Studies on the transesterification and macrolactonization of 2-pyridyl esters by intramolecular N-alkylation or metal ion coordination

Article abstract of DOI:10.1055/s-2005-918476

In a process analogous to use of the Mukaiyama reagent, ω-hydroxyalkyl 2-pyridyl ester derivatives were converted into lactones by N-alkylation or the coordination of copper(II) inflate and transacylation of the resultant electrophilic ω-hydroxyalkanecao boxypyridinium salts. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918476

PAPER
3253
Studies on the Transesterification and Macrolactonization of 2-Pyridyl Esters
by Intramolecular N-Alkylation or Metal Ion Coordination
M
asked/Unmasked
n
Pyridyl Est
t
er
s
for
h
Macrolacton
o
ization ny G. M. Barrett,* Mathias U. Frederiksen
Department of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, England, UK
Fax +44(207)5945805; E-mail: agmb@imperial.ac.uk
Received 6 September 2005
Dedicated to Professor Steven Ley, CBE, FRS, FMedSci, on the occasion of his 60th birthday – Happy Birthday my (now) old friend!!
This in turn should undergo macrolactonization and con-
Abstract: In a process analogous to use of the Mukaiyama reagent,
comitant cleavage affording the indolizinone 4 and the de-
w-hydroxyalkyl 2-pyridyl ester derivatives were converted into lac-
sired lactone 5 (Scheme 1). The system could be
translated to the corresponding solid-supported system 6,
which would potentially enable the synthesis of mac-
rolides using a macrolactonization–cyclorelease proto-
col.6
tones by N-alkylation or the coordination of copper(II) triflate and
transacylation of the resultant electrophilic w-hydroxyalkanecar-
boxypyridinium salts.
Key words: lactonization, 2-pyridyl ester, copper(II) triflate,
tetrahydroquinolizinone
OH
OH
n
n
The construction of macrocyclic systems is a frequent and
challenging problem in synthetic organic chemistry. The
most general solution to this task is that of cyclization of
linear precursors, which is inherently disfavored entropi-
cally, and frequently accompanied by significant levels of
polymerization. In the case of macrolides, ring closure is
usually carried out by lactonization of activated hydroxy-
acid derivatives,1,2 which are often unstable and difficult
to handle. As such they do not represent ideal synthetic in-
termediates. Moreover the highly reactive nature of the
activated esters means that they can only be introduced
just prior to the ring closure reaction. We considered the
alternative possibility of introducing the requisite active
ester at an early stage of a synthesis, in a masked format.
Ideally this would be a stable functional group, which
would tolerate diverse synthetic manipulations yet be
readily transformed into the active ester, which would un-
dergo cyclization. The benefits of such a system are two-
fold: firstly it would avoid polar seco-acid intermediates,
and secondly such a stable masked active ester could con-
stitute the linker in the polymer-supported synthesis of
macrolides.3
X
O
O
O
O
X
activation
N
N
1
2
OH
O
O
X
n
N
O
O
O
X
n
4
5
N
OH
n
3
O
O
N
6
Scheme 1 Armed/disarmed 2-pyridyl esters in lactonization reac-
tions.
Herein we describe the development of a masked active
ester process based on Mukaiyama pyridinium esters.2 We
considered that a 2-pyridyl ester would be converted into
a potent acylating reagent on intramolecular N-alkylation,
a process that has indirect analogy.4 Initially we sought to
mediate the activation process by intramolecular alkyla-
tion. Such an approach is related to the Fraser–Reid n-
pentenyl glycosidation methodology.5 Thus, a 6-(3-buten-
1-yl)-2-pyridyl ester 1 should undergo activation by reac-
tion with an electrophile to form ion 2, which should un-
dergo 5-exo-tet-cyclization to form the activated ester 3.
Our initial studies were focused on the benzoate 9, which
was synthesized from pyridone 7 by double deprotona-
tion, allylation and subsequent esterification with benzoyl
chloride in excellent yield (Scheme 2). We subsequently
examined the electrophile-induced transesterification re-
actions of benzoate 9 in neat EtOH or using BuOH in
CH2Cl2 as solvent (Table 1). Reaction of ester 9 with NIS
in EtOH gave ester 10 (R = Et; 95%) and indolizinone 4
(E = I) in excellent and equimolar yields (Table 1, entry
1). We found that transesterification also proceeded using
iodine or NBS (entries 2 and 3) but did not occur in the ab-
sence of the electrophile even after prolonged reaction
times (entry 4) underscoring the stability of 2-pyridyl es-
ters. Transesterification using BuOH in CH2Cl2 as solvent
proceeded with lower yields of ester 10, which was high-
SYNTHESIS 2005, No. 19, pp 3253–3256
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918476; Art ID: C06005SS
© Georg Thieme Verlag Stuttgart · New York

3254
A. G. M. Barrett, M. U. Frederiksen
PAPER
Allylatea
O
O
Esterifya
TBSO
TBSO
OH
O
14
N
O
N
O
N
14
H
H
11
12
7
8
PhCOClb
O
3 HF⋅Et3Nb
HO
O
N
PhCO2
N
14
13
9
O
O
IClc
Scheme 2 Reagents and conditions: (a) NaH (1 equiv), THF, 0–20
°C; n-BuLi (1 equiv), THF, 20 °C; allyl bromide, –78 °C (96%); (b)
PhCOCl (1.3 equiv), Et3N (1.3 equiv), MeCN, 0 °C, 80%.
14
14
Scheme 3 Reagents and conditions: (a) n-BuLi (1 equiv), Et2O, 0
°C; (COCl)2, DMF (10 mol%); 8, Et3N, CH2Cl2, 0–20 °C (79%); (b)
3HF·Et3N, MeCN, 20 °C (96%); (c) ICl, s-collidine, THF, 20 mM
(22%).
est using iodine monochloride in the presence of sym-col-
lidine (entry 10). While not fully optimized, these results
provided the sufficient proof-of-concept to move on to
more challenging macrolactonization reactions.
In the light of the successful transesterification reactions,
we sought to extend the method to lactonization. Ester 13
was prepared from acid 117 by deprotonation with n-bu-
tyllithium and sequential reaction with oxalyl chloride
and pyridone 8 followed by desilylation (Scheme 3). This
esterification method proceeded with reduced premature
desilylation compared to alternative methods. Much to
our dismay, attempted lactonization of ester 13 using io-
dine monochloride in the presence of sym-collidine gave
poor yields of lactone 148 (optimized yield 22%).
We assumed that the poor yield of lactone in Scheme 3
was the result of the low rate of formation or low equilib-
rium concentration of the key iodonium ion, under the
high dilution reaction conditions. We therefore examined
more potent alkylating agents to trigger lactonization. A
second-generation system was designed in which an alco-
hol was incorporated in the place of the alkene unit. We
believed that there should be sufficient difference in reac-
tivity between a primary and secondary alcohol in diol 17
Table 1 Iodocyclization and Transesterification
E, ROH
N
PhCO2R
PhCO2
N
solvent
additive, 0 °C
E
O
4
9
10
R
Entry
Solvent
E+
Additive
Time
8 h
Yield 10 (%)
1
2
EtOH
Et
NIS
I2
–
95
75
95
EtOH
Et
Et3N
24 h
100 h
165 h
1 h
3
EtOH
Et
NBS
–
–
4
EtOH
Et
–
0
a
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
NIS
IBr
ICl
ICl
ICl
ICl
ICl
–
6
–
1 h
23
43
53
58
65
20
7
–
1 h
8
Et3N
PVPb
TMPc
DTBPd
1.5 h
9
1.5 h
1.5 h
1.5 h
10
11
a Complex mixture.
b PVP = poly(4-vinylpyridine).
c TMP = 2,4,6-trimethylpyridine.
d DTBP = 2,6-di-tert-butylpyridine.
Synthesis 2005, No. 19, 3253–3256 © Thieme Stuttgart · New York

PAPER
Masked/Unmasked Pyridyl Esters for Macrolactonization
3255
to allow for selective triflation, which would trigger N-
alkylation and lactonization (Scheme 4).
7, basea
O
N
OTf
H
TBSO
TESO
O
22
23
OH
OTBS
OTBS
n
NH
OTES
OH
O
OH
11
OH
Esterifyb
13
O
O
15
16
O
N
24
OH
11
25
O
O
OH
OH
3HF⋅Et3Nc
n
n
Tf2O
OH
N
O
O
O
O
26
OH
N
N
Scheme 5 Reagents and conditions: (a) Pyridone 7, NaH (1.1
equiv), n-BuLi (1.1 equiv), THF, 0–20 °C; 22, THF, –78 °C to 20 °C
(15%); (b) 23, PyClU, Et3N, CH2Cl2, 0–20 °C (92%); (c) 3HF·Et3N,
MeCN (65%).
OTf
17
18
OH
n
31 was allowed to react with triflic anhydride under basic
conditions at high dilution (5 mM). Reaction at –78 °C
and warming to 20 °C over 12 hours smoothly and cleanly
gave lactone 3310,14 (75%) and quinolizinone 34, in
equimolar ratio, as the only products along with some un-
reacted starting material. Reaction at –40 °C and warming
to 20 °C over 12 hours resulted in a superior yield of lac-
tone 33 (82%). In contrast, attempted lactonization at –10
°C resulted only in decomposition. Attempted lactoniza-
tion of diol 32 was unsuccessful presumably on account of
triflation of the wrong alcohol unit.
O
O
N
19
O
O
O
N
n
20
21
Finally, we examined the use of Lewis acid mediated lac-
tonization of two w-hydroxyalkyl 2-pyridyl esters. Such
transformations have analogy in the earlier synthesis of
esters and lactones by the metal ion activation of 6-(2,2¢-
bipyridyl) esters and 2-pyridyl thioesters and the Brønsted
acid activation of 6-phenyl-2-pyridyl esters.4 Attempted
lactonization of ester 13 using silver nitrate or mercuric
acetate were unsuccessful. However, reaction of ester 13
with copper(II) triflate in THF at room temperature
smoothly gave lactone 14 (58%). The side chain pyridine
C-6 alkene unit was unchanged in this reaction. To further
study this Cu(II)-mediated reaction, 6-methyl-2-pyridone
35 was converted into corresponding hydroxy ester 37 by
condensation with the acyl chloride derived from acid 11
and desilylation (Scheme 7). Reaction of ester 37 with
copper(II) triflate in THF at room temperature smoothly
gave lactone 14 (83%).
Scheme 4 Second-generation approach.
Pyridone 23 was synthesized by alkylation of 7 with
triflate 22.9 Acid 24 was synthesised from cyclopenta-
decanone by a-methylation (92%),10 Bayer–Villiger oxi-
dation with urea·hydrogen peroxide and TFAA (77%),11
saponification with 1 M aqueous lithium hydroxide
(100%) and triethylsilylation (Et3SiCl, imidazole, DMAP,
DMF; 95%). Pyridyl ester coupling using PyClU12 and
desilylation gave the unstable diol 26 (Scheme 5). Unfor-
tunately all attempts to effect lactonization of diol 26
using triflic anhydride in the presence of Hünig’s base at
–78 °C were unsuccessful and gave only oligomer mix-
tures still containing 2-pyridyl ester and alkene residues
(1H NMR, MS). Clearly the required N-alkylation, via a 5-
exo-tet-cyclization, was not occurring efficiently and thus
we sought to accelerate this key step.
Pyridone 7 was alkylated with bromide 2713 and the re-
sulting adduct 28 coupled with acids 24 and 11 giving the
esters 29 and 30, respectively in good yields. These, in
turn, were desilylated giving the robust target diols 31 and
32 (Scheme 6). These systems were evaluated in the se-
lective O-sulfonylation activation (Scheme 6). Thus diol
In conclusion, we have described the application of both
intramolecular N-alkylation and copper(II) ion coordina-
tion to convert 2-pyridyl esters of low reactivity into more
electrophilic acylating reagents thereby readily bringing
about both intermolecular transacylation and lactoniza-
tion reactions at ambient or lower temperatures.
Synthesis 2005, No. 19, 3253–3256 © Thieme Stuttgart · New York

3256
A. G. M. Barrett, M. U. Frederiksen
PAPER
5614. (b) Masamune, S.; Kamata, S.; Schilling, W. J. Am.
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Am. Chem. Soc. 1989, 111, 8286. (g) Trost, B. M.;
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O
7, basea
NH
TBSO
Br
OTBS
27
28
O
R1O
O
N
12
Esterifyb
R2
TBSO
(2) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(3) For an example of macrolactonisation using solid-supported
DCC, see: Keck, G. E.; Sanchez, C.; Wager, C. A.
Tetrahedron Lett. 2000, 41, 8673.
29 R1 = TES, R2 = Me
30 R1 = TBS, R2 = H
(4) (a) For the conversion of 6-(2,2¢-bipyridyl) esters into
amides with Zn(II), Co(II) or Ni(II) catalysis see: Propst, R.
M. III; Trzupek, L. S. J. Am. Chem. Soc. 1981, 103, 3233.
(b) For the transesterification of 6-(2,2¢-bipyridyl)esters and
alcohols catalysed by CsF, see: Mukaiyama, T.; Pai, F.-C.;
Onaka, M.; Narasaka, K. Chem. Lett. 1980, 563. For the
macrolactonization of hydroxyacids by reflux of their 6-
phenyl-2-pyridyl esters and 4-toluenesulfonic acid in
CH2Cl2 see: (c) Narasaka, K.; Yamaguchi, M.; Mukaiyama,
T. Chem. Lett. 1977, 959. (d) Mukaiyama, T.; Narasaka, K.;
Kikuchi, K. Chem. Lett. 1977, 441. (e) For the conversion
of 2-pyridyl thioesters into esters using silver(I) salts, see:
Gerlach, H.; Thalmann, A. Helv. Chim. Acta 1974, 57,
2661. (f) For the use of related thioesters with CuBr2
activation for the synthesis of cyclic oligo-(R)-3-
hydroxybutanoic esters, see: Lengweiler, U. D.; Fritz, M. G.;
Seebach, D. Helv. Chim. Acta 1996, 79, 670.
(5) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.;
FraserReid, B. J. Am. Chem. Soc. 1988, 110, 5583.
(b) Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem.
Soc. 1988, 110, 2662. (c) Fraser-Reid, B.; Wu, Z.; Udodong,
U. E.; Ottosson, H. J. Org. Chem. 1990, 55, 6068.
(d) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.;
Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett
1992, 927.
O
3HF⋅Et3Nc
HO
O
N
12
R2
HO
31 R2 = Me
32 R2 = H
O
O
Tf2Od
N
O
Me
11
34
33
Scheme 6 Reagents and conditions: (a) Pyridone 7, NaH (1 equiv);
n-BuLi (1 equiv), THF, 0–20 °C; 27, THF, –40 °C to 20 °C (61%); (b)
24 or 11, PyClU,12 Et3N, CH2Cl2, 0–20 °C [29 (79%); 30 (64%)]; (c)
3HF·Et3N, MeCN, 20 °C [31 (52%); 32 (71%)]; (d) R2 = Me, Tf2O,
Hünig’s base, CH2Cl2, –78 °C to 20 °C [33 (75%)] or –40 °C to 20 °C
[33 (82%)].
O
Acylatea
TBSO
O
N
H
O
N
14
(6) (a) For a review, see: van Maarseveen, J. H. Comb. Chem.
High Throughput Screening 1998, 1, 185. For additional
examples, see: (b) Nicolaou, K. C.; Roschangar, F.;
Vourloumis, D. Angew. Chem., Int. Ed. Engl. 1998, 37,
2014. (c) Nicolaou, K. C.; Winssinger, N.; Pastor, J.;
Murphy, F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2534.
(d) Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F.
J. Am. Chem. Soc. 1998, 120, 5132.
35
36
O
3HF⋅Et3Nb
c
Cu(OTf)2
HO
14
O
N
14
37
Scheme 7 Reagents and conditions: (a) Acid 11, n-BuLi (1 equiv),
Et2O, 0 °C; (COCl)2, DMF (10 mol%); 35, Et3N, CH2Cl2, 0–20 °C
(38%); (b) 3HF·Et3N, MeCN, 20 °C (57%); (c) Cu(OTf)2 (1 equiv),
THF, 50 mM, 20 °C (83%).
(7) Rastetter, W. H.; Phillion, D. P. J. Org. Chem. 1981, 46,
3209.
(8) Sample identical (TLC, 1H and 13C NMR, GC–MS) with a
commercial sample.
(9) (a) For a related alkylation using a triflate, see: Bates, R. B.;
Taylor, S. R. J. Org. Chem. 1993, 58, 4469. (b) Prepared
from the addition of Tf2O to the corresponding alcohol and
anhyd PVP in CH2Cl2 at –78 °C (85%) and used directly
without purification: McDougal, P. G.; Rico, J. G.; Oh, Y. I.;
Condon, B. D. J. Org. Chem. 1986, 51, 3388.
(10) Graham, R. J.; Weiler, L. Tetrahedron Lett. 1991, 32, 1027.
(11) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W.
R. Synlett 1990, 533.
Acknowledgment
We thank GlaxoSmithKline for the generous endowment (to
A.G.M.B.), the Royal Society and the Wolfson Foundation for a
Royal Society Wolfson Research Merit Award (to A.G.M.B.), the
Norwegian Research Council for pre-doctoral fellowship support
(to M.U.F), the Wolfson Foundation for establishing the Wolfson
Centre for Organic Chemistry in Medical Sciences at Imperial Col-
lege London, and the Engineering and Physical Sciences Research
Council for generous support of our studies.
(12) PyClU = N,N,N¢,N¢-bis(tetramethylene)chloroform-
amidinium hexafluorophosphate. See: Coste, J.; Frérot, E.;
Jouin, P. Tetrahedron Lett. 1991, 32, 1967.
(13) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(14) Sample identical (TLC, 1H and 13C NMR, GCMS) with the
lactone intermediate in the synthesis of 24.
References
(1) (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96,
Synthesis 2005, No. 19, 3253–3256 © Thieme Stuttgart · New York