Planar chiral [2.2]paracyclophane-based phosphine-phenols: Use in enantioselective [3 + 2] annulations of allenoates and: N -tosylimines

Article abstract of DOI:10.1039/c8ob00248g

Planar chiral [2.2]paracyclophane-based phosphine-phenol catalysts, which have a benzene ring spacer inserted between the pseudo-ortho-substituted [2.2]paracyclophanol skeleton and the diarylphosphino group, are highly suitable for enantioselective [3 + 2

Full text of DOI:10.1039/c8ob00248g

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Planar chiral [2.2]paracyclophane-based phosphine–phenols: Use in enantioselective [3+2]
annulations of allenoates and N-tosylimines†
Shinji Kitagaki,* Kento Nakamura, Chiharu Kawabata, Asuna Ishikawa, Naoko Takenaga and Keisuke
Yoshida
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan Fax:
+81 52 834 8090; Tel.: +81 52 839 2657; E-mail: skitagak@meijo-u.ac.jp
Graphical and textual abstract
1

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Abstract
Planar chiral [2.2]paracyclophaneꢀbased phosphine–phenol catalysts, which have a benzene ring spacer
inserted between the pseudo-ortho-substituted [2.2]paracyclophanol skeleton and the diarylphosphino
group, are highly suitable for enantioselective [3+2] annulations of allenoates and Nꢀtosylimines. These
catalysts can be tuned by changing the substituent on the benzene rings of the diarylphosphino group. The
observed enantioselectivity of 92% is the highest reported to date for phosphineꢀcatalyzed annulations of
unsubstituted allenic esters and Nꢀtosylaldimines.
Introduction
[2.2]Paracyclophane ([2.2]PCP) has been widely used as a planar chiral backbone in ligands and
organocatalysts because of its intrinsic conformational rigidity, chemical and thermal stabilities, and
diverse substitution patterns.1,2 However, only a few examples of highly asymmetric induction using
PCPꢀbased ligands or organocatalysts have been reported, although [2.2]PhanePhos, the
pseudo-ortho-bis(diphenylphosphino)[2.2]PCP ligand, was used to achieve highly enantioselective
hydrogenation of olefins or ketones catalyzed by a rhodium or ruthenium complex.3 We are interested in
2

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the development of bifunctional4 organocatalysts5 based on planar chiral pseudo-ortho-substituted
aryl[2.2]PCP with no additional chiral source.6,7 The aryl group serves as a spacer, which offers
conformational flexibility and makes the distance between the two functional groups suitable for
performing dual activation of the substrate and reactant. Choice of an appropriate spacer should enable
construction of efficient chiral environments that differ from those of known functionalized PCPs. We
recently reported that a PCPꢀbased phosphine–phenol, (Sp)ꢀ1, in which one of the aryl groups on the
phosphorus atom of the triarylphosphine has a pseudo-ortho-hydroxyꢀsubstituted [2.2]PCP group at the
meta position, showed exceptionally high reactivity and good enantioselectivity in the azaꢀMorita–Baylis–
Hillman (MBH) reactions of Nꢀtosylbenzaldimines with various vinyl ketones (Scheme 1a).8
Since Lu’s pioneering work, phosphineꢀcatalyzed [3+2] annulation of electronꢀdeficient allenes and
unsaturated compounds has become one of the most reliable methods for the construction of highly
functionalized fiveꢀmembered carboꢀ and heteroꢀcycles.9 Asymmetric variants of this transformation with
chiral phosphine catalysts have recently been reported for reactions of allenes with various activated
alkenes, to afford monocyclic or spirocyclic cyclopentene derivatives.10 Enantioselective annulations
using imines instead of alkenes, to produce 2,5ꢀdihydropyrroles, have been studied by Marinetti,11
Jacobsen,12 Lu,13 Kwon,14 and other researchers,15 and excellent enantiocontrol has been achieved using
3

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Nꢀdiphenylphosphinoylimines. However, highly enantioselective reactions of Nꢀsulfonylated imines have
not yet been reported, except for those in Kwon’s work. The bicyclic phosphine catalysts developed by
Kwon’s group show high enantioselectivity in reactions of γꢀsubstituted allenoates with Nꢀsulfonylated
imines, providing 1ꢀsulfonylꢀ2,5ꢀdisubstitutedꢀ2,5ꢀdihydropyrroleꢀ3ꢀcarboxylates.14a,b However, for
unsubstituted allenoates, there is only one reported example of a highly enantioselective [3+2] annulation,
with an Nꢀnosylimine derived from NꢀBocꢀindoleꢀ3ꢀcarbaldehyde,14c,16 although
2ꢀarylꢀ1ꢀtosylꢀ2,5ꢀdihydropyrroleꢀ3ꢀcarboxylates have received considerable attention as potential protein
geranylgeranyltransferase inhibitors17 and antiarrhythmic agents.18 In this context, we planned to use our
planar chiral bifunctional PCPꢀbased phosphine–phenol catalysts (Sp)ꢀ1 for the [3+2] annulations of
unsubstituted allenoates with Nꢀtosylbenzaldimines (Scheme 1b). We now report that catalysis by either
the previously developed catalyst (Sp)ꢀ1 (Ar = m-xylyl)8 or the new catalyst (Sp)ꢀ1 (Ar = 3,5ꢀtꢀBu2C6H3)
enables the efficient construction of 2ꢀarylꢀ1ꢀtosylꢀ2,5ꢀdihydropyrroleꢀ3ꢀcarboxylates with good to high
enantioselectivities.
4

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Scheme 1. Planar chiral [2.2]PCPꢀbased phosphine–phenol (Sp)ꢀ1ꢀcatalyzed reactions.
Results and discussion
In a preliminary investigation, we surveyed the use of our [2.2]PCPꢀbased phosphine–phenols (Sp)ꢀ1 and
commercially available diphosphine (Sp)ꢀ2 as catalysts in the asymmetric [3+2] annulation of
Nꢀtosylꢀ4ꢀchlorobenzaldimine (3a) and ethyl allenoate (4a). mꢀXylylphosphine (Sp)ꢀ1a, which shows high
reactivity and enantioselectivity in the azaꢀMBH reaction, smoothly catalyzed the [3+2] annulation in
toluene at room temperature to produce the desired 2,5ꢀdihydropyrrole 5a in 96% yield with 40% ee
(Table 1, entry 1). Use of the Oꢀmethylated phosphine (Sp)ꢀ1b led to a significant loss of reactivity and
enantioselectivity, suggesting that the OH functionality in the (Sp)ꢀ1a structure is important (entry 2). To
improve the product ee, we prepared a new phosphine (Sp)ꢀ1c, in which both methyl groups of the xylyl
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moiety in (Sp)ꢀ1a were exchanged for the more sterically encumbered tꢀbutyl group,19 and used it in the
annulation reaction. The use of (Sp)ꢀ1c improved the product ee without any loss of reactivity (entry 3).
Neither [2.2]PhanePhos (Sp)ꢀ2a or xylylꢀ[2.2]PhanePhos (Sp)ꢀ2b gave good reactivity and
enantioselectivity (entries 4 and 5). The reactions in THF or CH2Cl2 with (Sp)ꢀ1c gave unsatisfactory
results (entries 6 and 7).
The reaction with this new phosphine–phenol catalyst (Sp)ꢀ1c in toluene was used to investigate the effects
of the allenoate substituent.20 Replacement of the ethyl ester moiety by a tꢀbutyl or phenyl ester led to a
decrease in the ee (entries 8 and 9). The reaction of a γꢀsubstituted allenoate was considerably less
efficient, although the product ee was similar to that for the unsubstituted allenoate (entry 10).21
Lowering the reaction temperature led to an increase in the enantioselectivity. For example, when the
reaction of the unsubstituted allenoate ethyl ester 4a in the presence of (Sp)ꢀ1c (5 mol%) was performed at
−30 °C, the cycloadduct was obtained with 80% ee (entry 11). Further lowering of the temperature led to a
low reaction rate and a modest increase in selectivity (83% ee) (entry 12).
Table 1. [2.2]PCP phosphineꢀcatalyzed [3+2] annulation of imine 3a and allenes 4.a
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Entry Allene R1
R2 Catalyst Solvent
Time
Product
Yield
Ee
(%)b
96
86
99
10
35
59
73
26
90
25
99
66
(%)c
1
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Oꢀt-Bu
OPh
OEt
OEt
OEt
H
H
H
H
H
H
H
H
H
(Sp)ꢀ1a toluene
(Sp)ꢀ1b toluene
25 min
19 h
40
1
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4a
4a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5a
5a
2
3
(Sp)ꢀ1c
toluene
25 min
40 h
58
14
5
4d
5d
6
(Sp)ꢀ2a toluene
(Sp)ꢀ2b toluene
40 h
(Sp)ꢀ1c
(Sp)ꢀ1c
(Sp)ꢀ1c
(Sp)ꢀ1c
THF
1 h
37
29
27
27
53
80
83
7
CH2Cl2
toluene
toluene
toluene
toluene
toluene
7
1 h
8d
9d
10d
11e
12f
50 min
10 min
24 h
Ph (Sp)ꢀ1c
H
H
(Sp)ꢀ1c
(Sp)ꢀ1c
7 h
4 d

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aReaction conditions: 3a (0.05 mmol), 4 (0.11 mmol), catalyst (0.0025 mmol) in solvent (0.5 mL) at room
temperature. bIsolated yield. cDetermined by HPLC analysis using a chiral stationary phase. dAllene (0.055
mmol) was used. eReaction performed at −30 °C. fReaction performed in the presence of (Sp)ꢀ1c (10
mol%) at −50 °C.
Having ascertained the effectiveness of the use of a combination of ethyl allenoate (4a) and the catalyst
(Sp)ꢀ1c, we then investigated the scope of this reaction with respect to the substituent on the benzene ring
of Nꢀtosylbenzaldimine 3. The results for the reactions in toluene at −30 °C are summarized in Table 2.
Both electronꢀwithdrawing and ꢀdonating substituents at the para or meta position on the benzene ring
were compatible with the reaction conditions, although substrates containing a nitro group gave relatively
low enantioselectivities (entries 1–7). The reaction of 2ꢀnaphthaldimine 3h proceeded smoothly to give
the desired product 5k in 97% yield, with 80% ee (entry 8). However, 1ꢀnaphthaldimine 3i was an
unsuitable substrate, with low reactivity and enantioselectivity (entry 9).
Table 2. [3+2] Annulations of various imines 3 catalyzed by [2.2]PCP phosphine (Sp)ꢀ1c.a
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When catalyst (Sp)ꢀ1a was used in this transformation at −25 °C, the corresponding cycloadduct 5l was
obtained in 98% yield with 82% ee (Table 3, entry 1). Substrates bearing a substituent at the ortho
position on the benzene ring were compatible with the conditions used with catalyst (Sp)ꢀ1a (entries 2–8),
and 2ꢀchloroꢀ and 2ꢀmethoxyꢀbenzaldimines 3j and 3o both provided the corresponding cycloadducts 5m
and 5r in good yields and with high enantioselectivities, i.e., 90% ee (entries 2, 7, and 8). The preferred
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absolute configurations of products 5j and 5m were established as R and S, respectively, by their
transformations into the known methyl esters and comparison of their optical rotations with the literature
data.16a The preferred absolute configurations of all the other products were assigned by analogy (R for
products 5 excluding 5n and S for 5n). It is worth noting that the preferred configurations of the
cycloadducts are the opposites of those of the azaꢀMBH adducts obtained using the same catalyst.8 The
observed enantioselectivity of 92% (entry 8) is the highest reported to date for phosphineꢀcatalyzed [3+2]
annulations of unsubstituted allenic esters and Nꢀtosylaldimines.
Table 3. [3+2] Annulations of various imines 3 catalyzed by [2.2]PCP phosphine (Sp)ꢀ1a.a
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The catalytic cycle proposed by Lu9 is shown in Scheme 2. It includes the following five steps: 1)
1,4ꢀaddition of the phosphine to the allenoate; 2) a Mannichꢀtype reaction of the obtained zwitterionic
intermediate to the imine; 3) 5ꢀendo cyclization of the amide ion; 4) proton transfer; and 5) regeneration of
the phosphine. Although the detailed mechanism of the asymmetric induction is not clear at this stage, a
transition state during step 2 in the catalytic cycle, shown in Scheme 2, is proposed to account for the
observed stereochemistry, based on our experimental results and the proposed transition states in
asymmetric imine–allene [3+2] annulations reported so far.12,13a,14b,15c,22a To avoid steric repulsion between
11

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the ester and the aryl group of the imine, nucleophilic attack of the phosphonium enolate, the ester moiety
of which has an O–P interaction with a neighboring phosphonium group,22 predominantly occurs from the
Siꢀface of the imine, activated by hydrogen bonding with the catalyst phenolic hydroxy group. When the
benzaldimine substrate has a substituent R (not a hydrogen atom) at the ortho position, the
3,5ꢀdimethylphenyllphosphine (Sp)ꢀ1aꢀderived enolate might be more suitable for Siꢀface attack on the
substrate than the 3,5ꢀdiꢀtꢀbutylphenylphosphine (Sp)ꢀ1cꢀderived enolate, because a sterically less hindered
xylyl group on the phosphorus atom minimizes the unfavorable interactions between R and the
phosphonium group.
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Scheme 2. Catalytic cycle and proposed transition state.
The obtained 2ꢀmethoxybenzaldimineꢀderived cycloadduct 5r (Table 3, entry 8) is readily transformed
into the hexahydrochromeno[4,3ꢀb]pyrrole 7; the scaffold of 7 has been proven to have
acetylcholinesterase inhibitory activity (Scheme 3).23
13

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Scheme 3. Transformation of (R)ꢀ5r to hexahydrochromeno[4,3ꢀb]pyrrole 7.
Conclusions
In summary, we found that the planar chiral [2.2]PCPꢀbased phosphine–phenol (Sp)ꢀ1a or (Sp)ꢀ1c
efficiently catalyzed the [3+2] annulations of Nꢀtosylbenzaldimines 3 and ethyl allenoate (4a) to produce
2ꢀarylꢀ1ꢀtosylꢀ2,5ꢀdihydropyrroleꢀ3ꢀcarboxylates 5 in high yields and with good to high
enantioselectivities. The catalysts (Sp)ꢀ1 can be tuned by changing the substituent on the benzene rings of
the diarylphosphino group. The appropriate catalyst for a given reaction depends on the substitution mode
of the aryl group on the arylaldimine. Further mechanistic investigations are currently underway in our
laboratory.
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Experimental section
General information
Melting point (mp) was measured by Yanaco melting point apparatus MPꢀ500D and uncorrected. 1H
NMR and 13C NMR spectra were recorded by a Bruker Avance III 600 spectrometer operating at 600
MHz (150 MHz for 13C NMR) at 25 °C with tetramethylsilane (
δ = 0.0 ppm) as an internal standard. The
data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), integration, and coupling constant (Hz). 31P NMR spectra were recorded with 85%
H3PO4 (δ = 0.0 ppm) as an external standard. High resolution mass spectra were measured with a JEOL
JMSꢀ3000. Analytical thinꢀlayer chromatography (TLC) was performed on MERCK silica gel, grade 60
F254. The spots and bands were detected by UV light of irradiation (254 nm) and/or by staining with 5%
phosphomolybdic acid followed by heating. Column chromatography for isolation of the products was
carried out on KANTO Sillica Gel 60 (230ꢀ400 mesh). HPLC analyses were performed using Interigent
UV/VIS Detector JASCO UVꢀ7500. The chiral columns included CHIRALCEL ODꢀH and CHIRALPAK
ADꢀH (Daicel Chemical Industries, Ltd., 0.46 Φ × 25 cm).
Typical procedure for the [3+2] annulation
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Method A: To a solution of imine 3a (14.7 mg, 0.0500 mmol) and allene 4a (12.6 ꢁL, 0.110 mmol) in
toluene (0.5 mL) was added (Sp)ꢀ1a (1.41 mg, 2.60 × 10ꢀ3 mmol, 5 mol%). After being stirred for 40 min,
the reaction mixture was absorbed on silica gel and purified by column chromatography (EtOAc/hexane,
1:5) to provide 5a (19.5 mg, 96 %). This method was used for entries 1,2,4,5,6,7,8,9 and 10 in Table 1.
Method B: To a cooled (–30 °C) stirred solution of imine 3k (16.8 mg, 0.0497 mmol) and (Sp)ꢀ1a (2.70
mg, 4.99 × 10ꢀ3 mmol, 10 mol%) in toluene (0.5 mL) was added allene 4a (12.6 ꢁL, 0.110 mmol). After
being stirred for 8 h, the reaction mixture was absorbed on silica gel and purified by column
chromatography on silica gel (EtOAc/hexane, 1:5) to provide 5n (18.4 mg, 82 %) as a yellowish oil. This
method was used for all entries in Table 2 and entries 3, 11 and 12 in Table 1.
Ethyl 2-(4-chlorophenyl)-2,5-dihydro-1-tosylpyrrole-3-carboxylate (5a) 15a
This compound was prepared using Method B. A yellowish oil (20.1 mg, 99 %): [α]25D = –143 (c = 1.00
in CHCl3) for entry 1 in Table 2; 1H NMR (600 MHz, CDCl3): δ 1.12 (t, 3H, J = 7.2 Hz), 2.39 (s, 3H),
4.01 (dq, 1H, J = 10.8, 7.2 Hz), 4.06 (dq, 1H, J = 10.8, 7.2 Hz), 4.40 (ddd, 1H, J = 17.4, 6.0, 2.4 Hz), 4.50
(dt, 1H, J = 17.4, 2.4 Hz), 5.68 (m, 1H), 6.78 (q, 1H, J = 2.4 Hz), 7.14ꢀ7.22 (m, 6H), 7.44 (dt, 2H, J = 8.4,
1.8 Hz); HPLC analysis (column, Daicel Chiralcel ODꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 1/9, flow rate
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1.0 mL/min; tR (min) = 15.6 for minor, tR (min) = 17.5 for major. Compound 5a was determined to be 80%
ee.
Ethyl 2-(4-bromophenyl)-2,5-dihydro-1-tosylpyrrole-3-carboxylate (5e) 15a
This compound was prepared using Method B. A yellowish oil (22.3 mg, 99 %): [α]26D = –122 (c = 1.18
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.12 (t, 3H, J = 7.2 Hz), 2.39 (s, 3H), 3.90ꢀ4.10 (m, 2H), 4.40
(ddd, 1H, J = 16.8, 6.0, 2.4 Hz), 4.50 (dt, 1H, J = 16.8, 2.4 Hz), 5.67 (dt, 1H, J = 6.0, 2.4 Hz), 6.78 (q, 1H,
J = 2.4 Hz), 7.09 (dt, 2H, J = 9.0, 2.4 Hz), 7.17 (d, 2H, J = 8.1 Hz), 7.34 (dt, 2H, J = 9.0, 2.4 Hz), 7.44 (dt,
2H, J = 8.1, 1.8 Hz); HPLC analysis (column, Daicel Chiralcel ODꢀH, λ = 254 nm, 2ꢀpropanol/hexane =
1/9, flow rate 1.0 mL/min; tR (min) = 18.4 for minor, tR (min) = 21.1 for major. Compound 5e was
determined to be 77% ee.
Ethyl 2,5-dihydro-2-(4-nitrophenyl)-1-tosylpyrrole-3-carboxylate (5f) 11b
This compound was prepared using Method B. A yellowish oil (20.6 mg, 99 %): [α]26D = –91.3 (c = 1.05
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.13 (t, 3H, J = 7.2 Hz), 2.40 (s, 3H), 3.97ꢀ4.09 (m, 2H),
4.45ꢀ4.55 (m, 2H), 5.76 (m, 1H), 6.83 (q, 1H, J = 1.8 Hz), 7.21 (d, 2H, J = 8.1 Hz), 7.45 (dt, 2H, J = 9.0,
2.4 Hz), 7.52 (d, 2H, J = 8.1 Hz), 8.12 (dt, 2H, J = 9.0, 2.4 Hz); HPLC analysis (column, Daicel Chiralpak
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ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 3/7, flow rate 1.0 mL/min; tR (min) = 26.9 for minor, tR (min) =
29.4 for major. Compound 5f was determined to be 40% ee.
Ethyl 2,5-dihydro-2-(4-methoxyphenyl)-1-tosylpyrrole-3-carboxylate (5g) 11b,15a
This compound was prepared using Method B. A yellowish oil (19.7 mg, 98 %): [α]27D = –119 (c = 0.83
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.11 (t, 3H, J = 7.2 Hz), 2.37 (s, 3H), 3.78 (s, 3H), 4.00 (dq, 1H,
J = 10.8, 7.2 Hz), 4.05 (dq, 1H, J = 10.8, 7.2 Hz), 4.36 (ddd, 1H, J = 16.8, 6.0, 2.4 Hz), 4.47 (dt, 1H, J =
16.8, 2.4 Hz), 5.70 (dt, 1H, J = 6.0, 2.4 Hz), 6.73ꢀ6.77 (m, 3H), 7.10ꢀ7.16 (m, 4H), 7.43 (d, 2H, J = 7.8
Hz); HPLC analysis (column, Daicel Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 3/7, flow rate 1.0
mL/min; tR (min) = 12.4 for minor, tR (min) = 17.0 for major. Compound 5g was determined to be 76% ee.
Ethyl 2-(3-bromophenyl)-2,5-dihydro-1-tosylpyrrole-3-carboxylate (5h)
This compound was prepared using Method B. A yellowish oil (19.1 mg, 85 %): [α]27D = –131 (c = 0.98
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.13 (t, 3H, J = 7.2 Hz), 2.39 (s, 3H), 4.01 (dq, 1H, J = 10.8,
7.2 Hz), 4.07 (dq, 1H, J = 10.8, 7.2 Hz), 4.41 (ddd, 1H, J = 17.4, 6.0, 1.8 Hz), 4.54 (dt, 1H, J = 17.4, 1.8
Hz), 5.66 (dt, 1H, J = 5.4, 1.8 Hz), 6.80 (q, 1H, J = 1.8 Hz), 7.13 (t, 1H, J = 7.8 Hz), 7.16 (d, 2H, J = 8.4
Hz), 7.17 (s, 1H), 7.22 (dt, 1H, J = 7.8 Hz), 7.34 (ddd, 1H, J = 8.4, 1.8, 1.2 Hz), 7.42 (dt, 2H, J = 8.4, 1.8
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Hz); 13C NMR (150 MHz, CDCl3): δ 13.9, 21.5, 55.0, 61.0, 68.4, 122.3, 126.9, 127.0 (2C), 129.6 (2C),
129.8, 130.6, 131.0, 135.5, 135.6, 136.0, 141.7, 143.7, 161.6; HPLC analysis (column, Daicel Chiralpak
ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 3/7, flow rate 1.0 mL/min; tR (min) = 9.07 for minor, tR (min) =
10.4 for major. Compound 5h was determined to be 74% ee. HRMS (MALDI) calcd for C20H20NO4SBrNa
[M+Na]+: 472.0189, found: 472.0189.
Ethyl 2,5-dihydro-2-(3-nitrophenyl)-1-tosylpyrrole-3-carboxylate (5i)
This compound was prepared using Method B. A yellowish oil (18.0 mg, 86 %): [α]26D = –130 (c = 0.74 in
CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.13 (t, 3H, J = 7.2 Hz), 2.37 (s, 3H), 4.03ꢀ4.09 (m, 2H),
4.49ꢀ4.58 (m, 2H), 5.77 (m, 1H), 6.85 (q, 1H, J = 1.8 Hz), 7.18 (d, 2H, J = 7.8 Hz), 7.45ꢀ7.50 (m, 3H),
7.70 (d, 1H, J = 7.8 Hz), 7.93 (t, 1H, J = 1.8 Hz), 8.10 (ddd, 1H, J = 7.8, 1.8, 1.2 Hz); 13C NMR (150
MHz, CDCl3): δ 13.9, 21.5, 55.3, 61.2, 68.2, 122.5, 123.0, 127.1 (2C), 129.2, 129.8 (2C), 134.4, 135.0,
135.1, 136.6, 142.0, 144.0, 148.2, 161.4; HPLC analysis (column, Daicel Chiralpak ADꢀH, λ = 254 nm,
2ꢀpropanol/hexane = 3/7 flow rate 1.0 mL/min; tR (min) = 13.3 for minor, tR (min) = 14.7 for major.
Compound 5i was determined to be 65% ee. HRMS (MALDI) calcd for C20H20N2O6SNa [M+Na]+:
439.0934, found: 439.0933.
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Ethyl 2,5-dihydro-2-(3-methylphenyl)-1-tosylpyrrole-3-carboxylate (5j)
This compound was prepared using Method B. A yellowish oil (19.1 mg, 99 %): [α]26D = –145 (c = 0.65 in
CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.10 (t, 3H, J = 7.2 Hz), 2.22 (s, 3H), 2.36 (s, 3H), 4.01 (dq, 1H, J
= 10.8, 7.2 Hz), 4.06 (dq, 1H, J = 10.8, 7.2 Hz), 4.38 (ddd, 1H, J = 16.8, 6.0, 1.8 Hz), 4.52 (dt, 1H, J =
16.8, 1.8 Hz), 5.70 (dt, 1H, J = 6.0, 1.8 Hz), 6.77 (q, 1H, J = 1.8 Hz), 6.90 (s, 1H), 7.01ꢀ7.03 (m, 2H), 7.11
(t, 1H, J = 7.8 Hz), 7.12 (d, 2H, J = 7.8 Hz), 7.93 (d, 2H, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3): δ 13.9,
21.3, 21.4, 54.9, 60.8, 69.0, 125.1, 127.1 (2C), 128.1, 128.4, 128.7, 129.4 (2C), 135.3, 135.7, 136.1, 137.7,
139.1, 143.1, 161.9; HPLC analysis (column, Daicel Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane =
1/9, flow rate 1.0 mL/min; tR (min) = 22.0 for minor, tR (min) = 26.1 for major. Compound 5j was
determined to be 84% ee. HRMS (MALDI) calcd for C21H23NO4SNa [M+Na]+: 408.1240, found:
408.1239.
Ethyl 2,5-dihydro-2-(naphthalen-2-yl)-1-tosylpyrrole-3-carboxylate (5k)
This compound was prepared using Method B. A yellowish oil (20.5 mg, 97 %): [α]27D = –146 (c = 1.00 in
CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.07 (t, 3H, J = 7.2 Hz), 2.24 (s, 3H), 3.94ꢀ4.03 (m, 2H), 4.48
(ddd, 1H, J = 16.8, 6.0, 1.8 Hz), 4.60 (dt, 1H, J = 16.8, 1.8 Hz), 5.90 (dt, 1H, J = 6.0, 1.8 Hz), 6.84 (q, 1H,
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J = 1.8 Hz), 6.95 (d, 2H, J = 7.8 Hz), 7.26 (dd, 1H, J = 8.4, 1.8 Hz), 7.35 (dt, 2H, J = 7.8, 1.8 Hz),
7.43ꢀ7.46 (m, 2H), 7.63 (d, 1H, J = 1.2 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.69ꢀ7.79 (m, 2H); 13C NMR (150
MHz, CDCl3): δ 13.9, 21.3, 55.1, 60.9, 69.1, 125.3, 126.0, 126.1, 127.0 (2C), 127.3, 127.5, 128.0, 128.1,
129.3 (2C), 133.06, 133.13, 135.5, 135.7, 136.0, 136.5, 143.2, 161.8; HPLC analysis (column, Daicel
Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 2/8, flow rate 1.0 mL/min; tR (min) = 19.4 for minor,
tR (min) = 33.0 for major. Compound 5k was determined to be 80% ee. HRMS (MALDI) calcd for
C24H23NO4SNa [M+Na]+: 444.1240, found: 444.1240.
Ethyl 2,5-dihydro-2-(naphthalen-1-yl)-1-tosylpyrrole-3-carboxylate (5l) 11b
This compound was prepared using Method B. A yellowish oil (20.6 mg, 98 %): [α]27D = –165 (c = 1.03
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 0.83 (t, 3H, J = 7.2 Hz), 2.25 (s, 3H), 3.83ꢀ3.90 (m, 2H), 4.54
(ddd, 1H, J = 17.4, 6.0, 2.4 Hz), 4.73 (dt, 1H, J = 17.4, 2.4 Hz), 6.54 (m, 1H), 6.88ꢀ6.93 (m, 3H),
7.18ꢀ7.26 (m, 4H), 7.43ꢀ7.48 (m, 2H), 7.70 (d, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 7.8 Hz), 8.19 (d, 1H, J =
7.8 Hz); HPLC analysis (column, Daicel Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 2/8, flow rate
1.0 mL/min; tR (min) = 15.1 for minor, tR (min) = 17.5 for major. Compound 5l was determined to be 82%
ee.
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Ethyl 2-(2-chlorophenyl)-2,5-dihydro-1-tosylpyrrole-3-carboxylate (5m)
This compound was prepared using Method B. A yellowish oil (17.4 mg, 86 %): [α]27D = –240 (c = 0.79
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.07 (t, 3H, J = 7.2 Hz), 2.39 (s, 3H), 3.97 (dq, 1H, J = 10.8,
7.2 Hz), 4.02 (dq, 1H, J = 10.8, 7.2 Hz), 4.44ꢀ4.54 (m, 2H), 6.14 (m, 1H), 6.81 (q, 1H, J = 1.8 Hz),
7.13ꢀ7.19 (m, 3H), 7.21 (d, 2H, J = 7.8 Hz), 7.29 (m, 1H), 7.60 (d, 2H, J = 7.8 Hz); 13C NMR (150 MHz,
CDCl3): δ 13.8, 21.5, 55.4, 61.0, 65.3, 126.9, 127.4 (2C), 129.0, 129.6 (2C), 129.8, 133.8, 134.8, 135.3,
136.2, 137.4, 143.6, 161.6; HPLC analysis (column, Daicel Chiralcel ODꢀH, λ = 254 nm,
2ꢀpropanol/hexane = 1/9, flow rate 1.0 mL/min; tR (min) = 24.4 for major, tR (min) = 37.9 for minor.
Compound 5m was determined to be 90% ee. C20H20NO4SCl Na [M+Na]+: 428.0694, found: 428.0694.
Ethyl 2-(2-bromophenyl)-2,5-dihydro-1-tosylpyrrole-3-carboxylate (5n)
This compound was prepared using Method B. A colorless oil (18.4 mg, 82 %): [α]27D = –201 (c = 0.90 in
CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.08 (t, 3H, J = 7.2 Hz), 2.40 (s, 3H), 3.98 (dq, 1H, J = 10.8, 7.2
Hz), 4.03 (dq, 1H, J = 10.8, 7.2 Hz), 4.46 (dt, 1H, J = 16.8, 2.4 Hz), 4.52 (ddd, 1H, J = 16.8, 6.0, 2.4 Hz),
6.14 (m, 1H), 6.81 (q, 1H, J = 2.4 Hz), 7.08 (m, 1H), 7.13ꢀ7.21 (m, 2H), 7.22 (d, 2H, J = 7.8 Hz), 7.50 (dd,
1H J = 7.8, 1.2 Hz), 7.65 (d, 2H, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3): δ 13.8, 21.5, 55.5, 60.9, 67.5,
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124.1, 127.5 (2C), 129.2, 129.6, 129.8 (2C), 132.9, 134.7, 135.6, 136.2, 139.1, 143.6, 161.6; HPLC
analysis (column, Daicel Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 2/8, flow rate 1.0 mL/min; tR
(min) = 14.3 for minor, tR (min) = 16.3 for major. Compound 5n was determined to be 89% ee. HRMS
(MALDI) calcd for C20H20NO4SBrNa [M+Na]+: 472.0189, found: 472.0188.
Ethyl 2,5-dihydro-2-(2-nitrophenyl)-1-tosylpyrrole-3-carboxylate (5o)
This compound was prepared using Method B. A yellowish oil (10.0 mg, 48 %): [α]27D = –281 (c = 0.45
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.04 (t, 3H, J = 7.2 Hz), 2.44 (s, 3H), 3.94ꢀ4.04 (m, 2H), 4.35
(dt, 1H, J = 17.4, 2.4 Hz), 4.60 (ddd, 1H, J = 17.4, 6.0, 2.4 Hz), 6.73 (m, 1H), 6.77 (q, 1H, J = 2.4 Hz),
7.34 (d, 2H, J = 7.8 Hz), 7.42 (m, 1H), 7.53ꢀ7.60 (m, 2H), 7.80 (d, 2H, J = 8.4 Hz), 7.94 (dd, 1H, J = 8.4,
1.2 Hz); 13C NMR (150 MHz, CDCl3): δ 13.8, 21.6, 55.6, 61.2, 62.3, 124.6, 127.8 (2C), 128.6, 128.8,
130.0 (2C), 133.2, 133.5, 135.4, 136.0, 136.4, 144.2, 148.7, 161.2; HPLC analysis (column, Daicel
Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 2/8, flow rate 1.0 mL/min; tR (min) = 19.9 for major,
tR (min) = 28.8 for minor. Compound 5o was determined to be 76% ee. HRMS (MALDI) calcd for
C20H20N2O6SNa [M+Na]+: 439.0934, found: 439.0932.
Ethyl 2,5-dihydro-2-(2-methylphenyl)-1-tosylpyrrole-3-carboxylate (5p) 11b
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This compound was prepared using Method B. A yellowish oil (13.7 mg, 89 %): [α]27D = –161 (c = 0.68
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.09 (t, 3H, J = 7.2 Hz), 2.35 (s, 3H), 2.55 (s, 3H), 3.96ꢀ4.06
(m, 2H), 4.38 (ddd, 1H, J = 16.8, 6.0, 1.8 Hz), 4.57 (dt, 1H, J = 16.8, 1.8 Hz), 6.06 (dt, 1H, J = 6.0, 1.8
Hz), 6.80 (q, 1H, J = 1.8 Hz), 6.82 (d, 1H, J = 7.8 Hz), 6.92 (m, 1H), 7.08ꢀ7.10 (m, 4H), 7.32 (d, 2H, J =
8.4 Hz); HPLC analysis (column, Daicel Chiralcel ODꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 1/9, flow rate
1.0 mL/min; tR (min) = 18.1 for major, tR (min) = 25.4 for minor. Compound 5p was determined to be 88%
ee.
Ethyl 2,5-dihydro-2-[2-(methoxymethoxy)phenyl]-1-tosylpyrrole-3-carboxylate (5q)
This compound was prepared using Method B. A yellowish oil (21.1 mg, 98 %): [α]27D = –165 (c = 1.03
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.07 (t, 3H, J = 7.2 Hz), 2.36 (s, 3H), 3.42 (s, 3H), 3.97 (dq, 1H,
J = 10.8, 7.2 Hz), 4.03 (dq, 1H, J = 10.8, 7.2 Hz), 4.37 (ddd, 1H, J = 16.8, 6.0, 2.4 Hz), 4.50 (dt, 1H, J =
16.8, 2.4 Hz), 4.96 (d, 1H, J = 6.6 Hz), 4.98 (d, 1H, J = 6.6 Hz), 6.06 (dt, 1H, J = 6.0, 2.4 Hz), 6.78 (q, 1H,
J = 2.4 Hz), 6.88ꢀ6.94 (m, 2H), 7.12 (d, 2H, J = 7.8 Hz), 7.14ꢀ7.20 (m, 2H), 7.40 (dt, 2H, J = 7.8, 1.8 Hz);
13C NMR (150 MHz, CDCl3): δ 13.9, 21.5, 55.2, 56.0, 60.6, 64.6, 94.3, 114.1, 121.5, 127.1 (2C), 127.6,
129.2 (2C), 129.3, 130.2, 134.9, 135.7, 135.8, 142.9, 155.2, 161.9; HPLC analysis (column, Daicel
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Chiralpak ADꢀH, λ = 254 nm, 2ꢀpropanol/hexane = 1/9, flow rate 1.0 mL/min; tR (min) = 30.9 for minor,
tR (min) = 33.6 for major. Compound 5q was determined to be 89% ee. HRMS (MALDI) calcd for
C22H25NO6SNa [M+Na]+: 454.1295, found: 454.1295.
Ethyl 2,5-dihydro-2-(2-methoxyphenyl)-1-tosylpyrrole-3-carboxylate (5r)
This compound was prepared using Method B. A yellowish oil (70.6 mg, 88 %): [α]26D = –203 (c = 1.00
in CHCl3); 1H NMR (600 MHz, CDCl3): δ 1.08 (t, 3H, J = 7.2 Hz), 2.35 (s, 3H), 3.57 (s, 3H), 3.96 (dq, 1H,
J = 10.8, 7.2 Hz), 4.01 (dq, 1H, J = 10.8, 7.2 Hz), 4.36 (ddd, 1H, J = 16.2, 6.0, 2.4 Hz), 4.50 (dt, 1H, J =
16.2, 2.4 Hz), 6.00 (dt, 1H, J = 6.0, 2.4 Hz), 6.65 (d, 1H, J = 8.4 Hz), 6.76 (q, 1H, J = 2.4 Hz), 6.86 (dt,
1H, J = 7.8, 1.8 Hz), 7.10 (d, 2H, J = 7.8 Hz), 7.17ꢀ7.20 (m, 2H), 7.38 (d, 2H, J = 7.8 Hz); 13C NMR (150
MHz, CDCl3): δ 13.8, 21.4, 55.2, 55.3, 60.6, 64.8, 110.9, 120.4, 126.9, 127.1 (2C), 129.1(2C), 129.2,
130.4, 134.6, 135.8, 135.9, 142.8, 157.4, 162.0; HPLC analysis (column, Daicel Chiralpak ADꢀH, λ = 254
nm, 2ꢀpropanol/hexane = 2/8, flow rate 1.0 mL/min; tR (min) = 21.3 for minor, tR (min) = 23.7 for major.
Compound 5r was determined to be 92% ee.
2-[2,5-Dihydro-3-(hydroxymethyl)-1-tosylpyrrol-2-yl]phenol (6)
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The following reactions were carried out under Ar. (Step 1) To a stirred solution of 5r (104 mg, 0.260
mmol) in CH2Cl2 (1.7 mL) was added boron tribromide (1.0 M in CH2Cl2) (0.86 mL, 0.86 mmol) at –
78 °C. After being stirred for 2 h at –30 °C, the mixture was quenched with MeOH and concentrated
under reduced pressure. The residue was partitioned between saturated solution of NaHCO3 (20 mL × 2)
and EtOAc (20 mL). The combined extracts were washed with saturated brine (20 mL), dried over Na2SO4
and concentrated to provide the crude product, which was purified by column chromatography
(EtOAc/hexane, 1:3) to provide the demethylated product (112.1 mg) as a yellowish oil.
(Step 2) To a cooled (–25 °C) solution of the product obtained in step 1 (112.1 mg) in CH2Cl2 (3.5 mL)
was added DIBAL (1.0 M in toluene) (0.86 mL, 0.86 mmol). The mixture was stirred for 25 min,
quenched with MeOH, and concentrated under reduced pressure. The residue was partitioned between
saturated aqueous solution of Rochell’s salt (20 mL × 2) and CH2Cl2 (20 mL). Then the organic layer was
washed with brine (20 mL), dried over Na2SO4 and concentrated under the reduced pressure. The residue
was purified by column chromatography (CH2Cl2/EtOAc/hexane, 4:4:7) to provide 6 (112.1 mg, >99%) as
a yellowish oil. [α]26D = –249 (c = 1.00 in CHCl3); 1H NMR (600 MHz, CDCl3): δ 2.36 (s, 3H), 2.93 (brs,
1H), 3.76 (d, 1H, J = 13.8 Hz), 3.86 (d, 1H, J = 13.8 Hz), 4.23ꢀ4.29 (m, 2H), 5.58 (d, 1H, J = 1.8 Hz), 5.90
(d, 1H, J = 1.8 Hz), 6.71 (d, 1H, J = 8.4 Hz), 6.83 (t, 1H, J = 7.8 Hz), 7.05 (td, 1H, J = 7.8, 1.2 Hz), 7.15
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(dd, 1H, J = 7.8, 1.2 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.30 (brs, 1H), 7.61 (d, 2H, J = 8.4 Hz); 13C NMR (150
MHz, CDCl3): δ 21.5, 54.8, 58.8, 64.2, 116.7, 119.6, 121.2, 126.2, 127.4 (2C), 128.1, 129.1, 129.8 (2C),
134.3, 142.6, 143.8, 153.3. HRMS (MALDI) calcd for C18H19NO4SNa [M+Na]+: 368.0927, found:
368.0926.
(3aR,9bS)-1,2,3,3a,4,9b-hexahydro-1-tosylchromeno[4,3-b]pyrrole (7) 24
(Step 1) To a cooled (0 °C) stirred solution of triphenylphosphine (62.6 mg, 0.225 mmol) and diol 6 (68.7
mg, 0.199 mmol) in CH2Cl2 (1.0 mL) was added diethyl azodicarboxylate (2.2 M in toluene) (99.5 ꢁL,
0.219 mmol). After being stirred for 25 min at room temperature, the mixture was absorbed to silica gel
and then purified by column chromatography (EtOAc/hexane, 1:4) to provide a yellowish oil.
(Step 2) The following reaction was carried out under H2. To a solution of the product obtained in step 1
(57.4 mg, 0.175 mmol) in MeOH/IPA (2.4 mL/1.0 mL) was added 10% Pd on carbon (21.2 mg) at room
temperature. The participated solids were removed and washed well with CH2Cl2. The filtrate was
concentrated and purified by column chromatography (CH2Cl2/EtOAc/hexane, 1:1:6) to provide 7 (42.7
mg, 74% for 2 steps) as a colorless oil: [α]25D = –80 (c = 1.00 in CHCl3); 1H NMR (600 MHz, CDCl3): δ
1.83 (m, 1H), 1.95ꢀ2.08 (m, 2H), 2.44 (s, 3H), 3.30ꢀ3.40 (m, 2H), 3.99 (dd, 1H, J = 11.4, 3.0 Hz), 4.07 (dd,
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1H, J = 11.4, 2.4 Hz), 5.01 (d, 1H, J = 7.8 Hz), 6.75 (dd, 1H, J = 7.8, 1.2 Hz), 7.00 (td, 1H, J = 7.8, 1.2
Hz), 7.15 (m, 1H), 7.34 (d, 2H, J = 7.8 Hz), 7.79 (d, 2H, J = 7.8 Hz), 7.86 (d, 1H, J = 7.8 Hz); 13C NMR
(150 MHz, CDCl3): δ 21.6, 25.9, 37.0, 47.6, 56.7, 65.1, 116.6, 121.3, 121.4, 127.6 (2C), 128.9, 130.0 (2C),
131.4, 135.2, 143.8, 154.2; HPLC analysis (column, Daicel Chiralcel ODꢀH, λ = 254 nm,
2ꢀpropanol/hexane = 5/95, flow rate 1.8 mL/min; tR (min) = 16.6 for major, tR (min) = 18.9 for minor.
Compound 7 was determined to be 87% ee.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number 15K07875.
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†Electronic Supplementary Information (ESI) available: Effects of the substituent on the imine nitrogen
atom, preparation of catalyst (Sp)ꢀ1c, determination of the absolute configuration, 1H and 13C NMR spectra,
and HPLC data. See DOI:
Notes and references
1
(a) S. E. Gibson and J. D. Knight, Org. Biomol. Chem. 2003, 1, 1256ꢀ1269; (b) V. Rosenberg, E.
Sergeeva and H. Hopf, in Modern Cyclophane Chemistry, ed. R. Gleiter and H. Hopf, WileyꢀVCH,
Weinheim, Germany, 2004, pp. 435ꢀ462; (c) A. A. Aly and A. B. Brown, Tetrahedron, 2009, 65, 8055;
(d) J. Paradies, Synthesis, 2011, 3749ꢀ3766; (e) Special Issue: Cyclophanes. Isr. J. Chem., 2012, 52, 1; (e)
O. R. P. David, Tetrahedron, 2012, 68, 8977ꢀ8993.
2
For selected recent examples of synthesis of PCPꢀbased chiral catalysts and their application, see: (a)
C. Braun, M. Nieger and S. Bräse, Chem. – Eur. J., 2017, 23, 16452ꢀ16455; (b) C. Braun, M. Nieger, W.
R. Thiel and S. Bräse, Chem. – Eur. J., 2017, 23, 15474ꢀ15483; (c) C. Braun, S. Bräse and L. L. Schafer,
Eur. J. Org. Chem., 2017, 1760ꢀ1764; (d) C. Braun, E. Spuling, N. B. Heine, M. Cakici, M. Nieger and S.
Bräse, Adv. Synth. Catal., 2016, 358, 1664ꢀ1670; (e) P. An, Y. Huo, Z. Chen, C. Song and Y. Ma, Org.
Biomol. Chem., 2017, 15, 3202ꢀ3206; (f) X. Wang, Z. Chen, W. Duan, C. Song and Y. Ma, Tetrahedron:
Asymmetry, 2017, 28, 783ꢀ790; (g) L. Wang, M. Ye, L. Wang, W. Duan, C. Song and Y. Ma,
Tetrahedron: Asymmetry, 2017, 28, 54ꢀ61; (h) J. Chen, W. Duan, Z. Chen, M. Ma, C. Song and Y. Ma,
RSC Adv., 2016, 6, 75144ꢀ75151; (i) K. P. Jayasundera, T. G. W. Engels, D. J. Lun, M. N. Mungalpara, P.
G. Plieger and G. J. Rowlands, Org. Biomol. Chem., 2017, 15, 8975ꢀ8984; (j) K. P. Jayasundera, D. N. M.
Kusmus, L. Deuilhé, L. Etheridge, Z. Farrow, D. J. Lun, G. Kaur and G. J. Rowlands, Org. Biomol. Chem.,
29