Synthesis and catalytic activity of TentaGel-supported asymmetric dihydroxylation (DHQ)2PHAL ligand

Article abstract of DOI:10.1016/j.tetasy.2008.04.007

An efficient scheme for the synthesis and catalytic activity of TentaGel-supported Sharpless's (DHQ)₂PHAL dihydroxylation ligand is described. Crown Copyright

Full text of DOI:10.1016/j.tetasy.2008.04.007

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1049–1051
Synthesis and catalytic activity of TentaGel-supported
asymmetric dihydroxylation (DHQ)2PHAL ligand
Jihane Achkar,a Joseph R. Hunt,b Rachel L. Beingessnerc and Hicham Fenniric,*
aDSM Nutritional Products Ltd, Nutrition Research and Development, Wurmisweg 576, CH-4303 Kaiseraugst, Switzerland
bDepartment of Chemistry and Biochemistry, University of California-Los Angeles, 607 Charles E. Young Drive East,
Los Angeles, CA 90095-1569, USA
cNational Institute for Nanotechnology and Department of Chemistry, University of Alberta,
11421 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9
Received 31 December 2007; accepted 3 April 2008
Available online 12 May 2008
Abstract—An efficient scheme for the synthesis and catalytic activity of TentaGel-supported Sharpless’s (DHQ)2PHAL dihydroxylation
ligand is described.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Since its discovery by Sharpless et al.,1 the ligand-acceler-
ated catalytic (LAC) asymmetric dihydroxylation (AD) of
olefins with cinchona alkaloid-based ligands such as
(DHQ)2PHAL has seen tremendous developments and
applications in organic synthesis.2 In particular, owing to
its cost, several solid phase-supported versions of the AD
ligand were reported3 in order to take advantage of the
recyclability of the catalyst, straightforward separation of
the reaction product and the amenability of this format
to automated and high throughput parallel synthesis. Both
insoluble3a–h and soluble3h–j polymeric supports were opti-
mized to produce high yields and enantioselectivities in the
LAC-AD of a variety of olefins. While each of these sup-
ports has its advantages, the insoluble polymeric ones pres-
ent the added convenience of being easier to isolate
through simple filtration. Building on this unique feature,
we report here the use of an alternative scaffold that com-
bines the advantages of insoluble polymeric matrices with
solution-like reactivity and solvent compatibility of poly-
ethylene glycol (PEG), thus providing more flexibility in
terms of substrate and solvent compatibility, yet preserving
all the advantages of an insoluble matrix. TentaGel, a graft
copolymer of polystyrene (PS) and PEG, was chosen to
highlight the feasibility and advantages of this approach.
The symmetrical (DHQ)2PHAL ligand 4 was prepared in
one step from 1,4-dichlorophthalazine and dihydroquinine
1 in 72% yield (Fig. 1).4 Quinine 2 was reacted with
1 equiv of 1,4-dichlorophthalazine under basic conditions
in anhydrous toluene with concurrent azeotropic distilla-
tion of water to give the monosubstituted chlorophthal-
azine 3 in 62% yield after crystallization. Similarly,
treatment of 3 under the same conditions with 1 equiv of
dihydroquinine 1 yielded the disubstituted phthalazine 5
in 64% yield after crystallization.3i Reacting 1,4-dichloro-
phthalazine with quinine
2 first rather than with
dihydroquinine 1 dramatically simplified the purification
of 3 and produced 5 in a very pure and crystalline form.
Chiral ligand 5 was then reacted with 3-mercaptopropionic
acid or methyl-3-mercaptopropionate under radical
conditions to yield the substituted (DHQ)2PHAL ligands
6 and 7 in 75% and 84%, respectively.5 The structure of 7
was confirmed by NMR and mass spectrometry data.
Compound 6 was then attached to the resin under standard
peptide coupling conditions, while the methyl ester 7 was
loaded by simply heating a 0.1 M solution of 7 in anhy-
drous N,N-dimethylformamide at 100 °C with 0.2 equiv
of TentaGel-S-NH2 until the Kaiser test6 turned negative
(indicating completion of the reaction, ꢀ48 h). After dry-
ing the beads under vacuum, the unreacted free amines
(inaccessible sites, <1%) were capped with acetic
anhydride.7–9
*
Corresponding author. Tel.: +1 780 641 1750; fax: +1 780 641 1601;
e-mail: hicham.fenniri@nrc-cnrc.gc.ca
0957-4166/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.007

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J. Achkar et al. / Tetrahedron: Asymmetry 19 (2008) 1049–1051
uble resin-supported AD catalyst.3a–h In addition, with the
R
K3Fe(CN)6 co-oxidant, attempts to recycle the resin-bound
catalyst 3 times (isolated each time by filtration and washed
with EtOAc and H2O and dried under high vacuum) re-
sulted in no apparent loss of activity or enantioselectivity.
N
N
N
N
OH
Cl
O
H
H
O
O
To further illustrate the catalytic activity of TentaGel-sup-
ported (DHQ)2PHAL, four styrene derivatives were
dihydroxylated in the presence of K3Fe(CN)6/K2CO3
(3 mol equiv/styrene) and t-BuOH/H2O (1/1) at 20 °C for
48 h (Table 2). With the exception of entry 7, the ee’s
obtained using the resin-supported ligand 8 were compara-
ble to those with the free ligand 4. These results again rep-
resent the un-optimized reaction conditions, thereby
illustrating the potential of TentaGel-supported
(DHQ)2PHAL for such transformations.
N
N
3
1, Dihydroquinine, R: CH2-CH3
2. Quinine, R: CH=CH2
R
N
N
N
N
O
O
H
H
O
Table 2. Asymmetric dihydroxylation of styrene derivatives (0.2 M)
O
Entry Styrene derivative
Liganda % ee of dihydroxylated
productb
N
N
1
8
4
8
4
8
4
8
4
96
98
86
93
82
74
63
82
2-Chlorostyrene
2
3
4
5
6
7
8
4, R: CH2-CH3
5, R: CH=CH2
2,6-Dichlorostyrene
6, R: CH2CH2SCH2CH2COOH
7, R: CH2CH2SCH2CH2COOCH3
4-(Trifluoromethyl)styrene
3-Fluorostyrene
8, R: CH2CH2SCH2CH2CONH-TentaGel
Figure 1. Synthesis of TentaGel-(DHQ)2PHAL catalyst.
a Sharpless’s dihydroxylation general reaction conditions.1,2 Styrene
derivative (0.2 M), OsO4 (0.2 mol %), ligand 4 or ligand 8 (1 mol %),
K3Fe(CN)6/K2CO3 (3 mol equiv/styrene), t-BuOH/H2O (1/1), 20 °C.
Reaction stopped after 48 h.
b Determined by chiral HPLC (CHIRALCEL OD-H, 0.46 cm i.d. ꢁ 25 cm
length, chiral phase: cellulose bis-3,5-dimethyl-phenylcarbamate on 5 lm
silica substrate, solvent: 2-propanol/hexane (95/5), flow rate 1 mL/min,
k = 254 nm). Results are based on a single experiment.
A comparison of the catalytic activity of ligands 4 and 8
using styrene for the LAC-AD reaction is summarized in
Table 1. As noted previously by Sharpless et al.,10 the ‘sec-
ond cycle’ problem is presumably responsible for the lower
enantiomeric excess (ee) observed with the 4-methylmor-
pholine-N-oxide (NMO) co-oxidant (entries 3 and 5). This
effect is even more pronounced with the resin-supported
catalyst (entry 5). Interestingly, the yields and ee’s were
remarkably higher with the K3Fe(CN)6 co-oxidant and
were comparable to those obtained with the free ligand.
Even though no attempts were made to improve the yield
and ee (e.g., lower temperature, slow addition of olefin,
higher ligand/olefin ratio), the 91% ee obtained under the
latter conditions is one of the highest reported for an insol-
3. Conclusion
In conclusion, ee’s obtained with the TentaGel-
(DHQ)2PHAL/K3Fe(CN)6 system are for the most part
analogous to those obtained with the free ligand and are
among the highest ever achieved for an insoluble poly-
mer-supported AD ligand under the reaction conditions
described in Tables 1 and 2.
Table 1. Asymmetric dihydroxylation of styrene (0.2 M) to 1-phenyl-1,2
ethanediol
Entry Ligand (1 mol %) Conditionsa Isolated yield % eeb
Acknowledgements
1
2
3
4
5
6
A
B
A
B
A
B
74
48
85
80
61
85
Racemic
Racemic
63
99
25
91
None
This work was supported by Research Corporation (Cott-
rell award to H.F.), the Trask Trust Fund, the National
Institute for Nanotechnology and the University of
Alberta.
4
8
a Sharpless’s dihydroxylation reaction conditions.1,2 Conditions A: OsO4
(0.2 mol %), NMO (3 mol equiv/styrene), acetone/H2O (10/1), 20 °C.
Reaction stopped after 12 h. Conditions B: OsO4 (0.2 mol %),
K3Fe(CN)6/K2CO3 (3 mol equiv/styrene), t-BuOH/H2O (1/1), 20 °C.
Reaction stopped after 12 h.
References
b Determined by chiral HPLC (CHIRALCEL OD-H, 0.46 cm i.d. ꢁ 25 cm
length, chiral phase: cellulose bis-3,5-dimethyl-phenylcarbamate on 5 lm
silica substrate, solvent: 2-propanol/hexane (95/5), flow rate 1 mL/min,
k = 254 nm).
1. Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schro¨der, G.;
´
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970.
2. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.

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3. (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1990, 31,
3003–3006; (b) Pini, D.; Petri, A.; Salvadori, P. Tetrahedron
1994, 50, 11321–11328; (c) Salvadori, P.; Pini, D.; Petri, A. J.
Am. Chem. Soc. 1997, 119, 6929–6930; (d) Song, C. E.; Yang,
J. W.; Ha, H. J.; Lee, S. G. Tetrahedron: Asymmetry 1996, 7,
645–648; (e) Nandanan, E.; Sudalai, A.; Ravindranathan, T.
Tetrahedron Lett. 1997, 38, 2577–2580; (f) Lohray, B. B.;
Nandanan, E.; Bhushan, V. Tetrahedron Lett. 1994, 35, 6559–
6562; (g) Fan, Q. H.; Li, Y. M.; Chan, A. S. C. Chem. Rev.
2002, 102, 3385–3466; (h) Bolm, C.; Gerlach, A. Eur. J. Org.
Chem. 1998, 21–27; (i) Han, H.; Janda, K. D. Tetrahedron
Lett. 1997, 38, 1527–1530; (j) Kuang, Y. Q.; Zhang, S. Y.;
Wei, L. L. Synth. Commun. 2003, 33, 3545–3550.
provide 7 as a white solid in 84% yield. H NMR (300 MHz,
CDCl3) 8.68–8.58 (m, 2H), 8.36–8.25 (m, 2H), 8.02–7.88 (m,
4H), 7.58 (br s, 2H), 7.42 (m, 2H), 7.39–7.31 (m, 2H), 7.12–
6.98 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.67 (s, 3H), 3.54–2.93
(m, 6H), 2.79–1.20 (m, 26H), 0.82 (t, J = 7.9 Hz, 3H). PDMS:
calcd [M] = 896.5; obsd [M+1] = 897.7.
9. Preparation of 8 from 6: TentaGel-S-NH2 (300 lmol/g, 0.47 g,
142 lmol), O-benzotriazol-1-yl-N,N,N0,N0-tetramethyluroni-
um hexafluorophosphate (HBTU, 0.16 g, 425 lmol), 1-
hydroxybenzotriazole
hydrate
(HOBtꢂH2O,
0.02 g,
100 lmol), diisopropylethylamine (0.11 g, 850 lmol) and 6
(0.25 g, 283 lmol, 0.1 M final concentration) were shaken at
20 °C for 30 h in anhydrous CH2Cl2 and N,N-dimethylform-
amide (1/1 v/v, 3 mL). The progress of the reaction was
followed using the Kaiser test.6 The resin beads were then
filtered and washed sequentially with DMF, CH2Cl2, DMF,
CH2Cl2 and diethylether (3 ꢁ 15 mL each). After drying the
beads under vacuum, the unreacted free amines (inaccessible
sites, <1%) were capped as follows: 3 min room temperature
treatment with 0.75 vol of 6.5% (w/v) 4-dimethylaminopyr-
idine in THF and 0.25 vol of 40% (v/v) acetic anhydride in
2,6-lutidine, followed by extensive washes of the resin with
THF, DMF, CH2Cl2 and MeOH. Preparation of 8 from 7:
4. Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.;
Davis, W. D.; Hartung, J.; Jeong, K. S.; Ogino, Y.; Shibata,
T.; Sharpless, K. B. J. Org. Chem. 1993, 58, 844–849.
5. Inagaki, M.; Hiratake, J.; Yamamoto, Y.; Oda, J. Bull. Chem.
Soc. Jpn. 1987, 60, 4121–4126.
6. Sarin, V. K.; Kent, S. B. H.; Tam, J. P.; Merrifield, R. B.
Anal. Biochem. 1981, 117, 147–157.
7. Spectral data of compounds 4,4 53i and 63i are in agreement
with the literature.
8. Preparation of 7 from 5: Compound 5 (0.23 g, 0.29 mmol),
methyl-3-mercaptopropionate (0.35 g, 2.93 mmol) and 2,20-
azobisisobutyronitrile (AIBN, 0.024 g, 0.15 mmol) were dried
under high vacuum and then refluxed in benzene (30 mL) for
24 h. Additional AIBN (0.021 g, 0.13 mmol) was then added
and refluxing was maintained for 12 more hours. Note that the
starting material and product have the same Rf by TLC (10%
MeOH/CH2Cl2), so the reaction must be pushed to comple-
tion. The solvent and excess methyl-3-mercaptopropionate
were removed under high vacuum and the solid was purified
by flash chromatography (SiO2, 0–5% MeOH/CH2Cl2) to
TentaGel-S-NH2 (300 lmol/g, 11 mg, 3.3 lmol) and
7
(13 mg, 14.5 lmol) were shaken at 100 °C for 48 h in
anhydrous DMF (enough to cover the resin with solvent).
The progress of the reaction was monitored using the Kaiser
test.6 The resin beads were then filtered and washed sequen-
tially with DMF, CH2Cl2, DMF, CH2Cl2 and diethylether
(3 ꢁ 3 mL each). After drying the beads under vacuum, the
unreacted free amines were capped as described previously.
10. Ogino, Y.; Chen, H.; Kwong, H. L.; Sharpless, K. B.
Tetrahedron Lett. 1991, 32, 3965–3968.