Asymmetric chlorination/ring expansion for the synthesis of α-quaternary cycloalkanones

Article abstract of DOI:10.1021/ol5005565

A highly enantioselective chlorination/ring expansion cascade for the construction of cycloalkanones with an all-carbon quaternary center was realized (up to 97% ee). Oxa-cyclobutanol substrates were employed for the first time in the ring expansion reactions, affording the functionalized dihydrofuranones in excellent enantioselectivity.

Full text of DOI:10.1021/ol5005565

Letter
pubs.acs.org/OrgLett
Asymmetric Chlorination/Ring Expansion for the Synthesis of
α‑Quaternary Cycloalkanones
Qin Yin and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A highly enantioselective chlorination/ring
expansion cascade for the construction of cycloalkanones
with an all-carbon quaternary center was realized (up to 97%
ee). Oxa-cyclobutanol substrates were employed for the first
time in the ring expansion reactions, affording the function-
alized dihydrofuranones in excellent enantioselectivity.
Scheme 1. Designed Chlorination/Ring Expansion Cascade
onstruction of chiral quaternary carbon centers, especially
Call-carbon quaternary centers, remains one of the most
challenging subjects in contemporary synthetic chemistry.1
Cycloalkanones with a chiral all-carbon quaternary center are
attractive synthetic targets, as they are widely utilized
intermediates for natural product syntheses.2 For example,
optically active 2-methyl-2-arylcyclopentanones have been
employed as the key intermediates in the total synthesis of
(−)-aphanorphine,3a,b (−)-isoeupamne,3c and tochiunyl ace-
tate.3d Several catalytic enantioselective approaches have been
developed for these synthetically useful building blocks. In this
regard, Buchwald and co-workers have realized the Pd-catalyzed
asymmetric α-arylation of alkyl-substituted cyclopentanones;
however, installation of a blocking group at the less substituted
α-carbon of 2-alkyl cyclopentanones is required.4 Later, Shi and
co-workers reported that enantioenriched 2-alkyl-2-aryl cyclo-
pentanones could be obtained by asymmetric epoxidation of
benzylidenecyclobutanes and subsequent epoxide rearrange-
ment promoted by Et2AlCl.5 Despite notable advances,
development of mild and straightforward methods for catalytic
enantioselective syntheses of cycloalkanones with an α-all-
carbon quaternary stereocenter is still in great demand.6 On the
other hand, catalytic asymmetric halofunctionalization of
alkenes has witnessed rapid progress during the past several
years.7,8 Among them, relatively little attention has been
focused toward catalytic asymmetric halogenation/semipinacol
rearrangement cascade reactions though they have been proven
to be highly efficient methods to construct chiral quaternary
carbon centers.9 Tu and co-workers recently reported highly
enantioselective syntheses of α-oxa-quaternary ketones via
chlorination, bromination, and fluorination-induced semi-
pinacol rearrangement of electron-rich cyclic enol ethers
(Scheme 1).10 Inspired by these elegant works, we envisaged
that catalytic enantioselective halogenation-initiated ring
expansion might provide an efficient synthesis of chiral
cycloalkanones.11 Herein we report such an asymmetric
synthesis of 2-alkyl-2-aryl cycloalkanones by a highly
enantioselective chlorination/ring expansion cascade. Oxa-
cyclobutanol substrates were found to be compatible for the
first time in the ring expansion reactions.12
We began our study by testing the reaction of cyclobutanol
1a with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) under
the catalysis of (DHQD)2PHAL. To our delight, in the
presence of 10 mol % of (DHQD)2PHAL and 20 mol % of N-
Boc-L-phenylglycine (NBLP),10b,13 the reaction could proceed
smoothly in CCl4 at 0 °C to give the desired cyclopentanone 2a
in 60% yield with 84% ee (Table 1, entry 1). Evaluation of the
solvent effect was subsequently carried out. As shown in Table
1, product 2a could be obtained in 72% yield in CHCl3, with
slightly decreased enantioselectivity (ee = 77%) (Table 1, entry
2). Other chlorine-containing solvents such as DCE and DCM
gave low enantioselectivity (Table 1, entries 3−4). The desired
product was obtained in almost racemic form when polar
solvent CH3CN was utilized (64% yield, ee = 5%) (Table 1,
entry 5). Further screening of solvents displayed that 2a could
be obtained in a slightly increased yield with increased
enantioselectivity in toluene (67% yield, ee = 86%) (Table 1,
entry 6). However, evaluation of other less polar solvents did
not give improved results (58−77% yield, ee = 50−64%)
(Table 1, entries 7−10). Further screening displayed that a low
reaction temperature could slightly increase the enantiocontrol
Received: February 20, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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Letter
a
96%) at the meta or para position of the benzene ring was well
tolerated. The corresponding products could all be obtained in
moderate to good yields with excellent enantioselectivity. To be
noted, the incomplete conversion of substrate 1e led to a
moderate yield (55%). The 3,3-disubstituted cyclobutanols
could give the corresponding spiro products in 70% yield with
excellent enantioselectivity (2h−2i) (ee = 93−94%). Substrate
1j (cis/trans = 2.7:1) with a phenyl group at the C3 position of
the cyclobutanol moiety could also be well tolerated, affording
product 2j in 53% yield with a slightly increased diaster-
eoselective ratio (4.5:1). Both of the diastereomers were
obtained with excellent enantioselectivity (94% ee and 92% ee,
respectively). We further tested the reaction between cyclo-
pentanol derivative 1k and DCDMH. The reaction gave the
desired cyclohexanone 2k in 58% yield and 77% ee. In addition,
substrate 1l derived from tetralone was also tested, and the
desired spiro ketone 2l could be obtained in 76% yield, 75% ee,
and excellent diastereoselectivity.
Encouraged by the above results obtained for the cyclo-
butanols, we further explored whether oxa-cyclobutanols are
suitable substrates. To the best of our knowledge, there is no
previous report on the utilization of oxa-cyclobutanols in ring
expansion while this method could provide a straightforward
route to functionalized dihydrofuran-3(2H)-one. The 3,3-
disubstituted tetrahydrofuran unit could be found in many
functional molecules such as Rhubafuran, a commercially
available odorous cyclic ether.14 To our great delight, the ring
expansion reaction proceeded smoothly for oxa-cyclobutanol
substrates. As shown in Scheme 3, with 20 mol % of the
Table 1. Evaluation of the Solvents
b
c
entry
solvent
temp (°C)
time (h)
yield (%)
ee (%)
1
CCl4
0
0
1
1
60
72
60
60
64
67
58
67
72
77
76
81
76
84
77
5
2
CHCl3
DCE
3
0
1
4
DCM
0
1
15
5
5
CH3CN
toluene
xylene
p-xylene
o-xylene
PhF
0
1
6
0
2
86
50
51
51
64
90
91
96
7
0
2
8
0
2
9
0
2
10
11
0
2
toluene
toluene
toluene
−20
−20
−40
10
6
d
12
d
13
96
a
Reactions were performed with 1a (0.2 mmol), DCDMH (0.3
mmol), 20 mol % NBLP, and 10 mol % of (DHQD)2PHAL. Isolated
yield. Determined by HPLC analysis. 80 mg of 3 Å molecular sieves
were utilized.
b
c
d
Scheme 3. Chlorination/Ring Expansion of Oxa-
cyclobutanols
while addition of molecular sieves could accelerate the reaction
and improve the yield (Table 1, entries 11−13). Finally, the
desired product could be obtained in 76% yield and 96% ee at
−40 °C (for complete optimization, see the Supporting
Information).
Under the optimized reaction conditions, the substrate scope
of the chlorination/ring expansion cascade was explored. The
results are summarized in Scheme 2. Either an electron-
donating group (2b−2d) (70−82% yield, ee = 91−97%) or an
electron-withdrawing group (2e−2g) (55−80% yield, ee = 92−
Scheme 2. Chlorination/Ring Expansion of Cyclobutanols
catalyst, all the substituted oxa-cyclobutanol substrates tested
could undergo the chlorination/ring expansion reactions,
affording the desired products in excellent enantioselectivity
(2m−2q) (63−73% yield, ee = 87−93%). To be noted,
substrates (2p, 2q) with a halogen atom on the benzene ring
displayed decreased reactivity compared with electron-donating
group containing substrates (2n, 2o).
To evaluate the practicality of this catalytic process, a gram-
scale reaction was carried out. As shown in Scheme 4, product
2a could be obtained in 92% yield and 94% ee.
The products obtained here contain a carbonyl group and
C−Cl bond that provide versatile handles for performing
subsequent transformations. Several transformations have been
carried out as shown in Scheme 5. Substitution of the chlorine
atom with sodium azide and sodium benzenethiolate could
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Organic Letters
Letter
and the Chinese Academy of Sciences for generous financial
support.
Scheme 4. Gram-Scale Reaction
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Scheme 5. Transformations of Product
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analysis data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: slyou@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
U.; Muller, C. H.; Frohlich, R. Org. Lett. 2011, 13, 860. (l) Denmark, S.
̈
̈
ACKNOWLEDGMENTS
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We thank the National Basic Research Program of China (973
Program 2010CB833300), the National Natural Science
Foundation of China (21025209, 21121062, 21361140373),
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