Multiple dendritic catalysts for asymmetric transfer hydrogenation

Article abstract of DOI:10.1021/jo0257795

The first and second generation multiple dendritic ligands based on chiral diamine were synthesized in a convergent approach and were well-characterized by NMR and MS techniques. Their ruthenium complexes prepared in situ had good solubility in the reaction medium (azeotrope of formic acid and triethylamine) and demonstrated high catalytic activity and enantioselectivity comparable to monomeric catalysts in the asymmetric transfer hydrogenation of ketones and imines. Quantitative yields and for some cases a slightly higher enantioselectivity (up to 98.7% ee) were obtained in the dendritic catalysis. Considering the high local catalyst concentrations at the periphery, diones were tested for the possible synergic reactivity between catalytic units at the surface, while no apparent differences were noted.

Full text of DOI:10.1021/jo0257795

Mu ltip le Den d r itic Ca ta lysts for Asym m etr ic Tr a n sfer
Hyd r ogen a tion
Ying-Chun Chen,† Tong-Fei Wu,† J in-Gen Deng,*,† Hui Liu,† Xin Cui,† J in Zhu,†
Yao-Zhong J iang,† Michael C. K. Choi,‡ and Albert S. C. Chan‡
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences, Chengdu 610041, China, and Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis§ and Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
jgdeng@cioc.ac.cn
Received March 31, 2002
The first and second generation multiple dendritic ligands based on chiral diamine were synthesized
in a convergent approach and were well-characterized by NMR and MS techniques. Their ruthenium
complexes prepared in situ had good solubility in the reaction medium (azeotrope of formic acid
and triethylamine) and demonstrated high catalytic activity and enantioselectivity comparable to
monomeric catalysts in the asymmetric transfer hydrogenation of ketones and imines. Quantitative
yields and for some cases a slightly higher enantioselectivity (up to 98.7% ee) were obtained in the
dendritic catalysis. Considering the high local catalyst concentrations at the periphery, diones were
tested for the possible synergic reactivity between catalytic units at the surface, while no apparent
differences were noted.
In tr od u ction
of their Ru(II) complexes in the asymmetric transfer
hydrogenation of acetophenone. High catalytic activity
and enantioselectivity were observed, and the higher
generation catalysts could be reused several times with-
out apparent loss of activity. However, in contrast to such
sterically crowded core-functionalized systems, the metal
complexes deposited at the surface of a dendrimer would
allow better accessibility to the substrate, thus higher
turnover numbers could be expected. On the other hand,
considering the relatively higher local catalyst concentra-
tion, the quest for potential cooperation among metal
complexes is still ongoing.5 Herein, we would like to
report the synthesis and application of dendritic catalysts
with up to 12 chiral diamine based ligands at the
periphery.
Dendrimers are perfect monodisperse macromolecules
with a regular and highly branched three-dimensional
architecture. One of the important developments in this
field of chemistry is the synthesis of catalytically active
dendritic systems,1 within which two general strategies
are evolved: one (or more) catalytic site(s) in the core of
dendrimer, the other, multiple catalytic sites at the
periphery of the dendrimer. As an interface between
homogeneous and heterogeneous catalysts, dendritic
catalysts have received considerable attention;2 however,
the application of chiral organometallic dendrimers in
asymmetric synthesis is a field still in its infancy.3
Recently we4 reported the synthesis of chiral TsDPEN
analogue enclosed dendritic ligands and the application
Resu lts a n d Discu ssion
† Chinese Academy of Sciences.
‡ The Hong Kong Polytechnic University.
Liga n d Syn th esis. In the construction of the dendritic
ligands, both ether and amide linkages were used so that
the relatively polar constitutions would favor the solution
§ The Institute of Molecular Technology for Drug Discovery and
Synthesis is supported by The Areas of Excellence Scheme (AoE/P-
10/01) established under The University Grants Committee of Hong
Kong SAR, China.
(1) For recent reviews on dendritic catalysts, see: (a) Astruc, D.;
Chardac, F. Chem. Rev. 2001, 101, 2991. (b) Oosterom, G. E.; Reek, J .
N. H.; Kamer, P. C. J .; van Leeuwen, P. W. N. M. Angew. Chem., Int.
Ed. 2001, 40, 1828.
(3) For examples of chiral dendritic catalysts, see: (a) Ko¨llner, C.;
Pugin, B.; Togni, A. J . Am. Chem. Soc. 1998, 120, 10274. (b) Yamago,
S.; Furukawa, M.; Azuma, A.; Yoshida, J . Tetrahedron Lett. 1998, 39,
3783. (c) Schneider, R.; Ko¨llner, C.; Weber, I.; Togni, A. Chem.
Commun. 1999, 2415. (d) Bolm, C.; Derrien N.; Seger, A. Chem.
Commun. 1999, 2087. (e) Rheiner P. B.; Seebach, D. Chem. Eur. J .
1999, 5, 3221. (f) Sato, I.; Shibata, T.; Ohtake, K.; Kodaka, R.;
Hirokawa, Y.; Shirai, N.; Soai, K. Tetrahedron Lett. 2000, 41, 3123.
(g) Fan, Q.-H.; Chen, Y.-M.; Chen, X.-M.; J iang, D.-Z.; Xi, F.; Chan, A.
S. C. Chem. Commun. 2000, 789. (h) Schmitzer, A.; Franceschi, S.;
Perez, E.; Rico-Lattes, I.; Lattes, A.; Erard, M.; Vidal, C. J . Am. Chem.
Soc. 2001, 123, 5956.
(2) For reports on achiral dendritic catalysts, see: (a) Reetz, M. T.;
Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed. Engl. 1997, 36,
1526. (b) Petrucci-Samija, M.; Guillemette, V.; Dasgupta, M.; Kakkar,
A. K. J . Am. Chem. Soc. 1999, 121, 1968. (c) Francavilla, C.; Bright,
F. V.; Detty, M. R. Org. Lett. 1999, 1, 1043. (d) Oosterom, G. E.; van
Haaren, R. J .; Reek, J . N. H.; Kamer, P. C. J .; van Leeuwen, P. W. N.
M. Chem. Commun. 1999, 1119. (e) Kleij, A. W.; Gossage, R. A.;
J astrzebski, J . T. B. H.; Boersma, J .; van Koten, G. Angew. Chem.,
Int. Ed. 2000, 39, 176. (f) Garber, S. B.; Kingsbury, J . S.; Gray, B. L.;
Hoveyda, A. H. J . Am. Chem. Soc. 2000, 122, 8168. (g) Ropartz, L.;
Morris, R. E.; Foster, D. F.; Cole-Hamilton, D. J . Chem. Commun. 2001,
361. (h) Davis, A. V.; Driffield, M.; Smith, D. K. Org. Lett. 2001, 3,
3075.
(4) Chen, Y.-C.; Wu, T.-F.; Deng, J .-G.; Liu, H.; J iang, Y.-Z.; Choi,
M. C. K.; Chan, A. S. C. Chem. Commun. 2001, 1488.
(5) Breinbauer, R.; J acobsen, E. N. Angew. Chem., Int. Ed. 2000,
39, 3604 and references therein.
10.1021/jo0257795 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/22/2002
J . Org. Chem. 2002, 67, 5301-5306
5301

Chen et al.
SCHEME 1. Syn th esis of F u n ction a lized
Mon om er ic Liga n d s
DMF and DMSO). Fortunately, after deprotection with
TFA, pure ligand 9 could be obtained in 40% yield in two
steps through flash chromatography on silica gel eluting
with DCM and methanol. On the other hand, the
introduction of a glycine residue could greatly improve
the solubility, and thus the coupling product 8 from 5
and 6 could be easily recrystallized from methanol.
Subsequently, dendritic ligand 10 was received after
deprotection of 8 with TFA in 84% overall yield.
In a similar convergent strategy, the second generation
dendrimer bearing 12 chiral ligands was synthesized by
coupling the poly(ether-amido) dendron previously de-
veloped by Newkome et al. (Scheme 3).7 It was found that
esterlysis of cyano groups in ethanol could be more
conveniently conducted with H2SO4 rather than HCl gas.
Thus, triacid 13 coupled with slightly excess 5 using
EDCI-HOBt as coupling reagent afforded 14 in 81% yield,
and after deprotection of the Cbz group, the air-dried
crude solid 15 was directly condensed with tetraacid 6
under above conditions without further purification. The
crude macromolecule 16 was insoluble in pure methanol,
DCM, THF, or acetone at ambient temperature, but very
soluble in DCM or acetone containing methanol. After
flash chromatography on silica gel, the obtained solid was
further recrystallized from methanol to give pure 16 in
34% yield. The dendritic ligand 17 could be obtained after
deprotection of all Boc groups of 16 with TFA in DCM.
SCHEME 2. P r ep a r a tion of G-1 Den d r itic Liga n d s
The high degree of symmetry in these dendrimers
enabled facile confirmation of both structure and purity
by NMR techniques. For example, in the 1H NMR
spectrum of dendritic ligand 9, the core protons observed
the resonance signals at 2.43 (t), 3.23 (s), and 3.49 (t)
ppm were clearly distinguishable from the resonances
arising from the wedges (DPEN ligands) at 4.10 (d) and
4.46 (t) ppm. Integration of the respective areas of the
core protons and methine protons of DPEN ligands
confirmed the complete coupling of the central core 6 and
ligand 3. A quite similar spectrum had been obtained
from dendritic ligand 10. For the second-generation
dendrimers 17, although some resonance signals were
not well resolved, the complete cascade reactions could
also be verified through comparison of integration areas
of the core protons at 2.37 (br s), 3.18 (br s), and 3.49 (br
s) ppm and methine protons of DPEN ligands at 4.06 (d)
and 4.42 (d) ppm. Moreover, 13C NMR spectra were also
in good agreement with those of the signed structures.
of the dendritic catalysts in the reaction medium (azeo-
trope of formic acid and triethylamine). Thus, amino-
functionalized monomer (R,R)-3 was initially prepared
from (R,R)-DPEN (1,2-diphenylethylenediamine) in three
steps in 81% overall yield. However, it was found that
the sulfonated group dramatically decreased the reactiv-
ity of the aromatic amino group in 3, and therefore the
amido linkage with the carboxylic group could not be
formed with EDCI-HOBt as the condensation reagent.
For the convenience of synthesis of dendrimers, a glycine
residue was previously introduced using more active
IBCF/NMM (mixed anhydride) or P(OPh)3 in pyridine6
as the coupling reagents. After hydrogenolysis of the Cbz
group under transfer hydrogenation conditions, the other
aliphatic amino-functionalized monomer 5 was obtained
in high yields (Scheme 1).
Furthermore, the structures of these dendrimers were
further verified by ESI HRMS or MALDI-TOF MS (Table
1). All of the spectra displayed a very prominent peak
corresponding to the dendrimers complexed with protons
or sodium cation except no signal was collected in
dendrimer 16. In case of 10, a peak complexed with two
protons (m/2e) was identified, while for dendritic ligand
17, a peak complexed with six protons (m/6e) was
observed.8 Moreover, MALDI-TOF MS was also applied
for confirming the structure of dendrimer 17. Although
no signal could be observed from 16, an apparent peak
of [M + Na]+ was determined for dendritic ligand 17, and
For the synthesis of the first generation dendrimers
(Scheme 2), tetrakis(2-carboxyethoxymethyl) methane 6
with four carboxylic groups was selected as the core unit.
After heating with 4.5 equiv of 3 and excess P(OPh)3 in
pyridine at 95 °C for 24 h, a white solid 7 was obtained,
which was almost insoluble in any solvents (including
(7) Newkome, G. R.; Lin, X. F. Macromolecules 1991, 24, 1443.
(8) Laufersweiler, M. J .; Rohde, J . M.; Chaumette, J .-L.; Sarazin,
D.; Parquette, J . R. J . Org. Chem. 2001, 66, 6440.
(6) Rabilloud, G.; Sillion, B. J . Heterocycl. Chem. 1980, 17, 1065.
5302 J . Org. Chem., Vol. 67, No. 15, 2002

Multiple Dendritic Catalysts
SCHEME 3. P r ep a r a tion of th e G-2 Den d r itic Liga n d
TABLE 1. MS Da ta of Den d r im er s
TABLE 2. Ch ir op tica la Da ta for Den d r im er s
b
c
dendrimer
M (calcd)
M (ms)
dendrimer
[R]23
[φ]23
D
D
Cbz-NH-triester(12)
Cbz-NH-triacid (13)
Cbz-NH-triNHBoc (14)
NH2-triNHBoc (15)
G-1-NH2 (9)
G-1-Gly-NHBoc (8)
G-1 -Gly-NH2 (10)
G-2-NHBoc (16)
612.3
528.2
613.5 (M + H)a
Cbz-NH-triNHBoc (14)
NH2-triNHBoc (15)
G-1-NH2 (9)
G-1-Gly-NHBoc (8)
G-1-Gly-NH2 (10)
G-2-NHBoc (16)
G-2-NH2 (17)
+39.0
+34.5
+62.1
+14.4
+37.6
+18.8
+45.6
797.9
659.5
1130
352.6
770.3
1504
3102
529.4 (M + H)a
2045.7840
1911.7433
1820.6576
2448.9532
2048.7435
8003.14
2069.9189 (M + Na)b
1913.7955 (M + H)b
1821.6863 (M + H)b
2471.8755 (M + Na)b
1025.3853 (M + 2H) b
b-d
-
a
Rotations measured in THF for 14 and 15, the others in
G-2-NH2 (17)
6802.5070
1135.4286 (M + 6H)b
6829 (M + Na)c
b
CH3OH/DCM (1:1). Specific rotation in 10-1 deg cm2 g-1
.
c Molar
rotation in 10-1 deg cm2 mol-1
.
a
b
d
API MS. ESI HRMS. c MALDI-TOF MS. No data was col-
lected.
aminophenylsulfonyl)-1,2-diphenylethylenediamine (19)
were selected as monomeric catalysts for comparison.
Initial experiments were conducted to test the catalytic
activity of ruthenium(II) complexes of the dendritic
ligands, and in the transfer hydrogenation reaction,
acetophenone was used as the model substrate and
the azeotrope of formic acid and triethylamine as the
hydrogen source.10 The average turnover frequencies
(TOFs, in relation to per mole of Ru(II) complex) and
enantioselectivity compared to monomeric catalysts 18
and 19 were summarized in Table 3.
the observed molecular mass gave the molecular weight
calculation at only 0.06% of the theoretical value.9
The chiroptical data for the dendrimers were sum-
marized in Table 2. Interestingly, the molar rotation of
amino-deprotected dendrimers was double that of the
amino-protected derivatives (Table 2, 8 vs 10 and 16 vs
17), and was increased from the first- to the second-
generation dendrimers (Table 2, 10 vs 17).
Asym m etr ic Tr a n sfer Hyd r ogen a tion . Ru(II) com-
plexes of (R,R)-TsDPEN (18) and (R,R)-N-(4-acetyl-
(9) Grayson, S. M.; Fre´chet, J . M. J . J . Am. Chem. Soc. 2000, 122,
10335.
(10) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J . Am. Chem. Soc. 1996, 118, 2521.
J . Org. Chem, Vol. 67, No. 15, 2002 5303

Chen et al.
TABLE 3. Com p a r ison of Den d r itic a n d Mon om er ic
Ca ta lysts in Asym m etr ic Tr a n sfer Hyd r ogen a tion of
Acetop h en on ea
TABLE 4. Asym m etr ic Tr a n sfer Hyd r ogen a tion of
Keton es a n d Im in esa
c
entry
ligand
conv (%)b
TOF (h-1
)
ee (%)d
1
2
3
4
5
18
19
9
10
17
>99
>99
99
99
97
14.8
13.2
13.8
12.6
10.6
97.7
97.1
97.6
96.4
97.1
a
Reactions were conducted at 28 °C for 20 h, S/C ) 100.
Conversions were determined by GC. c The average TOFs were
calculated over the 5 h reaction time. Determined by GC with a
b
d
Chrompack CP Chirasil-dex column (25 m × 0.25 mm).
entry
sub
ligand
time (h) conv (%)b
ee (%)c confd
1
2
3
4
5
20a
20b
20c
20c
20d
20d
20e
20e
21a
21a
21b
21b
22a
22a
22a
22a
22b
22b
22b
23
9
9
9
17
9
10
9
17
9
17
9
17
18
9
10
17
18
9
24
24
24
24
24
24
45
55
72
72
72
72
3
2
2
2
5
5
6
24
25
97
>99
>99
>99
>99
99
93.2
89.4
94.7
95.5
94.6
94.2
97.2
96.3
R
R
R
R
R
R
R
R
R,R
R,R
R,R
R,R
R
R
R
R
R
It was found that the macromolecular catalysts showed
no significant difference in activity and enantioselectivity
as compared with the monomeric catalysts 18 and 19.
Good retention of catalytic activity and high enantio-
selectivity were observed in these dendritic catalysis.
However, the glycine spacer had mild negative effects on
the catalytic activity (entries 3 vs 4).
6
7
>99
98
8
9e
71f
70f
69f
67f
99f
99f
99f
99f
98f
98f
97f
93
>99g,h
>99g,i
>99j,k
>99j,m
96.1g
98.7g
96.1g
95.9g
98.3g
98.3g
98.4g
45.0g
51.8g
10e
11e
12e
13n
14n
15n
16n
17n
18n
19n
20n
21n
For exploring the scope and limitations of this reaction
catalyzed by the dendritic catalysts, a variety of ketones
and imines were applied in the asymmetric transfer
hydrogenation with HCOOH-NEt3. In general, excellent
conversion and enantioselectivity were achieved (Table
4). Halogen-substituted acetophenones 20a -d tended to
lower the enantioselectivity, especially at the para-site
of the benzene ring with fluorine (entry 2), and an
electronic donating group at the para-site of the benzene
ring of acetophenone would decrease the reactivity
(entries 7 and 8).10 Considering the multimeric nature
of the dendritic catalysts, diones 21a ,b11 were tested for
the possible synergy between catalytic units at the
surface of the dendritic catalysts.5 Although excellent
enantioselectivity (entries 9-12) was obtained, no ap-
parent difference was noted for the diastereoselectivity
and the reaction proceeded slowly. Probably the space
between the metal complexes was still too far for such
possible cooperation. Interestingly, useful chiral sultam
auxiliaries could be obtained quantitatively from imines
22a ,b12 catalyzed by the dendritic catalysts with excellent
enantiomeric purity (up to 98.7%), in which a promoted
activity was also observed for 22a as compared with the
monomeric catalyst 18 (entries 13-16). Moreover, the
dendritic catalyst 9 was more enantioselective than the
monomeric catalyst 18 in the reduction of N-tert-butyl-
sulfonylketimine13 23 with high yield, moderate enantio-
selectivity, and similar reaction rate (entries 20 vs 21).
However, N-diphenylphosphinyl ketimine 24 was found
to be inactive under the same conditions and decomposed
during the reaction.14
R
R
R
R
17
18
9
23
92
a
b
Reactions were conducted at 28 °C, S/C)100. Based on GC
analysis. c Determined by GC with a Chrompack CP Chirasil-dex
d
column (25 m × 0.25 mm). Determined by comparison of optical
rotations with literature values. e Reaction was carried out in 2
M DMF solutions at 40 °C. f Isolated yield. g Determined by HPLC
h
i
j
with a Daicel Chiralcel OD column. 98.1% de. 94.7% de. De-
termined by HPLC with a Daicel Chiralcel OB and ChiralPak AD
column. 84.2% de. 82.6% de. Reaction was carried out in 0.5
M DCM solutions at 28 °C.
k
m
n
In conclusion, multiple dendritic ligands based on
(R,R)-1,2-diphenylethylenediamine were synthesized and
well characterized. Their ruthenium(II) complexes dem-
onstrated high catalytic activity and enantioselectivity
in the asymmetric transfer hydrogenation of ketones and
imines. Further work is being conducted to immobilize
these highly active dendritic catalysts on polymers to
facilitate the recycling,15 and to investigate their applica-
tions in other asymmetric catalysis.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined in open
capillaries and were uncorrected. NMR spectra were recorded
with tetramethylsilane as the internal standard. Chiral 1,2-
(11) The results catalyzed by (S,S)-TsDPEN-RuCl(cymene) in
HCOOH/NEt3 for 40 h: 21a : 96%, >99% ee, 97.8%de; 21b: 98%, >99%
ee, 84.2% de. See: Chen, Y.-C.; Deng, J .-G.; Wu, T.-F.; Cui, X.; J iang,
Y.-Z.; Choi, M. C. K.; Chan, A. C. S. Chin. J . Chem. 2001, 19, 807.
(12) (a) Ahn, K. H.; Ham, C.; Kim, S.-K.; Cho, C.-W. J . Org. Chem.
1997, 62, 7047. (b) Mao, J . M.; Baker, D. C. Org. Lett. 1999, 1, 841.
(13) Artman, G. D., III; Bartolozzi, A.; Franck, R. W.; Weinreb, S.
M. Synlett 2001, 232.
(15) (a) Sellner, H.; Seebach, D. Angew. Chem., Int. Ed. 1999, 38,
1918. (b) Arya, P.; Rao, N. V.; Singkhonrat, J .; Alper, H.; Bourque, S.
C.; Manzer, L. E. J . Org. Chem. 2000, 65, 1881. (c) Bourque, S. C.;
Alper, H.; Manzer, L. E.; Arya, P. J . Am. Chem. Soc. 2000, 122, 956.
(d) Arya, P.; Panda, G.; Rao, N. V.; Alper, H.; Bourque, S. C.; Manzer,
L. E. J . Am. Chem. Soc. 2001, 123, 2889.
(14) Spindler, F.; Blaser, H.-U. Adv. Synth. Catal. 2001, 343, 68.
5304 J . Org. Chem., Vol. 67, No. 15, 2002

Multiple Dendritic Catalysts
diphenylethylenediamine was prepared in our laboratory,
[R]D +106.7 (c 1.0, CH3OH, R,R-isomer). All other reagents
were used without purification as commercially available.
MHz) δ 28.5, 44.5, 59.5, 62.5, 65.9, 78.4, 118.5, 127.0, 127.1,
127.5, 127.9, 128.1, 128.2, 128.7, 135.7, 137.3, 139.8, 140.8,
142.0, 155.3, 157.0, 168.8; IR (KBr) 3366, 3301, 1690, 1521,
1156 cm-1; API-ES MS (m/z) 659.3 [M + H]+ (7), 559.2 [M -
99 (Boc)]+ (3). Anal. Calcd for C35H38N4O7S: C, 63.81; H, 5.81;
N, 8.50; S, 4.87. Found: C, 63.65; H, 5.98; N, 8.50; S, 4.71.
20
(R,R)-N-(4-Nitr op h en ylsu lfon yl)-1,2-d ip h en yleth ylen e-
d ia m in e (1). To a solution of (R,R)-DPEN (3.5 g, 16.5 mmol)
and NEt3 (3 mL, 21 mmol) in DCM (50 mL) cooled in an ice-
bath was added dropwise 4-nitrophenylsulfonyl chloride (3.7
g, 16.7 mmol) in DCM (15 mL). After the ice-bath was removed,
the mixture was stirred at ambient temperature overnight and
concentrated in vacuo. The residue was triturated with water,
and the resulting solid was filtered and dried in air. Subse-
quently, the crude solid was refluxed in ethyl acetate (30 mL)
for 2 h, cooled, and filtered to give monosulfonylated diamine
1 (5.5 g, 84%): mp 211-212 °C; [R]D23 +21.8 (c 0.48, THF); 1H
NMR (DMSO, 300 MHz) δ 3.98 (d, J ) 6.9 Hz, 1H), 4.38 (d, J
) 6.9 Hz, 1H), 6.96-7.12 (m, 10H), 7.61 (d, J ) 8.4 Hz, 2H),
8.03 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 60.6,
65.3, 124.1, 127.0, 127.7, 127.9, 128.0, 128.1, 139.6, 142.4,
(R,R)-(5). The hydrogenolysis of (R,R)-4 was performed with
the same procedure as 2 to afford 5 as a white powder (3.5 g,
91%): mp 216 °C dec; [R]D +45.0 (c 0.30, THF); 1H NMR
23
(DMSO, 300 MHz) δ 1.26 (s, 9H), 3.49 (s, 2H), 4.64 (d, J ) 6.3
Hz, 1H), 4.80 (d, J ) 5.4 Hz, 1H), 7.01-7.23 (m, 10H), 7.33 (d,
J ) 9.6 Hz, 2H), 7.43 (d, J ) 8.4 Hz, 2H), 8.32 (s, 1H); 13C
NMR (DMSO, 75 MHz) δ 28.5, 43.1, 59.5, 62.5, 78.4, 118.6,
126.9, 127.1, 127.4, 127.5, 127.9, 128.1, 135.9, 139.8, 140.8,
141.7, 155.3, 166.2; IR (KBr) 3389, 3296, 3194, 3112, 3031,
1689, 1595, 1156 cm-1; API-ES MS (m/z) 547.3 [M + Na]+ (6),
425.3 [M - 99 (Boc)]+ (100).
(R,R)-G-1-NH2 (9). Tetrakis(carboxyethoxymethyl)methane
6 (50 mg, 0.12 mmol), (R,R)-3 (230 mg, 0.49 mmol), and
(PhO)3P (0.16 mL, 0.62 mmol) were dissolved in pyridine (5
mL). The solution was heated at 95 °C for 24 h, cooled, and
then poured into ice water (30 mL). The resulting solid was
filtered, washed successively with 0.5 M citric acid, water,
saturated sodium hydrogen carbonate and water, and dried
in air to afford crude 7, which was almost insoluble in any
solvent (CH3OH, DCM, THF, DMSO, and DMF). Thus, to a
suspension of the crude 7 in DCM was added TFA (2 mL) in
an ice bath. The mixture was stirred and the solid was
dissolved rapidly. After 1 h, the solvent was removed in vacuo
and water (10 mL) was added. The mixture was neutralized
with ammonia and stirred at room temperature for 2 h. The
resulting solid was collected by filtration, washed with water,
and then dissolved in CH3OH-DCM (20 mL, v/v, 1:2). The
solution was dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatogra-
phy on silica gel with MeOH-DCM (1:15, 1:10, 1:4) to give
147.1, 149.1; IR (KBr) 3429, 3348, 3254, 1526, 1352, 1157 cm-1
;
API-ES MS (m/z) 420.2 [M + Na]+ (5), 398.2 [M + H]+ (100).
(R,R)-N-Boc-N′-(4-Nitr op h en ylsu lfon yl)-1,2-d ip h en yl-
eth ylen ed ia m in e (2). A solution of (R,R)-1 (5.3 g, 13.4 mmol),
(Boc)2O (3.4 g, 15.6 mmol), and DIPEA (3.0 mL, 17.0 mmol)
in DCM (40 mL) was stirred at ambient temperature for 24 h
and then washed successfully with 0.5 M citric acid, water,
saturated sodium bicarbonate, and brine and dried over Na2-
SO4. After concentration, the residue was triturated with
petroleum ether and filtered to afford 2 as a light yellow
23
powder (6.56 g, 99%): mp 213 °C dec; [R]D +54.3 (c 0.52,
1
THF); H NMR (CDCl3, 300 MHz) δ 1.52 (s, 9H), 4.74-4.84
(m, 2H), 5.25 (d, J ) 5.1 Hz, 1H), 6.76-7.21 (m, 10H), 7.60 (d,
J ) 6.9 Hz, 2H), 8.49 (d, J ) 6.9 Hz, 2H); 13C NMR (DMSO,
75 MHz) δ 28.2, 60.1, 65.0, 81.2, 123.4, 127.2, 127.4, 127.6,
127.8, 128.2, 128.7, 137.0, 146.8, 149.2, 157.5; IR (KBr) 3481,
3388, 3319, 1689, 1527, 1351, 1165 cm-1; API-ES MS (m/z)
496 [M - H]- (100). Anal. Calcd for C25H27N3O6S: C, 60.35;
H, 5.47; N, 8.45; S, 6.44. Found: C, 59.83; H, 5.47; N, 8.30; S,
6.27.
23
ligand 9 as a white solid (86 mg, 40% yield in two steps): [R]D
+62.1 [c 0.13, CH3OH/DCM (v/v, 1:1)]; 1H NMR (CD3OD, 400
MHz) δ 2.43 (t, J ) 5.6 Hz, 8H), 3.23 (s, 8H), 3.49 (t, J ) 5.6
Hz, 8H), 4.10 (d, J ) 9.2 Hz, 4H), 4.46 (t, J ) 9.2 Hz, 4H),
6.76-6.78 (m, 8H), 6.84-6.90 (m, 12H), 7.07-7.13 (m, 20H),
7.38-7.43 (m, 16H); 13C NMR (CD3OD, 50 MHz) δ 38.7, 46.7,
61.9, 65.7, 68.4, 70.5, 120.1, 128.3, 128.6, 128.8, 128.9,129.0,
129.4, 136.6, 139.1, 140.4, 143.4, 172.7; IR (KBr) 3430, 3369,
3192, 3063, 1677, 1592, 1534, 1317, 1155, 1093 cm-1; ESI
(R,R)-N-Boc-N′-(4-Am in op h en ylsu lfon yl)-1,2-d ip h en yl-
eth ylen ed ia m in e (3). To a suspension of Pd/C (10%, 500 mg)
in methanol were added (R,R)-2 (6.3 g, 12.6 mmol) and
ammonium formate (4 g, 64 mmol). The mixture was stirred
at room temperature under argon for 1 h, filtered through
Celite, and washed with methanol. After concentration, water
(40 mL) was added and the resulting solid was filtered, washed
with water, and dried in air to afford 3 as a white powder (5.86
g, 99%): mp 199.5 °C dec; [R]D23 +32.9 (c 0.33, THF); 1H NMR
(CDCl3, 300 MHz) δ 1.47 (s, 9H), 4.50 (t, J ) 8.4 Hz, 1H), 4.79
(t, J ) 9.0 Hz, 1H), 5.30 (d, J ) 7.8 Hz, 1H), 5.89 (s, 1H), 6.44
(d, J ) 8.7 Hz, 2H), 6.79-7.17 (m, 10H), 7.34 (d, J ) 8.7 Hz,
2H); 13C NMR (DMSO, 75 MHz) δ 28.5, 59.6, 62.2, 78.4, 93.8,
126.8, 126.9, 127.0, 127.5, 127.8, 128.1, 128.3, 140.2, 141.0,
152.2, 155.3; IR (KBr) 3463, 3381, 1690, 1521, 1156 cm-1; API-
ES MS (m/z) 506.2 [M + K]+ (5), 490.3 [M + Na]+ (60), 368.3
[M - 99 (Boc)]+ (100). Anal. Calcd for C25H29N3O4S: C, 64.22;
H, 6.25; N, 8.99; S, 6.86. Found: C, 63.77; H, 6.14; N, 8.77; S,
6.86.
HRMS calcd for
1821.6863.
C97H104N12O16S4 + H 1821.6654, obsd
(R,R)-G-1-Gly-NHBoc (8). To a stirred solution of tetraacid
6 (42 mg, 0.099 mmol), (R,R)-5 (230 mg, 0.44 mmol), EDCI
(100 mg, 0.52 mmol), and HOBt (85 mg, 0.55 mmol) in DCM
and DMF (10 mL/3 mL) cooled in an ice bath was added NEt3
(70 µL, 0.76 mmol). After the ice bath was removed, the
mixture was stirred at ambient temperature overnight. DCM
was removed under reduced pressure and water (30 mL) was
added to the residue. The resulting solid was filtered, washed
successively with 0.5 M citric acid, water, saturated sodium
hydrogen carbonate, and water, and dried in air. The crude
product was recrystallized from methanol twice to give 8 as a
white powder (190 mg). An additional crop of 8 (36 mg) was
obtained from the mother liquid by further purification on
Sephadex LH-20 with methanol as elutent (total 226 mg, 93%
yield): mp 182 °C dec; [R]D23 +14.4 [c 0.12, CH3OH/DCM (v/v,
1:1)]; 1H NMR (CD3COCD3, 400 MHz) δ 1.35 (s, 36H), 2.51 (t,
J ) 6.0 Hz, 8H), 3.38 (s, 8H), 3.64 (t, J ) 6.0 Hz, 8H), 4.10 (s,
8H), 4.71 (d, J ) 8.4 Hz, 4H), 4.95 (t, J ) 8.4 Hz, 4H), 7.02-
7.17 (m, 40H), 7.42 (d, J ) 8.0 Hz, 8H), 7.53 (d, J ) 8.8 Hz,
8H); 13C NMR (CD3COCD3 + DMSO, 75 MHz) δ 33.2, 41.4,
48.4, 50.6, 64.7, 67.8, 72.6, 74.5, 83.4, 123.6, 132.0, 132.1, 132.4,
132.6, 132.9, 133.2, 141.0, 145.0, 145.8, 147.1, 160.5, 173.6,
176.7; IR (KBr) 3374, 3116, 3064, 1690, 1533, 1156 cm-1; ESI
(R,R)-(4). To a stirred solution of (R,R)-3 (3.83 g, 8.2 mmol),
N-Cbz-glycine (2.6 g, 12.4 mmol), and NMM (1.6 mL, 14 mmol)
in dry THF cooled in an ice-salt bath was added slowly IBCF
(1.6 mL, 11.8 mmol). After 5 min, the ice bath was removed
and the mixture was stirred at ambient temperature for 24 h.
After THF was removed in vacuo, water was added to the
residue and then the aqueous phase was extracted with EtOAc
(50 mL). The organic phase was washed successfully with 0.5
M citric acid, water, saturated sodium bicarbonate, and brine
and dried over Na2SO4. After concentration, the solid was
recrystallized from acetone and hexane to give a white powder
23
1
(5.12 g, 95%): mp 204 °C dec; [R]D +34.6 (c 0.37, THF); H
NMR (DMSO, 300 MHz) δ 1.26 (s, 9H), 3.81 (d, J ) 3.0 Hz,
2H), 4.64 (d, J ) 4.8 Hz, 1H), 4.78 (t, J ) 4.5 Hz, 1H), 5.05 (s,
2H), 6.84-7.57 (m, 19H), 10.17 (s, 1H); 13C NMR (DMSO, 75
HRMS calcd for
2471.8755.
C125H148N16O28S4 + Na 2471.9430, obsd
J . Org. Chem, Vol. 67, No. 15, 2002 5305

Chen et al.
(R,R)-G-1-Gly-NH2 (10). Compound 8 was deprotected by
the same procedure as 7. After neutralization with ammonia,
10 was obtained as a white powder (125 mg, 92% yield): [R]D
with 8 to afford a crude product, which was insoluble in pure
CH3OH, DCM, THF, or acetone at ambient temperature, but
very soluble in DCM or acetone containing CH3OH. Flash
chromatography with CH3OH-DCM (v/v, from 1:25 to 1:20)
and recrystallization with methanol afforded 16 as a white
23
+37.6 [c 0.16, CH3OH/DCM (v/v, 1:1)]; 1H NMR (CD3OD +
CDCl3, 400 MHz) δ 2.47 (t, J ) 5.6 Hz, 8H), 3.34 (s, 8H), 3.61
(t, J ) 5.6 Hz, 8H), 3.99 (s, 8H), 4.04 (d, J ) 8.8 Hz, 4H), 4.42
(t, J ) 8.8 Hz, 4H), 6.76-6.78 (m, 8H), 6.85-6.91 (m, 12H),
7.07-7.11 (m, 20H), 7.39-7.41 (m, 16H); 13C NMR (CD3OD +
CDCl3, 50 MHz) δ 37.2, 44.1, 46.3, 61.7, 65.8, 68.2, 70.4, 119.9,
128.0, 128.2, 128.3, 128.4, 128.8, 129.1, 136.3, 139.2, 140.9,
142.8, 169.4, 174.3; IR (KBr) 3367, 3194, 3111, 3063, 1650,
1536, 1154 cm-1; ESI HRMS calcd for C105H116N16O20S4 + 2H
(m/ 2e) 1025.3978, obsd 1025.3853.
23
powder (160 mg, 34% yield): mp 186 °C dec; [R]D +18.8 [c
0.14, CH3OH/DCM (v/v, 1:1)]; 1H NMR (CD3COCD3 + CD3-
OD, 400 MHz) δ 1.34 (s, 108H), 2.51 (br s, 32H), 3.25 (s, 8H),
3.61-3.73 (m, 56H), 3.97 (s, 8H), 4.11 (br s, 24H), 4.70 (d, J )
7.6 Hz, 12H), 4.91-4.93 (m, 12H), 6.99 (br s, 8H), 7.05-7.15
(m, 120H), 7.40 (d, J ) 8.4 Hz, 24H), 7.51 (d, J ) 8.8 Hz, 24H);
13C NMR (CD3COCD3 + CD3OD, 50 MHz) δ 28.6, 37.0, 44.2,
47.9, 48.3, 48.8, 49.2, 49.6, 60.7, 61.1, 63.8, 68.2, 70.0, 79.7,
119.6, 127.9, 128.3, 128.4, 128.6, 128.8, 131.9, 139.8, 140.8,
142.7, 156.7, 169.2, 170.4, 173.4; IR (KBr) 3338, 1688, 1533,
1317, 1253, 1157, 1093 cm-1. No data were collected in ESI
HRMS and MALDI-TOF MS.
CbzNH-tr iester (12) was prepared by coupling amino
triester 11 and N-Cbz-glycine with MA (mixed anhydride) with
the same procedure for the preparation of 4. Purification by
flash chromatography on silica gel afforded 12 as an oil (680
mg, 84%): 1H NMR (CDCl3, 300 MHz) δ 1.27 (t, J ) 7.2 Hz,
9H), 2.53 (t, J ) 6.3 Hz, 6H), 3.50-3.71 (m, 12H), 3.87 (d, J )
5.1 Hz, 2H), 4.15 (q, J ) 8.7 Hz, 6H), 5.14 (s, 2H), 5.59 (s,
1H), 6.38 (s, 1H), 7.34-7.38 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 14.1, 34.8, 45.1, 59.8, 60.4, 66.7, 69.0, 127.9, 128.0,
128.4, 136.4, 156.5, 169.8, 171.6; IR (KBr) 3358, 3034, 1726,
1523, 1374, 1245, 1188, 1112 cm-1; API MS (m/z) 613.5 [M +
H]+.
(R,R)-G-2-NH2 (17). Compound 16 was deprotected by a
similar procedure as given above with 7. After neutralization
with ammonia, the mixture was stirred at room temperature
for 3 h. The resulting solid was filtered, washed with water,
dissolved in CH3OH-DCM (20 mL, v/v, 1/1), and then dried
over Na2SO4. After concentration, the residue was triturated
with pure DCM to afford 17 as a white powder (90 mg, 88%):
23
1
[R]D +45.6 [c 0.12, CH3OH/DCM (v/v, 1:1)]; H NMR (CD3-
OD + CDCl3, 400 MHz) δ 2.37 (br s, 8H), 2.46 (br s, 24H),
3.18 (br s, 8H), 3.49 (br s, 8H), 3.63-3.67 (m, 48H), 3.83 (s,
8H), 3.99 (s, 24H), 4.06 (d, J ) 6.4 Hz, 12H), 4.42 (d, J ) 8.8
Hz, 12H), 6.76-6.78 (m, 24H), 6.86-6.88 (m, 36H), 7.06-7.12
(m, 60H), 7.37 (br s, 48H); 13C NMR (CD3OD + CDCl3, 50 MHz)
δ 37.1, 44.0, 61.1, 61.5, 65.6, 68.1, 70.0, 119.8, 127.5, 128.1,
128.4, 128.7, 129.0, 129.4, 136.1, 139.0, 140.7, 142.6, 169.4,
170.7, 173.7, 174.0; IR (KBr) 3401, 3369, 3350, 3278, 3106,
3063, 1651, 1534, 1318, 1155, 1094 cm-1; ESI HRMS calcd for
CbzNH-tr ia cid (13). To a solution of triester 12 (500 mg,
0.82 mmol) in CH3OH-H2O (10 mL/10 mL) was added a
solution of NaOH (0.13 g, 3.2 mmol) in water (3 mL). The
mixture was stirred overnight, and then methanol was re-
moved. The aqueous solution was acidified with 1 M HCl,
extracted with EtOAc (2 × 20 mL), washed with brine, and
dried over Na2SO4. After concentration, recrystallization from
EtOAc/hexane afforded 13 as a white needle (360 mg, 85%):
mp 103-105 °C; 1H NMR (CDCl3, 300 MHz) δ 2.56 (br s, 6H),
3.46 (br s, COOH), 3.72-3.83 (m, 14H), 5.16 (s, 2H), 7.36-
7.38 (m, 5H); IR (KBr) 3339, 3299, 3034, 1713, 1637, 1546,
1210, 1120, 1088 cm-1; API MS (m/z) 529.4 [M + H]+.
(R,R)-CbzNH-tr iNHBoc (14) was prepared by a similar
procedure as given above with 8. Purification by flash chro-
matography with acetone-DCM (v/v, 1.5:1, 4:1 and 10:1)
C
341H388N56O72S12 + 6H (m/6e) 1134.7590, obsd 1135.4286;
MALDI-TOF MS calcd for C341H388N56O72S12 + Na 6825, obsd
6829.
Asym m etr ic Tr a n sfer Hyd r ogen a tion : Gen er a l P r o-
ced u r e for Asym m etr ic Tr a n sfer Hyd r ogen a tion of Ke-
ton es a n d Im in es. A solution of [RuCl2(cymene)]2 (1.3 mg,
0.002 mmol), dendritic ligand (0.0044 mmol of DPEN), and
NEt3 (1.3 µL, 0.008 mmol) in methanol was heated at 65 °C
for 2 h. After methanol was removed in vacuo, ketone 20 (0.4
mmol) and an azeotrope of formic acid and triethylamine (0.2
mL) were added in turn. The mixture was stirred at 28 °C
and monitored by TLC. After completion, the mixture was
diluted with diethyl ether (3 mL), washed with brine, and dried
over Na2SO4. The ether solution was passed through a short
column (silica gel) and concentrated in vacuo to afford the (R)-
alcohol.
23
afforded 14 as a white powder (520 mg, 81%): [R]D +39.0 (c
1
0.31, THF); H NMR (CD3COCD3, 400 MHz) δ 1.34 (s, 27H),
2.47 (t, J ) 5.6 Hz, 6H), 3.67 (t, J ) 5.2 Hz, 6H), 3.71 (s, 6H),
3.83 (d, J ) 6.0 Hz, 2H), 4.08 (d, J ) 6.0 Hz, 6H), 4.69 (d, J )
8.4 Hz, 3H), 4.92 (t, J ) 8.4 Hz, 3H), 5.08 (s, 2H), 7.00-7.77
(m, 30H), 7.41 (d, J ) 8.4 Hz, 6H), 7.52 (d, J ) 8.8 Hz, 6H),
9.55 (s, 3H); 13C NMR (CD3COCD3 + DMSO, 75 MHz) δ 28.7,
33.7, 45.3, 46.3, 61.6, 62.1, 64.7, 68.1, 69.6, 71.1, 80.3, 111.7,
120.6, 121.4, 126.5, 128.9, 129.0, 129.3, 129.5, 129.6, 129.8,
130.1, 130.4, 130.6, 138.0, 139.5, 142.0, 142.8, 144.1, 157.4,
159.0, 170.5, 171.5, 173.6; IR (KBr) 3370, 3342, 3064, 1690,
1532, 1157, 1094 cm-1; ESI HRMS calcd for C104H121N14O24S3
+ Na 2068.7738, obsd 2069.9189.
The transfer hydrogenation of diones 21 and imines 22-24
was conducted in 2 M DMF and 0.5 M DCM solutions,
respectively.
(R,R)-NH2-tr iNHBoc (15). Hydrogenolysis of 14 was per-
formed with a similar procedure as given above with 4 to afford
Ack n ow led gm en t. We are grateful for the financial
support of the National Science Fund for Distinguished
Young Scholars of China (No. 20025205) and The Hong
Kong Polytechnic University, ASD Fund.
23
1
15 (240 mg, 85%): [R]D +34.5 (c 0.20, THF); H NMR (CD3-
OD, 400 MHz) δ 1.39 (s, 27H), 2.49 (t, J ) 5.6 Hz, 6H), 3.20
(s, 2H), 3.67 (t, J ) 5.6 Hz, 6H), 3.73 (s, 6H), 4.00 (s, 6H), 4.57
(d, J ) 8.8 Hz, 3H), 6.88-7.09 (m, 30), 7.36-7.42 (m, 12H)
(the other three NCH groups are overlapped by the H2O of
CD3OD); IR (KBr) 3406, 3372, 3063, 1689, 1532, 1157, 1093
cm-1; ESI HRMS calcd for C96H115N14O22S3 + H 1912.7511,
obsd 1913.7955.
Su p p or tin g In for m a tion Ava ila ble: GC, HPLC, and [R]D
values of the reduction products and spectra of dendritic
ligands 9, 10, and 17. This material is available free of charge
via the Internet at http://pubs.acs.org.
(R,R)-G-2-NHBoc (16). Compound 15 was coupled with
tetraacid 6 according to a similar procedure as given above
J O0257795
5306 J . Org. Chem., Vol. 67, No. 15, 2002