Catalytic asymmetric [3 + 3] annulation of cyclopropanes with mercaptoacetaldehyde

Article abstract of DOI:10.1039/c6ob00948d

A highly diastereo- and enantioselective [3 + 3] annulation of donor-acceptor cyclopropanes with mercaptoacetaldehyde has been developed. In the presence of a N,N′-dioxide-Sc(iii) complex as the catalyst, a number of aromatic substituted cyclopropyl ketones reacted with mercaptoacetaldehyde smoothly, providing the corresponding chiral tetrahydrothiopyranols in moderate yields with excellent ee (up to 99% ee) and dr values (up to >19:1).

Full text of DOI:10.1039/c6ob00948d

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DOI: 10.1039/C6OB00948D
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Catalytic Asymmetric [3+3] Annulation of Cyclopropanes with
Mercaptoacetaldehyde
Xuan Fu, Lili Lin,* Yong Xia, Pengfei Zhou, Xiaohua Liu and Xiaoming Feng*
eceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly diastereo- and enantioselective [3+3] annulation of donor-
acceptor cyclopropanes with mercaptoacetaldehyde has been
developed. In the presence of N,N’-dioxide–Sc(III) complex as
catalyst, a number of aromatic substituted cyclopropyl ketones
reacted with mercaptoacetaldehyde smoothly, providing the
corresponding chiral tetrahydrothiopyranols in moderate yields with
excellent ee (up to 99% ee) and dr values (up to >19:1).
In the past decade, the ring-opening reactions of donor-acceptor
(D-A) cyclopropanes have attracted extensive attention due to
their abilities in construction of meaningful skeletons.1 The
ring-opening reactions of cyclopropanes with amines can
construct γ–amino products and pyrroles,2 while with indoles,3
thiols,4 alcohols,5 carboxylic acids6 and azides7 nucleophiles
can construct corresponding γ–functionalized products. The
[3+2] cycloadditions of D-A cyclopropanes with enolsilyl
ethers, aldehydes, aldimines and indoles were also developed to
produce five-membered cycloadducts.8 In the catalytic
Scheme 1 The [3+3] annulation of D-A cyclopropanes with 1,3-diplors.
mercaptoacetaldeyde is meaningful and desirable. What’s more, the
resulting tetrahydrothiopyranol structures present in a number of
bioactive compounds and show interesting pharmacological
properties.14 Herein, we report
a
highly diastereo- and
enantioselective [3+3] annulation of cyclopropyl ketones with
mercaptoacetaldehyde catalyzed by a N,N’-dioxide/scandium(Ⅲ)15
complex for the first time (Scheme 1b).
asymmetric field, Tang’s bisoxazoline/Cu(
Ⅱ) catalyst could
promote the asymmetric [3+2] annulation of D-A
cyclopropanes with enolsilyl ethers and 3-methylindoles.9 The
Initially, the [3+3] annulation of cyclopropyl ketone 1a and
mercaptoracetaldehyde 2 was selected as the model reaction to
optimize the reaction conditions. Firstly, various metal salts were
screened in the presence of N,N′-dioxide L-PiPr2 derived from L-
proline in DCM at 30 oC. The results showed that most of the tested
metal salts, such as Ni(OTf)2 and Yb(OTf)3, did not promote the
reaction (Table 1, entries 1, 2; for details, see SI). Fortunately, the
coordination of Sc(OTf)3 with L-PiPr2 was able to promote this
transformation to deliver tetrahydrothiopyranol 3a in 33% yield with
11.5:1 cis:trans and 89% ee (Table 1, entry 3). Subsequently, the
structure of N,N'-dioxide ligands was investigated. The chiral
backbone had some influence on both yield and enantioselectivity,
L-proline derived L-PrPr2 and L-ramipril derived L-RaPr2 gave
lower reactivity and enantioselectivity than (S)-pipecolic acid
derived L-PiPr2 did (Table 1, entries 4, 5 vs entry 3). The
substituents on the amide moiety showed significant influence on the
enantioselectivity (Table 1, entries 3-6). The ligand L-PiPr3 with a
more isopropyl group improved dramatically the enantioselectivity
(97% ee) (Table 1, entry 6). Further study revealed that solvent was
C2-symmetric bisoxazoline/Mg(
Ⅱ) catalyst was also used in
the asymmetric [3+2] annulation of D-A cyclopropanes with
aldehydes and aldimines by Johnson’s group.10 The [3+3]
annulation of D-A cyclopropanes could achieve six-membered
cycloadducts.11 For the catalytic asymmetric version, Tang’s
and Sibi’s groups realized successfully the [3+3] reactions of
D-A cyclopropanes with aromatic azomethine imines and
nitrones by appling chiral oxazoline/Ni(
Ⅱ
)
catalysts.12
However, for the reaction of D-A cyclopropanes with sulfur-
containing mercaptoacetaldeyde, only two racemic examples
were reported by Zhang’s and Sirinivasan’s groups (Scheme
1a).13 So, developing efficient chiral catalysts for the [3+3]
annulation of D-A cyclopropanes with
Key Laboratory of Green Chemistry
& Technology, Ministry of Education,
Collegeof Chemistry, Sichuan University, Chengdu 610064, P. R.China.
Fax: (+)86 28 85418249E-mail: lililin@scu.edu.cn,xmfeng@scu.edu.cn
†Electronic Supplementary Information (ESI) available: Additional experimental
and spectroscopic data. For ESI and crystallographic data in CIF or other electronic
formatsee DOI: 10.1039/x0xx00000x
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also crucial for both activity and enantioselectivity. Changing the
solvent to DCE caused the decrease of yield to 11% and ee to 89%
(Table 1, entry 7). When the reaction was performed in 1,1,2,2-
tetrachrloethane (TCE), the ee was improved to 99% (Table 1, entry
8). However, the activity of the reaction was still low. In order to
improve the reactivity of the reaction, the reaction temperature was
Table 2 Substrate scope for the asymmetric [3+3] annulations
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DOI: 10.1039/C6OB00948D
Yield b
(%)
drd
ee c (%)
o
Entrya
R1, R2
1
increased to 50 C and the ratio of 1a to 2 was increased to 5:1.
cis:trans
Excitingly, the yield was increased to 75% dramatically with the
diastereoselectivity and enantioselectivity maintained (12.5:1
cis:trans, 97% ee, Table 1, entry 9). In all cases, the ratios of
cis:trans were determined by NMR analysis, which also showed that
cis-products were the major ones. Therefore, the optimized reaction
conditions entailed the use of 1a (0.25 mmol), 2 (0.05 mmol), L-
PiPr3-Sc(OTf)3 as catalyst and 4 Å molecular sieve in TCE at 50 oC
for 24 h.
With the optimized reaction conditions in hand, the reaction
scope was then examined. As shown in Table 2, a number of
aromatic substituted cycloporpyl ketones could undergo this
asymmetric [3+3] annulation. The electronic effect of substituents on
aromatic R1 had an obvious influence on reactivity or
enantioselectivity. Electron-donating methyl substituent on m-
position of the phenyl group had no influence on the reactivity and
1
2
C6H5, C6H5
2-MeC6H4, C6H5
3-MeC6H4,C6H5
4-MeC6H4, C6H5
4-FC6H4, C6H5
3-ClC6H4, C6H5
4-ClC6H4, C6H5
2,4-Cl2C6H3, C6H5
3-BrC6H4, C6H5
4-BrC6H4, C6H5
1-Naphthyl, C6H5
2-Naphthyl, C6H5
C6H5, 4-MeC6H4
C6H5, 4-FC6H4
1a
1b
1c
1d
1e
1f
75 (3a)
80 (3b)
76 (3c)
72(3d)
56 (3e)
62 (3f)
51 (3g)
63 (3h)
50 (3i)
60 (3j)
38 (3k)
74 (3l)
52 (3m)
56 (3n)
97 (R, R)
89
12.5:1
>19:1
16.7:1
16.7:1
14.3:1
11.1:1
14.3:1
14.3:1
12.5:1
12.5:1
7.8:1
3
97 (R, R)
86 (R, R)
97 (R, R)
98
4
5
6
7
1g
1h
1i
99 (R, R)
99
8
9
98 (R, R)
99 (R, R)
84 (R, R)
96 (R, R)
97 (R, R)
99 (R, R)
10
11
12
13
14
1j
1k
1l
16.7:1
14.3:1
16.7:1
1m
1n
Table 1 Optimization of the reaction conditions
complex
(3o)
15
Vinyl, C6H5
1o
-
-
aUnless otherwise noted, all reactions were performed with ligand–metal (10
mol%, 1:1), 1 (0.25 mmol), 2 (0.05 mmol), 4 Å M.S. (20 mg) in TCE (1.0
mL) at 50 oC for 24 h. bIsolated yield. cDetermined by chiral HPLC analysis.
dDetermined by NMR analysis.
enantioselectivity (Table 2, entry 3). However, when the methyl
group was on the ortho- or para-position, the corresponding adducts
3b and 3d were obtained in lower ee (89%, 86%) (Table 2, entries 2,
4). Meanwhile, electron-withdrawing substituents caused somewhat
decrease of the yields, but the enantioselectivity and
diastereoselectivity were still excellent (Table 2, entries 5-10). Next,
naphthyl substituted cyclopropyl ketones were tested. The 2-
naphthyl substituted cyclopropyl ketone 1l gave a 74% yield, 16.7:1
cis:trans and 96% ee. However, the 1-naphthyl substituted
cyclopropyl ketone 1k transformed to the corresponding
tetrahydrothiopyranol 3k in much lower yield (38%) with a
decreased ee (84%) and dr value (7.8:1), which might be caused by
steric hindrance of the substrate with the catalyst (Table 2, entry 11).
Moreover, the R2 on the benzoyl group was also examined.
Cyclopropyl ketones 1m with para-methyl phenyl substituent
transformed to the corresponding 3m in 52% yield with 97% ee
(Table 2, entry 13), and 1n with para-fluoro phenyl substituent
transformed to the corresponding 3n in 56% yield with 99% ee
(Table 2, entry 14). Regrettably, the reaction resulted in unsuccessful
when vinyl substituted cyclopropyl ketone 1o was used. The
corresponding tetrahydrothiopyranol 3o was surely existed among
newly generated adducts, which was determined by NMR analysis
(For details, see SI). To evaluate the moderate yields of the reaction,
cyclopropyl ketone 1a was recovered in 56% yield after the reaction
was finished and tiny amounts of undesired products were detected
by thin layer chromatography (TLC).
Yield
(%)b
ee
drd
Entrya
Metal
Ligand
Solvent
(%)c
cis:transe
1
2
3
4
5
6
7
8
9f
Ni(OTf)2
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
L-PiPr2
L-PiPr2
L-PiPr2
L-PrPr2
L-RaPr2
L-PiPr3
L-PiPr3
L-PiPr3
L-PiPr3
DCM
DCM
DCM
DCM
DCM
DCM
DCE
TCE
nr
nr
-
-
-
-
33
27
23
23
11
18
75
89
81
81
97
89
99
97
11.5:1
11.1:1
10.5:1
11.1:1
12.5:1
12.5:1
12.5:1
TCE
aUnless otherwise noted, all reactions were performed with ligand–metal (10
mol%, 1:1), 1a (0.10 mmol), 2 (0.05 mmol), 4 Å M.S. (20 mg) in solvent (1.0
mL) under N2 at 30 oC for 24 h. bIsolated yield. cDetermined by chiral HPLC
analysis. dDetermined by NMR. eFor details, see SI. fThe reaction was
performed with with L–metal (10 mol%, 1:1), 1a (0.25 mmol), 2 (0.05
mmol), 4 Å M.S. (20 mg) in solvent (1.0 mL) under N2 at 50 C for 24 h.
DCM = dichloromethane, DCE = 1,2-dichloroethane, TCE = 1,1,2,2-
tetrachloroethane.
o
Furthermore, the kinetic resolution of cyclopropyl ketone 1a with
2 | Org. Biomol. Chem, 2012, 00, 1-3
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Acknowledgement
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DOI: 10.1039/C6OB00948D
We thank the National Natural Science Foundation of China
(Nos. 21321061, 21432006 and 21572136) for financial support.
Scheme 2 Kinetic resolution of cyclopropyl ketone with mercaptoacetaldehyde
Notes and references
1
For representative reviews, see: (a) S. Danishefsky, Acc.
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804; (f) T. F. Schneider, J. Kaschel and D. B. Werz, Angew.
Chem., Int. Ed., 2014, 53, 5504.
2
For selected examples of ring-opening reactions with amines,
see: (a) R. P. Wurz and A. B. Charette, Org. Lett., 2005,
2313; (b) O. Lifchits and A. B. Charette, Org. Lett., 2008, 10
7
,
,
2809; (c) S. S. So, T. J. Auvil, V. J. Garza and A. E. Mattson,
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Fukumoto, W. Hirota and T. Yakura, Org. Lett., 2014, 16
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4012; For selected examples of catalytic asymmetric ring-
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Wang, J. Li, X. L. Sun and Y. Tang, J. Am. Chem. Soc., 2012,
134, 9066; (g) Y. Xia, X. H. Liu, H. F. Zheng, L. L. Lin and
X. M. Feng, Angew. Chem., Int. Ed., 2015, 54, 227; (h) Y.
Xia, L. L. Lin, F. Z. Chang, X. Fu, X. H. Liu and X. M. Feng,
Angew. Chem., Int. Ed., 2015, 54, 13748.
Scheme 3 Synthetic transformation of [3+3] annulation adducts 3a
mercaptoacetaldehyde 2 was studied. When the amount of 1a was
reduced to 0.20 mmol, the [3+3] annulation product 3a was obtained
in 34% yield, 96% ee and 12.5:1 dr (Scheme 2). Meanwhile, the
cyclopropyl ketones 1a was recovered in 52% yield and 81% ee.
Therefore, this method could provide an easy access to both
tetrahydrothiopyranols and cyclopropyl ketones with high
enantiopurities.
3
For selected examples of ring-opening reactions with indoles,
see: (a) M. R. Emmett and M. A. Kerr, Org. Lett., 2011, 13
,
4180; For the example of catalytic asymmetric version, see:
(b) S. M. Wales, M. M. Walker and J. S. Johnson, Org. Lett.,
2013, 15, 2558.
In order to evaluate the synthetic potential of this methodology
and also to determine the absolute configuration of the products, the
adduct 3a was transferred to 3,6-dihydro-2H-thiopyran 4 in the
presence of TBSCl (tert-butyldimethylsilyl chloride) and Et3N in one
step (Scheme 3). The yield was good (71%) while the ee maintained
(96% ee). Moreover, the absolute configuration of 4 was confirmed
unambiguously as R by X-ray diffraction analysis.16 Thus, combined
with the relative configuration of 3a determined by NMR, the
absolute configuration of 3a could be determined to be (R, R).
Configurations of many tetrahydrothiopyranols were also determined
to be (R, R) by comparing the circular dichroism spectrum with that
of 3a (For details, see SI).
4
5
(a) L. Li, Z. Li and Q. Wang, Synlett., 2009, 1830; (b) C. M.
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6
7
8
Conclusions
In summary, we have, for the first time, realized the catalytic
asymmetric [3+3] annulation of cyclopropyl ketones with
mercaptoacetaldehyde by developing
Sc(OTf)3 complex system. The
a
N,N’-dioxide L-PiPr3-
corresponding chiral
B. Driega and M. A. Kerr, J. Am. Chem. Soc., 2008, 130
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tetrahydrothiopyranols were obtained in moderate yields with
excellent diastereoselectivities (up to >19:1 dr) and
enantioselectivities (up to 99% ee). This method provided a
promising access to chiral tetrahydrothiopyranols as well as an
effective kinetic resolution of cyclopropyl ketones. Moreover, the
configurations of chiral tetrahydrothiopyranols were determined.
Further studies on related mechanism are in progress.
9
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10 (a) A. T. Parsons, A. G. Smith, A. J. Neel and J. S. Johnson, J.
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Perreault, S. R. Goudreau, L. E. Zimmer and A. B. Charette,
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12 For selected examples of asymmetric [3+3] annulations, see:
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1
3
13 Lewis acid Sc(OTf)3 or AiCl3catalyzed the reaction, see: (a)
H. P. Wang, H. H. Zhang, X. Q. Hu, P. F. Xu and Y. C. Luo,
Eur. J. Org. Chem., 2015, 3486; (b) G. Sathishkannan and K.
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14 (a) D. C. Cook, T. W. Hart, I. M. Mclay, M. N. Palfreyman,
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(4
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contains the supplementary
Machauer, L. Jacobson, M. Staufenbiel, S. Desrayaud and U.
Neumann, J. Med. Chem., 2012, 55, 3364; (c) H. Kakinuma,
T. Oi, Y. Hashimoto-Tsuchiya, M. Arai, Y. Kawakita, Y.
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
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