An organic thiyl radical catalyst for enantioselective cyclization

Article abstract of DOI:10.1038/nchem.1998

A diverse array of chiral organocatalysts have been developed that rely on acid-base interactions to promote enantioselective ionic reactions via the movement of electron pairs. The stereocontrol of radical reactions using organocatalysts is an alternative approach, and several studies have shown that synthetically useful reactivity can result by controlling the movement of single electrons. However, in these studies, it is still an acid-based organocatalyst which forms a closed-shell intermediate with substrate prior to the radical reaction and imparts chiral information, and use of a chiral organic radical directly as catalyst has only rarely been explored. Here, we report the design of an organic thiyl radical catalyst with a carefully designed chiral pocket constructed around a chiral thiol precatalyst. The resulting catalyst was used to effect highly diastereo- and enantioselective C-C bond-forming radical cyclizations.

Full text of DOI:10.1038/nchem.1998

ARTICLES
PUBLISHED ONLINE: 13 JULY 2014 | DOI: 10.1038/NCHEM.1998
An organic thiyl radical catalyst for
enantioselective cyclization
Takuya Hashimoto, Yu Kawamata and Keiji Maruoka
*
A diverse array of chiral organocatalysts have been developed that rely on acid–base interactions to promote
enantioselective ionic reactions via the movement of electron pairs. The stereocontrol of radical reactions using
organocatalysts is an alternative approach, and several studies have shown that synthetically useful reactivity can result
by controlling the movement of single electrons. However, in these studies, it is still an acid–based organocatalyst which
forms a closed-shell intermediate with substrate prior to the radical reaction and imparts chiral information, and use of a
chiral organic radical directly as catalyst has only rarely been explored. Here, we report the design of an organic thiyl
radical catalyst with a carefully designed chiral pocket constructed around a chiral thiol precatalyst. The resulting catalyst
was used to effect highly diastereo- and enantioselective C–C bond-forming radical cyclizations.
symmetric organocatalysis has recently risen to prominence
CO2Bn
RS
CO2Bn
CO2Bn
as a third class of asymmetric catalysis, following metal cat-
tBuO
+
A
alysis and biocatalysis1. Whereas organocatalysis has clear
tBuO
CO2Bn
(2.0 equiv.)
1a
2a
advantages in terms of operational simplicity, low toxicity and mini-
mization of environmental impact, one critical limitation is the uni-
formity of the reaction mechanism compared with other catalyses.
Chiral organocatalysts are normally equipped with acidic and/or
basic functionalities to facilitate ionic reactions based on the move-
ment of two electrons, with catalyst–substrate interactions—such as
hydrogen bonding, ion pairing and enamine–iminium formation—
R´
R´
R´
R´
RS
R˝
Stereo-determining step
RS
playing a key role2–7
.
R´
R´
RS
R´
A radical reaction based on the movement of single electrons is
an alternative way to form bonds without the help of transition-
metal catalysts8 and is widely used in biocatalysis9. Several ground-
breaking approaches using chiral organocatalysts and Lewis acids
have already emerged in efforts to open up a new horizon in the
field of asymmetric catalysis10–17. These methods rely on the use
of the acid–base sites of a catalyst, which interact with a substrate
to form a closed-shell intermediate. This intermediate subsequently
undergoes radical reactions relying on an external source.
Accordingly, they are classified as asymmetric acid–base catalysis
mediating enantioselective radical reactions.
R´
R˝
Catalytic cycle
R˝
Condition A : 3 (5 mol%), hν (100 W Hg lamp), toluene, RT, 2 h
Si
O
3´
SiiPr3
(3b)
2´
Si = SiMe3
(3a)
2
PhSSPh
S
2
Ph
59% yield
83:17 d.r.
(trans / cis)
89% yield
80:20 d.r.
87% yield
83:17 d.r.
25% e.e.
3
13% e.e. (trans)
The thiyl radical is a unique functionality that has the ability to
directly generate a radical in a substrate and promote radical bond-
forming reactions8,18,19. Its utility in asymmetric catalysis is see-
mingly a promising way to enable a fully radical-mediated organo-
catalytic transformation. Despite the fact that such a possibility was
documented in the 1990s as a way to promote asymmetric C–H
bond formation20,21, this field has not been explored further, so
whether this strategy can be applied to radical C–C bond formation
remains undetermined. Given the proficiency of biocatalysis (for
example, by benzylsuccinate synthase22) to carry out this challen-
ging task, it should also be achievable by organic chemists. Here,
we succeed in designing a chiral organic thiyl radical catalyst that
promotes highly diastereo- and enantioselective radical cyclization
of electron-deficient vinylcyclopropanes and vinyl ethers with the
3
Condition B : 4 (5 mol%), BPO (20 mol%), hν, toluene, RT, 2 h
SiiPr3
Si =
SiPh3
(4a)
SitBuPh2
(4b)
SitBu(2-Np)2
2´
O
SH
(4c)
72% yield
90:10 d.r.
22% e.e.
74% yield
92:8 d.r.
36% e.e.
82% yield
91:9 d.r.
44% e.e.
Si
3
4
Figure 1 | Initial foray into the development of the chiral organic radical
catalyst. The reaction proceeds via (1) addition of the thiyl radical to
vinylcyclopropane and ring-opening of the cyclopropane, (2) reaction of the
radical species with vinyl ether and (3) stereo-determining radical cyclization
and regeneration of the thiyl radical. Catalyst design using a binaphthyl
rigorous stereocontrol of radical C–C bond formation23,24
.
Results and discussion
Catalyst design. As a starting point to this study we examined the scaffold provided a proof of concept, but underlined the need for the
catalytic activity of a variety of binaphthyl-modified catalysts complete redesign of the catalyst to achieve high enantioselectivity.
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan. e-mail: maruoka@kuchem.kyoto-u.ac.jp
*
702
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© 2014 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1998
ARTICLES
a
CO2Bn
OtBu
BnO2C
IV
I
SiiPr3
BnO2C
BnO2C
OtBu
S
SH
Ar Ar
Si
O
tBu
S
TIPS
2´
O
O
Si
3
III
II
TIPS
4
Unhindered quadrant
Hindered quadrant
Catalyst
redesign
Transition state (side view)
CO2Bn
Transition state (top view)
b
OtBu
BnO2C
R1
R1
OtBu
S
BnO2C
BnO2C
R1
SH
HO
Ar Ar
Si
OH
S
tBu
R1
OH
1
R1
Si
(R)-5
Me
R1
Me
Figure 2 | Design of a new scaffold for enantioselective radical cyclization. a, Analysis of binaphthyl catalyst 4 suggested that the bulky silyl groups at the
C3 position should effectively block the first and second quadrants around the sulfur atom and confine the movement of the alkyl radical intermediate.
Consequently, we concluded that the silyloxy group at C2′ did not block the third quadrant sufficiently, resulting in poor stereoselectivity. b, A redesigned
catalyst 5 was based on an indanol core. In this case the diarylsilyl moiety and the aryl group at C1 were expected to occupy each of the three quadrants to
deliver a more selective catalyst. TS, transition state; TIPS, SiiPr3.
S
O
Me2N
O
Ph Ph
Si
O
OH
Me
OH
Me
O
NMe2
Br
S
NMe2
Br
S
tBu
Br
O
O
O
O
Me2NC(S)Cl (2 equiv.)
DABCO (2.5 equiv.)
i. KHMDS (1.1 equiv.)
THF, 0 ºC, 30 min
Br
Br2 (1.0 equiv.)
210 ºC
ii. tBuPh2SiOTf (1.1 equiv.)
THF, 0 ºC, 1 h
CH2Cl2, 0 ºC
15 min
DMF, RT, 6 h
Neat, 30 min
Newman-Kwart
rearrangement
Me
Me
Me
6
7
8 92% yield (2 steps)
9 84% yield
10 98% yield
SH
Me
SH
Me
SH
Me
Ph Ph
Si
Ph Ph
Si
Ph Ph
O
OH
OH
Ph
Ph
tBuLi (5.0 equiv.)
Chiral HPLC
Si
PhMgBr (3 equiv.)
tBu
tBu
tBu
Et2O
–78 ºC, 5 min
THF, 0 ºC
5 min
Optical resolution
Retro thia-Brook
rearrangement
11 87% yield
(rac)-5a 76% yield
(R)-5a >99.5% e.e.
Figure 3 | Synthesis of a new chiral thiol. The key steps in the synthesis are the carbamoyl transfer from the thiol to the enol oxygen (9 to 10), and
successive retro thia-Brook rearrangement to install the bulky silyl group ortho to the thiol (10 to 11). The carbamoyl moiety is removed during the work-up
of the retro thia-Brook rearrangement. The synthesis is completed by addition of an aryl Grignard reagent to the unmasked ketone and resolution by high-
performance liquid chromatography (HPLC) provides the chiral catalyst.
in the reaction of dibenzyl vinylcyclopropanedicarboxylate 1a and the sulfur atom was apparently critical, and our attempt to
tert-butyl vinyl ether (Fig. 1). A thiyl radical was photolytically synthesize more congested disulfides failed. To circumvent this
generated from the corresponding chiral disulfides. For problem we opted to generate the thiyl radical from a chiral thiol
comparison, the benchmark reaction using diphenyl disulfide gave and benzoyl peroxide (BPO) under photo-irradiation (condition
cyclopentane 2a in 59% yield with modest diastereoselectivity. B). A follow-up experiment indicated that BPO was more likely to
This radical cyclization is known not to follow the Beckwith– function as an oxidant rather than a radical initiator. Catalysts 4b
Houk model and preferably gives the trans isomer24,25, and we and 4c bearing
a diaryl(tert-butyl)silyl group at C3 were
confirmed that the diastereoselectivity was not affected by a thiyl particularly effective, and enantioselectivities of ∼40%
radical-mediated hydrogen abstraction after the radical cyclization. enantiomeric excess (e.e.) were achieved. Notably, a catalyst-
In addition, it is complementary to the related Lewis-acid- and controlled increase in diastereoselectivity was also observed.
transition-metal-catalysed reactions in terms of the regioselectivity However, further attempts at improving the selectivities of this
and reactivity profile26,27. After extensive screening of chiral reaction using binaphthyl-based catalysts were in vain,
catalysts we identified lead catalysts 3 with which meaningful highlighting the difficulty of rigorously controlling this
enantioselectivities could be obtained. The steric bulk surrounding radical cyclization.
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© 2014 Macmillan Publishers Limited. All rights reserved.
703

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1998
Table 2 | Substrate scope.
ARTICLES
Table1 | Optimization of the catalyst structure.
(R)-5 (5 mol%)
BPO (20 mol%)
(R)-5h (3 mol%)
R2
CO2Bn
CO2Bn
R5
BPO (6 mol%)
R2
R3
4
3
CO2Bn
1
+
+
tBuO
CO2Bn
tBuO
R3
hν
hν
R4
R4
1a
R5
2a
toluene, 0 °C, 2 h
toluene, RT, 2 h
Entry Ar
R1
Yield
(%)*
d.r.
e.e.
CO2tBu
CO2tBu
Ac
Ac
CO2Me
CO2Me
(trans:cis)† (%)‡
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
H (5a)
75
79
82
80
95
75:25
79:21
82:18
92:8
95:5
24
22
36
63
67
67
tBuO
tBuO
tBuO
Ph (5b)
93% yield (2b)
93:7 d.r. (C3:C4)
88% e.e.
94% yield (2c)
94:6 d.r. (C3:C4)
89% e.e.
99% yield (2d)
>95:5 d.r. (C3:C4)
88% e.e.
tBu (5c)
SiPh3 (5d)
SiPh3 (5d)
4
5§
6§
CO2Bn
CO2Bn
CO2Bn
2,6-Me2-4-tBu-C6H2 64
(5e)
92:8
iPr3SiO
CO2Bn
CO2Bn
CO2Bn
iPr3SiO
93% yield (2e)
BocHN
95% yield (2g)
7§
Ph
10-Bu-9-anthryl (5f) 89
94:6
>95:5
95:5
95:5
95:5
95:5
77
81
87
86
86
86
Me
73% yield (2f)
65:35 d.r. (C3:C4)
74/45% e.e.
8§
9§
10||
11¶
2-naphthyl 10-Bu-9-anthryl (5g) 62
4-CF3C6H4 10-Bu-9-anthryl (5h) 69
4-CF3C6H4 10-Bu-9-anthryl (5h) 81
4-CF3C6H4 10-Bu-9-anthryl (5h) 90
>95:5 d.r. (C3:C4)
90% e.e.
34:66 d.r. (C3:C4)
51/12% e.e.
CO2Me
R6
=
H (2h)
Br (2i)
OMe (2j)
92% yield
67:33 d.r.
(C1:C3-4)
99% yield
60:40 d.r.
(C1:C3-4)
90% yield
58:42 d.r.
(C1:C3-4)
12||,# 4-CF3C6H4 10-Bu-9-anthryl (5h) 95
R6
tBuO
O
>93:7 d.r. (C3:C4)
Performed with 1a (0.07 mmol), vinyl ether (0.14 mmol) and 5 (5 mol%) in toluene (0.7 ml).
*Isolated yield of the major diastereomer. †Diastereomeric ratio, determined by 1H NMR analysis
of the crude material. ‡e.e. of the major diastereomer, determined by chiral HPLC. §Performed
at 0 °C. ||5 (3 mol%) and BPO (6 mol%) at 0 °C on 0.1 mmol scale. ¶Performed with 1a
(1.0 mmol), vinyl ether (1.5 mmol), 5h (1 mol%) and BPO (3 mol%) in toluene (3 ml) at 0 °C.
#Under sunlight.
88/72% e.e. 87/73% e.e. 90/71% e.e.
CO2Me
R7
R7
=
iPr (2m)
Me (2k)
Bu (2l)
Cy (2n)
98% yield
56:44 d.r.
(C1:C3-4)
95% yield
59:41 d.r.
(C1:C3-4)
99% yield
61:39 d.r.
(C1:C3-4)
93/75% e.e.
94% yield
55:45 d.r.
(C1:C3-4)
93/77% e.e.
tBuO
O
90/89% e.e. 90/85% e.e.
>95:5 d.r. (C3:C4)
CO2H
To overcome this hurdle we decided to design an unprecedented
chiral scaffold using the lessons learned in the above experiments
(Fig. 2). We postulated that the bulky silyl group of 4 at C3 is essen-
tial for blocking the first and second quadrants around the sulfur
atom and for confining the movement of the alkyl radical intermedi-
ate (Fig. 2a). Its failure as chiral catalyst is assumed to arise from the
poor steric influence provided by the silyloxy group at C2′, which
fills the third quadrant. To be successful as a catalyst, this third
quadrant must be filled with a bulky substituent that effectively
shields one prochiral face of the alkene moiety. To fulfil this cri-
terion we designed a chiral thiol 5 based on an indanol unit
(Fig. 2b). The diarylsilyl moiety and the aryl group at C1 were
expected to occupy each of the three quadrants to deliver a deep
and concise chiral pocket. From molecular modelling, we postulated
the extension of 3,5-substituents of the C1 aryl group would have a
significant influence on the enantioselectivity.
95% yield (2o)
62:38 d.r.
(C1:C3-4)
tBuO
>95:5 d.r. (C3:C4)
84/75% e.e.
O
(entry 10). We also confirmed that the catalyst loading could be
further lowered to 1 mol% in a scaled-up (1 mmol scale) experiment
(entry 11), thereby offsetting the high molecular weight of the cat-
alyst28. Although, for convenience, a ultraviolet lamp was routinely
used, the reaction also proceeded smoothly using sunlight as a
benign source of photo-irradiation (entry 12). On the other hand,
the reaction did not proceed at all in the dark. The absolute con-
figuration of 2a was unambiguously determined by X-ray crystallo-
graphic analysis after derivatization (see Supplementary Fig. 4), and
matched our prediction (Fig. 2b).
As shown in Fig. 3, the simplest catalyst, 5a, which has a phenyl Diastereo- and enantioselective radical cyclization. With the
group at C1, was synthesized by a high-yielding six-step sequence optimal reaction conditions in hand we turned our attention to
and with optical resolution, starting from hydroxyindanone 6. the examination of the substrate scope (Table 2). The use of other
This procedure was designed to minimize the number of steps alkyl esters gave the corresponding products 2b and 2c with
and to allow access to a variety of catalysts by using 9 and 11 as slightly higher enantioselectivities. In addition to diesters, a
branching points.
diketone could also be utilized, affording diacetyl cyclopentane 2d
We initially examined several catalysts with different aryl groups in good yield and high stereoselectivity. Among other electron-
at the C1 position (Table 1, entries 1–4). This study demonstrated rich alkenes, triisopropylsilyl vinyl ether was utilized to give trans-
that the introduction of sterically bulky groups at 3,5-positions of cyclopentane 2e exclusively with 90% e.e. A tertiary alcohol
the aryl group was effective in achieving higher enantioselectivities, moiety was incorporated in the product (2f) by the use of a
as underlined by the result using 3,5-di(triphenylsilyl)phenyl-sub- 2-propenyl silyl ether, albeit with lower stereoselectivities. Use of
stituted thiol 5d (entry 4). At this stage the reaction temperature ene-carbamate gave chiral cyclopentyl amine 2g with modest
was optimized to 0 °C, which improved the stereoselectivities to stereoselectivity. Use of simple alkenes such as styrene and
95:5 diastereomeric ratio (d.r.) and 67% e.e. (entry 5). Further elab- 1-hexene resulted in poor conversion and selectivities (data not
oration of the catalyst led to the identification of 5f, bearing a shown). Further modification of the catalyst structure and reaction
10-butyl-9-anthryl group (entries 6 and 7). We then turned our conditions could possibly resolve these issues in the future.
focus to the ortho silyl moiety of the catalyst. Of the several diaryl
We then turned our attention to the use of vinylcyclopropanes
(tert-butyl)silyl-substituted catalysts screened (for example, entry with a keto ester unit. Even though the remote stereocentre at C1
8), catalyst 5h, bearing 4-(trifluoromethyl)phenyl groups, was stemming from the keto ester moiety could not be effectively con-
found to be optimal (entry 9). Although this reaction proceeded trolled by the catalyst, the diastereoselectivity across the C3–4
in a variety of solvents, including ethers, alcohols and haloalkanes, stereocentres remained high (over 93:7 in every case). Both aryloyl
toluene was found to be the best in terms of stereoselectivities. and alkanoyl esters, which were used as a mixture of diastereomers,
Under the optimized reaction conditions, the catalyst loading was underwent radical cyclization to give 2h–2n with high enantioselec-
lowered to 3 mol% without deteriorating the yield and selectivities tivities. Finally, to highlight the distinctive reactivity of radicals,
704
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1998
ARTICLES
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the reaction using an unprotected vinylcyclopropanecarboxylic acid.
The desired product 2o was obtained without any difficulty in good
yield and enantioselectivity. This orthogonal reactivity of this radical
catalysis compared with conventional acid–base catalysis could be
harnessed to enable streamlined stereoselective synthesis free from
protecting groups.
Conclusion
We have designed a novel chiral organic thiyl radical catalyst for
achieving highly diastereo- and enantioselective radical cyclization.
Given the inability of conventional chiral scaffolds to provide an
efficient chiral environment for this reaction, it was imperative to
build a new chiral motif from scratch. By doing so, we have
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to asymmetric radical C–C bond formation. This study should
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Received 24 February 2014; accepted 6 June 2014;
published online 13 July 2014
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Acknowledgements
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Additional information
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Competing financial interests
The authors declare no competing financial interests.
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