Desymmetrization of cyclic 1,3-diketones via Ir-catalyzed hydrogenation: An efficient approach to cyclic hydroxy ketones with a chiral quaternary carbon

Article abstract of DOI:10.1039/c9sc01769k

We herein report an efficient method to synthesize cyclic hydroxy ketones with a chiral quaternary center. Catalyzed by an Ir/f-ampha complex, cyclic α,α-disubstituted 1,3-diketones were hydrogenated, giving mono-reduced products with both high enantiosel

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DOI: 10.1039/C9SC01769K
ARTICLE
Desymmetrization of cyclic 1,3-diketones via Ir-catalyzed
hydrogenation: an efficient approach to cyclic hydroxy ketones
with a chiral quaternary carbon
Received 00th January 20xx,
Accepted 00th January 20xx
Quan Gong,a Jialin Wen* b,a and Xumu Zhang* a,c
DOI: 10.1039/x0xx00000x
We herein report an efficient method to synthesize cyclic hydroxy ketones with a chiral quaternary center. Catalyzed by an
Ir/f-ampha complex, cyclic α,α-disubstituted 1,3-diketones were hydrogenated, giving mono-reduced products with both
high enantioselectivies and diastereoselectivities. In addition, C=C and C≡C bonds could survive in this catalytic system.
This method was applied in the preparation of (+)-estrone. No diols were observed in this chemical transformation. The
enantiomeric and diastereomeric induction were achieved as
a
result of steric hindrance.
Fig. 1 Chiral cyclic hydroxy ketones in total synthesis.
Introduction
The construction of this important synthon, however, is
limited to enzyme catalyzed reduction12, 13, Ru-catalyzed
Desymmetrization reactions have been proved to be an
efficient method to generate compounds bearing chiral
quaternary carbons1 which have historically been problematic
in synthetic chemistry2, 3. A successful example of this strategy
is mono-reduction of cyclic α,α-disubstituted 1,3-diketone,
which typically gives hydroxy ketones with two vicinal
stereogenic center1. This product has been demonstrated to
be a versatile synthon that attracts synthetic chemists. Many
synthetic works were documented to use this 5- or 6-member
ring synthon to construct complex molecules with multiple
stereogenic centers. Successful examples include coriolin4,
anguidine5, (+)-crotogoudin6, (+)-paspaline7, 8, (+)-estrone9,
15
transfer hydrogenation14,
and Corey-Bakshi-Shibata9
reduction with borane. These methods suffer from the
drawbacks of narrow substrate scope, moderate selectivity or
high catalyst loading. The challenges of mono-reduction of
cyclic α,α-disubstituted 1,3-diketone lie in such areas as (1)
enantioselectivity and diastereoselectivity being realized in
one step and (2) the prevention of over-reduction to diol. In
the hydride transfer step, different facial approaches towards
the substrate lead to two pairs of diastereomers (marked with
blue and red arrows in Fig. 2). Enantioselectivity originates in
the differentiation of a quaternary carbon from a methylene
Enzyme catalysis, Brooks
cortistatins10 and aplysiasecosterol A11.
OH
O
O
baker's yeast
Me
Glaucopine C
70% yield
10/1 dr
>99/1 er
Me
O
O
Me
Me
HO
pH = 7
40oC, 24 h
Me
OH
OH
Me
Me
O
O
H
Me
Me
OH
Cyrneine A
Br
Me
Ru-catalyzed transfer hydrogenation, Chiu / Metz
H
(-)-Hamigeran B
CHO
Me
H
Me
O
O
(S,S)-TsDPEN]Ru(p-cymene)
CHO
11%
Me
81% yield
12/1 dr
93% ee
OH
O
HO
Me
H
OTBS
OTBS
Me
H
iPrOH
O
OH
H
O
OH
O
H
R2
R1
H
CBS reduction, Corey
Ph
H
n
HO
HO
Aplysiasecosterol A
O
n = 1, 2
O
H
Ph
(+)-estrone
O
O
O
BH
Me
O
N
O
73% yield
94% ee
B
Me
Me
1.8 eq
Me
OH
nBu
10 mol%
HO
OH
O
-60oC, PhNEt2, tol
Me
O
Me
O
Me2
N
O
This work:
O
(+)-crotogoudin
Me
Me
N
H
O
R2
R1
Me
H
Ir / f-Ampha
N
cortistatins A
up to 10000 TON
up to 99% ee
up to > 25/1 dr
R2
R1
H
O
H
n
DCM, NaOtBu, rt, 40 atm H2
n
OH
paspaline
O
OH
n = 1, 2
n = 1, 2
group (Fig. 2).
Scheme 1 Methods of mono-reduction of cyclic 1,3-diketone
to generate a chiral quaternary carbon.
Our group has been dedicated to transition metal catalyzed
ketone reduction during recent two decades and has
developed a series of ferrocene-based tridentate ligands for
a Department of Chemistry, b Academy of Advanced Interdisciplinary Studies,c
Shenzhen Grubbs Institute, Southern University of Science and Technology, 1088
Xueyuan Road, Shenzhen, 518055, China.
Email: wenjl@sustech.edu.cn, zhangxm@sustech.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
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ARTICLE
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iridium catalyzed hydrogenation16-18. A variety of simple or
functionalized ketones can be hydrogenated to chiral alcohols
View Article Online
DOI: 10.1039/C9SC01769K
Elongating the reaction time and increasing the hydrogen
with remarkably high ee’s and turnover numbers (TONs). To pressure drove this reaction to a full conversion. Interestingly,
the best of knowledge, direct hydrogenation has not been no over-reduction product (diol) was observed under harsher
applied in the preparation of the aforementioned synthon. conditions. After careful optimization [for detailed condition
Due to our continuous interest in construction of chiral screening, see supplementary information], we finally
molecules via transition metal catalyzed asymmetric
O
O
H
N
[Ir(COD)Cl]2 / f-ampha
S/C = 1000
R1
R2
O
R1
R2
hydrogenation, we envisioned that this efficient catalytic
Ar2P
diastereoselectivity:
enantioselectivity:
OH
n
tBuONa, DCM, 40 atm H2
rt, 14 h
n
Fe
O
OH
f-ampha
O
Me
1
2
O
O
O
O
O
O
quaternary carbon
secondary carbon
2a
2b
2c
OH
OH
OH
system could be applied in the mono-reduction of 1,3-
diketones.
ee 99%
dr 21:1
yield 95%
ee 97%
dr 16:1
yield 95%
ee 98%
dr 14:1
yield 93%
Fig. 2 Origin of stereoselectivities in mono-reduction of 1,3-
O
O
O
O
F
Cl
Br
diketone.
2d
OH
2e
2f
2g
OH
OH
OH
ee 98%
dr 14:1
yield 90%
ee 98%
dr 11:1
yield 93%
ee 99%
dr 8:1
yield 95%
ee 99%
dr 9:1
yield 94%
Results and discussion
We initiated our investigation by screening a suitable ligand.
Although simple ketones such as acetophenone could be
reduced efficiently with all these ligands (f-amphox16, f-
amphol17 and f-ampha18), their performances in functionalized
ketones were different. We selected 2-benzyl-2-
methylcyclopentane-1,3-dione as the model substrate and
conducted hydrogenation with iridium in isopropanol with
potassium tert-butoxide. To prevent further reduction, less
forced conditions (20 atm H2) and a short reaction time (1 h)
were applied. Those ligands performed differently: f-amphox
and f-ampha gave promising results in the preliminary
assessment (Table 1).
O
O
O
O
OMe
NO2
2h
ee 99%
dr >50:1
OH
2i
OH
2j
OH
2k[a]
OH
ee 99%
dr >50:1
yield 96%
ee 99%
dr 18:1
yield 91%
ee 96%
dr 8:1
yield 93%
yield 94%
O
O
O
O
2n[a]
OH
OH
OH
2l
2m
OH
2o
ee 97%
dr >50:1
yield 93%
ee >99%
dr 3:1
yield 95%
ee 95%
dr 22:1
yield 93%
ee 85%
dr 10:1
yield[c] 80%
O
O
O
O
OH
Table 1. Preliminary investigation of ligands in hydrogenation
of cyclic 1,3-diketonea
OH
OH
OH
2q[b]
2r[b]
2s[b]
2p
ee 95%
dr 12:1
yield 94%
ee 96%
dr >50:1
yield 90%
ee 82%
dr 6:1
yield 83%
ee 95%
dr >50:1
yield 92%
O
O
[Ir(COD)Cl]2 / ligand, S/C = 500
tBuOK, iPrOH, 20 atm H2, r.t, 1h
1a
2a
O
OH
O
H
N
H
N
H
N
O
O
O
Ph2
P
Ph2P
N
N
N
H
OH
Fe
Fe
Ar2P
OH
2t[b]
Fe
Ar2
P
HO
ee 93%
Fe
dr >50:1
yield 93%
Ar = 3,5-(tBu)2-C6H3
f-ampha
(SC ,SC ,RFC)-f-amphox
Indan-f-amphox
f-amphol
obtained a satisfactory condition: catalyzed by an Ir/f-ampha
complex (0.1 % loading), the symmetric 1,3-diketone was
reduced in dichloromethane in the present of sodium tert-
butoxide, giving the corresponding chiral hydroxy ketone with
99% ee and 21/1 dr. To our delight, no diol was observed in
the crude reaction mixture. The turnover number of this
reaction could reach 10000 without obvious erosion of
stereoselectivities19.
Scheme 2 Reaction scope of desymmetrization of cyclic 1,3-
diketones via hydrogenation. Reaction condition: 1 (0.2 mmol,
0.2 M), 1/[Ir(COD)Cl]2/f-amphox/tBuONa = 1000/0.5/1.1/10,
40 atm H2, rt, 14 h; isolated yields; dr and ee were determined
by HPLC on a chiral stationary phase. a Substrate/catalyst/base
= 200/1/10, 15 min. b Substrate/catalyst/base = 200/1/10, 14 h.
c Volatile compound, > 99% conversion.
Conversio
entry
ligand
drc
eec
nb
7.3/
5.4/
4.1/
10.1
1
2
3
f-amphox
24%
11%
50%
84%
93%
28%
37%
1
indan-f-amphox
f-amphol
1
1
4
f-ampha
95%
M),
/1
a
Reaction
condition:
1a
(0.1
mmol,
0.1
1a/[Ir(COD)Cl]2/ligand/base = 500/0.5/1.1/10, 20 atm H2, rt, 1 h.
b Conversion was determined by 1H NMR analysis, no by product
c
was observed. dr and ee were determined by HPLC on a chiral
stationary phase.
2 | J. Name., 2012, 00, 1-3
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We applied the optimized condition to explore the scope of
ARTICLE
This reaction could be scaled up smoothly (Scheme 3, top).
View Article Online
this method with 0.1% catalyst loading. Various substation In order to exploit the potential applicatDioOnI: o10f.1t0h3i9s/Cm9eSCth0o17d69inK
groups on the benzene ring, no matter electron-withdrawing synthetic chemistry, we chose (+)-estrone as a target. This
or electron-donating groups, did not bring significant changes molecule plays a key role in steroidogenesis20 and chemical
in both of the stereoselectivity and conversion (2a to 2j). 1,3- synthesis of steroids7, 21, 22. We followed Corey’s route9, as well
Diketones with an allyl group, instead of benzyl, were as List’s route23, to synthesize Torgov’s 1,3-diketone24 in a sub-
hydrogenated with high enantioselectivities as well as gram scale. Hydrogenation of this diketone under the
satisfactory diastereoselectivities (2k to 2m). In addition to optimized condition quantitatively give hydroxy ketone with >
alkene, alkynyl group also survives in this chemical 99% ee and 8:1 dr. After Prins cyclization/dehydration and
transformation (2n). The preference of reducing polar C=O oxidation with IBX, Torgov’s diene24 was obtained25 which
bonds demonstrated its chemoselectivity. To our surprise, could be easily converted to (+)-estrone by a two-step
dialkyl substrate also worked well in this reaction (2o and 2p). transformation23.
This excellent stereoselectivity indicated that this catalytic
Our curiosity was drawn by the phenomenon of only one
system could discriminate the two different alkyl groups carbonyl group being reduced. When applying a harsh
(methyl vs ethyl and methyl vs propyl). Discrimination condition, it was also difficult to form diol (Scheme 4, eq. 1).
between simple alkyl groups has always been a top challenge Purified product 2a could not yield diol under this forced
in asymmetric catalysis, while alkyl and aryl group are easy to condition as well (eq. 2). Hydrogenation under the same
differentiate (2q). When we expanded the ring size of the condition with the other enantiomer of the ligand, however,
substrate from five to six, the performance faded and also failed in this transformation (eq. 3). The chiral pocket of
moderate stereoselectivities were obtained (2r). α,α- both catalyst enantiomers seemed not to be compatible with
Disubstituted 1,3-indandiones could also be hydrogenated, the hydroxy ketone. Reduction of 2a with sodium borohydride
giving desired yields and stereoselectivities (2s and 2t).
exclusively gave a chiral trans-diol in a quantitative yield. After
protecting the hydroxyl group, however, reduction this ketone
with sodium borohydride under the same conditions
exclusively gave cis-diol (Scheme 4, eq. 5). Plausible
explanations included an intramolecular hydride transfer after
the formation of a boron alkoxide, which could be a result of
O
O
[Ir(COD)Cl]2 / f-ampha, S/C = 2500
tBuONa (1%), DCM, 40 atm H2
25 oC, 4h
1a
2a
O
OH
>99% conversion
99% yield
98.5 % ee
dr 19:1
20 mmol
4.04 g
0.50 M
O
O
transesterification of borate26-28
.
HO
O
Scheme 5 Comparison of Ir-catalyzed hydrogenation and
sodium borohydride reduction in desymmetrization of cyclic
diketone.
MgBr
THF, 0 o
O
O
C
MeO
MeO

MeO
1u
84%
Torgov's diketone
38%, 1.1 g
OH
OH
While reduction of five-member-ring cyclic 1,3-diketone by
both of sodium borohydride and iridium catalyzed
hydrogenation gave the same diastereoselectivity, the
reduction of six-member-ring substrate was different.
Hydrogenation under the optimized condition gave an alcohol
with the -OH cis to the larger benzyl group, but mono-
[Ir(COD)Cl]2 / f-ampha
S/C = 1000
HCl in MeOH
reflux, 1h
1u
O
DCM, H2, rt, 14 h
600 mg
MeO
MeO
2u
3u
> 99% conversion
> 99% ee
dr = 8:1
80% yield for two steps
O
O
IBX
DMSO, rt, 2 h
ref. 25
OH
O
O
H
Ir / (SC ,SC ,RFC)-f-ampha
S/C = 200
H
H
+
(1)
tBuONa, DCM, 80 atm H2
80 oC, 24 h
HO
MeO
2a
> 95%
1a
2a
2a
OH
< 5%
OH
OH
O
O
4u
(+) - estrone
Torgov's diene
94.5% ee, 86% yield
Ir / (SC ,SC ,RFC)-f-ampha
S/C = 200
(2)
Scheme
3
Scale-up reaction and application of
desymmetrization via hydrogenation in the synthesis of (+)-
tBuONa, DCM, 80 atm H2
80 oC, 24 h
yield < 5%
OH
OH
OH
O
O
O
O
ent-catalyst, S/C = 200
(3)
(4)
Ir cat.
H2
NaBH4
tBuONa, DCM, 80 atm H2
80 oC, 24 h
MeOH, 0 o
C
yield < 5%
OH
OH
O
OH
O
OH
OH
2a
yield 95%
dr = 21:1
via
yield 92% )
dr = 6.1:1
1a
Me
O
1 eq. NaBH4
H
Bn
O
O
MeOH, 25 o
C
O
O
H
2a
trans-3a
OH
OH
ee 99%
Ir cat.
H2
NaBH4
B
H
H
0.5 mmol
dr 97:3
MeOH, 0 o
C
dr 97:3
OH
O
OH
ee 99%
yield: 96%
2p
yield 83%
dr = 6:1
O
OH
yield 96% )
dr = 10:1
1p
1 eq. NaBH4
MeOH, 25 o
(5)
C
estrone.
OMOM
OMOM
2a-MOM
cis-3a-MOM
Scheme 4 Attempts of further reduction of the hydroxy
ketone.
0.5 mmol
dr 93:7
ee 99%
dr 93:7
yield: 99%
reduction with sodium borohydride29 yielded the other
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J. Name., 2013, 00, 1-3 | 3
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ARTICLE
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diastereomer30 (Scheme 5). These results indicated the same
facial preference of iridium catalyzed hydrogenation and
sodium borohydride reduction in five-member ring but a
different facial preference in six-member ring.
14. B. Shi, S. Merten, D. K. Y. Wong, J. C. K. Chu, L. L. VLiieuw,ASrt.icKle. OLnalmine,
A. Jäger, W.-T. Wong, P. Chiu and P. Metz, Adv. Synth. Catal.
DOI: 10.1039/C9SC01769K
2009, 351, 3128-3132.
15. L. Kuang, L. L. Liu and P. Chiu, Chem. Eur. J. 2015, 21, 14287-
14291.
16. W. Wu, S. Liu, M. Duan, X. Tan, C. Chen, Y. Xie, Y. Lan, X.-Q.
Dong and X. Zhang, Org. Lett. 2016, 18, 2938-2941.
17. J. Yu, M. Duan, W. Wu, X. Qi, P. Xue, Y. Lan, X.-Q. Dong and X.
Zhang, Chem. Eur. J. 2017, 23, 970-975.
18. J. Yu, J. Long, Y. Yang, W. Wu, P. Xue, L. W. Chung, X.-Q. Dong
and X. Zhang, Org. Lett. 2017, 19, 690-693.
19. Reaction condition: 2.0 mmol of 1a, S/C = 10000, base 1%, 60
atm H2, rt, 48h. Conversion 100%, yield 95%, 95% ee, 10:1 dr.
20. G. M. Anstead, K. E. Carlson and J. A. Katzenellenbogen,
Steroids, 1997, 62, 268-303.
21. F. J. Zeelen, Natural Product Reports, 1994, 11, 607-612.
22. R. T. Blickenstaff, A. C. Ghosh and G. C. Wolf, Organic Chemistry:
A Series of Monographs, eds. Academic Press, 1974, vol. 30.
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24. S. N. Ananchenko and I. V. Torgov, Tetrahedron Lett. 1963, 4,
1553-1558.
Conclusions
We applied the strategy of transition metal catalyzed
hydrogenation in the mono-reduction of cyclic 1,3-diketones.
This desymmetrization reaction efficiently gave chiral hydroxy
ketones with high stereoselectivities. Gratefully, further
reduction that leads to diol was not observed in the
hydrogenation step. This catalytic system was highly
compatible with C=C and C≡C bonds, therefore making it a
practical method to prepare complicated molecules with a
chiral quaternary carbon.
Conflicts of interest
There are no conflicts to declare.
25. Slight erosion of ee was probably caused by the other pair of
diastereomers which were hardly removed by flash
chromatography. According to ref. 16, recrystalization could be
a good alternative.
Acknowledgements
We thank Prof. Yong-gui Zhou (Dalian Institute of Chemical 26. For methanolysis of sodium borohydride, see: R. E. Davis and J.
A. Gottbrath, J. Am. Chem. Soc. 1962, 84, 895-898.
27. Exchange of ligands on substituted borane, see: D. A. Evans, K.
T. Chapman and E. M. Carreira, J. Am. Chem. Soc. 1988, 110,
3560-3578.
28. Substrate directed reaction, see review: A. H. Hoveyda, D. A.
Evans and G. C. Fu, Chem. Rev. 1993, 93, 1307-1370.
29. The results of sodium borohydride reduction of cyclic diketones
were shown in the HPLC chromatograms racemic samples in the
supporting information.
Physics) and Prof. Pauline Chiu (the University of Hong Kong)
for their constructive advice in the preparation of manuscript.
This work was supported by the SZDRC Discipline Construction
Program, Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101) and the Shenzhen Commission of Science,
Technology and Innovation (JCYJ20170817104853520,
JSGG20160608140847864).
30. R. V. Kolakowski, M. Manpadi, Y. Zhang, T. J. Emge and L. J.
Williams, J. Am. Chem. Soc. 2009, 131, 12910-12911.
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DOI: 10.1039/C9SC01769K
O
O
O
Ir / f-ampha, base
H2
R2
R1
R2
R1
H
N
n
n = 1, 2
n
O
HO
n = 1, 2
Ar2P
OH
Fe
O
(+) - estrone
up to 10000 TON
up to > 99% ee
up to > 50/1 dr
f-ampha
H
no over-reduction
H
H
HO