Versatile synthesis of amphiphilic oligo(Aliphatic-Glycerol) layer-block dendrons with different hydrophilic-lipophilic balance values

Article abstract of DOI:10.1055/s-0032-1317929

A series of amphiphilic oligo(glycerol-aliphatic) layer-blocked dendrons with different hydrophilic-lipophilic balance values (3.5-15.0) was prepared for use in controlled drug delivery and self-assembly studies. The synthetic strategies involved first a convergent growth of the inner hydrophobic sector followed by a divergent growth of the outer hydrophilic sector. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317929

LETTER
▌201
lVetteerrsatile Synthesis of Amphiphilic Oligo(Aliphatic-Glycerol) Layer-Block
Dendrons with Different Hydrophilic-Lipophilic Balance Values
Amphiphilic Dendrons
Lai-Sheung Choi,a Hak-Fun Chow*a,b
a
Department of Chemistry, and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
SAR
b
Institute of Molecular Functional Materials, UGC-AoE Scheme, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR
Fax +85226035057; E-mail: hfchow@cuhk.edu.hk
Received: 05.11.2012; Accepted: 27.11.2012
phobic aliphatic inner core to ensure good structural ho-
mogeneity, while the allylation–dihydroxylation
sequence reported by Haag9b was employed for the rapid
outward growth of the hydrophilic polyglycerol outer sec-
Abstract: A series of amphiphilic oligo(glycerol-aliphatic) layer-
blocked dendrons with different hydrophilic-lipophilic balance val-
ues (3.5–15.0) was prepared for use in controlled drug delivery and
self-assembly studies. The synthetic strategies involved first a con-
vergent growth of the inner hydrophobic sector followed by a diver- tor. This synthesis allows a library of amphiphilic den-
gent growth of the outer hydrophilic sector.
drons of different HLB values to be rapidly assembled in
good yields for various applications.
Key words: dendrimers, dihydroxylation, Mitsunobu reaction
The starting material was 5-hydroxylmethyl-2,2,5-tri-
methyl-1,3-dioxane (2; Scheme 1).14 The acetonide moi-
ety served as the protective group of the 1,3-diol that
could be elaborated into the hydrophilic polyglycerol lay-
er later in the synthesis. Alcohol 2 was subjected to Swern
oxidation and the resulting aldehyde was immediately re-
acted with Ph3P=CHCO2Me to give the trans-α,β-unsatu-
rated ester 3 in 85% overall yield.15,16 Ester 3 was then
reduced to the corresponding trans-allylic alcohol 4 by di-
isobutylaluminum hydride (DIBAL-H) in 93% yield. Re-
action of two equivalents of 4 with Meldrum’s acid in the
presence of diisopropyl azodicarboxylate (DIAD) in tolu-
ene at –10 °C gave the C-diallylation product 5 in 73%
yield. The acetonide group at the focal point was then
cleaved by NaOMe to produce the monoacid-monoester 6
in 79% yield. Decarboxylation of 6 in pyridine at 110 °C
proceeded smoothly to give diene-ester 7 in 78% yield.
The double bonds were then hydrogenated in the presence
of 10% Pd/C to afford saturated ester 8 in 89% yield. A
small amount of powdered K2CO3 was required to prevent
cleavage of the acetonide groups under the reaction con-
ditions. Finally, the ester was reduced to the correspond-
ing alcohol 9 in 99% yield by lithium aluminum hydride
(LAH). This series of reactions then completed the con-
vergent iterative reaction cycle. The overall yield from
dendron G[0+0]-(dioxane)1(OH) 2 to compound G[0+1]-
(dioxane)2(OH) 9 was 31%.
Amphiphilic dendrimers are an interesting class of mole-
cules with novel self-assembling properties.1 They are of-
ten prepared either by attaching linear hydrophilic groups
such as oligoethyleneglycol,2 anionic carboxylate3 or cat-
ionic ammonium4 groups to the periphery of a hydropho-
bic dendrimer, or by anchoring linear fatty acid chains to
the surface of a hydrophilic dendrimer.5 They are useful
compounds for gene transfection and for biomedical and
controlled drug delivery applications.6 Hence, the synthe-
sis of amphiphilic dendrimers with new internal hydro-
philic or hydrophobic repeating architecture and
interesting guest-encapsulating properties is still in
demand. To date, only a limited number of hydrophilic
dendritic/hyperbranched compounds based on penta-
erythritol,7 tris(hydroxymethyl)methane,8 or glycerol9 re-
peating units are known, as are hydrophobic dendrimers
based on tetrakis(butylene)methane10 or isoprene11 re-
peating units. For controlled release applications, mole-
cules with an optimal hydrophilic-lipophilic balance
(HLB) are needed.12 Therefore, the availability of a series
of amphiphilic dendrimers with different HLB values is
highly desirable. Herein, we wish to report the synthesis
of a new series of amphiphilic dendrons G[m+n]-(X)k(Y)
(e.g., 1; Figure 1) bearing m outer layers of polyglycerol
and n inner layers of isoprene hydrophobic units with k X
surface groups and a focal point functionality Y. This set
of amphiphilic dendrons possesses a range of HLB (3.5–
15.0) values to cater for different controlled delivery ap-
plications. The present synthetic protocol also makes use
of the advantages of both convergent (fewer defective
products) and divergent (rapid growth of dendrimer) syn-
thetic strategies. Hence, the di-C-allylation of Meldrum’s
acid13 was used for the inward construction of the hydro-
For the synthesis of the G[0+2] dendrons, alcohol 9 was
subjected to Swern oxidation followed by reaction with
Ph3P=CHCO2Me to give the trans-α,β-unsaturated ester
10 in 96% overall yield (Scheme 2). The ester was then
converted into the corresponding allylic alcohol 11 in
96% yield through DIBAL-H mediated reduction. Mitsu-
nobu C-diallylation of Meldrum’s acid with 11 gave an in-
separable 9:1 mixture of C-diallylation product 12 and O-
monoallylation product 13 in a combined yield of 81%.
Upon treatment of the mixture with NaOMe in MeOH fol-
lowed by chromatographic purification, monoacid-mono-
ester 14 was obtained in pure form in 85% yield.
SYNLETT 2013, 24, 0201–0206
Advanced online publication: 13.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317929; Art ID: ST-2012-U0949-L
© Georg Thieme Verlag Stuttgart · New York

202
L.-S. Choi, H.-F. Chow
LETTER
HO
OH
HO
HO
OH
OH
HO
OH
HO
O
OH
O
HO
OH
HO
OH
O
O
HO
HO
OH
OH
O
O
O
O
HO
OH
O
O
O
O
O
O
HO
OH
O
O
HO
HO
HO
HO
OH
OH
OH
OH
O
O
O
O
O
O
O
O
HO
OH
CH2OBn
1
Figure 1 Structure of amphiphilic dendron 1
Compound 14 was then similarly converted into the cor- issues were identified. First, for the Mitsunobu reaction
responding G[0+2]-(dioxane)4(OH) 17 in overall 82% between the G[0+2]-(dioxane)4(allylic-OH) 18 with Mel-
yield through a decarboxylation, hydrogenation and drum’s acid, the C-diallylation product 1917 could only be
LAH-mediated reduction sequence.
obtained in 40% yield. The yield could not be improved
by changing the reaction solvent or by adding
[Pd(PPh3)4].13a Second, the C=C double bonds of product
The same reaction sequence was then applied to the syn-
thesis of the G[0+3]-dendrons (Scheme 3), however, two
1. DMSO, (COCl)2,
CH2Cl2, –78 °C
O
O
O
O
O
O
2. Et3N, –78 to 0 °C
DIBAL-H
CH2OH
toluene, –78 °C
3. Ph3P=CHCO2Me,
THF, 65 °C
CO2Me
CH2OH
2
3
4
O
O
O
O
O
O
O
O
O
O
O
O
MeOH, NaOMe
20 °C
DIAD, Ph3P
toluene, –10 °C
O
O
O
O
O
O
OH
OMe
5
6
O
O
O
O
O
O
O
O
H2, 10% Pd/C
K2CO3, EtOAc, 20 °C
pyridine
110 °C
CO2Me
X
8 X = CO2Me
9 X = CH2OH
LiAlH4, THF
0–20 °C
7
Scheme 1 Synthesis of G[0+1]-dendrons
Synlett 2013, 24, 201–206
© Georg Thieme Verlag Stuttgart · New York

LETTER
Amphiphilic Dendrons
203
20 could not be saturated when the reduction was con- um iodide (TBAI) in THF/water (1:1) at 45 °C proceeded
ducted in EtOAc, and the reaction was carried out in ace- very slowly. Although the starting octa-alcohol disap-
tic acid/acetone/2,2-dimethoxypropane. Finally, G[0+3]- peared after two days, only partially allylated intermedi-
(dioxane)8(OH) 21 was obtained in an overall yield of ates were formed. After seven days, only a small amount
17% from compound 17.
of the octa-allylated product 23 was isolated. Alternative
reaction conditions employing Williamson ether synthesis
(NaH, allyl bromide, DMF) gave the octa-allylation prod-
uct 23, albeit in poor conversion (ca. 10%). The starting
octa-alcohol was still present in large quantities even us-
ing excess NaH (80 equiv). Interestingly, no partially al-
lylated compounds were found. Hence, it appeared that
once one of the hydroxyl groups was allylated, subsequent
allylations proceeded much faster to give the octa-allylat-
ed compound under the Williamson conditions. Because
Haag’s procedure could afford a mixture of partially al-
After successfully synthesizing the G[0+n]-dendrons, the
divergent growth of the hydrophilic oligo(glycerol) outer
sector employing Haag’s method9b was examined. Thus,
G[0+2]-(dioxane)4(OH) 17 was first converted into the
corresponding benzyl ether G[0+2]-(dioxane)4(OBn) in
98% yield through application of the Williamson synthe-
sis (Scheme 4). The acetonide protecting groups were
then removed in the presence of acetic acid in MeOH to
give the octa-alcohol 22 in 87% yield. Initial O-allylation
of 22 with allyl bromide, NaOH, and tetrabutylammoni-
O
O
O
O
O
O
O
O
1. DMSO, (COCl)2,
CH2Cl2, –78 °C
2. Et3N, –78 to 0 °C
DIBAL-H
9
toluene, –78 °C
3. Ph3P=CHCO2Me,
THF, 65 °C
CO2Me
CH2OH
10
11
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
+
O
O
DIAD, Ph3P
toluene, –10 °C
O
O
O
O
O
O
13
12
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
pyridine
110 °C
MeOH
H2, 10% Pd/C
K2CO3, EtOAc, 20 °C
NaOMe, 20 °C
O
O
CO2Me
X
OH
OMe
16 X = CO2Me
17 X = CH2OH
LiAlH4, THF
0–20 °C
14
15
Scheme 2 Synthesis of G[0+1]-dendrons
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 201–206

204
L.-S. Choi, H.-F. Chow
LETTER
R
R
R
R
R
R
R
O
R
R
R
R
R
O
1. DMSO, (COCl)2,
CH2Cl2, –78 °C
O
O
2. Et3N, –78 to 0 °C
17
O
O
DIAD, Ph3P
3. Ph3P=CHCO2Me,
toluene, –10 °C
THF, 65 °C
4. DIBAL-H, toluene, –10 °C
CH2OH
(CH2)3
O
O
18
O
O
19
R =
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
MeOH
1. pyridine, 110 °C
NaOMe, 20 °C
2. H2, 10% Pd/C, AcOH,
acetone, Me2C(OMe)2,
20 °C
O
O
CH2OH
3. LiAlH4, THF
0–20 °C
OH OMe
20
21
Scheme 3 Synthesis of G[0+3]-dendrons
lylated products, the Haag and Williamson procedures ture was subjected to Williamson conditions to produce
were then employed sequentially to ensure complete al- the octa-allylated compound 23 in 85% yield. Compound
lylation. Hence, the octa-alcohol 22 was first subjected to 23 was unstable at room temperature and was immediate-
Haag’s conditions for two days. After workup, the mix- ly dihydroxylated using a catalytic amount of OsO4 and 4-
HO
OH
OH
HO
OH HO
HO
HO
OH
OH
HO
OH
HO
OH
O
O
O
O
O
O
O
O
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
O
O
O
O
O
O
O
O
1. H2C=CHCH2Br,
NaOH, TBAI,
H2O, 45 °C
1. NaH, DMF, 0 °C
2. BnBr, 20 °C
OsO4, NMO
acetone, H2O, 20 °C
17
3. AcOH,
MeOH, 20 °C
2. workup
3. NaH, DMF, 0 °C
4. H2C=CHCH2Br, 20 °C
CH2OBn
1. H2C=CHCH2Br, NaOH
TBAI, H2O, 45 °C
2. workup
CH2OBn
CH2OBn
22
23
24
1. (MeO)2CMe2, TsOH
MeOH, CH2Cl2,
20 °C
1. (MeO)2CMe2, TsOH
MeOH, CH2Cl2, 20 °C
2. H2, Pd/C, K2CO3
EtOAc, 20 °C
1
3. NaH, DMF, 0 °C
4. H2C=CHCH2Br, 20 °C
5. OsO4, NMO, acetone
H2O, 20 °C
O
O
O
O
O
O
2. H2, Pd/C, K2CO3
EtOAc, 20 °C
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CH2OH
CH2OH
26
25
Scheme 4 Synthesis of G[1+2]- and G[2+2]-dendrons
Synlett 2013, 24, 201–206
© Georg Thieme Verlag Stuttgart · New York

LETTER
Amphiphilic Dendrons
205
methylmorpholine N-oxide (NMO) in aqueous acetone to and convergent strategies to enable their efficient synthe-
give the G[1+2]-(OH)16(OBn) 24 as a mixture of diaste- sis and good structural homogeneity. The divergent
reoisomers in 64% yield. The allylation–dihydroxylation growth strategy, in principle, can also be applied to the
sequence was once again employed on 24 to give the cor- G[0+1]- and G[0+3]-dendrons to furnish amphiphilic
responding G[2+2]-(OH)32(OBn) 1,18 after purification by dendrimers with a broader range of HLB values for future
dialysis in MeOH, in overall 87% yield. Compound 1 has self-assembly and controlled release property studies.
24 chiral centers and is a mixture of more than 106 stereo-
isomers. The peripheral 1,2-diols in compounds 24 and 1
could be protected as the dioxalanes using 2,2-dimethoxy-
Acknowledgment
This work was substantially supported by a grant from the UGC of
the HKSAR, P. R. of China (Project No. AoE/P-03/08).
propane and the focal point benzyl ether functionality
could be removed by hydrogenolysis to produce com-
pounds 25 (64%) and 26 (70%), respectively. The focal
point alcohol functionality can serve as a handle for its
attachment to other molecular entities.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
The conversion efficiency of the divergent allylation–
dihydroxylation reaction was assessed by mass spectros-
copy using either electrospray or MALDI-TOF ionization
techniques.16 For example, the MALDI-TOF mass spec-
trum of G[2+2]-(OH)32(OBn) 1 showed a major peak at
m/z 2569 [M + Na]+, and several structurally defective
peaks of less than 10% relative intensity corresponding to
peaks with one or two non-allylated, or one non-dihydrox-
ylated species (Figure 2). Based on the relative intensities
of these defective peaks, one could estimate that 80% of
the sample was the defect-free dendron after two iterative
growth cycles, highlighting the good efficiency of Haag’s
divergent synthetic protocol.
References and Notes
(1) Wang, Y.; Grayson, S. M. Adv. Drug Delivery Rev. 2012, 64,
852.
(2) Pan, Y.; Ford, W. T. Macromolecules 2000, 33, 3731.
(3) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders,
M. J.; Grossman, S. H. Angew. Chem., Int. Ed. Engl. 1991,
30, 1178.
(4) Lee, J.-J.; Ford, W. T.; Moore, J. A.; Li, Y. Macromolecules
1994, 27, 4632.
(5) Cho, B.-K.; Jain, A.; Nieberle, J.; Mahajan, S.; Wiesner, U.;
Gruner, S. M.; Türk, S.; Räder, H. J. Macromolecules 2004,
37, 4227.
(6) Svenson, S.; Tomalia, D. A. Adv. Drug Delivery Rev. 2012,
in press; doi: 10.1016/j.addr.2012.09.030.
(7) Padias, A. B.; Hall, H. K. Jr.; Tomalia, D. A.; McConnell, J.
R. J. Org. Chem. 1987, 52, 5305.
(8) (a) Jayaraman, M.; Fréchet, J. M. J. J. Am. Chem. Soc. 1998,
120, 12996. (b) Grayson, S. M.; Jayaraman, M.; Fréchet, J.
M. J. Chem. Commun. 1999, 1329.
(9) (a) Nemoto, H.; Wilson, J. G.; Nakamura, H.; Yamamoto, Y.
J. Org. Chem. 1992, 57, 435. (b) Haag, R.; Sunder, A.;
Stumbé, J.-F. J. Am. Chem. Soc. 2000, 122, 2954.
(10) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Johnson,
A. L.; Behera, R. K. Angew. Chem. Int. Ed. Engl. 1991, 30,
1176.
(11) Shi, Z.-F.; Chai, W.-Y.; An, P.; Cao, X.-P. Org. Lett. 2009,
11, 4394.
(12) (a) Burakowska, E.; Quinn, J. R.; Zimmerman, S. C.; Haag,
R. J. Am. Chem. Soc. 2009, 131, 10574. (b) Buyukozturk, F.;
Benneyan, J. C.; Carrier, R. L. J. Controlled Release 2010,
142, 22.
(13) (a) Shing, T. K. M.; Li, L.-H.; Narkunan, K. J. Org. Chem.
1997, 62, 1617. (b) Chow, H.-F.; Ng, K.-F.; Wang, Z.-Y.;
Wong, C.-H.; Luk, T.; Lo, C.-M.; Yang, Y.-T. Org. Lett.
2006, 8, 471.
(14) Ouchi, M.; Inoue, Y.; Wada, K.; Iketani, S.-i.; Hakushi, T.;
Weber, E. J. Org. Chem. 1987, 52, 2420.
(15) The structural properties of all compounds were
characterized by 1H and 13C NMR spectroscopy, mass
spectrometry, and/or elemental analysis. Their good purities
were also confirmed by a polydispersity index of <1.02 by
size-exclusion chromatographic analysis.
(16) See the Supporting Information for details.
(17) Synthesis of 19: A solution of DIAD (0.53 mL, 2.67 mmol)
in toluene (6 mL) was added dropwise to a stirred solution of
allylic alcohol 18 (1.78 g, 2.06 mmol), Ph3P (0.70 g, 2.67
mmol), and Meldrum’s acid (0.15 g, 1.03 mmol) in toluene
(6 mL) at –10 °C. The progress of the reaction was
monitored by TLC. When the reaction was complete
Figure 2 MALDI-TOF spectrum of G[2+2]-(OH)32(OBn) 1
The aqueous solubility of G[0+2]-(OH)8(OBn) 22,
G[1+2]-(OH)16(OBn) 24 and G[2+2]-(OH)32(OBn) 1
were found be to <10–3, 2.9 and >7.5 M, respectively, re-
flecting the gradual increase of HLB value [22 (3.5), 24
(10.7) and 1 (15.0)].16 Apparently, the highly polar nature
of the larger-sized oligo(glycerol) sector overwhelmed
the non-polar nature of the aliphatic core and enabled
compounds 24 and 1 to become miscible with water
through unimolecular micelle and aggregate formation.
In summary, we have reported the versatile synthesis of a
series of new amphiphilic layer-block dendrons. The syn-
thesis made use of favorable attributes of both divergent
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 201–206

206
L.-S. Choi, H.-F. Chow
LETTER
(ca. 30 min), hexane (30 mL) was added to the mixture to
precipitate Ph3PO, which was removed by filtration. The
excess solvent was removed and the yellow residue was
purified by flash column chromatography on silica gel
(hexane–EtOAc, 3:1→1:1, in the presence of 1% Et3N) to
afford the target compound 19 (0.76 g, 40%) as a colorless
oil. Rf = 0.54 (hexane–acetone, 2:1); 1H NMR (300 MHz,
CDCl3): δ = 0.91 (s, 24 H, CH2CCH3), 1.00–1.50 (m, 76 H),
1.38 (s, 24 H, OCCH3), 1.39 (s, 24 H, OCCH3), 1.64 (s, 6 H,
CO2CCH3), 1.78–1.95 (m, 2 H, CHC=C), 2.66 (d, J =
6.9 Hz, 4 H, CH2C=C), 3.45 (AB system, J = 11.4 Hz, 16 H,
COCHH), 3.55 (AB system, J = 11.4 Hz, 16 H, COCHH),
5.20 (dt, J = 15.3, 7.2 Hz, 2 H, CH2CH=CH), 5.36 (dd, J =
15.0, 8.4 Hz, 2 H, CH2CH=CH); 13C NMR (75 MHz,
CDCl3): δ = 19.8, 20.2, 23.7, 24.1, 24.5, 30.2, 32.7, 34.0,
34.5, 34.6, 35.6, 36.0, 37.4, 42.7, 43.1, 56.1, 69.6, 97.9,
solution of 16-ene 32 (873 mg, 0.44 mmol) and NMO (1.23
g, 10.46 mmol) in acetone–H2O (20 mL, 10:1, v/v) at 0 °C.
The mixture was stirred at 20 °C for 48 h and the progress of
the reaction was monitored by NMR analysis until all allyl
groups had reacted. The solvent was removed in vacuo and
the dark-brown residue was purified by membrane dialysis
in MeOH using regenerated cellulose (MWCO = 1,000) to
give the target compound 1 (1.02 g, 92%) as a viscous brown
liquid. Rf = 0.08 (EtOAc–MeOH, 1:3); 1H NMR (300 MHz,
DMSO-d6): δ = 0.78 (s, 12 H, CH3), 0.92–1.45 (m, 38 H),
1.45–1.61 (m, 1 H, CHCH2OBn), 3.00–3.23 (m, 16 H,
CH3CCHHO), 3.23–3.46 (m, 90 H, OCHCH2O and
CHCH2OBn), 3.46–3.68 (m, 32 H, OCHCH2O), 4.42 (t,
J = 5.7 Hz, 10 H, OH and PhCH2O), 4.47 (t, J = 5.7 Hz, 8 H,
OH), 4.51 (t, J = 4.8 Hz, 8 H, OH), 4.60 (dd, J = 4.8, 1.2 Hz,
8 H, OH), 7.16–7.45 (m, 5 H, ArH); 13C NMR (75 MHz,
DMSO-d6): δ = 19.6, 20.0, 23.4, 31.8, 33.7, 34.6, 35.1, 36.8,
37.8, 38.7, 63.4, 63.5, 70.7, 70.9, 71.0, 71.3, 71.89, 71.93,
72.4, 73.1, 75.5, 78.1, 127.6, 127.8, 128.4, 139.0; HRMS
(MALDI-TOF): m/z calcd for (C117H228O57 + Na)+:
105.3, 121.8, 142.3, 168.8; MS (FAB): m/z (%) = 1823 (100)
+
[M – CH3 ]; HRMS (FAB): m/z calcd for (C110H196O20
–
CH3)+: 1822.4080; found: 1822.4113.
(18) Synthesis of G[2+2]-(OH)32(OBn) 1: OsO4 (2.5 wt% in t-
BuOH, 0.44 mL, 0.044 mmol) was added dropwise to a
2569.4869; found: 2569.4974.
Synlett 2013, 24, 201–206
© Georg Thieme Verlag Stuttgart · New York