction rates of 5a–7a with less water), a survey of the pH-dependence of this process
than five carbons are almost equal. There appears to was conducted. For example, ester 14b was methano-
be no notable difference in acylation rate between the lysed in buffer solutions (MeOH/aqueous buffer/
secondary and the primary alcohol. With increasing THF=2/1/0.5) at pH values ranging from 4 to above
spacer length, the reaction rate drops rapidly and the 9. Initially, no significant differences of the reaction
nitrogen almost has no apparent inductive effect if rates were observed within a large pH range around
connected by a six-atom tether (cf. 8a/b). Although 7a pH 7, indicating that the methanolysis of the amino
108
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Amino Alcohols in Organocatalysed Acylation and Deacylation
FULL PAPERS
Figure 2. Acylation of amino alcohols influenced by steric effect (control: 1:1 mixture of 2-propanol/triethylamine).
Figure 3. Acylation of amino alcohols influenced by electronic effects.
Figure 4. Methanolysis of amino esters (408C, THF/MeOH, buffer. Not shown: addition of 1 equivalent of TFA quenches
the reaction altogether).
ester is not significantly catalysed by (external) base residue of 11b imposes less hindrance than the dieth-
(Figure 4). However, the methanolysis was fully im- ylamine residue of 14b. In contrast to this, the second
peded in the presence of a stoichiometric amount of nitrogen in 13b inhibits methanolysis almost com-
TFA.
pletely. This result again suggests that additional
Finally, thee methanolysis of 11b and 13b in buffer amino groups may act in competition with the original
(pH 7.0, MeOH/buffer/THF=2/1/0.5) was compared ones and inhibit the reaction, for example, by slowing
with that of ester 14b (also shown in Figure 4). The protonation at the correct ester-proximal amino
slight rate enhancement seen with 11b might be rea- group.
soned by steric effects: the more confined piperidine
Adv. Synth. Catal. 2008, 350, 107 – 112
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Ludger A. Wessjohann and Mingzhao Zhu
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Scheme 2.
The observed decrease in activity upon protonation, scribed in literature, the structures used were mainly
especially if quantitative, is a strong argument against restricted to b-amino alcohols. In our kinetic studies,
a general acid catalysis, including activation of the a series of dialkylamino alcohols was acylated to ex-
carbonyl groups by the intramolecular ammonium. plore spatial, steric, and electronic parameters to
The lack of a significant pH-dependence – except for adjust acylation speed. The following factors have
complete protonation – also does not support a gener- been found to decrease the acylation speed: a
al base mechanism. It might indicate that an internal (carbon) spacer longer than four to five atoms, in a
nucleophilic activation is important, or/and a hydro- strained or rigid assembly that inhibits OH$NR2
gen bond-mediated proximity effect of the incoming proximity, bulky substituents on the amino group, or
nucleophile as proposed by Waddell et al.[7,9]
extra heteroatoms close to the amino group. Deacyla-
After the detailed investigations of the structure-re- tion of amino esters follows similar lines, and in addi-
activity relationship of amino alcohols and their tion is not very dependent on the pH value (pH 4.0–
esters, we turned to applications in synthesis. Amino 9.0) of the solvent, revealing that this is a self-cata-
alcohols are common functional groups occurring in lysed mechanism. Our results give clues on how to
many important compounds, including natural prod- optimise the structure of amino alcohols to generate
ucts. For instance, erythromycin[10] and desmycosin[11] more effective organocatalysts. Through the selective
are antibiotics possessing b-amino sugar moieties. acylation of desmycosin (15), we have also proven
Based on the high reactivity of amino alcohols, selec- that the property of amino alcohols can be applied as
tive acylation/deacylation can be realised.[11,12] In the a protection-deprotection strategy in organic synthe-
case of the more sensitive aldehyde desmycosin (15), sis. Since amino alcohols are common structural ele-
its C-17 and C-19 hydroxy groups on the mycaminose ments in natural products and drugs, the effects de-
sugar residue are adjacent to a dimethylamino group, scribed here must be accounted for during synthetic
hence they should have higher reactivity than C-3and
planning, or even can be utilised to circumvent selec-
C-24-OH towards acylation. For a demonstration, 15 tivity problems in total syntheses.
was treated with excess butyric anhydride (4 equivs.)
in pure THF, and 17,19-O-dibutyryldesmycosin (16)
was obtained as the only product. Further regioselec- Experimental Section
tive acylation on C-24-OH with Et3N and DMAP af-
Details of experimental conditions, instrumentation, and fur-
ther examples can be found in the Supporting Information.
forded 17,19,24-O-tributyryldesmycosin (17). When
heated in methanol, again only the C-17 and C-19-
ester of 17 was methanolysed to give 24-O-butyryldes-
mycosin (18), the product selectively deprotected in
proximity to the diethylamino group (Scheme 2).
Chromatographic Analyses
Reversed phase HPLC analyses were performed with Merck
RP 18, LiChrospher 100, 5 mm silica gel, 4”250 mm,
1 mLminꢀ1, at 51 bar. GC analyses were performed on a
DB-5MS column, 20 m”0.25 mm, film 0.25 mm, flow
0.8 mLminꢀ1 He. GC conditions A: 0–4 min: 608C; 4–
25 min: 608C!2908C (108Cminꢀ1); 26–29 min: 2908C;
Conclusions
Although the catalytic ability of amino alcohols as
(trans-)acylation catalyst has been suggested and de- pressure: 65 kPa. Conditions B: 0–6 min: 608C; 7–25 min:
110
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Amino Alcohols in Organocatalysed Acylation and Deacylation
FULL PAPERS
608C!2908C (128Cminꢀ1); 26–30 min: 2908C; pressure: 65
kPa. Conditions C: 0–6 min: 808C; 7–27 min: 608C!2908C
(118Cminꢀ1); 28–30 min: 2908C; pressure: 65 kPa.
(1 mL). The solution was shaken on a LabMate Organic
SynthesizerTM at 408C. In every given time interval (cf.
Figure 4), 0.9 mL of the solution was taken out and diluted
with 50 mL ethyl acetate. The organic layer was washed
with H2O (2”5 mL) and brine (1”5 mL), and was dried
over Na2SO4. The solvent was completely removed under
General Procedure for the Preparation of trans-b-
Aminocyclohexanols 11a–14a
1
vacuum and the residue was submitted to H NMR to deter-
To a solution of cyclohexene oxide (1.43mL, 14.2 mmol)
and dialkylamine (14.2 mmol) in 5 mL of dry CH3CN,
mine the composition (conversion rate). There was no need
to purify the resulting amino alcohols 11a, 12a, and 13a
after completion of the reaction.
ground Ca(OTf)2 (600 mg, 0.13equiv.) was added. The reac-
A
tion tube was sealed with a Teflonꢀ cap. The solution was
pre-stirred for 30 s, then was irradiated in the microwave
(300 Watt, 708C) for 5 min. After the tube had been cooled
to 508C by gas-jet cooling, the solvent turned red and homo-
geneous. After the CH3CN had been evaporated, the resi-
due was extracted with 200 mL of Et2O and washed with sa-
turated NaHCO3 (3”10 mL), water (3”10 mL) and brine
(1”10 mL). The solvent was dried over Na2SO4 and re-
moved in vacuum to give the product. No further purifica-
tion was needed.
trans-2-Piperidinylcyclohexanol (11a): According to the
general procedure, amino alcohol 11a was obtained as a col-
ourless oil; yield: 99%; Rf: 0.24 (petroleum ether:ethyl ace-
tate:Et3N=2:1:0.01); GC (conditions B): 14.15 min; GC
purity: >97%; 1H NMR (399.9 MHz, CDCl3, TMS): d=
1.12–1.26 (m, 4H), 1.43–1.45 (m, 2H), 1.48–1.64 (m, 4H),
1.67–1.72 (m, 1H), 1.75–1.79 (m, 2H), 2.09–2.16 (m, 2H),
2.32 (m, 2H), 2.64–2.69 (m, 2H), 3.32–3.44 (m, 1H), 4.13
(bs, 1H); ESI-MS: m/z (%)=184 (96%) [M+H]+.
29-O-Butyryldesmycosin (18)
A solution of 17 (15 mg, 16 mmol) in 5 mL of methanol was
refluxed for 5 h. The solvent was removed under vacuum
and the residue was purified by flash chromatography on
silica gel (petroleum ether:acetone=2 : 1) to give 18 as a
colourless oil; yield: 13mg (95%); Rf: 0.15 (petroleum
ether:acetone:Et3N=50:50:1);
RP-HPLC:
4.27 min
(CH3CN:H2O:Et3N=90:10:0.01, column size: 4”250 mm,
5 mm); LC purity: 100%; 1H NMR (399.9 MHz, CDCl3,
TMS): d=0.93(t, J=7.5 Hz, 3H), 0.97 (t, J=7.5 Hz, 3H),
1.01 (d, J=6.6 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H), 1.20 (d, J=
6.7 Hz, 3H), 1.27 (d, J=5.9 Hz, 3H), 1.44–1.52 (m, 2H),
1.56–1.66 (m, 1H), 1.68 (sextet, J=7.5 Hz, 2H), 1.79 (d, J=
1.0 Hz, 3H), 1.84–1.88 (m, 1H), 1.85–1.91 (m, 1H), 1.94 (d,
J=16.6 Hz, 1H), 2.08–2.20 (m, 1H), 2.2.28–2.35 (m, 1H),
2.34 (t, J=7.5 Hz, 2H), 2.39 (t, J=10.7 Hz, 1H), 2.50 (t, J=
10.4 Hz, 1H), 2.52 (s, 6H), 2.51–2.54 (m, 1H), 2.92 (dd, J=
18.1 Hz, J=9.6 Hz, 1H), 2.94–2.99 (m, 14H), 3.05 (dd, J=
8.0 Hz, J=2.8 Hz, 1H), 3.06 (t, J=9.6 Hz, 1H), 3.24–3.31
(m, 1H), 3.47 (dd, J=10.9 Hz, J=9.9 Hz, 1H), 3.48 (s, 3H),
3.52 (s, 3H), 3.56 (dd, J=9.7 Hz, J=6.5 Hz, 1H), 3.74 (d,
J=9.6 Hz, 1H), 3.84 (d, J=10.5 Hz, 1H), 3.89 (t, J=2.4 Hz,
1H), 3.91 (dd, J=10.0 Hz, J=6.1 Hz, 1H), 4.00 (dd, J=
9.7 Hz, J=4.0 Hz, 1H), 4.26 (d, J=7.1 Hz, 1H), 4.46 (dd,
J=10.0 Hz, J=2.7 Hz, 1H), 4.63(d, J=8.1 Hz, 1H), 4.98
(td, J=9.8 Hz, J=2.5 Hz, 1H), 5.89 (d, J=10.3Hz, 1H),
6.26 (d, J=15.7 Hz, 1H), 7.32 (d, J=15.7 Hz, 1H), 9.70 (s,
1H); 13C NMR (75.5 MHz, CDCl3, TMS): d=9.82, 10.38,
13.12, 13.75, 17.62, 17.49, 17.92, 18.53, 25.58, 29.56, 36.28,
39.41, 41.84, 41.92, 43.85, 44.73, 45.07, 59.59, 61.60, 67.40
(2”CH), 69.24, 70.56, 70.49, 70.79, 70.83, 73.29, 74.41, 75.20,
77.76, 80.58, 100.97 (2”CH), 118.62, 134.82, 141.89, 147.86,
172.59, 173.73, 202.57, 202.83; ESI-MS: m/z (%)=842 (70)
[M+H]+, 874 (100) [M+Na]+, 840 (100) [MꢀH]ꢀ; HR-ESI-
MS: m/z=842.49050, calcd. for C43H72O15N [M+H]+:
842.48965, 864.47158, calcd. for C43H71O15NNa [M+Na]+:
864.47159.
Kinetic Study and General Procedure for the
Acylation of Amino Alcohols
An amino alcohol (0.23mmol) and butyric anhydride
(21 mL, 0.25 mmol) were dissolved with CDCl3 (0.67 mL) in
1
an NMR tube. The sample was scanned for H NMR, moni-
toring the acylation process at 188C. When the test was fin-
ished, the sample was transferred to 100 mL of Et2O. The
solution was washed with NaHCO3 (3”10 mL), H2O (1”
10 mL), and brine (1”10 mL), and was dried over Na2SO4.
After the solvent had been evaporated under vacuum, the
crude product was purified by flash chromatography to give
the butyric ester.
trans-2-Piperidinylcyclohexyl butyrate (11b): Ester 11b
was prepared from 11a according to the general procedure,
and purified by flash chromatography on silica (petroleum
ether:ethyl acetate:Et3N=10:1:0.01) to afford a pale yellow
oil; Rf: 0.65 (petroleum ether:acetone=5:1); GC (condi-
tions A): 15.60 min; GC purity: >99%; 1H NMR
(399.9 MHz, CDCl3, TMS): d=0.98 (t, J=7.4 Hz, 3H), 1.14–
1.51 (m, 10H), 1.68 (sextet, J=7.4 Hz, 2H), 1.63–1.1.75 (m,
2H), 1.82–1.85 (m, 1H), 1.93–1.98 (m, 1H), 2.28 (dt, J=
1.5 Hz, J=7.4 Hz, 2H), 2.31–2.40 (m, 3H), 2.57–2.63 (m,
2H), 4.84–4.90 (m, 1H); 13C NMR (100.6 MHz, CDCl3,
TMS): d=13.83, 18.65, 24.44, 24.68, 25.00, 25.13, 26.79,
32.06, 36.75, 50.22, 67.79, 71.61, 173.04; ESI-MS: m/z (%)=
254 (100) [M+H]+, 276 (30) [M+Na]+.
Acknowledgements
We are grateful for a grant from the German Research Coun-
cil (DFG We 1467/7–1).
Kinetic Study of the Methanolysis of Amino Esters
11b, 13b, and 14b
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[4] For references on amino alcohols acting similar to
DMAP see: a) K. I. Skorey, V. Somayaji, R. S. Brown,
J. Am. Chem. Soc. 1989, 111, 1445–1452; b) T. Samma-
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