Conjugate Addition of Carbon Acids to β,γ-Unsaturated α-Keto Esters: Product Tautomerism and Applications for Asymmetric Synthesis of Benzo[ a]phenazin-5-ol Derivatives

Article abstract of DOI:10.1021/acs.joc.9b02021

A correlation between the equilibrium ratio of tautomeric products generated by the asymmetric Michael reactions of cyclic carbon acids with β,γ-unsaturated α-keto esters and the chemical shift of the α-proton in starting nucleophilic substrates was revealed which makes equilibration predictable. New tetrahydropyran-fused benzo[a]phenazins were enantioselectively (up to 99% ee) synthesized from β,γ-unsaturated α-keto esters and benzo[a]phenazin-5-ol, a powerful anti-cancer agent sAJM589. Facile recyclability of catalyst Ia in the catalytic reactions was demonstrated.

Full text of DOI:10.1021/acs.joc.9b02021

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Article
Conjugate Addition of Carbon acids to #,#-Unsaturated #-
Keto Esters: Product Tautomerism and Application for
Asymmetric Synthesis of Benzo[a]phenazin-5-ol Derivatives.
Rinat S. Tukhvatshin, Alexander Sergeevich Kucherenko, Yulia V. Nelyubina, and Sergei G. Zlotin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02021 • Publication Date (Web): 30 Sep 2019
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Conjugate Addition of Carbon acids to β,γ-Unsaturated α-Keto Esters:
Product Tautomerism and Application for Asymmetric Synthesis of
Benzo[a]phenazin-5-ol Derivatives
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,
Rinat S. Tukhvatshin, † ‡ Alexander S. Kucherenko,* ,† Yulia V. Nelyubina‡ and
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Sergei G. Zlotin*,†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky
Prospect, 119991, Moscow, Russian Federation
*E-mail: zlotin@ioc.ac.ru, alexkucherenko@ya.ru
‡A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28,
Vavilova Str, 119991, Moscow, Russian Federation
CO2R'
OH
O
HO
HO
O
CO2R'
R
R
N
O
Ia
(10 mol%)
89-99%
OH
CO2R'
O
R
OR'
11 cycles
R
N
O
97%
up to
ee
99%
up to ee
ABSTRACT: A correlation between the equilibrium ratio of tautomeric products generated by
the asymmetric Michael reactions of cyclic carbon acids with β,γ-unsaturated α-keto esters and
the chemical shift of the -proton in starting nucleophilic substrates was revealed which makes
equilibration predictable. New tetrahydropyran-fused benzo[a]phenazins were enantioselectively
(up to 99% ee) synthesized from β,γ-unsaturated α-keto esters and benzo[a]phenazin-5-ol, a
powerful anti-cancer agent sAJM589. Facile recyclability of catalyst Ia in the catalytic reactions
was demonstrated.
Introduction
The ring-chain tautomerism of organic compounds is of great significance in Nature and
organic chemistry.1 A classic example of this phenomena is the gradual interconversion of linear
carbohydrates into their cyclic forms, which results in the change in the optical rotation
(mutarotation).2 The capability of linear  and hydroxycarbonyl compounds to transform
reversibly into cyclic hemiacetals or hemiketals enables a large scale production of useful
heterocyclic compounds, such as furaldehyde,3 chromanes, chromenes,4 β-nicotinamide riboside
and its analogues5 etc.
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The ring-chain tautomerism also occurs in some recently developed asymmetric reactions,6
particularly, in bifunctional tertiary amine-catalyzed7 asymmetric addition of 4-hydroxycoumarin
to β,γ-unsaturated α-keto esters.8 Regardless of the catalyst used (C, D or E), the reaction
produces a mixture of linear Michael adducts A and fused tetrahydropyran derivatives B, bearing
a quaternary stereogenic center (Scheme 1). The tetrahydropyran unit is found in numerous
natural compounds and pharmaceuticals.9 In some cases, heterocycles B were isolated and their
structure was confirmed by the single-crystal X-ray analysis.8a,c,10 However, the rate and
stereoselectivity of the A/B equilibrium have not been examined to date that restricts application
of the cascade process in the asymmetric synthesis of valuable heterocyclic products (for
applications of asymmetric Michael reactions to enantioselective synthesis of pharmacology-
relevant compounds see ref.11).
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Herein we first investigated the correlation between the -C-H bond polarization in
nucleophilic substrates (1H NMR data) and the A ↔ B equilibrium ratio in the corresponding
reaction products and applied it for designing configurationally stable 2-
hydroxytetrahydropyrans fused with benzo[a]phenazine, the key structural unit of powerful anti-
cancer agent sAJM589.12
Scheme 1. The ring-chain tautomerism between compounds A and B
OH
H
O
HO
O
CO2R'
R
C-E
Cat.
O
O
OR'
OR'
R
R
O
O
A
B
OMe
N
S
N
H
H
NH
N
N
N
CF3
HN
N
NH
R
S
CF3
CF3
O
NH
R2
F3C
C
D
E
O
Cao et al.[8a]
Yield 78-99%, 84-96% ee
Wang et al.[8c]
Yield 91-98%, 90-98% ee
Xu et al.[8b]
Yield 65-94%, 86-99% ee
Results and Discussion
To evaluate the role of the acceptor component, we examined the reaction of 4-
рydroxycoumarin 1a with 2-oxo-4-arylbut-3-enoates 2 in the presence of bifunctional tertiary
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amine – squaramide catalyst Ia modified with ionic group (THF, r.t.) (Scheme 2). This catalyst,
recently developed by our research group,13 exhibited better stereoinduction in the model
reaction than similar catalysts14 Ib and Ic without ionic groups and allowed asymmetric
synthesis of the corresponding tautomeric products 3 and 4 in nearly quantitative yield with up to
97% ee (for experimental details, see Supporting Information). The equilibrium ratio between
cyclic and linear components 4 / 3 in the raw adducts ranged from ~1.1 : 1 to ~3.2 : 1 being the
highest for compounds 4h / 3h bearing 4-cyano group in the aromatic ring (1H NMR data).
Crystallization of an oily 4b / 3b mixture resulted in a crystalline cyclic tautomer 4b. According
to X-ray diffraction data, the key stereocenter in thus obtained crystals has the (S)-absolute
configuration (Fig. 1). Similar (S)- configuration was assigned to the other products 4 / 3 by
analogy.
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Scheme 2. Ia-Catalyzed asymmetric reactions of 1a with β,γ-unsaturated α-keto esters 2
O
O
O
O
O
O
Ar
N
H
N
Ar
N
H
N
H
N
Ar
N
H
N
H
N
H
N
Ia
PF6
Ib
Ic
O
[ ]
N
4
N
Ar = 3,5-(CF3)2C6H3
O
HO
O
CO2R
OH
O
OH Ar
O
O
(S)
OR
Ia (
10 mol%)
OR
(S)
Ar
Ar
THF, r.t., 2 - 6 h,
yield 89-99 %,
89-97% ee
O
O
O
O
O
O
O
2
1a
3
4
4 3
/
ratio = 1.1 : 1 - 4.4 : 1
2 4
a
b
c
d
e
f
- : R = Me, Ar = Ph ( ), 4-MeC6H4 ( ), 4-F3CC6H4 ( ), 4-NCC6H4 ( ), 2-Furyl ( ), 2-Thienyl ( );
g
h
R = Et, Ar = 2-ClC6H4 ( ), 2-NCC6H4 ( );
i
j
k
R = i-Pr, Ar = 4-MeC6H4 ( ), 4-F3CC6H4 ( ), 4-NCC6H4 ( );
l
R = t-Bu, Ar = Ph ( )
1
Tautomeric equilibration between 4 and 3 proved to be a dynamic process. The H NMR
spectra of the crystalline compound 4b recorded 5 min after dissolution in CDCl3 exhibited only
characteristic signals of the methyl protons of semi-ketal 4b at 2.35 and 3.90 ppm (Fig. 1, line 1,
1
red picks). However, in the H NMR spectra of the same solution recorded 2 h after, the
corresponding proton signals of linear adduct 3b appeared at 2.34 and 3.94 ppm (line 2, blue
picks) and their intensity gradually increased with the solution ageing time (lines 3 and 4, blue
picks). The equilibrium ratio 4b / 3b ~2 : 1 was attained 16 h after dissolution of 4b (line 5) and
showed no further changes (line 6). Catalyst Ia exerted no influence on the tautomerization
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process: similar 1H NMR experiment with solution of 4b in CDCl3 in the presence of Ia (10 mol
%) showed that 4b / 3b ratio was ~6 : 1 after 5 h and ~2.1 : 1 after 24 h. On the other hand, in
more polar solvent (DMSO) the equilibrium ratio 4b / 3b ~2 : 1 was attained already 5 h after
dissolution of 4b (see SI). Crystalline product 4e (was obtained by crystallization of the raw
product 4e / 3e) in the CDCl3 solution also gave equilibrium mixture of the two tautomers (~1 :
1) (see Experimental Section and in SI).
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1
Figure 1. X-ray image of crystalline product 4b and fragments of the H NMR spectra of the
CDCl3 solution of 4b recorded after specified times (characteristic signals of CH3 protons in 4b
and 3b are shown by red and blue lines, respectively).
Then, to evaluate the impact of the donor counterpart, we studied the corresponding
reactions of cyclic 1,3-dicarbonyl compounds 1b-d with β,γ-unsaturated α-keto ester 2a in the
presence of catalyst Ia. The reactions afforded mixtures of cyclic (4ba-4da) and linear products
(3ba-3da) in nearly quantitative yield and 90-97% ee (Scheme 3). We noticed that the larger the
-protone chemical shift (H, H NMR) in the corresponding substrates 1, the higher the 4 / 3
1
ratio in the synthesized mixtures [1.7 : 1 for 4ba / 3ba (H1b 5.2 ppm), 2.1 : 1 for 4a / 3a (H
1a
5.6 ppm), 3.4 : 1 for 4ca / 3ca (H1c 5.9 ppm) and 4.4 : 1 for 4da / 3da (H1d 6.1 ppm)]. Most
likely, this range correlates with the polarity order of substrates 1 and Michael adducts 3.
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Apparently, the enhanced -proton chemical shift reflects a higher electron-withdrawing ability
of cyclic moiety in -dicarbonyl compound 1a-d. The latter leads in turn to increasing both
nucleophilicity of the hydroxyl group and electrophilicyty of the carbonyl group in
corresponding linear Michael adducts 3 which makes the ketalization step energetically more
favorable (Scheme 3). Pure adduct 4da was isolated from the equilibrium 4da / 3da mixture by
crystallization (see Experimental Section and in SI).
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Scheme 3. Asymmetric reactions of cyclic carbon acids 1a-d with β,γ-unsaturated α-keto ester
2a catalyzed by Ia
HO
O
CO2Me
H
H
CO2Me
Ia
O
O
O
Ph
O
O
H
O
(10 mol %)
THF, r.t., 4-6 h
+
Ph
O
OMe
O
Ph
2a
1a-d
3a 3ba-3da
,
4a 4ba-4da
,
4a 3a
/
(2.1 : 1): Yield: 98%, 90% ee;
/
(1.7 : 1): Yield: 99%, 93% ee (Lit. 91% ee,[8a] 45% ee[10a]);
4ba 3ba
4ca 3ca
/
(3.4 : 1): Yield: 98%, 90% ee;
(4.4 : 1): Yield: 97%, 93% ee (Lit. 77% ee,[8a] 50% ee[10a]
)
4da 3da
/
OH
 6.1 ppm
H
OH
OH
OH
O
 5.2 ppm
 5.9 ppm
 5.6 ppm
O
H
H
H
O
O
O
1c
O
O
1b
1a
1d
We expected that the usage of stronger carbon acids would further enhance
chemoselectivity of their reactions with β,γ-unsaturated α-keto esters 2. To verify this
hypothesis, we studied the reactions of compounds 2 with benzo[a]phenazin-5-ol 5 (H 7.2
ppm) in the presence of catalyst Ia. Indeed, these reactions afforded exclusively novel cyclic
hemiketals 6a-e in 85-95% yields regardless the substituents R1 and R2 in keto esters 2 (Scheme
4). According to 1H NMR and chiral HPLC analysis data, heterocycles 6 are the mixtures of two
diastereomers in a 1 : 1–1.5 : 1 ratio. We succeeded to isolate the major diastereomer of 6a by
crystallization of a raw reaction product from n-hexane-EtOAc (5 : 1) and determine its absolute
(R,S) configuration (X-ray diffraction analysis). The same (R,S) configuration was assigned to
the major diastereomers of products 6c-e by analogy. To our delight, cyclic hemiketals 6a-e did
not undergo reversible opening of the tetrahydropyran ring to give the corresponding linear
Michael adducts. 1H NMR spectra of fresh solution and a one-week aged solution of 6a in CDCl3
or d6-DMSO were identical. To the best of our knowledge, compounds 6a-e are the first stable
chiral cyclic hemi-ketals.10a
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The phenazine scaffold is an important pharmacophoric motif and is present in various
natural compounds and medications.15 For instance, benzo[a]phenazin-5-ol 5 used as the starting
substrate in this research is a powerful anti-cancer agent sAJM589.12 The developed approach
may be useful for enantioselective synthesis of biologically active compounds in this series of
pharmacology-relevant heterocyclic system. The practicality of the proposed catalytic approach
was clearly demonstrated by recyclability of ionic liquid supported catalyst Ia, which could be
readily separated from the reaction mixture and 11 times reused in the catalytic reaction between
compounds 1a and 2a without a significant decrease in the yield or ee values of products 3a / 4a
(for details, see Experimental Section and SI).
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Scheme 4. Asymmetric reactions of benzo[a]phenazin-5-ol 5 with β,γ-unsaturated α-keto esters
2 catalyzed by Ia
HO CO2R2
HO CO2R2
(R)
(S)
O
OH
N
O
 7.2 ppm
(R)
H
(R)
CO2R2
Ia
R1
R1
O
(10 mol %)
THF, r.t., 4-6 h
+
+
N
N
N
N
N
R1
5
2
6
(R,R)-
6
(R,S)-
1
2
6a
6b
6c
6d
6e
(R = Ph, R = Me): Yield: 85%, R,S/R,R 1.3 : 1,
ee 97% (R,S), 97% (R,R);
1
2
(R = 2-ClC6H4, R = Et): Yield: 91%, S,S/R,S 1 : 1,
ee 97% (S,S), 96% (S,R);
1
2
(R = 4-NCC6H4, R = Et): Yield: 90%, R,S/R,R 1.3 : 1,
ee 98% (R,S), 96% (R,R);
1
2
i
(R = 4-F3CC6H4, R = Pr): Yield: 93%, R,S/R,R 1.5 : 1,
ee 95% (R,S), 99% (R,R);
1
2
i
(R = 2-Thienyl, R = Pr): Yield: 95%, R,S/R,R 1.4 : 1,
ee 92% (S,S), 94% (S,R).
6a
X-Ray image of (R,S)-
Conclusions
In summary, in the present work we revealed the correlation between the equilibrium ratio of
tautomeric products 3 / 4 generated upon the asymmetric Michael reactions of carbon acids 1
with β,γ-unsaturated α-keto esters 2 and the chemical shift of the -proton of the starting carbon
acids 1. Previously unknown benzo[a]phenazine derivatives fused with tetrahydropyran moieties
were enantioselectively (up to 99% ee) synthesized from β,γ-unsaturated α-keto esters 2 and
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benzo[a]phenazin-5-ol 5. The developed enantioselective approach is applicable for synthesizing
potentially bioactive compounds which contain this pharmacology-relevant heterocyclic motif.
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Experimental Section
General information. High-resolution electrospray ionization mass spectrometry (HRMS (ESI))
was performed on a Fluka time-of-flight (TOF) instrument. The measurements were taken in the
positive ion mode (interface capillary voltage 4500 V) in the mass range from m/z = 50 Da tom/z
= 3000 Da; external or internal calibration was done with an electrospray calibrant solution.
1
13
NMR spectra were recorded on a 300 MHz spectrometer. The H and C chemical shifts were
measured relative to Me4Si, CDCl3, respectively. Optical rotations were measured on a
polarimeter calibrated with pure solvent as a blank. Atoms in the X-ray image of compound 4b
and 6a are represented by thermal ellipsoids at the 50% probability level. CCDC 1870961 (4b)
and 1878178 (6a) contains the supplementary crystallographic data for this paper. The HPLC
analyses were performed on chiral stationary phase columns Chiralpak AD-H and Chiralpak AS-
H, detection at 254 nm. Silica gel (0.060−0.200 mm) was used for column chromatography. All
reagents and solvents were purified according to standard methods. Centrifugation was
performed at 3500 rpm. All β,γ-unsaturated α-keto-esters 2 were prepared according to the
reported procedures.16 Racemic compounds 3/4 and 6 were prepared from 1 or 5 and 2 using
TEA (10 mol %) as a catalyst.
1
Methyl 4-(4-cyanophenyl)-2-oxobut-3-enoate (2d). Yellow powder, m.p. 149-151 °C. H NMR
(300 MHz, CDCl3) δ 7.86 (d, J = 16.2 Hz, 1H), 7.74 (s, 4H), 7.47 (d, J = 16.2 Hz, 1H), 3.97 (s,
13
3H). C{1H} NMR (75 MHz, CDCl3) δ 181.8, 161.9, 145.5, 138.1, 132.7, 129.2, 123.3, 118.1,
114.5, 53.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C12H10NO3 216.0655, found 216.0658.
1
Ethyl 4-(2-chlorophenyl)-2-oxobut-3-enoate (2g). Yellow oil. H NMR (300 MHz, CDCl3) δ
8.27 (d, J = 16.2 Hz, 1H), 7.73 (dd, J = 7.1, 2.3 Hz, 1H), 7.46 – 7.27 (m, 4H), 4.39 (q, J = 7.1
Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 182.8, 162.1, 143.9, 136.1,
132.3, 130.4, 127.9, 127.3, 122.8, 62.6, 14.1, 13.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C12H12ClO3 239.0470 and 241.0440, found 239.0471 and 241.0446.
1
Ethyl 4-(4-cyanophenyl)-2-oxobut-3-enoate (2h). Yellow powder, m.p. 139-141 °C. H NMR
(300 MHz, CDCl3) δ 7.81 (d, J = 16.2 Hz, 1H), 7.71 (s, 4H), 7.43 (d, J = 16.1 Hz, 1H), 4.38 (q, J
= 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 177.0, 156.4, 140.1,
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132.9, 127.5, 123.9, 118.1, 112.9, 109.1, 57.5, 8.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C13H12NO3 230.0812, found 230.0825.
5
6
7
1
Isopropyl 4-(4-cyanophenyl)-2-oxobut-3-enoate (2k). Yellow powder, m.p. 93-95 °C. H NMR
8
9
(300 MHz, CDCl3) δ 7.80 (d, J = 16.2 Hz, 1H), 7.71 (s, 4H), 7.43 (d, J = 16.1 Hz, 1H), 5.22
(sept, J = 6.3 Hz, 1H), 1.39 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 182.6, 161.3,
145.1, 138.2, 132.4, 129.1, 123.5, 118.1, 114.3, 71.1, 21.6. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C14H14NO3 244.0968, found 244.0976.
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General Procedure for Asymmetric Michael Reaction:
A mixture of carbon acid 1a-d or 5 (0.2 mmol), β,γ-unsaturated α-keto esters 2a-n (0.21 mmol),
organocatalyst Ia (16.3 mg, 0.02 mmol) in THF (0.3 mL) was stirred at ambient temperature for
specified time (TLC–monitoring). The solvent was evaporated under reduced pressure (50 oC, 50
Torr), diethyl ether (6 mL) was added to the residue and the resulting suspension was subjected
to centrifugation. Clear organic solution was decanted from solid catalyst Ia. The combined
organic extracts were evaporated under reduced pressure (20 Torr) and the residue was purified
by silica gel column chromatography (n-hexane/ EtOAc 1:1) to afford the corresponding
1
Michael adduct 4/3 or 6. The H NMR data for all compounds are given in Supporting
Information. Physicochemical properties of all compounds are given bellow.
(S)-Methyl 2-hydroxy-5-oxo-4-phenyl-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-carboxylate
(4a) / Methyl (S)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-phenylbutanoate (3a).8d Yield
73 mg (99%). Colorless solid, m.p. 161-163 °C (lit.8a 88-89 °C). 1H NMR (300 MHz, ): δ 7.87 –
7.74 (m, 1.28H), 7.61 – 7.48 (m, 1.44H), 7.40 – 7.28 (m, 5.26H), 7.24 – 7.19 (m, 1.41H), 4.40 –
4.31 (m, 0.34H), 4.28 – 4.14 (m, 0.91H), 3.92 (s, 0.96H), 3.88 (s, 2H), 2.80 (dd, J = 14.3, 7.4 Hz,
0.34H), 2.58 (dd, J = 13.8, 10.4 Hz, 0.40H), 2.46 (d, J = 9.4 Hz, 1.50H) ppm. HPLC data: 91%
ee (Chiralpak AD-H, n-hexane : i-PrOH = 70 : 30; 254 nm, flow rate: 0.8 mL/min, tminor= 6.5
min, tmajor = 10.1 min).
(S)-Methyl 2-hydroxy-5-oxo-4-(p-tolyl)- 2,3,4,5-tetrahydropyrano [3,2-c]chromene-2-carbo
xylate (4b)/ Methyl (S)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(p-tolyl)butanoate (3b).8d
1
Yield 70 mg (91%). Colorless solid, m.p. 165-167 °C (lit.8a 164-166 °C). H NMR (300 MHz,
CDCl3): δ 7.83 (ddd, J = 16.8, 7.9, 1.4 Hz, 1.05H), 7.64 – 7.50 (m, 1.09H), 7.42 – 7.24 (m, 2H),
7.20 – 7.08 (m, 4.16H), 4.34 (dd, J = 7.3, 3.1 Hz, 0.37H), 4.19 (t, J = 9.2 Hz, 0.75H), 3.94 (s,
0.96H, 3ab), 3.90 (s, 2.04H, 4ab) , 2.80 (dd, J = 14.3, 7.4 Hz, 0.37H), 2.55 (dd, J = 14.3, 3.2 Hz,
13
0.43H), 2.47 (d, J = 9.2 Hz, 1.40H), 2.34 (s, 2.11H), 2.33 (s, 0.88H) ppm. C{1H} NMR (75
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MHz, CDCl3): δ 169.0, 160.7, 157.9, 152.8, 139.2, 136.2, 131.8, 129.4, 126.9, 123.7, 122.7,
116.5, 115.3, 105.0, 95.6, 53.8, 38.2, 34.1, 21.1 ppm. HPLC data: 90% ee (Chiralpak AD-H, n-
hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 0.8 mL/min, tminor= 11.0 min, tmajor = 19.7 min).
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(S)-Methyl 2-hydroxy-5-oxo-4-(p-tolyl)-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-carboxylate
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(4b). Colorless crystals, m.p. 164-166 °C. H NMR (300 MHz, CDCl3): δ 7.80 (dd, J = 7.8, 0.8
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Hz, 1H), 7.59–7.51 (m, 1H), 7.35 – 7.27 (m, 2H), 7.19 – 7.11 (m, 4H), 4.77 (br s, 1H), 4.19 (t, J
= 9.2 Hz, 1H), 3.90 (s, 3H), 2.47 (d, J = 9.2 Hz, 2H), 2.34 (s, 3H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 168.9, 160.8, 158.0, 152.8, 139.2, 136.2, 131.8, 129.4, 126.9, 123.7, 122.7, 116.5,
115.3, 104.9, 95.6, 53.8, 38.2, 34.1, 21.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C21H19O6 367.1176, found 367.1182.
(S)-Methyl
2-hydroxy-5-oxo-4-(4-(trifluoromethyl)phenyl)
-2,3,4,5-tetrahydropyrano[3,2-
c]chromene-2-carboxylate (4c) / Methyl (S)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(4-
(trifluoromethyl)phenyl)butanoate (3c). Yellow wax. Yield 86 mg (98%). [α]20D: +3.0 (c 0.5,
1
CH2Cl2). H NMR (300 MHz, CDCl3): δ 7.87 – 7.75 (m, 1H), 7.64 – 7.48 (m, 3H), 7.43 – 7.24
(m, 4.29H), 4.99 (br s, 0.41H), 4.73 (br s, 0.31H), 4.39 (d, J = 5.1 Hz, 0.35H), 4.29 (dd, J = 11.2,
7.3 Hz, 0.64H), 3.92 (s, 0.90H, 3c), 3.89 (s, 1.70H, 4c), 2.83 (dd, J = 14.0, 7.6 Hz, 0.36H), 2.58 –
2.36 (m, 1.53H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 168.6, 160.6, 158.7, 158.4, 152.8,
146.6, 145.9, 132.3, 132.1, 127.9, 127.5, 125.6, 125.2, 124.1, 123.9, 122.9, 122.8, 116.7, 116.6,
115.1, 104.0, 102.1, 95.9, 95.3, 54.1, 53.9, 37.8, 35.1, 34.5, 33.6 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C21H16F3O6 421.0893, found 421.0906. HPLC data: 89% ee (Chiralpak AD-
H, n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 0.8 mL/min, tminor = 8.2 min, tmajor = 18.6
min).
(S)-Methyl
4-(4-cyanophenyl)-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
carboxylate (4d) / Methyl (S)-4-(4-cyanophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-
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oxobutanoate (3d). Yellow wax. Yield 74 mg (94%). [α]20D: +153.1 (c 1.0, CH2Cl2). H NMR
(300 MHz, CDCl3): δ 7.85 (m, 1H), 7.66 – 7.51 (m, 2.44H), 7.43 – 7.25 (m, 3.82H), 4.39 – 4.33
(m, 0.27H), 4.28 (dd, J = 11.5, 6.8 Hz, 0.46H), 3.94 (s, 0.63H, 3d), 3.91 (s, 1.22H, 4d), 2.84 (dd,
J = 14.3, 7.7 Hz, 0.27H), 2.56 – 2.34 (m, 1.21H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 168.6,
168.4, 166.5, 162.0, 161.2, 159.3, 159.1, 153.6, 152.7, 148.2, 147.7, 132.5, 132.4, 132.1, 128.5,
128.1, 124.4, 124.2, 123.5, 122.9, 118.8, 116.5, 115.0, 114.8, 110.4, 110.1, 103.3, 101.6, 96.1,
95.6, 91.9, 54.1, 53.9, 37.6, 35.1, 34.8, 33.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C21H16NO6 378.0972, found 378.0964. HPLC data: 89% ee (Chiralpak AD-H, n-hexane : i-PrOH
= 70 : 30; 254 nm, flow rate: 0.8 mL/min, tminor= 10.9 min, tmajor = 20.5 min).
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(R)-Methyl
4-(furan-2-yl)-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
Methyl (R)-4-(furan-2-yl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-
carboxylate (4e)
/
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oxobutanoate (3e).8a Yield 69 mg (97%). Yellow solid, m.p. 140-142 °C (lit.8a 136-138 °C).1H
NMR (300 MHz, CDCl3): δ 7.85 – 7.77 (m, 0.98H), 7.61 – 7.49 (m, 1.03H), 7.37 – 7.23 (m,
3.12H), 6.34 – 6.29 (m, 0.97H), 6.16 (d, J = 3.2 Hz, 0.63H), 6.10 (d, J = 3.2 Hz, 0.34H), 5.10 (br
s, 0.57H), 4.90 (br s, 0.3H), 4.45 – 4.31 (m, 1.01H), 3.95 (s, 1.05H, 3ae), 3.82 (s, 1.9H, 4ae),
2.84 – 2.70 (m, 1H), 2.62 (dd, J = 14.4, 6.9 Hz, 0.36H), 2.44 – 2.34 (m, 0.64H) ppm. HPLC data
(Chiralpak AD-H, n-hexane : i-PrOH = 70 : 30; 254 nm, flow rate: 0.8 mL/min, tminor= 6.7 min,
tmajor = 8.3 min).
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(R)-Methyl
4-(furan-2-yl)-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
carboxylate (4e). Yellow crystals, m.p. 159-161 °C. 1H NMR (300 MHz, CDCl3): δ 7.80 (d, J =
7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.38 – 7.24 (m, 3H), 6.38 – 6.32 (m, 1H), 6.20 (d, J = 3.1
Hz, 1H), 4.81 (br s, 1H), 4.37 (dd, J = 10.2, 6.5 Hz, 1H), 3.87 (s, 3H), 2.76 (dd, J = 13.8, 10.4
Hz, 1H), 2.41 (dd, J = 13.9, 6.5 Hz, 1H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 168.6, 160.9,
158.1, 153.2, 152.7, 141.3, 132.1, 123.8, 122.9, 116.5, 115.1, 110.4, 106.6, 102.1, 95.7, 53.8,
34.3, 28.4 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C18H15O7343.0812, found 343.0815.
(R)-Methyl
2-hydroxy-5-oxo-4-(thiophen-2-yl)-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
carboxylate (4f) / Methyl (R)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(thiophen-2-
yl)butanoate (3f).17 Yield 53 mg (99%). Yellow solid, m.p. 95-97 °C (lit. no data). 1H NMR (300
MHz, CDCl3): δ 7.88 – 7.76 (m, 0.96H), 7.63 – 7.51 (m, 1.12H), 7.41 – 7.29 (m, 1.96H), 7.23 –
7.15 (m, 1.04H), 7.00 – 6.90 (m, 1.86H), 4.87 (br s, 0.49H), 4.71 – 4.52 (m, 1.35H), 3.95 (s,
1.44H, 3af), 3.88 (s, 1.71H, 4af), 2.86 – 2.52 (m, 2.05H) ppm. HPLC data: 90% ee (Chiralpak
AD-H, n-hexane : i-PrOH = 70 : 30; 254 nm, flow rate: 0.8 mL/min, tminor= 7.2 min, tmajor = 10.5
min).
(R)-Ethyl
4-(2-chlorophenyl)-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
carboxylate (4g) / Ethyl (R)-4-(2-chlorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-
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oxobutanoate (3g). Colorless wax. Yield 79 mg (95%). [α]20D: -24.6 (c 0.7, CH2Cl2). H NMR
(300 MHz, CDCl3): δ 7.91 – 7.78 (m, 1.H), 7.65 – 7.52 (m, 1.20H), 7.46 – 7.28 (m, 2.98H), 7.24
– 7.08 (m, 2.69H), 5.46 (dd, J = 8.2, 4.7 Hz, 0.10H), 5.01 (dd, J = 11.2, 6.5 Hz, 0.27H), 4.81 –
4.65 (m, 1H), 4.47 – 4.28 (m, 1.97H), 2.80 (dd, J = 14.5, 7.6 Hz, 0.40H, 3g), 2.65 – 2.50 (m,
0.81H, 4g), 1.44 – 1.32 (m, 3.58H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 168.6, 168.3,
161.3, 160.5, 158.9, 152.8, 138.4, 133.3, 132.1, 131.9, 129.6, 129.2, 128.0, 127.9, 127.1, 126.3,
124.0, 123.8, 122.8, 122.7, 116.7, 116.5, 104.2, 102.4, 96.0, 95.5, 63.6, 63.5, 32.5, 31.5, 31.2,
14.0, 13.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C21H18ClO6 401.0786 and 403.0759,
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found 401.0780 and 403.0760. HPLC data: 91% ee (Chiralpak AD-H, n-hexane : i-PrOH = 80 :
20; 254 nm, flow rate: 1.0 mL/min, tminor = 7.7 min, tmajor = 9.7 min).
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carboxylate (4h)
/
Ethyl (S)-4-(4-cyanophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-
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oxobutanoate (3h). Yellow wax. Yield 78 mg (95%). [α]20D: +100.8 (c 1.0, CH2Cl2). H NMR
(300 MHz, CDCl3): δ 7.87 – 7.77 (m, 1.07H), 7.66 – 7.53 (m, 2.95H), 7.43 – 7.29 (m, 4H), 4.39
(dd, J = 14.1, 7.0 Hz, 2.42H, 4h), 4.27 (dd, J = 11.7, 6.8 Hz, 0.81H, 3h), 2.86 (dd, J = 14.3, 7.5
Hz, 0.38H), 2.54 – 2.31 (m, 1.68H), 1.49 – 1.33 (m, 3.24H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 168.2, 168.1, 161.6, 160.6, 158.9, 158.6, 152.8, 148.3, 147.5, 132.6, 132.5, 132.3,
132.0, 128.5, 128.0, 124.2, 124.0, 122.9, 122.8, 118.8, 116.8, 116.6, 115.1, 110.6, 110.3, 103.6,
101.6, 95.7, 95.2, 63.7, 37.5, 34.9, 34.7, 33.8, 14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+: calcd.
for C22H18NO6 392.1129, found 392.1122. HPLC data: 93% ee (Chiralpak AD-H, n-hexane : i-
PrOH = 7 : 3; 254 nm, flow rate: 0.8 mL/min, tminor= 8.4 min, tmajor = 9.5 min).
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(S)-Isopropyl
carboxylate
2-hydroxy-5-oxo-4-(p-tolyl)-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
Isopropyl (S)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(p-
(4i)
/
tolyl)butanoate (3i). Colorless wax. Yield 80 mg (97%). [α]20D: +35.3 (c 1.0, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ 7.82 – 7.75 (m, 0.95H), 7.64 – 7.50 (m, 1.06H), 7.41 – 7.26 (m, 2.37H),
7.23 – 7.09 (m, 3.73H), 5.29 – 5.15 (m, 1H), 4.33 (d, J = 4.5 Hz, 0.35H), 4.27 – 4.10 (m, 3H),
2.80 (dd, J = 14.1, 7.3 Hz, 0.33H), 2.52 (dd, J = 14.3, 2.5 Hz, 0.32H), 2.46 – 2.39 (m, 1.21H, 3i).
2.35 (s, 2.9H, 4i), 1.43 – 1.32 (m, 7.66H) ppm. 13C NMR{1H} (75 MHz, ) δ 168.2, 158.0, 152.9,
139.6, 138.5, 136.3, 136.2, 132.0, 131.8, 129.5, 129.2, 127.3, 127.0, 124.0, 123.7, 122.7, 116.7,
116.6, 116.4, 115.4, 115.2, 105.1, 102.9, 96.1, 95.3, 71.9, 71.8, 38.1, 35.4, 34.3, 33.3, 21.7, 21.5,
21.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C23H23O6 395.1489, found 395.1458.
HPLC data: 91% ee (Chiralpak AD-H, n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 0.8
mL/min, tminor = 8.8 min, tmajor = 17.1 min).
(S)-Isopropyl 2-hydroxy-5-oxo-4-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydropyrano [3,2-
c]chromene-2-carboxylate (4j) / Isopropyl (S)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-
(4-(trifluoromethyl)phenyl)butanoate (3j). Yellow wax. Yield 92 mg (98%). [α]20D: +10.1 (c 0.5,
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CH2Cl2). H NMR (300 MHz, CDCl3): δ 7.88 – 7.76 (m, 1H), 7.68 – 7.50 (m, 2.94H), 7.46 –
7.31 (m, 3.35H), 5.29 – 5.16 (m, 1.02H), 4.43 – 4.36 (m, 0.39H, 3j), 4.29 (dd, J = 11.5, 7.0 Hz,
0.66H, 4j), 2.86 (dd, J = 14.2, 7.4 Hz, 0.37H), 2.55 – 2.32 (m, 1.60H), 1.46 – 1.32 (m, 6.62H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 167.8, 160.6, 158.4, 152.9, 146.8, 132.3, 132.1, 127.9,
127.5, 125.7, 125.7, 125.1, 124.1, 123.9, 122.7, 116.7, 116.6, 115.2, 104.1, 95.7, 95.2, 72.2,
72.1, 37.7, 34.8, 34.6, 33.6, 21.5 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C23H20F3O6
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449.1206, found 449.1201. HPLC data: 93% ee (Chiralpak AD-H, n-hexane : i-PrOH = 80 : 20;
254 nm, flow rate: 1.0 mL/min, tminor + 8.9 min, tmajor = 12.8 min).
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carboxylate (4k) / Isopropyl (S)-4-(4-cyanophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-
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oxobutanoate (3k). Yellow wax. Yield 83 mg (98%). [α]20D: +85.8 (c 1.0, CH2Cl2). H NMR
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(300 MHz, CDCl3): δ 7.86 – 7.74 (m, 1.05H), 7.66 – 7.51 (m, 3.28H), 7.44 – 7.29 (m, 3.77H),
5.28 – 5.15 (m, 1.40H), 4.89 (br s, 0.33H), 4.36 (d, J = 6.4 Hz, 0.40H, 3k), 4.27 (dd, J = 11.8,
6.6 Hz, 0.70H, 4k), 2.84 (dd, J = 14.2, 7.5 Hz, 0.39H), 2.53 – 2.26 (m, 1.81H), 1.43 – 1.31 (m,
6.53H) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ 167.7, 167.6, 161.6, 160.7, 159.1, 158.7, 152.8,
148.4, 147.6, 132.6, 132.5, 132.3, 132.0, 128.5, 128.1, 124.2, 124.0, 122.8, 118.9, 118.8, 116.7,
116.6, 115.1, 114.9, 110.5, 110.2, 103.6, 101.6, 95.8, 95.2, 72.1, 37.5, 34.9, 34.7, 33.8, 21.5
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C23H20NO6 406.1285, found 406.1280. HPLC
data: 90% ee (Chiralpak AD-H, n-hexane : i-PrOH = 70 : 30; 254 nm, flow rate: 1.0 mL/min,
tminor = 7.3 min, tmajor = 15.0 min).
(S)-Tert-butyl
2-hydroxy-5-oxo-4-phenyl-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
carboxylate (4l) / Tert-butyl (S)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-phenylbutanoate
(3l). Yellow wax. Yield 73 mg (89%). [α]20D: +13.8 (c 0.5, CH2Cl2, 80% ee). H NMR (300
1
MHz, CDCl3): δ 7.81 (dd, J = 17.9, 7.7 Hz, 1.18H), 7.67 – 7.47 (m, 1.38H), 7.44 – 7.20 (m,
9.40H), 4.95 (br s, 0.58H), 4.40 – 4.30 (m, 0.49H), 4.21 (dd, J = 11.5, 7.2 Hz, 0.95H), 2.79 (dd, J
= 14.3, 7.4 Hz, 0.51H), 2.57 – 2.28 (m, 2.13H), 1.58 (s, 5.33H, 4l), 1.55 (s, 3.39H, 3l) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 167.6, 160.6, 158.2, 152.8, 142.7, 141.8, 131.9, 131.7,
128.7, 128.3, 127.4, 127.1, 126.7, 126.6, 123.9, 123.7, 122.7, 122.7, 116.6, 116.5, 115.5, 105.0,
103.0, 96.2, 95.4, 85.1, 85.0, 38.1, 35.5, 34.8, 34.1, 29.7, 27.7 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C23H23O6 395.1489, found 395.1484. HPLC data: 89% ee (Chiralpak AD-H,
n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 1.0 mL/min, tminor = 10.6 min, tmajor = 15.6 min).
(S)-Methyl
2-hydroxy-7,7-dimethyl-5-oxo-4-phenyl-3,4,5,6,7,8-hexahydro-2H-chromene-2-
carboxylate (4ba) / Methyl (S)-4-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-2-oxo-4-
phenylbutanoate (3ba).8d Yield 69 mg (99%). Colorless solid, m.p. 154-156 °C (lit. no data). 1H
NMR (300 MHz, CDCl3): δ 7.32 – 7.24 (m, 2.23H), 7.22 – 7.12 (m, 2.87H), 4.15 – 4.07 (m,
0.37H), 3.97 – 3.90 (m, 0.49H), 3.87 (s, 1.06H), 3.75 (s, 1.86H), 2.66 – 2.18 (m, 6H), 1.21 (d, J
= 7.1 Hz, 2.79H), 1.12 (d, J = 6.7 Hz, 2.92H) ppm. HPLC data: 93% ee (Chiralpak AD-H, n-
hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 1.0 mL/min, tminor= 6.0 min, tmajor = 9.4 min).
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(S)-Methyl
2-hydroxy-7-methyl-5-oxo-4-phenyl-2,3,4,5-tetrahydropyrano[4,3-b]pyran-2-
carboxylate (4ca)
/
Methyl (S)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-
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phenylbutanoate (3ca).8d Yield 65 mg (98%). White solid, m.p. 115-117 °C (lit. no data). H
NMR (300 MHz, CDCl3): δ 7.37 7.27 (m, 2H), 7.22 – 7.16 (m, 3H), 5.87 (s, 1H), 4.23 – 3.98 (m,
1.13H), 3.89 (s, 0.79H), 3.81 (s, 2.29H), 2.69 (dd, J = 14.3, 7.4 Hz, 0.27H), 2.45 (dd, J = 14.2,
3.4 Hz, 0.21H), 2.35 (d, J = 9.0 Hz, 1.36H), 2.27 (s, 0.65H), 2.23 (s, 2.20H) ppm. HPLC data:
90% ee (Chiralpak AD-H, n-hexane : i-PrOH = 8 : 2; 254 nm, flow rate: 1.0 mL/min, tminor= 8.0
min, tmajor = 11.9 min).
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(S)-Methyl
2-hydroxy-5,10-dioxo-4-phenyl-3,4,5,10-tetrahydro-2H-benzo[g]chromene-2-
carboxylate (4da) / Methyl (S)-4-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-oxo-4-
1
phenylbutanoate (3da).10a Yield 74 mg (97%). Yellow solid, m.p. 115-117 °C (lit. no data). H
NMR (300 MHz, CDCl3): δ 8.20 – 7.88 (m, 2.12H), 7.78 – 7.62 (m, 2.40H), 7.49 (d, J = 7.4 Hz,
0.66H), 7.37 – 7.18 (m, 4H), 5.08 – 4.96 (m, 0.40H), 4.49 – 4.09 (m, 1.30H), 3.90 (s, 0.53H,
3da), 3.87 (s, 2.33H, 4da), 3.79 – 3.64 (m, 0.50H), 3.37 – 3.08 (m, 0.41H), 2.80 – 2.65 (m,
0.29H), 2.55 – 2.36 (m, 1.35H), 2.15 – 2.04 (m, 0.24H) ppm. HPLC data: 93% ee (Chiralpak
AD-H, n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 1.0 mL/min, tminor= 12.0 min, tmajor
=
16.9 min).
(S)-Methyl
2-hydroxy-5,10-dioxo-4-phenyl-3,4,5,10-tetrahydro-2H-benzo[g]chromene-2-
carboxylate (4da). Yellow crystals, m.p. 118-120 °C. 1H NMR (300 MHz, CDCl3): δ 8.16 – 8.11
(m, 1H), 7.96 – 7.91 (m, 1H), 7.72 – 7.66 (m, 2H), 7.34 – 7.23 (m, 5H), 4.79 (br s, 1H), 4.33 –
4.27 (m, 1H), 3.90 (s, 3H), 2.47 – 2.41 (m, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ 183.1,
179.3, 168.6, 152.9, 142.7, 135.1, 134.2, 133.2, 132.1, 130.8, 128.8, 128.6, 128.4, 128.2, 127.6,
127.2, 126.7, 126.4, 126.3, 125.1, 95.3, 53.9, 37.9, 34.7 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C21H17O6 365.1020, found 365.1019.
(1R,3S)-Methyl
3-hydroxy-1-phenyl-2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine-3-
carboxylate (6a, R,S/R,R = 1.3 : 1). Yellow solid (59 mg, 85%), m.p. 196-197 °C. 1H NMR (300
MHz, CDCl3): δ 9.48 – 9.29 (m, 0.99H), 8.42 – 8.15 (m, 2.01H), 7.96 (d, J = 8.0 Hz, 0.46H),
7.89 – 7.57 (m, 4.6H), 7.31 – 7.05 (m, 5.17H), 5.47 – 5.37 (m, 0.43H), 5.10 (t, J = 9.0 Hz,
0.57H), 4.78 (br s, 0.44H), 4.35 (s, 1H), 3.94 (s, 1.27H), 3.89 (s, 1.6H), 3.03 (dd, J = 14.1, 7.2
Hz, 0.44H), 2.87 – 2.68 (m, 1.56H) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ 169.9, 150.4, 150.3,
145.9, 143.9, 142.8, 142.4, 141.7, 140.4, 140.1, 139.9, 131.1, 129.8, 129.6, 129.4, 129.3, 129.3,
129.1, 128.8, 128.7, 128.4, 128.2, 128.1, 127.8, 125.9, 125.6, 125.2, 125.1, 122.6, 122.3, 114.2,
112.2, 95.9, 95.1, 53.6, 53.5, 38.9, 35.8, 35.6, 33.5 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C27H21N2O4 437.1496, found 437.1487. HPLC data: (R,S) 97%/(R,R) 97% ee, (Chiralpak
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AD-H, n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 0.8 mL/min, Diastereomer (R,S): tmajor
6.39 min, tminor = 7.05 min. Diastereomer (R,R): tminor = 8.51 min, tmajor = 9.39 min).
=
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(1S,3S)-Ethyl 1-(2-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine-
3-carboxylate (6b, S,S/S,R = 1 : 1). Yellow solid (70 mg, 91%), m.p. 196-198 °C. 1H NMR (300
MHz, CDCl3): δ 9.48 – 9.40 (m, 0.45H), 9.39 – 9.32 (m, 0.46H), 8.40 – 8.21 (m, 1.85H), 7.92 (d,
J = 8.2 Hz, 0.46H), 7.88 – 7.61 (m, 4.15H), 7.48 (d, J = 7.8 Hz, 1.09H), 7.32 (br s, 0.4H), 7.12 –
7.01 (m, 0.95H), 6.97 – 6.78 (m, 1.75H), 6.34 – 6.27 (m, 0.23H), 5.71 – 5.62 (m, 0.44H), 5.60 –
5.49 (m, 0.46H), 4.76 (br s, 0.36H), 4.55 (s, 0.42H), 4.49 – 4.37 (m, 1.88H), 3.02 (dd, J = 14.3,
7.7 Hz, 0.44H), 2.87 – 2.76 (m, 0.89H), 2.75 – 2.62 (m, 0.5H), 1.48 – 1.36 (m, 3.1H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 169.6, 169.4, 150.7, 150.5, 143.7, 142.6, 142.4, 142.0,
141.3, 140.3, 140.0, 139.9, 133.9, 133.4, 131.0, 130.9, 130.4, 129.8, 129.7, 129.4, 129.3, 129.1,
129.0, 128.8, 128.4, 128.2, 128.0, 127.2, 126.8, 126.7, 125.8, 125.2, 122.5, 122.3, 117.9, 115.9,
114.3, 112.1, 95.6, 95.1, 67.1, 63.2, 36.3, 32.6, 31.4, 14.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C28H22ClN2O4 485.1263 and 487.1236, found 485.1254 and 487.1236. HPLC data:
(S,S) 97%/(S,R) 96% ee (Chiralpak AD-H, n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 0.8
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mL/min, Diastereomer (R,S): tmajor = 10.04 min, tminor = 11.57 min. Diastereomer (R,R): tminor
=
15.09 min, tmajor = 16.44 min).
(1R,3S)-Ethyl 1-(4-cyanophenyl)-3-hydroxy-2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine-3-
1
carboxylate (6c, R,S/R,R = 1.3 : 1). Yellow solid (68 mg, 90%), m.p. = 189-191 °C. H NMR
(300 MHz, CDCl3): δ 9.46 – 9.39 (m, 0.43H), 9.37 – 9.29 (m, 0.5H), 8.36 – 8.28 (m, 0.86H),
8.27 – 8.19 (m, 1.01H), 7.94 – 7.62 (m, 5.02H), 7.49 (t, J = 8.7 Hz, 1.86H), 7.42 – 7.31 (m,
1.97H), 5.41 – 5.34 (m, 0.41H), 5.09 (dd, J = 11.5, 7.3 Hz, 0.54H), 4.88 (br s, 0.4H), 4.55 (s,
0.4H), 4.50 – 4.36 (m, 1.95H), 3.07 (dd, J = 14.0, 7.7 Hz, 0.47H), 2.77 – 2.55 (m, 1.5H), 1.48 –
1.34 (m, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 169.3, 169.1, 152.3, 150.7, 150.6, 150.4,
142.4, 142.2, 141.5, 140.5, 140.2, 140.1, 132.1, 131.6, 131.1, 129.9, 129.8, 129.7, 129.3, 129.2,
129.1, 129.0, 128.9, 128.7, 128.5, 128.1, 127.8, 125.3, 125.2, 122.5, 122.3, 119.2, 119.1, 112.9,
110.9, 109.4, 109.3, 95.3, 94.7, 63.3, 38.3, 36.4, 34.7, 34.0, 14.1 ppm. HRMS (ESI) m/z:
[M+H]+ calcd. for C29H22N3O4: 476.1605, found 476.1615. HPLC data: (R,S) 98%/(R,R) 96% ee
(Chiralpak AD-H, n-hexane : i-PrOH = 80 : 20; 254 nm, flow rate: 0.8 mL/min, Diastereomer
(R,S): tminor = 11.53 min, tmajor = 12.65 min. Diastereomer (R,R): tminor = 14.62 min, tmajor = 21.06
min).
(1R,3S)-Isopropyl 3-hydroxy-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[a]pyrano[2,3-
c]phenazine-3-carboxylate (6d, R,S/R,R = 1.5 : 1). Yellow solid (79 mg, 93%), m.p. 246-248 °C.
1H NMR (300 MHz, CDCl3): δ 9.50 – 9.42 (m, 0.41H), 9.41 – 9.34 (m, 0.45H), 8.40 – 8.19 (m,
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1.79H), 7.96 (d, J = 8.4 Hz, 0.43H), 7.90 – 7.79 (m, 1.86H), 7.78 – 7.62 (m, 2.45H), 7.58 – 7.34
(m, 4.31H), 5.44 (d, J = 6.2 Hz, 0.45H), 5.34 – 5.19 (m, 1.02H), 5.16 – 5.05 (m, 0.7H), 4.75 (br
s, 0.47H), 4.52 (s, 0.57H), 3.07 (dd, J = 13.9, 7.6 Hz, 0.48H), 2.79 – 2.57 (m, 1.43H), 1.54 – 1.11
(m, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 168.8, 150.8, 148.6, 142.5, 142.2, 141.6,
140.4, 140.2, 139.9, 131.1, 129.9, 129.8, 129.7, 129.6, 129.3, 129.1, 128.9, 128.5, 128.4, 128.1,
125.3, 125.2, 125.1, 125.0, 124.7, 124.6, 122.5, 122.3, 113.4, 111.5, 95.4, 94.7, 84.1, 71.6, 71.4,
38.5, 36.1, 34.8, 33.7, 21.6 ppm. HRMS (ESI) m/z: [M+H]+ calcd. for C30H24F3N2O4 533.1683,
found 533.1674. HPLC data: (R,S) 95%/(R,R) 99% ee (Chiralpak AS-H, n-hexane : i-PrOH = 90
: 10; 254 nm, flow rate: 0.8 mL/min, Diastereomer (R,R): tmajor = 17.74 min, tminor = 23.86 min.
Diastereomer (R,S): tmajor = 21.0 min, tminor = 29.87 min).
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(1S,3S)-Isopropyl
3-hydroxy-1-(thiophen-2-yl)-2,3-dihydro-1H-benzo[a]pyrano[2,3-
c]phenazine-3-carboxylate (6e, S,S/S,R = 1.4 : 1). Yellow solid (71 mg, 95%), m.p. = 167-169
1
°C. H NMR (300 MHz, CDCl3) δ 9.46 – 9.40 (m, 0.56H), 9.37 – 9.31 (m, 0.36H), 8.37 – 8.30
(m, 1.17H), 8.28 – 8.20 (m, 0.77H), 8.15 – 8.09 (m, 0.55H), 7.98 – 7.93 (m, 0.4H), 7.89 – 7.68
(m, 4H), 7.13 (d, J = 4.6 Hz, 0.59H), 7.06 (d, J = 4.8 Hz, 0.35H), 6.91 – 6.80 (m, 1.4H), 6.76 (d,
J = 3.3 Hz, 0.56H), 5.70 (d, J = 5.4 Hz, 0.58H), 5.44 (dd, J = 9.9, 7.9 Hz, 0.4H), 5.33 – 5.17 (m,
1.06H), 4.84 (br s, 0.25H), 4.58 (s, 0.61H), 3.03 (dd, J = 14.1, 6.6 Hz, 0.62H), 2.96 – 2.74 (m,
1.46H), 1.45 – 1.35 (m, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 168.7, 168.6, 150.1,
149.5, 147.9, 142.7, 142.6, 142.3, 141.6, 140.5, 140.0, 139.9, 131.1, 131.0, 129.8, 129.7, 129.6,
129.5, 129.3, 129.1, 128.9, 128.8, 128.5, 128.4, 128.3, 128.0, 126.3, 126.2, 125.2, 125.1, 124.9,
124.4, 123.4, 122.6, 122.5, 122.4, 113.9, 112.3, 95.6, 95.0, 71.4, 71.1, 39.3, 35.4, 31.1, 28.9,
21.6, 21.6 ppm. HRMS (ESI) m/z: [M+H]+ calcd. for C27H23N2O4S 471.1373, found 471.1362.
HPLC data: (S,S) 92%/(S,R) 94% ee (Chiralpak AD-H, n-hexane : i-PrOH = 80 : 20; 254 nm,
flow rate: 0.8 mL/min, Diastereomer (R,S): tminor = 13.06 min, tmajor = 14.25 min. Diastereomer
(R,R): tminor = 16.02 min, tmajor = 23.61 min).
Synthesis of 6a. Scaling procedure.
The reaction with 5 (1.00 g, 4.08 mmol), 2a (0.85 g, 4.48 mmol), Ia (0.33 g, 0.40 mmol), and
THF (4.0 mL) was performed as described above to afford 1.44 g (81%) of 6a with 97% ee (6a
R,S/R,R = 1.3 : 1).
1H NMR monitoring of the 4b/3b ratio in the CDCl3 solution: Compound 4b (20 mg, 0.054
1
mmol) was placed in a NMR-tube and dissolved in CDCl3 (0.4 mL). H NMR spectra of the
resulting solution were recorded in 5 min, 2 h, 4 h, 6 h, 16 h and 24 h after dissolution of 4b (see
Fig. 1).
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Recycling procedure: Catalyst Ia recovered by centrifugation was dried under reduced pressure
o
(60 C, 50 Torr, 30 min). Then the fresh portions of the starting substrates 1a (37.2 mg, 0.20
5
6
mmol) and 2a (38.0 mg, 0.20 mmol) and THF (0.3 mL) were added to the catalyst and the
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reaction was re-performed as described above.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
http://pubs.acs.org.
Copies of 1H, 13C, and HPLC spectra (PDF)
X-ray of 4b (CIF)
X-ray of 6a (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: zlotin@ioc.ac.ru, alexkucherenko@ya.ru
ORCID
Sergei G. Zlotin: 0000-0002-2280-3918
Rinat S. Tukhvatshin 0000-0003-3655-5473
Alexander S. Kucherenko: 0000-0002-6423-7627
Yulia Nelyubina 0000-0002-9121-0040
Notes
The authors declare no competing financial interest
Acknowledgements
The research was supported by the Russian Science Foundation (Grant 16-13-10470-P).
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