Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations

Article abstract of DOI:10.1002/ejoc.201901003

A catalytic asymmetric strategy for the total synthesis of quinuclidine natural products, which includes the completed enantioselective synthesis of the classical targets quinine and quinidine is disclosed. It is based on catalytic asymmetric cascade transformations, which paves the road for the synthesis of both enantiomers of the crucial C4 stereocenter with high enantioselectivity (up to 99 % ee) in one pot. Next, developing a route to all possible stereoisomers of a common early-stage intermediate sets the stage for the total synthesis of different enantiomers or epimers of quinine, quinidine and analogues with high selectivity.

Full text of DOI:10.1002/ejoc.201901003

A Journal of
Accepted Article
Title: Total Asymmetric Syntheses of Quinine, Quinidine
and Analogues via Catalytic Enantioselective Cascade
Transformations
Authors: Yan Jiang, Luca Deiana, Kaiheng Zhang, Shuangzheng Lin,
and Armando Cordova
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901003
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901003
Supported by

10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
Total Asymmetric Synthesis of Qunine, Quinidine and Analogues
via Catalytic Enantioselective Cascade Transformations
Yan Jiangb,c, Luca Deiana b,c, Kaiheng Zhang a, Shuangzheng Lin b,c and Armando Córdova*a-c
Abstract: A catalytic asymmetric strategy for the total
synthesis of quinuclidine natural products, which includes the
completed enantioselective synthesis of the classical targets
quinine and quinidine is disclosed. It is based on catalytic
asymmetric cascade transformations, which paves the road
for the synthesis of both enantiomers of the crucial C4
stereocenter with high enantioselectivity (up to 99% ee) in
one pot. Next, developing a route to all possible stereoisomers
of a common early-stage intermediate sets the stage for the
total synthesis of different enantiomers or epimers of quinine,
quinidine and analogues with high selectivity.
and catalysis has made it possible to reach targets such
as cinchona alkaloids through novel strategies based on
various enantioselective synthetic methodologies
during this century (Figure 1).[8] In this context, the first
catalytic asymmetric total synthesis of quinine and
quinidine was disclosed by Jacobsen and co-workers in
2004.[8a] Asymmetric multi-component tandem and
cascade transformations are powerful and economic
techniques for the synthesis of chiral synthons and
natural products.[9] They have the advantage of creating
multiple chemical bonds and chiral stereocenters in one
pot while still applying the logics of retrosynthetic
analysis.[10] In this context, a small molecule catalyzed
enantioselective cascade transformation has the
potential to be used as an entry for the enantioselective
synthesis of all of the possible stereoisomers of an early
stage intermediate that next can be converted to
different enantiomers and epimers of the legendary
quinuclidine natural products. Herein, we demonstrate
this strategy by the concise total synthesis of quinine,
quinidine (2) and analogues (3,4) via one-pot catalytic
asymmetric cascade transformations.
Keywords: total synthesis; asymmetric catalysis; quinidine;
one-pot enantioselective cascade reactions; cinchona
alkaloids
In memory of Prof. Gilbert Stork
Introduction
Cinchona alkaloids and their derivatives have
contributed to the history of organic chemistry by
enabling the foundations of stereochemistry and
modern chiral technology as well as being important
targets for structural determination and total
synthesis.[1] They are also an exceptionally resourceful
class of natural products, which serve as
pharmaceuticals, sensors, flavors, catalysts, ligands,
OMe
OMe
OMe
OMe
N
OH
OH
OH
N
N
N
OH
N
N
N
N
1
4
2
3
In one of the total synthesis strategies to quinine, the
quinuclidine moiety is successfully constructed via a
late-stage C8-N1 disconnection as first disclosed by
Uskovic (Figure 1).[6c] In this context, Jacobsen’s
elegant approach to construction of the required epoxide
5 was via Sharpless asymmetric dihydroxylation (OsO4,
cinchona alkaloid derived chiral ligands) of late stage
olefin intermediate 6.[8a] This reaction is highly
chemoselective and introduces the relative and absolute
stereochemistry at the C8 and C9 positions of 1. A new
strategy for the asymmetric synthesis of the crucial C4
stereocenter and the important C3 position of quinine 1,
which is responsible for modulating antimalarial
activity,[8g,11] is to use catalytic enantioselective cascade
sequences and relay catalysis (Figure 1). According to
this retrosynthetic analysis a catalytic enantioselective
synthesis of intermediate 9 in one-pot can next be
followed by the synthesis of the modular early stage
intermediate 8. Next, integration of this tactic with the
resolving
agents
and
chiral-selectors
for
enantioselective analytics.[1,2] Among them, quinine (1)
is one of the oldest medicines and it has been estimated
to have saved the largest number of human lives by a
drug introduced to therapy.[3] The first formal total
synthesis of quinine was disclosed by Woodward in
1944.[4-8] The remaining steps relies on Rabe’s
conversion of d-quinotoxine to quinine.[5] However, it
was not until 2001 that the first stereoselective total
synthesis was accomplished by Stork and co-workers.[7]
In parallel, the developments in asymmetric synthesis
[a]
Kaiheng Zhang and Prof. Dr. Armando Córdova*
Department of Natural Sciences, Mid Sweden University, SE-851 70
Sundsvall, Sweden, Fax: +(46) 8-154908, E-mail:
armando.cordova@miun.se
[b]
[c]
Dr. Yan Jiang, Dr. Luca Deiana and Dr. Luca Deiana
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, 106 91 Stockholm, Sweden
The Berzelii Center EXSELENT, Stockholm University, SE-106 91
Stockholm, Sweden.
vide
supra
described
late-stage
C8-N1
disconnection/stereoselective oxidation sequence via
Supporting information for this article is given via a link at the end of
the document
intermediate 7 and Kobayashi’s phosphonate 16[8b]
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
would complete the total syntheses of different multi-gram scale to afford 9a in high yield and ee (Table
cinchona alkaloids as well as their opposite enantiomer 1, entry 2, Scheme 2).
depending upon the choice of chiral catalysts and
ligands during the total syntheses.
Table 1. Screening of the catalytic asymmetric
Michael/cyclization cascade sequence for construction of
Uskovic (1970, 1978)
Jacobsen (2004)
Kobayashi (2004)
Krische (2008)
Aggarwal (2010)
Hatakeyama (2011)
lactam 9a in one-pot.[a]
Jacobsen’s late-stage
olefine intermediate
One-pot Enantioselective
Cascade Transformation
Wittig
OMe
O
O
MeO2
BnO
C
Bn
N
MeO2
BnO
C
Bn
N
O
O
1. Cat 11, EtOH, rt
OMe
+
+
CHO
3
MeO
OMe
BnO
PN
OMe
2
2. BnNH2, NaBH(OAc)3
CH2Cl2, rt
,
10
7
9a’
4
9a
PN
O
N
8
1
6
N
Ph
Ph
Ph
Ph
6
Ph
Ph
5
Intramolecular
SN
OH
9
N
H
N
N
H
2
N
O
N
H
OTMS
OTBS
OTBS
1
11a
11b
ent-11b
O
P
OEt
OEt
X
O
P
P
N
MeO2C
P1O
P
MeO
N
N
Yield[b] Dr
Ee (%)[d]
+
Entry
Entry Prod
Cat.
O
P1O
Modular early stage-intermediates
N
9
8
(anti:syn)
7: X = OP2 or CH2=
16
[c]
1
1
9a
9a
9a
11a
11a
11b
86
85
75
6:1
6:1
6:1
5:1
97
97
99
99
MeO2C
P
CO2Me
NH2
P1O
P1O
O
or
2[e,f]
2[e,f]
OH
3
3
4
4
ent-
9a
ent-11b 78
4[g]
5[g]
ent-
9a
ent-11b 80
4:1
97
Figure 1. Retrosynthetic analysis to quinine. P = protective
group.
a)10 (0.25 mmol), dimethyl malonate (0.75 mmol, 3 equiv)
and 11 (10 mol%) were mixed in EtOH (0.5 mL) for 48-72h.
Next, the solvent was removed under reduced pressure and
CH2Cl2 (1.25 mL), MgSO4 (50 mg) and benzyl amine (0.75
mmol, 3 equiv) were sequentially added at room temperature.
After stirring for 1h, the reaction temperature was decreased
to to 0oC and NaBH(OAc)3 (158 mg, 0.75 mmol, 3 eq.) was
added portion-wise. Next, the resulting mixture was stirred at
room temperature for 16h. b) Isolated yield. c) Determined by
NMR analysis on the crude reaction. d) Determined by chiral
HPLC analysis. e) 3.8 g scale of 10. f) 20 mL EtOH. g) 0.25
mL EtOH.
Results and Discussion
Our synthesis of quinine and quinidine began with
investigation of the catalytic enantioselective assembly
of g-lactam 9 in one pot. Two approaches where
selected using chiral amines 11 as catalysts: (1) the
enantioselctive-Michael/iminium/reductive
amination/cyclization cascade sequence[12a] (Table 1)
and (2) the catalytic aerobic oxidation/enantioselctive-
Michael/iminium/reductive amination/cyclization relay
cascade sequence (Scheme 1).[12b] The first approach
worked well and g-lactam 9 was isolated in 75-85%
yield with 5:1-6:1 dr and 97-99% ee, respectively,
starting from aldehyde 10 (Table 1). Changing the chiral
amine catalyst to ent-11a gave the opposite enantiomer
of g-lactam ent-9, which is the precursor to the unnatural
enantiomers of the cinchona alkaloids (+)-quinine and
O
O
O
MeO
OMe
MeO2C
BnO
Bn
1. Cat 11a, EtOH, rt
N
(a)
CHO
BnO
BnO
OH
2. BnNH2, NaBH(OAc)3,
CH2Cl2, rt
10
9a: 54% yield, 6:1 dr, 97% ee
Scheme 1. One-pot catalytic enantioselective synthesis of 9a.
(a) i. 5 mol% Pd(0)-AmP-MCF, O2, toluene, 70 °C 3.5h, ii. 3
eq, dimethyl malonate, 10 mol% 11a, EtOH, rt, 24h; iii. 3 eq.
benzylamine, MgSO4, 3 eq. NaBH(OAc)3, CH2Cl2, 16h.
(+)-quinidine.
The
catalytic
aerobic
oxidation/enantioselctive-Michael/iminium/reductive
amination/cyclization relay cascade sequence[12b]
starting from the allylic alcohol precursor of 10 was
next investigated. The one-pot cascade reaction gave
the corresponding lactam 9a in 54% yield, 6:1 dr and
97% ee (Scheme 1). With these results in hand, the first
one-pot cascade reaction sequence was performed at a
The total synthesis was continued by reducing lactam
9a to alcohol anti-14 followed by oxidation to aldehyde
8a, which is a key early-stage intermediate (Scheme 2).
Mild and catalytic epimerization of 8a allowed for
isolation of the syn-8a diastereoisomer (>21:1 dr).
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
followed by Swern oxidation gave aldehyde anti-7a,
which was further manipulated in a synthetic sequence
involving two Wittig reactions to afford key
intermediate 6b (Scheme 4). Next, catalytic chemo- and
enantioselective dihydroxylation of 6b using ADmix-a
gave diol 21b, which was converted to epoxide 22b.
Deprotection gave the corresponding quinidine epimer
3 in 29% overall yield from anti-8a. Using this route
and ADmix-b instead would have given access to the
corresponding quinine epimer.
O
(b)
(a)
Bn
MeO2C
BnO
Bn
HO
BnO
N
N
CHO
BnO
10
anti-14a
9a
anti:syn = 6:1 (crude)
anti:syn = 9:1 (crude)
(c)
OHC
Bn
OHC
Bn
N
N
+
BnO
BnO
anti-8a
syn-8a
anti:syn = 15:1 (crude)
(d)
OHC
2 cycles
peformed
Bn
+
OHC
Bn
N
N
Bn
Bn
OHC
Bn
HO
BnO
N
BnO
TBSO
BnO
N
BnO
Isolated >21:1 dr
anti:syn = 3:1 (crude)
N
(b)
(a)
anti-8a
syn-8a
BnO
syn-8a
syn-14a
syn-15a
(c)
Teoc
TBSO
N
Teoc
Teoc
(e)
N
(d)
TBSO
BnO
TBSO
OHC
N
Scheme 2. a) One-pot: i. 3 eq. CH3O2CCH2CO2CH3, 10
mol% 11a, EtOH, rt, 64h. ii. 3 eq. BnNH2, 3 eq.
NaBH(OAc)3, CH2Cl2, rt, 1h, 6:1 dr, 97% ee, 85%,; b) 10 eq.
LiAlH4, THF, 0 ºC, 30 min. then reflux 20h, >21:1 dr
(isolated), 78%; c) 1.5 eq. ClCOCOCl, 3 eq. DMSO, CH2Cl2,
N2, -78 ºC, 1.5 h then 6 eq. TEA, 1h, 9:1 dr (isolated), 82%;
d) 20 mol% pyrrolidine, 20 mol% CH3CO2H, CH2Cl2, rt, 1h,
96%..
syn-15b
7a
MeO
N
17a
Teoc
N
Teoc
HO
N
(f)
(g)
MeO
MeO
N
N
6a
Reduction of syn-8a gave syn-14a in excellent yield.
Next, O-TBS-protection of syn-14a and protective
group exchange[8c] of intermediate 15a gave
intermediate 15b in high yield (Scheme 3).
Deprotection of 15b by catalytic hydrogenation (Pd/C
(10 mol%), H2) was followed by oxidation to give
aldehyde syn-7a. Subsequent reaction of this
intermediate with phosphonate 16 gave olefin 17,[8b]
which was efficiently converted to key-intermediate
diolefin 6a via 18a. Catalytic chemo- and
enantioselective dihydroxylation of 6a using AD-mix-b
gave diol 19a,[13] which was converted to epoxide
20.[8a,14] Final deprotection gave (-)-quinine 1 in 20%
overall yield from syn-8a. After this milestone, we
embarked on the total synthesis of quinidine 2 (Scheme
3). Subsequently we used the same initial synthetic
strategy as for quinine by construction of syn-8a
followed by its manipulation to the diene 6a. Next,
performing the chemoselective catalytic asymmetric
dihydroxylation on 6a gave diol 21a, which was
converted to epoxide 22a in 76% yield. Final
deprotection gave (-)-quinidine 2 in 21% overall yield
from syn-8a. Having completed the total synthesis of
quinine and quinidine, we began the asymmetric
synthesis of quinidine analogues 3 and 4, respectively
(Schemes 4 and 5). Their syntheses began with
expeditious assembly of anti-14a and anti-8a (Scheme
2) as common precursors. In the case of the synthesis of
quinidine analogue 3, protective group manipulations
18a
(i)
(h)
Teoc
N
Teoc
N
HO
OH
MeO
HO
OH
MeO
N
21a
Teoc
N
N
19a
(j)
(j)
N
O
N
Teoc
MeO
O
N
22a
MeO
(k)
(k)
20a
OMe
OMe
OH
N
N
OH
N
2
N
1
Scheme 3. a) 2 eq. NaBH4, MeOH, 0 ºC, 2h, 92%; b) 1.2 eq.
TBSCl, 2.5 eq. imidazole, DMF (dry), rt, 24h, 85%; c) 3 eq.
TMSCH2CH2OH, 1 eq. triphosgene, 10 eq. K2CO3, toluene,
rt, 40h, 87%; d) i. 10 mol% Pd/C, H2 (atm), MeOH, rt, 30 min,
ii. 1.5 eq. ClCOCOCl, 3 eq. DMSO, CH2Cl2, N2, -78 ºC, 1.5
h then 6 eq. TEA, 1h, 82%; e) 1 eq. 16, 3 eq. NaH, THF, rt,
20h, 81%; f) 3 vol% HCl/MeOH, rt, 20 min, 96%; g) i. 1.5 eq.
ClCOCOCl, 3 eq. DMSO, CH2Cl2, N2, -78 ºC, 30 min then 6
eq. TEA, 30 min; ii. 2 eq. Ph3P+CH3Br-, 2 eq. KOtBu, THF,
rt, 24h, 77%; h) ADmix-b, CH3SO2NH2, tBuOH, H2O, rt, 17h,
t
>21:1 dr, 82%; i) ADmix-a, CH3SO2NH2, BuOH, H2O, rt,
17h, >21:1 dr, 83%; j) i. trimethylorthoacetate, PPTS (cat.),
CH2Cl2; ii. 3 eq. TMSCl, CH2Cl2, rt, 6h; iii. 3 eq. K2CO3,
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
t
MeOH, 30 min, 76%; k) 5 eq. CsF, BuOH, DMF, 110 ºC, CH2Cl2, rt, 6h; iii. 3 eq. K2CO3, MeOH, 30 min, 79%; j) 5 eq.
12h, 98%.
CsF, tBuOH, DMF, 110 ºC, 12h, 90%.
The total synthesis of quinidine analogue 4 began with
a Wittig reaction of anti-8a to give 23, which was
followed by protective group exchange and isolation of
intermediate 24. Next, catalytic hydrogenation was
followed by Swern oxidation and Wittig reaction to give
olefin 25 in 69% yield (Scheme 5). Catalytic
asymmetric dihydroxylation of 25 using AD-mix-a
gave diol 26, which was converted to epoxide 27. Final
deprotection gave the corresponding dihydroquinidine
epimer 4 in 35% overall yield from anti-8a. It is
noteworthy that starting from syn-8a instead of anti-8a
both dihydroquinine and dihydroquinidine can be
synthesized following this route.
Bn
OHC
Bn
Teoc
N
(a)
(b)
N
N
BnO
BnO
BnO
anti-8a
23
24
(c)
Teoc
Teoc
Teoc
N
N
N
(e)
(d)
O
N
HO
OH
MeO
MeO
MeO
N
N
27
26
25
(f)
OMe
OH
N
N
4
OHC
Bn
Scheme 5. a) a) 2 eq. Ph3P+CH3Br-, 2 eq. KOtBu, THF, rt,
24h, 95%; b) 3 eq. TMSCH2CH2OH, 1 eq. triphosgene, 10 eq.
K2CO3, toluene, rt, 40h, 81%; c) i. 10 mol% Pd/C, H2 (atm),
MeOH, rt, 30 min; ii. 1.5 eq. ClCOCOCl, 3 eq. DMSO,
CH2Cl2, N2, -78 ºC, 1.5 h then 6 eq. TEA, 1h; iii. 1 eq. 16, 3
eq. NaH, THF, rt, 20h, 69%; d) ADmix-a, CH3SO2NH2,
tBuOH, H2O, rt, 17h, >21:1 dr, 88%; e) i.
trimethylorthoacetate, PPTS (cat.), CH2Cl2; ii. 3 eq. TMSCl,
CH2Cl2, rt, 6h; iii. 3 eq. K2CO3, MeOH, 30 min, 82%; f) 5 eq.
CsF, tBuOH, DMF, 110 ºC, 12h, 92%.
N
BnO
anti-8a
(aa)
Bn
MeO2C
BnO
Bn
Bn
(a)
HO
BnO
N
(b)
N
TBSO
BnO
N
anti-15a
(c)
anti-14a
anti-9a
Teoc
TBSO
N
Teoc
Teoc
(d)
(e)
TBSO
OHC
N
TBSO
BnO
N
anti-7a
anti-15b
MeO
N
17b
Teoc
Teoc
N
Teoc
(h)
HO
N
N
Conclusions
(f)
(g)
HO
A strategy for the concise total synthesis of both
enantiomers of quinine, quinidine and analogues has
been disclosed. It was demonstrated by the asymmetric
total synthesis of quinine, quinidine and 2 epimers of
quinidine. The total syntheses are initiated by catalytic
OH
MeO
MeO
MeO
N
21b
N
18b
N
(i)
6b
Teoc
N
asymmetric
cascade
transformations,
which
OMe
N
O
N
accomplished the assembly of the crucial C4
stereocenter with high enantioselectivity (up to 99% ee)
in one pot. Next, conversion to different early-stage
intermediates allowed for the total synthesis of quinine,
quinidine and analogues with high selectivity. It is
noteworthy that the synthetic strategy allows for
asymmetric total synthesis of analogues with different
configuration and substitution at the important C3
position responsible for modulating antimalarial
activity.
OH
(j)
MeO
N
3
22b
Scheme 4. a) 10 eq. LiAlH4, THF, 0 ºC, 30 min. then reflux
20h, >21:1 dr, 78%; aa) 2 eq. NaBH4, MeOH, 0 ºC, 2h, 93%;
(b) 1.2 eq. TBSCl, 2.5 eq. imidazole, DMF (dry), rt, 24h,
84%; (c) 3 eq. TMSCH2CH2OH, 1 eq. triphosgene, 10 eq.
K2CO3, toluene, rt, 40h, 91%; d) i. 10 mol% Pd/C, H2 (atm),
MeOH, rt, 30 min, ii. 1.5 eq. ClCOCOCl, 3 eq. DMSO,
CH2Cl2, N2, -78 ºC, 1.5 h then 6 eq. TEA, 1h, 83%; e) 1 eq.
16, 3 eq. NaH, THF, rt, 20h, 89%; f) 3 vol% HCl/MeOH, rt,
20 min, 94%; g) i. 1.5 eq. ClCOCOCl, 3 eq. DMSO, CH2Cl2,
N2, -78 ºC, 30 min then 6 eq. TEA, 30 min; ii. 2 eq.
Ph3P+CH3Br-, 2 eq. KOtBu, THF, rt, 24h, 89%; h) ADmix-a,
Experimental Section
t
Typical experimental procedure for the synthesis of
lactam 9: Catalyst 11a (0.65 g, 2 mmol, 0.1 eq) was added to
a solution of enal 10 (3.8 g, 20 mmol, 1 eq) in EtOH (20 mL).
CH3SO2NH2, BuOH, H2O, rt, 17h, >21:1 dr, 94%; i) i.
trimethylorthoacetate, PPTS (cat.), CH2Cl2; ii. 3 eq. TMSCl,
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
After stirring for 2 min, dimethyl malonate (6.9 mL, 60 mmol, anti-14a (4.45 g, 13.1 mmol, 1 eq) in CH2Cl2 (10 mL) is
3 eq) was added and the reaction mixture was stirred at room slowly added dropwise. After stirring for 1h at -78oC, Et3N
temperature for 64h to reach full conversion. The solvent was (11.0 mL, 78.6 mmol, 6 eq) was slowly added dropwise and
removed under reduced pressure and CH2Cl2 (100 mL), the resulting mixture stirred for 1 h. Next, the cold bath was
MgSO4 (4 g) and benzyl amine (6.5 mL, 60 mmol, 3 eq) were removed and the mixture was stirred for an additional 30 min
sequentially added. The resulting mixture was stirred at room at room temperature. Water was added to quench the reaction,
temperature for 1h and next cooled to 0oC followed by the phases were separated, and the aqueous phase was
addition of NaBH(OAc)3 (12.7 g, 60 mmol, 3 eq) in small extracted with CH2Cl2 two times. The organic phases were
portions. The resulting mixture was stirred at room combined and quickly washed with diluted cold NaClO (aq)
temperature for 17h and next neutralized by NaHCO3 (aq) to remove the smelly dimethyl sulfide and next washed with
and extracted three times with CH2Cl2. The combined organic brine. The organic phase was dried over anhydrous Na2SO4,
phases were washed with brine and dried over anhydrous filtered and concentrated under reduced pressure. The residue
Na2SO4, filtered and concentrated in vacuo. Silica gel column was purified by silica gel column chromatography
chromatography (pentane: EtOAc = 5:1 to 2:1) gave product (PE:EtOAc, 5:1) to give aldehyde anti-8a (yellow oil, 3.62 g,
9a (orange oil, 6.27 g, 85% yield, anti:syn = 6:1). HRMS 82% yield, anti:syn
=
9:1). calcd for [M+Na]+
(ESI): calcd for [M+Na]+ (C23H27NNaO4)+ requires m/z (C22H27NNaO2)+ requires m/z 360.1934, found 360.1934.
25
404.1832, found 404.1840. [α]D25 = +9.1 (c=1.0, CHCl3). 1H [α]D = -2.6 (c=1.0, CHCl3).1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CDCl3): δ 7.35-7.26 (m, 10H), 4.70 (d, J = (8a): δ 9.64 (d, J = 2.3 Hz, 1H), 7.37-7.25 (m, 10H), 4.51-
14.6 Hz, 1H), 4.55-4.44 (m, 3H), 3.79 (s, 3H), 3.53 (t, J = 6.3 4.44 (m, 2H), 3.53-3.49 (m, 4H), 2.84-2.81 (m, 1H), 2.75-
Hz, 2H), 3.29-3.20 (m, 3H), 2.48-2.40 (m, 1H), 2.05-1.98 (m, 2.70 (m, 1H), 2.38-2.32 (m, 1H), 2.21 (t, J = 10.8 Hz, 1H),
1H), 1.80-1.72 (m, 1H), 1.62-1.45 (m, 2H). 13C NMR (100 2.16-2.09 (m, 1H), 2.03-1.94 (m, 1H), 1.86-1.77 (m, 2H),
MHz, CDCl3): δ 171.41, 165.94, 138.31, 136.82, 128.76, 1.60-1.53 (m, 1H), 1.41-1.32 (m, 1H). 13C NMR (100 MHz,
128.50, 127.75, 127.72, 127.61, 73.05, 67.41, 55.82, 52.53, CDCl3) (8a): 204.16, 138.48, 138.19, 129.10, 128.48, 128.37,
50.39, 45.74, 34.01, 33.85, 26.77. The enantiomeric excess 127.73, 127.68, 127.23, 72.99, 67.81, 63.25, 53.86, 52.39,
was determined by HPLC analysis in comparison with 52.09, 33.29, 31.78, 29.65.
authentic racemic material (ODH column, n-hexane/i-PrOH Epimerization of anti-8a and isolation of syn-8a: To a
= 85/15, λ = 210 nm, 1.0 ml/min) tr (major enantiomer) = 31.0 solution of aldehyde anti-8a (3.62 g, 10.7 mmol, 1 eq) in
min, tr (minor enantiomer) = 36.9 min.
CH2Cl2 (20 mL), was added pyrrolidine (0.18 mL, 2.1 mmol,
0.2 eq) and HOAc (0.12 mL, 2.1 mmol, 0.2 eq). After stirring
Synthesis of anti-14a: LiAlH4 (168 mL, 168 mmol, 10 eq, 1 at room temperature for 1 h, the solution was concentrated
1
M in THF) was added dropwise to a solution of compound 9a (crude H NMR showed the anti:syn ratio was 3:1) and the
(6.21 g, 16.8 mmol, 1 eq) in dry THF (150 mL) at 0oC under residue was purified by sikica gel column chromatography
a N2 atmosphere. After stirring at this temperature for 30 min, (PE:EtOAc, 1:1) to get the pure syn aldehyde syn-8a (0.71 g)
the reaction mixture was refluxed for 20 h. After cooling to and a mixture of both isomers (anti-8a major) (2.75 g). Next,
0oC with an ice-bath, the reaction mixture was carefully the isolated anti-isomer mixture (2.75g) was run for a second
quenched by adding small amounts of MeOH and NaOH time using this procedure to get additional pure syn-8a
(2M). The mixture was dried over anhydrous Na2SO4, filtered, aldehyde (0.55 g) and anti-aldehyde (2.09 g). syn-8a: HRMS
concentrated in vacuo (crude 1H NMR showed the anti:syn of (ESI): calcd for [M+Na]+ (C22H27NNaO2)+ requires m/z
9a to be 9:1). Purification by silica gel column 360.1934, found 360.1927. [α]D25 = +21.2 (c=1.0, CHCl3). 1H
chromatography (PE:EtOAc, 1:1 to EtOAc:MeOH, 10:1) NMR (400 MHz, CDCl3) (syn-8a): δ 9.86 (d, J = 0.5 Hz, 1H),
furnished alcohol anti-14a (slightly yellow oil, 4.45 g, 78% 7.34-7.23 (m, 10H), 4.48 (s, 2H), 3.58-3.42 (m, 4H), 3.07 (d,
yield, pure anti-isomer). HRMS (ESI): calcd for [M+Na]+ J = 10.4 Hz, 1H), 2.88 (d, J = 10.8 Hz, 1H), 2.37 (br s, 1H),
(C22H29NNaO2)+ requires m/z 362.2091, found 362.2088. 2.28 (d, J = 11.4 Hz, 1H), 2.19-2.13 (m, 1H), 1.89 (br s, 1H),
[α]D25 = -20.0 (c=1.0, CHCl3). 1H NMR (400 MHz, CDCl3): 1.84-1.77 (m, 2H), 1.72-1.68 (m, 1H), 1.66-1.59 (m, 1H). 13C
δ 7.36-7.23 (m, 10H), 4.53-4.46 (m, 2H), 3.65-3.64 (m, 2H), NMR (100 MHz, CDCl3) (syn-8b): δ 205.72, 138.60, 128.87,
3.57-3.45 (m, 4H), 2.87-2.84 (m, 1H), 2.73-2.69 (m, 1H), 128.48, 128.37, 127.74, 127.69, 127.16, 73.00, 67.86, 63.12,
2.50 (br s, 1H), 2.11-2.04 (m, 2H), 1.93-1.86 (m, 1H), 1.83- 54.12, 53.68, 50.15, 34.32, 32.44, 29.04.
1.80 (m, 1H), 1.53-1.46 (m, 3H), 1.38-1.33 (m, 1H). 13C Synthesis of syn-14a: To a flask containing MeOH (20 mL)
NMR (100 MHz, CDCl3): δ 138.34, 138.24, 129.33, 128.53, was added compound syn-8a (1.21 g, 3.6 mmol, 1 eq) and the
128.33, 127.83, 127.78, 127.14, 73.24, 68.54, 64.98, 63.61, resulting solution was cooled to 0oC with an ice-water bath.
56.57, 52.90, 42.73, 33.77, 32.88, 30.86.
Next, NaBH4 (0.27 g, 7.2 mmol, 2 eq) was slowly added in
Synthesis of anti-8a: To a solution of oxalyl chloride (1.7 small portions. After stirring for two hours at 0oC, the reaction
mL, 19.6 mmol, 1.5 eq) in a well dried three-neck round flask was quenched by saturated NH4Cl (aq.) and extracted with
in dry CH2Cl2 (75 mL) at -78oC under N2 atmosphere is added EtOAc three times. The combined organic extracts were
dropwise a solution of DMSO (2.8 mL, 39.3 mmol, 3 eq) in washed with brine, dried over anhydrous Na2SO4, filtered and
CH2Cl2 (5 mL). After 30 min of stirring, a solution of alcohol concentrated under reduced pressure. The residue was
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
purified by silica gel column cromatography (EtOAc:MeOH, Synthesis of 7a: To a flask containing compound syn-15b
10:1) to give the corresponding alcohol syn-14a (slightly (1.0 g, 1.97 mmol, 1 eq) and Pd/C (0.21 g, 0.20 mmol, 0.1 eq)
yellow oil, 1.12 g, 92% yield). HRMS (ESI): calcd for in MeOH (10 mL) was connected a H2 containing balloon.
[M+H]+ (C22H30NO2)+ requires m/z 340.2271, found The reaction was monitored by TLC. After 30 minutes, the
25
1
340.2264. [α]D = +15.2 (c=1.0, CHCl3). H NMR (400 reaction was finished and the mixture was filtered through
MHz, CDCl3): δ 7.33-7.27 (m, 10H), 4.49 (s, 2H), 3.93-3.90 celite and concentrated in vacuo to afford the corresponding
(m, 1H), 3.79 (dd, J = 3.4, 11.0 Hz, 1H), 3.52-3.47 (m, 4H), alcohol, which was used for the next step without further
3.06 (d, J = 11.1 Hz, 1H), 2.90 (d, J = 10.9 Hz, 1H), 2.33-2.29 purification. To a solution of oxalyl chloride (0.25 mL, 2.95
(m, 1H), 2.06-2.00 (m, 1H), 1.83-1.69 (m, 4H), 1.60-1.54 (m, mmol, 1.5 eq) in a well dried three-neck round flask in dry
2H). 13C NMR (100 MHz, CDCl3): δ 138.63, 137.67, 129.19, CH2Cl2 (10 mL) at -78oC under N2 atmosphere is added
128.58, 128.51, 127.75, 127.71, 127.46, 73.09, 68.23, 64.60, dropwise a solution of DMSO (0.42 mL, 5.91 mmol, 3 eq) in
63.48, 59.31, 53.99, 37.91, 34.67, 33.15, 29.76.
CH2Cl2 (2 mL). After 30 min of stirring, a solution of the
Synthesis of syn-15a: To a mixture of syn-14a (1.05 g, 3.1 alcohol (from the last step, 1 eq) in CH2Cl2 (3 mL) is slowly
mmol, 1 eq) in dry DMF (5 mL) was added imidazole (0.53 added dropwise. After stirring for 1 h at -78oC, Et3N (1.66 mL,
g, 7.8 mmol, 2.5 eq.) and TBSCl (0.56 g, 3.7 mmol, 1.2 eq.). 11.82 mmol, 6 eq) was slowly added dropwise and the
After stirring at room temperature for 24 h, the reaction resulting mixture stirred for 1 h. Next, the cold bath was
mixture was diluted with EtOAc, washed with NaHCO3 (aq.), removed and the mixture was stirred for an additional 30 min
brine, dried over anhydrous Na2SO4,filtrated and at room temperature. Water was added to quench the reaction,
concentrated under reduced pressure. Purification of the the phases were separated, and the aqueous phase was
residue by silica gel column chromatography (PE:EtOAc, extracted with CH2Cl2 two times. The organic phases were
6:1) gave TBS ether syn-15a (slightly yellow oil, 1.19 g, 85 % combined and quickly washed with diluted cold NaClO (aq)
yield). HRMS (ESI): calcd for [M+H]+ (C28H44NO2Si)+ to remove the smelly dimethyl sulfide and then washed with
requires m/z 454.3136, found 454.3130. [α]D25 = +18.5 (c=1.0, brine. The organic phase was dried over anhydrous Na2SO4,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.34-7.26 (m, 10H), filtered and concentrated. The residue was purified by silica
4.49 (s, 2H), 3.78 (t, J = 9.0 Hz, 1H), 3.62 (dd, J = 5.0, 9.6 gel column chromatography (PE:EtOAc, 5:1) to give the
Hz, 1H), 3.52-3.46 (m, 2H), 3.46-3.38 (m, 2H), 2.79 (br s, aldehyde 7a (yellow oil, 671 mg, 82% yield). HRMS (ESI):
1H), 2.65 (br s, 1H), 2.10-2.04 (m, 2H), 1.80 (br s, 1H), 1.74- calcd for [M+Na]+ (C20H41NNaO4Si2)+ requires m/z 438.2466,
1.64 (m, 2H), 1.56-1.55 (m, 1H), 1.47-1.39 (m, 2H), 0.85 (s, found 438.2471. [α]D25 = +4.5 (c=1.0, CHCl3). 1H NMR (400
9H), 0.01 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 139.19, MHz, CDCl3): δ 9.77 (d, J = 1.6 Hz, 1H), 4.21-4.12 (m, 2H),
138.76, 129.06, 128.51, 128.21, 127.78, 127.66, 126.85, 3.74 (br s, 2H), 3.57 (d, J = 6.6 Hz, 2H), 3.19 (br s, 2H), 2.66-
73.10, 68.81, 63.51, 61.42, 55.17, 53.10, 41.28, 33.89, 28.90, 2.63 (m, 1H), 2.44-2.35 (m, 2H), 1.58-1.52 (m, 2H), 1.48-
26.11, 18.42, -5.20, -5.21
Synthesis of syn-15b: To
1.41 (m, 1H), 0.98 (t, J = 8.4 Hz, 2H), 0.88 (s, 9H), 0.03 (s,
a
mixture of 2- 15H). 13C NMR (100 MHz, CDCl3): δ 201.76, 156.14, 63.60,
trimethylsilylethanol (1.1 mL, 7.8 mmol, 3 eq.) and 44.96, 42.56, 40.39, 28.46, 26.04, 18.34, 17.97, -1.31, -5.33,
potassium carbonate (3.59 g, 26 mmol, 10 eq) in toluene (15 -5.39.
mL) was added dropwise a solution of triphosgene (0.77 g, Synthesis of 17a: To a flask containing a solution of
2.6 mmol, 1 eq) in toluene (5 mL) at 0oC. After stirring the phosphonate 16 (478 mg, 1.55 mmol, 1 eq) in THF (15 mL)
resulting mixture at room temperature for 1 h, it was re- was added in small portions NaH (186 mg, 4.65 mmol, 3 eq,
cooled to 0oC and syn-15a (1.17 g, 2.6 mmol, 1 eq) in toluene 60% w) at 0oC. After stirring the reaction mixture at room
(5 mL) was slowly added dropwise at this temperature. After temperature for 1 h, it was re-cooled to 0oC. Next, a solution
stirring the mixture at room temperature for 40 h, the reaction of aldehyde 7a (643 mg, 1.55 mmol, 1 eq) in THF (5 mL) was
was quenched by H2O and extracted with EtOAc three times. added dropwise at this temperature. After stirring the
The combined organic extracts were dried over anhydrous resulting reaction mixture at room temperature for 20 h, the
Na2SO4, filtered, concentrated and purified by silica hel reaction was quenched by water and extracted with 3 times
chromatography (PE:EtOAc, 20:1 to 10:1) to give syn-15b with EtOAc. The combined organic phases were washed with
(colorless oil, 1.15 g, 87% yield). HRMS (ESI): calcd for brine and dried over anhydrous Na2SO4, filtered,
[M+Na]+ (C27H49NNaO4Si2)+ requires m/z 530.3092, found concentrated and purified by silica gel column
25
1
530.3090. [α]D = +12.0 (c=1.0, CHCl3). H NMR (400 chromatography (PE:EtOAc, 1:1) to give 17a (colorless oil,
MHz, CDCl3): δ 7.36-7.28 (m, 5H), 4.51 (s, 2H), 4.25-4.12 717 mg, 81% yield). HRMS (ESI): calcd for [M+H]+
(m, 2H), 3.94 (br s, 2H), 3.57-3.51 (m, 4H), 3.03 (br s, 2H), (C31H51N2O4Si2)+ requires m/z 571.3382, found 571.3387.
1.88 (br s, 1H), 1.79 (br s, 1H), 1.69 (br s, 1H), 1.63-1.57 (m, [α]D25 = +18.9 (c=1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
1H), 1.51-1.47 (m, 1H), 1.39 (br s, 1H), 1.01 (t, J = 8.4 Hz, δ 8.69 (d, J = 4.6 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.40-7.37
2H), 0.90 (s, 9H), 0.05-0.03 (m, 15H). 13C NMR (100 MHz, (m, 2H), 7.29 (d, J = 2.7 Hz, 1H), 7.02 (d, J = 15.6 Hz, 1H),
CDCl3): δ 156.39, 138.53, 128.47, 127.73, 127.68, 73.10, 6.48-6.41 (m, 1H), 4.21-4.09 (m, 3H), 3.95 (s, 3H), 3.69-3.63
68.31, 63.32, 44.92, 43.04, 40.72, 33.81, 31.46, 27.96, 26.02, (m, 2H), 3.10 (br s, 2H), 2.46 (br s, 1H), 2.41-2.33 (m, 1H),
18.30, 17.91, -1.37, -5.34, -5.40.
1.95 (br s, 2H), 1.63-1.48 (m, 3H), 1.00 (t, J = 8.9 Hz, 2H),
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
0.90 (s, 9H), 0.06-0.04 (m, 15H). 13C NMR (100 MHz, chromatography (PE:EtOAc, 1:1) to give olefine 6a (slightly
CDCl3): δ 157.96, 147.38, 131.28, 127.29, 126.58, 121.98, yellow oil, 244 mg, 77% yield). HRMS (ESI): calcd for
117.85, 101.86, 63.55, 55.70, 44.92, 40.92, 29.85, 27.84, [M+H]+ (C26H37N2O3Si)+ requires m/z 453.2568, found
25
1
26.07, 18.39, 17.99, -1.31, -5.22, -5.29.
453.2574. [α]D = +19.5 (c=1.0, CHCl3). H NMR (400
Synthesis of 18a: To a solution of compound 17a (500 mg, MHz, CDCl3): δ 8.69 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 9.2 Hz,
0.87 mmol, 1 eq) in MeOH (5 mL) was added a solution of 1H), 7.38-7.35 (m, 2H), 7.27 (d, J = 2.6 Hz, 1H), 6.99 (d, J =
3% HCl in MeOH (5 mL) at room temperature. The reaction 15.6 Hz, 1H), 6.42-6.34 (m, 1H), 5.94-5.85 (m, 1H), 5.21-
progress was monitored by TLC and after 20 min the reaction 5.18 (m, 2H), 4.19-4.06 (m, 4H), 3.94 (s, 3H), 3.05 (dd, J =
was completed. The reaction was quenched by addition of 2.8, 13.2 Hz, 1H), 2.92-2.86 (m, 1H), 2.43-2.32 (m, 2H),
water to the mixture followed by extraction with EtOAc three 2.28-2.21 (m, 1H), 1.87-1.82 (m, 1H), 1.62-1.50 (m, 2H),
times. The combined organic phases were washed with brine 0.99 (t, J = 7.7 Hz, 2H), 0.03 (s, 9H). 13C NMR (100 MHz,
and dried over anhydrous Na2SO4, filtered, concentrated and CDCl3): δ 157.88, 156.18, 147.68, 144.67, 142.25, 135.68,
purified by silica gel column chromatography (EtOAc) to 131.48, 127.28, 126.88, 121.87, 117.82, 117.54, 101.76,
afford alcohol 18a (colorless oil, 381 mg, 96% yield). HRMS 63.66, 55.67, 43.91, 42.73, 39.25, 37.33, 27.60, 17.93, -1.29.
(ESI): calcd for [M+H]+ (C25H37N2O4Si)+ requires m/z Synthesis of 19a: To a flask containing a solution of AD-
t
457.2517, found 457.2519. [α]D25 = +2.5 (c=1.0, CHCl3). 1H mix-β (0.73 g) in water (3.5 mL) and BuOH (3.5 mL) was
NMR (400 MHz, CDCl3): δ 8.67 (d, J = 4.6 Hz, 1H), 7.80 added methanesulfonamide (69 mg, 0.72 mmol, 3 eq) and the
(d, J = 9.2 Hz, 1H), 7.38-7.34 (m, 2H), 7.26-7.25 (m, 1H), mixture was left stirring until a clear yellow solution was
7.02 (d, J = 15.5 Hz, 1H), 6.41-6.33 (m, 1H), 4.22-4.18 (m, obtained. Next, this solution was added to a round bottom
2H), 4.14-4.10 (m, 1H), 3.95 (s, 3H), 3.74-3.70 (m, 1H), 3.56 flask containing olefin 6a (109 mg, 0.24 mmol, 1 eq). After
(br s, 1H), 2.94-2.82 (m, 2H), 2.41-2.34 (m, 1H), 2.31-2.24 stirring at room temperature for 17h, the reaction was
(m, 1H), 2.00 (br s, 3H), 1.58-1.55 (m, 1H), 1.48-1.38 (m, completed and Na2SO3 was added to the mixture. After
1H), 1.01 (t, J = 7.7 Hz, 2H), 0.04 (s, 9H). 13C NMR (100 stirring for an additional hour, the mixture was poured onto
MHz, CDCl3): δ 157.92, 147.59, 144.59, 142.09, 135.18, water and extracted with CH2Cl2 (three times). The combined
131.41, 127.26, 127.10, 121.91, 117.91, 101.76, 64.20, 57.84, organic layers were dried over anhydrous Na2SO4, filtered
55.72, 45.64, 44.94, 39.67, 38.45, 37.14, 27.71, 18.00, -1.33. and concentrated under reduced pressure. Purification by
Synthesis of 6a: To a solution of oxalyl chloride chloride (89 silica gel column chromatography (EtOAc) gave syn-diol 19a
µL, 1.05 mmol, 1.5 eq)in dry CH2Cl2 (3 mL) in a well dried (colorless oil, 112 mg, 82% yield). HRMS (ESI): calcd for
schlenk tube at -78oC under N2 atmosphere is added dropwise [M+H]+ (C26H39N2O5Si)+ requires m/z 487.2623, found
a solution of DMSO (0.15 mL, 2.10 mmol, 3 eq) in CH2Cl2 487.2628. [α]D25 = -12.2 (c=1.0, CHCl3). 1H NMR (400 MHz,
(1 mL). After 15 min of stirring, a solution of alcohol 18a CDCl3): δ 8.42 (d, J = 4.4 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H),
(320 mg, 0.70 mmol, 1 eq) in CH2Cl2 (2 mL) is slowly added 7.34 (d, J = 4.5 Hz, 1H), 7.29 (dd, J = 2.6, 9.2 Hz, 1H), 7.14
dropwise. After stirring for 30 min. at -78oC, Et3N (0.6 mL, (d, J = 2.6 Hz, 1H), 5.58 (dt, J = 16.6, 10.0 Hz, 1H), 5.05 (d,
4.20 mmol, 6 eq) was slowly added dropwise and the J = 4.7 Hz, 1H), 4.83-4.72 (m, 2H), 4.13-4.07 (m, 3H), 4.03-
resulting mixture stirred for 30 min. Next, the cold bath was 4.00 (m, 1H), 3.93 (br s, 1H), 3.88 (s, 3H), 2.89 (br s, 1H),
removed and the mixture was stirred for an additional 30 min 2.77 (br s, 1H), 2.26 (br s, 1H), 1.97-1.88 (m, 1H), 1.57-1.50
at room temperature. Water was added to quench the reaction, (m, 1H), 1.40-1.34 (m, 2H), 1.31-1.26 (m, 1H), 1.24 (t, J =
the phases were separated, and the aqueous phase was 7.1 Hz, 1H), 0.93 (t, J = 7.8 Hz, 2H), 0.00 (s, 9H). 13C NMR
extracted with CH2Cl2 two times. The combined organic (100 MHz, CDCl3): δ 157.86, 156.13, 147.20, 146.19,
phases were quickly washed with diluted cold NaClO (aq) to 143.82, 131.23, 126.93, 121.45, 119.31, 117.33, 101.97,
remove the smelly dimethyl sulfide and brine. The organic 73.65, 71.29, 63.61, 60.54, 55.70, 49.19, 44.15, 36.85, 35.02,
phase was dried over anhydrous Na2SO4, filtered and 28.69, 17.85, -1.33.
concentrated to afford the intermediate aldehyde, which was Synthesis of 20a: To a well dried round-bottom flask
used for the next step without further purification. In a containing a solution of 19a (71 mg, 0.146 mmol, 1 eq) in
separate flask, methyltriphenylphosphonium bromide (500 freshly distilled CH2Cl2 (3 mL) was added
mg, 1.40 mmol, 2 eq) was suspended in dry THF (10 mL) at trimethylorthoacetate (55 µL, 0.438 mmol, 3 eq) and PPTS (4
0oC and kept under N2 atmosphere. To this solution, KOtBu mg, 0.015 mmol, 0.1 eq) under N2 atmosphere. After stirring
(157 mg, 1.40 mmol, 2 eq) was added in small portions. After at room temperature for 12 h, the volatiles were removed in
stirring for 1 h at room temperature, the mixture was re- vacuo and the light yellowish residue was re-dissolved in
cooled to 0oC and a solution of aldehyde (from the last step, freshly distilled CH2Cl2 (3 mL) under nitrogen and the
1 eq) in THF (5 mL) was added dropwise. After stirring at reaction mixture was cooled to 0oC. Next, TMSCl (55 µL,
room temperature for 24 h, water was added to quench the 0.438 mmol, 3 eq) was added using a syringe. After stirring
reaction and the resulting mixture was extracted with EtOAc the reaction mixture at room temperature for 6 h, the volatiles
three times. The combined organic phases were washed with were removed in vacuo and the yellow residue was re-
brine, dried over anhydrous Na2SO4, filtered, concentrated dissolved in anhydrous MeOH (3 mL). K2CO3 (60 mg, 0.438
and crude product was purified by silica gel column mmol, 3 eq) was added and the mixture was stirred at room
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
temperature for 30 min. Next, the reaction was quenched by (colorless oil, 73 mg, 83% yield). HRMS (ESI): calcd for
addition of brine and was followed by extraction with EtOAc [M+H]+(C26H39N2O5Si)+ requires m/z 487.2623, found
(three times). The combined organic layers were dried over 487.2621. [α]D25 = +63.7 (c=1.0, CHCl3).1H NMR (400 MHz,
anhydrous Na2SO4, filtered and concentrated in vacuo. CDCl3): δ 8.53 (d, J = 4.3 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H),
Purification using silica gel column chromatography 7.43 (d, J = 4.5 Hz, 1H), 7.34 (dd, J = 2.6, 9.2 Hz, 1H), 7.12
(PE:EtOAc, 1:1) gave product 20a (colorless oil, 51 mg, 75% (s, 1H), 5.75-5.65 (m, 1H), 5.16-5.01 (m, 3H), 4.14-3.98 (m,
yield). HRMS (ESI): calcd for [M+H]+ (C26H37N2O4Si)+ 5H), 3.91 (s, 3H), 3.04 (d, J = 11.6 Hz, 1H), 2.82-2.80 (m,
requires m/z 469.2517, found 469.2525. [α]D25 = -25.9 (c=1.0, 1H), 2.30-2.29 (m, 1H), 1.96-1.93 (m, 1H), 1.72-1.65 (m, 1H),
CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 3.2 Hz, 1.50-1.43 (m, 1H), 1.27-1.21 (m, 3H), 0.97-0.93 (m, 2H),
1H), 8.08 (d, J = 9.2 Hz, 1H), 7.42 (dd, J = 2.7, 9.2 Hz, 1H), 0.01 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 158.05, 156.12,
7.29 (d, J = 4.4 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 5.91-5.82 154.78, 147.08, 143.77, 135.87, 131.29, 126.87, 121.95,
(m, 1H), 5.18-5.12 (m, 2H), 4.19-4.02 (m, 5H), 3.95 (s, 3H), 119.00, 117.31, 101.41, 73.50, 71.77, 63.64, 60.55, 55.69,
3.11 (dd, J = 3.0, 13.2 Hz, 1H), 3.01-2.98 (m, 2H), 2.46 (br s, 43.95, 43.57, 37.45, 34.96, 26.78, 17.90, -1.31.
1H), 2.05-1.95 (m, 2H), 1.67-1.53 (m, 3H), 0.99 (t, J = 7.8 Synthesis of 22a: To a well dried round-bottom flask
Hz, 2H), 0.03 (s, 9H). 13C NMR (100 MHz, CDCl3): δ containing a solution of 21a (61 mg, 0.125 mmol, 1 eq) in
158.24, 156.16, 147.85, 143.79, 142.10, 135.58, 131.75, freshly distilled CH2Cl2 (3 mL) was added
127.57, 121.84, 117.86, 116.96, 101.23, 63.71, 61.32, 55.78, trimethylorthoacetate (47 µL, 0.376 mmol, 3 eq) and PPTS (3
55.52, 43.68, 42.66, 37.32, 35.71, 31.06, 28.05, 17.93, -1.29. mg, 0.0125 mmol, 0.1 eq) under N2 atmosphere. After stirring
Synthesis of quinine 1: To a solution of 20a (34 mg, 0.073 at room temperature for 12 h, the volatiles were removed in
mmol, 1 eq) in dried DMF (3.6 mL) and tBuOH (0.4 mL) was vacuo and the light yellowish residue was re-dissolved in
added CsF (55 mg, 0.365 mmol, 5 eq). After stirring the freshly distilled CH2Cl2 (3 mL) under nitrogen and the
resulting reaction mixture at 110oC for 12 h, the reaction reaction mixture was cooled to 0oC. Next, TMSCl (47 µL,
temperature was decreased to room temperature and 0.376 mmol, 3 eq) was added using a syringe. After stirring
quenched by addition of water and next extracted with EtOAc the reaction mixture at room temperature for 6 h, the volatiles
(three times). The combined organic extracts were washed were removed in vacuo and the yellow residue was re-
with brine, dried over anhydrous Na2SO4, filtered and dissolved in anhydrous MeOH (3 mL). K2CO3 (52 mg, 0.376
concentrated under reduced pressure. The residue was mmol, 3 eq) was added and the mixture was stirred at room
purified by silica gel column chromatography (MeOH) to temperature for 30 min. Next, the reaction was quenched by
afford quinine 1 as a colorless solid (28 mg, 98% yield). All addition of brine and was followed by extraction with EtOAc
spectra and optical rotation was in accordance with an (three times). The combined organic layers were dried over
authentic sample and the literature (see ref 8a). HRMS (ESI): anhydrous Na2SO4, filtered and concentrated in vacuo.
calcd for [M+H]+ (C20H25N2O2)+ requires m/z 325.1911, Purification using silica gel column chromatography
25
found 325.1913. [α]D = -153.8 (c=1.0, EtOH)). mp = 172- (PE:EtOAc, 1:1) gave product 22a (colorless oil, 45 mg, 76%
174 oC. 1H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 4.5 Hz, yield). HRMS (ESI): calcd for [M+H]+ (C26H37N2O4Si)+
1H), 7.98 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.32 requires m/z 469.2517, found 469.2527. [α]D25 = +66.0 (c=1.0,
(dd, J = 2.6, 9.1 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 5.78-5.69 CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 2.9 Hz,
(m, 1H), 5.61 (d, J = 4.2 Hz, 1H), 4.99-4.91 (m, 2H), 3.88 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.41 (dd, J = 2.7, 9.2 Hz, 1H),
3H), 3.53-3.45 (m, 1H), 3.19-3.08 (m, 2H), 2.73-2.66 (m, 2H), 7.29 (d, J = 4.4 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 5.89-5.80
2.30 (br s, 1H), 1.84-1.82 (m, 1H), 1.78-1.71 (m, 2H), 1.59- (m, 1H), 5.20-5.16 (m, 2H), 4.19-4.15 (m, 4H), 4.03 (br s,
1.49 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 157.97, 1H), 3.95 (s, 3H), 3.08 (dd, J = 2.8, 13.1 Hz, 1H), 2.99-2.96
147.75, 147.29, 144.49, 141.72, 131.83, 126.73, 121.73, (m, 1H), 2.91 (br s, 1H), 2.40 (br s, 1H), 2.00 (br s, 1H), 1.83-
118.57, 114.71, 101.35, 71.97, 60.10, 57.01, 55.88, 43.38, 1.72 (m, 2H), 1.68-1.65 (m, 1H), 1.58-1.51 (m, 1H), 1.01-
39.94, 27.96, 27.62, 21.88.
0.97 (m, 2H), 0.03 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
Synthesis of 21a: To a flask containing a solution of AD- 158.20, 156.15, 147.98, 143.90, 141.97, 135.22, 131.85,
mix- (0.55 g) in water (2.5 mL) and tBuOH (2.5 mL) was 127.52, 121.77, 118.01, 116.80, 101.12, 63.72, 61.58, 56.01,
added methanesulfonamide (52 mg, 0.54 mmol, 3 eq) and the 55.75, 43.71, 43.22, 37.05, 36.09, 29.93, 27.49, 17.93, -1.30.
mixture was left stirring until a clear yellow solution was Synthesis of quinidine 2: To a solution of 22a (36 mg, 0.077
obtained. Next, this solution was added to a round bottom mmol, 1 eq) in dried DMF (3.6 mL) and tBuOH (0.4 mL) was
flask containing olefin 6a (82 mg, 0.18 mmol, 1 eq). After added CsF (58 mg, 0.38 mmol, 5 eq). After stirring the
stirring at room temperature for 17h, the reaction was resulting reaction mixture at 110oC for 12 h, the reaction
completed and Na2SO3 was added to the mixture. After temperature was decreased to room temperature and
stirring for an additional hour, the mixture was poured onto quenched by addition of water and next extracted with EtOAc
water and extracted with CH2Cl2 (three times). The combined (three times). The combined organic extracts were washed
organic layers were dried over anhydrous Na2SO4, filtered with brine, dried over anhydrous Na2SO4, filtered and
and concentrated under reduced pressure. Purification by concentrated under reduced pressure. The residue was
silica gel column chromatography (EtOAc) gave syn-diol 21a purified by silica gel column chromatography (MeOH) to
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
COMMUNICATION
afford quinidine 2 as a colorless solid (24 mg, 98% yield). All [3] D. A. Castel, Antimalarial Agents, In Burger’s
spectra and optical rotation was in accordance with an
medicinal chemistry and drug discovery (M. E. Wolff,
Ed.), 1997, Vol. 5, Wiley, New York, 3.
authentic sample and the literature (see ref 8a). HRMS (ESI):
calcd for [M+H]+ (C20H25N2O2)+ requires m/z 325.1911, [4] a) R. B. Woodward, W. E. Doering, J. Am. Chem. Soc.
25
found 325.1916. [α]D = +245.8 (c=1.0, EtOH)). mp = 170-
1944, 66, 849. b) R. B. Woodward, W. E. Doering, J.
Am. Chem. Soc. 1945, 67, 860.
172 oC. 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 4.5 Hz,
1H), 8.00 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 4.5 Hz, 1H), 7.33 [5] a) P. Rabe, K. Kindler, Chem. Ber. 1918, 51, 466; b) A.
(dd, J = 2.6, 9.2 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.03-5.94
(m, 1H), 5.66 (d, J = 4.2 Hz, 1H), 5.05-5.01 (m, 2H), 3.88 (s,
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3H), 3.34-3.28 (m, 1H), 3.14-3.08 (m, 1H), 2.96-2.87 (m, 2H), 6] a) M. R. Uskovic, J. Gutzwiller, T. Hendersson, J. Am.
2.83-2.75 (m, 1H), 2.28-2.21 (m, 1H), 2.05-1.94 (m, 2H),
1.78 (br s, 1H), 1.55-1.51 (m, 2H), 1.23-1.16 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 157.92, 147.82, 147.13, 144.49,
140.26, 131.92, 126.70, 121.68, 118.64, 114.99, 101.30,
71.76, 59.91, 55.77, 50.18, 49.59, 39.88, 28.31, 26.28, 21.21.
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Acknowledgements
We gratefully acknowledge financial support from the
European Union, Mid Sweden University and Swedish
National Research Council. The Berzelii Center EXSELENT
was financially supported by VR and the Swedish
Governmental Agency for Innovation Systems (VINNOVA).
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Y.-G.Wang, H.P. Acharya,Y. Kobayashi, Tetrahedron
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10.1002/ejoc.201901003
European Journal of Organic Chemistry
A versatile catalytic
asymmetric strategy
for the total synthesis
of quinuclidine natural
products and the
completed asymmetric
synthesis of the
classical targets
quinine and quinidine
is disclosed.
Total Synthesis*
Yan Jiang, Luca Deiana a,
Kaiheng Zhang a,
OMe
N
OH
N
OMe
N
OH
N
Shuangzheng Lin and
Armando Córdova*a
O
O
O
O
X
X
N
H
MeO2
BnO
Gives acces to
C
Bn
N
H
MeO2
BnO
C
Bn
N
N
MeO
BnO
OMe
+
BnNH2
,
BnNH2,
CHO
NaBH(OAc)3
CH2Cl2, rt
,
NaBH(OAc)3
,
OMe
N
Page No. – Page No.
CH2Cl2, rt
N
opposite enantiomers of
cinchona alkaloids
O2
Pd-AmP-MCF
BnO
OH
Total Asymmetric
OH
Syntheses of Quinine,
Quinidine and Analogues
via Catalytic
OMe
N
OH
N
Enantioselective Cascade
Transformations
*Total Synthesis, Catalytic Asymmetric Cascade Transformations, Enantioselective Catalysis, Cinchona Alkaloids
This article is protected by copyright. All rights reserved.