Role of Configuration at C6 in Catalytic Activity of l-Proline-Derived Bifunctional Organocatalysts

Article abstract of DOI:10.1021/acs.orglett.7b01000

l-Proline-derived chiral bifunctional (thio)urea organocatalysts epi-PTU and epi-PU were newly synthesized, and their catalytic performances were compared with their C6 epimeric catalysts PTU and PU in various Michael reactions of nitrostyrene in terms of reactivities and stereoselectivities. The experimental results indicate that a proper relative stereochemistry at C2 and C6 in l-proline-derived bifunctional organocatalysts is important for successful catalysis and that catalysts (PTU and PU) with the 2S,6R configuration are much more efficient.

Full text of DOI:10.1021/acs.orglett.7b01000

Letter
pubs.acs.org/OrgLett
Role of Configuration at C6 in Catalytic Activity of L‑Proline-Derived
Bifunctional Organocatalysts
Hui Jin, Soo Min Cho, Juyeol Lee, and Do Hyun Ryu*
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
S
* Supporting Information
ABSTRACT: L-Proline-derived chiral bifunctional (thio)urea organocatalysts epi-
PTU and epi-PU were newly synthesized, and their catalytic performances were
compared with their C6 epimeric catalysts PTU and PU in various Michael
reactions of nitrostyrene in terms of reactivities and stereoselectivities. The
experimental results indicate that a proper relative stereochemistry at C2 and C6 in
L-proline-derived bifunctional organocatalysts is important for successful catalysis
and that catalysts (PTU and PU) with the 2S,6R configuration are much more
efficient.
s one of the most important classes of noncovalent
Without a doubt, amino acid proline occupied a “privileged”
status in the development of enantioselective catalysis.
Developing efficient chiral ligands or organocatalysts based
on the proline scaffold has attracted much attention.7 Recently,
we reported a series of novel L-proline-derived tertiary amine
bifunctional organocatalysts, which were applied to asymmetric
Michael additions to nitroolefins using dithiomalonates8a and 2-
oxochroman-3-carboxylate esters8b as nucleophiles. In both of
our cases, our thiourea catalyst PTU (Figure 2) showed better
A
organocatalysts,1 tertiary amine−(thio)urea organocata-
lysts have proven quite successful in accomplishing various
asymmetric organic transformations. The first tertiary amine−
thiourea bifunctional organocatalyst using (1R,2R)-diaminocy-
clohexane as a chiral scaffold was reported by Takemoto in
2003.2 Subsequently, new kinds of bifunctional organocatalysts
based on different chiral scaffolds, such as chiral binaphthyl,3
cinchona alkaloid,4 amino acid,5 and saccharide,6 have been
developed and applied to a broad spectrum of reactions.
́
In a 2005 report by Soos, chiral thiourea organocatalysts
QTU and epi-QTU (Figure 1) derived from quinine and
Figure 2. L-Proline-derived tertiary amine−(thio)urea catalysts.
efficiency than quinine-derived thiourea QTU. Compared to
the performance of the C6 diphenyl-substituted catalyst Ph-PU
(Figure 2), PU showed significantly higher catalytic activity and
stereoselectivity, which implies an important role of the newly
formed C6 stereocenter on the catalytic activity of our catalysts.
On the other hand, Kesavan and co-workers reported the C6
epimeric catalyst epi-PTU (Figure 2), which was successfully
applied to many asymmetric reactions with good yields and
stereoselectivities.9 These results would suggest that both C6
diastereomers of proline-derived thioureas (PTU and epi-PTU)
are efficient catalysts, in contrast to the cinchona-derived
(thio)urea catalysts (QTU and epi-QTU). These results
stimulated our curiosity and compelled us to further investigate
the role of the C6 stereocenter on the catalytic activity of these
series of catalysts. However, through careful comparison of the
reported analytical data of epi-PTU and intermediates with our
Figure 1. Quinine- and epiquinine-derived tertiary amine−thiourea
catalysts.
epiquinine, respectively, were applied to the Michael addition
between nitromethane and chalcones.4c The catalyst QTU
showed good activity and enantioselectivity (71% yield, 95%
ee); in contrast, epi-QTU with the “natural” configuration was
completely inactive (0% yield). Independently, Connon4d
examined the Michael addition of dimethyl malonate to
nitroolefins catalyzed by similar catalysts and arrived at the
same conclusion that the C8−C9 configuration of the cinchona
scaffold is crucial for successful catalysis. C9 epimeric catalysts
are remarkably more efficacious than analogues with the
“natural” cinchona alkaloid stereochemistry. Since these
ground-breaking studies, tremendous progress in other
applications has been presented.4
Received: April 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01000
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Organic Letters
Letter
and Juaristi’s data,8a,10 we found that Kesavan’s and our
catalysts actually possess the same stereochemistry. In this
paper, in order to better understand the effects of the relative
stereochemistry at C2/C6 on the catalytic activity, the actual
C6 epimeric catalysts epi-PTU and epi-PU (see Scheme 2) and
the C6 unsubstituted catalyst H-PU (see Scheme 3) were
newly synthesized and evaluated as organocatalysts in Michael
additions of 2,4-pentanedione, dithiomalonate, and 2-oxochro-
man-3-carboxylate ester with nitrostyrene.
Scheme 2. Our Route for the Synthesis of Catalysts epi-PTU
and epi-PU
In 2014, Kesavan and co-workers reported the synthesis of
epi-PTU starting from phenyl-substituted N-tritylprolinol 1 via
the key intermediate azide 2 (Scheme 1, a).9a They reported
Scheme 1. Kesavan’s Route for the Synthesis of Catalyst epi-
PTU
atom due to the inductive effect of the Boc protecting group
prevented formation of aziridinium ion intermediate 7.
Next, we turned our attention to the key question: the role of
the (R)-C6 chiral center of catalyst (S,R)-PTU. To answer this
question, we prepared the actual (2S,6S)-epi-PTU and epi-PU
catalysts along with C6-unsubstituted H-PU catalyst. In order
to synthesize the real C6 epimeric catalysts epi-PTU and epi-
PU, the Boc protecting group of 5 was changed to trityl,
furnishing N-tritylprolinol (S,S)-1 in 40% yield (two steps)
(Scheme 2). Next, (S,S)-1 was converted to azide (S,S)-2 (76%
yield) under Mitsunobu conditions, with retention of the
configuration through the aziridinium ion intermediate epi-4
(Scheme 2). The absolute configuration of (S,S)-2 was
confirmed by comparison of NMR (1H and 13C) and optical
rotation data of benzyl derivative (S,S)-3 with Juaristi’s data.10
The key intermediate (S,S)-2 was then transformed to 8 by N-
detritylation using 5 N HCl followed by N-methylation. Finally,
azide 8 was reduced with LiAlH4 to the amine, which was
reacted in situ with 3,5-bis(trifluoromethyl)phenyl isothiocya-
nate or 3,5-bis(trifluoromethyl)phenyl isocyanate to provide
epi-PTU and epi-PU in 82% and 63% yield, respectively.
For the synthesis of the C6-unsubstituted catalyst H-PU
(Scheme 3), azide 912 was converted to 10 through N-Boc
that they obtained (S,S)-2 through Mitsunobu reaction to give
the inverted chiral center. Thereafter, (S,S)-2 was transformed
to benzyl derivative 3 and recorded [α]25 −105.0 (c 1.0,
D
CHCl3) for their (S,S)-3.9a However, Juaristi10 and co-workers
synthesized both (S,S)-3 and (S,R)-3, of which the stereo-
chemistries were unambiguously confirmed by X-ray analysis
and recorded [α]25D +84 (c 1.0, CHCl3) for (S,S)-3 and [α]25
D
−97 (c 1.0, CHCl3) for (S,R)-3. In our case, we8a also prepared
(S,R)-3 and obtained [α]20D −100.4 (c 1.0, CHCl3), which is in
accordance with the optical rotation reported by Juaristi and co-
workers. Additionally, the NMR spectra10 (1H and 13C) of
(S,S)-3 and (S,R)-3 are very different, and the NMR data9a (1H
and 13C) of (S,S)-3 reported by the Kesavan group are
consistent with those of (S,R)-3. These results indicate that
Kesavan’s key intermediate azide is not (S,S)-2 but (S,R)-2. We
hypothesize that their Mitsunobu reaction proceeded with
retention of configuration,11 actually affording azide (S,R)-2
(Scheme 1, b). The observed retention of configuration of
(S,R)-2 in the Mitsunobu reaction is probably due to the
involvement of aziridinium ion intermediate 4 (Scheme 1, b).
Similar intermediates have previously been proposed by
Scheme 3. Synthesis of Catalyst H-PU
deprotection and N-methylation. Then azide 10 was trans-
formed to the amine through the Staudinger reaction, followed
by addition with 3,5-bis(trifluoromethyl)phenyl isocyanate to
afford the desired catalyst H-PU.
With several newly synthesized catalysts in hand, their
catalytic activities were first examined in the Michael addition
of 2,4-pentanedione 11 to nitrostyrene 12 catalyzed by PTU
and the newly synthesized epi-PTU. The reactions of 11 (0.5
mmol) and 12 (0.15 mmol) were performed in the presence of
5 mol % catalyst in 1.5 mL of MTBE at rt for 48 h. When PTU
Cossy,11a Juaristi,10 Kałuza,11b and Yamagiwa11c as typical
̇
examples of anchimeric assistance of adjacent heteroatom.11
In our synthesis, we applied Cossy’s method for the
preparation of phenyl-substituted N-Boc-prolinol 5 (Scheme
2),11a which was further transformed to key intermediate azide
6 under Mitsunobu conditions with inversion of the chiral
center. The normal Mitsunobu reaction proceeded well,
probably because the reduced nucleophilicity of the nitrogen
B
DOI: 10.1021/acs.orglett.7b01000
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was used as catalyst, the R-form of 13 was produced as the
major enantiomer in 95% ee (Table 1, entry 1), which is
C6 single-phenyl-substituted catalysts (PU and epi-PU) and C6
unsubstituted catalyst H-PU showed similar reactivities,
producing adduct 15 in >95% conversion within 60 min. In
contrast, bulky C6 diphenyl-substituted catalyst Ph-PU
exhibited the lowest reactivity. It is noteworthy that the
reaction did not occur without catalyst.
Table 1. Michael Addition of 2,4-Pentanedione 11 to
a
Nitrostyrene 12 Catalyzed by PTU and epi-PTU
In terms of enantioselectivity, catalysts PTU and PU (Table
2, entries 1 and 3) furnished product 15 with high
enantioselectivity (81% ee and 90% ee, respectively). In
contrast, the C6 epimeric catalysts epi-PTU and epi-PU
exhibited different and much lower enantioselectivity, produc-
ing adduct 15 in −59% and −72% ee, respectively (Table 2,
entries 2 and 4). Catalyst Ph-PU also showed poor
enantioselectivity, affording 15 in 49% ee (Table 2, entry 5).
Catalyst H-PU, despite its good reactivity, promoted the
reaction with the lowest enantioselectivity (Table 2, entry 6).
Based on these results, a single phenyl group substitution at the
C6 position and the 6R configuration are optimal for L-proline-
derived bifunctional organocatalysts.
b
c
entry
cat.
PTU
yield (%)
ee (%)
1
2
70
88
95
95
−65
96
epi-PTU
epi-PTU
d
3
a
The reaction of 11 (0.5 mmol) and 12 (0.15 mmol) was performed
b
c
in 1.5 mL of MTBE. Isolated yield. Determined by chiral HPLC
analysis. Data collected from the literature.9a
d
consistent with Kesavan’s result (Table 1, entry 3).9a In
contrast, when the reaction was catalyzed by epi-PTU, the (S)-
enantiomer of 13 was obtained as the primary enantiomer in
moderate enantioselectivity (65% ee) (Table 1, entry 2). The
above results demonstrated that 6R catalyst PTU exhibited
superior enantioselectivity compared to the C6 epimeric
catalyst epi-PTU, although it had slightly lower activity.
When the catalysts were investigated in the Michael addition
of nitrostyrene 12 with the less reactive, unsymmetrical Michael
donor 2-oxochroman-3-carboxylate ester 16, the differences in
catalyst performance were amplified (Figure 4 and Table 3).
For a systematic investigation into the effects of the relative
stereochemistry at C2 and C6 of (thio)urea-substituted L-
proline-derived organocatalysts, their catalytic activities were
examined in the Michael addition of symmetric Michael donor
dithiomalonate 14 to nitrostyrene 12 (Figure 3 and Table 2).
Figure 4. Plots of conversion vs time for the Michael addition of 16 to
12 catalyzed by proline-derived urea catalysts. For details, see the
Supporting Information.
Table 3. Catalyst Evaluation in the Michael Addition of 2-
a
Oxochroman-3-carboxylate Esters 16 to Nitrostyrene 12
Figure 3. Plots of conversion vs time for the Michael addition of 14 to
12 catalyzed by proline-derived urea catalysts. For details, see the
Supporting Information.
b
c
d
entry
cat.
PTU
time (h)
yield (%)
dr
ee (%)
Table 2. Catalyst Evaluation in the Michael Addition of
Dithiomalonate 14 to Nitrostyrene 12
a
1
2
3
4
5
6
24
72
24
72
72
30
92
82
91
78
32
92
18:1
4:1
99
−38
99
epi-PTU
PU
10:1
4:1
epi-PU
Ph-PU
H-PU
−63
70
2:1
b
c
3:1
18
entry
cat.
PTU
yield (%)
ee (%)
a
d
The reaction of 12 (0.15 mmol) and 16 (0.075 mmol) was
performed in 1 mL of MTBE. Isolated yield. Determined by H
NMR analysis of the crude reaction mixture. Determined by chiral
1
94
90
96
92
53
93
81
−59
90
b
c
1
2
epi-PTU
PU
d
d
3
HPLC analysis.
4
epi-PU
Ph-PU
H-PU
−72
49
d
5
6
−13
Figure 4 shows the conversion vs time graph for the Michael
addition of 16 to 12 catalyzed by proline-derived urea catalysts.
This graph clearly illustrates the effect of the C6 stereocenter of
the catalyst on reactivity. Catalyst PU with the S,R
configuration showed remarkably better reactivity, promoting
the reaction with up to 98% conversion within 24 h, while
catalysts epi-PU, H-PU, and Ph-PU furnished the product with
a
The reaction of 12 (0.15 mmol) and 14 (0.17 mmol) was performed
b
c
in 1.5 mL of MTBE. Isolated yield. Determined by chiral HPLC
analysis. Data collected from the literature.8a
d
Figure 3 shows plots of conversion vs time for the Michael
addition of 14 to 12 catalyzed by proline-derived urea catalysts.
C
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Organic Letters
Letter
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77%, 89%, and 23% conversion, respectively, in the same period
of time.
In addition, the stereoselectivities of the catalysts in the
Michael addition of 16 to 12 were determined, and the results
are outlined in Table 3. When the reaction was catalyzed by 6R-
catalysts PTU and PU (Table 3, entries 1 and 3), the desired
product 17 was obtained with excellent stereoselectivity (18:1
dr, 99% ee and 10:1 dr, 99% ee, respectively). In contrast, the
C6 epimeric catalysts epi-PTU and epi-PU exhibited dramat-
ically poorer stereoselectivity, producing adduct 17 in 4:1 dr at
−38% ee and 4:1 dr at −63% ee, respectively (Table 3, entries 2
and 4). Consistent with the previous analysis, catalysts Ph-PU
and H-PU exhibited deficient stereoselectivity in this case as
well (Table 3, entries 5 and 6). The above results demonstrate
that the (S,R) configuration of catalysts PTU and PU is crucial
for successful catalysis.
In summary, comparison of the catalytic activities of (2S,6R)-
catalysts (PTU and PU), (2S,6S)-catalysts (epi-PTU and epi-
PU), C6 diphenyl-substituted catalyst Ph-PU, and C6
unsubstituted catalyst H-PU revealed that a proper relative
stereochemistry at C2 and C6 in the L-proline-derived
bifunctional organocatalyst plays a key role in successful
catalyst performance. The (2S,6R)-form catalysts PTU and
PU are remarkably more efficacious in terms of stereoselectivity
in various Michael reactions of nitrostyrene. Additionally, we
revised the original configurational misassignment of epi-PTU
catalyst from (2S,6S)-epi-PTU to (2S,6R)-PTU. Studies aimed
at investigating the mechanism and developing new organo-
catalysts based on this efficient chiral scaffold are underway and
will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01000.
Experimental procedures and full analytical data (PDF)
AUTHOR INFORMATION
■
(10) Vargas-Caporali, J.; Cruz-Hernan
2012, 86, 1275.
̀
dez, C.; Juaristi, E. Heterocycles
Corresponding Author
*E-mail: dhryu@skku.edu.
ORCID
(11) Mitsunobu reactions can proceed with retention of config-
uration via anchimeric assistance of the adjacent heteroatom in the
substrate. For examples, see: (a) Cochi, A.; Burger, B.; Navarro, C.;
Pardo, D. G.; Cossy, J.; Zhao, Y.; Cohen, T. Synlett 2009, 2157.
Do Hyun Ryu: 0000-0001-7615-4661
Notes
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̇
Asymmetry 2015, 26, 1083. (c) Yamagiwa, N.; Watanuki, S.; Nishina,
T.; Suto, Y.; Iwasaki, G. Chem. Lett. 2016, 45, 54. (d) Dondoni, A.;
Richichi, B.; Marra, A.; Perrone, D. Synlett 2004, 1711. (e) Jeong, L. S.;
Yoo, S. J.; Moon, H. R.; Kim, Y. H.; Chun, M. W. J. Chem. Soc., Perkin
Trans. 1 1998, 3325. For a review, see: (f) Hughes, D. Org. Prep.
Proced. Int. 1996, 28, 127.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by National Research Foundation
of Korea (NRF) grants funded by the Korean government
(MSIP) (Nos. NRF-2016R1A2B3007119 and NRF-
2016R1A4A1011451).
(12) Dahlin, N.; Bøgevig, A.; Adolfsson, H. Adv. Synth. Catal. 2004,
346, 1101.
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