Asymmetric synthesis of warfarin and its analogs catalyzed by C 2-symmetric squaramide-based primary diamines

Article abstract of DOI:10.1039/c8ob01576g

Novel C₂-symmetric N,N′-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,β-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.

Full text of DOI:10.1039/c8ob01576g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. V. Kochetkov,
A. Kucherenko and S. G. Zlotin, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01576G.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
Asymmetric synthesis of warfarin and its analogs catalyzed by C2ꢀ
symmetric squaramideꢀbased primary diamines
S. V. Kochetkov, A. S. Kucherenko* and Sergei G. Zlotin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia
*Corresponding author. Fax: (+7)–499–135–53–28 Eꢀmail: zlotin@ioc.ac.ru, alexkucherenko@ya.ru
Keywords: Organocatalysis / Squaramides/ Michael addition / Warfarin
Abstract: Novel C2ꢀsymmetric N,N’ꢀbis(2ꢀaminoꢀ1,2ꢀdiphenylethyl) squaramides with 1,2ꢀ
di(pyridinꢀ2ꢀyl)ethane and 1,2ꢀdiphenylethane spacer groups were designed and applied as
organocatalysts in asymmetric additions of 4ꢀhydroxycoumarin and 4ꢀhydroxyꢀ6ꢀmethylꢀ2Hꢀ
pyranꢀ2ꢀone to α,βꢀunsaturated ketones. Both enantiomers of anticoagulant warfarin and its
analogs were prepared in up to 96% yield and with 96% ее. Recyclability of the developed
catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of
potential chiral medications via acylation reactions were demonstrated.
Introduction
Asymmetric organocatalysis is a vigorously developing area of current organic chemistry1 that
shows great promise for medicinal chemistry.[2] Enantioselective Michael addition of
βꢀ
dicarbonyl compounds to ꢀunsaturated ketones is especially important among pharmacologyꢀ
α,β
oriented organocatalytic transformations.3 Useful products of these reactions, in particular of
those between 4ꢀhydroxycoumarin and benzylideneacetone derivatives, are a clinically valuable
indirect action anticoagulant of warfarin (the WHO assigns it to the most efficacious, safe and
cost–effective medicines for priority conditions4) and some of its analogs used as rodenticides.5
Of the two warfarin enantiomers, the (S)ꢀenantiomer proved to be 2–5 times more active than the
(R)ꢀenantiomer.6 Various chiral 1,2ꢀdiamines7 or their derivatives bearing thiourea,8
12
imidazolidine9 or acyl groups,10 Cinchona alkaloid derivatives11 and some other chiral amines
are used as catalysts of these asymmetric transformations. Among them, primary diamines IꢀIII
provided the best yield and enantiomeric purity of the drug product (> 90% ee) (Fig. 1).
1

Organic & Biomolecular Chemistry
Page 2 of 16
View Article Online
DOI: 10.1039/C8OB01576G
Fig. 1 Most efficient catalysts for asymmetric addition of 4ꢀhydroxycoumarin to α,βꢀenones.
In the presence of 9ꢀaminoꢀ9ꢀdeoxyepiquinine I / TFA salt, warfarin was generated with 96% ее
in CH2Cl2 at 0oС, although the reaction was rather sluggish (it took 96 h to achieve full
conversion).11 A noticeable acceleration was observed at room temperature, yet at the expense of
selectivity (92% ee). Excellent stereoinduction (95% ee) was reported for simple primary amine–
thiourea catalyst IIa,8 whereas its activity was moderate under the proposed conditions (CH2Cl2,
r.t.). Primary amine phosphinamide bifunctional catalyst IIb7e (10 mol%) in combination with 4ꢀ
methylbenzoic acid (20 mol%) also exhibited excellent results (99% yield and 94% ee) in
toluene, though, a prolonged reaction time (72 h) was needed for complete conversion. C2ꢀ
Symmetric 1,2ꢀdiamine III, bearing 8ꢀquinoline fragments (Figure 1), in combination with
mandelic acid (МА) has been recently identified as catalyst of choice for asymmetric synthesis
of warfarin in pure water.13 Nearly complete conversion was attained in 24 h at room
temperature and generated warfarin had a record optical purity 91% ee (99% ее after single reꢀ
crystallyzation) ever detected in the aqueous medium. However, water, a perspective solvent in
terms of green chemistry, dissolves poorly a majority of organic reagents, which significantly
restricts applicability of the aqueous environment to organic synthesis.7c
We anticipated that chiral primary amines with the squaramide fragment would be suitable
promotors for asymmetric synthesis of warfarin. Seminal works by Rawal,14 Du,15 Jørgensen16
17
and other chemists revealed a high stereocontrolling potential of this fragment. Similar to the
thiourea group, it favorably locates reagents at corresponding transition states via stereoselective
formation of hydrogen bonds and is more robust than thiourea analogs in catalytic reactions.18
2

Page 3 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
C2ꢀSymmetric squaramideꢀtype organocatalysts may be particularly useful. They are easier to
prepare, and the doubled number of incorporated squaramide groups may enhance reaction
selectivity especially in the presence of a properly designed linker group (for example,
containing heteroaromatic fragments).
Recently, we have prepared C2ꢀsymmetric N,N’ꢀbisꢀ[(pyrrolidinꢀ2ꢀyl)methylꢀsquaramide]
TFA salts IV bearing (R,R)ꢀ or (S,S)ꢀ1,2ꢀdi(pyridinꢀ2ꢀyl)ethane spacer groups which acted as
efficient recyclable organocatalysts of enamineꢀtype asymmetric additions of cyclohexanone
derivatives to βꢀnitrostyrenes (Fig. 2).19 However, as far as we know, C2ꢀsymmetric primary
amine–squaramides capable of catalyzing iminiumꢀtype asymmetric Michael reactions have not
been reported so far. Furthermore, squaramideꢀbased organocatalysts frequently utilized in the
stereoselective synthesis of various bioactive compounds20 have never been used for the
enantioselective preparation of warfarin and its analogs.
Fig. 2 Research strategy.
Results and discussion
A synthesis of C2ꢀsymmetric catalysts V demanded selective protection of one of the two
amino groups present in chiral 1,2ꢀdiamine 1a. However, reported yields for NꢀCbzꢀ1a and Nꢀ
Cbzꢀ1b were moderate (< 61%).7d Furthermore, we expected that subsequent deprotection
(catalytic hydrogenation) of catalyst precursors bearing a pyridine fragment would be
complicated by their ability to poison palladium catalysts21. Therefore, we decided to use the
Boc group, easily removable by TFA, as an appropriate protective group in this case. There are
surprisingly few reports on monoꢀBocꢀprotection of chiral 1,2ꢀdiamines in the literature.
Commonly, a large excess of expensive diamine had to be consumed and product yields were not
high.22 The recently developed procedures are based on preꢀdeactivation of one of the amino
groups by its protonation with the stoichiometric amount of strong Brønsted acid (HBr or HCl)
3

Organic & Biomolecular Chemistry
Page 4 of 16
View Article Online
DOI: 10.1039/C8OB01576G
taken as an alcohol solution.23 The solution has to be carefully titrated before each run because of
the acid volatility, which creates major inconvenience.23b In this research, we simplified the
procedure by replacing gaseous HCl for available and readily measurable TMSCl that reacted
with MeOH directly in the reaction vessel to avoid the requirement of the strictly defined amount
of HCl required for protonation of just one amino group in compound 1a. Byꢀproduced
TMSOMe (b.p. 57ꢀ58 °C, 1 bar) did not interfere with the bocylation reaction and could be
readily removed. The procedure is applicable to monoꢀbocylation of chiral 1,2ꢀdiamines 1aꢀc
bearing aromatic, aliphatic and heteroaromatic groups (Table 1). Yields of known compounds 2a
and 2b (85ꢀ86%) were higher than those reported in the literature. The reaction is readily
scalable and practicable for synthesizing tens of grams of valuable chiral synthons 2 in a single
operation.
Table 1 Selective monoꢀBoc protection of chiral diamines 1aꢀd with TMSClꢀMeOH system.a
Entry
Diamine 1, R
(R,R)ꢀ1a, Ph
(S,S)ꢀ1a, Ph
Product 2
(R,R)ꢀ2a
(S,S)ꢀ2a
(R,R)ꢀ2b
(R,R)ꢀ2c
Yield, %
85 (80b)
1
2
3
4
86 [80c, 65d]
85 [78c, 80e,72f]
78 [n.d.]
(R,R)ꢀ1b, ꢀ(CH2)4ꢀ
(R,R)ꢀ1c, 2ꢀPyridyl
a
The reactions were carried out with TMSCl (0.01 mol, 1.26 mL), 1,2ꢀdiamine 1aꢀc (0.01 mol) and (Boc)2O
(0.012 mol, 2.6 g) in MeOH for 1.5 h. For more information see Experimental Section. b Diꢀamine 1a loading was
10 g.c Ref [23b]. d Ref [23d] e Ref [23a]. f Ref [23с].
A further synthetic scheme included halfꢀamidation of dimethyl squarate 3 with 1a or 1c,
reactions of the prepared bisꢀamidoesters 4 or 5 with monoꢀprotected (S,S)ꢀ or (R,R)ꢀ2a, and
deprotection of corresponding bisꢀamides with TFA (Scheme 1). The reactions were carried out
under simple experimental conditions (MeOH, r.t.) on air without moisture protection.
Intermediates 4, 5 and products 6, 7 were obtained in the pure form without resort to
chromatography. The absolute configuration of stereogenic centers in enantiomerically pure
primary amines 6 and 7 was consistent with their configuration in chiral synthons 1 and 2 (Fig.
3).
4

Page 5 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
Scheme 1 Synthesis of catalysts 6 and 7.
Fig. 3 Absolute configuration of stereogenic centers in C2ꢀsymmetric squaramides 6 and 7.
At first, we compared catalytic performance of compounds 6a, 6b, 7a and 7b having the
(S)ꢀconfiguration of stereogenic centers at primary amino groups in the asymmetric reaction of
4ꢀhydroxycoumarin 8a with benzylidene acetone 9a under comparable conditions (catalyst
loading 10 mol%, CH2Cl2, r.t., 24 h) (Table 2, entries 1ꢀ4). In all cases, (S)ꢀwarfarin 10a was
generated as the main product. However, the yield and enantiomeric enrichment of (S)ꢀ10a were
superior with pyridineꢀcontaining catalysts 7 than in the presence of diamines 6 bearing the 1,2ꢀ
diphenylethaneꢀ1,2ꢀdiamine linker group. Furthermore, of two diastereomeric catalysts 7a and
5

Organic & Biomolecular Chemistry
Page 6 of 16
View Article Online
DOI: 10.1039/C8OB01576G
7b, compound 7a, in which all chiral carbon atoms had similar configuration, appeared a more
efficient activator (yield 94% vs. 91%) and stereoinductor (82% ee vs. 65% ee, entries 3 and 4).
Having in hand 7a as catalyst of choice, we decided to further optimize the reaction conditions.
Testing of various aprotic (THF, PhMe, EtOAc) or protic solvents (iꢀPrOH or H2O) did not bring
positive results (entries 5ꢀ8). Nonetheless, we managed to improve the enantiomeric purity of
(S)ꢀ10a up to 96% ee by carrying out the reaction in the presence of AcOH as an acidic additive
(10 equiv. with respect to 8a, entry 9). This condition proved to be optimal: higher temperature
o
(50 C, entry 10), reduced catalyst loading (5 mol%, entry 11) or an alternative proton source
(TFA, BzOH or H2O, entries 12ꢀ14) led to inferior stereochemical results. The procedure is
stereodivergent: (R)ꢀ10a was obtained with similar yield and enantioselectivity in the presence of
antipode entꢀ7a (Entry 9). It should be highlighted that diamine 7a is one of the best known
catalysts for asymmetric synthesis of warfarin in terms of activity and stereoinduction.
Table 2 Optimization of asymmetric synthesis of warfarin. a
ee, 10a %c
(сonfiguration)
Entry
Cat
Solvent
Additive
Yield, 10a %b
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
–
–
–
–
–
76
67
94
91
72
49 (S)
33 (S)
82 (S)
65 (S)
6a
6b
7a
7b
7a
78 (S)
–
6
PhMe
60
74 (S)
7a
–
–
7
8
9
EtOAc
69
77 (S)
n.d.
96 (S) [94 (R)]
84 (R)
7a
7a
iPrOH or H2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10ꢀ15
96 (94)
97
7a (entꢀ7a)
entꢀ7a
entꢀ7a
entꢀ7a
entꢀ7a
entꢀ7a
AcOH
AcOH
AcOH
TFA
BzOH
H2O
10d
11e
12
13
14
81
10
92
64
93 (R)
n.d.
78 (R)
55 (R)
a Unless otherwise specified, the reactions were performed with 8a (16.0 mg, 0.126 mmol), 9a (22 mg, 0.151 mmol),
b
catalyst 6 or 7 (10.0 mg, 12.6 µmol), additive (1.26 mmol, entries 9ꢀ14) in the corresponding solvent (300 µL).
Isolated yield of product 10 after flashꢀchromatography on silica gel. c HPLC data (Chiralpak ADꢀH, nꢀhexane /
iPrOH 7/3, 0.8 mL minꢀ1, 254 n.m., tR = 5.1 min ((S)ꢀisomer), tR = 9.5 min ((R)ꢀisomer)). The absolute configuration
20
of (S)ꢀ10a was determined by comparing its optical rotation [α]D = ꢀ10.2 (c, 1, MeCN, 96% ee) with the reported
data [α]D = ꢀ10.7 (c, 1, MeCN, >99% ee) [7c]. d The reaction was carried out at 50˚С, e The catalyst loading was 5
20
mol%.
6

Page 7 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
The developed 7a/AcOH catalytic system appeared suitable for asymmetric synthesis of
warfarin analogs. In the optimal conditions, α,βꢀenones 9aꢀc reacted with 4ꢀhydroxycoumarin
(8a) or nonꢀannelated 4ꢀhydroxyꢀ6ꢀmethylꢀ2Hꢀpyranꢀ2ꢀone (8b) to afford corresponding
Michael adducts 10aꢀс and 11aꢀс in high yield (91ꢀ97%) with enantioselectivity 84ꢀ96% ee
(Table 3). Such data for 11a, the only known 8bꢀderived product, were superior to those reported
in the literature.9 Cyclohexenone (9d) also reacted with 8a and 8b in the presence of catalyst 7a,
although stereoinduction in these reactions was significantly lower (50ꢀ67% ee, entries 4 and 8)
than in corresponding reactions with linear α,βꢀenones 9aꢀc. It should be mentioned that 4ꢀ
hydroxyꢀ2Hꢀpyranꢀ2ꢀone derivative 11c was studied along with warfarin 10a for efficient
treatment of thromboses.24
Table 3 Asymmetric synthesis of Warfarin analogs. a
Entry
Carbon
acid
8a
R1,R2
Product
Yieldb, 10 %
eec, 10 %
[lit]
[lit]
1
2d
3d
4
5
6
(9a) C6H5, CH3
96
93
91
96 (S)
84 (R)
88 (R)
10a
10b
10c
10d
11a
11b
11c
11d
(9b) 4ꢀCH3OC6H4, CH3
(9c) 4ꢀClC6H4, CH3
(9d) ꢀ(CH2)3ꢀ
8a
8a
8a
8b
8b
8b
8b
89
50 (S)
(9a) C6H5, CH3
97 [76e]
95
94 (S) [85e]
86 (S)
(9b) 4ꢀCH3OC6H4, CH3
(9c) 4ꢀClC6H4, CH3
(9d) ꢀ(CH2)3ꢀ
7
8
95
91
89 (S)
67 (S)
a Unless otherwise specified, the reactions were performed with 8a or 8b (0.126 mmol), 9aꢀd (0.151 mmol), catalyst
7a (10.0 mg, 12.6 µmol), AcOH (70 µL) in DCM (0.3 mL). b Isolated yield of products after flashꢀchromatography
c
on silica gel. HPLC data (Chiralpak ADꢀH, Chiralpak ASꢀH, Chiralcel ODꢀH or Chiralcel OJꢀH); Absolute
d
configurations were assigned to adducts 10bꢀd and 11aꢀd by analogy with 10a. Catalyst entꢀ7a was used. e Ref.
[9].
7

Organic & Biomolecular Chemistry
Page 8 of 16
View Article Online
DOI: 10.1039/C8OB01576G
Most likely, α,βꢀenones 9 are activated in the catalytic reactions via the formation of
highly electrophilic iminium cation with a primary amino group of catalyst 7a. Simultaneously,
adjacent squaramide and pyridinium fragments of the bifunctional catalyst activate βꢀdicarbonyl
compound 8 through establishing a rigid network of hydrogen bonds with oxygen atoms which
ensure highly enantioselective reꢀface attack of 8 in the transition state TS (Fig. 4). An important
role of the protonated with AcOH pyridine fragment of catalyst 7a is in agreement with
significantly lower activity and stereoinduction of corresponding pyridineꢀfree catalyst 6a unable
to form the extra Hꢀbond with the nucleophilic reagent (see Table 2, entry 1 vs entry 3).
O
O
N
N
HN
HO
H
H
Attack
from
O
N
CH3
re-fase
H
O
Extra
H-bond
Ar
TS
Fig. 4 Plausible transition state for 7a/AcOHꢀcatalyzed Michael reaction between 8 and 9.
Catalyst 7a poorly soluble in a majority of organic solvents could be recovered from the
reaction mixtures and reused in the same reaction. After attaining high conversion, product 10a
was extracted with Et2O, then new portions of reagents, AcOH and the solvent were added to the
remaining catalyst and the reaction was reꢀperformed. The scalable (1.62 g of 8a was used)
procedure was repeated thrice with a somewhat reduced conversion and, to a less extent,
enantioselectivity (Table 4). The recorded gradual deactivation of catalyst 7a may be attributed
to byꢀside reactions of key iminium ions characteristic of primary amineꢀderived catalysts which
gradually transferred them out of the catalytic cycle [see ref. 7d].
Table 4 Recycling of catalyst 7a in the asymmetric reaction between 8a and 9a.a
Cycle
T, h
24
24
30
30
Yield,%
96
ee,%
96
94
92
89
1
2
3
4
88
82
53
8

Page 9 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
a
The reactions were performed with catalyst 7a (0.79 g, 1 mmol), 8a (1.62 g,
10.0 mmol), 9a (1.75 g, 12.0 mmol), AcOH (0.57 mL) and CH2Cl2 (5 mL).
The synthetic utility of the prepared compounds was demonstrated by selective acylation
of warfarin 10a with bioactive acids, namely acetylsalicylic (12a), 5,9ꢀdimethyldecaꢀ4,8ꢀdienoic
(12b), and 2ꢀcyclohexylꢀ5,9ꢀdimethyldecaꢀ4,8ꢀdienoic (12c – the active ingredient of the wound
healing medication Cygerol),25 in the presence of DCC/DMAP (Scheme 2). Corresponding chiral
esters 13aꢀc were obtained in high yield 75ꢀ86% and had the same enantiomeric purity as
starting compound 10a (HPLC data). Esters 13aꢀc containing two privileged pharmacophoric
groups are likely to selectively bind with different cellular receptors and have exotic
pharmacological profiles (the ‘twin drugs’ concept26).
Scheme 2 Derivatization of Warfarin (10a) with bioactive carboxylic acids 12aꢀc.
Conclusion
In summary, novel C2ꢀsymmetric N,N’ꢀbis(2ꢀaminoꢀ1,2ꢀdiphenylethyl) squaramides with 1,2ꢀ
di(pyridinꢀ2ꢀyl)ethane and 1,2ꢀdiphenylethane spacer groups have been synthesized from readily
available chiral 1,2ꢀdiamines. In the presence of catalysts 7a and entꢀ7a in combination with
AcOH, 4ꢀhydroxycoumarin and 4ꢀhydroxyꢀ6ꢀmethylꢀ2Hꢀpyranꢀ2ꢀone reacted with linear or
cyclic α,βꢀunsaturated ketones to afford corresponding Michael adducts in 89–97% yield with
moderate to high enantioselectivity (50–96% ее). The developed procedure appeared particularly
promising for asymmetric synthesis of the most active (S)ꢀenantiomer of warfarin, a clinically
useful anticoagulant. It was produced under the proposed conditions in 96% yield with 96% ee
which are among the best ever reported results. Potential recyclability of catalyst 7a poorly
soluble in organic solvents was demonstrated. (S)ꢀWarfarin esters which contain two privileged
pharmacophoric groups were prepared by selective esterification of the drug molecule with
bioactive acetyl salicylic and isoprenoid acids.
9

Organic & Biomolecular Chemistry
Page 10 of 16
View Article Online
DOI: 10.1039/C8OB01576G
Experimental section
General information
1
The NMR H and 13C spectra were recorded by Bruker AM 300 in CDCI3 and DMSO–d6. The
chemical shifts of 1H and 13C were measured relative to Me4Si or CDCl3, respectively. The high
resolution mass spectra (HRMS) were measured by Bruker microTOF II with electrospray
ionization (ESI). The optical rotations were measured on a polarimeter and calibrated with a pure
solvent as a blank. The HPLC analyses were performed on an HPLC system equipped with
chiral stationary phase columns, detection at 220 or 254 nm. Silica gel 0.060 – 0.200 was used
for column chromatography. Linaloolꢀderived isoprenoid acids 12b and 12c were used as
mixtures of isomers with regard to the double bond at C5 (E/Z ~4:1).25
General procedure for selective monoꢀBoc protection of diamines 1aꢀc
TMSCl (0.01 mol, 1.26 mL) was added to MeOH and the resulting solution was stirred for 10
min at 0˚C. Next, diamines 1aꢀc (0.01 mol) were added at 0˚C. The mixture was stirred for 15
min at room temperature and the solution of (Boc)2O (0.01 mol, 2.16 g) in MeOH (15 mL) was
added dropwise for 10 min. The resulting solution was stirred for 1.5 h. The mixture was
concentrated in vacuo. The residue was transferred to a filter and washed by diethyl ether (3 × 30
mL). The resulting paleꢀyellow solid was successively treated with the 3 N NaOH solution (25
mL) and water (3 × 10 mL). The product was dried in vacuo to afford monoꢀBoc amines 2aꢀc as
colorless solids. Characterization data on known products 2a and 2b is given in Supporting
Information.
Tertꢀbutyl ((1S,2S)ꢀ2ꢀaminoꢀ1,2ꢀdi(pyridinꢀ2ꢀyl)ethyl)carbamate (R,R-2c).
1
Colorless solid, 2.45 g (78%). Mp: 123ꢀ125 °C, H NMR (300 MHz, CDCl3): δ 8.56 (d, J = 4.4
Hz, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.26 – 6.99 (m, 4H), 6.15 (d, J = 6.2 Hz, 1H), 5.22 – 5.03 (m,
1H), 4.58 (d, J = 4.4 Hz, 1H), 2.62 (s, 2H), 1.36 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): δ
160.4, 159.3, 155.7, 148.9, 148.8, 136.2, 136.1, 122.1, 122.1, 121.9, 79.2, 60.2, 28.2 ppm.
HRMS (ESI): m/z [M]+ calcd for C17H22N4O2: 315.1816; found 315.1809; [M + Na]+ calcd
337.1635; found 337.1631; [M + K]+ calcd 353.1374 found 353.1369.
General procedure for Michael addition
The mixture of 4ꢀhydroxycoumarin 8a or 4ꢀhydroxyꢀ6ꢀmethylꢀ2Hꢀpyranꢀ2ꢀone 8b (0.126 mmol),
α,βꢀunsaturated ketone 9 (0.151 mmol), catalyst 7a or entꢀ7a (10 mg, 12.6 µmol), AcOH (70
ꢁL), and CH2Cl2 (300 ꢁL) was stirred at ambient temperature for 24 h. The solvent and AcOH
10

Page 11 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
were removed under reduced pressure (15 Torr) and the residue was extracted with Et2O (5 x 3
mL). The combined organic extracts were evaporated under reduced pressure (15 Torr).
Corresponding products 10 or 11 were purified via flashꢀchromatography on silica gel (nꢀ
hexane/EtOAc 2:1). Characterization data on all products is given in Supporting Information.
Scaling catalytic reaction and catalyst recovery
The mixture of 4ꢀhydroxycoumarin 8a (1.62 g, 10.0 mmol), α,βꢀunsaturated ketone 9a (1.75 g,
12.0 mmol), catalyst 7a (0.79 g, 1.0 mmol), AcOH (0.57 mL), and CH2Cl2 (5 mL) was stirred at
ambient temperature for 24 h. The solvent and AcOH were removed under reduced pressure (15
Torr) and the residue was extracted with Et2O (5 x 30 mL). The combined organic extracts were
evaporated under reduced pressure (15 Torr) to afford the product 10a. After extraction of
product 10a with Et2O, remained catalyst 7a was dried under reduced pressure (1.0 Torr, 30
min). Fresh portions of 8a, 9a, AcOH and CH2Cl2 were added to the recovered catalyst and the
reaction was reꢀperformed.
General procedure for Warfarin esterification
Warfarin 10a (0.154 g, 0.5 mmol), acid 12 (0.5 mmol), DCC (0.11 g, 0.5 mmol), DMAP (cat.)
and DCM (0.5 mL) were stirred for 24 h. The precipitate was filtered off and washed with DCM
(3×5 mL). The combined organic washings were evaporated and the residue was purified by
column chromatography on silica gel (eluent: nꢀhexane/EtOAc, 4:1ꢀ2:1) to afford ester 13.
2ꢀOxoꢀ3ꢀ(3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2Hꢀchromenꢀ4ꢀyl 2ꢀacetoxybenzoate (13a).
22
Colorless oil, 0.2 g (85%). [α]D = +4.8 (c, 0.2, CHCl3, 96 % ee), [HPLC Daicel Chiralcel ASꢀ
H; nꢀhexane/2ꢀpropanol, 99:1; flow rate = 0.8 mL/min; λ = 254 nm: t1 = 22.22 min., t2 = 24.19
min.]. 1H NMR (300 MHz, DMSOꢀd6) δ 7.85 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.54 –
7.05 (m, 11H), 4.06 – 3.82 (m, 1H), 3.00 – 2.69 (m, 1H), 2.16ꢀ2.06 (m, 1H), 2.05 (s, 3H), 1.94
(s, 3H) ppm. 13C NMR (75 MHz, DMSOꢀd6) δ 168.9, 160.1, 157.7, 152.8, 143.3, 132.8, 128.8,
127.6, 126.7, 124.7, 123.1, 116.7, 115.1, 104.8, 103.0, 41.0, 34.9, 24.3, 22.1 ppm. HRMS (ESI):
m/z [M]+ calcd for C28H22O7: 471.1438; found 471.1435; [M + NH4]+ calcd 488.1704, found
488.1703.
2ꢀOxoꢀ3ꢀ(3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2Hꢀchromenꢀ4ꢀyl 5,9ꢀdimethyldecaꢀ4,8ꢀdienoate (13b).
Colorless oil, 0.21 g (86%). 1H NMR (300 MHz, DMSOꢀd6) δ 7.84 (d, J = 7.5 Hz, 1H), 7.66 (t, J
= 7.8 Hz, 1H), 7.49 – 7.07 (m, 7H), 5.05 – 4.84 (m, 2H), 3.98 – 3.80 (m, 1H), 2.83 (m, 1H), 2.33
11

Organic & Biomolecular Chemistry
Page 12 of 16
View Article Online
DOI: 10.1039/C8OB01576G
(m, 2H), 2.13 (m, 2H), 2.05 – 1.83 (m, 6H), 1.78 (m, 2H), 1.66 – 1.39 (m, 9H) ppm. 13C NMR
(75 MHz, DMSOꢀd6) δ 170.9, 160.0, 157.7, 152.7, 143.2, 136.5, 136.4, 132.8, 131.3, 131.1,
128.8, 127.5, 126.7, 124.6, 124.4, 123.2, 123.0, 122.4, 116.7, 115.1, 104.8, 102.9, 102.9, 41.2,
35.2, 35.1, 31.8, 26.5, 26.3, 25.9, 25.8, 24.2, 23.5, 23.4, 17.9, 17.8, 16.2 ppm. HRMS (ESI): m/z
[M]+ calcd for C31H34O5: 487.2479; found 487.2469; [M + NH4]+ calcd 504.2744, found
504.2734; [M + Na]+ calcd 509.2298, found 509.2288.
2ꢀOxoꢀ3ꢀ(3ꢀoxoꢀ1ꢀphenylbutyl)ꢀ2Hꢀchromenꢀ4ꢀyl
2ꢀcyclohexylꢀ5,9ꢀdimethyldecaꢀ4,8ꢀ
dienoate (13c).
1
Colorless oil, 0.21 g (75%). H NMR (300 MHz, CDCl3) δ 7.69 – 7.07 (m, 9H), 5.43 – 5.24 (m,
1H), 5.21 – 5.02 (m, 1H), 4.90 – 4.76 (m, 1H), 3.93 – 3.51 (m, 1H), 3.50 – 3.11 (m, 1H), 2.90 –
2.70 (m, 1H), 2.69 – 2.54 (m, 1H), 2.53 – 2.30 (m, 1H), 2.28 – 1.43 (m, 21H), 1.26 (m, 6H) ppm.
13C NMR (75 MHz, CDCl3) δ 206.1, 171.8, 171.8, 160.9, 152.5, 140.0, 138.2, 131.7, 131.6,
128.3, 127.8, 127.7, 126.7, 124.1, 124.0, 123.7, 121.2, 121.1, 116.6, 116.1, 109.9, 77.5, 77.1,
76.7, 52.0, 45.2, 40.0, 39.9, 39.8, 37.5, 36.5, 36.5, 31.4, 31.2, 30.3, 29.9, 27.0, 26.6, 26.4, 26.3,
26.2, 25.7, 23.5, 22.4, 17.8, 17.7, 16.3 ppm. HRMS (ESI): m/z [M]+ calcd for C37H44O5:
569.3262, found 569.3257; [M + NH4]+ calcd 586.3527, found 586.3524; [M + Na]+ calcd
591.3081, found 591.3076; [M + K]+ calcd 607.2820, found 607.2821.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The research was supported by the Russian Science Foundation (Grant 16ꢀ13ꢀ10470).
Notes and references
1. (a) Science of Synthesis: Asymmetric Organocatalysis. (Eds. B. List and K. Maruoka),
volumes 1 and 2. Thieme, Stuttgart, 2012, 1928 pp.; (b) Comprehensive Enantioselective
Organocatalysis: Catalysts, Reactions, and Applications. (Ed. P.I. Dalco). WileyꢀVCH,
Weinheim, 2013, p. 1638.
2. J. Alemán, S. Cabrera, Chem. Soc. Rev., 2013, 42, 774.
3. (a) A. Mondal, S. Bhowmick, A. Ghosh, T. Chanda, K. C. Bhowmick, Tetrahedron:
Asymmetry, 2017, 28, 849; (b) O. V. Maltsev, I. P. Beletskaya, S. G. Zlotin, Russ. Chem.
Rev., 2011, 80, 11, 1067.
12

Page 13 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
4. "WHO Model List of Essential Medicines (20th List)" (PDF). World Health
Organization. March 2017.
5. (a) J.ꢀCh. Jung, O.ꢀS. Park. Molecules, 2009, 14, 4790; (b) W. R. Porter, J Comput Aided
Mol Des., 2010, 24, 553; (c) C. Moreau, M.ꢀA. Loriot, V. Siguret, Ann Biol Clin, 2012,
70, 5, 539.
6. T. Meinertz, W. Kasper, C. Kahl, E. Jähnchen, J. Clin. Pharmacol., 1978, 5, 187.
7. (a) H. Kim, C. Yen, P. Preston and J. Chin, Org. Lett., 2006, 8, 5239; (b) H.ꢀM. Yang, L.
Li, K.ꢀZh. Jiang, J.ꢀX. Jiang, G.ꢀQ. Lai, L.ꢀW. Xu Tetrahedron, 2010, 66, 9708; (c) M.
Rogoziґnska, A. Adamkiewicz, J. Mlynarski, Green Chem., 2011, 13, 1155; (d) A. S.
Kucherenko, D. E. Siyutkin, A. G. Nigmatov, A. O. Chizhov, S. G. Zlotin, Adv. Synth.
Catal., 2012, 354, 3078; (e) J. Dong, D.ꢀM. Du, Org. Biomol. Chem., 2012, 10, 8125; (f)
Y. J. Lim, D. Y. Kim, Bull. Korean Chem. Soc., 2012, 33, 6, 1825; (g) A. S. Kucherenko,
V. G. Lisnyak, A. O. Chizhov, S. G. Zlotin, Eur. J. Org. Chem., 2014, 3808.
8. R. Q. Mei, X. Y. Xu, Y. C. Li, J. Y. Fu, Q. C. Huang, L. X. Wang, Tetrahedron Lett.,
2011, 52, 1566.
9. N. Halland, T. Hansen , K. A. Jørgensen, Angew. Chem. Int. Ed., 2003, 42, 4955.
10. Z. Dong, L. Wang, X. Chen, X. Liu, L. Lin, X. Feng, Eur. J. Org. Chem., 2009, 5192.
11. J. W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J. G. Deng, Y. C. Chen, Org. Lett., 2007, 9,
413.
12. (a) T. E. Kristensen, K. Vestli, F. K. Hansen, T. Hansen, Eur. J. Org. Chem., 2009,
5185; (b) M. Leven, J. M. Neudörfl and B. Goldfuss Beilstein, J. Org. Chem., 2013, 9,
155; (c) T. Shi, Zh. Guo, H. Yu, J. Xie, Y. Zhong, W. Zhu, Adv. Synth. Catal., 2013, 355,
2538; (d) R. Porta, F. Coccia, R. Annunziata, A. Puglisi, ChemCatChem., 2015, 7, 1490;
(e) L. B. Wingard, R. A. O’Reilly, G. Levy, Clin. Pharmacol. Ther., 1978, 23, 212.
13. A. S. Kucherenko, A. A. Kostenko, G. M. Zhdankina, O. Yu. Kuznetsova, S. G. Zlotin, Green
Chem., 2018, 20, 754.
14. (a) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem. Soc., 2008, 130, 14416; (b)
Y. Zhu, J. P. Malerich, V. H. Rawal, Angew. Chem. Int. Ed., 2010, 49, 153; (c) H.
Konishi, T. Y. Lam, J. P. Malerich, V. H. Rawal, Org. Lett., 2010, 12, 2028.
13

Organic & Biomolecular Chemistry
Page 14 of 16
View Article Online
DOI: 10.1039/C8OB01576G
15. (a) W. Yang, D.ꢀM. Du, Org. Lett., 2010, 12, 5450–5453; (b) W. Yang, D.ꢀM. Du, Adv.
Synth. Catal., 2011, 353, 1241; (c) W. Yang, D.ꢀM. Du, Chem. Commun., 2011, 47,
12706.
16. Ł. Albrecht, G. Dickmeiss, F. C. Acosta, C. RodríguezꢀEscrich, R. L. Davis, K. A.
Jørgensen, J. Am. Chem. Soc., 2012, 134, 2543.
17. (a) Y.ꢀF. Wang, R.ꢀX. Chen, K. Wang, B.ꢀB. Zhang, Zh.ꢀB. Lib, D.ꢀQ. Xu, Green Chem.,
2012, 14, 893; (b) A. Noole, I. Jarving, Franz Werner, Margus Lopp, Andrei Malkov, T.
Kanger, Org. Lett., 2012, 14, 18, 4922; (c) P. Kasaplar, P. Riente, C. Hartmann, M. A.
Pericas, Adv. Synth. Catal., 2012, 354, 2905.
18. J. Aleman, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J., 2011, 17, 6890.
19. A. S. Kucherenko, V. G. Lisnyak, A. A. Kostenko, S. V. Kochetkov, S. G. Zlotin, Org.
Biomol. Chem., 2016, 14, 9751.
20. X. Han, H. B. Zhou, C. Dong, Chem. Rec., 2016, 16, 897.
21. M. D. Argyle, C. H. Bartholomew, Catalysts, 2015, 5, 145.
22. (a) A. P. Krapcho, C. S. Kuell, Synt. Commun., 1990, 20, 16, 2559; (b) P. D. Garimella,
A. Datta, D. W. Romanini, K. N. Raymond, M. B. Francis, J. Am. Chem. Soc., 2011, 133,
14704; (с) B. Seema Joshi, N. Kumar, S. Kidwai, R. Singh, D. S. Rawa, Arch. Pharm.
Chem. Life Sci., 2012, 345, 896; (d) S. M. Kirk, P. McKeown, M. F. Mahon, G. Kociokꢀ
Köhn, T. J. Woodman, M. D. Jones, Eur. J. Inorg. Chem., 2017, 5417; (e) L. Yan, G.
Huang, H. Wang, F. Xiong, H. Peng, F. Chen, Eur. J. Org. Chem., 2018, 99.
23. (a) D. W. Lee, H. J. Ha, Synth. Commun., 2007, 37, 737; (b) G. J. Zhu, C. S. Da, Y. N.
Jia, X. Ma, L. Yi, Letters in Organic Chemistry, 2010, 7, 15; (c) M. O. Darwish, A.
Wallace, G. J. Clarkson, M. Wills, Tetrahedron Letters, 2013, 54, 4250; (d) T. Takeda,
M. Terada, J. Am. Chem. Soc., 2013, 135, 15306; (e) Sh. Yian; R. Chao; P. Hongjie; L.
Mao; T. Hua, Chinese Academy Of Sciences Chemical Institute; CN106749011, 2017, A
Location in patent: Paragraph 0042; 0070.
24. K. Rehse, W. Schinkel, Arch. Pharm., 1983, 316, 12, 988.
25. (a) L. S. Bondar, R. A. Okunev, Brit. Pat. GB 1,173,419; Chem. Abstr., 1970, 72,
54770f; (b) Bondar, L. S.; Okunev, R. A. Ger. Offen. DE 1,801,868; Chem. Abstr., 1970,
14

Page 15 of 16
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01576G
73, 34814r; (c) L. S. Bondar, R. A. Okunev, A.s. 333162 USSR; Chem. Abstr., 1972, 77,
100910e; (d) J. Nichols, G. F. Bulbenko, Ger. Offen. DE 2,335,067; Chem. Abstr., 1976,
80, 146380x.
26. (a) H. Fujii, Top. Curr. Chem., 2011, 299, 239. (b) J.ꢀM. Contreras, W. Sippl, in The
Practice of Medicinal Chemistry, 3rd edn., (Ed. C. G. Wermuth), Academic Press,
Amsterdam, 2008, p. 380.
15

Organic & Biomolecular Chemistry
Page 16 of 16
View Article Online
DOI: 10.1039/C8OB01576G
138x70mm (300 x 300 DPI)