Selective Acylation of Nucleosides, Nucleotides, and Glycerol-3-phosphocholine in Water

Article abstract of DOI:10.1055/s-0036-1588626

A convenient selective synthesis of 2′,3′-di-O-acetyl-nucleotide-5′-phosphates, 2′,3′-di-O-acetyl-nucleotide-5′-triphosphates and 2′,3′,5′-tri-O-acetyl-nucleosides in water has been developed. Furthermore, a long-chain selective glycerol-3-phosphocholine diacylation is elucidated. These reactions are environmentally benign, rapid, high yielding, and the products are readily purified. Importantly, this reaction may indicate a prebiotically plausible reaction pathway for the selective acylation of key metabolites to facilitate their incorporation into protometabolism.

Full text of DOI:10.1055/s-0036-1588626

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
cluster
A
C. Fernández-García, M. W. Powner
Cluster
Synlett
Selective Acylation of Nucleosides, Nucleotides, and Glycerol-3-
phosphocholine in Water
Christian Fernández-García
Matthew W. Powner*
O
O
HO
HO
O
O
n = 0
Base
Base
O
P
P
O
O
O
O
HO
OH
O
n
O
O
University College London, 20 Gordon
Street, London WC1H 0AJ, UK
matthew.powner@ucl.ac.uk
X
O
O
O
O
RO
O
RO
O
P
P
O
O
O
OH
n ≠ 0 or 2
n = 4, 6 or 8
n
O
OH
n
R = (CH2)2NMe3
X = imidazole
O
Received: 03.08.2016
Accepted after revision: 20.09.2016
Published online: 11.10.2016
igins of life. Acetylation is one of the most widely exploited
strategies for hydroxyl modification; protocols often em-
ploy acetic anhydride or acetyl chloride in (toxic) solvents,
such as pyridine,5 and afford peracetylated products with-
out discriminating between functional groups. To improve
the selectivity and environmental impact, a wide range of
additives (principally under solvent-free conditions) have
been explored6 and numerous N-deacetylation methods re-
ported to address the deviation from ester selectivity.7
However, these methods are incompatible with certain car-
bohydrates, nucleotides, and nucleosides. To avoid these
harsh conditions, Schwartz’s reagent8 or superheated
methanol9 have been exploited but cost, time, and tedious
reaction protocols are drawbacks to their application. Fur-
thermore, biologically important highly polar or charged
groups, such as (poly)phosphates or sulfates, result in low
solubility in the organic solvents predominately used for
acetylation, which adversely affects product yields and re-
action times. Formation of n-alkylammonium salts10 or ion-
ic liquids11 have been reported to improve solubility. How-
ever, groups such as triphosphates do not tolerate harsh
conditions and can be difficult to separate from ionic liq-
uids. Aqueous acetylation protocols have received limited
attention because the typical acetylating agents acetic an-
hydride and acetyl chloride hydrolyse quickly in water.12
However, acylation is an essential reaction motif in living
systems,13–16 though biochemical acylation processes are
enzyme (or ribosome) catalysed, before the advent of so-
phisticated enzymatic control, biologically essential acyl-
transfer reactions must have been controlled by predis-
posed reactivity.1 Accordingly, the role of prebiotic acyl-
group transfer warrants further investigation.
DOI: 10.1055/s-0036-1588626; Art ID: st-2016-s0507-c
Abstract A convenient selective synthesis of 2′,3′-di-O-acetyl-nucleo-
tide-5′-phosphates, 2′,3′-di-O-acetyl-nucleotide-5′-triphosphates and
2′,3′,5′-tri-O-acetyl-nucleosides in water has been developed. Further-
more, a long-chain selective glycerol-3-phosphocholine diacylation is
elucidated. These reactions are environmentally benign, rapid, high
yielding, and the products are readily purified. Importantly, this reac-
tion may indicate a prebiotically plausible reaction pathway for the se-
lective acylation of key metabolites to facilitate their incorporation into
protometabolism.
Key words prebiotic chemistry, nucleotides, lipids, water, acylation
Life is the quintessential example of a complex chemical
system; the molecular choreography involved in sustained
cellular evolution is not only one of the most remarkable
phenomena in nature, but is also astonishingly a process
that must have self-initiated under geochemically plausible
constraints. Although clues to the chemical origins of life
are built into the universally conserved metabolites of bio-
chemistry, understanding the origins of these metabolites
remains an unmet challenge.1 Historical evidence from the
Hadean and early Archean eons (>3.5 billon years ago) – the
time life arose on earth – is severely limited,2 therefore it is
widely recognised that the origins of life must be reinvent-
ed rather than discovered.3,4 Accordingly, the role synthetic
chemistry must play in elucidating the origins of life cannot
be overestimated, and we have set out to expand our
knowledge of chemistry in relation to this question.
Protecting-group strategies are ubiquitous for the con-
trol of multistep organic syntheses,5 and although such
strategies remain almost unexplored in prebiotic chemistry,
there is no fundamental reason that temporary modifica-
tion of reactive functionalities to direct chemical reactivity
towards advantageous pathways should not apply at the or-
The chemoselective O2′-acetylation of nucleotide-3′-
phosphates in water, via intermolecular mixed anhydride
synthesis followed by intramolecular acyl transfer (employ-
ing thioesters, N-carboxyanhydrides, and N-acetyl imidaz-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
C. Fernández-García, M. W. Powner
Cluster
Synlett
ole (1a) as prebiotic acetylating agents) has been report-
ed.17,18 This strategy for temporary acetylation has been ex-
ploited to control regioselective ligation of (natural) 5′-3′-
RNA under prebiotically plausible conditions.17 Imidazole
1a has also been reported to regioselectively acetylate car-
bohydrates and simple diols in aqueous tetramethylammo-
nium hydroxide.19 Here, we further outline the utility of ac-
ylation as a methodology for the robust and reversible
modification of nucleotide hydroxyl moieties. Specifically,
we report an aqueous acetylation protocol and the chemo-
selective synthesis of 2′,3′-di-O-acetyl-nucleotides and
2′,3′,5′-tri-O-acetyl-nucleosides by using activated thio-
esters or imidazole 1a in water. We also demonstrate a re-
markable long-chain effect that promotes the long-chain
(≥C6) diacylation of the zwitterion glycerol-3-phosphocho-
line (10).
Protecting-group strategies have received limited atten-
tion in prebiotic synthesis.17 Therefore, we were intrigued
to investigate the acetylation of (natural) nucleotide 5′-
phosphates (2a–e; Table 1). The reaction of cytidine-5′-
phosphate (2a) with thioacid 320 and cyanoacetylene (4)17
proceeds at a wide range of pH values (pH 6–12), but
acetylation occurred solely at the 2′ and 3′-hydroxyl groups.
Nucleobase acetylation was not observed. A mixture of cy-
tidine-5′-phosphate 2a (33%), mono-O-acetyl-cytidine-5′-
phosphates 6a/7a (33%) and diacetyl-cytidine-5′-phosphate
5a (33%) was obtained 30 minutes after the addition of 3
and 4 (10 equiv each) to 2a at pH 8 (Supporting Informa-
tion, Figure S1).21 We next investigated the acetylation of 2a
with 3 and ferricyanide (10 equiv each),22 which afforded
diacetyl-cytidine-5′-phosphate 5a in good yield (80%),
alongside mono-O-acetyl-cytidine-5′-phosphates 6a and 7a
(5% combined yield) and, intriguingly, pyrophosphate de-
rivative 8 (15%).23 Increasing the amounts of 3 and ferricya-
nide to 20 equivalents further promoted phosphate activa-
tion and synthesis of pyrophosphate 8 (40%; Supporting In-
formation, Figure S2). Finally, we investigated the reaction
of imidazole 1a. Little acetylation of 2a was observed at pH
5 or 6, even with excess 1a (10 equiv), likely due rapid hy-
drolysis at acidic pH.24 Conversely, 2′,3′-di-O-acetyl cyti-
dine-5′-phosphate 5a (98%) was the major product at pH 7–
8 (Supporting Information, Figure S3). The reaction was
complete after <10 minutes, then only slow hydrolysis of
excess 1a was observed and 5a was stable to the reaction
conditions for >24 hours. Lower stoichiometries of 1a (6 or
8 equiv) afforded 5a in 77% and 85% yield, respectively. We
next investigated the reaction of uridine-5′-phosphate (2b)
with imidazole 1a (1–10 equiv) at pH 8. Acetylation was ob-
served at all stoichiometries, but diacetylation became effi-
cient with 1a (4 equiv) to furnish diacetyl-uridine-5′-phos-
phate 5b in 77% yield, alongside two monoacetyl-uridine-
5′-phosphates 6b and 7b (23%), after four hours. Higher
stoichiometries of 1a (6–10 equiv) furnished diacetyl-uri-
dine-5′-phosphate 5b in 95% yield (Supporting Information,
Figure S5). We next investigated the acetylation of nucleo-
tides 2c–h (100 mM; Table 1).25 All nucleotides were effec-
tively acetylated to furnish 5c–h (80–95%), and no nucleo-
base or phosphate derivatives were observed.26
It is of particular note that the mild conditions of our
protocol avoid cleavage of the triphosphate moiety whilst
achieving completely selective O-acetylation. It has previ-
ously been proposed that the predominant pathway for nu-
cleotide acetylation in water occurs via mixed anhydride 9
(Scheme 1),17,27 however, our observation that triphos-
phates are readily acetylated suggests direct hydroxyl
group acetylation.28 To evaluate these proposed mecha-
nisms, we next investigated the acetylation of cytidine 2i
(100 mM), which lacks a phosphate moiety. Upon incuba-
tion of 2i with imidazole 1a (10 equiv) in D2O–H2O (1:1) at
room temperature and pH 5–8, a remarkably similar pH
profile to that of nucleotides 2a–h was observed, with little
acetylation at pH 5 and an excellent 80% yield of tri-O-ace-
tyl-cytidine 5i at pH 8 (Supporting Information, Figure S6).
O
P
O
P
O
O
B
B
a)
O
O
O
O
O
O
HO
OH
HO
OH
O
9
2
X
O
P
O
O
B
b)
O
O
O
O
O
OH
6
Scheme 1 Potential pathways for nucleotide acetylation: a) intramo-
lecular acyl transfer from mixed anhydride 9; b) direct hydroxyl acyla-
tion; B = nucleobase; X = nucleofuge.
Pleasingly, we again found our acetylation protocol was
general to all the nucleosides investigated (2i–n). Although
guanosine 2l (100 mM) was insoluble in water, incubation
of a suspension of 2l at room temperature and pH 8 with
imidazole 1a furnished a homogenous solution after 30
minutes, and continued incubation led to the direct precip-
itation of guanosine 5l (53%, unoptimised) after four hours.
Incubation of inosine 2m and imidazole 1a in water also
furnished inosine 5m (70%) as a white precipitate after one
hour. Finally, to investigate the effect of diol stereochemis-
try on nucleoside acetylation, we next examined the reac-
tion of arabino-nucleosides (2o–s) with imidazole 1a. Good
yields (75–92%) were obtained for all arabinosides, except
insoluble arabino-adenine 1r (47%, unoptimised), and the
trans-2′,3′-stereochemistry was not observed to hinder or
decrease the rate of acetylation. However, upon exploring
lower stoichiometries of imidazole 1a (1–4 equiv) we inter-
estingly observed that arabino-cytidine 2p exhibited sig-
nificantly greater 3′-OH acetylation than 2′-OH acetylation
(1a (2 equiv): 6p/7p = 87:13; 1a (4 equiv): 6p/7p = 78:22;
Supporting Information, Figure S7).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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C. Fernández-García, M. W. Powner
Cluster
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Table 1 Selective O-Acetylation of Nucleotides 2 in Water
O
O
B
O
N
+
B
N
R1O
R1O
R3
R2
R3
1a
HO
R4O
5a–s R4 = Ac
6a R2 = OH, R3 = H, R4 = Ac
6p R2 = H, R3 = OH, R4 = Ac
7a R2 = OAc, R3 = H, R4 = H
7p R2 = H, R3 = OAc, R4 = H
R2
or
CN
AcSH
2a–s
3
4
3 + [Fe(CN)6]3–
or
Nucleoside/nucleotide (2)
O-Acetyl-nucleoside/nucleotide (5)
B
R1
PO3
R2
R3
R1
R2
R3
Yield (%)a
Yield (%)b
85c
–
98c
33d
80e
95c
87c
83c
86c
82c
90c
80c
80c
75c
75c
56c,f
78c
63c
92c
80c
85c
–
2–
2–
2–
2–
2–
2–
2–
2–
2–
2–
2–
2–
2–
2–
a
a
a
b
c
d
e
f
Cyt
Cyt
Cyt
Ura
Ade
Gua
Ino
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
PO3
OAc
H
PO3
PO3
PO3
PO3
PO3
PO3
H
PO3
PO3
PO3
PO3
PO3
PO3
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
H
H
H
H
–
H
H
67c
85c
70c
71c
73c
76c
76c
77c
74c
74c
53c,f
70c
63c
91c
66c
78c
47c,f
74c
H
H
H
H
H
H
4–
4–
4–
4–
4–
4–
Ade
Cyt
Ura
Cyt
Ura
Ade
Gua
Ino
P3O9
P3O9
P3O9
H
H
P3O9
P3O9
P3O9
OAc
OAc
OAc
OAc
OAc
OAc
H
g
h
i
H
H
H
H
H
H
j
H
H
H
k
l
H
H
H
H
H
H
m
n
o
p
q
r
H
H
H
Xan
Ade
Cyt
Uri
H
H
H
2–
2–
PO3
PO3
H
OH
OH
OH
OH
OH
PO3
PO3
OAc
OAc
OAc
OAc
OAc
2–
2–
H
H
H
OAc
OAc
OAc
H
Ade
Xan
H
H
H
s
H
H
H
75c
a Isolated yield.
b NMR yield.
c Nucleoside/nucleotide 2 (100 mM) and 1a (10 equiv) at pH 8 and r.t. after 4 h.
d Nucleotide 2a (100 mM), thioacid 3 (10 equiv), and cyanoacetylene (4; 10 equiv) at pH 8 and r.t. after 4 h. A mixture of 2′/3′-mono-O-acetyl-cytidines 6a/7a
(33%) and 2′,3′-di-O-acetyl-cytidine 5a (33%) was observed.
e Nucleotide 2a (100 mM), thioacid 3 (10 equiv), and ferricyanide (10 equiv) at pH 8 and r.t. after 4 h. Pyrophosphate derivative 8 was observed in 15% yield.23
f Unoptimised; insoluble starting material.
We have a long-standing interest in the generational re-
lationship between nucleotides and lipids,29 two classes of
metabolite thought to be essential to the origins of life,3,29,30
and having investigated the acetylation of (natural) nucleo-
tide 5′-phosphates 2a–e we were intrigued to investigate
the synthesis of diacyl phospholipids. Modern cell mem-
branes are composed primarily of diacyl (or dialkyl) glycer-
ol phospholipids, and double-chain amphiphiles exhibit in-
creased hydrophobicity relative to single-chain amphi-
philes,31 which promotes self-assembly at lower
concentrations and (competitive) growth in lipid mix-
tures.32 Furthermore, the increased volume of the alkyl
chains of the double-chain amphiphiles, which are cylindri-
cal to a first approximation, favours bilayer packing over
micelles.33 We were also attracted to zwitterionic head
groups, which are not cross-linked by Mg2+ or Ca2+ and are
much more stable to the ionic conditions necessary for RNA
folding, catalysis, and ligation with respect to acidic head
groups.34 Accordingly, we chose to investigate the acylation
of glycerol-3-phosphocholine 10 as a model zwitterionic
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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C. Fernández-García, M. W. Powner
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head group. Upon incubation of glycerol 10 with imidazole
1a (10 equiv) we observed remarkably a low yield of di-
acetylation at neutral pH: only 15% and 40% at pH 7 and 8,
respectively (Supporting Information, Figure S8). It is of
note that glycerol 10 diacetylation is considerably less effi-
cient than nucleotide 2 acetylation, even 20 equivalents of
imidazole 1a only furnished partial diacetylation (53%).
Therefore, to investigate this apparent differentiation in nu-
cleotide versus glycerol acetylation, we next incubated uri-
dine-5′-phosphate 2b/glycerol 10 (1:1) with imidazole 1a
(10 equiv) at pH 7. Intriguingly, we observed near-quantita-
tive diacetylation of 2b to afford diacyl-uridine-5′-phos-
phate 5b (>90%; Supporting Information, Figure S11), and
minimal diacetylation of 10 (9%), which demonstrates an
efficient differentiation of RNA and lipid precursors by
aqueous acetylation. We next turned our attention to long-
chain acyl imidazoles 1b–e that could potentially promote
esterification and retard hydrolysis by aggregation.35 Ac-
cordingly, we investigated the reaction of glycerol 10 with
N-butyryl (1b), N-hexanoyl (1c), N-octanoyl (1d), and N-de-
canoyl imidazoles (1e).36 Unsurprisingly, no reaction was
observed in pure water due to insolubility of the long-chain
acyl imidazole reagents. However, when water–acetonitrile
mixture (20:1 to 1:1) was used, to promote a biphasic as-
sembly of N-hexanoyl, N-octanoyl, or N-decanoyl imidazole
(1c–e), vigorous stirring with 10 at pH 7.0 resulted in re-
markably efficient long-chain diacylation (Figure 1).
acetonitrile ratio (20:1 to 4:1), whereas highly efficient
synthesis of long-chain diacylglycerols 11c–e (>95% NMR
yield) was observed (Figure 1).37 Accordingly, we suggest
that this reactivity switch, and apparent long-chain effect,
may have been important during the selective assembly of
prebiotic amphiphiles and vesicles. Further investigation
into the mechanism of amphiphile self-assembly, which
likely promotes long-chain diacylation through reagent/re-
actant co-localization, and the application of these model
reactions into prebiotic amphiphile synthesis and vesicle
assembly, nucleotide activation, and photo protection38 are
currently underway in our laboratory.
Acknowledgment
We thank the EPSRC (EP/K004980/1), Simons Foundation (318881)
and, posthumously, Harry Lonsdale for financial support, Dr K. Karu,
UCL MS Facility, and Dr. A. E. Aliev UCL NMR Facility.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588626.
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References and Notes
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gart, 2003. (b) Levy, D. E.; Fügedi, P. The Organic Chemistry of
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V. P. J. Mol. Catal. A: Chem. 2005, 226, 57. (d) Tai, C.-A.; Kulkarni,
S. S.; Hung, S.-C. J. Org. Chem. 2003, 68, 8719. (e) Ishihara, K.;
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(j) Hosseini Sarvari, M.; Sharghi, H. Tetrahedron 2005, 61,
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Lett. 2002, 43, 4261.
Figure 1 a) Long-chain selective diacylation of glycerol 10 with N-acyl
imidazoles 1c–e. b) 1H NMR spectra (400 MHz, δ = 3.5–5.5 ppm) show-
ing the reaction of glycerol 10 (100 mM) with: A) N-acetyl imidazole (1a
n = 0); B) N-butyryl imidazole (1b n = 2); C) N-hexanoyl imidazole (1c n
= 4); D) N-octanoyl imidazole (1d n = 6); E) N-decanoyl imidazole (1e n
= 8) in H2O–MeCN (4:1), pH 7 and r.t. after 4 h.
We were also intrigued to observe a clear switch in re-
activity between the short-chain (n = 0 and 2) and long-
chain (n = 4, 6, and 8) acylation. Minimal short-chain diacy-
lation (<5%) was observed at any concentration or water–
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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C. Fernández-García, M. W. Powner
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Synlett
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(25) General Nucleoside Acetylation Protocol
Nucleoside/nucleotide (2; 100 mM) and N-acetyl imidazole (1a;
10 equiv) were dissolved in water (pH 8; adjusted with 4 M
NaOH). The solution was incubated at r.t. for 4 h, and NMR
spectra were periodically acquired. The product was purified by
reverse-phase (C18) flash coumn chromatography (eluted at pH
4 with 100 mM NH4HCO2/MeCN = 98:2 to 80:20). The fractions
containing 5 were lyophilised to yield a white powder.
Selected Data: 2′,3′-Di-O-acetyl-β-cytidine-5′-phosphate (5a)
Starting from 1a (160 mg, 0.50 mmol), 5a (172 mg, 85%) was
1
obtained as a white powder. H NMR (600 MHz, D2O): δ = 8.08
[d, J = 7.9 Hz, 1 H, H-(C6)], 6.22 [d, J = 7.9 Hz, 1 H, H-(C5)], 6.11
[d, J = 5.1 Hz, 1 H, H-(C1′)], 5.41 [dd, J = 5.4, 5.1 Hz, 1 H, H-(C2′)],
5.38 [dd, J = 5.4, 4.4 Hz, 1 H, H-(C3′)], 4.48 [ddd, J = 4.9, 4.4, 2.4
Hz, 1 H, H-(C4′)], 4.13 [ABXY, J = 11.9, 4.4, 2.4 Hz, 1 H, H-(C5′)],
4.02 [ABXY, J = 11.9, 4.9, 2.4 Hz, 1 H, H-(C5′′)], 2.09 [s, 3 H, Ac-
(C3′)], 2.05 [s, 3 H, Ac-(C2′)]. 13C NMR (151 MHz, D2O): δ = 173.4
(3′-OAc), 173.1 (2′-OAc), 160.7 (C4), 150.1 (C2), 144.3 (C6), 96.5
(C5), 88.2 (C1′), 82.5 (d, C4′), 74.5 (C2′), 71.5 (C3′), 64.4 (d, C5′),
20.6 (3′-OAc), 20.5 (2′-OAc). 31P NMR (162 MHz, D2O, 1H-decou-
pled): δ = 0.30. IR (neat): 1746, 1660, 1489, 1462, 1429, 1375,
1075 cm–1. ESI-HRMS: m/z [M + H+] calcd for C13H19N3O10P:
408.0803; found: 408.0810.
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thiodiacrylonitrile (12) was observed (Figure 2).17
S
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NC
CN
12
Figure 2
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O
O
Cyt
O
P
O
(37) Example Procedure for Glycerol-3-phosphocholine Acylation
(11d)
O
AcO
OAc
2
8
Glycerol 10 (130 mg, 100 mM) and N-octanoyl imidazole (1d;
10 equiv) were suspended in H2O–MeCN (4:1). The resulting
biphasic solution was stirred vigorously for 4 h and lyophilised.
The residue was purified by SiO2 flash coumn chromatography
(CH2Cl2–MeOH = 90:10 to 40:60 and then CH2Cl2–MeOH–H2O
Figure 3
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
C. Fernández-García, M. W. Powner
Cluster
Synlett
(10%) = 40:54:6 to 10:81:9). The fractions containing 11d were
concentrated in vacuo and purified by reverse-phase (C18) flash
column chromatography (H2O–MeOH = 9:1 to 0:10). The frac-
tions containing 11d were lyophilised to yield 173 mg (67%)
of 1,2-di-O-octanoyl-sn-glycero-3-phosphocholine (11d) as a
white powder.
H, (CH2)4], 0.76–0.84 (m, 6 H, CH2CH3). 13C NMR (151 MHz,
CD3OD): δ = 175.1 (COCH2), 174.8 (COCH2), 72.0 (C2), 67.6 (C2′),
65.0 (C3), 63.8 (C1), 60.6 (C1′), 54.8 [N(CH3)3], 35.2, 35.0
(COCH2), 33.0, 30.3, 30.2, 26.2, 26.1, 23.8 [(CH2)6], 14.57
(CH2CH3). 31P NMR (162 MHz, D2O, 1H-decoupled): δ = –0.57.
ESI-HRMS: m/z [M + H+] calcd for C24H49NO8P: 510.3190; found:
510.3193.
1H NMR (600 MHz, CD3OD): δ = 5.09–5.16 [m, 1 H, H-(C2)], 4.32
[dd, J = 12.0, 3.3 Hz, 1 H, H-(C1)], 4.12–4.22 [m, 2 H, H-(C1′)],
4.07 [dd, J = 12.0, 6.8 Hz, 1 H, H-(C1)], 3.86–3.93 [m, 2 H, H-
(C3)], 3.49–3.57 [m, 2 H, H-(C2′)], 3.12 [s, 9 H, N(CH3)3], 2.18–
2.27 (m, 4 H, COCH2), 1.44–1.56 (m, 4 H, CH2), 1.15–1.28 [m, 16
(38) (a) Powner, M. W.; Sutherland, J. D. ChemBioChem 2008, 9,
2386. (b) Powner, M. W.; Anastasi, C.; Crowe, M. A.; Parkes, A. L.;
Raftery, J.; Sutherland, J. D. ChemBioChem 2007, 8, 1170.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F