Quantitation in the regioselectivity of acylation of glycosyl diglycerides: total synthesis of a Streptococcus pneumoniae α-glucosyl diglyceride

Article abstract of DOI:10.1039/c6cc09584d

The fidelity of acylation regioselectivity in the synthesis of mixed glycosyl diacylglycerols can be accurately measured by quantitative ¹³C NMR spectroscopy using a 1-¹³C-labelled fatty acid and a paramagnetic relaxation enhancement agent. Exquisite regioselectivity is achieved using a stepwise acylation/substitution of a glycosyl β-bromohydrin, which is applied to the total synthesis of Streptococcus pneumoniae Glc-DAG-s2.

Full text of DOI:10.1039/c6cc09584d

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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Quantitation in the regioselectivity of acylation of glycosyl
diglycerides: Total synthesis of a Streptococcus pneumonia α-
glucosyl diglyceride
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
DOI: 10.1039/x0xx00000x
Mark B. Richardson,* Dylan G.M. Smith, Spencer J. Williams*
www.rsc.org/
The fidelity of acylation regioselectivity in the synthesis of mixed case of the B. burgdorferi glycolipids, Xꢀray structures revealed
glycosyl diacylglycerols can be accurately measured by preferential binding for oleoyl (C18:0) groups in the A' pocket
13
13
quantitative C NMR spectroscopy using a 1- C-labelled fatty acid irrespective of their location at the snꢀ1 or snꢀ2 positions,
and a paramagnetic relaxation enhancement agent. Exquisite leading to different orientations of the galactosyl moiety and
6
regioselectivity is achieved using a stepwise acylation/substitution distinct structures of the glycolipidꢀCD1d antigen complex.
O
of a glycosyl β-bromohydrin, which is applied to the total a)
synthesis of Streptococcus pneumoniae Glc-DAG-s2.
O
2
R2
O
R1
β-hydroxy-ester intermediate
1
i)
O
O
ii)
O
desired O
product
+
Glycosyl diacylglycerols (glycosyl diglycerides) are a diverse
group of glycolipids produced by terrestrial and marine plants,
bacteria, and archaea. The sugar residue is typically found at
OH
2
R1
acyl migration
R1
R2
HO
OH
2
O
2
HO
OH
O
R1
OH
1
O
1
1
1
O
R1
O
O
R2
the primary position (usually snꢀ3), and distinct fatty acyl
groups located at the snꢀ1 and snꢀ2 positions. The arrangement
of acyl groups is critical for immune recognition of glycosyl
diglycerides. Glycosyl diglycerides bind to the antigenꢀ
presenting molecule CD1d, and the resulting CD1dꢀglycolipid
complex is displayed on the cell surface where the complex can
2
1
O
acyl migration
product
b)
c)
δ ~172.5 ppm
i)
O
O
O
1
O
OH
R1
δ ~173 ppm
R2
HO
ii)
O
2
R
O
2
O
2
R
1
O
OH
R1
+
O
O
O
O
2
O
Cr
O
1
1
R2
= 13
HO
[
O
O
be recognized by T cell receptors (TCR) on invariant natural
desired
product
acyl migration
product
Cr(acac)3
C
]
2
killer
T
(iNKT) cells. iNKT cells are stimulated by
Figure 1 a) Stepwise acylation can lead to mixtures of regioisomers through
acyl migration of β-hydroxy-ester intermediates. b) Monitoring
Streptococcus pneumoniae GlcꢀDAGꢀs2
αꢀglucosyl diglyceride
(
1
, Scheme 1), bearing a palmitoyl group at the snꢀ1 position,
13
regioselective acylation fidelity using a C-labelled fatty acid probe. c)
and a cisꢀvaccenoyl group at the snꢀ2 position (snꢀ1/snꢀ2,
C16:0/C18:1ꢀcisꢀꢀ11), but not the C18:1ꢀcisꢀ ꢀ11/C16:0 regioisomer.
3
Cr(acac) , a paramagnetic relaxation enhancement agent.
3
Similar observations extend to Borrelia burgdorferi BbGLꢀIIc
Owing to their trace concentrations and heterogeneity from
natural sources, and frequent ambiguities in structure, chemical
synthesis has been central to defining the structures of
glycoglycerolipids, overcoming limited supply, and providing
homogeneous samples of known structure for biomedical
research. A critical challenge in the chemical synthesis of these
compounds is ensuring that the glycerol is regioselectively
acylated with high fidelity. Installation of two different acyl
α
ꢀgalactosyl diglyceride (C18:1/C16:0), but not the C16:0/C18:1
4
regioisomer; and Mycobacterium smegmatis GlꢀA
glucuronosyl diglyceride (C19:0/C16:0 where C19:0 is
tuberculostearic acid), but not the (C16:0/C19:0) regioisomer.
α
ꢀ
;
R
ꢀ
5
The structural basis for sensitivity to the acyl group
arrangement is well understood. CD1d has two lipidꢀchain
binding pockets (A' and F') and glycosyl diglycerides bind with
their lipids within these pockets and the carbohydrate headꢀ
group projecting at the surface of CD1d for TCR binding. In the
groups is typically performed in a stepwise manner through a βꢀ
hydroxyꢀester intermediate in which acyl group migration is
7
facile, occurring under both acidic and basic conditions, and
even during chromatography on silica gel or florasil (Figure
8
,9
1
a). While methods have been described that are claimed to
mitigate acyl migration, it is difficult to quantify the degree of
migration and thus any erosion of regioselectivity owing to the
similar chromatographic mobilities and essentially identical
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NMR characteristics of the regioisomers. Preformed 1,2ꢀ
Using a representative glycosyl diglyceride from previous
ꢀ[13ꢀmethyltetradecanoyl]ꢀsnꢀglyceryl 2,3,4,6ꢀ
diacylglycerols have been used as glycosyl acceptors in work (1,2ꢀdiꢀ
glycosylation reactions, but as ꢀhydroxyꢀesters are also prone tetraꢀ ꢀbenzylꢀβꢀ
to acyl group migration; commercial 1,2ꢀdiacylglycerols have the ester carbonyls were estimated using the signꢀinversion
O
1
5
β
O
D
ꢀglucopyranoside)
1
T relaxation times of
1
0
17
13
been reported to be contaminated with their regioisomers.
Detection and quantification of acyl group migration is a
challenging analytical problem. Fragmentationꢀmass samples containing 0.05 M Cr(acac)
spectrometry has been widely used for the structural reduced to 0.5–1.0 s, comparable to published values. In order
recovery method. In the absence of PRE agent, carbonyl
relaxation times of around 15 s were measured; however, in
relaxation times were
C
T
1
3
T
1
1
8
1
1,12
characterization of acylation patterns,
and relies upon to reduce the potential for complicating nOe distortion an
qualitative differences in the rates of fragmentation of esters at inverseꢀgated protonꢀdecoupled experiment was employed in
the primary (snꢀ1) and secondary (snꢀ2) positions of a glycerol which the proton decoupler was switched off during the
1
7
chain. While adequate for gross structural determination, it does relaxation delay, and turned on only during data acquisition.
not allow quantitation of low levels of regioisomers as Excellent results were obtained with a 10 s relaxation delay and
significant fragmentation still occurs through the minor a minimum of 2000 scans, which gave carbon resonances that
channel. Mazur et al
quantification of regioselectivity in the esterification of glycerol
derivatives, which relies upon a subtle upfield shift of the ω−
.
reported an NMR method for could be integrated to <1% error across a spectrum.
1
3
For regioselective acylation experiments, commercial 1ꢀ Cꢀ
1
3
3
palmitic acid was employed. The atom% C labelling at C1
C atoms of primary esters of octanoic acid and decanoic was determined to be 99.4% using negative ion electrospray
acids, relative to the secondary esters, and allows measurement ionization mass spectrometry, assuming that the remaining
1
3
1
3
of the ratio of positional isomers to an accuracy of about 5%.
positions had isotope composition at natural abundance. The
The approach has not been applied to longer or more complex percentage ratio of regioisomers (
R
) can be calculated from the
1
3
fatty acyl groups. Other studies have reported the use of NMR individual integrations of
for the quantification of regioisomers of mixed glycerides resonances at
containing longꢀ and shortꢀchain (acetyl, propionyl, butyryl) (unlabelled position) using an acid of
C resonances for carbonyl
δ
x
ppm (labelled position) and
δ
y
ppm
1
3
L
C atom% labelling,
1
3
acyl groups that rely on distinctive chemical shift differences where
between the short and long chain groups, but cannot be used
for glycerides bearing just longꢀchain acyl groups.
N
is the natural C abundance, eqn (1):
1
4
ꢄ ꢅ
ꢄ ꢆ
ꢁ
− ꢂ ∙ ꢃ
ꢇ
In the present work, we report an NMR method that allows
accurate determination of the regioselective fidelity in acylation
ꢀ
=
ꢈ
× 100
(1)
ꢄ ꢅ
ꢄ ꢅ
ꢁ
∙ ꢃ ꢇ − ꢂ ∙ ꢃ ꢇ + ꢁ − ꢂ
ꢄ ꢆ ꢄ ꢆ
1
3
reactions. By inclusion of a C label into the carbonyl group of
one of the fatty acyl groups, and use of a paramagnetic
relaxation enhancement (PRE) agent with appropriate
We first investigated the application of the method to the
1
5
acquisition times, the abundance of the label at each position, nonꢀselective acylation of the diol
2
with a 1:1 mixture of
1
3
13
(
and hence the fidelity of regioselective acylation) can be commercial 1ꢀ Cꢀpalmitic acid (1ꢀ CꢀC16:0
)
and 10ꢀ
methyldodecanoic acid (isoꢀC13:0). This reaction should exhibit
In previous work, we prepared a range of glycosyl no regioselectivity, and assuming no significant differences in
1
3
measured by quantitative C NMR spectroscopy.
1
5
diglycerides including
β
ꢀgentiobiosyl diglycerides,
α
α
ꢀglucosyl kinetic isotope effects for reactions at either of the snꢀ1 and snꢀ
1
6
11
diglycerides,
and
ꢀglucuronosyl diglycerides.
We 2 positions, a equimolar ratio of four compounds should be
1
3
consistently observed a chemical shift difference for the obtained, namely: double 1ꢀ Cꢀpalmitic acidꢀincorporation (
3
),
carbonyl group of an ester attached as a primary ester at the indiscriminate incorporation of 1ꢀ Cꢀpalmitic acid and 10ꢀ
glycerol snꢀ1 position (
~173 ppm), versus a secondary ester at methyldodecanoic acid at the snꢀ1 and snꢀ2 positions ( ), and
the snꢀ2 position (
~172.5 ppm), which was independent of the double 10ꢀmethyldodecanoic acid incorporation ( ), leading to
length of or functionalization within the fatty acyl chain. We equal amounts of C label incorporation at each site. In
1
3
δ
4/5
δ
6
1
3
1
3
reasoned that incorporation of a C label into the carbonyl accordance with this expectation, the resulting mixture of
1
3
group of one fatty acyl group would enable us to track whether compounds displayed C NMR signals for the snꢀ1 and snꢀ2
this acyl chain was incorporated into the snꢀ1 or snꢀ2 positions. carbonyls of equal intensity, indicating no regioselectivity.
1
3
While C NMR is usually not considered to be quantitative,
owing to differences in spinꢀlattice relaxation times (
) of utilizing stepwise Steglich esterifications of
nuclei, compounded by very long relaxation times (>10 s) for glycerol. Compound
quaternary carbons, paramagnetic relaxation enhancement methyldodecanoic acid, DMAP and 1.05 eq DCC in CH
We next explored a standard regioselective acylation
glycosyl
was treated with 1.05 eq of 10ꢀ
Cl at
PRE) agents can dramatically reduce T
1
times of quaternary 0 ºC for 12 h. To remove trace amounts of unreacted diol and
T
1
a
1
0
2
2
2
(
1
3
17
carbons, allowing quantitative
C
NMR analysis.
We residual acid, the monoglyceride was purified by flash
focussed on Cr(acac)
solubility in organic solvents.
reagents, Cr(acac)
exhibits no angular dependence of its silica gel such that the temperature never exceed 10 ºC at any
electronꢀnuclear dipoleꢀdipole relaxation interaction.
3
, a nonꢀshifting PRE agent with a high chromatography. To limit the potential for acyl migration,
1
8
Unlike lanthanide shift purification was achieved in <15 min using chilled solvents and
3
point. Fractions were evaporated in vacuo and then
2
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COMMUNICATION
a)
O
BnO
BnO
BnO
O
1-13C-C16:0, iso-C13:0
O
R2
O
OH
R1
BnO
O
OH
DCC
2
O
R1
R2
1-13C-C16:0 1-13C-C16:0
:
3
4/5:
-13C-C16:0/iso-C13:0
1
6:
iso-C13:0
iso-C13:0
b)
c)
BnO
BnO
O
BnO
2
1. iso-C13:0, DCC, 0 °C
R1
R2
BnO
OH
4: 1-13C-C16:0
iso-C13:0
2. 1-13C-C16:0, DCC, rt
O
OH
5
:
iso-C13:0
1-13C-C16:0
i) lauryl chloride
ii) CAN
BnO
BnO
R1
R2
O
BnO
OPMB
OH
iii) 1-13C-C16:0, COMU
8: 1-13C-C16:0
C12:0
BnO
O
9:
C12:0
1-13C-C16:0
7
d) MAcO
i) palmityl chloride
R1
R2
MAcO
MAcO
O
OH
1-13
ii) 1-13C-C16:0-NBu4
C-C16:0
C16:0
C16:0
1
1:
MAcO
O
Br
1-13C-C16:0
12:
1
0
ppm
1
3
Figure 2 Quantitation of acylation fidelity by C NMR spectroscopy. a) Acylation using a mixture of labelled and unlabelled fatty acids. b)
Stepwise acylation using Steglich esterification, with purification of the intermediate -hydroxy-ester by flash chromatography. c) Stepwise
esterification with protecting group-control. d) A stepwise acylation/substitution process via a -bromoester intermediate.
β
β
1
3
immediately treated with 1.2 eq of 1ꢀ Cꢀpalmitic acid, DMAP first with lauryl chloride and DMP/pyr, affording the PMBꢀ
and 1.2 eq DCC in CH Cl at room temperature, to afford after protected monoglyceride. The PMB group was removed by
purification, the diester. Analysis of the diester revealed a 10:1 treatment with CAN in CH CN/water, and in order to limit acyl
ratio of C carbonyl signals, corresponding to R = 92% in migration the crude monoglyceride without purification was
2
2
3
1
3
1
3
favour of the desired regioisomer
may arise through either imperfect regioselectivity in the COMU/ Pr
Steglich method or through acyl migration of the ꢀhydroxyꢀ ratio of snꢀ2 and snꢀ1 carbonyl resonances of 25:1, allowing
ester of the monoglyceride intermediate; the equilibrium calculation of = 97.2% in favour of the desired product
position for monoglycerides of longꢀchain fatty acids is with regioisomer arising from acyl migration.
Finally, we examined a strategy that avoids
intermediates and should provide high fidelity regioselective
5. The unwanted regioisomer directly acylated by treatment with 1ꢀ Cꢀpalmitic acid and
i
4
2
NEt in DMF. Analysis of the product revealed a
β
R
9,
8
approximately 9:1 of the snꢀ1 and snꢀ2 regioisomers,
respectively.
βꢀhydroxyꢀester
8
We next explored a stepwise acylation strategy that does not acylation. We previously reported an approach to prepare
require chromatography, based on our reported approach to the glycosyl diglycerides via a glycidolꢀderived bromohydrin 10
1
1
α
ꢀglucuronosyl diglyceride GlꢀA. Compound
7
was treated (MAc
=
methoxylacetyl) that avoids
βꢀhydroxy ester
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Chem Commun
3
intermediates by first esterification to afford a
β
ꢀbromoꢀester reported. See Ref.
then bromide substitution with the carboxylate of the second
1
a) J. Zhang, C. Li, G. Yu and H. Guan, Mar. Drugs, 2014,
12, 3634; b) G. Holzl and P. Dormann, Prog. Lipid Res.,
007, 46, 225.
a) D. G. Smith and S. J. Williams, Carbohydr. Res., 2016,
20, 32; b) J. Rossjohn, S. Gras, J. J. Miles, S. J. Turner,
1
6
fatty acid chain. Treatment of 10 with palmitoyl choride and
DMAP/pyr afforded an intermediate ꢀbromoꢀester, which was
purified then treated with the tetrabutylammonium salt of 1ꢀ
2
β
2
4
1
3
Cꢀpalmitic acid in toluene at reflux. Analysis of the resulting
diglyceride revealed a 57:1 ratio of snꢀ2 and snꢀ1 carbonyl
resonances, corresponding to >99%.
We applied the bromohydrin method to the total synthesis
of S. pneumoniae GlcꢀDAGꢀs2 ( ). Acylation of bromohydrin
with cisꢀvaccenoyl chloride afforded the bromide 13
D. I. Godfrey and J. McCluskey, Annu. Rev. Immunol.,
2015, 33, 169.
3
Y. Kinjo, P. Illarionov, J. L. Vela, B. Pei, E. Girardi, X. Li,
Y. Li, M. Imamura, Y. Kaneko, A. Okawara, Y. Miyazaki,
A. GomezꢀVelasco, P. Rogers, S. Dahesh, S. Uchiyama,
A. Khurana, K. Kawahara, H. Yesilkaya, P. W. Andrew,
C. H. Wong, K. Kawakami, V. Nizet, G. S. Besra, M.
Tsuji, D. M. Zajonc and M. Kronenberg, Nat. Immunol.,
2011, 12, 966.
R
1
‡
1
6
10
.
Substitution of bromide with the tetrabutylammonium salt of
palmitic acid in refluxing toluene afforded 14, and deprotection
4
5
Y. Kinjo, E. Tupin, D. Wu, M. Fujio, R. GarciaꢀNavarro,
M. R. Benhnia, D. M. Zajonc, G. BenꢀMenachem, G. D.
Ainge, G. F. Painter, A. Khurana, K. Hoebe, S. M. Behar,
B. Beutler, I. A. Wilson, M. Tsuji, T. J. Sellati, C. H.
Wong and M. Kronenberg, Nat. Immunol., 2006, 7, 978.
A. P. Uldrich, O. Patel, G. Cameron, D. G. Pellicci, E. B.
Day, L. C. Sullivan, K. Kyparissoudis, L. KjerꢀNielsen, J.
P. Vivian, B. Cao, A. G. Brooks, S. J. Williams, P.
Illarionov, G. S. Besra, S. J. Turner, S. A. Porcelli, J.
McCluskey, M. J. Smyth, J. Rossjohn and D. I. Godfrey,
Nat. Immunol., 2011, 12, 616.
of the methoxyacetyl groups using
afforded GlcꢀDAGꢀs2.
MAcO
t
ꢀBuNH
2
in MeOH/THF
MAcO
O
4 steps
O
MAcO
MAcO
MAcO
MAcO
OH
MAcO
Ref 16
MAcO
O
O
Br
1
0
vaccenoyl chloride,
pyridine, CH2Cl2
87%
MAcO
O
11
O
MAcO
MAcO
6
J. Wang, Y. Li, Y. Kinjo, T. T. Mac, D. Gibson, G. F.
Painter, M. Kronenberg and D. M. Zajonc, Proc. Natl.
Acad. Sci. USA, 2010, 107, 1535.
O
MAcO
O
Br
13
tetrabutylammonium palmitate
toluene, 85 °C
7
8
9
E. Fischer, Ber. Deutschen Chem. Gesellschaft, 1920, 53,
1
621.
F. H. Mattson and R. A. Volpenhein, J. Lipid Res., 1962,
, 281.
52%
RO
O
O
11
RO
RO
3
O
RO
M. S. F. Lie Ken Jie, J. L. Harwood and F. D. Gunstone, in
The lipid handbook, eds. F. D. Gunstone, J. L. Harwood
and A. J. Dijkstra, CRC Press, Boca Raton, 2007, pp. 355.
V. Pozsgay, J. KublerꢀKielb, B. Coxon, A. Marques, J. B.
Robbins and R. Schneerson, Carbohydr. Res., 2011, 346,
O
O
O
t-BuNH2
MeOH, CHCl3
7%
14 R = MAc
R = H (Glc-DAG-s2)
1
1
0
1
1
5
1
551.
B. Cao, X. Chen, Y. YamaryoꢀBotte, M. B. Richardson, K.
L. Martin, G. N. Khairallah, T. W. Rupasinghe, R. M.
O'Flaherty, R. A. O'Hair, J. E. Ralton, P. K. Crellin, R. L.
Coppel, M. J. McConville and S. J. Williams, J. Org.
Chem., 2013, 78, 2175.
Scheme 1 Synthesis of Streptococcus pneumonia Glc-DAG-s2.
1
3
In conclusion, we report a quantitative C NMR method to
assess the fidelity of regioselective acylation methodologies.
We estimate that the method can be used to detect ~1% of a 12
regioisomer. We show that a stepwise Steglich procedure based
on widely used literature approaches afforded diglycerides with
a) G. Guella, R. Frassanito and I. Mancini, Rap. Commun.
Mass Spectrom., 2003, 17, 1982; b) R. V. Tatituri, M. B.
Brenner, J. Turk and F. F. Hsu, J. Mass Spectrom., 2012,
4
7, 115; c) J. Sauvageau, J. Ryan, K. Lagutin, I. M. Sims,
B. L. Stocker and M. S. Timmer, Carbohydr. Res., 2012,
57, 151.
ratio of regioisomers
R = 92%, a composition commensurate
with the known equilibrium position of monoacyl glycerols. A
stepwise, protecting group controlled regioselective acylation
that avoided chromatography provided better regioselective
3
1
3
A. W. Mazur, G. D. Hiler, 2nd, S. S. Lee, M. P. Armstrong
and J. D. Wendel, Chem. Phys. Lipids, 1991, 60, 189.
a) J. M. Henderson, M. Petersheim, G. J. Templeman and
B. J. Softly, J. Agric. Food Chem., 1994, 42, 435; b) P.
Kalo, A. Kemppinen and I. Kilpelainen, Lipids, 1996, 31,
fidelity (
R
= 97.2%), but was surpassed by a stepwise 14
ꢀhydroxy ester
acylation/substitution process that avoided
β
intermediates, and which yielded a glycosyl diglyceride that
was regioselectively acylated within limits of detection. This
work should support the development of preparative methods
for homogeneous diglycerides bearing two distinct acyl chains.
We thank the Australian Research Council (FT130100103,
DP130102763, DP160100597) for financial support.
3
31.
1
1
5
6
M. B. Richardson, S. Torigoe, S. Yamasaki and S. J.
Williams, Chem. Commun., 2015, 51, 15027.
S. Shah, M. Nagata, S. Yamasaki and S. J. Williams,
Chem. Commun., 2016, 52, 10902.
17
D. J. Cookson and B. E. Smith, J. Magnetic Res., 1984, 57,
3
55.
G. C. Levy and R. A. Komoroski, J. Am. Chem. Soc.,
974, 96, 678.
1
8
Notes and references
1
‡
While a previous report has disclosed an apparently synthetic version of
this interesting natural product, no details for the synthetic approach were
4
| Chem. Commun., 2017, 00, 1-3
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