Cooperative, highly enantioselective phosphinothiourea catalysis of imine - Allene [3 + 2] cycloadditions

Article abstract of DOI:10.1021/ja801344w

A new family of phosphinthiourea catalysts was developed for the highly enantioselective synthesis of 2-aryl-2,5-hydropyrroles via a [3 + 2] cycloaddition of an electron-deficient allene with aryl and heteroaryl diphenylphosphinoylimines. The presence of

Full text of DOI:10.1021/ja801344w

Published on Web 04/08/2008
Cooperative, Highly Enantioselective Phosphinothiourea
Catalysis of Imine-Allene [3 + 2] Cycloadditions
Yuan-Qing Fang and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Massachusetts 02138
Received February 27, 2008; E-mail: jacobsen@chemistry.harvard.edu
Scheme 1
Several classes of polyfunctional small molecule catalysts have
been identified capable of inducing enantioselective additions
through cooperative activation of nucleophilic and electrophilic
reacting partners.1 Very recently, catalysts bearing hydrogen-
bonding motifs in addition to nucleophilic functionality, such as
proline and thiourea-based systems, have been utilized successfully
in a variety of such transformations.2 We became interested in the
possibility of incorporating reactive phosphine groups into chiral
H-bonding catalyst frameworks, with the goal of taking advantage
of their high nucleophilicity and low Brønsted basicity in coopera-
tive reaction pathways.3,4 Among the large number of known,
synthetically valuable phosphine-catalyzed reactions, [3 + 2]
cycloadditions of electron-deficient allenes with electron-deficient
olefins and imines to form cyclopentenes and pyrrolidines are
particularly interesting targets for asymmetric catalysis. Zhang and
Fu have shown that chiral monodentate phosphines designed
originally as ligands for transition metal catalysts effectively
promote the enantioselective formation of cyclopentenes.5 More
recently, Miller has demonstrated that R-amino acid-derived
phosphines induce analogous allene-alkene cycloadditions with high
ee and opposite regioselectivity.6 In contrast, the enantioselective
construction of dihydropyrroles by formal [3 + 2] cycloaddition
between allenes and imines has met with very limited success,7
despite the clear utility that such transformations would hold.8 Here,
we describe the development of a new class of chiral bifunctional
thiourea catalysts derived from readily accessible trans-2-amino-
1-(diphenylphosphino)cyclohexane (1),9 and its application to the
highly enantioselective synthesis of a wide range of 2-aryl-2,5-
dihydropyrrole derivatives (see Scheme 1).
Exploratory studies on the model reaction between allene 2 and
tosyl imine 3a led to the observation that phosphinothioureas
derived from 1 and (L)-t-Leu amides displayed promising reactivity
and enantioselectivity (6a, 68% ee, and 6b, 62% ee). Variation of
the imine N-substituent with sterically and electronically modified
sulfonyl, phosphinoyl, or carbamate groups revealed that diphe-
nylphosphinoyl (DPP) imine 4a afforded highest enantioselectivities
(93% ee with 6b). However, the use of DPP imine 4a led to
significantly diminished reactivity (Table 1, entry 1) and variable
yields on >0.2 mmol scale. These problems may be attributed in
part to the diminished electrophilicity of the DPP imine, and are
consistent with Lu’s observations in PPh3-catalyzed imine-allene
[3 + 2] cycloaddition reactions.3b
as well, as inclusion of 3Å molecular sieves led to both suppressed
rates and formation of a variety of undesired byproduct (Table 1,
entry 3). In contrast, addition of 0.2 equiv of H2O afforded
improved reaction rates (Table 1, entries 5 and 6).
Thiourea catalysts derived from tert-leucine have proven optimal
in a wide range of enantioselective reactions,12 and this was the
impetus for selecting this amino acid for the construction of catalyst
6. However, we were intrigued by the observation that the relative
stereochemistry in 6 leading to highest product ee values in the [3
+ 2] cycloadditions was opposite from that of all diaminocyclo-
hexane/t-Leu-derived thiourea catalysts identified to date. This led
us to investigate whether the t-Leu component in 6 is in fact optimal
or even necessary in the phosphinothiourea catalysts. Indeed,
variation of the R-amino acid as its dibenzyl amide in thioureas
derived from 1 revealed that the simplified Ala-derived catalyst
7a afforded markedly improved enantioselectivity (98% ee, Table
1, entry 7). Interestingly, use of the diastereomeric Ala-derived
catalyst 7b or Gly-derived 7c resulted in slightly diminished ee
values (87-88%), but significantly poorer reactivity (Table 1,
entries 8-9). Thus, the amino amide plays a secondary role relative
to the aminophosphine component of the catalyst with respect to
enantioinduction, but is nonetheless important for catalyst activity.
Consistent with this notion, 3,5-bistrifluoromethylphenyl thiourea
catalyst 8 displayed very poor reactivity (Table 1, entry 10), despite
the fact that analogous arylthiourea derivatives are effective
catalysts in a wide range of other applications.
Inclusion of a combination of both basic and weakly acidic
additives resulted in significant enhancements in reaction rate. The
serendipitous observation was made that traces of Et3N contamina-
tion (∼2%) remaining from the synthesis of allene 210 led to
improved substrate conversion and cleaner product formation with
no detrimental effect on ee. In recent computational and experi-
mental studies, Yu and co-workers identified an important beneficial
role for water in phosphine-catalyzed alkene-allene [3 + 2]
cycloadditions.11 This proved to be the case in the present system
Under the optimized conditions and in the presence of catalyst
7a, the [3 + 2] cycloaddition of allene 2 with DPP imines
displays broad scope (Table 2). Excellent enantioselectivities
were obtained for a variety of aryl and heteroaryl imines.13
Electron-rich imines exhibited low reactivity and required the
use of higher catalyst loadings (20 mol %) to achieve complete
conversion within 48 h (entries 3, 6). Substantially higher
catalytic activity was observed with electron-deficient DPP
9
5660 J. AM. CHEM. SOC. 2008, 130, 5660–5661
10.1021/ja801344w CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Additive Effects in the [3 + 2] Cycloaddition of 2 and 4aa
Scheme 2
additives
entry catalyst Et3N (mol%) H2O (mol%) time (h) conversion (%)b
ee (%)
1
2
3
4
5
6
7
8
9
10
6b
6b
6b
6b
6b
6b
7a
7b
7c
8
48
48
48
24
24
24
48
48
48
48
45
70
70e
70
86f
88g
100
17
23
5
93 (R)
n.d.c
2
5
5
d
n.d.c
n.d.
n.d.
93 (R)
98 (S)
87 (S)
88 (S)
42 (S)
20
20
20
20
20
20
5
5
5
5
5
a Reaction conditions: 4a (0.1 mmol), 2 (0.12 mmol), catalyst (0.01
mmol), in toluene (0.1 M) at -30 °C. b Determined by 1H NMR using
p-xylene as an internal standard. c Not determined. d Reaction run with
the addition of 3Å molecular sieves (20 mg). e Complex mixture,
desired product <20% f Yield of 5: 70%. g Yield of 5: 76%.
Table 2. Imine-Allene [3 + 2] Cycloadditions Catalyzed by 7a
is prepared readily by classical resolution with tartaric acid and
that alanine is the optimal amino acid component enables
straightforward access to both catalyst enantiomers. Mechanistic
investigation and application of this class of catalysts toward
new transformations are currently underway.
Acknowledgment. This work was supported by the NIH
(Grants GM-43214 and GM-69721). Y.-Q. F. thanks the NSERC
for postdoctoral fellowship support. Dr. Jingwei Huang and Dr.
Richard Staples are acknowledged for crystal structure determination.
entry
Ar
7a (mol %)
isolated yield (%)
ee (%)a
1
Ph (4a)
10
10
20
10
10
20
10
2.5
10
10
20
20
20
84
72
80
81
70
70
90
77
85
70
79
68
77
98
95
97
96
95
95
95
95
95
94
94
94
97
2
p-FC6H4 (4b)
p-MeOC6H4 (4c)
p-PhC6H4 (4d)
m-NO2C6H4 (4e)
3,4,5-(MeO)3C6H2 (4f)
o-BrC6H4 (4g)
o-BrC6H4 (4g)
3-pyridyl (4h)
4-pyridyl (4i)
2-furyl (4j)
3
4
5
Supporting Information Available: Catalyst and substrate
optimization studies, calculated energy profile of 4a, complete
experimental procedures, characterization data, ee determinations,
and crystallographic data for (R)-5f. This material is available free
of charge via the Internet at http://pubs.acs.org.
6
7
8
9
10
11
12
13
3-furyl (4k)
2-thienyl (4l)
References
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a The absolute configuration of the product derived from 4f was established
by X-ray crystallography. All other products are assigned by analogy.
imines (e.g., TON of >30 for o-bromophenyl imine 4g, entry
9). Aliphatic imines proved to be unsuitable substrates, undergo-
ing decomposition under these conditions.
The beneficial effect of Et3N and H2O on the rate of the
cycloaddition reaction is accompanied by negligible effects on
enantioselectivity, suggesting that these additives are not
involved in the ee-determining step(s). Consistent with the
stepwise [3 + 2] cycloaddition mechanism proposed by Lu and
others,3b,11 it is likely that H2O effects protonation of the basic
ylide intermediate 10 to form a pentavalent hydroxyphosphorane
intermediate 11 (Scheme 2). The role of Et3N is most likely to
promote elimination and liberation of the phosphine catalyst
via either E2 or E1cb mechanisms.
We propose that the thiourea binds and activates the imine
by association to the oxygen atom of the phosphinoyl group.14
The DPP imine has a strong preference for adopting an s-cis
conformation (dihedral angle C-N-P-O ) 0°),15 and the
observed preferential attack at the imine Re face with 7a is
consistent with intramolecular delivery of the phosphonium ion
enolate (Scheme 2). Secondary interactions (π-π stacking or
CdO· · ·Ar)16 between the amide portion of the catalyst and
the diphenyl portion of the imine may also provide additional
selective stabilization of the lowest energy transition state.
In summary, we have developed a new family of phosphi-
nothiourea derivatives for the highly enantioselective synthesis
of substituted 2-aryl-2,5-dihydropyrroles via imine-allene [3 +
2] cycloaddition. The fact that enantiopure aminophosphine 1
(13) N-Deprotection of product 5a was accomplished with HCl (1.5 equiv) in
EtOH at room temp for 24 h (52% unoptimized yield) without detectable
racemizaton.
(14) H-bonding of N,N′-dimethylthioure to a simple, dimethylphosphinoyl imine was
modeled using DFT (B3LYP at the 6-31G(d,p) level). Interaction with the oxygen
was found to be favored by ca. 6 kcal/mol over bonding to the nitrogen.
(15) The s-cis conformer of 4a is computed to be 9.1 kcal/mol more stable than
the s-trans conformer (see Supporting Information).
(16) For a discussion of lone-pair-aromatic interactions, see: Egli, M.; Sarkhel,
S. Acc. Chem. Res. 2007, 40, 197.
JA801344W
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J. AM. CHEM. SOC. VOL. 130, NO. 17, 2008 5661