Asymmetric rearrangement of racemic epoxides catalyzed by chiral Br?nsted acids

Article abstract of DOI:10.1039/c3ob27285k

This paper describes a chiral Br?nsted acid catalyzed asymmetric 1,2-rearrangement of racemic epoxides via a hydrogen-shift process for the synthesis of chiral aldehydes, and, followed by a reduction, a variety of optically active alcohols can be furnished in moderate yields with up to 50% ee. Especially, a facile one-pot synthesis of chiral alcohols directly from simple alkenes by a sequential epoxidation, rearrangement, and reduction has also been realized.

Full text of DOI:10.1039/c3ob27285k

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ARTICLE TYPE
Asymmetric Rearrangement of Racemic Epoxides Catalyzed by Chiral
Brønsted Acids†
Minyang Zhuang and Haifeng Du*a
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI:
This paper describes a chiral Brønsted acid catalyzed
asymmetric 1,2-rearrangement of racemic epoxides via a
hydrogen-shift process for the synthesis of chiral aldehydes,
and followed by a reduction, a variety of optically active
Scheme 1. Strategy for Brønsted Acid catalyzed Asymmetric H-
50
Shift of Epoxides
10 alcohols can be furnished in moderate yields with up to 50%
ee. Especially, a facile one pot synthesis of chiral alcohols
directly from simple alkenes by a sequential epoxidation,
rearrangement, and reduction, has also been realized.
Scheme 2. Selected Brønsted Acid Catalysts8 for the
Chiral aldehydes are important chemicals for the straightforward
15 synthesis of optically active amines, imines, alcohols, acids and
so on. Accordingly, their asymmetric synthesis attracts broad
interest, and significant progress has been made in this area.1,2
Epoxides are versatile functional groups in synthetic chemistry,
and the asymmetric 1,2-rearrangement of epoxides via either a
20 semi-pinacol or Meinwald rearrangement process also provides
an elegant approach to chiral aldehydes.3,4 Various Lewis acids
have been reported to promote the substrate-controlled
asymmetric rearrangement of chiral epoxides to produce optically
active aldehydes.5 For example, in 1989, Yamamoto and
25 coworkers reported an organoaluminum-promoted rearrangement
of chiral epoxy silyl ethers to siloxy aldehydes.5a In 2004, the
Rearrangement of Epoxides
Suda group successfully employed
a chromium-porphyrin
complex for the same transformation.5c Very recently, the
Schreiner group accomplished a challenging stereospecific 1,2-
30 rearrangement reaction of readily accessible enantioenriched tri-
substituted epoxides to quaternary aromatic carbaldehydes under
the catalysis of silicon-thiourea Lewis acids.5g However, to the
best of our knowledge, chiral catalyst controlled asymmetric 1,2-
rearrangement of racemic epoxides has rarely been reported and
35 still remains as a challenge.
Chiral Brønsted-acid catalysis has witnessed a rapid growth in
recent years,6 and has also been successfully applied to several
types of asymmetric rearrangement reactions.7 In contrast to the
wide usage of Lewis acids for the 1,2-rearrangement of
40 epoxides,5 Brønsted acids have seldom been employed for this
transformation. To realize the challengeable of chiral Brønsted
acid catalyzed 1,2-rearrangement of racemic epoxides, we
envision that 1,1-disubstituted epoxides 1 may be suitable
substrates which will ensure the regiospecific generation of cation
45 immediate 2 and exclude the competition between H-shift and
alkyl-shift for tri-substituted epoxides to furnish the desired
enantioenriched aldehydes 3 (Scheme 1). Herein, we report our
efforts on this subject.
55
Initially, -methylstyrene epoxide (1a) was chosen as a
substrate for the chiral Brønsted acid catalyzed asymmetric 1,2-
rearrangement, and due to its instability, the obtained aldehyde 3a
60 was directly converted to the corresponding alcohol 4a (Scheme
2). With the use of BINOL-derived phosphoric acid 5a, the
rearrangement of epoxide 1a can occur at 40 ºC, but gave a
racemic product. Several N-triflyl phosphoramides 5b-e with a
stronger acidity were then synthesized in order to improve the
65 reactivity and enantioselectivity. We were pleased to find that the
complete rearrangement of epoxide 1a can be realized within 15
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Organic & Biomolecular Chemistry
Page 2 of 3
minutes to give the desired product with 26% ee under the
Subsequently, we examined the scope of epoxides for the
catalysis of 10 mol % of phosphoramides 5d (Scheme 2). A
controlled experiment with enantioenriched 1a (40% ee)9 as
asymmetric 1,2-rearrangement reaction with the use of 5.0 mol %
of phosphoramide 5e as catalyst. As shown in TableV1ie,waAvrtaicrlieeOtynline
substrate also gave 26% ee, which suggests this reaction was 35 of epoxides derived from substituted -methylstyrenes were well
5
controlled by catalysts instead of substrates. Prolonged the
reaction time from 15 min to 8 h, no changes for the
enantioselectivity were observed, which can partially exclude the
racemization possibility for the generated chiral aldehydes under
tolerated to give the desired products 4 in 48-74% yield11 with
19-48% ee’s (entries 1-13). When using epoxide 1n derived from
-ethylstyrene as substrate, the reaction can also proceed
efficiently to give the desired product 4n in 68% yield with 20%
the reaction condition. Moreover, phosphoramide 5e containing a 40 ee (Table 1, entry 14).
10 chiral spirobiindane scaffold10 can also promote this reaction with
a relatively lower ee.
Since the 1,2-rearrangement of trisubstituted epoxides is a
more challenging transformation,5g epoxide 6 has also been
The reaction condition was next optimized for the
rearrangement of epoxide 1a under the catalysis of
subjected as
a
substrate under the current condition.
Disappointingly, no reaction was observed to occur. When
phosphoramides 5d and 5e. It was found that solvents had 45 increasing the temperature from -78 ºC to room temperature,
15 obvious impacts on the enantioselectivity (Table S1, Supporting
Information). Although phosphoramide 5d was a better catalyst
than 5e in toluene (Scheme 1), phosphoramide 5e was more
sensitive for solvents. For example, CH2Cl2 gave a higher
reactivity (>99% conv, 14% ee), but tetrahydrofuran (THF) gave
20 a better ee value (21% conv, 32% ee). A mixture of THF and
CH2Cl2 (1/1 in volume) as solvent was therefore tested for this
transformation, and product 4a can be afforded in >99% conv
with 54% ee (Scheme 1). When the amount of phosphoramide 5e
was reduced to 5 mol %, the asymmetric H-shift of epoxide 1a
allylic alcohol 7 was obtained in 84% yield instead of the
expected aldehydes or ketones generated by either alkyl-shift or
H-shift (Scheme 3).11
50 Scheme 3. Brønsted Acid Catalyzed Reaction of Trisubstituted Epoxide
25 can still proceed efficiently with only
a slight loss of
Interestingly, a facile one-pot direct transformation of -
methylstyrene (8) to chiral alcohol was successfully realized to
55 give the desired product 4a in 54% yield with 50% ee by
sequential oxidation with m-CPBA, asymmetric 1,2-arrangement
with chiral Brønsted acid 5e, and reduction with NaBH4 (Scheme
4).
enantioselectivity (>99% conv, 48% ee) (Table S1, Supporting
Information).
Table 1 Chiral Brønsted Acid Catalyzed Rearrangement of Epoxidesa
60
Scheme 4. One Pot Synthesis of Chiral Alcohol from Alkene
yield
(%)b
68
ee
(%)c
48
entry
product 4
time (h)
1d,e
2
3 e, f
4 f
5e
4a: R = H
3
5
4b: R = 4-F
4c: R = 4-Cl
4d: R = 4-Br
4e: R = 4-Me
65
33
12
5
61
41
59
33
Conclusion
4
62
33
In summary, a chiral Brønsted acid catalyzed asymmetric 1,2-
rearrangement of readily accessible racemic epoxides to chiral
6
4f: R = 4-nBu
5
48
33
7
8
9 f
4g: R = 4-iPr
4h: R = 4-Ph
4i: R = 3-F
5
4.5
18
5
59
53
67
67
61
65
74
68
35
33
38
35
37
42
19
20
65 aldehydes has been successfully realized, followed by a further
reduction, a variety of optically active alcohols can be obtained in
moderate yield with up to 50% ee. Significantly, chiral alcohols
can also be furnished by a one pot sequential transformation of
alkenes via epoxidation, rearrangement, and reduction. Although
70 the enantioselectivity and the substrate scope are still not
satisfactory, this work represents the first example of catalyst-
controlled rearrangement of racemic epoxides and provides an
alternative approach for the synthesis of chiral aldehydes from
simple starting materials.
10
11
4j: R = 3-Me
4k: R = 3-OMe
4l: R = 3-Ph
4m: R = 2-Ph
4n: R = H
9
12
13g
14 e, f
5
3
12
aAll reactions were carried out with epoxide
1 (0.40 mmol),
phosphoramide 5e (0.02 mmol), and THF/CH2Cl2 (v/v = 1/1) (1.0 mL) at
-78 ºC until complete conversion of epoxide indicated by TLC. b Isolated
c
d
yield for two steps. The ee was determined by chiral HPLC. The ee
was determined by chiral GC. e The absolute configuration was assigned
75 Acknowledgements
f
as R by comparing the optical rotation with the reported one. The
This work was generously supported by the National Basic
Research Program of China (2011CB808600).
reaction was run at -60 ºC. g The reaction was run at -20 ºC.
30
2
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Organic & Biomolecular Chemistry
10 For reviews, see: (a) K. Ding, Z. Han and Z. Wang, Chem. Asian J.,
Notes and references
2009, 4, 32; (b) J.-H. Xie and Q.-L. Zhou, Acc. Chem. Res., 2008,
41, 581; (c) S.-F. Zhu and Q.-L. Zhou, Acc. Chem.VRieews.A,r2ti0cl1e2O,n4li5n,e
1365.
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China. Fax: 0086-10-62554449;
5 Tel: 0086-10-62652117; E-mail: haifengdu@iccas.ac.cn
† Electronic Supplementary Information (ESI) available: The
characterization and data for the determination of enantiomeric excess of
products along with the NMR spectra. See DOI:
75 11 Despite of complete conversion for epoxides, only moderate isolated
yields were obtained, which can probably be attributed to the
volatile character of alcohol products and a small amount of allylic
alcohols generated by side reactions.
12 For a review on rearrangement of epoxides to allylic alcohols, see: J.
1
For selected reviews on asymmetric hydroformylation, see: (a) F.
Agbossou, J.-F. Carpentier and A. Mortreux, Chem. Rev., 1995, 95,
2485; (b) M. Diéguez, O. Pàmies and C. Claver, Tetrahedron
Asymmetry, 2004, 15, 2113; (c) J. Klosin and C. R. Landis, Acc.
Chem. Res., 2007, 40, 1251.
80
G. Smith, Synthesis, 1984, 629.
10
15
20
25
30
35
40
45
50
55
60
65
70
2
For selected reviews on the generation of chiral aldehydes via
organocatalysis, see: (a) M. Marigo and K. A. Jørgensen, Chem.
Commun., 2006, 2001; (b) S. G. Ouellet, A. M. Walji and D. W. C.
MacMillan, Acc. Chem. Res., 2007, 40, 1327; (c) P. Melchiorre,
Angew. Chem., Int. Ed., 2009, 48, 1360; (d) U. Scheffler and R.
Mahrwald, Synlett, 2011, 12, 1660; (e) K. L. Jensen, G. Dickmeiss,
H. Jiang, L. Albrecht and K. A. Jørgensen, Acc. Chem. Res., 2012,
45, 248.
For leading reviews, see: (a) T. J. Snape, Chem. Soc. Rev., 2007, 36,
1823; (b) Z.-L. Song, C.-A. Fan and Y.-Q. Tu, Chem. Rev., 2011,
111, 7523; (c) B.-M. Wang and Y.-Q. Tu, Acc. Chem. Res., 2011, 44,
1207.
(a) H. O. House, J. Am. Chem. Soc., 1954, 76, 1235; (b) H. O.
House, J. Am. Chem. Soc., 1955, 77, 3070; (c) S. M. Naqvi, J. P.
Horwitz and R. Filler, J. Am. Chem. Soc., 1957, 79, 6283; (d) J.
Meinwald, S. S. Labana and M. S. Chadha, J. Am. Chem. Soc.,
1963, 85, 582.
For selected examples, see: (a) K. Maruoka, T. Ooi and H.
Yamamoto, J. Am. Chem. Soc., 1989, 111, 6431; (b) K. Maruoka, T.
Ooi, S. Nagahara and H. Yamamoto, Tetrahedron, 1991, 47, 6983;
(c) K. Suda, T. Kikkawa, S. Nakajima and T. Takanami, J. Am.
Chem. Soc., 2004, 126, 9554; (d) K. Suda, S. Nakajima, Y. Satoh
and T. Takanami, Chem. Commun., 2009, 1255; (e) G. Islas-
González, J. Benet-Buchholz, M. A. Maestro, A. Riera and M. A.
Pericàs, J. Org. Chem., 2006, 71, 1537; (f) E. Ertürk, M. Göllü and
A. S. Demir, Tetrahedron, 2010, 66, 2373; (g) R. Hrdina, C. E.
Müller, R. C. Wende, K. M. Lippert, M. Benassi, B. Spengler and P.
R. Schreiner, J. Am. Chem. Soc., 2011, 133, 7624.
For leading reviews, see: (a) T. Akiyama, J. Itoh and K. Fuchibe,
Adv. Synth. Catal., 2006, 348, 999; (b) T. Akiyama, Chem. Rev.,
2007, 107, 5744; (c) A. G. Doyle and E. N. Jacobsen, Chem. Rev.,
2007, 107, 5713; (d) D. Kampen, C. M. Reisinger and B. List, Top.
Curr. Chem., 2010, 291, 395; (e) M. Terada, Synthesis, 2010, 12,
1929; (f) C. H. Cheon and H. Yamamoto, Chem. Commun., 2011,
47, 3043.
For selected examples, see: (a) S. Xu, Z. Wang, X. Zhang, X. Zhang
and K. Ding, Angew. Chem., Int. Ed., 2008, 47, 2840; (b) S. Xu, Z.
Wang, Y. Li, X. Zhang, H. Wang and K. Ding, Chem. Eur. J., 2010,
16, 3021; (c) S. Xu, Z. Wang, X. Zhang and K. Ding, Eur. J. Org.
Chem., 2011, 110; (d) S. Xu, Z. Wang, X. Zhang, and K. Ding, Chin.
J. Chem., 2010, 28, 1731; (e) M. Rueping and A. P. Antonchick,
Angew. Chem., Int. Ed., 2008, 47, 10090; (f) C. Uyeda and E. N.
Jacobsen, J. Am. Chem. Soc., 2008, 130, 9228; (d) Q.-W. Zhang, C.-
A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P. Gu and Z.-M. Chen,
Angew. Chem., Int. Ed., 2009, 48, 8572; (g) T. Liang, Z. Zhang and J.
C. Antilla, Angew. Chem., Int. Ed., 2010, 49, 9734; (h) Q.-W. Zhang,
K. Xiang, Y.-Q. Tu, S.-Y. Zhang, X.-M. Zhang, Y.-M. Zhao and T.-C.
Zhang, Chem. Asian J., 2012, 7, 894.
For references on 5a-d, see: (a) T. Akiyama, J. Itoh, K. Yokota and
K. Fuchibe, Angew. Chem., Int. Ed., 2004, 43, 1566; (b) D.
Uraguchi and M. Terada, J. Am. Chem. Soc., 2004, 126, 5356; (c) D.
Enders, A. A. Narine, F. Toulgoat and T. Bisschops, Angew. Chem.,
Int. Ed., 2008, 47, 5661; (d) D. Nakashima and H. Yamamoto, J. Am.
Chem. Soc., 2006, 128, 9626.
This compound was prepared according to the reported method, see:
L.-L. Lou, K. Yu, F. Ding, W. Zhou, X. Peng and S. Liu,
Tetrahedron Lett., 2006, 47, 6513.
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