Catalytic Enantioselective Aza-Piancatelli Rearrangement

Article abstract of DOI:10.1002/anie.201607714

An efficient organocatalytic enantioselective aza-Piancatelli rearrangement is disclosed. The powerful process provides rapid access to valuable chiral 4-amino-2-cyclopentenone building blocks from readily available 2-furfurylcarbinols with excellent chemo-, enantio-, and diastereoselectivities under mild reaction conditions.

Full text of DOI:10.1002/anie.201607714

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201607714
German Edition: DOI: 10.1002/ange.201607714
Organocatalysis
Catalytic Enantioselective Aza-Piancatelli Rearrangement
Huilin Li, Rongbiao Tong, and Jianwei Sun*
Abstract: An efficient organocatalytic enantioselective aza-
Piancatelli rearrangement is disclosed. The powerful process
provides rapid access to valuable chiral 4-amino-2-cyclo-
pentenone building blocks from readily available 2-furfuryl-
carbinols with excellent chemo-, enantio-, and diastereoselec-
tivities under mild reaction conditions.
T
he Piancatelli rearrangement, first discovered in 1976,[1]
represents one of most direct strategies to access highly
functionalized 2-cyclopentenones, a family of valuable struc-
tural units (Scheme 1).[2,3] The power of this reaction has also
been demonstrated in the synthesis of a range of useful
Scheme 2. Proposed mechanism and asymmetric induction for the
aza-Piancatelli rearrangement.
Nevertheless, intrigued by the presence of hydrogen-bonding
sites in the key intermediate IV and the possible asymmetric
induction by a chiral counter anion, we envisioned that chiral
Brønsted acids might be able to render these reactions
asymmetric.[9]
The aza-Piancatelli rearrangement, in which an amine is
used as a nucleophile, was first used to test our hypothesis,
partly because IV is an imine/iminium in nature, whose
asymmetric induction by hydrogen bonding/counter anions
has been established.[10] Another asset of this process is the
valuable utility of the 4-amino-2-cyclopentenone products.
They themselves and their simple derivatives are ubiquitous
substructures in numerous natural products and pharmaceuti-
cally important molecules, such as stemonamine, homohar-
ringtonine, etc.[11]
We began our study with 2-furfurylcarbinol (1a) as the
representative substrate and aniline (2a) as the nucleophile.
Chiral phosphoric acids were employed as catalysts in view of
their superior performance in asymmetric induction of imines
and iminiums.[10] Unfortunately, at room temperature, the
representative catalyst (R)-A1 (TRIP) could not promote the
reaction between 1a and 2a in acetonitrile, which is the best
solvent for most racemic examples (Table 1, entry 1).[5] The
reaction could proceed slowly at 808C, but no desired product
3a was observed. Indeed, the only product was 3a’, which was
formed by exocyclic addition of the amine nucleophile to the
intermediate I (Scheme 2).[5k] We reasoned that the weak
basicity of acetonitrile might reduce the catalyst activity by
competitive binding. In fact, the same reaction in DCM
proceeded with good conversion at room temperature,
although the major product was still 3a’. Encouragingly, the
desired product 3a was observed, albeit in low yield and with
moderate enantioselectivity (Table 1, entry 2). Further
screening of different phosphoric acid catalysts identified
that (R)-B4[12] provided the best enantioselectivity (84% ee)
and a promising yield of 3a (entry 7). Evaluation of other
parameters indicated that the enantioselectivity could be
further improved with DCE as the solvent at a 0.025m
concentration (entries 9–14). It is known that 3a’ can be
Scheme 1. The general Piancatelli rearrangement.
molecules, including cyclopentenone prostaglandins.[3,4] As
a result, in the past few decades the prototype reaction,
initially with water as a nucleophile and promoted by
a stoichiometric amount of acid, has been extended to
a large family of catalytic transformations which are compat-
ible with various internal and external nucleophiles, thus
providing rapid access to more diversely substituted cyclo-
pentenones (Scheme 1).[5–7] A range of catalytic systems,
including those based on Lewis acids, such as Dy(OTf)3,
Ca(NTf2)2, and In(OTf)3, have also been developed for these
reactions. However, it is important to note that all these
reactions are racemic. A catalytic enantioselective version of
this reaction has remained as an unmet but highly desirable
goal.
Mechanistically, the Piancatelli rearrangement process
involves a series of bond-formation and bond-cleavage steps
together with ring-opening and ring-closing events
(Scheme 2).[8] It is believed that the key 4p conrotatory
electrocyclization step (IV to V) determines both diastereo-
and enantioselectivity. However, the stereocontrol in this key
step is expected to be challenging because of the limited
defined stereochemistry in the linear precursor IV, as well as
the elusive interaction with chiral metal/ligand systems.
[*] Dr. H. Li, Prof. R. Tong, Prof. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607714.
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Table 1: Reaction optimization.[a]
A range of variously substituted electron-deficient ani-
lines and 2-furfurylcarbinols participated smoothly in the
efficient intermolecular aza-Piancatelli rearrangement pro-
cess under mild reaction conditions (Table 2 and Scheme 3).
The corresponding 4-amino-2-cyclopentenones were formed
with good to excellent enantioselectivities. In general the
Table 2: Scope with respect to anilines.[a]
Entry
Catalyst
Solvent
Conv. [%]
Yield [%]
3a 3a’
ee [%]
3a
Entry
R
t [h]
3
Yield [%]
ee [%]
1
2[c]
3
3,5-(CF3)2
2,5-(CF3)2
2-CF3-4-Cl
2-CF3-4-CN
2-Br-4-CF3
2-NO2
2-F-4-NO2
3-CF3-4-NO2
2-Me-4-NO2
2-OMe-4-NO2
75
22
34
48
45
31
42
21
26
31
3a
3b
3c
3d
3e
3 f
3g
3h
3i
66 (73)
83
92
76
76
72
76
92
78
90 (89)[b]
93
89
94
85
82
92
90
84
1
2
3
4
5
6
7
8
9
(R)-A1
(R)-A1
(S)-A2
(S)-B1
(S)-B2
(R)-B3
(S)-B4
(R)-C1
(S)-B4
(S)-B4
(S)-B4
(S)-B4
(S)-B4
(S)-B4
(S)-B4
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
EtOAc
toluene
DCE
DCE
DCE
0
80
100
66
100
100
100
100
42
–
–
–
34
3
71
26
26
33
62
70
4
77
0
À66
4
5
40
74
22
35
0
38
67
48
33
0
37
46
6[d]
7
À68
84
8
9
10
73
50
58
85
86
86
90
90
3j
79
80
10
11
12
13[b]
14[c]
15[c,d]
76
9
[a] Yield of isolated product. [b] Yield and ee values within parentheses
are those for a reaction on 2 mmol scale. [c] 12:1 d.r. [d] 8:1 d.r.
100
100
100
100
100
33
49
36
44
74
55
14
DCE
[a] Yield and conversion were determined by 1H NMR analysis of the
crude reaction mixture using CH2Br2 as an internal standard. The ee
values were determined by chiral-phase HPLC. [b] Run at 0.2m concen-
tration. [c] Run at 0.025m concentration. [d] Run for 64 h. DCE=1,2-
dichloroethane, DCM=dichloromethane.
possibly converted into 3a via intermediate I.[5k] Indeed, the
yield of 3a was successfully improved by increasing the
reaction time (entry 15).
We carried out more studies to probe the reactivity and
role of 3a’. First of all, it was found that 3a’ was formed in
essentially racemic form, even though a chiral catalyst was
employed. Furthermore, when pure racemic 3a’ was sub-
jected to the standard reaction conditions, with or without
additional 2a, 3a was formed with enantioselectivity com-
parable to the case with 1a [Eq. (1)]. These results proved
that the formation of 3a’ is reversible, and 3a’ serves as an off-
cycle reservoir for I. It is also consistent with the proposed
mechanism which has a late enantiodetermining step (i.e., the
4p electrocyclization). Thus, the chirality of the preceding
intermediates/substrates does not have direct influence on the
stereochemical outcome. Moreover, subjection of 3a to the
standard reaction conditions did not lead to a change of its
enantiopurity. Therefore, the product formation is irreversi-
ble under the given reaction conditions.
Scheme 3. Scope with respect to the 2-furfurylcarbinols.[a] Presented
yield is that of the isolated product. [a] Run at À208C. [b] 10:1 d.r.
[c] 13:1 d.r. [d] 8:1 d.r.
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diastereoselectivity was excellent, except for a few cases. The
mild protocol is compatible with a range of functional groups.
Heterocycles can also be incorporated in the products.
Electron-rich or electron-neutral anilines can deactivate the
catalyst. Therefore, no reaction was observed for them. Other
nucleophiles, such as alcohols and arenes, did not afford the
desired products. While alkyl-substituted or primary furfuryl
alcohols (R = alkyl or H) exhibited no reactivity, we were
pleased to find that an alkenyl-substituted one could lead to
the desired product (3x). It is noteworthy that this protocol
represents one of the most efficient and direct strategies to
assemble these valuable enantioenriched 4-amino-2-cyclo-
pentenones from achiral or racemic starting materials.
Previous strategies either require a long synthetic sequence
or kinetic resolution.[13] More importantly, the 2-furfurylcar-
binol substrates can be easily prepared from the raw material
furfural, a cheap and abundantly available commodity
product from agricultural waste.[14]
We also examined the intramolecular version of this
reaction using the substrate 1n [Eq. (2)]. Under the standard
reaction conditions, the reaction proceeded to form the
desired product 3y in quantitative yield, but in racemic form
(0% ee). However, after optimization, we found that A3
could catalyze this transformation with reasonably good
enantioselectivity.
a large family of powerful transformations which provide
rapid access to valuable cyclopentenone building blocks. With
the proper choice of a chiral Brønsted acid catalyst, the
intermolecular aza-Piancatelli reaction proceeds with excel-
lent chemo-, enantio-, and diastereoselectivity under mild
reaction conditions. It provides expedient access to a wide
range of highly enantioenriched 4-amino-cyclopentenone
products from readily available 2-furfurylcarbinols. These
products can also be easily converted into other useful chiral
molecules which are not previously generally or efficiently
accessible. This process is also a demonstration of using chiral
phosphoric acids for a new type of asymmetric reaction.
Further investigations on other members of the Piancatelli
rearrangement family are underway.
To demonstrate the utility of our protocol, we carried out
some product derivatizations [Eqs. (3)–(5); DMF = N,N-
dimethylformamide, mCPBA = m-chloroperbenzoic acid,
THF = tetrahydrofuran]. For example, 3a could undergo
mild a-alkylation to form the cyclopentenone 4 bearing an
a all-carbon quaternary stereocenter. Selective 1,2-addition
of allyl Grignard reagent generated the tertiary alcohol 5 with
high efficiency. Furthermore, after hydrogenation and
Baeyer–Villiger oxidation, 3a was smoothly converted into
the g-amino-d-valerolactone 6. Notably, in all these trans-
formations, the high enantiopurity essentially remained with-
out erosion. It is worth noting that previous assembly of these
valuable chiral building blocks has not been so straightfor-
ward.
Acknowledgments
Financial support was provided by Hong Kong RGC
((GRF604513, 16304115, ECS605812, and M-HKUST607/
12) and Shenzhen STIC (JCYJ20160229205441091). We
thank Dr. Herman Sung for assistance in structure determi-
nation.
Keywords: asymmetric catalysis · carbocycles · cyclization ·
organocatalysis · rearrangements
Finally, our protocol is not limited to access specific
arylamino-substituted cyclopentenones. As shown in Equa-
tion (6), the para-nitro aryl group in product 3h could be
turned into an electron-rich aryl group by reduction. A
subsequent oxidative cleavage successfully delivered the
highly enantioenriched free amine 8, which is poised for
further transformations into other chiral amine derivatives,
thereby representing an indirect expansion of the scope with
respect to the nucleophile.[15]
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Received: August 8, 2016
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Revised: September 29, 2016
Published online: && &&, &&&&
4
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Organocatalysis
H. Li, R. Tong, J. Sun*
&&&& — &&&&
Catalytic Enantioselective Aza-Piancatelli
Rearrangement
Piancatelli rapido: An efficient organo-
catalytic enantioselective aza-Piancatelli
rearrangement is disclosed. The powerful
process provides rapid access to valuable
chiral 4-amino-2-cyclopentenone building
blocks from readily available 2-furfuryl-
carbinols with excellent chemo-, enantio-,
and diastereoselectivities under mild
reaction conditions.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!