New chiral thiols and C2-symmetrical disulfides of Cinchona alkaloids: ligands for the asymmetric Henry reaction catalyzed by CuII complexes

Article abstract of DOI:10.1016/j.tetasy.2009.07.020

Seven Cinchona alkaloids were reacted with thioacetic acid and Bu₃P/diethyl diazadicarboxylate in THF at 0-25 °C to give the corresponding thiolacetates with complete inversion of configuration at the substitution center. The thus obtained chir

Full text of DOI:10.1016/j.tetasy.2009.07.020

Tetrahedron: Asymmetry 20 (2009) 1992–1998
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New chiral thiols and C2-symmetrical disulfides of Cinchona alkaloids:
ligands for the asymmetric Henry reaction catalyzed by CuII complexes
*
_
´
Mariola Zielinska-Błajet, Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Seven Cinchona alkaloids were reacted with thioacetic acid and Bu3P/diethyl diazadicarboxylate in THF at
0–25 °C to give the corresponding thiolacetates with complete inversion of configuration at the substitu-
tion center. The thus obtained chiral thiolesters were converted into thiols and these compounds were
oxidized to the respective disulfides of C2-symmetry. Both C-9 thioles and disulfides were tested as chiral
ligands in the Cu-catalyzed asymmetric Henry reaction. When the thiol derivatives of an 8,9-like config-
uration were applied in the reaction of benzaldehyde and nitromethane, the obtained nitroaldol was of
the same absolute configuration as the catalyst and the observed enantioselectivity was up to 83% ee.
These ligands gave higher ees than the corresponding thioethers, disulfides, and thioles of 8,9-unlike con-
figuration. The results obtained are in agreement with the proposed transition-state model involving
nucleophilic attack of a deprotonated nitromethane directed preferably at one side of the O-complexed
benzaldehyde.
Received 26 June 2009
Accepted 2 July 2009
Available online 10 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
disulfides as prospective chiral ligands in the Cu(II) catalyzed nitro-
aldol reaction.7
The most noteworthy achievements in asymmetric synthesis
can be ascribed to the application of privileged catalysts, effective
in numerous mechanistically different, enantioselective transfor-
mations.1 Among these successful catalysts are derivatives of
Cinchona alkaloids. In some cases, the C2-symmetry of such chiral
ligands plays an important role in their effectiveness, as is well
documented for the Sharpless dihydroxylations, Michael additions,
and other asymmetric processes.2 Recently, we have synthesized a
series of 9-phenylsulfenyl- and 9-phenylselenyl-derivatives of
Cinchona alkaloids and demonstrated their catalytic performance
in the enantioselective Tsuji-Trost allylic alkylation.3 Both types
of derivatives constitute chiral bifunctional chalcogen/nitrogen-
donating ligands. The ligands of this sort have been successfully
used in various transition-metal catalyzed stereoselective reac-
tions.4 However, their chiral complexes with copper have hardly
been tested5 and their use as S/N-donating ligands in the enantio-
selective copper-catalyzed nitroaldol (Henry) reaction have not yet
been described. Moreover, only a few derivatives of Cinchona alka-
loids have already been described as catalysts for the asymmetric
Henry reaction.6
2. Results and discussion
2.1. Ligands synthesis
Commercially available Cinchona alkaloids, namely cinchoni-
dine (CD), quinine (QN), and quinidine (QD), the respective dihydro
derivatives (DHQN/DHQD), and their synthetic C-9-epi-configured
analogues (epi-QN/epi-QD)9 were used as starting materials
(Fig. 1). In order to transform these secondary alcohols into thiols
we attempted the nucleophilic substitution of the corresponding
mesylates with thiocyanate, thiourea, or thioacetate sodium salt.
All these efforts failed and finally, the native and epi-alkaloids
1a–g were directly converted into the corresponding thiolesters
2a–g using a Mitsunobu reaction.8 The mixtures of 1a–g and thio-
acetic acid were treated with the preformed adduct of Ph3P and
DEAD in THF at 0 °C and then left at room temperature for 3–
7 days. The resulting thioacetates 2a–g were isolated by chroma-
tography in 42–59% yield along with the recovered alkaloids (ca.
20–30%) and a small amount of unidentified compounds with the
rearranged alkaloid skeleton. In all cases the thiolesters were ob-
tained as a single diastereomer and inversion of configuration at
the stereogenic center C-9 of alkaloids was observed. The results
are summarized in Scheme 1 and Table 1.
Herein we report the synthesis of unknown Cinchona alkaloid
C-9 thiols, which were subsequently oxidized to the corresponding
dimeric disulfides of C2 symmetry. We examined both thiols and
In the next step, we reduced the thiolesters obtained with
lithium aluminum hydride to obtain the required thiols 3a–g in
* Corresponding author. Tel.: +48 71 320 2464; fax: +48 71 328 4064.
_
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skarzewski).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.020

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´
1993
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 20 (2009) 1992–1998
R1
2.2. Catalytic asymmetric Henry reaction
R1
R
N
R
N
With the aforementioned set of chiral thiols and disulfides in
hand, we examined their catalytic performance in the nitroaldol
reaction. The model reaction between benzaldehyde and nitro-
methane was carried out in the presence of 12 mol % of chiral li-
gand and 10 mol % of hydrated copper acetate (Scheme 2). The
screening experiments are summarized in Table 3. We tested a ser-
ies of solvents (dichloromethane, acetonitrile, isopropanol, etc.)
and i-PrOH was chosen as the most appropriate one. Moreover,
we noted that in the absence of a ligand, the expected nitroaldol
product did not form at all. Thus, all the ligands formed complexes
that catalyzed the reaction giving nitroaldol in good yield. Gener-
ally, higher enantioselectivities were obtained for the thiols of
8,9-like configuration [e.g., (8S,9S)] 3a–d (43– 83% ee) in compari-
son to the respective disulfides 4a–d (34–52% ee). However, the
thiols of 8,9-unlike configuration, obtained from epi-quinine 3f
and epi-quinidine 3g performed worse (14% and 17% ee, respec-
tively). The best result was observed for 3b (9-HS-epi-QN) in
i-PrOH (70% yield and 83% ee), while for dichloromethane or aceto-
nitrile, the yield and selectivity were significantly less (13–18%,
43–44% ee). Moreover, the addition of 5 mol % of Et3N lowered
the enantioselectivity from 83% to 28%. We tested the reaction of
cyclohexanecarboxaldehyde with nitromethane which gave the
corresponding Henry product in 64% yield and 75% ee. For compar-
ison the thioether available from the earlier study (9-PhS-epi-QN)3
was also tested (Table 3, entry 13).
N
(8S)
N
(8S)
(9R)
(9S)
OH
OH
R=H, R1=C2H3: CD 1a
R=OMe, R1=C2H3: QN 1b
R=OMe, R1=C2H5: DHQN 1c
R=OMe, R1=C2H3: epi-QN 1f
R1
R
R
R1
OH
(9R)
OH
N
(8R)
N
(9S)
(8R)
N
N
R=OMe, R1=C2H3: epi-QD 1g
R=OMe, R1=C2H3: QD 1d
R=OMe, R1=C2H5: DHQD 1e
Figure 1. The structure of Cinchona alkaloids.
excellent chemical yields (up to 93%). These products were easily
oxidized by iodine in ethanol to give the corresponding disulfides
of Cinchona alkaloids 4a–g (80–99%) (Table 2). Compounds 4 are
clearly C2-symmetric, as shown by their NMR spectra, which
resemble those of the corresponding thiols. Simultaneously, smal-
ler values of the specific rotation were recorded for disulfides than
for the parent thiols. As expected, the shelf-life of the thiols was
rather limited. The more stable disulfides can be regarded as their
‘protected derivatives’, and could be regenerated to the appropri-
ate pure thiols with LAH.
The encouraging results obtained for the addition of nitrometh-
ane prompted us to extend this reaction to other nitroalkanes. Thus
the reaction of nitroethane with benzaldehyde as carried out be-
fore in the presence of 3b/Cu(OAc)2 at 0 °C mainly gave the syn-
product in 76% ee. Lowering the temperature to ꢀ20 °C led to an
improvement in both diastereo- and enantioselectivity (Table 4).
Furthermore, the addition of bulkier 2-phenylnitroethane to benz-
LiAlH4
CH3COSH, Ph3P/DEAD
I2/NaOH
THF, 0 °C to rt
OH
Et2O
65-93%
EtOH, rt
82-99%
S
SCCH3
SH
44-59%
2
O
3a-g
4a-g
1a-g
2a-g
Scheme 1.
Table 1
Synthesis of thiolacetates 2
Entry
Alkaloid 1
Config.
Thiolester 2
Yield (%)
[
a
]
D
(CH2Cl2)
Config.
1
2
3
4
5
6
7
CD 1a
QN 1b
(8S,9R)
(8S,9R)
(8S,9R)
(8R,9S)
(8R,9S)
(8S,9S)
(8R,9R)
9-CH3COS-epi-CD 2a
9-CH3COS-epi-QN 2c
9-CH3COS-epi-DHQN 2c
9-CH3COS-epi-QD 2d
9-CH3COS-epi-DHQD 2e
9-CH3COS-QN 2f
59
43
53
42
44
49
44
ꢀ21.8
ꢀ11.0
ꢀ14.2
+87.0
+62.5
+38.1
+64.9
(8S,9S)
(8S,9S)
(8S,9S)
(8R,9R)
(8R,9R)
(8S,9R)
(8R,9S)
DHQN 1c
QD 1d
DHQD 1e
epi-QN 1f
epi-QD 1g
9-CH3COS-QD 2g
Table 2
Synthesis of thiols 3 and disulfides 4
Entry
Thiol 3
Yield (%)
[
a
]
D
(CH2Cl2)
Disulfides 4
Yield (%)
[
a
]
D
(CH2Cl2)
Config.
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
73
80
84
93
77
93
65
ꢀ58.1
ꢀ72.8
ꢀ46.0
9-epi-CD-S-)2 4a
9-epi-QN-S-)2 4b
9-epi-DHQN-S-)2 4c
9-epi-QD-S-)2 4d
9-epi-DHQD-S-)2 4e
9-QN-S-)2 4f
90
99
98
96
88
98
82
ꢀ35.0
ꢀ25.8
ꢀ9.1
(8S,9S)
(8S,9S)
(8S,9S)
(8R,9R)
(8R,9R)
(8S,9R)
(8R,9S)
+148.9
+141.4
+23.7
+94.1
+46.8
+15.4
+73.0
3g
+106.0
9-QD-S-)2 4g

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M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 20 (2009) 1992–1998
1994
OH
*
−
O
Ligand, Cu(OAc)2 nH2O
NO2
PhCHO + CH3NO2
N+
OAc
Ph
i-PrOH, 0 °C
O
H
OH
N
Scheme 2.
NO2
Cu
H
(S)
S
Re favored
O
H
N
Table 3
a
Nitroaldol reaction of benzaldehyde and nitromethane catalyzed by ligand/Cu(OAc)2
H
O
Entry
Ligand
Yield (%)
eeb (%) abs. config.c
1
2
3
4
5
6
7
8
9
10
11
12
13
9-HS-epi-CD 3a
9-HS-epi-QN 3b
9-HS-epi-QN 3b
9-HS-epi-QN 3bd
9-HS-epi-QN 3be
9-HS-epi-DHQN 3c
9-HS-epi-QD 3d
9-HS-QN 3f
93
70
64f
13
18
43
48
63
51
72
80
79
99
55 (S)
83 (S)
75 (S)f
43 (S)
44 (S)
54 (S)
44 (R)
14 (S)
17 (R)
47 (S)
52 (S)
34 (R)
18 (R)
Figure 2. Proposed geometry of the transition-state model for the Cu(II)ꢁ(8S,9S)-3b
complex.
enantiomeric situation, hence the corresponding positioning of the
reactants seems favorable for the nitronate ion approaching benz-
aldehyde from the Si face to give the (R)-product, in fact obtained
as a main product in this case.
9-HS-QD 3g
Interestingly, we observed also an opposite stereochemical out-
come of the catalytic reaction when instead of 9-HS-epi-QN 3b, the
corresponding thioether 9-PhS-epi-QN was used (see Table 3, entry
13). In this case, a large phenyl moiety placed instead of the sulfhy-
dryl hydrogen strongly hampers the previously favored orienta-
tion. Here, the stereochemical result seems to depend on which
of the two free electron pairs of sulfur better coordinate the copper
ion, thus stabilizing the respective catalytic complex. The same ap-
plies to the reaction catalyzed by C2-symmetric disulfides. The
lowest enantioselectivities observed for the ligands of 8,9-unlike-
configuration 3f and 3g suggest that they form at least two com-
plexes of similar energy, differing in their coordination modes. A
similar outcome was previously observed for the Tsuji-Trost reac-
tion catalyzed by the respective phenylsulfenyl Cinchona deriva-
tives, namely for 9-PhS-epi-QD, 78% ee and for 9-PhS-QD, 12% ee.3
Interestingly, the experiments testing the scope of the catalytic
Henry reaction (Scheme 3, Table 4) show that other nitronates add
to benzaldehyde mainly from the Re face, in the fashion depicted in
Figure 2, leading to (1S)-propanols as the major products. The process
is kinetically controlled, so lowering temperature (to ꢀ20 °C) in-
creased its selectivity. However, if the observed diastereoselectivity
for nitroethane (42% de, syn) can be accounted for by the preferred
configuration of the corresponding nitronate anion, a loss of diastere-
oselectivity in the reaction of 2-phenylnitroethane remains unclear.
9-epi-CD-S-)2 4a
9-epi-QN-S-)2 4b
9-epi-QD-S-)2 4d
9-PhS-epi-QN
a
The reactions were carried out on a 0.5 mmol scale, 12 mol % of respective
ligand, 10 mol % of Cu(OAc)2ꢁH2O, 10 equiv of CH3NO2 in i-PrOH (2 mL) at 0 °C for
3 days.
b
Enantiomeric excess determined by HPLC analysis.
Determined by comparison of the specific rotation value and retention time
c
(chiral HPLC) with literature values.
d
Reaction was performed in MeCN.
Reaction was performed in CH2Cl2.
The reaction of cyclohexanecarboxaldehyde with nitromethane.
e
f
Table 4
a
Henry reaction of benzaldehyde and nitroalkanes catalyzed by 3b/Cu(OAc)2
Entry
R
T (°C)
Yieldb (%)
syn/antic
ee [syn](%)d,e
ee [anti](%)d,e
1
2
3
Me
Me
PhCH2
0
98
98
71
65:35
71:29
43:57
76 (1S,2S)
86 (1S,2S)
74 (1S,2S)
37 (1S,2R)
50 (1S,2R)
61 (1S,2R)
ꢀ20
ꢀ20
a
The reactions were carried out on a 0.5 mmol scale, 12 mol % of respective
ligand, 10 mol % of Cu(OAc)2ꢁH2O, 10 equiv of CH3NO2 in i-PrOH (2 mL) for 3 days.
b
Combined yields of syn and anti isomers.
c
Determined by 1H NMR spectroscopy of the crude product.
d
Determined by chiral HPLC.
The absolute configurations were established by comparison with literature
e
3. Conclusion
data.
In conclusion, we have presented a useful stereospecific synthe-
sis of C-9 thiols and disulfides of Cinchona akaloids. The thiols of
8,9-like configuration obtained from the native alkaloids were suc-
cessful chiral ligands in the copper-catalyzed asymmetric nitroal-
dol reaction. The reaction of benzaldehyde with nitromethane in
the presence of 12 mol % of ligand and 10 mol % of Cu(OAc)2 in iso-
propanol gave the corresponding product in good yield and with
up to 83% ee. The reaction stereochemical outcome is in agreement
with the generally accepted transition-state model involving coor-
dination of both reacting species to the central metal ion.
aldehyde afforded both anti- and syn-products in almost equal
amounts, although with similar enantioselectivity.
In agreement with the previously reported transition-state
models,7h,9a,b we assume that in the Cu(II)ꢁ(8S,9S)-3b catalytic
complex the carbonyl oxygen atom is coordinated at one of the
equatorial positions. As a consequence, deprotonated nitrometh-
ane binds its oxygen atom to the metal center from the axial side.
This positioning of the reactants seems to be the most favorable
orientation when taking into account both steric repulsion and
electronic activation. Moreover, it seems that the hydrogen bonds
formed by the sulfhydryl group additionally stabilize such a molec-
ular arrangement. This clearly leads to the favored Re face attack
(Fig. 2), giving the observed (S)-product. The absence of a methoxy
group in the ligand structure 9-HS-epi-CD, (8S,9S)-3a leads to the
less-stabilized transition-state and 55% ee only (Table 3, entry 1).
This transition-state model is also in agreement with the ob-
served reversal of the stereochemical outcome of the catalytic
reaction for (8R,9R)-3d. For that complex, one may expect a nearly
4. Experimental
4.1. General
Melting points were determined using a Boetius hot-stage
apparatus and are uncorrected. IR spectra were recorded on a Per-
kin Elmer 1600 FTIR spectrophotometer. 1H NMR and 13C NMR
spectra were measured on a Bruker CPX (1H, 300 MHz) spectrom-
eter using TMS as an internal standard. Optical rotations at 578 nm

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M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 20 (2009) 1992–1998
OH
OH
3b (12 mol%)
O
Cu(OAc)2 H2O (10 mol%)
R
R
+
+ RCH2NO2
Ph
Ph
i-PrOH
Ph
H
NO2
NO2
R=Me: syn-7
R=PhCH2: syn-8
anti-7
anti-8
Scheme 3.
were measured using an Optical Activity Ltd. Model AA-5 auto-
matic polarimeter. The enantiomeric composition of the nitroald-
ols was determined by HPLC analysis using a chiral stationary
phase (Chiracel OD-H or Daicel Chiralpak AD-H). The absolute con-
figuration was assigned by comparison of the retention time and
the sign of the specific rotation with the literature.
Separations of products by chromatography were performed on
Silica Gel 60 (230–400 mesh) purchased from Merck. TLC was per-
formed using Silica Gel 60 precoated plates (Merck). All solvents
were purified and dried by standard methods. The starting Cin-
chona alkaloids were commercially available, epi-quinine and epi-
quinidine were prepared according to a general procedure de-
scribed in the literature.3a
23.9, 27.6, 39.5, 42.4, 55.8, 56.4, 58.9, 73.5, 101.4, 114.8, 118.7,
122.0, 126.9, 131.8, 141.4, 143.4, 144.7, 147.4, 158.0, 170.0; IR (film):
2942, 1746, 1622, 1509, 1474, 1371, 1231, 1030, 853, 755, 718,
665 cmꢀ1. Rf = 0.52 (CHCl3/MeOH, 40:3).
4.2.3. (1S,3R,4S,8S,9S)-10,11-Dihydro-60-methoxy-9-acetylthiocin
chonan (9-acetylthio-epi-dihydroquinine, 9-CH3COS-epi-DHQN) 2c
Yield 53%, brown oil; [
a]
D = ꢀ14.2 (c 0.20, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d 0.86 (t, J = 7.3 Hz, 3H, Me), 1.27–1.35 (m, 2H),
1.51–1.66 (m, 3H), 1.73–1.87 (m, 3H), 2.16 (s, 3H, SCOMe), 2.36–
2.41 (m, 1H), 2.70–2.79 (m, 1H), 3.08–3.22 (m, 2H), 3.36 (q,
J = 7.9 Hz, 1H), 4.00 (s, 3H, OMe), 6.62 (d, J = 5.5 Hz, 1H, C9H),
7.33–7.41 (m, 2H, ArH), 7.46 (d, J = 2.5 Hz, 1H, ArH), 8.01 (d,
J = 9.2 Hz, 1H, ArH), 8.74 (d, J = 4.5 Hz, 1H, ArH); 13C NMR
(75 MHz, CDCl3) d 12.0, 21.1, 23.2, 25.2, 27.5, 27.9, 37.0, 42.5,
55.9, 57.9, 58.6, 73.2, 101.3, 118.4, 122.0, 126.8, 131.7, 143.2,
144.7, 147.3, 158.1, 169.7; IR (film): 2946, 1713, 1621, 1589,
4.2. General procedure for the synthesis of thiolacetates of
cinchona alkaloids 2
To a solution of triphenylphosphine (1.049 g, 4 mmol) in dry
THF (10 mL) was added DEAD (0.697 g, 0.622 mL, 04 mmol). The
mixture was stirred at 0 °C under an argon atmosphere for
30 min. A yellow precipitate resulted. Then solutions of appropri-
ate alkaloids (2 mmol) in THF (10 mL) and thiolacetic acid
(0.304 g, 0.286 mL, 4 mmol) in THF (5 mL) were added for 10 min
by a syringe and the mixture was stirred for additional 1 h at
0 °C. Next the mixture was allowed to warm to rt and it was further
stirred for 3–7 days. Thereafter a yellow or brown solution was
concentrated and then purified by column chromatography on sil-
ica gel (first CHCl3/t-BuOMe, 1:1, next CHCl3/MeOH, 40:3) gave the
products as a yellow or brown oils.
1509, 1364, 1229, 1024, 855, 751, 718, 614 cmꢀ1
(CHCl3/MeOH, 40:4).
. Rf = 0.56
4.2.4. (1S,3R,4S,8R,9R)-60-Methoxy-9-acetylthiocinchonan
(9-acetylthio-epi-quinidine, 9-CH3COS-epi-QD) 2d
Yield 42%, yellow oil; [a]
D = +87.0 (c 0.50, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d 1.44–1.58 (m, 3H), 1.82–1.91 (m, 2H), 2.15 (s,
3H, SCOMe), 2.23–2.32 (m, 1H), 2.68–2.86 (m, 2H), 2.93 (d,
J = 8.9 Hz, 2H), 3.29 (q, J = 8.9 Hz, 1H), 3.96 (s, 3H, OMe), 5.07–
5.14 (m, 2H, CH2@), 5.98–6.09 (m, 1H, CH@), 6.54 (d, J = 6.8 Hz,
1H, C9H), 7.33–7.41 (m, 3H, ArH), 8.01 (d, J = 9.0 Hz, 1H, ArH),
8.73 (d, J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 21.2,
23.3, 26.4, 27.9, 39.8, 49.2, 49.9, 55.6, 59.0, 73.6, 101.4, 114.9,
118.5, 121.9, 127.0, 131.8, 140.3, 143.8, 144.7, 147.4, 157.9,
170.0; IR (film): 2937, 2873, 1747, 1622, 1593, 1508, 1455, 1372,
1229, 1029, 847, 756, 717, 663 cmꢀ1. Rf = 0.46 (CHCl3/MeOH, 40:3).
4.2.1. (1S,3R,4S,8S,9S)-9-Acetylthiocinchonan (9-acetylthio-epi-
cinchonidine, 9-CH3COS-epi-CD) 2a
Yield 59%, yellow oil; [
a
]
D = ꢀ21.8 (c 0.87, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d 1.49–1.55 (m, 2H), 1.65–1.72 (m, 1H), 1.86–
1.90 (m, 2H), 2.11 (s, 3H, SCOMe), 2.25–2.28 (m, 1H), 2.54–2.65
(m, 2H), 2.99–3.13 (m, 2H), 3.39 (q, J = 8.0 Hz, 1H), 4.98–5.04 (m,
2H, CH2@), 5.78–5.89 (m, 1H, CH@), 6.53 (d, J = 7.3 Hz, 1H, C9H),
7.39 (d, J = 4.5 Hz, 1H, ArH), 7.59 (t, J = 8.2 Hz, 1H, ArH), 7.71 (t,
J = 8.2 Hz, 1H, ArH), 8.13 (d, J = 8.5 Hz, 1H, ArH), 8.23 (d,
J = 8.5 Hz, 1H, ArH), 8.89 (d, J = 4.5 Hz, 1H, ArH); 13C NMR
(75 MHz, CDCl3) d 21.1, 24.5, 27.6, 27.8, 39.7, 42.4, 56.6, 59.6,
74.0, 114.5, 118.8, 123.4, 126.0, 126.9, 129.2, 130.5, 141.7, 145.3,
148.6, 150.0, 170.0; IR (film): 2943, 2866, 1747, 1637, 1509,
1453, 1372, 1232, 1024, 914, 758, 666 cmꢀ1. Rf = 0.52 (CHCl3/
MeOH, 40:3).
4.2.5. (1S,3R,4S,8R,9R)-10,11-Dihydro-60-methoxy-9-acetylthiocin
chonan (9-acetylthio-epi-dihydroquinidine, 9-CH3COS-epi-DHQD)
2e
Yield 44%, brown oil; [a]
D = +62.5 (c 0.26, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d 0.95 (t, J = 7.2 Hz, 3H, Me), 1.23–1.35 (m, 2H),
1.53–1.67 (m, 5H), 1.83–1.89 (m, 1H), 2.21 (s, 3H, SCOMe), 2.94–
3.35 (m, 5H), 4.04 (s, 3H, OMe), 6.96 (s, 1H, C9H), 7.27–7.29 (m,
1H, ArH), 7.38 (dd, J = 9.2, 2.3 Hz, 1H, ArH), 7.51 (d, J = 2.3 Hz, 1H,
ArH), 8.01 (d, J = 9.2 Hz, 1H, ArH), 8.71 (d, J = 4.5 Hz, 1H, ArH);
13C NMR (75 MHz, CDCl3) d 11.6, 20.6, 21.1, 22.1, 25.0, 25.6, 35.9,
49.2, 49.8, 56.4, 58.0, 71.7, 100.9, 117.4, 122.8, 126.2, 131.4,
142.1, 144.4, 146.8, 158.7, 168.7; IR (film): 2946, 1755, 1621,
4.2.2. (1S,3R,4S,8S,9S)-60-Methoxy-9-acetylthiocinchonan
(9-acetylthio-epi-quinine, 9-CH3COS-epi-QN) 2b
1509, 1368, 1229, 1027, 858, 753, 719, 663 cmꢀ1
(CHCl3/MeOH, 40:3).
. Rf = 0.38
Yield 43%, yellow oil; [
a
]
D = ꢀ11.0 (c 0.90, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d 1.49–1.61 (m, 2H), 1.68–1.75 (m, 1H), 1.84–
1.89 (m, 2H), 2.13 (s, 3H, SCOMe), 2.25–2.28 (m, 1H), 2.57–2.71
(m, 2H), 3.01–3.14 (m, 2H), 3.36 (q, J = 8.2 Hz, 1H), 3.96 (s, 3H,
OMe), 4.98–5.05 (m, 2H, CH2@), 5.78–5.90 (m, 1H, CH@), 6.49 (d,
J = 7.3 Hz, 1H, C9H), 7.36 (d, J = 4.4 Hz, 1H, ArH), 7.38 (d, J = 2.7 Hz,
1H, ArH), 7.43 (d, J = 2.7 Hz, 1H, ArH), 8.01 (d, J = 9.2 Hz, 1H, ArH),
8.74 (d, J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 21.2, 22.1,
4.2.6. (1S,3R,4S,8S,9R)-60-Methoxy-9-acetylthiocinchonan
(9-acetylthio-quinine, 9-CH3COS-QN) 2f
Yield 49%, yellow oil; [a]
D = +38.1 (c 0.42, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d 0.83–0.90 (m, 1H), 1.35–1.41 (m, 1H), 1.65–
1.73 (m, 3H), 2.09 (s, 3H, SCOMe), 2.36–2.41 (m, 1H), 2.83–2.94
(m, 2H), 3.26–3.40 (m, 2H), 3.61 (q, J = 7.4 Hz, 1H), 3.99 (s, 3H,
OMe), 4.99–5.06 (m, 2H, CH2@), 5.70–5.82 (m, 1H, CH@), 6.40 (d,

_
´
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 20 (2009) 1992–1998
1996
J = 10.5 Hz, 1H, C9H), 7.37ꢀ7.44 (m, 1H, ArH), 7.60 (d, J = 2.7 Hz, 1H,
ArH), 8.04 (d, J = 9.2 Hz, 1H, ArH), 8.77 (d, J = 4.5 Hz, 1H, ArH); 13C
NMR (75 MHz, CDCl3) d 16.6, 20.4, 22.6, 23.4, 34.7, 36.5, 50.8, 50.9,
51.1, 54.2, 97.0, 109.9, 115.9, 117.2, 123.0, 127.1, 136.6, 137.1,
140.2, 142.8, 153.4, 165.8; IR (film): 2937, 2865, 1738, 1622,
1508, 1475, 1367, 1239, 1031, 854, 754, 716, 633 cmꢀ1. Rf = 0.36
(EtOAc/MeOH/Et3N, 7:3:0.5).
4.3.3. (1S,3R,4S,8S,9S)-10,11-Dihydro-60-methoxy-9-mercaptocin
chonan (9-mercapto-epi-dihydroquinine, 9-HS-epi-DHQN) 3c
Yield 84%, solidified brown oil; [
a]
D = ꢀ46.0 (c 0.42, CH2Cl2). 1H
NMR (300 MHz, CDCl3) d 0.79 (t, J = 7.3 Hz, 3H, Me), 1.17–1.27 (m,
2H), 1.40–1.43 (m, 3H), 1.71–1.78 (m, 3H), 2.34–2.44 (m, 1H),
2.60–2.68 (m, 1H), 3.01–3.09 (m, 2H), 3.46ꢀ3.51 (m, 1H), 3.86 (s,
3H, OMe), 4.71 (br s, 1H, SH), 5.57 (d, J = 3.3 Hz, 1H, C9H), 7.22–
7.30 (m, 2H, ArH), 7.50 (d, J = 4.5 Hz, 1H, ArH), 7.93 (d, J = 9.2 Hz,
1H, ArH), 8.59 (d, J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d
11.9, 20.9, 25.3, 27.5, 27.8, 37.2, 43.3, 55.8, 58.3, 59.7, 71.1, 101.2,
118.5, 121.4, 126.5, 131.3, 144.0, 147.4, 147.9, 157.6; IR (film):
4.2.7. (1S,3R,4S,8R,9S)-60-Methoxy-9-acetylthiocinchonan
(9-acetylthio-quinidine, 9-CH3COS-QD) 2g
Yield 44%, yellow oil; [
(300 MHz, CDCl3) 0.87–0.96 (m, 1H), 1.11–1.19 (m, 1H),
a]
D = +64.9 (c 0.98, CH2Cl2). 1H NMR
2931, 2870, 1621, 1508, 1461, 1241, 1030, 829, 717, 642 cmꢀ1
.
d
1.52ꢀ1.64 (m, 3H), 2.09 (s, 3H, SCOMe), 2.24–2.31 (m, 1H), 2.98–
3.07 (m, 4H), 3.35 (q, J = 9.5 Hz, 1H), 3.99 (s, 3H, OMe), 5.05–5.14
(m, 2H, CH2@), 5.82–5.93 (m, 1H, CH@), 6.44 (d, J = 10.0 Hz, 1H,
C9H), 7.38–7.43 (m, 2H, ArH), 7.55 (d, J = 2.7 Hz, 1H, ArH), 8.02
(d, J = 9.2 Hz, 1H, ArH), 8.76 (d, J = 4.5 Hz, 1H, ArH); 13C NMR
(75 MHz, CDCl3) d 21.4, 24.2, 26.5, 27.4, 39.2, 47.7, 49.3, 55.6,
59.3, 70.5, 101.4, 114.7, 120.3, 122.2, 127.8, 131.8, 140.4, 142.4,
144.8, 147.5, 158.1, 170.6; IR (film): 2938, 2873, 1740, 1622,
1508, 1476, 1368, 1238, 1031, 851, 756, 716, 666 cmꢀ1. Rf = 0.41
(CHCl3/MeOH, 40:3).
4.3.4. (1S,3R,4S,8R,9R)-60-Methoxy-9-mercaptocinchonan
(9-mercapto-epi-quinidine, 9-HS-epi-QD) 3d
Yield 93%, solidified yellow oil; [a]
D = +148.9 (c 0.90, CH2Cl2). 1H
NMR (300 MHz, CDCl3) d 1.11ꢀ1.15 (m, 1H), 1.47–1.59 (m, 2H),
1.74–1.78 (m, 1H), 2.03ꢀ2.11 (m, 1H), 2.23–2.28 (m, 1H), 2.74–
3.08 (m, 4H), 3.39ꢀ3.46 (m, 1H), 3.77 (s, 3H, OMe), 5.00–5.12 (m,
3H, CH2@, SH), 5.66 (d, J = 3.6 Hz, 1H, C9H), 5.98–6.10 (m, 1H,
CH@), 7.15 (d, J = 2.6 Hz, 1H, ArH), 7.25–7.29 (m, 1H, ArH), 7.53
(d, J = 4.5 Hz, 1H, ArH), 7.93 (d, J = 9.2 Hz, 1H, ArH), 8.60 (d,
J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 20.8, 26.2, 28.2,
39.9, 49.5, 50.1, 55.6, 59.7, 71.5, 101.1, 114.8, 118.5, 121.5, 126.5,
131.5, 140.4, 144.1, 147.5, 147.7, 157.7; IR (film): 3070, 2938,
4.3. Representative procedure for the preparation of thiols of
alkaloids 3
2871, 1621, 1509, 1262, 1041, 832, 757, 664 cmꢀ1
.
The appropriate thiolacetate of alkaloid (1.5 mmol) was dis-
solved in abs. Et2O or THF (10 mL) and was added to a well-stirred
suspension of LiAlH4 (0.228 g, 6 mmol) in Et2O or THF (10 mL) un-
der an argon atmosphere. The reaction mixture was stirred at rt for
1–3 days and then quenched by the careful addition of ether satu-
rated with water (5 mL) and aqueous solution of 20% NaOH (ca.
10 mL). The aqueous layer was extracted with Et2O (3 ꢂ 15 mL)
and the combined organic phase was washed with H2O, brine,
dried (Na2SO4) and the solvent was evaporated to afford a yellow
solid or brown oil.
4.3.5. (1S,3R,4S,8R,9R)-10,11-Dihydro-60-methoxy-9-mercaptocin
chonan (9-mercapto-epi-dihydroquinidine, 9-HS-epi-DHQD) 3e
Yield 77%, solidified brown oil; [a]
D = +141.4 (c 0.29, CH2Cl2). 1H
NMR (300 MHz, CDCl3) d 0.78 (t, J = 7.1 Hz, 3H, Me), 0.98–1.07 (m,
1H), 1.35–1.49 (m, 5H), 1.60–1.64 (m, 1H), 1.87–1.95 (m, 1H),
2.66–2.74 (m, 1H), 2.78–2.85 (m, 2H), 2.96–3.08 (m, 2H), 3.72 (s,
3H, OMe), 5.63 (s, 1H, C9H), 7.08 (d, J = 2.5 Hz, 1H, ArH), 7.21 (d,
J = 2.5 Hz, 1H, ArH), 7.46 (d, J = 4.5 Hz, 1H, ArH), 7.86 (d, J = 9.2 Hz,
1H, ArH), 8.58 (d, J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d
11.9, 20.6, 25.0, 26.1, 26.1, 37.0, 50.1, 51.0, 55.7, 59.8, 71.1, 101.0,
118.5, 121.5, 126.4, 131.5, 144.1, 147.2, 147.5, 157.7; IR (film):
2933, 2870, 1622, 1509, 1471, 1241, 1030, 830, 718, 641 cmꢀ1
.
4.3.1. (1S,3R,4S,8S,9S)-9-Mercaptocinchonan (9-mercapto-epi-
cinchonidine, 9-HS-epi-CD) 3a
4.3.6. (1S,3R,4S,8S,9R)-60-Methoxy-9-mercaptocinchonan
Yield 73%, light yellow solid, mp 188ꢀ193 °C; [ D = ꢀ58.1 (c
a
]
0.74, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.34–1.41 (m, 2H),
1.65–1.70 (m, 3H), 2.13–2.16 (m, 1H), 2.48ꢀ2.57 (m, 2H),
2.90ꢀ2.98 (m, 2H), 3.37ꢀ3.42 (m, 1H), 4.78–4.89 (m, 3H, CH2@,
SH), 5.54–5.66 (m, 2H, CH@, C9H), 7.24 (t, J = 7.2 Hz, 1H, ArH),
7.48 (d, J = 4.5 Hz, 1H, ArH), 7.53 (t, J = 7.2 Hz, 1H, ArH), 7.86 (d,
J = 8.2 Hz, 1H, ArH), 7.97 (d, J = 8.2 Hz, 1H, ArH), 8.67 (d,
J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 21.3, 27.5, 27.8,
39.8, 43.1, 56.9, 60.3, 71.5, 114.3, 118.2, 122.9, 125.6, 126.5,
128.9, 130.0, 141.7, 148.0, 149.7, 149.8; IR (film): 3072, 2940,
(9-mercapto-quinine, 9-HS-QN) 3f
Yield 93%, solidified yellow oil; [a]
D = +23.7 (c 0.38, CH2Cl2). 1H
NMR (300 MHz, CDCl3) d 0.88–0.95 (m, 1H), 1.37–1.46 (m, 1H),
1.54ꢀ1.67 (m, 3H), 2.21–2.30 (m, 1H), 2.70–2.79 (m, 2H), 3.03–
3.26 (m, 3H), 3.89 (s, 3H, OMe), 4.88–5.06 (m, 4H, CH2@, C9H,
SH), 5.63–5.75 (m, 1H, CH@), 7.30–7.36 (m, 2H, ArH), 7.59 (d,
J = 2.6 Hz, 1H, ArH), 7.97 (d, J = 9.2 Hz, 1H, ArH); 8.69 (d,
J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 23.4, 25.2, 28.1,
40.0, 40.8, 55.5, 56.0, 61.6, 71.4, 102.7, 114.7, 120.2, 121.3, 128.2,
131.7, 141.5, 144.4, 144.9, 147.6, 157.5; IR (film): 2927, 2861,
2866, 1719, 1590, 1507, 1452, 1098, 901, 804, 756, 635 cmꢀ1
.
1622, 1508, 1474, 1241, 1031, 832, 716, 640 cmꢀ1
.
4.3.2. (1S,3R,4S,8S,9S)-60-Methoxy-9-mercaptocinchonan
(9-mercapto-epi-quinine, 9-HS-epi-QN) 3b
4.3.7. (1S,3R,4S,8R,9S)-60-Methoxy-9-mercaptocinchonan
Yield 80%, white solid, mp 145ꢀ150 °C; [ D = ꢀ72.8 (c 0.92,
a
]
(9-mercapto-quinidine, 9-HS-QD) 3g
CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.41–1.59 (m, 2H), 1.68–
1.81 (m, 3H), 2.23–2.28 (m, 1H), 2.61–2.69 (m, 2H), 3.04–3.16
(m, 2H), 3.40–3.46 (m, 1H), 3.89 (s, 3H. OMe), 4.03 (br s, 1H. SH),
4.89–4.99 (m, 2H, CH2@), 5.51 (d, J = 4.3 Hz, 1H, C9H), 5.68–5.80
(m, 1H, CH@), 7.22 (d, J = 2.7 Hz, 1H, ArH), 7.31 (dd, J = 9.2,
2.7 Hz, 1H, ArH), 7.48 (d, J = 4.5 Hz, 1H, ArH), 7.96 (d, J = 9.2 Hz,
1H, ArH), 8.60 (d, J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3)
d 21.7, 27.6, 27.9, 39.9, 43.2, 55.7, 57.0, 59.9, 71.9, 101.3, 114.4,
118.5, 121.5, 126.6, 131.4, 141.8, 144.1, 147.5, 147.8, 157.7; IR
(film): 3073, 2933, 2859, 1622, 1508, 1470, 1241, 1032, 823, 717,
Yield 65%, solidified yellow oil; [a]
D = +106.0 (c 0.50, CH2Cl2). 1H
NMR (300 MHz, CDCl3) d 1.00–1.06 (m, 1H), 1.31–1.39 (m, 1H),
1.54ꢀ1.60 (m, 2H), 1.71–1.73 (m, 1H), 2.33–2.36 (m, 2H), 2.92–
3.02 (m, 4H), 3.94 (s, 3H, OMe), 5.05–5.16 (m, 4H, CH2@, C9H,
SH), 5.86–5.96 (m, 1H, CH@), 7.37 (dd, J = 9.2, 2.7 Hz, 1H, ArH);
7.48 (d, J = 4.5 Hz, 1H, ArH), 7.58 (d, J = 2.7 Hz, 1H, ArH), 8.02 (d,
J = 9.2 Hz, 1H, ArH); 8.75 (d, J = 4.5 Hz, 1H, ArH); 13C NMR
(75 MHz, CDCl3) d 24.0, 26.6, 27.3, 39.0, 46.8, 49.2, 55.4, 62.2,
70.1, 101.9, 114.7, 119.9, 121.6, 128.0, 131.6, 140.2, 144.7, 144.9,
147.6, 157.4; IR (film): 2935, 2870, 1621, 1507, 1474, 1241,
645 cmꢀ1
.
1030, 827, 715, 639 cmꢀ1
.

_
´
1997
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 20 (2009) 1992–1998
4.4. Representative procedure for the preparation of disulfides
of alkaloids 4
J = 11.2 Hz, 1H), 2.32–2.35 (m, 1H), 2.82–3.16 (m, 5H), 3.77 (s,
3H. OMe), 5.08–5.13 (m, 2H, CH2@), 5.97–6.10 (m, 2H, CH@,
C9H), 7.14 (d, J = 2.1 Hz, 1H, ArH), 7.23 (dd, J = 9.2, 2.0 Hz 1H,
ArH), 7.58 (d, J = 4.4 Hz, 1H, ArH), 7.90 (d, J = 9.2 Hz, 1H, ArH),
8.65 (d, J = 4.4 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 24.4,
27.6, 29.5, 38.2, 40.1, 48.4, 49.2, 55.6, 56.3, 60.0, 101.7, 116.3,
118.9, 121.6, 126.3, 131.6, 138.4, 144.2, 147.4, 157.9; IR (film):
2934, 2871, 1621, 1591, 1508, 1455, 1241, 1028, 831, 718, 640,
570 cmꢀ1. Anal. Calcd for C40H46N4O2S2 (M = 678.95): C, 70.76; H,
6.83; N, 8.25; S, 9.45. Found: C, 70.51; H, 6.98; N, 7.92; S, 9.07.
An aqueous solution of 20% NaOH (0.060 g, 1.5 mmol) was
added to a stirred solution of the appropriate thiols of alkaloids
(1 mmol) dissolved in EtOH (10 mL). Then
a solution of I2
(0.095 g, 0.75 mmol) in EtOH (ca. 5 mL) was added dropwise until
the color of the mixture become permanent. The reaction mixture
was stirred at rt overnight. Thereafter EtOH was evaporated and
the residue was quenched by the addition of satd Na2S2O3
(10 mL) and extracted with CH2Cl2 (3 ꢂ 10 mL) and the combined
organic phase was washed with water, brine, dried (Na2SO4), and
evaporated under reduced pressure to afford a yellow solid.
4.4.5. Bis((1S,3R,4S,8R,9R)-10,11-Dihydro-60-methoxycinchonan-9-yl)
disulfide (bis(9-epi-dihydroquinidinyl)disulfide, 9-epi-DHQD-S-)2) 4e
Yield 88%, light brown solid, mp >230 °C with decomposition;
4.4.1. Bis((1S,3R,4S,8S,9S)-cinchonan-9-yl)disulfide (bis(9-epi-
cinchonidinyl)disulfide, 9-epi-CD-S-)2) 4a
[a]
D = +46.8 (c 0.24, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 0.94 (t,
J = 7.3 Hz, 3H, Me), 1.56–1.81 (m, 5H), 1.94–2.02 (m, 2H), 2.38 (t,
J = 11.4 Hz, 1H), 3.02–3.13 (m, 1H), 3.24ꢀ3.39 (m, 2H), 3.63 (s,
3H, OMe), 3.89–3.98 (m, 1H), 4.15ꢀ4.22 (m, 1H), 6.59 (s, 1H,
C9H), 6.92 (d, J = 2.1 Hz, 1H, ArH), 7.01 (dd, J = 9.2, 2.1 Hz, 1H,
ArH), 7.68ꢀ7.75 (m, 2H, ArH), 8.68 (d, J = 4.4 Hz, 1H, ArH); 13C
NMR (75 MHz, CDCl3) d 11.6, 17.6, 23.8, 24.3, 25.1, 35.2, 49.4,
50.1, 57.2, 60.1, 66.3, 99.7, 118.6, 122.3, 125.2, 131.2, 143.6,
144.1, 146.9, 158.1; IR (film): 2930, 2875, 1620, 1591, 1508,
1460, 1241, 1026, 832, 718, 641, 568 cmꢀ1. Anal. Calcd for
C40H50N4O2S2 (M = 682.98): C, 70.34; H, 7.38; N, 8.20; S, 9.39.
Found: C, 69.98; H, 7.07; N, 7.96; S, 9.46.
Yield 90%, yellow solid, mp >220 °C with decomposition;
[
a]
D = ꢀ35.0 (c 0.52, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.34–
1.46 (m, 2H), 1.72–1.76 (m, 3H), 2.22–2.26 (m, 1H), 2.58ꢀ2.66
(m, 2H), 3.00ꢀ3.08 (m, 2H), 3.54ꢀ3.58 (m, 1H), 4.80–4.89 (m,
2H, CH2@), 5.52–5.64 (m, 1H, CH@), 5.77 (s, 1H, C9H), 7.26 (t,
J = 7.4 Hz, 1H, ArH), 7.50ꢀ7.55 (m, 2H, ArH), 7.89ꢀ7.98 (m, 2H,
ArH), 8.71 (d, J = 4.4 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d
20.3, 26.3, 27.5, 38.8, 43.6, 56.1, 60.4, 69.6, 115.5, 118.4, 122.9,
125.1, 126.5, 129.1, 130.0, 139.9, 147.9, 148.0, 150.0; IR (film):
3072, 2939, 2866, 2726, 1590, 1508, 1452, 1097, 901, 804, 756,
635, 576 cmꢀ1. Anal. Calcd for C38H42N4S2 (M = 618.90): C, 73.75;
H, 6.84; N, 9.05; S, 10.36. Found: C, 73.45; H, 6.54; N, 9.27; S, 10.18.
4.4.6. Bis((1S,3R,4S,8S,9R)-60-methoxycinchonan-9-yl)disulfide
(bis(9-quininyl)disulfide, 9-QN-S-)2) 4f
4.4.2. Bis((1S,3R,4S,8S,9S)-60-methoxycinchonan-9-yl)disulfide
(bis(9-epi-quininyl)disulfide, 9-epi-QN-S-)2) 4b
Yield 98%, brown solid, mp 138ꢀ144 °C with decomposition;
[a]
D = +15.4 (c 0.26, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.04–
Yield 99%, yellow solid, mp >220 °C with decomposition;
1.11 (m, 1H), 1.52–1.63 (m, 1H), 1.68ꢀ1.85 (m, 3H), 2.45–2.51
(m, 1H), 2.97–3.07 (m, 2H), 3.43–3.66 (m, 3H), 3.95 (s, 3H, OMe),
5.03–5.12 (m, 2H, CH2@), 5.26 (d, J = 10.0 Hz, 1H, C9H), 5.67–5.73
(m, 1H, CH@), 7.34ꢀ7.43 (m, 2H, ArH); 7.67 (d, J = 2.6 Hz, 1H,
ArH), 8.02 (d, J = 9.2 Hz, 1H, ArH), 8.73 (d, J = 4.4 Hz, 1H, ArH);
13C NMR (75 MHz, CDCl3) d 23.4, 25.4, 26.4, 29.7, 37.6, 54.5, 55.6,
56.4, 61.9, 102.3, 116.8, 120.4, 122.0, 125.1, 131.7, 138.1, 142.6,
144.8, 147.5, 158.1; IR (film): 2924, 1621, 1590, 1505, 1455,
1230, 1024, 920, 831, 715, 619 cmꢀ1. Anal. Calcd for C40H46N4O2S2
(M = 678.95): C, 70.76; H, 6.83; N, 8.25; S, 9.45. Found: C, 69.81; H,
6.31; N, 7.88; S, 9.12.
[
a
]
D = ꢀ25.8 (c 0.66, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.44–
1.58 (m, 2H), 1.81–1.88 (m, 3H), 2.36–2.39 (m, 1H), 2.63–2.79
(m, 2H), 3.07–3.23 (m, 2H), 3.63–3.75 (m, 1H), 3.88 (s, 3H. OMe),
4.92–5.00 (m, 2H, CH2@), 5.63–5.74 (m, 1H, CH@), 5.80 (s, 1H,
C9H), 7.19 (d, J = 2.6 Hz, 1H, ArH), 7.26ꢀ7.30 (m, 1H, ArH), 7.52
(d, J = 4.5 Hz, 1H, ArH), 7.92 (d, J = 9.2 Hz, 1H, ArH), 8.62 (d,
J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 19.5, 25.4, 26.4,
37.9, 42.8, 55.4, 55.6, 59.0, 68.8, 99.8, 114.5, 117.6, 120.9, 125.2,
130.3, 139.0, 142.9, 145.4, 146.3, 157.0; IR (film): 2927, 2866,
1620, 1590, 1508, 1453, 1241, 1097, 1028, 825, 717, 641,
569 cmꢀ1. Anal. Calcd for C40H46N4O2S2 (M = 678.95): C, 70.76; H,
6.83; N, 8.25; S, 9.45. Found: C, 70.49; H, 6.71; N, 8.36; S, 9.21.
4.4.7. Bis((1S,3R,4S,8R,9S)-60-methoxycinchonan-9-yl)disulfide
(bis(9-quinidinyl)disulfide, 9-QD-S-)2) 4g
4.4.3. Bis((1S,3R,4S,8S,9S)-10,11-Dihydro-60-methoxycinchonan-9-yl)
disulfide (bis(9-epi-dihydroquininyl)disulfide, 9-epi-DHQN-S-)2) 4c
Yield 98%, light brown solid, mp 220 °C with decomposition;
Yield 82%, brown solid, mp 135ꢀ142 °C; [
a]D = +73.0 (c 0.28,
CH2Cl2). 1H NMR (300 MHz, CDCl3) d 0.98–1.30 (m, 3H), 1.53–
1.67 (m, 3H), 2.30ꢀ2.32 (m, 1H), 3.01–3.03 (m, 4H), 3.85 (s, 3H,
OMe), 5.04–5.13 (m, 3H, CH2@, C9H), 5.74–5.80 (m, 1H, CH@),
7.24ꢀ7.29 (m, 1H, ArH); 7.39 (d, J = 4.0 Hz, 1H, ArH), 7.47 (d,
J = 2.2 Hz, 1H, ArH), 7.92 (d, J = 9.2 Hz, 1H, ArH); 8.65 (d,
J = 4.4 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 23.7, 25.8, 27.2,
38.3, 46.7, 49.1, 55.5, 62.5, 69.3, 101.8, 115.5, 120.0, 121.8, 127.8,
131.6, 139.2, 144.3, 144.7, 147.6, 157.7; IR (film): 2934, 2873,
1620, 1590, 1507, 1455, 1227, 1026, 829, 715, 639, 617 cmꢀ1. Anal.
Calcd for C40H46N4O2S2 (M = 678.95): C, 70.76; H, 6.83; N, 8.25; S,
9.45. Found: C, 71.02; H, 6.58; N, 7.96; S, 9.80.
[
a]
D = ꢀ9.1 (c 0.32, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 0.73 (t,
J = 7.2 Hz, 3H, Me), 1.10–1.24 (m, 2H), 1.70–1.81 (m, 3H), 1.96–
2.17 (m, 3H), 2.59–2.64 (m, 1H), 3.00–3.06 (m, 1H), 3.23 (t,
J = 9.1 Hz, 1H), 3.36 (t, J = 10.9 Hz, 1H), 3.62 (s, 3H, OMe), 4.47–
4.91 (m, 1H), 6.38 (s, 1H, C9H), 6.86 (d, J = 2.3 Hz, 1H, ArH), 6.93
(dd, J = 9.3, 2.4 Hz, 1H, ArH), 7.61ꢀ7.66 (m, 2H, ArH), 8.61 (d,
J = 4.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 10.4, 17.0, 23.5,
23.6, 25.9, 34.4, 43.3, 56.0, 56.7, 59.0, 65.0, 99.1, 118.1, 122.1,
124.6, 129.0, 140.9, 144.7, 144.9, 157.6; IR (film): 2930, 2875,
1620, 1591, 1508, 1459, 1241, 1025, 856, 718, 643, 566 cmꢀ1. Anal.
Calcd for C40H50N4O2S2 (M = 682.98): C, 70.34; H, 7.38; N, 8.20; S,
9.39. Found: C, 70.56; H, 7.62; N, 7,98; S, 9.11.
4.5. General procedure for the copper-catalyzed Henry reaction
The ligand (0.06 mmol, 12 mol %) and Cu(OAc)2ꢁH2O (10.0 mg,
0.05 mmol, 10 mol %) were dissolved in i-PrOH (1 mL) and the mix-
ture was stirred for 3 h at rt to give either a blue or dark green solu-
tion. Then the respective aldehyde (0.5 mmol, 1 equiv) and
nitroalkane (5.0 mmol, 10 equiv) were added with an additional
1 mL of i-PrOH. The reaction mixture was cooled to 0 °C (or
4.4.4. Bis((1S,3R,4S,8R,9R)-60-methoxycinchonan-9-yl)disulfide
(bis(9-epi-quinidinyl)disulfide, 9-epi-QD-S-)2) 4d
Yield 96%, yellow solid, mp >220 °C with decomposition;
[a]
D = +94.1 (c 0.34, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.05–
1.14 (m, 1H), 1.50–1.75 (m, 2H), 1.81–1.85 (m, 1H), 2.18 (t,

_
´
M. Zielinska-Błajet, J. Skarzewski / Tetrahedron: Asymmetry 20 (2009) 1992–1998
1998
ꢀ20 °C). After 3 days, the crude product was isolated by column
chromatography (hexane/AcOEt 6:1) to give b-nitroalcohol.
(dd, J = 11.1, 7.4 Hz, 1H), 4.82ꢀ4.89 (m, 1H), 5.04 (d, J = 6.5 Hz, 1H),
6.97ꢀ7.02 (m, 2H, ArH), 7.14ꢀ7.23 (m, 3H, ArH), 7.28ꢀ7.38 (m, 5H,
ArH).
4.5.1. 2-Nitro-1-phenylethanol 5
Chromatographic purification (hexane/AcOEt 6:1), Rf = 0.16.
Enantiomeric excess was determined by HPLC (Chiracel OD-H), hex-
ane/i-PrOH 90:10, 1 mL/min, 225 nm, enantiomer I tR = 13.9 min,
enantiomer (S) tR = 17.3 min. The absolute configuration was as-
signed by comparison of the retention times in HPLC and specific
rotation signs with literature data.7d,h 1H NMR (300 mHz, CDCl3) d
2.88 (d, J = 3.3 Hz, 1H), 4.51 (dd, J = 13.3, 3.2 Hz, 1H), 4.62 (dd,
J = 13.3, 9.4 Hz, 1H), 5.48 (dd, J = 9.4, 3.2 Hz, 1H).
Acknowledgment
We are grateful to the Ministry of Science and Higher Education
for financial support (Grant No. N204 161036).
References
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4.5.2. 1-Cyclohexyl-2-nitro-ethanol 6
Chromatographic purification (hexane/AcOEt 6:1), Rf = 0.29,
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(m, 1H), 1.59ꢀ1.65 (m, 2H), 1.71ꢀ1.79 (m, 3H), 2.38 (d, J = 4.4 Hz,
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4.5.3. 2-Nitro-1-phenylpropanol 7
Chromatographic purification (hexane/AcOEt 6:1), Rf = 0.20. Dia-
stereomeric ratios were determined by 1H NMR. Enantiomeric ex-
cesses were determined by HPLC (Chiralpak AD-H), hexane/i-PrOH
95:5, 1 mL/min, 225 nm, antimajor (1S,2R) tR = 13.5, antiminor (1R,2S)
tR = 15.3, synmajor (1S,2S) tR = 18.7, synminor (1R,2R) tR = 21.0. The abso-
lute configurationof both diastereomers was assigned by comparison
of the retention times in HPLC with literature data;7d,f,j,9c syn isomer
(1S,2S): 1H NMR (300 MHz, CDCl3) d 1.48 (d, J = 6.8 Hz, 3H), 2.69 (d,
J = 3.4 Hz, 1H), 4.67 (dq, J = 6.8, 3.6 Hz, 1H), 5.38 (t, J = 3.3 Hz, 1H),
7.30ꢀ7.40 (m, 5H, ArH); anti isomer (1S,2R): 1H NMR (300 MHz,
CDCl3) d 1.48 (d, J = 6.8 Hz, 3H), 2.69 (d, J = 3.4 Hz, 1H), 4.67 (dq,
J = 6.8, 3.6 Hz, 1H), 5.38 (t, J = 3.3 Hz, 1H), 7.30ꢀ7.40 (m, 5H, ArH).
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3.35 (dd, J = 14.9, 10.9 Hz, 1H), 4.82ꢀ4.89 (m, 1H), 5.23 (d,
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7.28ꢀ7.38 (m, 5H, ArH); syn isomer (1S,2S), 74% ee: 1H NMR
(300 MHz, CDCl3) d 2.53 (s, 1H), 2.71 (dd, J = 14.4, 3.8 Hz, 1H), 3.08
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