Construction of adjacent spiro-quaternary and tertiary stereocenters through phosphine-catalyzed asymmetric [3+2] annulation of allenoates with alkylidene azlactones

Article abstract of DOI:10.1039/c2cc17709a

A novel axially chiral spiro-phosphine-catalyzed highly regio-, diastereo- and enantioselective [3+2] cycloaddition of alkylidene azlactones with various allenic esters has been developed, affording the corresponding functionalized spirocyclic products in

Full text of DOI:10.1039/c2cc17709a

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COMMUNICATION
Construction of adjacent spiro-quaternary and tertiary stereocenters
through phosphine-catalyzed asymmetric [3+2] annulation of allenoates
with alkylidene azlactonesw
De Wang,a Yin Weib and Min Shi*ab
Received 9th December 2011, Accepted 18th January 2012
DOI: 10.1039/c2cc17709a
A novel axially chiral spiro-phosphine-catalyzed highly regio-,
diastereo- and enantioselective [3+2] cycloaddition of alkylidene
azlactones with various allenic esters has been developed, affording
the corresponding functionalized spirocyclic products in moderate
to excellent yields under mild conditions. These spirocyclic products
as masked amino acids can be easily transformed into aspartic
amino acid analogues.
Scheme 1 Reaction model.
The catalytic asymmetric construction of quaternary stereo-
of cyclopentene derivatives in good yields with high diastereo-
and enantioselectivities under mild conditions.9
centers has been intensively studied in the past few decades and
has reached a high level of productivity for various reaction
types.1 In contrast, as for the simultaneous formation of adjacent
As part of our ongoing investigation on the phosphine
catalyzed [3+2] cycloaddition,10 herein we wish to report an
highly diastereo- and enantioselective protocols are available.1,2
interesting chiral phosphine catalyzed asymmetric [3+2]
quaternary and tertiary stereocenters, only a limited number of
cycloaddition of allenoates with alkylidene azlactones, furnishing
substituted olefins to form cyclopentene molecular complexity3,4
the spiro cycloadducts in good yields with excellent diastereo-
Among those, phosphine catalyzed allenoate addition of tri-
and enantioselectivities. This new asymmetric [3+2] cycloaddition
is a brilliant strategy to construct two adjacent stereocenters.
catalyzed by chiral phosphines features the simultaneous
Besides, these cycloaddition adducts are useful in both organic
and medicinal chemistry.5 Regarding the asymmetric version of
formation of adjacent spiro-quaternary and tertiary stereo-
this reaction,6 since the pioneering work of catalytic asymmetric
centers in a single step and the obtained spiro cycloadducts
could generate an interesting family of conformation constrained
Lu’s [3+2] cycloaddition of allenes with olefins was reported by
a-amino acids.11 The corresponding reaction model has been
depicted in Scheme 1. Since two regioisomers derived from
g-attack and a-attack could be produced at the same time in the
presence of tertiary phosphine, we first attempted to carefully
examine the reaction outcome with various chiral phosphines.
Initial examinations using alkylidene azlactone 1a and
benzyl 2,3-butadienoate 2a as the substrates in the presence of
various chiral phosphines CP1–CP10 (10 mol%) (see Fig. S1 in
the ESIw) in toluene were aimed at determining their catalytic
activities in this [3+2] cycloaddition reaction system. The results
of these experiments are summarized in Table S1 (ESIw). We
found that only product 3a derived from g-attack was
obtained with these chiral phosphines. The corresponding
spiro-cycloadduct 3a was obtained in low yields and low ee
values in the presence of axially chiral binaphthyl skeleton
containing phosphines CP1–CP3 at room temperature. Using
CP1 as the catalyst gave 3a in 8% yield with 20% ee and the
other two chiral phosphines afforded barely no product (Table S1,
entries 1–3 (ESIw)). Subsequently we examined several multi-
functional chiral phosphines derived from natural amino acids
(CP4–CP6) and some commercially available chiral phosphines
(CP7–CP10). Using CP4 or CP7 as the chiral phosphine
Zhang in 1997,6a Fu and co-workers have recently developed a
series of axially chiral binaphthyl framework containing phosphines
catalyzed asymmetric cycloaddition of allenoates with electron-
deficient olefins to afford the corresponding cycloadducts in
good yields with excellent diastereo- and enantioselectivities.7
Moreover, Marinetti and co-workers have also discovered that
chiral phosphines based on a planar chiral 2-phospha[3]ferro-
cenophane scaffold were efficient catalysts for this asymmetric
reaction as well.8 Furthermore, various multifunctional chiral
phosphines derived from natural amino acids have been also
realized as powerful catalysts to promote [3+2] cycloaddition
of allenoates with electron-deficient olefins, affording a variety
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, P. R. China
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of new compounds. CCDC
853417 (3b). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc17709a
c
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Table 1 Scope of the asymmetric [3+2] annulation to afford products
3b–3q
Entrya 1 (R1)
2 (R2)
Yieldb (%) drc
eed (%)
Scheme 2 Screening of chiral phosphines.
1
2
3
4
5
6
7
1b (4-BrC6H4)
2a (Bn) 3b: 80
2a (Bn) 3c: 96
2a (Bn) 3d: 90
2a (Bn) 3e: 85
>19 : 1 96e
1c (3-BrC6H4)
1d (2-BrC6H4)
1e (4-CIC6H4)
1f (3,4-CI2C6H3) 2a (Bn) 3f: 75
1g (4-CH3C6H4) 2a (Bn) 3g: 76
1h (4-CH3OC6H4) 2a (Bn) 3h: 66
>19 : 1 95
>19 : 1 85
>19 : 1 95
>19 : 1 93
15 : 1
13 : 1
99
96
Scheme 3 Optimization of the reaction conditions.
8
9
1i (4-NO2C6H4)
1j (4-CNC6H4)
1k (2-furyl)
1l (2-thienyl)
1m (2-naphthyl)
1n (ipr)
1a (Ph)
1a (Ph)
1a (Ph)
2a (Bn) 3i: 69
2a (Bn) 3j: 83
2a (Bn) 3k: 65
2a (Bn) 3l: 66
2a (Bn) 3m: 68
2a (Bn) 3n: 68
2b (Et) 3o: 77
2c (iPr) 3p: 91
2d (tBu) 3q: 89
>19 : 1 93
>19 : 1 93
>19 : 1 95
>19 : 1 94
>19 : 1 96
>19 : 1 79
>19 : 1 95
>19 : 1 94
>19 : 1 91
10
11
12
13
14
15
16
produced 3a in 23% yield with >10 : 1 dr and 14% ee value or
in 38% yield with 9 : 1 dr and 32% ee value (Table S1, entries
4 and 7 (ESIw)). The use of CP5, CP6, and CP8 as the catalysts
gave the desired product in low yields but with no ee value
(Table S1, entries 5, 6 and 8 (ESIw)). Chiral phosphine CP9
was also inefficient in this reaction (Table S1, entry 9 (ESIw)).
Gratefully, we found that using chiral phosphine CP10
(R)-SITCP12 as the catalyst, 3a was produced in 20% yield
with 19 : 1 dr and 94% ee (Scheme 2).
a
The reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol),
CP10 (0.02 mmol) and 4 A MS (30 mg) in DCM (3.0 mL) at rt for 8 h.
b
c
Isolated yield by column chromatography. Diastereomeric ratios
determined by 1H NMR spectroscopy. Determined by chiral HPLC
e
analysis. The absolute configuration of 3b has been determined by
d
With the identification of the best catalyst in this reaction,
we next attempted to further optimize reaction conditions by
screening of the solvent and reaction temperature (see Table S2 in
the ESIw for details). We found that using 20 mol% CP10 as the
catalyst, 4 A MS as the additive and carrying out the reaction in
dichloromethane (DCM) at room temperature for 8 h gave 3a in
78% yield with 12 : 1 dr and 97% ee value, which served as the
best reaction conditions for this reaction (Scheme 3).
X-ray diffraction as (4R, 5S).
With the identification of the optimal reaction conditions, the
generality of this CP10 catalyzed asymmetric [3+2] annulation
was examined using a variety of aryl or alkyl-substituted
azlactones 1 and allenic esters 2. The results are summarized
in Table 1. All of the reactions proceeded smoothly to give the
corresponding products 3 in moderate to good yields with high
diastereo- and excellent enantioselectivities under the optimal
reaction conditions (Table 1). Whether R1 is an electron-rich
or -deficient aromatic ring, the reactions proceeded smoothly to
give the corresponding spiro-cycloadducts 3b–3j in good yields
with 85–99% ee values, respectively (Table 1, entries 1–9). Only
in the case of ortho-BrC6H4 azlactone 1d, the corresponding
adduct 3d was obtained in good yields along with relatively lower
ee value (85% ee), perhaps due to the steric influence (Table 1,
entry 3). When R1 is a heteroaromatic group (R1 = 2-furan,
2-thiophene) or a sterically more bulky 2-naphthalene moiety,
the reactions also proceeded efficiently to afford the corres-
ponding products 3k–3m in 65–68% yields with 94–96% ee
values (Table 1, entries 10–12). Changing the aromatic group
to aliphatic group provided the corresponding product 3n in
68% yield with 79% ee (Table 1, entry 13). The other allenic
esters such as ethyl-, isopropyl- and tert-butyl 2,3-butadienoates
are also suitable substrates to this asymmetric [3+2] cyclo-
addition, giving the corresponding products in 77–91% yields
with 91–95% ee values and excellent diastereoselectivities. The
absolute configuration of 3b has been assigned by X-ray
Fig. 1 A plausible transition state.
diffraction as 4R, 5S. The ORTEP drawing of 3b and the
CIF data are summarized in the ESI.w
The possible transition state of this asymmetric [3+2]
annulation is illustrated in Fig. 1 which may account for the
stereoselectivity. The azlactone 1 could approach the zwitterionic
intermediate3e,13 generated from a chiral phosphine and an
allenoate through Re face or Si face. In our case, the azlactone 1
may attack the zwitterionic intermediate from the Re face to
form the products due to the steric interaction, which is also in
accordance with the experimental results.
The synthetic utility of the reaction products was demon-
strated by nucleophilic ring opening of the cycloaddition
product 3a (Scheme 4). Treatment with 6 M HCl for 4 h at
80 1C provided N-Bz protected a-amino acid 4 in good yield
and >10 : 1 dr.14 Moreover, a simple ring opening reaction of
3a with (R)-phenylethylamine gave a peptide bond containing
product 5 in 63% yield as a single stereoisomer.2b,15
c
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Scheme 4 Ring opening products.
Scheme 5 Chiral phosphine catalyzed [3+2] annulation of MBH
carbonate 6 with 1a.
Furthermore, O-Boc protected aliphatic Morita–Baylis–Hillman
(MBH) adduct 6 was taken instead of allenoate in this asymmetric
reaction under the same reaction conditions. The desired spiro-
cycloadduct 7 was obtained in 62% yield along with 68% ee
value and excellent diastereoselectivity (Scheme 5).
In summary, we have developed a novel axially chiral spiro-
phosphine-catalyzed highly regioselective, diastereoselective and
enantioselective [3+2] annulation of allenoates with azlactones,
affording the corresponding functionalized cycloadducts in good
to excellent yields with adjacent spiro-quaternary and tertiary
stereocenters under mild conditions. These products as masked
amino acids could be easily transformed into a variety of useful
amino acid analogues such as different aspartic acid analogues.16
Financial support from the Shanghai Municipal Committee
of Science and Technology (11JC1402600), the National Basic
Research Program of China (973)-2010CB833302, the Funda-
mental Research Funds for the Central Universities and the
National Natural Science Foundation of China for financial
support (20902019, 20872162, 20672127, 20821002, 20732008,
20772030 and 20702059) is greatly acknowledged. We especially
thank Prof. Qi-Lin, Zhou and Dr Shou-Fei Zhu from Nankai
University for providing the chiral phosphine.
9 Selected papers on the chiral amino acid derived phosphines catalyzed
asymmetric cyclization of allenoates: (a) B. J. Cowen and S. J. Miller,
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(e) Y.-W. Sun, X.-Y. Guan and M. Shi, Org. Lett., 2010, 12, 5664;
(f) X.-C. Zhang, S.-H. Cao, Y. Wei and M. Shi, Org. Lett., 2011,
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14 (a) During the preparation of this manuscript, Xiao and coworkers
have reported this [3+2] cycloaddition methodology with initial
asymmetric try in low yield along with moderate ee and dr values,
see: Y.-Q. Zou, C. Li, J. Rong, H. Yan, J.-R. Chen and W.-J. Xiao,
Synlett, 2011, 1000; Please also see: (b) M. Steurer, K. L. Jensen,
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Notes and references
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2 Selected papers on the construction of adjacent quaternary and tertiary
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c
2766 Chem. Commun., 2012, 48, 2764–2766
This journal is The Royal Society of Chemistry 2012