Sugar-based monodentate phosphoramidite ligands for Cu-catalyzed enantioselective conjugate addition to enones

Article abstract of DOI:10.1016/j.tet.2012.12.049

In this paper we present new, monodentate phosphoramidite ligands based on amines derived from the easy available monosaccharide d-xylose and BINOLs. Ligands were used for copper-catalyzed conjugate addition to acyclic and cyclic enones. The highest enantioselectivity achieved in this study was 77% ee for the conjugate addition to trans-chalcone, which is comparable to the best results published to date for phosphoramidite ligands based on carbohydrate-derived amines.

Full text of DOI:10.1016/j.tet.2012.12.049

Tetrahedron 69 (2013) 1930e1939
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sugar-based monodentate phosphoramidite ligands
for Cu-catalyzed enantioselective conjugate addition to enones
,
a
a,b
Tomasz Bauer a , Maciej Majdecki , Janusz Jurczak
*
a Department of Chemistry, Warsaw University, Pasteura 1, PL-02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper we present new, monodentate phosphoramidite ligands based on amines derived from the
Received 5 September 2012
Received in revised form 4 December 2012
Accepted 17 December 2012
Available online 31 December 2012
easy available monosaccharide D-xylose and BINOLs. Ligands were used for copper-catalyzed conjugate
addition to acyclic and cyclic enones. The highest enantioselectivity achieved in this study was 77% ee for
the conjugate addition to trans-chalcone, which is comparable to the best results published to date for
phosphoramidite ligands based on carbohydrate-derived amines.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
D
-Xylose
Phosphoramidite
Conjugate addition
trans-Chalcone
Enantioselective
1. Introduction
The asymmetric copper-catalyzed conjugate addition is one
of the most important methods for the formation of a new ster-
eogenic center.1 Phosphoramidite ligands based on atropoisomeric
binaphthols and chiral amines play a leading role among chiral li-
gands used for this reaction.2 There are only single examples of
phosphoramidite ligands originating from carbohydrate-derived
amines.3e5 These reports concentrated on mixed phosphonic-
phosphoramidite and diphosphoramidite ligands. Having in mind
that many of the successful ligands were monophosphoramidites,
we decided to synthesize sugar-derived ligands of general structure
I (Fig. 1), expecting a possible control of asymmetric induction by
variation of the steric demands of the protecting group R and the
amine substituent R0.
Fig. 1. Furanoside-monophosphoramidite ligands I.
We decided to synthesize a series of ligands bearing an amino
group at position C3 of the furanoside ring with various sterically
demanding protecting groups at position C5, and use them for
the synthesis of respective phosphoramidites. The efficacy of the
thus obtained ligands has been checked by addition of diethylzinc
to trans-chalcone and 2-cyclohexenone catalyzed by copper(II)
triflate.
2. Results and discussion
-Xylose was chosen as a substrate, and after preliminary ex-
D
periments we decided to use a one-pot method for the synthesis of
diol 2.6 The original procedure did not work in our hands, and
mainly D-xylose was obtained as a result of complete removal of
both isopropylidene groups in 1. After increasing the amount of
sodium carbonate in order to achieve a more efficient neutraliza-
tion of sulfuric acid, monoprotected derivative 2 was obtained in
good yield. Nevertheless, flash chromatography was required to
* Corresponding author. Tel.: þ48 22 822 02 11x273; fax: þ48 22 822 59 96;
e-mail address: tbauer@chem.uw.edu.pl (T. Bauer).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.049

T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
1931
obtained a high purity crystalline product. The primary hydroxyl
was protected as a pivaloyl ester leaving the secondary one at po-
sition C3 ready for the transformation into the amino group.7
The hydroxy group in compound 3 was oxidized to ketone 4
with PDC. Conversion into oxime 5 was performed using a classi-
cal procedure with sodium bicarbonate in aqueous ethanolic so-
lution,8 and oxime 5 was reduced to primary amine 6 with LiAlH4
(Scheme 1).7 The primary hydroxyl that was deprotected in the last
step was then re-protected as tert-butyldimethylsilyl (7a), tert-
butyldiphenylsilyl (7b) and trityl ethers (7c), and simple alkyl ether
(7d). The pivaloyl derivative (7e) was efficiently obtained by the
modified synthetic routedreduction of oxime 5 with sodium bo-
rohydride in the presence of nickel(II) chloride gave amine 7e with
preserved pivaloyl ester (Scheme 2). The synthesis of 7e was based
on the methodology reported earlier for the reduction of nitriles to
amines,9 and as far as we know, never used for stereoselective re-
duction of sugar oximes.
Amines 7 were then reacted with (S)-1,10-binaphthyl-2,20-diyl
phosphorochloridate in the presence of triethylamine to give sec-
ondary phosphoramidite ligands L1aeL5a (Scheme 3).
With new ligands L1eL5 in hand we evaluated their ability to
induce asymmetric induction in the copper-catalyzed conjugate
addition of diethylzinc to trans-chalcone. The catalytic system was
generated using a standard approach. Copper(II) triflate was mixed
with the appropriate ligand, stirred for 1 h and the enone was added
followed by diethylzinc. The results are summarized in Table 1.
The results presented in Table 1 clearly show that the high steric
congestion does not lead to higher enantioselectivity as seen from
comparison of n-propyl ether L4 with TBDPS ether L2 and pivaloyl
ester L5 (Table 1, entries 4, 2, and 5, respectively). Experiments with
an increased amount of catalyst (Table 1, entry 6) did not sub-
stantially improve the asymmetric induction. Extremely low
enantioselectivity was observed for the very bulky trityl ether L3
(Table 1, entry 3). Quite surprisingly the best enantioselectivity was
Scheme 1. Reagents and conditions: (i): acetone, H2SO4/rt then Na2CO3, H2O, 68%; (ii): PivCl, Et3N, DMAP, CH2Cl2, 0 ꢀC, 81%; (iii): PDC, Ac2O, CH2Cl2, reflux, 96%; (iv): NH4Cl$H2O,
EtOH/H2O, reflux, 84%; (v): LiAlH4, THF, reflux, 54%.
Scheme 2. Reagents and conditions: (i): LiAlH4, THF, reflux, 54%; (ii): TrCl, Et3N, CH2Cl2, rt, 88%; (iii): TBDMSCl, imidazole, CH2Cl2, 0 ꢀC, 85%; (iv): TBDPSCl, imidazole, CH2Cl2, 0 ꢀC,
78%; (v): n-PrCl, n-Bu4HSO4, THF/50%NaOH, 78%; (vi): NiCl2$6H2O, NaBH4, MeOH, 0 ꢀC, 72%.

1932
T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
Scheme 3. Reagents and conditions: (i): (S)-1,10-binaphthyl-2,20-diyl phosphorochloridate, Et3N, THF.
Table 1
Conjugate addition of diethylzinc to trans-chalcone in the presence of ligands
L1eL5a
Entry
Ligand
t [h]
Yieldc [%]
eed [%]
1
2
3
4
5
6
7
L1a
L2a
L3a
L4a
L5a
L5ab
L1b
4
4
4
4
4
4.5
4
72
75
78
74
73
73
48
59 (R)
37 (R)
4 (R)
45 (R)
37 (R)
54 (R)
21 (S)
Fig. 2. Secondary amines used in ligands L6eL10.
studies. Amines 10aec and 10e were obtained by reductive amina-
tion of the appropriate aldehyde or ketone as shown in Scheme 4.11
The synthesis of ligand 10d was performed by a more efficient
way. The primary hydroxyl in diol 2 was protected as a TBDMS
ether. Then, the secondary one was oxidized to a ketone and one-
pot reductive amination with benzylamine in the presence of
2,2,2-trifluoroethanol gave 10d in 79% yield from 2 (Scheme 5).12
Amines 10 were reacted with (S)-1,10-binaphthyl-2,20-diyl
phosphorochloridate in the presence of triethylamine to give ter-
tiary phosphoramidite ligands L6aeL10a (Scheme 6).
Novel ligands L5eL10 were used under standard conditions in
the reaction with trans-chalcone and the results are presented in
Table 2.
As shown in Table 2 ligands derived from secondary amines
performed much better. The second substituent of the nitrogen
atom plays an important role and enantioselectivity was highest for
the benzyl one in L9a and L10a (Table 2, entries 4 and 5, re-
spectively), followed by its saturated analog (L7a, Table 2, entry 2).
A bulky isopropyl moiety substantially lowered catalytic activity of
the ligand and led to very low asymmetric induction (L8a, Table 2,
a
Reagents ratio: L:Cu(OTf)2:chalcone:Et2Zn 0.02:0.01:1:1.15.
6 mol % of L5a was used.
b
c
Isolated yield.
d
Determined by HPLC on Chiracel OD-H column.
obtained for a protection group with intermediate bulkiness,
namely TBDMS ether L1 (Table 1, entry 1). In order to determine
whether we have a ‘matched’ or ‘mismatched’ pair, we synthesized
compound L1b bearing (R)-BINOL moiety and used it as ligand for
this reaction. As shown in Table 1 (entry 7) much lower enantio-
selectivity in the opposite sense was observed, indicating that
amine 7a and (S)-BINOL make the ‘matched’ pair.
The low to moderate selectivity obtained for ligands based on
primary amines prompted us to synthesize a series of secondary
amines 10 (Fig. 2).
Secondary amines are known as better partners for BINOLs and
should lead to more efficient ligands.10 As starting primary amines
we have chosen amines 7a and 7d, which gave the best results in our
Scheme 4. Reagents and conditions: (i): (a) RR0C]O, Ti(OiPr)4; (b) NaBH4, MeOH.

T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
1933
Scheme 5. Reagents and conditions: (i): TBDMSCl, imidazole, CH2Cl2, rt, 96%, (ii): PDC, Ac2O, CH2Cl2, reflux, 98%; (iii): BnNH2, NaBH4, TFE, 37 ꢀC, 84%.
Scheme 6. Reagents and conditions: (i): (S)-1,10-binaphthyl-2,20-diyl phosphorochloridate, Et3N, THF.
Again, (R)-BINOL makes a ‘mismatched’ pair with our amines (L9b,
Table 2, entry 6).
Additionally, we have tested our new ligands in conjugate ad-
dition to a cyclic enone using 2-cyclohexenone as a model com-
pound. Results obtained for five ligands are presented in Table 3.
Table 2
Conjugate addition of diethylzinc to trans-chalcone in the presence of ligands
L6eL10a
Table 3
Entry
Ligand
t [h]
Yieldb [%]
eec [%]
Conjugate addition of diethylzinc to 2-cyclohexenonea
1
2
3
4
5
6
L6a
L7a
L8a
L9a
L10a
L9b
3
4
10
3.5
3
82
79
30
81
81
85
75 (R)
71 (R)
16 (R)
77 (R)
76 (R)
23 (S)
3.5
a
Reagents ratio: L/Cu(OTf)2/chalcone/Et2Zn 0.02:0.01:1:1.15.
Isolated yield.
Determined by HPLC on Chiracel OD-H column.
b
c
Entry
Ligand
t [h]
Yieldb [%]
eec [%]
1
2
3
4
5
L1a
L1b
L7a
L9a
L9b
2
2
2
2
2
49
50
52
51
62
40 (S)
38 (R)
57 (S)
46 (S)
43 (R)
entry 3). Introduction of the electron donating substituent at the
phenyl ring in L6a did not influence enantioselectivity. Similarly to
ligands L1 and L5, the type and bulkiness of the protection group at
C5 did not influence the asymmetric induction and for all ligands
except L8a enantioselectivity was in the narrow range 71e77% ee.
a
Reagents ratio: L/Cu(OTf)2/chalcone/Et2Zn 0.02:0.01:1:1.15.
b
c
Isolated yield.
Determined by GC on Supelco-b-Dex 225 column.

1934
T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
The asymmetric induction for 2-cyclohexenone is lower than
as colorless oil (8.46 g, 44.6 mmol, 68% yield) solidifying upon
that observed for trans-chalcone. We have chosen the best ligands
based on primary and secondary amines and, quite surprisingly,
we do not observe substantial differences in inductive ability of
both types of ligands (Table 3, entries 1 vs 3, vs 4), albeit the
highest enantioselectivity was again recorded for secondary
amine-based ligand L7a. The most interesting feature of the ad-
dition to the cyclic enone is the almost negligible influence of
the sugar part of the ligand on the asymmetric induction. Ligands
bearing the same sugar amine and opposite enantiomers of
BINOL gave an opposite sense of the asymmetric induction with
almost equal values of enantiomeric excess (Table 3, entries 1 vs 2
and 4 vs 5).
standing in freezer.
20
20
[
a
]
D
ꢁ19.6 (c 1.0, CHCl3), lit.17
[
a
]
ꢁ13.9 (c 0.34, CHCl3), lit.18
D
[
a
]
20 ꢁ22.4 (c 1.1, CHCl3).
D
1H NMR: 6.00 (d, J¼3.6 Hz, 1H), 4.53 (d, J¼3.6 Hz, 1H), 4.20e3.85
(m, 4H), 3.10e2.80 (m, 1H), 1.49 (s, 3H), 1.33 (s, 3H).
13C NMR: 112.1, 150.1, 85.9, 78.8, 61.4, 27.0, 26.4.
4.3. 1,2-O-Isopropylidene-5-O-pivaloilo-a-D
-xylofuranoside 37
Magnetically stirred solution of 2 (8.46 g, 44.6 mmol) in pyridine
(40 mL) containing catalytical amount of DMAP (10 mg) was cooled
to 0 ꢀC, and pivaloyl chloride (5.51 mL, 44.6 mmol) was added
dropwise. The mixture was stirred for 1.5 h at ambient tempera-
ture. After TLC showed the disappearance of substrate, the reaction
was quenched with water, diluted with Et2O (80 mL), washed
several times with diluted solution of CuSO4, and finally with brine.
Organic phase was dried over anhydrous MgSO4, filtered, and
evaporated under vacuum. Residue was purified by flash chroma-
tography (EtOAc/hexanes 3:7 v/v) to give 3 (9.88 g, 36.1 mmol, 81%
yield) as colorless oil.
3. Conclusions
We have presented new, monodentate phosphoramidite ligands
based on amines derived from the readily available mono-
saccharide D-xylose and BINOLs. Ligands built on secondary amines
10 were more efficient in the addition to both acyclic and cyclic
substrates. The highest enantioselectivity achieved in this study
was 77% ee for conjugate addition to trans-chalcone, which is
comparable to the best results published to date for phosphor-
amidite ligands based on carbohydrate-derived amines. We are
currently working on modifications of the monosaccharide part of
the ligand, which will hopefully enable further increase of enan-
tioselectivity. These ligands can be also used in several other
enantioselective reactions catalyzed by phosphoramidites and
studies on hydrogenation and asymmetric allylic substitution are
currently in progress.
þ19.0 (c 1.0, CHCl3), lit.19
[
a
]
þ16.6 (c 1.062, CHCl3).
20
28
[
a
]
D
D
1H NMR: 5.92 (d, J¼3.4 Hz, 1H), 4.62e4.50 (m, 2H), 4.26e4.08
(m, 2H), 4.07e3.98 (m, 1H), 3.34 (s, 1H), 1.51 (s, 3H), 1.33 (s, 3H), 1.22
(s, 9H).
13C NMR: 180.1, 112.1, 104.9, 85.1, 78.7, 74.4, 60.7, 39.2, 27.4,
27.0, 26.4.
4.4. 1,2-O-Isopropylidene-5-O-pivaloilo-3-oxo-a-D-xylofur-
anoside 47
4. Experimental
4.1. General
To the magnetically stirred solution of 3 (9.88 g, 36.1 mmol) in
CH2Cl2 (100 mL) PDC (9.5 g, 25.2 mmol) and freshly distilled Ac2O
(11.25 mL, 119.13 mmol) were added and the mixture was refluxed
for 1 h. After TLC showed the disappearance of substrate, the re-
action mixture was cooled to room temperature and solvents were
evaporated. The residue was dissolved in EtOAc (100 mL), filtered
through a pad of silica gel. Solids were thoroughly washed with
EtOAc and the filtrate was evaporated under high vacuum to give 4
Melting points were determined using a Kofler hot stage ap-
paratus. Specific rotations were recorded using a PerkinElmer PE-
241 polarimeter with a thermally jacketed 10-cm cell. 1H and 13C
NMR spectra were recorded in CDCl3using a Varian 200 Unity Plus
and Varian 500 Unity Plus spectrometers. All chemical shifts are
quoted in parts per million relative to tetramethylsilane (d,
0.00 ppm). Mass spectra were recorded on a Mariner instrument
(Biosystem), Quatro LC Micromass, and LCT Micromass TOF HiRes
apparatus. Infrared spectra were recorded on FTIR Jasco 6200
spectrometer in CH2Cl2 solution of KBr pellet. Reactions were
carried out under argon using Schlenk techniques when neces-
sary. Flash column chromatography was made on silica gel (Kie-
selgel-60, Merck, 230e400 mesh). High performance liquid
chromatography was conducted on using Diacel Chiracel OD-H
column, gas chromatography was conducted on using Supelco-
(9.42 g, 34.6 mmol, 96% yield) as a pale yellow oil.
20
[
a
]
D
þ41.5 (c 1.0, CHCl3), lit.19
[a
]
20 þ42.6 (c 1.31, CHCl3).
D
1H NMR: 6.10 (d, J¼4.6 Hz, 1H), 4.57 (dt, J¼4.0, 1.0 Hz, 1H),
4.40e4.34 (m, 2H), 4.22 (dd, J¼12.0, 3.2 Hz, 1H), 1.50 (s, 3H), 1.44 (s,
3H), 1.18 (s, 9H).
13C NMR:
27.7, 27.3.
d 208.2, 177.8, 114.6, 103.3, 77.5, 76.4, 63.5, 38.8,
4.5. 1,2-O-Isopropylidene-5-O-pivaloilo-3-oxo-a-D-xylofur-
anoside oxime 57
b
-Dex 225 column. Compounds 2,6 3e6,7 7a,13 7c,14 10d,15 11, and
To the magnetically stirred solution of 4 (9.42 g, 34.6 mmol) in
50% EtOH (100 mL) NH2OH$HCl (7.7 g, 111 mmol) and NaHCO3
(9.6 g, 114 mmol) were added and the mixture was refluxed for
3.5 h. After cooling, the mixture was extracted with Et2O
(3ꢂ50 mL), combined extracts were washed with brine and dried
over anhydrous MgSO4, filtered, and evaporated under vacuum.
Residue was purified by flash chromatography (EtOAc/hexanes 3:7
v/v) to give 5 (8.35 g, 29.1 mmol, 84% yield) as a colorless oil.
1216 are known and were prepared by our own or modified lit-
erature method.
4.2. 1,2-O-Isopropylidene-a-D
-xylofuranoside 26
To the round bottom flask containing acetone (260 mL) and
concentrated sulfuric acid (10 mL), -xylose (10 g, 67 mmol) was
D
þ15.5 (c 1.0, CHCl3), lit.20
[
a]
þ167 (c 1.55, CH2Cl2).
20
20
added. The mixture was stirred for 30 min and solution of Na2CO3
(13 g, 66 mmol) in water (12 mL) was slowly added. The mixture
was further stirred for 3 h, and solid Na2CO3 (7 g, 36 mmol) was
added in order to neutralize sulfuric acid. Inorganic salts were fil-
tered off, and the remaining solution was evaporated under vac-
uum. Crude product was purified by flash chromatography (EtOAc/
[
a
]
D
D
1H NMR: 6.00 (t, J¼4.6 Hz, 1H), 5.34e4.22 (m, 1H), 5.16e4.94 (m,
1H), 4.59 (dd, J¼11.6, 2.6 Hz, 1H), 4.42e4.18 (m, 1H), 1.61e1.36 (m,
6H), 1.19 (s, 9H).
13C NMR: 178.40, 178.23, 158.44, 157.38, 114.46, 113.92, 105.28,
104.98, 78.66, 76.045, 75.87, 73.77, 65.12, 64.26, 38.99, 38.86, 28.00,
27.66, 27.55, 27.46, 27.40, 27.36.
hexanes 6:4 v/v) to give 1,2-O-isopropylidene-a-D-xylofuranoside 2

T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
1935
4.6. 1,2-O-Isopropylidene-3-amino-3-deoxy-
a
-
D
-ribofurano-
(5 mL) was added and the solution was extracted with Et2O
(2ꢂ10 mL). Combined extracts were washed with brine and dried
over anhydrous MgSO4, filtered, and evaporated under vacuum.
Residue was purified by flash chromatography (EtOAc/hexanes 3:7
v/v) to give 7c (0.1 g, 0.23 mmol, 88% yield) as a white solid.
side 67
Magnetically stirred solution of 5 (8.35 g, 29.1 mmol) in THF
(100 mL) was cooled to 0 ꢀC, LiAlH4 (2.76 g, 72.8 mmol) was added in
portions and the mixture was refluxed for 1.5 h. The mixture was
cooled to 0 ꢀC, diluted with Et2O (100 mL) and H2O (2.7 mL), 15%
NaOH (2.7 mL) and H2O (8.28 mL) were added dropwise. The sus-
pension was stirred for 30 min, inorganic salts were filtered of using
Celite pad and washed thoroughly with CH2Cl2 (3ꢂ30 mL). Combined
extracts were washed with brine and dried over anhydrous MgSO4,
filtered, and evaporated under vacuum. Residue was purified by flash
chromatography (CH2Cl2/MeOH95:5v/v)togive 6 (2.97 g,15.7 mmol,
54% yield) as pale yellow oil, which solidified upon standing.
[
a
]
20 þ21.5 (c 1.0, CH2Cl2).
D
Mp 120e121 ꢀC.
1H NMR:
d 7.62e7.44 (m, 6H), 7.36e7.18 (m, 9H), 5.32 (d,
J¼3.6 Hz, 1H), 4.26e3.96 (m, 2H), 3.96e3.82 (m, 1H), 3.20e2.94 (m,
1H), 2.62 (d, J¼11.6 Hz, 1H), 2.41 (t, J¼3.6 Hz, 1H), 1.81 (dd, J¼7.5,
5.5 Hz, 1H), 1.41 (s, 3H), 0.98 (s, 3H).
13C NMR: 146.4, 129.1, 128.8, 128.4, 128.1, 126.8, 111.4, 103.7, 81.0,
77.7, 70.8, 61.33, 56.7, 26.8, 25.9.
20
20
[
a]
þ46.5 (c 1.0, CHCl3), lit.7
[
a]
þ54.6 (c 1.0, CHCl3), mp
4.10. 1,2-O-Isopropylidene-3-amino-3-deoxy-5-O-n-propyl-a-D-
ribofuranoside 7d
D
D
44e45 ꢀC, lit.21 mp 63e67 ꢀC (petroleum ether).
1H NMR: 5.80 (d, J¼3.6 Hz, 1H), 4.90 (t, J¼4.2 Hz, 1H), 3.98e3.83
(m, 1H), 3.83e3.62 (m, 2H), 3.20 (dd, J¼9.4, 4.8 Hz, 1H), 2.04 (s, 3H),
1.55 (s, 3H), 1.36 (s, 3H).
To the magnetically stirred solution of amino alcohol 6 (0.12 g,
0.63 mmol) in THF (10 mL), 50% NaOH solution (5 mL) was added,
followed by n-Bu4NHSO4 (0.04 g, 0.13 mmol). After 15 min, n-
C3H7Cl (0.56 mL, 6.3 mmol) was added and the mixture was stirred
for 48 h. Water (20 mL) was added and the solution was extracted
with Et2O (3ꢂ20 mL). Combined extracts were washed with brine
and dried over anhydrous MgSO4, filtered, and evaporated under
vacuum. Residue was purified by flash chromatography (CH2Cl2/
MeOH 95:5 v/v) to give 7d (0.11 g, 0.48 mmol, 78% yield) as col-
orless oil.
13C NMR: 112.3, 104.5, 81.1, 80.9, 61.4, 55.2, 26.8, 26.6.
4.7. 1,2-O-Isopropylidene-3-amino-3-deoxy-5-O-tert-butyldi-
methylsilyl-a-D
-ribofuranoside 7a13
To the solution of 6 (0.13 g, 0.69 mmol) and imidazole (0.11 g,
1.73 mmol) in CH2Cl2 (5 mL) TBDMSCl (0.17 g, 1.10 mmol) was
added and the mixture was stirred for 1 h at room temperature.
Water (5 mL) was added and the solution was extracted with Et2O
(2ꢂ20 mL). Combined extracts were washed with brine and dried
over anhydrous MgSO4, filtered, and evaporated under vacuum.
Residue was purified by flash chromatography (CH2Cl2/MeOH 95:5
v/v) to give 7a (0.18 g, 0.59 mmol, 85% yield) as a pale yellow oil.
[a
]
20 þ45.3 (c 1.0, CH2Cl2).
D
1H NMR: 5.81 (d, J¼3.8 Hz, 1H), 4.45 (t, J¼4.4 Hz, 1H), 3.86e3.70
(m, 1H), 3.45 (dt, J¼6.8, 1.9 Hz, 1H), 3.13 (dd, J¼9.6, 4.8 Hz, 1H), 1.61
(dt, J¼7.2 Hz, 1H), 1.54 (s, 3H), 1.47 (s, 2H), 1.35 (s, 3H), 0.91 (t,
J¼1.6 Hz, 3H). HR ESI-MS [MþþNa] calcd for [C11H21NO4þNa]
ꢁ254.1368. Found ꢁ254.1373.
[
a
]
20 ꢁ11.0 (c 1.0, CH2Cl2).
D
1H NMR: 5.77 (d, J¼3.6 Hz, 1H), 4.50 (t, J¼4.2 Hz, 1H), 3.84 (d,
J¼4.0 Hz, 2H), 3.78e3.60 (m, 1H), 3.18 (s, 1H), 1.54 (s, 3H), 1.35 (s,
3H), 0.89 (s, 9H), 0.07 (s, 6H).
13C NMR: 112.0, 104.4, 80.7, 80.7, 73.7, 69.9, 56.1, 26.8, 26.6,
22.9, 10.7.
nmax(CH2Cl2) 3387, 3330, 2936, 1373, 1107, 1016, 875 cmꢁ1
.
13C NMR: 112.00, 104.36, 81.09, 62.43, 55.74, 26.87, 26.60, 26.12,
25.85, 18.58, ꢁ3.39, ꢁ5.11, ꢁ5.17.
HR ESI-MS [MþþNa] calcd for [C11H21NO4þNa] ꢁ254.1368.
Found ꢁ254.1373.
4.8. 1,2-O-Isopropylidene-3-amino-3-deoxy-5-O-tert-butyldi-
4.11. 1,2-O-Isopropylidene-3-amino-3-deoxy-5-O-n-pivaloyl-
phenylsilyl-
a-
D-ribofuranoside 7b
a-
D-ribofuranoside 7e
To the solution of 6 (0.12 g, 0.69 mmol) and imidazole (0.08 g,
1.26 mmol) in CH2Cl2 (5 mL) TBDPSCl (0.17 g, 1.10 mmol) was added
at 0 ꢀC and the mixture was stirred for 1 h at room temperature.
Water (5 mL) was added and the solution was extracted with Et2O
(2ꢂ20 mL). Combined extracts were washed with brine and dried
over anhydrous MgSO4, filtered, and evaporated under vacuum.
Residue was purified by flash chromatography (CH2Cl2/MeOH 97:3
v/v) to give 7b (0.23 g, 0.54 mmol, 78% yield) as a colorless oil.
Magnetically stirred solution of 5 (0.5 g, 1.74 mmol) and
NiCl2$H2O (0.42 g, 1.76 mmol) in MeOH (15 mL) was cooled to 0 ꢀC
and NaBH4 (0.4 g, 10.44 mmol) was added in portions (CAUTION:
EXOTHERMIC REACTION). The mixture was stirred for 30 min,
volatiles were evaporated and the residue was redissolved in EtOAc
(20 mL) and filtered through a silica gel pad. Solids were washed
with EtOAc (3ꢂ20 mL), solvent was evaporated, and the crude
product was purified by flash chromatography to give pure 7e
(0.34 g, 1.25 mmol, 72% yield) as a colorless oil.
[
a]
20 þ21.1 (c 1.0, CH2Cl2).
D
1H NMR: 7.76e7.60 (m, 4H), 7.50e7.30 (m, 6H), 5.80 (d, J¼3.6,
1H), 4.52 (t, J¼4.4, 1H), 4.00e3.78 (m, 2H), 3.78e3.64 (m, 1H),
3.40e3.20 (m, 1H), 1.53 (s, 3H), 1.35 (s, 3H), 1.05 (s, 9H).
13C NMR: 135.9, 135.8, 133.6, 133.4, 130.0, 129.9, 127.9, 127.9,
112.1, 104.4, 82.2, 81.1, 62.9, 55.6, 27.1, 26.9, 26.6, 19.5.
[a
]
20 þ21.7 (c 1.0, CH2Cl2).
D
1H NMR: 5.79 (d, J¼4.0 Hz, 1H), 4.50 (t, J¼4.4 Hz, 1H), 4.45e4.33
(m, 1H), 4.33e4.14 (m, 1H), 3.83 (ddd, J¼9.4, 4.9, 3.0 Hz, 1H),
3.10e3.04 (m, 1H), 1.55 (s, 3H), 1.36 (s, 3H), 1.22 (s, 9H).
13C NMR: 178.6, 117.1, 112.2, 104.3, 80.6, 79.8, 63.0, 55.9, 39.1,
27.7, 27.4, 26.8, 26.6.
nmax(CH2Cl2) 3393, 3330, 3071, 2931, 1215, 1112, 1019, 704 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C24H33NO4SiþNa] ꢁ450.2063.
Found ꢁ450.2062.
nmax(KBr) 3380, 3315, 2980, 1722, 1182, 1014, 876 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C13H23NO5þNa] ꢁ296.1474.
Found ꢁ296.1485.
4.9. 1,2-O-Isopropylidene-3-amino-3-deoxy-5-O-trityl-a-D-ri-
bofuranoside 7c14
4.12. General procedure for the synthesis of secondary amines
10aec and 10d
To the solution of 6 (0.05 g, 0.26 mmol) and Et3N (63
mL,
0.44 mmol) in CH2Cl2 (2 mL) TrCl (0.09 g, 0.31 mmol) was added
and the mixture was stirred for 30 min at room temperature. Water
To the amine 7a (0.152 g, 0.5 mmol) or 7d (0.115 g, 0.5 mmol)
were added Ti(OiPr)4 (223
mL, 0.75 mmol) and appropriate

1936
T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
aldehyde (0.51 mmol) and the mixture was stirred at room tem-
perature for 1 h. The solution of NaBH4 (0.038 g, 1.0 mmol) in
MeOH (2 mL) was added dropwise and stirring was continued for
4.13. 1,2-O-Isopropylidene-5-O-tert-butyldimethylsilyl-a-D-
lyxofuranoside 1116
further 10 min. Reaction was quenched by addition of NH4F(aq)
,
To the solution of 2 (2.0 g, 10.58 mmol) and imidazole (1.0 g,
14.81 mmol) in CH2Cl2 (30 mL) TBDMSCl (0.17 g, 1.10 mmol) was
added and the mixture was stirred for 1 h at room temperature.
Water (30 mL) was added and the solution was extracted with Et2O
(3ꢂ30 mL). Combined extracts were washed with brine and dried
over anhydrous MgSO4, filtered, and evaporated under vacuum.
Residue was purified by flash chromatography (EtOAc/hexanes 2:8
v/v) to give 11 (3.07 g, 10.1 mmol, 96% yield) as a pale yellow oil.
diluted with water (5 mL), and the mixture was extracted
with CH2Cl2 (3ꢂ15 mL). Combined extracts were washed with
brine and dried over anhydrous MgSO4, filtered, and evaporated
under vacuum. Residue was purified by flash chromatography
(EtOAc/hexanes 1:9 v/v) to give respective secondary amine as
colorless oil.
20
20
4.12.1. 1,2-O-Isopropylidene-3-(4-methoxy)benzylamino-3-deoxy-5-
[
a
]
ꢁ11.8 (c 1.0, CHCl3), lit.16
[
a
]
ꢁ9.3 (c 1.0, CHCl3).
D
D
O-tert-butyldimethylsilyl-
a
-
D
-ribofuranoside 10a. Yield 86% (183 mg).
1H NMR: 5.96 (d, J¼3.6 Hz, 1H), 4.51 (d, J¼3.8 Hz, 1H), 4.41 (d,
J¼2.6 Hz, 1H), 4.33 (t, J¼2.5 Hz, 1H), 4.20e4.14 (m, 3H), 1.49 (s, 3H),
1.32 (s, 3H), 0.90 (s, 9H), 0.11 (s, 6H). 13C NMR: 111.7, 105.2, 85.8,
78.3, 77.3, 62.6, 27.0, 26.3, 25.9, 18.3, ꢁ5.3, ꢁ5.5.
[a
]
20 þ81.7 (c 1.0, CH2Cl2).
D
1H NMR: 7.28 (d, J¼9.0 Hz, 2H), 6.86 (d, J¼8.8 Hz, 2H), 5.76
(d, J¼3.2 Hz, 1H), 4.55 (t, J¼4.2 Hz, 1H), 3.98e3.82 (m, 2H),
3.80 (s, 3H), 3.79e3.60 (m, 3H), 3.08 (dd, J¼9.5, 4.7 Hz,
1H), 1.79 (s, 1H), 1.51 (s, 3H), 1.35 (s, 3H), 0.87 (s, 9H), 0.07e0.00
(m, 6H).
4.14. 1,2-O-Isopropylidene-3-deoxy-3-oxo-5-O-tert-butyldi-
methylsilyl-a-D
-ribofuranoside 1216
13C NMR: 158.9, 132.6, 129.4, 113.9, 111.9, 104.8, 81.4, 62.0, 59.8,
55.5, 51.8, 27.0, 26.8, 26.2, 18.6, ꢁ5.0, ꢁ5.1.
To the magnetically stirred solution of 9 (3.07 g, 10.1 mmol) in
CH2Cl2 (40 mL) PDC (2.66 g, 7.07 mmol) and freshly distilled Ac2O
(3.16 mL, 33.33 mmol) were added and the mixture was refluxed for
1 h. After TLC showed the disappearance of substrate, the reaction
was cooled to room temperature and solvents were evaporated.
The residue was dissolved in 100 mL of EtOAc, filtered through
a pad of silica gel. Solids were thoroughly washed with EtOAc and
the filtrate was evaporated under vacuum to give 12 (2.99 g,
nmax(CH2Cl2) 3340, 2929, 2064, 1882, 1513, 1249, 1018, 836 cmꢁ1
.
HR ESI-MS [MþþHþ] calcd for [C28H37NO5SiþHþ] ꢁ424.2519.
Found ꢁ424.2525.
4.12.2. 1,2-O-Isopropylidene-3-(cyclohexylmethyl)amino-3-deoxy-5-
O-tert-butyldimethylsilyl-a-D-ribofuranoside 10b. Yield 77% (154 mg).
[a
]
20 þ72.7 (c 1.0, CH2Cl2).
D
1H NMR: 5.77 (d, J¼3.8 Hz, 1H), 4.60 (t, J¼4.2 Hz, 1H), 3.92
(dd, J¼11.4, 2.0 Hz, 1H), 3.82e3.58 (m, 2H), 3.03 (dd, J¼9.3,
4.5 Hz, 1H), 2.59 (dd, J¼11.4, 7.0 Hz, 1H) 1.90e1.58 (m, 6H), 1.51
(s, 3H), 1.35 (s, 3H), 1.30e1.10 (m, 4H), 1.00e0.80 (m, 12H),
0.12e0.02 (m, 6H).
9.9 mmol, 98% yield) as yellowish crystals.
20
[
a
]
D
þ124.1 (c 1.0, CHCl3), lit.16
[a
]
20 þ114.0 (c 1.0, CHCl3).
D
Mp¼32e33 ꢀC, lit.16 mp 32 ꢀC.
1H NMR: 6.13 (d, J¼4.6 Hz, 1H), 4.40e4.32 (m, 1H), 4.28 (dd,
J¼4.4, 1.4 Hz, 1H), 3.94e3.96 (m, 2H), 1.45 (s, 6H), 0.86 (s, 9H), 0.06
(s, 3H), 0.03 (s, 3H).
13C NMR: 111.8, 104.7, 81.4, 78.1, 61.9, 60.8, 55.3, 38.6, 31.7, 31.5,
26.9, 26.7, 26.3, 26.2, 18.6, ꢁ5.0, ꢁ5.2.
13C NMR: 211.3, 114.3, 103.9, 81.9, 77.3, 6.12, 27.9, 27.4, 25.9,
18.3, ꢁ5.3, ꢁ5.5.
nmax(CH2Cl2) 3300, 2925, 1252, 1215, 1094, 1018, 835 cmꢁ1
.
HR ESI-MS [MþþHþ] calcd for [C21H41NO4SiþHþ] ꢁ400.2883.
Found ꢁ400.2891.
4.15. 1,2-O-Isopropylidene-3-benzylamino-3-deoxy-5-O-tert-
butyldimethylsilyl-a-D
-ribofuranoside 10d15
4.12.3. 1,2-O-Isopropylidene-3-isopropylamino-3-deoxy-5-O-tert-
butyldimethylsilyl-
a
-
D
-ribofuranoside 10c. Yield 75% (129 mg).
Magnetically stirred solution of 12 (0.3 g, 1.0 mmol) in 2,2,2-
trifluoroethanol (2 mL) was warmed to 37 ꢀC and, after 5 min,
benzylamine (0.11 mL, 1.01 mmol) was added dropwise. The mix-
ture was stirred at this temperature for 5 min, filtered through silica
gel pad, and solids were washed twice with EtOAc (10 mL). Volatiles
were evaporated and the residue was purified by flash chroma-
tography (EtOAc/hexanes 1:9 v/v) to give 10d (0.33 g, 0.84 mmol,
[a
]
20 þ77.8 (c 1.0, CH2Cl2).
D
1H NMR: 5.77 (d, J¼4.0 Hz, 1H), 4.56 (t, J¼4.2 Hz, 1H), 3.91 (dd,
J¼11.6, 1.8 Hz, 1H), 3.82e3.58 (m, 2H), 3.18 (dd, J¼9.4, 4.8 Hz, 1H),
2.92 (septet, J¼6.1 Hz, 1H), 1.60 (s, 1H), 1.52 (s, 3H), 1.34 (s, 3H), 1.06
(dd, J¼8.6, 6.1 Hz, 6H), 0.89 (s, 9H), 0.06 (s, 6H).
13C NMR: 111.8, 104.6, 81.6, 78.6, 61.5, 57.7, 47.3, 26.9, 26.7, 26.1,
24.2, 23.1, 18.6, ꢁ5.0, ꢁ5.2.
20
25
84% yield) as a colorless oil. [
a]
þ93.6 (c 1.0, CH2Cl2), lit.15
[a]
D
D
nmax(CH2Cl2) 3324, 2957, 1253, 1090, 1021, 837 cmꢁ1
.
þ96.0 (c 1.0, CHCl3).
HR ESI-MS [MþþNa] calcd for [C17H35NO4SiþNa] ꢁ368.2233.
Found ꢁ368.2231.
1H NMR: 7.42e7.20 (m, 5H), 5.76 (d, J¼3.8 Hz, 1H), 4.56 (t,
J¼4.2 Hz,1H), 4.02e3.84 (m, 2H), 3.84e3.64 (m, 2H), 3.10 (dd, J¼9.6,
4.6 Hz,1H),1.93 (s,1H),1.52 (s, 3H),1.35 (s, 3H), 0.87 (s, 9H), 0.05 (m,
6H).
4.12.4. 1,2-O-Isopropylidene-3-benzylamino-3-deoxy-5-O-n-propyl-
a
-
D
-ribofuranoside 10e. Yield 64% (102 mg).
13C NMR: 140.4, 128.5, 128.3, 127.2, 111.6, 104.8, 81.3, 77.8, 62.0,
60.0, 52.3, 27.0, 26.7, 26.2, 18.6, ꢁ5.0, ꢁ5.1.
[
a
]
20 þ84.1 (c 1.0, CH2Cl2).
D
1H NMR: 7.42e7.18 (m, 5H), 5.80 (d, J¼3.8 Hz, 1H), 4.55 (t,
J¼4.2 Hz, 1H), 3.96 (d, J¼13.6 Hz, 1H), 3.78e3.68 (m, 1H), 3.60e3.48
(m, 1H), 3.48e3.28 (m, 2H), 3.01 (dd, J¼10.0, 4.6 Hz, 1H), 1.86 (s,
1H), 1.57 (m, J¼7.1 Hz, 2H), 1.52 (s, 3H), 1.35 (s, 3H), 0.88 (t,
J¼7.4 Hz, 3H).
4.16. General procedure for the synthesis of ligands L1eL5
The amine 7 (0.5 mmol) was placed in the Schlenk tube and
dissolved in THF (1 mL). Subsequently, Et3N (140
mL, 1 mmol)
13C NMR: 140.4, 128.5, 128.3, 127.2, 111.9, 104.8, 79.9, 77.4, 73.6,
69.6, 60.7, 52.3, 26.9, 26.7, 22.9, 10.7.
was added, the mixture was cooled to 0 ꢀC and 0.35 M solution
of (S)-1,10-binaphthyl-2,20-diyl phosphorochloridate (1.57 mL,
0.55 mmol) in toluene was added dropwise. The mixture was
stirred at room temperature for 4 h, diluted with Et2O (10 mL),
filtered through silica gel pad, and solids were washed twice with
Et2O (20 mL). Volatiles were evaporated and the residue was
nmax(CH2Cl2) 3339, 3029, 2934, 1455, 1251, 1215, 1093,
1014 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C18H27NO4þNa] ꢁ344.1838.
Found ꢁ344.1840.

T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
1937
purified by flash chromatography (EtOAc/hexanes 1:9 v/v) to give
ligands L1eL5 as white solids.
nmax(KBr) 3323, 3056, 2980, 1231, 1006, 945, 822 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C47H40NO6PþNa] ꢁ768.2491.
Found ꢁ768.2471.
4.16.1. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-ylamino)-3-deoxy-5-O-tert-butyldimethylsilyl-
a
-
4.16.5. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
D
-ribofuranoside L1a. Yield 54% (166 mg).
dioxaphosphepin-4-ylamino)-3-deoxy-5-O-n-propyl-a-D-ribofurano-
side L4. Yield 57% (155 mg).
[
a]
20 þ321.5 (c 1.0, CHCl3).
D
Mp¼170e171 ꢀC.
[
a
]
20 þ350.1 (c 1.0, CHCl3).
D
1H NMR: 8.10e7.76 (m, 4H), 7.58e7.26 (m, 8H), 5.82 (d, J¼3.8 Hz,
Mp¼82e83 ꢀC.
1H), 4.63 (t, J¼4.2 Hz, 1H), 4.05e3.46 (m, 5H), 1.43 (s, 6H), 0.93 (s,
9H), 0.13 (s, 3H), 0.11 (s, 3H).
1H NMR: 8.04e7.84 (m, 4H), 7.34e7.56 (m, 6H), 7.34e7.20 (m,
2H), 5.85 (d, J¼3.6 Hz, 1H), 4.63 (t, J¼3.6 Hz, 1H), 3.90e3.70 (m, 3H),
3.67e3.38 (m, 4H),1.66 (m, J¼7.1 Hz, 2H),1.43 (d, J¼4.0 Hz, 6H), 0.96
(t, J¼7.5 Hz, 3H).
13C NMR: 132.9, 131.6, 131.3, 130.5, 129.5, 128.6, 128.5, 127.2,
127.1, 126.4, 126.3, 125.1, 125.0, 123.1, 121.7, 112.2, 104.3, 81.6, 81.3,
80.3, 60.7, 53.4, 52.8, 26.9, 26.8, 26.3, ꢁ5.0, ꢁ4.9.
13C NMR: 132.8, 131.5, 131.3, 130.5, 129.5, 128.5, 127.6, 127.2,
127.1, 126.4, 126.3, 125.2, 125.0, 124.5, 124.2, 123.0, 121.8, 119.2,
118.0, 80.0, 73.7, 69.2, 68.3, 54.2, 53.6, 26.8, 26.7, 26.3, 25.8, 23.0,
22.8, 10.8, 10.6.
nmax(KBr) 3323, 3056, 2980, 1231, 1006, 945, 822 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C34H40NO6PSiþNa] ꢁ640.2260.
Found ꢁ640.2230.
nmax(KBr) 3058, 2929, 1212, 1065, 1023, 963, 816 cmꢁ1
.
4.16.2. 1,2-O-Isopropylidene-3-((11bR)-dinaphtho[2,1-d:10,20-f][1,3,2]
HR ESI-MS [MþþNa] calcd for [C31H32NO6PþNa] ꢁ568.1865.
Found ꢁ568.1862.
dioxaphosphepin-4-ylamino)-3-deoxy-5-O-tert-butyldimethylsilyl-
a-
D
-ribofuranoside L1b. (R)-1,10-Binaphthyl-2,20-diyl phosphoro-
chloridate was used.
Yield 51% (157 mg).
4.16.6. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-ylamino)-3-deoxy-5-O-pivaloyl-a-D-ribofurano-
[
a]
20 ꢁ182.0 (c 1.0, CHCl3).
side L5. Yield 53% (156 mg).
D
31P NMR: 148.74.
[
a
]
20 þ409.7 (c 1.0, CHCl3).
D
1H NMR: 8.02e7.84 (m, 4H), 7.58e7.18 (m, 8H), 5.70 (d, J¼3.6 Hz,
1H), 4.40 (t, J¼3.9 Hz, 1H), 4.16e3.98 (m, 1H), 3.84 (dd, J¼11.8,
3.4 Hz, 1H), 7.78e3.52 (m, 2H), 1.46 (s, 3H), 1.31 (s, 3H), 0.83 (s 9H),
0.06 to ꢁ0.03 (m, 6H).
Mp¼168e169 ꢀC.
31P NMR: 151.35.
1H NMR: 8.06e7.80 (m, 4H), 7.60e7.18 (m, 8H), 5.81 (d, J¼3.6 Hz,
1H), 4.65 (t, J¼3.7 Hz, 1H), 4.47 (dd, J¼12.4, 2.2 Hz, 1H), 4.17 (dd,
J¼12.4, 4.8 Hz, 1H), 3.96e3.78 (m, 1H), 3.78e3.52 (m, 2H), 1.44 (d,
J¼5.6 Hz, 6H), 1.24 (s, 9H).
13C NMR: 149.4, 147.7, 132.9, 131.6, 131.1, 130.5, 129.7, 128.5, 128.5,
127.2, 127.2, 126.4, 126.4, 125.2, 1251, 122.1, 121.9, 121.9, 104.2, 82.3,
82.2, 80.4, 80.3, 61.0, 53.1, 52.7, 26.8, 26.6, 26.2, 18.6, 0.20, ꢁ5.13,
13C NMR: 178.5, 149.1, 147.3, 132.9, 131.7, 131.3, 130.6, 129.6,
128.6,128.5,127.2,127.1,126.4,126.4,125.2,125.1,122.8,121.9,112.5,
104.2, 79.9, 78.4, 78.3, 62.5, 54.9, 54.3, 39.1, 27.5, 26.8, 26.7.
ꢁ5.14. nmax(KBr) 3368, 3058, 2927, 1253, 1232, 1021, 951, 822 cmꢁ1
.
HR ESI-MS [MþþH] calcd for [C34H40NO6PSiþHþ] ꢁ618.2441.
Found ꢁ618.2443.
nmax(KBr) 3325, 3052, 2979, 1734, 1233, 1167, 1012, 951 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C33H34NO7PþNa] ꢁ610.1971.
Found ꢁ610.1979.
4.16.3. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-ylamino)-3-deoxy-5-O-tert-butyldiphenylsilyl-a-
D
-ribofuranoside L2. Yield 85% (315 mg).
4.17. General procedure for the synthesis of ligands L6eL10
[
a
]
20 þ262.5 (c 1.0, CHCl3).
D
31P NMR: 152.42.
The amine 10 (0.5 mmol) was placed in the Schlenk tube and
dissolved in THF (1 mL). The mixture was cooled to ꢁ78 ꢀC and n-
1H NMR: 8.04e7.82 (m, 4H), 7.82e7.68 (m, 4H), 7.52e7.33 (m,
12H), 7.33e7.18 (m, 2H), 5.86 (d, J¼3.8 Hz,1H), 4.68 (t, J¼4.1 Hz,1H),
4.12e3.92 (m, 2H), 3.85 (dd, J¼11.9, 3.1 Hz, 1H), 3.78e3.64 (m, 1H),
3.85 (dd, J¼11.9, 3.1 Hz, 1H), 3.78e3.64 (m, 1H), 3.66 (dd, J¼11.9,
3.9 Hz, 1H), 1.43 (s, 6H), 1.08 (s, 9H).
BuLi (2.2 M in toluene, 227 mL, 0.5 mL) was added dropwise. After
10 min, the reaction mixture was allowed to warm up to 0 ꢀC and
0.35
M
solution of (S)-1,10-binaphthyl-2,20-diyl phosphoro-
chloridate (1.57 mL, 0.55 mmol) in toluene was added dropwise.
The mixture was stirred at room temperature for 5 h, diluted with
Et2O (10 mL), filtered through silica gel pad, and solids were
washed twice with Et2O (20 mL). Volatiles were evaporated and the
residue was purified by flash chromatography (EtOAc/hexanes 1:9
v/v) to give ligands L6eL10 as white solids.
13C NMR: 149.3, 135.9, 133.7, 132.9, 131.7, 131.3, 130.5, 129.9,
129.8, 129.5, 128.7, 128.4, 128.0, 127.9, 127.2, 127.1, 126.4, 126.3,
123.1, 121.9, 112.3, 104.3, 81.4, 81.2, 80.5, 80.4, 61.2, 53.5, 52.9, 27.1,
26.9, 26.8, 19.6. nmax(KBr) 3352, 3051, 2929, 1233, 1113, 1020, 951,
822 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C44H44NO6PSiþNa] ꢁ764.2573.
Found ꢁ764.2589.
4.17.1. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-yl(4-methoxybenzyl)amino)-3-deoxy-5-O-tert-
4.16.4. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-ylamino)-3-deoxy-5-O-trityl-
L3. Yield 80% (298 mg).
butyldimethylsilyl-a-D-ribofuranoside L6. Yield 36% (133 mg).
a
-
D
-ribofuranoside
[a
]
20 þ215.4 (c 1.0, CHCl3).
D
31P NMR:
d
144.03.
[
a]
20 þ246.0 (c 1.0, CHCl3).
1H NMR: 8.06e7.76 (m, 4H), 7.66e7.50 (m, 1H), 7.48e7.30 (m,
4H), 7.30e7.10 (m, 5H), 6.84e6.70 (m, 2H), 5.61 (d, J¼4.0 Hz, 1H),
4.62e4.40 (m, 1H), 4.15e3.82 (m, 4H), 3.75 (s, 3H), 3.63 (dd, J¼14.9,
1.8 Hz, 1H), 3.49 (ddd, J¼13.9, 10.3, 4.4 Hz, 1H), 1.67 (s, 3H), 1.35 (s,
3H), 0.96 (s, 9H), 0.16 (s, 3H), 0.09 (s, 3H).
D
31P NMR: 140.78.
1H NMR: 8.04e7.80 (m, 4H), 7.60e7.00 (m, 23H), 5.36 (d,
J¼3.6 Hz, 1H), 4.70e4.50 (m, 1H), 4.10e4.30 (m, 1H), 3.84 (m, 1H),
3.2e3.00 (m, 1H), 2.54 (d, J¼11.8 Hz, 1H), 2.4 (t, J¼3.6 Hz, 1H), 1.36
(s, 3H), 0.97 (s, 3H).
13C NMR: 158.96, 150.39, 149.70, 133.05, 132.81, 131.62, 131.06,
130.81, 130.53, 130.19, 130.06, 128.51, 128.39, 127.28, 127.15, 126.28,
125.05, 124.73, 122.27, 113.69, 112.33, 104.07, 78.85, 60.41, 55.41,
50.38, 29.89, 26.86, 26.23, 18.63, ꢁ4.82, ꢁ5.05.
13C NMR: 147.8, 146.3, 133.1, 132.8, 131.7, 131.8, 130.6, 130.1, 129.1,
128.6, 128.5, 128.0, 127.3, 127.2, 126.7, 126.4, 125.2, 125.1, 122.2,
121.8, 111.3, 103.7, 79.9, 79.8, 70.7, 62.8, 62.7, 56.8, 26.9, 26.0, 21.3.

1938
T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
nmax(KBr) 3060, 2927, 1511, 1251, 1228, 1021, 824 cmꢁ1
.
31P NMR: 139.79.
HR ESI-MS [MþþNa] calcd for [C42H48NO7PSiþNa] ꢁ760.2835.
Found ꢁ760.2821.
1H NMR: 8.04e7.84 (m, 4H), 7.70e7.54 (m, 2H), 7.48e7.32 (m,
4H), 7.30e7.26 (m, 1H), 7.26e7.14 (m, 6H), 5.78 (d, J¼4.0 Hz, 1H),
4.90e4.60 (m, 2H), 4.22 (dd, J¼14.7, 1.7 Hz, 1H), 3.86 (dd, J¼12.0,
1.6 Hz, 1H), 3.58 (dd, J¼12.0, 4.4 Hz, 1H), 3.34e3.08 (m, 2H), 1.70 (s,
3H), 1.53 (s, 3H), 0.82 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).
13C NMR: 150.5, 150.4, 149.9, 138.1, 133.0, 132.7, 131.6, 131.0,
130.4, 130.4, 128.7, 128.5, 127.5, 127.3, 127.2, 126.3, 125.0, 124.8,
122.5, 112.8, 104.3, 77.0, 76.0, 61.5, 60.3, 60.0, 49.7, 27.5, 27.0, 26.2,
18.7, ꢁ5.0.
4.17.2. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-yl) (cyclohexylmethyl)amino-3-deoxy-5-O-tert-
butyldimethylsilyl-a-D-ribofuranoside L7. Yield 45% (161 mg).
[
a
]
20 þ260.2 (c 1.0, CHCl3).
D
Mp¼102e103 ꢀC.
31P NMR: 147.81.
1H NMR: 8.00e7.82 (m, 4H), 7.51 (dd, J¼8.8, 0.8 Hz, 1H),
7.46e7.28 (m, 5H), 7.28e7.16 (m, 2H), 5.76 (d, J¼3.8 Hz, 1H),
4.66e4.25 (m, 1H), 4.50 (t, J¼4.2 Hz, 1H), 4.20e3.92 (m, 2H), 3.47
(ddd, J¼13.4,10.2, 4.4 Hz,1H), 2.77e2.54 (m, 2H), 1.90e1.68 (m, 1H),
1.65 (s, 3H), 1.60e1.56 (m, 3H), 1.41 (s, 4H), 1.38e1.10 (m, 2H), 0.96
(s, 9H), 0.18 (s, 3H), 0.14 (s, 3H).
nmax(KBr) 3059, 2928, 1254, 1230, 1023, 947, 821 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C41H46NO6SiPþNa] ꢁ730.2729.
Found ꢁ730.2704.
4.17.6. 1,2-O-Isopropylidene-3-(11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-yl(benzyl amino)-3-deoxy-5-O-n-propyl-a-D-ri-
13C NMR: 149.8, 133.1, 133.0, 132.8, 131.5, 130.7, 130.5, 129.8,
128.5, 128.3, 127.3, 126.2, 126.1, 125.0, 124.6, 122.7, 122.4, 122.3,
122.0, 112.5, 104.2, 79.3, 78.3, 77.9, 77.3, 61.0, 60.6, 60.2, 53.8, 37.1,
30.9, 30.4, 26.9, 26.9, 26.6, 26.1, 26.2, 26.0, 18.6, ꢁ4.8, ꢁ5.0.
bofuranoside L10. Yield 41% (130 mg).
20
[
a
]
D
þ165.4 (c 1.0, CHCl3).
Mp¼104e105 ꢀC.
31P NMR: 143.61.
nmax(KBr) 3056, 2926, 1254, 1230, 1021, 947, 822 cmꢁ1
.
1H NMR: 8.06e7.89 (m, 2H), 7.89e7.78 (m, 2H), 7.64e7.54 (m,
1H), 7.48e7.14 (m, 12H), 5.65 (d, J¼4.2 Hz, 1H), 4.70e4.54 (m, 1H),
4.16e3.96 (m, 2H), 3.88e3.58 (m, 3H), 3.58e3.34 (m, 3H), 1.86e1.52
(m, 5H), 1.36 (s, 3H), 0.98 (t, J¼7.0 Hz, 3H).
HR ESI-MS [MþþH] calcd for [C41H52NO6PSiþHþ] ꢁ714.3380.
Found ꢁ714.3376.
4.17.3. 1,2-O-Isopropylidene-3-((11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-yl(isopropyl)amino)-3-deoxy-5-O-tert-butyldi-
13C NMR: 150.4, 150.2, 149.6, 139.0, 133.0, 132.8, 131.6, 130.8,
130.6, 130.2, 128.8, 128.5, 128.4, 127.5, 127.3, 126.3, 125.1, 124.8,
122.3, 122.1, 112.4, 104.1, 78.6, 76.2, 75.7, 73.7, 68.1, 61.4, 61.1, 50.9,
26.8, 23.0, 10.9.
methylsilyl-a-D-ribofuranoside L8. Yield 42% (139 mg).
[a
]
20 þ350.8 (c 1.0, CHCl3).
D
31P NMR: 144.09.
nmax(KBr) 3058, 2927, 1229, 1214, 1024, 947, 822 cmꢁ1
.
1H NMR: 8.00e7.80 (m, 4H), 7.54e7.16 (m, 8H), 5.86 (d, J¼4.2 Hz,
1H), 4.62e4.48 (m, 1H), 4.44 (t, J¼4.5 Hz, 1H), 4.16e3.90 (m, 2H),
3.64 (ddd, J¼12.6, 10.2, 5.1 Hz, 1H), 3.54e3.38 (m, 1H), 1.68 (s, 3H),
1.46 (s, 3H), 1.05 (d, J¼6.6 Hz, 2H), 0.97 (d, J¼6.6 Hz, 2H), 0.94 (s,
9H), 0.14e0.00 (m, 6H).
HR ESI-MS [MþþNa] calcd for [C38H38NO6PþNa] ꢁ658.2324.
Found ꢁ658.2335.
4.18. General procedure for the addition of diethylzinc to
trans-chalcone
13C NMR: 151.2, 151.0, 150.1, 133.0, 131.5, 130.6, 130.5, 129.6,
128.5, 128.4, 127.5, 127.3, 126.2, 126.0, 124.9, 124.5, 122.5, 121.4,
112.5, 104.8, 79.6, 78.9, 78.3, 60.0, 55.3, 55.0, 45.9, 27.2, 26.9, 26.8,
26.2, 23.2, 21.7, 18.6, ꢁ4.8, ꢁ5.2.
The ligand Lnx (0.01 mmol) and Cu(OTf)2 (1.6 mg, 0.005 mmol)
were placed in Schlenk tube and dissolved in toluene (5 mL). After
1 h stirring trans-chalcone (104 mg, 0.5 mmol) was added, the
solution was cooled to ꢁ20 ꢀC and 1.1 M solution of Et2Zn in toluene
nmax(KBr) 3056, 2928, 1254, 1225, 1028, 948, 822 cmꢁ1
.
HR ESI-MS [MþþNa] calcd for [C37H46NO6PSiþNa] ꢁ682.2729.
Found ꢁ682.2738.
(523 mL, 0.575 mmol) was added.
The reaction was stirred for the time indicated in Table 1 or 2
and quenched with the addition of saturated NH4Faq (5 mL). The
mixture was extracted with Et2O (2ꢂ20 mL). Combined extracts
were washed with brine and dried over anhydrous MgSO4, filtered,
and evaporated under vacuum. Residue was purified by flash
chromatography (EtOAc/hexanes 5:95 v/v) to give 9.
4.17.4. 1,2-O-Isopropylidene-3-(11bS)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-yl(benzyl amino)-3-deoxy-5-O-tert-butyldime-
thylsilyl-a-D-ribofuranoside L9a. Yield 47% (166 mg).
[
a
]
20 þ275.5 (c 1.0, CHCl3).
D
Mp¼104e105 ꢀC.
31P NMR: 143.81.
4.18.1. (R)-1,3-Diphenylpentan-1-one. 1H NMR:
d 8.00e7.70 (m,
1H NMR: 8.06e7.76 (m, 1H), 7.66e7.54 (m, 1H), 7.50e7.14 (m,
12 H), 5.61 (d, J¼3.8 Hz, 1H), 4.60e4.42 (m, 1H), 4.20e4.02 (m, 1H),
4.02e3.80 (m, 3H), 3.80e3.62 (m, 1H), 3.52 (ddd, J¼13.6, 10.3,
4.4 Hz, 1H), 1.68 (s, 3H), 1.35 (s, 3H), 0.16 (s, 3H), 0.09 (s, 3H).
13C NMR: 156.0, 150.4, 150.3, 149.6, 139.1, 133.0, 133.0, 132.8,
132.7, 131.6, 130.8, 130.5, 130.2, 128.8, 128.5, 128.4, 128.3, 127.4,
127.3, 127.2, 126.3, 126.2, 125.1, 124.7, 122.4, 122.3, 122.2, 112.4,
104.0, 78.9, 60.8, 60.4, 51.0, 51.0, 26.9, 26.8, 26.2, 18.6, ꢁ4.8, ꢁ5.0.
2H), 7.70e7.00 (m, 8H), 3.40e3.05 (m, 3H), 2.00e1.45 (m, 2H), 0.80
(t, 3H).
13C NMR:
d 199.2, 144.6, 137.2, 132.9, 128.5, 128.4, 128.0, 127.6,
126.3, 45.6, 43.0, 29.2, 12.1.
Daicel Chiralcel OD-H, hexane/iPrOH¼95:5,flow rate¼1.0 mL/
min, detected at 254 nm. tR¼16.5 min for enantiomer (S), and
tR¼19.2 min for enantiomer (R).
nmax(KBr) 3060, 2927, 1254, 1230, 1022, 947, 822 cmꢁ1
.
4.19. General procedure for the addition of diethylzinc to 2-
cyclohexenone
HR ESI-MS [MþþNa] calcd for [C41H46NO6SiPþNa] ꢁ730.2729.
Found ꢁ730.2754.
The ligand Lnx (0.01 mmol) and Cu(OTf)2 (1.6 mg, 0.005 mmol)
were placed in Schlenk tube and dissolved in toluene (5 mL). After
4.17.5. 1,2-O-Isopropylidene-3-(11bR)-dinaphtho[2,1-d:10,20-f][1,3,2]
dioxaphosphepin-4-yl(benzyl amino)-3-deoxy-5-O-tert-butyldime-
1 h stirring 2-cyclohexenone (48
mL, 0.5 mmol) was added, the
thylsilyl-
a-D
-ribofuranoside L9b. (R)-1,10-Binaphthyl-2,20-diyl phos-
solution was cooled to ꢁ20 ꢀC and 1.1 M solution of Et2Zn in toluene
phorochloridate was used.
Yield 52% (184 mg).
(523 mL, 0.575 mmol) was added.
The reaction was stirred for the time indicated in Table 3 and
quenched with the addition of saturated NH4Faq (5 mL). The
[a
]
20 ꢁ140.2 (c 1.0, CHCl3).
D

T. Bauer et al. / Tetrahedron 69 (2013) 1930e1939
1939
4. Raluy, E.; Pamies, O.; Dieguez, M.; Rosset, S.; Alexakis, A. Tetrahedron: Asym-
metry 2009, 20, 1930.
mixture was extracted with Et2O (2ꢂ20 mL). Combined extracts
were washed with brine and dried over anhydrous MgSO4, filtered,
and evaporated under vacuum. Residue was purified by flash
chromatography (EtOAc/hexanes 5:95 v/v) to give 14.
5. Zhao, Q.-L.; Wang, L.-L.; Xing, A.-P. Tetrahedron: Asymmetry 2010, 21, 2993.
ꢂ
ꢀ
ꢀ
ꢂ
6. Moravcova, J.; Capkova, J.; Stanek, J. Carbohydr. Res. 1994, 263, 61.
7. Shie, J.-J.; Fang, J.-M.; Wang, S.-J.; Tsai, K.-C.; Cheng, Y.-S.; Yang, A.-S.; Hsiao,
S.-C.; Su, C.-Y.; Wong, C. H. J. Am. Chem. Soc. 2007, 129, 11892.
8. Hall, A.; Bailey, P. D.; Rees, D. C.; Rosair, G. M.; Wightman, R. H. J. Chem. Soc.,
Perkin Trans. 1 2000, 329.
4.19.1. (S)-3-Ethylcyclohexanone. 1H NMR:
d 2.52e2.14 (m, 3H),
9. Caddick, S.; Judd, D. B.; Lewis, A. K. de; Reich, M. T.; Williams, M. R. V.
Tetrahedron 2003, 59, 5417.
2.14e1.82 (m, 3H), 1.82e1.50 (m, 2H), 1.15e1.20 (m, 3H), 1.00e0.75
(t, 3H).
10. For examples of copper-catalyzed conjugate additions with dialkyl zinc re-
agents see: (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem., Int.
Ed. 1996, 35, 2374; (b) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de
Vries, A. H. M. Angew. Chem., Int. Ed. 1997, 36, 2620 For examples of copper-
catalyzed conjugate additions with trialkyl aluminum reagents see: (c) Alex-
akis, A.; Albrow, V.; Biswas, K.; d’Augustin, M.; Prieto, O.; Woodward, S. Chem.
Commun. 2005, 2843; (d) Alexakis, A.; Polet, D. Tetrahedron Lett. 2005, 46, 1529.
11. Bhattacharyya, S. J. Chem. Soc., Perkin Trans. 1 1995, 1845.
12. Tajbakhsh, M.; Hosseinzadeh, R.; Alinezhad, H.; Ghahari, S.; Heydari, A.;
Khaksar, S. Synthesis 2011, 490.
13C NMR:
d 212.4, 48.1, 41.7, 41.0, 31.1, 29.5, 25.5, 11.4.
Supelco
b
-dex 225 column at 105 ꢀC constant. tR¼8.7 min for
enantiomer (S), and tR¼9.3 min for enantiomer (R).
Acknowledgements
This research was financed by the European Union within the
European Regional Development Fund, Project POIG.01.01.02.-14-
102/09.
13. Abboud, K. A.; Parr, I. B.; Horenstein, B. A. Acta Crystallogr. Sect. C 1997, 53, 245.
14. Postel, D.; Nhien, A. N. V.; Pillon, M.; Villa, P.; Ronco, G. Tetrahedron Lett. 2000,
41, 6403.
ꢀ
15. Sanchez-Eleuterio, A.; Quintero, L.; Sartillo-Piscil, F. J. Org. Chem. 2011, 76, 5466.
References and notes
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Hoboken, NJ, 2010; p 439.
2. For review see: Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
ꢀ
ꢁ
3. Mata, Y. ,; Dieguez, M.; Pamies, O.; Biswas, K.; Woodward, S. Tetrahedron:
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21. Weiss, J. J. Org. Chem. 1966, 31, 3404.