Synthesis of quinine and quinidine using sulfur ylide-mediated asymmetric epoxidation as a key step

Article abstract of DOI:10.1016/j.tetasy.2010.04.046

The epoxidation of meroquinene aldehyde with a chiral sulfur ylide as the key step in the synthesis of quinine and quinidine is described. The epoxidation reactions proceed under reagent control with high selectivity and good yield. The effect of sulfide and ylide substituents on the stereochemical outcome of the reaction is discussed.

Full text of DOI:10.1016/j.tetasy.2010.04.046

Tetrahedron: Asymmetry 21 (2010) 1771–1776
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Tetrahedron: Asymmetry
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Synthesis of quinine and quinidine using sulfur ylide-mediated asymmetric
epoxidation as a key step
*
Muhammad Arshad, M. Alejandro Fernández, Eoghan M. McGarrigle, Varinder K. Aggarwal
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The epoxidation of meroquinene aldehyde with a chiral sulfur ylide as the key step in the synthesis of
quinine and quinidine is described. The epoxidation reactions proceed under reagent control with high
selectivity and good yield. The effect of sulfide and ylide substituents on the stereochemical outcome
of the reaction is discussed.
Received 13 April 2010
Accepted 28 April 2010
Available online 16 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Henri Kagan on the occasion of
his 80th birthday
1. Introduction
nitrogen atoms are unstable and so protection of the nitrogen
was required.
Asymmetric sulfur ylide methodology provides a complemen-
tary route to epoxides but, perhaps more importantly, it offers a
different disconnection to alkene oxidation.1 The optimum ylide
substrates are those derived from semi-stabilized ylides (aryl or
alkenyl) since they often react with aromatic and aliphatic alde-
hydes with good levels of diastereo- and enantiocontrol when
appropriate chiral sulfides are employed. The most important car-
bonyl electrophiles are aliphatic or alkenyl aldehydes rather than
aromatic aldehydes as these lead to the more synthetically useful
arylalkyl or alkenylalkyl epoxides.2 Over recent years we have de-
scribed two chiral sulfides 1 and 2 that deliver high enantio- and
good diastereoselectivity with aliphatic aldehydes (Scheme 1).3,4
For example, sulfide 1, available in five steps from camphor sul-
fonic acid,5 gave 90:10 dr and 99:1 er in the reaction of the corre-
sponding benzyl sulfonium salt with valeraldehyde.6 Sulfide 2,
available in one step from limonene, gave 91:9 dr and 99:1 er.3a
The high selectivities achieved prompted us to test this methodol-
ogy in the synthesis of complex molecules.7
Herein, we describe the application of chiral sulfur ylide epoxi-
dations to the synthesis of quinine, a molecule with a long and ven-
erable history, spanning folklore, medicine, synthesis, and catalysis
and not without controversy as well.8 Our retrosynthetic analysis
(Scheme 2) led us back to epoxide 3, a strategy which had been
previously used by Uskokovic, Jacobsen, and Kobayashi.9 Jacobsen
and Kobayashi were able to control the stereochemistry of the
epoxide through Sharpless dihydroxylation of the corresponding
trans-alkene. However, the epoxide can also be disconnected back
to sulfonium salt 4 and meroquinene aldehyde 5 leading to a more
convergent synthesis. Sulfonium salts like 4 bearing nucleophilic
We have previously described the protection of the amino
group as a carbamate moiety—using sulfide 2 gave the sulfonium
O
Ph
O
S
S
Ph
H
Sulfide Conditions
Yield
d.r.
e.r.
S
=
1
KHMDS, THF
87% 90:10 99:1
O
−78 °C
S
2
CH3CN:t-BuOH
(15:1), KOH, 0 °C
56% 91:9
99:1
2
1
Scheme 1. Epoxidation of valeraldehyde with sulfides 1 and 2.
O
OCH3
OCH3
OCH3
H
N
N
PG
S
O
OH
N
PG
N
N
N
Quinine
3
4
5
OCH3
OCH3
S
S
or
N
N
Teoc
Br
6
7
* Corresponding author. Tel.: +44 117 954 6315; fax: +44 117 925 1295.
E-mail address: V.Aggarwal@bristol.ac.uk (V.K. Aggarwal).
Scheme 2. Retrosynthesis of quinine.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.046

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M. Arshad et al. / Tetrahedron: Asymmetry 21 (2010) 1771–1776
salt 6. In the key step, epoxidation of meroquinene aldehyde 5
with the ylide derived from 6 gave a mixture of trans/cis epox-
ides (89:11) with complete control over relative stereochemistry
(i.e., only one of the two possible trans-epoxides was formed;
Scheme 3).3a
substituent would hinder the quinoline nitrogen and thereby re-
duce its nucleophilicity. We elected to test both sulfides 1 and 2
in this strategy.
2. Results and discussion
We were interested in alternative protecting groups and ex-
pected that by keeping the quinoline ring intact, higher trans/cis
selectivity might be achieved. We therefore focused on the 2-bro-
mo quinolyl sulfonium salt 7. We hypothesized that the bromo-
Scheme 4 shows the synthesis of the required sulfonium salts.
Reaction of acetyl acetamide 8 with Br2 in CHCl3 gave the bromo
derivative 9 in 98% yield.10 Subsequent cyclization of 9 with 49%
H2SO4 followed by bromination using POBr3 gave dibromide 10
in 75% yield over two steps.11 Reaction of the dibromide 10 with
sulfides 1 and 2 afforded the corresponding sulfonium salts 11
and 12. However, whilst sulfonium salt 11 was indefinitely stable,
salt 12 began to decompose to sulfide 13 in solution over a short
period of time (Scheme 5). A brief investigation revealed that the
source of instability was not the nature of the 2-substituent since
sulfonium salts bearing H or SiMe3 decomposed in a similar
manner. In contrast, the 1-naphthyl sulfonium salt 15 prepared
from 1-(bromomethyl) naphthalene 14 was stable, thus it seems
that the quinoline nitrogen was primarily responsible for the insta-
bility of sulfonium salt 12 (Scheme 5). We therefore progressed
with the stable sulfonium salt 11.
O
OCH3
N
OCH3
H
KOH (1.3 eq)
N
Teoc
S
O
CH3CN:t-BuOH
(15:1), 0 °C, 24 h
OTf
N
N
Teoc
Teoc
Teoc
81% yield
6
5
89:11 (trans:cis)
Scheme 3. Epoxidation of meroquinene aldehyde 5 using sulfide 2.
Br2 (1 eq)
CHCl3, 0 °C
to r.t. 18 h
OCH3
OCH3
OCH3
Treatment of the salt 11 with KOH in the presence of meroquin-
ene aldehyde 512 gave the required epoxide 16 with perfect trans
selectivity and as a 93:7 mixture of the two trans-diastereomers
16 and 18 (Scheme 8).
49% H2SO4
80 °C, 2 h
Br
air bubbling,
r.t. 2 h, 98%
Br POBr3 (4 eq)
100 °C, 3 h
N
HN
HN
The high trans/cis selectivity and diastereoselectivity can be ac-
counted for by considering the fate of the betaine intermediates
(Scheme 6).13 The trans/cis selectivity is determined by the extent
of reversibility in the formation of syn-betaine 19A. In the case of
unhindered aliphatic aldehydes the extent of reversibility is usu-
ally only partial, leading to only moderate trans/cis selectivity.
The very high trans-selectivity observed here most likely arises be-
cause the ylide is especially stable (the negative charge can be
delocalized onto the amine nitrogen) and so syn-betaine formation
becomes fully reversible. Under such Curtin-Hammett conditions
the reaction funnels through the betaine with the lower barrier
to epoxide formation which delivers the trans-epoxide with high
selectivity.
Diastereomers 16 and 18 arise from the fact that the steps for
the formation of two diastereomeric anti-betaines (which lead to
the trans epoxides) are also reversible but not to the same extent.
Dissociation of anti-betaine C (which would give the minor diaste-
reomer of the epoxide) to ylide conformer B is less favored since it
leads to a more hindered (and therefore less stable) ylide con-
former. Thus, even though the more hindered ylide conformer B
is likely to be present in much smaller amounts than A, the re-
duced tendency for its corresponding betaine C to revert back to
starting materials results in an ‘over-expression’ of this pathway
and so lower the dr (Scheme 7).
75% (2 steps)
Br
O
O
O
O
10
8
9
AgOTf (1.1 eq)
CH2Cl2, r.t. 4 h
NaBF4 (5 eq)
H2O/CH2Cl2
45 °C, 96 h
66%
OCH3
S
S
2 (3 eq)
S
S
OTf
N
O
O
78%
BF4
ent-1
(2 eq)
Br
70%
12
1
(2 eq)
OCH3
OCH3
BF4
S
S
N
N
O
O
Br
Br
17
11
Scheme 4. Synthesis of sulfonium salts 11, 12, and 17.
OCH3
OCH3
S
S
H
H
R
CDCl3
H
H
R2S
O
R2S
H
O
OTf
O
H
R
Ar
N
R
N
X
R
O
Ar
Ar
Br
13
anti-betaine
syn-betaine
trans-epoxide
R2S
X = Br, H. TMS
Ar
H
LiOTf (5 M, 5 eq)
R
H
H
R2S
O
R2S
R
O
n-BuOH/CH2Cl2
R
Br
S
Ar
R
45 °C, 48 h, 68%
O
H
S
O
Ar
Ar
H
OTf
15 stable salt
19A
19B
cis-epoxide
14
2 (3 eq)
Scheme 5. Comparison of the stability of sulfonium salts.
Scheme 6. Rationalisation of trans:cis selectivity.

M. Arshad et al. / Tetrahedron: Asymmetry 21 (2010) 1771–1776
1773
The synthesis of quinine was completed by CsF-mediated
deprotection/cyclization9d in DMF/t-BuOH (9:1) followed by Zn/
AcOH reduction11a of the C–Br bond to furnish the target quinine
in 73% yield over two steps from the corresponding epoxide 16
(Scheme 8).
H
H
H
H
R
H
H
S
Ar
O
H
O
S
R
O
O
O
Ar
Ar
R
S
Ar
H
Reaction of the opposite enantiomer of the sulfide 1 with dibro-
mide 10 gave the sulfonium salt 17, which on epoxidation with
meroquinene aldehyde 5 led to preferential formation of the other
diastereoisomer of epoxide 18 and with similar diastereoselectivi-
ty (89:11 dr, complete trans selectivity) (Scheme 8). This shows
that the selectivity in the epoxidation reaction is dominated by
the stereochemistry of the sulfide (reagent control); the existing
stereochemistry of the meroquinene aldehyde 5 does not influence
the outcome of reaction. The synthesis of quinidine was completed
by CsF-mediated deprotection/cyclization9d in DMF/t-BuOH (9:1)
followed by Zn/AcOH reduction11a of the C–Br bond to furnish
the target quinidine in 72% yield over two steps from the corre-
sponding epoxide 18.
trans epoxide
R
anti-betaine
(major)
A
H
H
Ar
Ar
Ar
R
S
H
O
R
H
H
O
H
O
S
O
Ar
R
O
S
R
H
trans epoxide
H
B
C
anti-betaine
(minor)
Scheme 7. Effect of reversibility in anti-betaine formation on diastereoselective
formation of trans-epoxides.
3. Conclusions
In conclusion, we have described the use of a chiral sulfur ylide
in the epoxidation of meroquinene aldehyde as the key step in the
synthesis of quinine and quinidine. In the course of our studies we
discovered an unexpected instability issue surrounding the quino-
lyl sulfonium salt derived from the hindered sulfide 2, which has
an inherent tendency to undergo base-promoted elimination. The
less hindered sulfide 1 gave a much more stable quinolyl sulfo-
nium salt, which reacted with meroquinene aldehyde 5 with high
trans selectivity (>95:5) and high diastereoselectivity (93:7) for the
desired trans-epoxide. Despite the subtle factors governing selec-
tivity, no matched/mis-matched issues arose since the opposite
sulfide enantiomer gave essentially the same high trans selectivity
(>95:5) and diastereoselectivity (89:11) but now in favor of the
other trans stereoisomer. This study highlights how subtle effects
in the structure of the sulfide and the ylide substituent can affect
the stereochemical outcome of epoxidations with aliphatic
aldehydes.14
The diastereoselectivity was dependent on the reaction condi-
tions and increased with increasing amounts of t-BuOH (83:17
with MeCN:t-BuOH, 15:1, versus 93:7 with MeCN:t-BuOH, 1:5).
Protic solvents are known to assist the bond rotation step and
thereby reduce the extent of reversibility in betaine formation.
Interestingly, in the reaction of the ylide derived from 11 with mer-
oquinene aldehyde 5 we needed to minimise reversibility in beta-
ine formation (by using a high concentration of protic solvent) to
maximise the diastereoselectivity of the reaction (perfect trans:cis
selectivity was observed) whilst with the ylide derived from 6
we needed to maximise reversibility in betaine formation (by using
a low concentration of protic solvent) to maximise the trans:cis
selectivity of the reaction (perfect diastereoselectivity was
observed).
The dr is thus determined by the degrees of reversibility in the
formation of the two diastereomeric anti-betaines. Had there been
essentially no reversibility in formation of the anti-betaines, the
selectivity of trans-epoxide would have been higher still. Interest-
ingly, if sulfonium salt 12 had been stable enough to use, we now
predict that it would have given lower selectivity for the desired
trans-epoxide since sulfide 2 is more hindered and so would have
led to a greater degree of reversibility in anti-betaine formation.
Based on structure, the extent of betaine reversibility is dependent
on the bulk of the sulfide and the stabilization of the ylide afforded
by the ylide substituent.
4. Experimental
4.1. 4-Bromo-N-(4-methoxyphenyl)-3-oxobutanamide 9
A solution of bromine (6.2 ml, 0.12 mol) in CHCl3 (60 ml) was
added dropwise (over a period of 2.5 h) to a 0 °C cooled stirred
solution of p-acetoacetanisidide 8 (25.0 g, 121 mmol) in CHCl3
OCH3
KOH (3 eq)
OCH3
BF4
OCH3
CH3CN:t-BuOH
N
Teoc
(1:5), 0 °C, 48 h
H
O
N
S
N
74% yield
93:7 (16:18)
trans only
O
OH
O
N
Br
1) CsF (5 eq)
N
H
DMF:t-BuOH (9:1)
110 °C, 12 h
Br
11
Quinine
73% (over 2 steps)
16
2) Zn (2 eq)
AcOH:H2O (9:1)
70 °C, 5 h
N
OCH3
Teoc
OCH3
KOH (3 eq)
CH3CN:t-BuOH
(1:5), 0 °C, 48 h
OCH3
5
BF4
(2 eq)
O
OH
N
S
N
Teoc
N
81% yield
N
18:16
89:11 (
)
O
N
H
Br
trans only
Br
18
Quinidine
17
72% (over 2 steps)
Scheme 8. The synthesis of quinine and quinidine.

1774
M. Arshad et al. / Tetrahedron: Asymmetry 21 (2010) 1771–1776
(120 ml) under a nitrogen atmosphere. After complete addition,
the reaction mixture was stirred at rt for 18 h. Additional CHCl3
(50 ml) was then added and air was bubbled through the reaction
mixture for 2 h. The reaction mixture was filtered and the solid res-
idue was washed with a mixture of acetone/pet. ether (1:4) to get a
colorless solid, which was recrystallized from methanol to afford
ketobromide 9 (33.84 g, 98%) as colorless needles. Mp 133–
135 °C (MeOH), lit.15 mp 131–134 °C (EtOH); Rf (EtOAc/pet. ether,
2:3) 0.45; mmax (CHCl3, neat)/cmÀ1 3297 (N–H), 3011, 2938 (C–H),
1729 (C@O), 1648 (NHC@O), 1602, 1546, 1510, 1027; dH
(400 MHz, CD3OD) 7.47–7.39 (2H, m, ArH), 6.90–6.85 (2H, m,
ArH), 4.28 (2H, s, CH2Br), 3.95 (2H, s, CH2), 3.76 (3H, s, OCH3); dC
(100 MHz, CD3OD) 196.5 (C@O), 167.2 (HNC@O), 156.8 (4C),
131.1 (4C), 121.7 (CH Â 2), 113.6 (CH Â 2), 54.5 (OCH3), 34.5
(CH2), 28.9 (CH2); m/z (CI+) 286 [M+H, 79Br]+ (100%), 288
[M+H+2, 81Br]+ (98%), 206 [M+H]+ÀBr; HRMS (CI+) C11H13BrNO3
(MH+) requires: 286.0078; found: 286.0079.
4.4. (1S,3S,4R)-2-((2-Bromo-6-methoxyquinolin-4-yl)methyl)-
3-((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-2-
thioniabicyclo[2.2.1]heptane tetrafluoroborate 11
Sulfide 1 (1.0 g, 4.0 mmol) was added to a solution of dibro-
mide 10 (0.662 g, 2.00 mmol) in CH2Cl2 (4.0 ml) followed by
addition of a solution of NaBF4 (1.10 g, 10.0 mmol) in water
(2.0 ml, 5 M) and the resulting mixture was heated at 45 °C for
96 h. Water (30 ml) was added and the aq layer was extracted
with CH2Cl2 (4 Â 20 ml). The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated
in vacuum. The crude material was purified by passing though a
short silica plug (eluting with CH2Cl2 and then with MeOH/
CH2Cl2 1:9), which afforded the sulfonium salt 11 (0.92 g, 78%,
95% brsm) as light yellow foam; Rf (CH2Cl2/MeOH, 9:1) 0.32;
dH (400 MHz, CDCl3) 7.81 (1H, d, J = 9.2, ArH), 7.60 (1H, s,
ArH), 7.36 (1H, dd, J = 9.2, 2.7, ArH), 7.15 (1H, d, J = 2.7, ArH),
5.13 (1H, d, J = 14.0, CHHS), 4.69 (1H, d, J = 14.0, CHHS), 4.37
(2H, br s., CHS, CHS), 4.00 (3H, s, OCH3), 3.22 (1H, br s.), 2.94
(1H, d, J = 13.4), 2.50–2.55 (1H, m), 2.29 (1H, d, J = 13.0), 2.06–
2.23 (3H, m), 1.98 (1H, d, J = 3.3), 1.79–1.89 (2H, m), 1.55–1.72
(2H, m), 1.25 (1H, ddd, J = 12.5, 9.2, 3.5), 1.18 (3H, s), 1.09
(3H, s), 1.02–1.08 (1H, m); dC (100 MHz, CDCl3) 215.4 (C@O),
159.6 (4C), 144.5 (4C), 137.6 (4C), 135.1 (4C), 131.0 (CH),
127.5 (CH), 125.9 (4C), 124.6 (CH), 100.5 (CH), 70.5 (CH), 60.0
(4C), 59.5 (CH), 56.3 (CH3), 50.0 (4C), 45.2 (CH), 44.0 (CH2),
43.6 (CH), 42.7 (CH2), 41.6 (CH2), 33.6 (CH2), 26.7 (CH2), 26.5
(CH2), 24.5 (CH2), 21.9 (CH3), 19.0 (CH3); m/z (ESI+) 500
[M+ÀBF4], 502 [M+2ÀBF4]+, 284, 286, 250 [MÀBF4ÀC15H22OS]+,
252 [M++2ÀBF4ÀC15H22OS]; HRMS (ESI+) C26H3179BrNO2S (M+)
requires: 500.1253; found: 500.1236.
4.2. 4-(Bromomethyl)-6-methoxyquinolin-2(1H)-one16
A solution of ketobromide 9 (0.285 g, 1.0 mmol) and 49%
H2SO4 (prepared by adding 5 ml of concd H2SO4 (98%) to 5 ml
of distilled water) was heated at 80 °C for 2 h. The reaction mix-
ture was cooled to rt and poured onto crushed ice. The yellow
precipitate generated was filtered with suction, and then washed
with cold water, saturated aq NaHCO3 and again with cold
water. The solid product was dried in air for 15 h and in vacuum
over P2O5 for 6 h. The resulting yellow solid was recrystallized
using a mixture of EtOH/H2O (1:1) to afford 2-quinolone as yel-
low wafers (0.235 g, 88%); mp dec. > 280 °C; mmax (CHCl3, neat)/
cmÀ1 2993, 2825, 1663 (NHC@O), 1622, 1503, 1199, 1037; dH
(400 MHz, DMSO-d6) 11.75 (1H, br s, NH) 7.33–7.28 (2H, m,
ArH), 7.21 (1H, dd, J = 9.0, 3.0, ArH), 6.74 (1H, s, ArH), 4.93
(2H, s, CH2Br), 3.82 (3H, s, OCH3); dC (100 MHz, DMSO-d6)
161.5 (HNC@O), 154.6 (4C), 146.9 (4C), 134.2 (4C), 123.1 (CH),
120.1 (CH), 118.3 (4C), 117.6 (CH), 107.6 (CH), 56.1 (OCH3),
30.5 (CH2).
4.5. (3R,4S)-2-(Trimethylsilyl)ethyl 4-(((2R,3R)-3-(2-bromo-6-
methoxyquinolin-4-yl)oxiran-2-yl)methyl)-3-vinylpiperidine-
1-carboxylate 16
Manually ground KOH (28.6 mg, 0.511 mmol) was added to a
solution of sulfonium salt 11 (100 mg, 0.170 mmol) in CH3CN/t-
BuOH (1:5) (0.6 ml, 0.3 M) containing meroquinene aldehyde 6
(101 mg, 0.340 mmol) at 0 °C under an argon atmosphere. The
resulting turbid yellow solution was stirred at 0 °C for 48 h. CH3CN
was evaporated under vacuum and water (10 ml) was added and
the aq layer was extracted with EtOAc (4 Â 10 ml). The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material (dr
93:7 trans:trans) was purified by flash silica gel column chromatog-
raphy (Et2O/pentane 1:2) to afford a mixture of the two trans epox-
ides 16 and 18 (94:6, 69 mg, 74%) as a light yellow gum; Rf (Et2O/
pentane 1:1) 0.30; 16: dH (400 MHz; acetone-d6) 7.90 (1H, d,
J = 9.3 Hz, ArH), 7.53 (1H, d, J = 2.7 Hz, ArH), 7.47 (1H, dd, J = 9.3,
2.7 Hz, ArH), 7.36 (1H, d, J = 0.5 Hz, ArH), 5.92 (1H, ddd, J = 17.3,
10.5, 8.8 Hz, CH@CHH), 5.18 (1H, ddd, J = 17.3, 2.1, 1.1 Hz,
CH@CHH), 5.13 (1H, dd, J = 10.5, 2.1 Hz, CH@CHH), 4.45 (1H, dd,
J = 2.0, 0.5 Hz, OCH–Ar), 4.11–4.17 (3H, m, Me3Si–CH2–CH2O and
CHHN), 4.02–4.10 (1H, m, CHHN), 3.98 (3H, s, OCH3), 3.15 (1H,
ddd, J = 7.2, 4.0, 2.0 Hz, CH2CH–OCH), 2.87–3.04 (1H, m, NCHH),
2.45–2.48 (1H, m, NCHH), 2.10–2.16 (1H, m, ring CH), 2.00 (1H,
ddd, J = 14.3, 6.5, 4.0 Hz, CHO–CHHCH), 1.51–1.72 (4H, m,
CHOCHH–CH and ring CH2, CH), 0.96–1.02 (2H, m, Me3Si–CH2–
CH2O), 0.05 (9H, s, SiMe3); dC (100 MHz; acetone-d6) 159.4 (4C),
156.1 (N(O)C@O), 147.0 (4C), 145.0 (4C), 139.6 (4C), 137.1 (CH),
131.3 (CH), 127.5 (4C), 123.6 (CH), 121.5 (CH), 117.6 (CH2), 102.8
(CH), 63.6 (CH2), 62.8 (CH), 56.3 (CH3), 55.8 (CH), 49.0 (CH2), 44.2
(CH2), 43.5 (CH), 38.0 (CH), 36.3 (CH2), 28.6 (CH2), 18.4 (CH2),
À1.3 (CH3 Â 3).
4.3. 2-Bromo-4-(bromomethyl)-6-methoxyquinoline 10
POBr3 (22.94 g, 80.0 mmol) was powdered in a mortar and pes-
tle and then mixed with 2-quinolone (5.36 g, 20.0 mmol). This
mixture was transferred into an RB flask fitted with a condenser.
The system was evacuated and flushed with nitrogen; the reaction
mixture was heated at 100 °C for 3 h under a nitrogen atmosphere
ensuring that the two solids were well mixed. After cooling to rt,
hot water was added very slowly and cautiously, and then the mix-
ture was poured onto crushed ice. The resulting pale yellow precip-
itate was filtered with suction and washed with water. The
precipitate was dissolved in CH2Cl2, dried over MgSO4, and filtered.
Decolorizing charcoal was added to the filtrate and stirred for 1 h.
The charcoal was removed by filtration and the filtrate was evapo-
rated under reduced pressure to give a pale yellow solid, which
was purified by passing though a short silica plug and eluting with
CH2Cl2 to afford dibromide 10 (5.65 g, 85%, 90% br sm) as pale yel-
low needles, mp 159–161 °C (acetone); Rf (CH2Cl2/pet. ether, 1:1)
0.37; mmax (CHCl3, neat)/cmÀ1 2932, 2836, 1619, 1504, 1236,
1020; dH (400 MHz, CDCl3) 7.96 (1H, d, J = 9.0, ArH), 7.50 (1H, s,
ArH), 7.39 (1H, dd, J = 9.0, 2.5, ArH), 7.26 (1H, d, J = 2.5, ArH),
4.72 (2H, s, CH2Br), 3.97 (3H, s, OCH3); dC (100 MHz, CDCl3) 158.3
(4C), 145.0 (4C), 143.2 (4C), 138.3 (4C), 131.0 (CH), 126.1 (4C),
125.8 (CH), 123.0 (CH), 102.0 (CH), 55.7 (OCH3), 27.6 (CH2); m/z
(EI) 329 [M+] (79Br  2) (50%), 331 [M++2] (79Br, 81Br) (100%), 333
[M++2+2] (81Br  2) (48%), 250 [M+ÀBr], (100%), 252 [M++2ÀBr],
(99%), 171 [M+ÀBr2]; HRMS (EI) C11H9Br2NO (M+) requires:
328.9062; found: 328.9051.

M. Arshad et al. / Tetrahedron: Asymmetry 21 (2010) 1771–1776
1775
4.6. Quinine
89:11 trans/trans) was purified by flash silica gel column chroma-
tography (Et2O/pentane 1:2) to afford the mixture of trans epox-
ides 18:16 (90:10, 111 mg, 81%) as a light yellow gum; Rf (Et2O/
pentane 1:1) 0.30; 18: dH (400 MHz; acetone-d6) 7.89 (1H, d,
J = 9.3 Hz, ArH), 7.55 (1H, d, J = 2.7 Hz, ArH), 7.46 (1H, dd, J = 9.3,
2.7 Hz, ArH), 7.34 (1H, d, J = 0.5 Hz, ArH), 5.89 (1H, ddd, J = 17.2,
10.4, 8.8 Hz, CH@CHH), 5.20 (1H, ddd, J = 17.2, 2.1, 1.0 Hz,
CH@CHH), 5.13 (1H, dd, J = 10.5, 2.1 Hz, CH@CHH), 4.49 (1H, dd,
J = 2.0, 0.5 Hz, OCH–Ar), 4.10–4.18 (3H, m, Me3Si–CH2–CH2O and
CHHN), 4.05–4.10 (1H, m, CHHN), 3.99 (3H, s, OCH3), 3.12 (1H,
ddd, J = 5.9, 5.9, 2.0 Hz, CH2CH–OCH), 2.85–3.02 (1H, m, NCHH),
2.41–2.48 (1H, m, NCHH), 2.07–2.14 (1H, m, ring CH), 1.79–1.87
(1H, m, CHO–CHHCH), 1.66–1.76 (2H, m, CHOCHH–CH and ring
CH), 1.51–1.64 (2H, m, ring CH2), 0.95–1.02 (2H, m, Me3Si–CH2–
CH2O), 0.05 (9H, s, SiMe3); dC (100 MHz; acetone-d6) 159.4 (4C),
156.1 (N(O) C@O), 147.0 (4C), 145.1 (4C), 139.6 (4C), 137.0 (CH),,
131.4 (CH), 127.6 (4C), 123.7 (CH), 121.4 (CH), 117.6 (CH2), 102.8
(CH), 63.6 (CH2), 63.1 (CH), 56.3 (CH3), 55.4 (CH), 49.0 (CH2), 44.3
(CH2), 43.9 (CH), 37.6 (CH), 36.5 (CH2), 28.3 (CH2), 18.4 (CH2),
À1.2 (CH3 Â 3).
CsF (160 mg, 1.05 mmol) was added to a solution of epoxides
16/18 (4:1 trans/trans, 115 mg, 0.211 mmol) in DMF/t-BuOH (9:1,
1.5 ml) and the mixture was heated at 110 °C for 12 h. The reaction
mixture was diluted with water (10 ml), basified with aq NaOH
(6 M), and extracted with EtOAc (4 Â 10 ml). The combined organic
layers were washed with water (4 Â 20 ml), dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude mate-
rial was dissolved in a mixture of glacial acetic acid/water (9:1,
3 ml). Granulated Zn (20 mesh, 27.5 mg, 0.42 mmol) was added
and the resulting mixture was heated at 70 °C for 5 h, diluted with
water (10 ml), basified by aq NH3, and extracted with EtOAc
(4 Â 10 ml). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude material was purified by flash silica gel column
chromatography (CH2Cl2/MeOH 20:1 containing 0.75% Et3N) to af-
ford a mixture of quinine and quinidine (4:1, 50 mg, 73%) as a col-
orless solid, with spectroscopic data (1H NMR, 13C NMR) matching
the reported data.3a
4.7. (1S,3S,4R)-2-((2-Bromo-6-methoxyquinolin-4-yl)methyl)-
3-((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-2-
thioniabicyclo[2.2.1]heptane tetrafluoroborate 17
4.9. Quinidine
CsF (111 mg, 0.731 mmol) was added to a solution of epoxides
18:16 (4.2:1 trans/trans, 80.0 mg, 0.146 mmol) in DMF/t-BuOH
(9:1, 1.0 ml) and the mixture was heated at 110 °C for 12 h. The reac-
tion mixture was diluted with water (10 ml), basified with aq NaOH
(6 M), and extracted with EtOAc (4 Â 10 ml). The combined organic
layers were washed with water (4 Â 20 ml), dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude material
was dissolved in a mixture of glacial acetic acid/water (9:1, 2 ml).
Granulated Zn (20 mesh, 19.1 mg, 0.292 mmol) was added and the
resulting mixture was heated at 70 °C for 5 h. The reaction mixture
was diluted with water (10 ml), basified by aq NH3, and extracted
with EtOAc (4 Â 10 ml). The combined organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude material was purified by flash silica gel
column chromatography (CH2Cl2/MeOH 20:1 containing 0.75%
Et3N) to afford a mixture of quinidine and quinine (4.2:1, 34 mg,
72%) as colorless solid, with spectroscopic data (1H NMR, 13C NMR)
matching the reported data.3a
Sulfide ent-1 (1.50 g, 6.00 mmol) was added to a solution of
dibromide 10 (0.993 g, 3.00 mmol) in CH2Cl2 (6.0 ml) followed by
the addition of a solution of NaBF4 (1.65 g, 15.0 mmol) in water
(3.0 ml, 5 M) and the resulting mixture was heated at 45 °C for
96 h. Water (20 ml) was added and the aq layer was extracted with
CH2Cl2 (3 Â 20 ml). The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated in vac-
uum. The crude material was subjected to flash silica gel column
chromatography (eluting with CH2Cl2 and then with MeOH/CH2Cl2
1:9), which afforded the sulfonium salt 17 (1.237 g, 70%, 95% brsm)
as a light yellow foam; Rf (CH2Cl2/MeOH, 9:1) 0.31; mmax (CHCl3,
neat)/cmÀ1 2964, 1735 (C@O), 1619, 1556, 1506, 1239, 1020; dH
(400 MHz, CDCl3) 7.82 (1H, d, J = 9.2, ArH), 7.59 (1H, s, ArH), 7.36
(1H, dd, J = 9.2, 2.7, ArH), 7.16 (1H, d, J = 2.7, ArH), 5.14 (1H, d,
J = 14.0, CHHS), 4.69 (1H, d, J = 14.0, CHHS), 4.33–4.41 (2H, m,
CHS, CHS), 4.00 (3H, s, OCH3), 3.22 (1H, br s.), 2.95 (1H, d,
J = 13.4), 2.48–2.58 (1H, m), 2.29 (1H, d, J = 13.0), 2.06–2.23 (3H,
m), 1.98 (1H, d, J = 3.3), 1.79–1.89 (2H, m), 1.55–1.72 (2H, m),
1.25 (1H, ddd, J = 12.5, 9.2, 3.5), 1.18 (3H, s), 1.10 (3H, s), 1.01–
1.08 (1H, m); dC (100 MHz, CDCl3) 215.4 (C@O), 159.6 (4C), 144.5
(4C), 137.6 (4C), 135.1 (4C), 131.0 (CH), 127.4 (CH), 125.9 (4C),
124.6 (CH), 100.5 (CH), 70.5 (CH), 60.0 (4C), 59.5 (CH), 56.3
(CH3), 50.0 (4C), 45.2 (CH), 44.0 (CH2), 43.6 (CH), 42.7 (CH2), 41.6
(CH2), 33.6 (CH2), 26.7 (CH2), 26.5 (CH2), 24.5 (CH2), 21.9 (CH3),
19.0 (CH3 m/z (ESI+) 500 [M+ÀBF4], 502 [M+2ÀBF4]+, 284, 286,
250 [MÀBF4ÀC15H22OS]+, 252 [M++2ÀBF4ÀC15H22OS]; HRMS
(ESI+) C26H3179BrNO2S (M+) requires: 500.1253; found: 500.1253.
Acknowledgments
We thank Ona Illa and Abel Ros for their help in studies on the
stability of certain sulfonium salts. M.A. thanks the Higher Educa-
tion Commission of Pakistan for a studentship and Saima Naurin
for overall help in funding. V.K.A. thanks the RS for a Wolfson Re-
search Merit Award, the EPSRC for a Senior Research Fellowship
and Merck for research support.
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6

1776
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