Toward a Predictive Understanding of Phosphine-Catalyzed [3 + 2] Annulation of Allenoates with Acrylate or Imine

Article abstract of DOI:10.1021/acs.joc.8b01259

Both theoretical and experimental studies were performed to explore the mechanism, regioselectivity, and enantioselectivity of phosphine-catalyzed [3 + 2] annulation between allenoates and acrylate or imine. Using density functional theory computations, w

Full text of DOI:10.1021/acs.joc.8b01259

Subscriber access provided by EKU Libraries
Article
Toward a Predictive Understandings of Phosphine-Catalyzed
[3+2] Annulation of Allenoates with Acrylate or Imine
Zhaoyuan Yu, Zhichao Jin, Meng Duan, Ruopeng Bai, Yixin Lu, and Yu Lan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01259 • Publication Date (Web): 16 Aug 2018
Downloaded from http://pubs.acs.org on August 16, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
induction. The theoretical calculation results agreed with experimental observations, and these results
provide valuable insight into catalyst design and understanding of mechanisms of related reactions.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
INTRODUCTION
Organophosphorus compounds have received considerable attention in the past few decades.1
Phosphines are typically used as ligands2 in transition metalꢀmediated processes,3 but they are also
widely used as nucleophilic catalysts in organic synthesis owing to their nucleophilicity.4 The past
decade has seen remarkable progress of phosphineꢀcatalyzed organic reactions, e.g. the Rauhut–
Currier reaction,5 Morita–Baylis–Hillman reaction,6 and Michael addition,7 among others.8 In
1995, Lu and coꢀworkers disclosed a phosphineꢀcatalyzed [3+2] cycloaddition of allenoates to
activated alkenes, which has become one of the most wellꢀestablished methods for the construction
of fiveꢀmembered ring systems (Scheme 1, eq. a).9 Over the time, various chiral phosphine catalysts
have been developed for asymmetric [3+2] annulation reactions. Zhang et al. developed a chiral
phosphine with a unique fused bicyclic [2.2.1] ring, which was shown to catalyze the [3+2]
cyclization between 2,3ꢀbutadienoates and activated alkenes with excellent regioꢀ and
enantioselectivity (eq. b).10 The Fu group reported a highly enantioselective [3+2] cycloaddition of
allenoates to enones catalyzed by a C2ꢀsymmetric chiral phosphine catalyst (eq. c).11 Miller and
coꢀworkers designed a multifunctional phosphineꢀcontaining αꢀamino acid, which was utilized to
catalyze an enantioselective [3+2] cycloaddition of allenoate to tetralone (eq. d).12 Undoubtedly,
phosphineꢀcatalyzed asymmetric [3+2] annulations of allenes with activated alkenes have been well
recognized as one of the most efficient synthetic methods for the construction of enantiomerically
enriched fiveꢀmembered cyclic structural motifs.13
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
1
2
3
4
Scheme 1. Selected Examples of Phosphine Catalyzed [3+2] Cycloaddition Reactions
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For the creation of new stereogenic centers in a catalytic reaction, the asymmetric induction is
determined by the chiral catalysts utilized, the chiral environments of which are of vital
importance.14 Amino acids are arguably the most abundant, inexpensive, and readily available chiral
building blocks in nature,15 thus they are widely used in asymmetric synthesis.16 In 2011, we
introduced a new family of dipeptideꢀbased phosphine catalysts, and showed their effectiveness in
17
promoting asymmetric [3+2] annulation reactions.
As illustrated in Scheme 2,
DꢀThrꢀLꢀtertꢀLeuꢀbased phosphine P1 catalyzed allenoate−acrylate [3+2] cyclization and afforded
the desired adduct in 95% yield and 74% ee. Subsequently, we demonstrated application of this
powerful catalyst in asymmetric [3+2] annulation between imines and allenoates.18 Although the
mechanisms of phosphineꢀcatalyzed [3+2] annulations have been investigated by experimentally and
computationally in previous studies,19 elucidation of stereoselectivities of phosphineꢀpromoted
catalytic processes is still very limited. In our initial disclosures, we proposed that our bifunctional
phosphine catalysts interact with substrates, e.g. acrylate or imine, through hydrogen bonding
interactions, which were believed to be the key to the observed stereoselectivity. Herein, we carry out
3
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
computational studies to elucidate the reaction mechanism, and present the origin of
enantioselectivity observed in the phosphineꢀcatalyzed [3+2] annulation between allenoates and
acrylate or imine.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Dipeptide-functionalized Phosphine Catalyzed [3+2] Cycloaddition between
Allenoates and Acrylate or Imine.
COMPUTATIONAL METHODS
All the DFT calculations were carried out with the GAUSSIAN 09 series of programs.20 Density
functional B3LYP21 with a standard 6ꢀ31G(d) basis set22 was used for geometry optimizations.
Harmonic vibrational frequency calculations were performed with the same method for all stationary
points to confirm them as a local minima or transition structures and to derive the thermochemical
corrections for the enthalpies and free energies. Recent works from our group23 showed that M11
functional,24 recently proposed by the Truhlar group could give more accurate energetic information.
Here we used the M11 functional with the larger basis set 6ꢀ311+G(d)25 to derive singleꢀpoint
energies on B3LYP/6ꢀ31G(d) optimized geometries. The solvent effects were considered by single
point calculations using IEFPCM model (toluene).26 The thermal corrections evaluated from the
vibrational frequencies at B3LYP/6ꢀ31G(d) level on the optimized geometries were then added to the
M11/6ꢀ311+G(d) electronic energies to obtain the free energies. The NCIPLOT analyses were
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
1
2
3
4
5
6
conducted with Multiwfn27 and VMD.28 The 3D images of the calculated structures were prepared
using CYLview.29
7
8
9
RESULTS AND DISCUSSION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mechanism for Phosphine-Catalyzed [3+2] Cycloaddition. On the basis of Lu’s pioneering work9
and relevant computational studies,30 the commonly accepted mechanism of phosphineꢀcatalyzed
[3+2] cycloaddition is shown in Scheme 3. Phosphine catalyst P1 adds on to allenoate 4 to yield the
zwitterionic intermediate A. In the left cycle (allenoate−acrylate cyclization), the [3+2] the
cycloaddition process between intermediate A and acrylate 5a is stepwise and affords intermediate
C. The following proton transfer gives intermediate D, which then eliminates catalyst P1 and forms
the annulation product 7. For the allenoate−imine cyclization, the addition of the zwitterionic
intermediate A to imine 6 generates intermediate E, which undergoes intramolecular cyclization
followed by proton transfer to furnish intermediate G. Subsequent elimination of the phosphine then
affords annulation product 8. In the above proposal, the first C−C bondꢀforming step was deemed to
be the enantiodetermining step in both cycles, and the nonꢀcovalent interactions between catalysts
and substrates are believed to be crucial in stabilizing the key transition states, leading to the
formation of major stereoisomer.
Scheme 3. Mechanism for [3+2] Cycloaddition Catalyzed by Dipeptide-Functionalized
Phosphine P1
5
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jacobsen, 31 Jørgensen, 32 Goodman, 33 Houk 34 and others 35 have shown that nonꢀcovalent
interactions between catalysts and substrates have marked effects in controlling the
enantioselectivities through a combination of experimental and theoretical investigations.36 Cowen
and Miller proposed the intramolecular hydrogen bond induced the selectivity in
phosphineꢀcatalyzed [3+2] cycloaddition of allenoates and enones.12 The intermolecular hydrogen
bond model was also proposed by Fang and Jacobsen for the [3+2] annulation of an imine with
37
allenoate.
Our experimental and theoretical results also validated the importance of
hydrogenꢀbonding interactions between substrates and catalysts in the phosphineꢀcatalyzed
γꢀadditions of oxazolones to 2,3ꢀbutadienoates.38
In our dipeptideꢀbased bifunctional phosphine P1, there are two possible hydrogen donors (two N−H
moieties), however, their exact roles in controlling the stereoselectivities of the reaction remain to be
clarified. In the previous investigation (Table 1), catalyst P2 was identified as a slightly superior
catalyst to P1 (78% ee versus 74% ee) (entries 1 & 2). Among the different acrylate esters, alkyl
substituted acrylate (iꢀPr) was found to be an inferior substrate (entry 3), in contrast, arylꢀsubstituted
6
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
1
2
3
4
5
6
7
8
9
acrylates were excellent substrates, furnishing the desired adducts in good yields and high ee values
(entries 4, 5 and 6). Strikingly, acrylate bearing a 9ꢀphenanthryl group led to excellent
enantioselectivity (91 % ee), this was in comparison to the acrylates bearing a 2ꢀnaphthyl group (84
% ee) or phenyl group (76 % ee). The employment of acrylates with different aryl substituents
resulted in the formation of [3+2] annulation products with much differentiated enantioselectivities,
which simply suggested that those substituents may play an important role in asymmetric induction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of Reaction Condition[a]
Entry
1
Catalyst
R1
R2
α:γ[b]
94:6
Yield [%][c]
95
ee [%][d]
P1
Bn
74
2ꢀnaphthyl
P2
P2
Bn
96
72
92
94
95
78
24
76
84
91
2
3
4
5
6
2ꢀnaphthyl
95:5
97:3
97:3
96:4
>99:1
tꢀBu
iꢀpr
P2
P2
P2
tꢀBu
tꢀBu
tꢀBu
Ph
2ꢀnaphthyl
9ꢀphenanthryl
[a] Reactions were performed with 5 (0.05 mmol), 4 (0.075 mmol) and Phosphine catalysts (10 mol
1
%) in toluene (1.0 mL) at room temperature. [b] Determined by H NMR analysis of the crude
reaction mixture. [c] Isolated yield. [d] The ee value of the major stereoisomer, determined by HPLC
analysis on a chiral stationary phase.
7
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To further probe the reaction mechanistically, we designed a number of analogous LꢀValꢀcontaining
dipeptide phosphine catalysts and examined their catalytic effects in the [3+2] annulation between
allenoates and acrylates (Table 2). Synthetically, catalysts P3 to P5 were more readily accessible, and
the catalytic effects of P3 is comparable to that of catalyst P1. When the hydrogen at the terminal
amino group of the LꢀVal residue was substituted by a methyl group (catalyst P4), the observed ee
value was 60%, not substantially lower than that attainable by using catalyst P3. However,
substitution of the amide N−H with a methyl group (catalyst P5), led to much decreased ee value of
18%, and the configuration of the product was also reversed. The above results suggested that the
amide N−H group is of pivotal importance in asymmetric induction, and the presence of the
carbamate N−H seems to be less important.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Different phosphine catalyzed [3+2] cycloaddition reaction[a]
Entry
1
catalyst
P3
Yield [%][b]
>99%
ee [%][c]
73
P4
>99%
59%
60
2
3
P5
ꢀ18
[a] Reactions were performed with 5 (0.05 mmol), 4a (0.075 mmol) and phosphine catalysts (10 mol %) in toluene (1.0 mL) at room
temperature. [b] Isolated yield. [c] The ee value of the major stereoisomer, determined by HPLC analysis on a chiral stationary phase.
Scheme 4. Proposed Structures of Transition States in Enantioselectivity Determining Step
8
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Based on the above experimental results, we proposed two possible models and further explored the
[3+2] annulations computationally (Scheme 4). In the intermolecular Hꢀbond model (Scheme 4a), the
interactions between amide moiety of the catalyst with acrylate or imine contribute significantly to
the key transition state leading to the formation of the major stereoisomer. Both acrylate and imine
are arranged in the bulky pocket of the catalyst, and there are significant steric repulsion between
catalyst and substrates. Alternatively, we propose that the carbonyl group of allenoate interacts with
amide through intramolecular Hꢀbond, thus ensuring selectivity in the subsequent nucleophilic attack
(Scheme 4b). When acrylates are used as a substrate, the nonꢀcovalent interactions between the
2ꢀnaphthyl group of the acrylate and the phenyl group of phosphine catalyst stabilize the
cycloaddition transition states. Similarly, when imines are used as a reaction partner, the
nonꢀcovalent interactions between phenyl group of imine and catalyst possible exists only in the
energetically favored transition state leading to the major enantiomer.
Activation Barrier of Phosphine Addition to Allenoate. A complete energy profile of a model
reaction based on the phosphine catalyst P1 was described. As shown in Figure 1, the
9
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
hydrogenꢀbonding complex 9-A is formed from the active catalyst P1 and allenoate 4a with a free
energy increase of 3.7 kcal/mol, although the bonding energy of the formed hydrogen bond is about
7.2 kcal/mol as the reaction enthalpy. The nucleophilic addition of phosphine takes place via
transition state Ts1-A with an overall barrier of 20.4 kcal/mol, leading to intermediate 10-A. When
substrate is replaced by allenoate 4b, the calculations predict an overall barrier of 18.8 kcal/mol for
nucleophilic addition step.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Energy profile for the nucleophilic attack step.
10
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. The DFT computed competing pathways of dipeptideꢀfunctionalized phosphine P1
catalyzed [3+2] annulation of acrylate with allenoates.
Reaction with Acrylate. We initially chose 2ꢀnaphthylꢀsubstituted acrylate to perform DFT
computations to elucidate the reaction mechanism, as well as origins of observed enantioselectivities.
As shown in Figure 2, from intermediate 10-A, both intermolecular Hꢀbond and intramolecular
Hꢀbond model were investigated in detail. In the intramolecular Hꢀbond pathway, the amide group of
catalyst interacts with allenoate by a single hydrogen bond, and the lowest energy transition state
Ts2-A-S2 was located for the nucleophilic attack step with a barrier of 9.8 kcal/mol. The subsequent
ring closure occurs via transition state Ts3-A-S2 to form the intermediate 13-A-S2 with a
fiveꢀmembered ring (the free energy surface for proton transfer from 13-A-S2, regenerate phosphine
catalyst P1 is given in Fig. S6 of Supporting Information.). Ts3-A-S2 is 3.4 kcal/mol more stable
11
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
than Ts2-A-S2. The intermolecular Hꢀbond pathway was also considered. However, the transition
state Ts2-A-S1 is energetically less favorable compared to Ts2-A-S2 by 2.5 kcal/mol. The
computational studies illustrate that phosphine catalyst P1 catalyzes allenoate−acrylate [3+2]
annulation through intramolecular Hꢀbond model more favorable than intermolecular Hꢀbond, and
the enantioselectivity is determined at the step where the zwitterionic species is added to the acrylate
substrate.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Free energy profiles for phosphine P1 catalyzed [3+2] annulation of acrylate with
allenoates leading to the enantiomer 7-R (green dashed line) and 7-S (green line).
In order to elucidate the origin of enantioselectivity, the alternative pathway (the siꢀface attack) was
calculated. As shown in Figure 3, the reaction pathway via the transition states Ts2-A-R2 and
Ts3-A-R2 leads to the formation of enantiomer 7-R. The relative free energy of the transition state
12
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
1
2
3
4
5
6
7
8
9
Ts2-A-S2 is 1.1 kcal/mol lower than that of Ts2-A-R2, which indicates that 7-S is the major product.
The energy difference between Ts2-A-R2 (siꢀface) and Ts2-A-S2 (reꢀface) corresponds to an ee
value of 73%, which agrees well with the experimental observations.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
On the basis of the above calculations, we compare the two competing transition states (Ts2-A-R2
and Ts2-A-S2) (Figure 4a). Both have an almost linear Hꢀbond between amide group of catalyst and
allenoate. However, the forming C−C bond length in Ts2-A-S2 is 0.09Å longer than that in
Ts2-A-R2, therefore, the transition state Ts2-A-S2 occurs earlier than Ts2-A-R2. In the case of
Ts2-A-R2, the C−C bond length is 3.86 Å, suggested that the phenyl group of acrylate associations
with TBDPS group of phosphine catalyst P1 via weak nonꢀcovalent interaction. Inspection of
Ts2-A-S2 shows that carbonyl group of acrylate is orientated towards one of the phenyl ring of the
catalyst (O…H distance 2.28 Å), and the distance between the bigger aromatic ring naphthalenyloxy
with OTBDPS is 4.00 Å. Consequently, the stronger nonꢀcovalent interactions in Ts2-A-S2 make the
reꢀface pathway more favorable than siꢀface pathway (Ts2-A-R2). To better describe the
nonꢀcovalent interactions, a visualization analysis39 is made to understand the nature of nonꢀcovalent
interactions in Ts2-A-S2 and Ts2-A-R2. As shown in Figure 4b, the critical interactions are labelled
with red circles. In Ts2-A-R2, the phenyl group of acrylate is perpendicular to the phenyl group of
TBDPS group and it brings about significant nonꢀcovalent interactions. Whereas in Ts2-A-S2,
2ꢀnaphthyl group is perpendicular to the phenyl group of TBDPS group. Furthermore, in Ts2-A-S2,
the carbonyl group of acrylate orients towards one of phenyl ring on the phosphine atom, thereby
increases nonꢀcovalent interactions. As a result, Ts2-A-S2 is more stable than Ts2-A-R2, leading to
the formation of the major enantiomer 7-S.
13
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. (a) Optimized structures of Ts2-A-R2 and Ts2-A-S2. Noncritical hydrogen atoms are
omitted for clarity. Distances are given in angstroms and angles in degrees. (b) NCIPLOT of
Ts2-A-R2 and Ts2-A-S2 transition states. The s = 0.6 au isosurface is colored according to a BGR
scheme over the range ꢀ0.05 < sign(λ2)ρ < 0.05 au. Blue indicates strong attraction weak interaction,
green indicates very weak interaction, and red indicates strong repulsion.
Reaction with Imine. The reaction mechanism is similar to that of the annulation between acrylates
and alleonoates. Both intermolecular Hꢀbond pathway and intramolecular Hꢀbond pathway of
phosphine catalyzed [3+2] annulation of imine with allenoates are summarized in Figure 5. In the
intramolecular Hꢀbond pathway, intermediate 10-I undergoes C−C bond formation via transition
state Ts2-I-R2 to give the 12-I-R2 with a barrier of 14.1 kcal/mol. Subsequent C−N bond formation
14
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
1
2
3
4
5
6
7
8
9
(Ts3-I-R2) requires an even higher activation energy than Ts2-I-R2 and gives the stable intermediate
13-I-R2. On the other hand, the catalyst could activate the cyclization by forming an intermolecular
hydrogen bond with imine substrate. From intermediate 11-I, initial C−C bond formation via
intermolecular Hꢀbond transition state Ts2-I-R1 has a barrier of 7.3 kcal/mol, leading to a more
stable intermediate 12-I-R1, which then undergoes C−N bond formation via transition state
Ts3-I-R1, requiring a barrier of 14.5 kcal/mol (the free energy surface for proton transfer from
13-I-R1, regenerate phosphine catalyst P1 is given in Fig. S7 of Supporting Information). Therefore,
phosphineꢀcatalyzed [3+2] annulation of imine with allenoate prefers the intermolecular Hꢀbond
model.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. The DFT computed competing pathways of dipeptideꢀfunctionalized phosphine P1
catalyzed [3+2] annulation of imine with allenoates.
15
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To explore the origins of enantioselectivity, we then examined the free energy profile of the reꢀface
attack pathway. As shown in Figure 6, the reꢀface attack pathway is predicted to be unfavorable than
siꢀface attack pathway. The free energy of C−C bond forming transition state Ts2-I-S1 is almost the
same as that in Ts2-I-R1. For reꢀface attack pathway, generate 12-I-S1 via Ts2-I-S1 is an easy
process. However, the subsequent ring closure take place via Ts3-I-S1 is a hard process, causing
12-I-S1 prefer regenerate 11-I via Ts2-I-S1. Because of intermediate 12-I-R1 is more stable than
12-I-S1, leading to the position of equilibrium between 12-I-S1 and 12-I-R1 must favor 12-I-R1.
Therefore, the formation Sꢀconfiguration intermediate 13-I-S1 through transition state Ts3-I-S1 with
an energy barrier of 18.9 kcal/mol relate to 12-I-R1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Free energy profiles for phosphine P1 catalyzed [3+2] annulation of imine with allenoates
leading to the enantiomer 8-R (blue line) and 8-S (blue dashed line).
16
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
1
2
3
4
5
6
7
8
9
The optimized structures of Ts2-I-R1 and Ts3-I-S1 are shown in Figure 7(a), structural analysis
indicates that the steric interactions would be the major factors controlling the observed
enantioselectivity. The hydrogen atom is oriented toward the pocket of catalyst in Ts2-I-R1, the
shortest H−H distance between imine and catalyst is 2.79 Å. In contrast, the sterically demanding
nꢀpropyl group is oriented toward the pocket of catalyst and responsible for the unfavorable steric
interactions in Ts3-I-S1. Thus, phosphineꢀcatalyzed [3+2] annulation of imine with allenoate
preferentially proceeds via the siꢀface attack pathway. As shown in Figure 7b, there are weak
repulsions between imine and catalyst (red circles labelled) in Ts3-I-S1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7. (a) Optimized structures of Ts2-I-R1 and Ts3-I-S1. Noncritical hydrogen atoms are
omitted for clarity. Distances are given in angstroms and angles in degrees. (b) NCIPLOT of
Ts2-I-R1 and Ts2-3-S1 transition states. The s = 0.6 au isosurface is colored according to a BGR
17
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
scheme over the range ꢀ0.05 < sign(λ2)ρ < 0.05 au. Blue indicates strong attraction weak interaction,
green indicates very weak interaction, and red indicates strong repulsion.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalyst Evaluation. Based on our calculation analysis, we look forward provide theoretical
guidance and facilitate the design of more effective catalytic systems. As shown in Table 1 (entry 1
and 2), phosphine catalyst P1 catalyzed [3+2] cycloaddition between allenoate 4a and acrylate 5
afford the Sꢀconfiguration product with 74% ee value. As mentioned above, the terminal NHBoc
group seems to have less impact for enantioselectivity and this moiety should be replaceable.
Therefore, we suspect that the catalyst P6 could provide better result, due to the trifluoromethyl
group substituted phenyl ring is coplanar with amide group and leading to an additional nonꢀcovalent
interactions between allenoate and catalyst. The NCIPLOT of 10-A-P6 verified our hypothesis, apart
from the Hꢀbond between allenoate and catalyst, additional stabilizing nonꢀcovalent interactions
between allenoate and substituted phenyl ring on the catalyst were identified (Figure 9b). More
importantly, as shown in Figure 8, calculated free energy profile indicate that reꢀface attack pathway
is much favor than siꢀface attack pathway and in consistent with experimental observed (>99 yield,
92% ee).
18
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
1
2
3
4
5
6
7
8
9
OTBDPS
PPh2
OTBDPS
PPh2
O
NH
O
NH
O
O
O
NH
a)
b)
cat (10 mol%)
toluene, 0.5 h
•
Ph
Ph
Boc
O
CO2Bn
4a
+
F3
C
CF3
P6
>99% yield
P1
95% yield
74% ee
CO2Bn
7-S
5
92% ee
Ph
OTBDPS
Ph
Ph
OTBDPS
P
R2
O
Ph
Ph
ꢀG (kcal/mol)
(ꢀH (kcal/mol))
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P
Ph
Ph
OTBDPS
R2
O
O
Ph
N
H
O
O
P
Ph
R2
O
O
BnO
N
H
O
O
BnO
O
Ph
N
F3
C
OTBDPS
H
O
Ph
O
CF3
F3
C
BnO
P
Ts2-A-R2-P6
Ph
CF3
R2
O
R2
=
8.9
Ts3-A-R2-P6
5.7
(ꢀ27.4)
F3
C
(ꢀ24.0)
N
O
H
O
CF3
Ts2-A-R2-P6
O
12-A-R2-P6
BnO
O
R2
R2
Ph
Ts3-A- -P6
O
ꢀ1.3
(ꢀ33.0)
12-A-R2-P6
F3
C
CF3
3.7
ꢀ4.9
(ꢀ21.7)
13-A-R2-P6
(ꢀ28.8)
ꢀ0.2
(ꢀ34.9)
Ts3-A-S2-P6
Ts2-A-S2-P6
ꢀ10.4
(ꢀ41.6)
13-A-R2-P6
ꢀ9.1
(ꢀ41.2)
10-A-P6
Ph
OTBDPS
Ph
12-A- -P6
S2
OTBDPS
Ph
Ph
OTBDPS
Ph
OR2
Ph
P
O
ꢀ13.4
(ꢀ47.0)
13-A- -P6
Ph
Ph
P
OTBDPS
OR2
P
O
Ph
OR2
P
O
Ph
S2
N
H
O
N
H
Ph
O
O
OTBDPS
Ph
N
H
O
O
Ph
OR2
BnO
O
BnO
N
H
O
BnO
P
O
O
BnO
F3
C
F3C
Ph
CF3
F3
C
N
CF3
10-A-P6
H
O
F3
C
CF3
Ts3-A-S2-P6
O
Ts2-A-S2-P6
BnO
CF3
12-A-S2-P6
F3
C
CF3
13-A-S2-P6
re-face attack
si-face attack
Figure 8. The DFT computed competing pathways of dipeptideꢀfunctionalized phosphine P6
catalyzed [3+2] annulation of acrylate with allenoates.
19
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Figure 9. (a) Optimized structures of 10-A and 10-A-P6. (b) NCIPLOT of 10-A and 10-A-P6. The s
= 0.6 au isosurface is colored according to a BGR scheme over the range ꢀ0.05 < sign(λ2)ρ < 0.05 au.
Blue indicates strong attraction weak interaction, green indicates very weak interaction, and red
indicates strong repulsion.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In summary, we studied the mechanism and the origins of enantioselectivities of phosphineꢀcatalyzed
[3+2] cycloadditions between allenoates and acrylate or imine. The combination of theoretical and
experimental studies confirmed that appropriate hydrogen bond model and nonꢀcovalent interactions
are crucial for observed enantioselectivities. For the acrylate substrates, the reaction preferentially
proceeds via an intramolecular Hꢀbond model. The hydrogen bond between allenoate and amide
group of catalyst locks the configuration of zwitterionic catalystꢀactivated allenoate. The NCIPLOT
analysis suggest that 2ꢀnaphthyl ester moiety exhibits stronger nonꢀcovalent interactions than the
phenyl moiety, and such a significant substituent effect of acrylate substrate leads to the favorable
reꢀface attack pathway. For imine substrate, the intermolecular Hꢀbond model is more appropriate. In
transition state Ts3-I-S1, nꢀpropyl group is oriented toward the pocket of catalyst, whereas in
transition state Ts2-I-R1, hydrogen atom arranged in the bulky pocket of the catalyst. Therefore,
steric factors make the more crowded transition state Ts3-I-S1 less stable than transition state
Ts2-I-R1.
All the theoretical studies carried out in this report agreed well with our experimental observations.
More importantly, the insights gained in this study, the single hydrogen bond interacting model in
particular, provide theoretical guidance for screening of catalysts and facilitate the design of more
20
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
1
2
3
4
5
6
effective catalytic systems. We are currently evolving more simplified amino acidꢀderived
bifunctional phosphines based on the findings disclosed herein.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Information. Commercially available materials purchased from Alfa Aesar, SigmaꢀAldrich,
or TCI were used as received. Proton nuclear magnetic resonance (1H NMR) spectra were recorded
on a Bruker (400 MHz) spectrometer. Chemical shifts were recorded in parts per million (ppm, δ)
relative to tetramethylsilane (δ 0.00) or chloroform (δ = 7.26, singlet). 1H NMR splitting patterns are
designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets); m (multiplets),
and etc. All firstꢀorder splitting patterns were assigned on the basis of the appearance of the
multiplet. Splitting patterns that could not be easily interpreted are designated as m (multiplet) or br
(broad). Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Bruker (400
MHz) (100 MHz) spectrometer. The determination of ee was performed via chiral HPLC analysis
using Shimadzu LCꢀ20AD HPLC workstation. Visualization was performed using a UV lamp.
General procedures. Substrate 4 and 517 and catalyst P116g was synthesized according to the
literature procedures.
To a 4 mL vial equipped with a magnetic stirring bar were added the phosphine catalyst P1 (0.01
mmol) and acrylate 5 (0.1 mmol), followed by the addition of toluene (1 mL). Allenoate 4 (0.12
mmol) was then added, and the reaction mixture was stirred at room temperature for 1h. Then the
mixture was subjected directly to flash column chromatographic separation using a mixture of
hexane/ethyl acetate (10 : 1) as the eluent to afford cycloaddtion products 7-S.
21
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
1
2
3
4
Characterization of substrates and products.
5
6
7
8
9
naphthalen-2-yl 2-phenylacrylate (5)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
White solid. 1H NMR (400 MHz, CDCl3) δ 7.90ꢀ7.82 (m, 3H), 7.67 (d, J = 2.0 Hz, 1H), 7.58ꢀ7.56 (m,
2H), 7.53ꢀ7.46 (m, 2H), 7.45ꢀ7.37 (m, 3H), 7.33 (dd, J = 8.8, 2.2 Hz, 1H), 6.68 (d, J = 0.7 Hz, 1H),
6.13 (d, J = 0.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.4, 148.5, 140.9, 136.4, 133.8, 131.5,
129.4, 128.5, 128.4, 128.3, 127.8, 127.7, 126.6, 125.8, 121.1, 118.6; LCMS (ESI, m/z): calcd. for
+
C19H15O2 275.1, found 275.1.
3-benzyl 1-(naphthalen-2-yl) (S)-1-phenylcyclopent-3-ene-1,3-dicarboxylate (7-S)
1
Colorless oil. H NMR (400 MHz, CDCl3) δ 7.82ꢀ7.74 (m, 3H), 7.51ꢀ7.32 (m, 13H), 7.03 (dd, J =
8.9, 2.3 Hz, 1H), 6.93 (m, 1H), 5.26 (s, 2H), 3.92 (dd, J = 16.5, 1.4 Hz, 1H), 3.83 (d, J = 17.6 Hz,
1H), 3.27 (dq, J = 16.5, 2.2 Hz, 1H), 3.09 (dq, J = 18.3, 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
174.0, 164.2, 148.6, 142.1, 141.6, 136.0, 134.7, 133.7, 131.5, 129.4, 128.9, 128.6, 128.3, 128.2,
127.8, 127.6, 127.5, 126.6, 125.7, 120.6, 118.2, 66.3, 58.6, 43.5, 41.4; LCMS (ESI, m/z): calcd. for
+
C30H25O4 449.2, found 449.2; HPLC analysis (Chiralcel IB, Hexane/2ꢀPrOH = 95/5, 1.00 mL/min),
Rt = 10.6 min & 12.0 min.
22
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
1
2
3
4
5
6
7
ASSOCIATED CONTENT
8
9
Supporting Information. Cartesian coordinates and energies of all reported structures, full
authorship of Gaussian 09 and NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Author
*(R. Bai) Eꢀmail: ruopeng@cqu.edu.cn
*(Y. Lu) Eꢀmail: chmlyx@nus.edu.sg
*(Y. Lan) Eꢀmail: lanyu@cqu.edu.cn
ORCID
Zhaoyuan Yu: 0000ꢀ0002ꢀ9570ꢀ3512
Ruopeng Bai: 0000ꢀ0002ꢀ1097ꢀ8526
Yixin Lu: 0000ꢀ0002ꢀ5730ꢀ166X
Yu Lan: 0000ꢀ0002ꢀ2328ꢀ0020
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (Grants 21372266
and 21772020). This work was supported by the China Scholarship Council.
23
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
1
2
3
4
5
REFERENCES
1
(a) Rewcastle, G. W.; Baguley, B. C.; Cain, B. F. Potential Antitumor Agents. 37. Organophosphorus Derivatives
of 9ꢀAnilinoacridine. J. Med. Chem. 1982, 25, 1231–1235. (b) Serdar, C. M.; Gibson, D. T. Enzymatic Hydrolysis
of Organophosphates: Cloning and Expression of A Parathion Hydrolase Gene from Pseudomonas Diminuta.
Bio/Technology 1985, 3, 567–571. (c) Leca, D.; Fensterbank, L.; Lacôte, E.; Malacria, M. Recent Advances in the
Use of Phosphorusꢀcentered Radicals in Organic Chemistry. Chem. Soc. Rev. 2005, 34, 858–865. (d) Baumgartner,
T.; Réau, R. Organophosphorus πꢀConjugated Materials. Chem. Rev. 2006, 106, 4681–4727. (e) Gaunt, M. J.;
Johansson, C. C. C.; McNally, A.; Vo, N. T. Enantioselective Organocatalysis. Drug Discovery Today 2007, 12, 8–
27. (f) Pandey, V. K.; Dwivedi, A.; Pandey, O. P.; Sengupta, S. K. Organophosphorus Derivatives Containing
Isatinꢀ3ꢀhydrazones as Chemotherapeutants against Fungal Pathogens of Sugarcane. J. Agric. Food Chem. 2008, 56,
10779–10784. (g) Grondal, C.; Jeanty, M.; Enders, D. Organocatalytic Cascade Reactions as a New Tool in Total
Synthesis. Nature Chem. 2010, 2, 167–178. (h) Joly, D.; Bouit, P. A.; Hissler, M. Organophosphorus Derivatives for
Electronic Devices. J. Mater. Chem. C 2016, 4, 3686–3698.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
(a) Noyori, R. BINAP: An Efficient Chiral Element for Asymmetric Catalysis. Acc. Chem. Res. 1990, 23, 345–
350. (b) Hayashi, T. Chiral Monodentate Phosphine Ligand MOP for TransitionꢀMetalꢀCatalyzed Asymmetric
Reactions. Acc. Chem. Res. 2000, 33, 354–362. (c) Tang, W.; Zhang, X. New Chiral Phosphorus Ligands for
Enantioselective Hydrogenation. Chem. Rev. 2003, 103, 3029–3069. (d) Tietze, L. F.; Ila, H.; Bell, H. P.
Enantioselective PalladiumꢀCatalyzed Transformations. Chem. Rev. 2004, 104, 3453–3516. (e) Xie, J.ꢀH.; Zhou,
Q.ꢀL. Chiral Diphosphine and Monodentate Phosphorus Ligands on
a
Spiro Scaffold for
TransitionꢀMetalꢀCatalyzed Asymmetric Reactions. Acc. Chem. Res. 2008, 41, 581–593. (f) Teichert, J. F.; Feringa,
B. L. Phosphoramidites: Privileged Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49, 2486–2528.
3
(a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. An Improved Catalyst System for Aromatic Carbon−Nitrogen Bond
Formation: The Possible Involvement of Bis(Phosphine) Palladium Complexes as Key Intermediates. J. Am. Chem.
Soc. 1996, 118, 7215–7216. (b) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto, H.
Enantioselective Aldol Reaction of Tin Enolates with Aldehydes Catalyzed by BINAP·Silver(I) Complex. J. Am.
Chem. Soc. 1997, 119, 9319–9320. (c) Evans, D. A.; Thomson, R. J. Ni(II) TolꢀBINAPꢀCatalyzed Enantioselective
Orthoester Alkylations of NꢀAcylthiazolidinethiones. J. Am. Chem. Soc. 2005, 127, 10506–10507. (d) Wang, S.ꢀY.;
Ji, S.ꢀJ.; Loh, T.ꢀP. Cu(I) TolꢀBINAPꢀCatalyzed Enantioselective Michael Reactions of Grignard Reagents and
Unsaturated Esters. J. Am. Chem. Soc. 2007, 129, 276–277.
4
(a) Lu, X.; Zhang, C.; Xu, Z. Reactions of ElectronꢀDeficient Alkynes and Allenes under Phosphine Catalysis.
Acc. Chem. Res. 2001, 34, 535–544. (b) Methot, J. L.; Roush, W. R. Nucleophilic Phosphine Organocatalysis. Adv.
Synth. Catal. 2004, 346, 1035–1050. (c) Ye, L.ꢀW.; Zhou, J.; Tang, Y. PhosphineꢀTriggered Synthesis of
Functionalized Cyclic Compounds. Chem. Soc. Rev. 2008, 37, 1140–1152. (d) Cowen, B. J.; Miller, S. J.
Enantioselective Catalysis and Complexity Generation from Allenoates. Chem. Soc. Rev. 2009, 38, 3102–3116. (e)
Marinetti, A.; Voituriez, A. Enantioselective Phosphine Organocatalysis. Synlett 2010, 174–194. (f) Wang, T.; Han,
X.; Zhong, F.; Yao, W.; Lu, Y. Amino AcidꢀDerived Bifunctional Phosphines for Enantioselective Transformations.
Acc. Chem. Res. 2016, 49, 1369–1378.
5
(a) Aroyan, C. E.; Dermenci, A.; Miller, S. J. The Rauhut–Currier Reaction: A History and its Synthetic
24
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
1
2
3
4
5
6
7
8
9
Application. Tetrahedron 2009, 65, 4069–4084. (b) Takizawa, S.; Nguyen, T. M.ꢀN.; Grossmann, A.; Enders, D.;
Sasai, H. Enantioselective Synthesis of αꢀAlkylideneꢀγꢀButyrolactones: Intramolecular Rauhut–Currier Reaction
Promoted by Acid/Base Organocatalysts. Angew. Chem., Int. Ed. 2012, 51, 5423–5426. (c) Shi, Z.; Tong, Q.; Leong,
W. W. Y.; Zhong, G. [4+2] Annulation of Vinyl Ketones Initiated by a PhosphineꢀCatalyzed AzaꢀRauhut–Currier
Reaction: A Practical Access to Densely Functionalized Tetrahydropyridines. Chem.—Eur. J. 2012, 18, 9802–9806.
(d) Su, X.; Zhou, W.; Li, Y.; Zhang, J. Design, Synthesis, and Application of a Chiral Sulfinamide Phosphine
Catalyst for the Enantioselective Intramolecular Rauhut–Currier Reaction. Angew. Chem., Int. Ed. 2015, 54, 6874–
6877.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
(a) Cho, C.ꢀW.; Kong, J.ꢀR.; Krische, M. J. PhosphineꢀCatalyzed Regiospecific Allylic Amination and Dynamic
Kinetic Resolution of Morita−Baylis−Hillman Acetates. Org. Lett. 2004, 6, 1337–1339. (b) Masson, G.;
Housseman, C.; Zhu, J. The Enantioselective Morita–Baylis–Hillman Reaction and Its Aza Counterpart. Angew.
Chem., Int. Ed. 2007, 46, 4614–4628. (c) Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H. Enantioselective Synthesis
of Isoindolines: An Organocatalyzed Domino Process Based On the azaꢀMorita–Baylis–Hillman Reaction. Angew.
Chem., Int. Ed. 2010, 49, 9725–9729. (d) Takizawa, S.; Kiriyama, K.; Ieki, K.; Sasai, H. A Bifunctional Spiroꢀtype
Organocatalyst With High Enantiocontrol: Application to the azaꢀMorita–Baylis–Hillman Reactions. Chem.
Commun. 2011, 47, 9227–9229. (e) Hu, F.ꢀL.; Wei, Y.; Shi, M. PhosphineꢀCatalyzed Asymmetric [4+1] Annulation
of Activated α,βꢀunsaturated Ketones with Morita–Baylis–Hillman Carbonates: Enantioselective Synthesis of
Spirooxindoles Containing Two Adjacent Quaternary Stereocenters. Chem. Commun. 2014, 50, 8912–8914.
7
(a) Sriramurthy, V.; Barcan, G. A.; Kwon, O. BisphosphineꢀCatalyzed Mixed DoubleꢀMichael Reactions:
Asymmetric Synthesis of Oxazolidines, Thiazolidines, and Pyrrolidines. J. Am. Chem. Soc. 2007, 129, 12928–
12929. (b) Li, G.ꢀZ.; Randev, R. K.; Soeriyadi, A. H.; Rees, G.; Boyer, C.; Tong, Z.; Davis, T. P.; Becer, C. R.;
Haddleton, D. M. Investigation into Thiolꢀ(meth)acrylate Michael Addition Reactions using Amine and Phosphine
Catalysts. Polym. Chem. 2010, 1, 1196–1204. (c) Baslé, O.; Porcel, S.; Ladeira, S.; Bouhadir, G.; Bourissou, D.
Phosphineꢀboronates: Efficient Bifunctional Organocatalysts for Michael Addition. Chem. Commun. 2012, 48,
4495–4497.
8
(a) Vedejs, E.; Diver, S. T. Tributylphosphine: A Remarkable Acylation Catalyst. J. Am. Chem. Soc. 1993, 115,
3358–3359. (b) Trost, B. M.; Li, C.ꢀJ. Novel “Umpolung” in C−C Bond Formation Catalyzed by
Triphenylphosphine. J. Am. Chem. Soc. 1994, 116, 3167–3168. (c) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi,
J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O. PhosphineꢀCatalyzed
Annulations of Azomethine Imines: AlleneꢀDependent [3+2], [3+3], [4+3], and [3+2+3] Pathways. J. Am. Chem.
Soc. 2011, 133, 13337–13348. (d) Yu, P.; Zheng, S.ꢀC.; Yang, N.ꢀY.; Tan, B.; Liu, X.ꢀY. PhosphineꢀCatalyzed
Remote βꢀC−H Functionalization of Amines Triggered by Trifluoromethylation of Alkenes: OneꢀPot Synthesis of
Bistrifluoromethylated Enamides and Oxazoles. Angew. Chem., Int. Ed. 2015, 54, 4041–4045. (e) Zhang, J.; Lin,
S.ꢀX.; Cheng, D.ꢀJ.; Liu, X.ꢀY.; Tan, B. Phosphoric AcidꢀCatalyzed Asymmetric Classic Passerini Reaction. J. Am.
Chem. Soc. 2015, 137, 14039–14042.
9
Zhang, C.; Lu, X. PhosphineꢀCatalyzed Cycloaddition of 2,3ꢀButadienoates or 2ꢀButynoates with
ElectronꢀDeficient Olefins. A novel [3+ 2] Annulation Approach to Cyclopentenes. J. Org. Chem. 1995, 60, 2906–
2908.
25
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
1
2
3
4
10
Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. Asymmetric [3+2] Cycloaddition of 2,3ꢀButadienoates
5
6
7
8
with ElectronꢀDeficient Olefins Catalyzed by Novel Chiral 2,5ꢀDialkylꢀ7ꢀphenylꢀ7ꢀphosphabicyclo[2.2.1]heptanes.
J. Am. Chem. Soc. 1997, 119, 3836–3837.
11
Wilson, J. E.; Fu, G. C. Synthesis of Functionalized Cyclopentenes through Catalytic Asymmetric [3+2]
9
Cycloadditions of Allenes with Enones. Angew. Chem., Int. Ed. 2006, 45, 1426–1429.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12
Cowen, B. J. Miller, S. J. Enantioselective [3+2]ꢀCycloadditions Catalyzed by a Protected, Multifunctional
PhosphineꢀContaining αꢀAmino Acid. J. Am. Chem. Soc. 2007, 129, 10988–10989.
13
(a) Xiao, H.; Chai, Z.; Zheng, C.ꢀW.; Yang, Y.ꢀQ.; Liu, W.; Zhang, J.ꢀK.; Zhao, G. Asymmetric [3+2]
Cycloadditions of Allenoates and Dual Activated Olefins Catalyzed by Simple Bifunctional NꢀAcyl
Aminophosphines. Angew. Chem., Int. Ed. 2010, 49, 4467–4470. (b) Sampath, M.; Loh, T.ꢀP. Highly Enantioꢀ,
Regioꢀ and DiastereoꢀSelective oneꢀpot [2+3]ꢀCycloaddition Reaction via Isomerization of 3ꢀButynoates to
Allenoates. Chem. Sci. 2010, 1, 739–742. (c) Zhong, F.; Chen, G.ꢀY.; Han, X.; Yao, W.; Lu, Y. Asymmetric
Construction of Functionalized Bicyclic Imides via [3+2] Annulation of MBH Carbonates Catalyzed by
DipeptideꢀBased Phosphines. Org. Lett. 2012, 14, 3764–3767. (d) Zhang, X.ꢀN.; Shi, M. PhosphineꢀCatalyzed [3+2]
Cycloaddition of 4,4ꢀDicyanoꢀ2ꢀmethylenebutꢀ3ꢀenoates with Benzyl Butaꢀ2,3ꢀdienoate and Pentaꢀ3,4ꢀdienꢀ2ꢀone.
ACS Catal. 2013, 3, 507–512. (e) Gicquel, M.; Zhang, Y.; Aillard, P.; Retailleau, P.; Voituriez, A.; Marinetti, A.
Phosphahelicenes in Asymmetric Organocatalysis: [3+2] Cyclizations of γꢀSubstituted Allenes and ElectronꢀPoor
Olefins. Angew. Chem., Int. Ed. 2015, 54, 5470–5473. (f) Lee, S. Y.; Fujiwara, Y.; Nishiguchi, A.; Kalek, M.; Fu, G.
C. PhosphineꢀCatalyzed Enantioselective Intramolecular [3+2] Annulations To Generate Fused Ring Systems. J.
Am. Chem. Soc. 2015, 137, 4587–4591.
14
(a) Pellissier, H. Asymmetric Domino Reactions. Part B: Reactions Based on the Use of Chiral Catalysts and
Biocatalysts. Tetrahedron 2006, 62, 2143–2173. (b) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Protonated Chiral
Catalysts: Versatile Tools for Asymmetric Synthesis. Angew. Chem., Int. Ed. 2005, 44, 1758–1763. (c) Deng, H.ꢀP.;
Wei, Y.; Shi, M. Highly Regioꢀ and Diastereoselective Construction of Spirocyclopenteneoxindoles through
PhosphineꢀCatalyzed [3+2] Annulation of Morita–Baylis–Hillman Carbonates with Isatylidene Malononitriles. Org.
Lett. 2011, 13, 3348–3351. (d) Tan, B.; Candeias, N. R.; Barbas, C. F., III CoreꢀStructureꢀMotivated Design of a
PhosphineꢀCatalyzed [3+2] Cycloaddition Reaction: Enantioselective Syntheses of Spirocyclopenteneoxindoles. J.
Am. Chem. Soc. 2011, 133, 4672–4675. (e) Fujiwara, Y.; Fu, G. C. Application of a New Chiral Phosphepine to the
Catalytic Asymmetric Synthesis of Highly Functionalized Cyclopentenes That Bear an Array of
HeteroatomꢀSubstituted Quaternary Stereocenters. J. Am. Chem. Soc. 2011, 133, 12293–12297.
15
(a) Jarvo, E. R.; Miller, S. J. Amino Acids and Peptides as Asymmetric Organocatalysts. Tetrahedron 2002, 58,
2481–2495. (b) List, B. ProlineꢀCatalyzed Asymmetric Reactions. Tetrahedron 2002, 58, 5573–5590. (c) Notz, W.;
Tanaka, F.; Barbas, C. F., III EnamineꢀBased Organocatalysis with Proline and Diamines: The Development of
Direct Catalytic Asymmetric Aldol, Mannich, Michael, and DielsꢀAlder Reactions. Acc. Chem. Res. 2004, 37, 580–
591. (d) Xu, L.ꢀW.; Lu, Y. Primary Amino Acids: Privileged Catalysts in Enantioselective Organocatalysis. Org.
Biomol. Chem. 2008, 6, 2047–2053. (e) MacMillan, D. W. C. The Advent and Development of Organocatalysis.
Nature 2008, 455, 304–308. (f) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Natural Products as Inspiration for the
Development of Asymmetric Catalysis. Nature 2008, 455, 323–332. (g) Wennemers, H. Asymmetric catalysis with
26
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
1
2
3
4
5
6
Peptides. Chem. Commun. 2011, 47, 12036–12041.
16
(a) Notz, W.; List, B. Catalytic Asymmetric Synthesis of antiꢀ1,2ꢀDiols. J. Am. Chem. Soc. 2000, 122, 7386–
7387. (b) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. The ProlineꢀCatalyzed Direct Asymmetric
ThreeꢀComponent Mannich Reaction: Scope, Optimization, and Application to the Highly Enantioselective
Synthesis of 1,2ꢀAmino Alcohols. J. Am. Chem. Soc. 2002, 124, 827–833. (c) Kumaragurubaran, N.; Juhl, K.;
Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. Direct LꢀProlineꢀCatalyzed Asymmetric αꢀAmination of Ketones. J. Am.
Chem. Soc. 2002, 124, 6254–6255. (d) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Dual Catalyst Control in the
Amino AcidꢀPeptideꢀCatalyzed Enantioselective Baylis−Hillman Reaction. Org. Lett. 2003, 5, 3741–3743. (e)
Wang, W.; Wang, J.; Li, H. Direct, Highly Enantioselective Pyrrolidine Sulfonamide Catalyzed Michael Addition of
Aldehydes to Nitrostyrenes. Angew. Chem., Int. Ed. 2005, 44, 1369–1371. (f) Zhou, L.; Tan, C. K.; Jiang, X.; Chen,
F.; Yeung, Y.ꢀY. Asymmetric Bromolactonization Using Aminoꢀthiocarbamate Catalyst. J. Am. Chem. Soc. 2010,
132, 15474–15476. (g) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Highly enantioselective [4 + 2] annulations catalyzed
by amino acidꢀbased phosphines: Synthesis of functionalized cyclohexenes and 3ꢀspirocyclohexeneꢀ2ꢀoxindoles.
Chem. Sci. 2012, 3, 1231–1234. (h) Ni, H.; Tang, X.; Zheng, W.; Yao, W.; Ullah, N.; Lu, Y. Enantioselective
PhosphineꢀCatalyzed Formal [4+4] Annulation of α,βꢀUnsaturated Imines and Allene Ketones: Construction of
EightꢀMembered Rings. Angew. Chem., Int. Ed. 2017, 56, 14222–14226.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17
Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Enantioselective [3+2] Cycloaddition of Allenes to Acrylates Catalyzed by
DipeptideꢀDerived Phosphines: Facile Creation of Functionalized Cyclopentenes Containing Quaternary
Stereogenic Centers. J. Am. Chem. Soc. 2011, 133, 1726–1729.
18
Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Versatile Enantioselective [3+2] Cyclization between Imines and Allenoates
Catalyzed by DipeptideꢀBased Phosphines. Angew. Chem., Int. Ed. 2012, 51, 767–770.
19
(a) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P.ꢀ Y.; Houk, K. N. Theory of Asymmetric
Organocatalysis of Aldol and Related Reactions: Rationalizations and Predictions. Acc. Chem. Res. 2004, 37, 558–
569. (b) Taylor, M. S.; Jacobsen, E. N. Asymmetric Catalysis by Chiral HydrogenꢀBond Donors. Angew. Chem., Int.
Ed. 2006, 45, 1520–1543. (c) Yu, X.; Wang, W. HydrogenꢀBondꢀMediated Asymmetric Catalysis. Chem.—Asian J.
2008, 3, 516–532. (d) Lam, Y.ꢀH.; Grayson, M. N.; Holland, M. C.; Simon, A.; Houk, K. N. Theory and Modeling
of Asymmetric Catalytic Reactions. Acc. Chem. Res. 2016, 49, 750–762. (e) Wheeler, S. E.; Seguin, T. J.; Guan, Y.;
Doney, A. C. Noncovalent Interactions in Organocatalysis and the Prospect of Computational Catalyst Design. Acc.
Chem. Res. 2016, 49, 1061–1069. (f) Reid, J. P.; Simón, L.; Goodman, J. M. A Practical Guide for Predicting the
Stereochemistry of Bifunctional Phosphoric Acid Catalyzed Reactions of Imines. Acc. Chem. Res. 2016, 49, 1029–
1041. (g) Cui, C.ꢀX.; Shan, C.; Zhang, Y.ꢀP.; Chen, X.ꢀL.; Qu, L.ꢀB.; Lan, Y. Mechanism of PhosphineꢀCatalyzed
Allene Coupling Reactions: Advances in Theoretical Investigations. Chem.—Asian J. 2018, 13, 1076–1088.
20
Frisch, M. J.; et al. Gaussian 09; Revision D.01; Gaussian, Inc.: Wallingford, CT, 2013.
21
(a) Becke, A. D. DensityꢀFunctional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993,
98, 5648–5652. (b) Lee, C.; Yang, W.; Parr, R. G. Development of the ColleꢀSalvetti CorrelationꢀEnergy Formula
into a Functional of the Electron Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785–789. (c)
Stephens, P. J.; Devlin, F. J. Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and
Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623–11627.
27
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
1
2
3
4
22
(a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self—Consistent Molecular Orbital Methods. XII. Further
5
6
7
8
Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem.
Phys. 1972, 56, 2257–2261. (b) Dill, J. D.; Pople, J. A. Selfconsistent Molecular Orbital Methods. XV. Extended
Gaussiantype Basis Sets for Lithium, Beryllium, and Boron. J. Chem. Phys. 1975, 62, 2921–2923. (c) Francl, M.
M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.; Gordon, M. S.; DeFrees, D. J.; Pople, J. A. Selfconsistent Molecular
Orbital Methods. XXIII. A Polarizationtype Basis Set for Second Row Elements. J. Chem. Phys. 1982, 77, 3654–
3665.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23
(a) Yao, W.; Yu, Z.; Wen, S.; Ni, H.; Ullah, N.; Lan, Y.; Lu, Y. Chiral Phosphineꢀmediated Intramolecular [3+2]
Annulation: Enhanced Enantioselectivity by Achiral Brønsted Acid. Chem. Sci. 2017, 8, 5196–5200. (b) Ni, H.; Yu,
Z.; Yao, W.; Lan, Y.; Ullah, N.; Lu, Y. CatalystꢀControlled Regioselectivity in Phosphine Catalysis: The Synthesis
of Spirocyclic Benzofuranones via Regiodivergent [3+2] Annulations of Aurones and an Allenoate. Chem. Sci.
2017, 8, 5699–5704. (c) Yu, Z.; Lan, Y. Mechanism of RhodiumꢀCatalyzed Carbon–Silicon Bond Cleavage for the
Synthesis of Benzosilole Derivatives: A Computational Study. J. Org. Chem. 2013, 78, 11501–11507. (d) Duan, M.;
Zhu, L.; Qi, X.; Yu, Z.; Li, Y.; Bai, R.; Lan, Y. From Mechanistic Study to Chiral Catalyst Optimization:
Theoretical Insight into Binaphthophosphepineꢀcatalyzed Asymmetric Intramolecular [3+2] Cycloaddition. Sci.
Rep. 2017, 7, 7619–7631.
24
Peverati, R.; Truhlar, D. G. Improving the Accuracy of Hybrid MetaꢀGGA Density Functionals by Range
Separation. J. Phys. Chem. Lett. 2011, 2, 2810–2817.
25
(a) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. SelfꢀConsistent Molecular Orbital Methods. XX. A Basis
Set for Correlated Wave Functions. J. Chem. Phys. 1980, 72, 650–654. (b) McLean, A. D.; Chandler, G. S.
Contracted Gaussian Basis Sets for Molecular Calculations. I. Second Row Atoms, Z=11–18. J. Chem. Phys. 1980,
72, 5639–5648.
26
(a) Cancès, E.; Mennucci, B.; Tomasi, J. A New Integral Equation Formalism for the Polarizable Continuum
Model: Theoretical Background and Applications to Isotropic and Anisotropic Dielectrics. J. Chem. Phys. 1997,
107, 3032–3041. (b) Cancès, E.; Mennucci, B. New Applications of Integral Equations Methods for Solvation
Continuum Models: Ionic Solutions and Liquid Crystals. J. Math. Chem. 1998, 23, 309–326. (c) Mennucci, B.;
Cancès, E.; Tomasi, J. Evaluation of Solvent Effects in Isotropic and Anisotropic Dielectrics and in Ionic Solutions
with a Unified Integral Equation Method: Theoretical Bases, Computational Implementation, and Numerical
Applications. J. Phys. Chem. B, 1997, 101, 10506–10517. (d) Scalmani, G.; Frisch, M. J. Continuous Surface
Charge Polarizable Continuum Models of Solvation. I. General Formalism. J. Chem. Phys. 2010, 132, 114110–
114124.
27
Lu, T.; Chen, F. Multiwfn: A Multifunctional Wavefunction Analyzer. J. Comput. Chem. 2012, 33, 580–592.
28
Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual Molecular Dynamics. J. Molec. Graphics. 1996, 44, 33–
38.
29
Legault, C. Y. CYLview, 1.0b; Université de Sherbrooke, 2009 (http://www.cylview.org).
30
(a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu, Z.ꢀX. An Unexpected Role of a
Trace Amount of Water in Catalyzing Proton Transfer in PhosphineꢀCatalyzed (3+2) Cycloaddition of Allenoates
28
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
1
2
3
4
5
6
7
8
9
and Alkenes. J. Am. Chem. Soc. 2007, 129, 3470–3471. (b) Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.;
Dudding, T. Phosphine Triggered [3+2] Allenoate–Acrylate Annulation: A Mechanistic Enlightenment. Tetrahedron
Lett. 2007, 48, 3617–3620. (c) Zhao, L.; Wen, M.; Wang, Z.ꢀX. Reaction Mechanism of PhosphaneꢀCatalyzed [4+2]
Annulations between αꢀAlkylallenoates and Activated Alkenes: A Computational Study. Eur. J. Org. Chem. 2012,
3587–3597. (d) Qiao, Y.; Han, K.ꢀL. Elucidation of the Reaction Mechanisms and Diastereoselectivities of
PhosphineꢀCatalyzed [4+2] Annulations between Allenoates and Ketones or Aldimines. Org. Biomol. Chem. 2012,
10, 7689–7706. (e) Huang, G.ꢀT.; Lankau, T.; Yu, C.ꢀH. A Computational Study: Reactivity Difference between
Phosphineꢀand AmineꢀCatalyzed Cycloadditions of Allenoates and Enones. J. Org. Chem. 2014, 79, 1700–1711.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
31
(a) Knowles, R. R.; Jacobsen, E. N. Attractive Noncovalent Interactions in Asymmetric Catalysis: Links between
Enzymes and Small Molecule Catalysts. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20678–20685. (b) Uyeda, C.;
Jacobsen, E. N. TransitionꢀState Charge Stabilization through Multiple Nonꢀcovalent Interactions in the
GuanidiniumꢀCatalyzed Enantioselective Claisen Rearrangement. J. Am. Chem. Soc. 2011, 133, 5062–5075. (c) Lin,
S.; Jacobsen, E. N. ThioureaꢀCatalysed Ring Opening of Episulfonium Ions with Indole Derivatives by Means of
Stabilizing NonꢀCovalent Interactions. Nature Chem. 2012, 4, 817–824. (d) Brown, A. R.; Uyeda, C.; Brotherton, C.
A. Jacobsen, E. N. Enantioselective ThioureaꢀCatalyzed Intramolecular CopeꢀType Hydroamination. J. Am. Chem.
Soc. 2013, 135, 6747–6749.
32
(a) Jiang, H.; Paixão, M. W.; Monge, D.; Jørgensen, K. A. Acyl Phosphonates: Good Hydrogen Bond Acceptors
and Ester/Amide Equivalents in Asymmetric Organocatalysis. J. Am. Chem. Soc. 2010, 132, 2775–2783. (b)
Albrecht, L.; Dickmeiss, G.; Acosta, F. C.; RodríguezꢀEscrich, C.; Davis, R. L.; Jørgensen, K. A. Asymmetric
Organocatalytic Formal [2+2]ꢀCycloadditions via Bifunctional HꢀBond Directing Dienamine Catalysis. J. Am.
Chem. Soc. 2012, 134, 2543–2546.
33
(a) Simón, L.; Goodman, J. M. Mechanism of Amination of β‑Keto Esters by Azadicarboxylates Catalyzed by
an Axially Chiral Guanidine: Acyclic Keto Esters React through an E Enolate. J. Am. Chem. Soc. 2012, 134,
16869–16876. (b) Overvoorde, L. M.; Grayson, M. N.; Luo, Y.; Goodman, J. M. Mechanistic Insights into a
BINOLꢀDerived Phosphoric AcidꢀCatalyzed Asymmetric Pictet−Spengler Reaction. J. Org. Chem. 2015, 80, 2634–
2640.
34
(a) Holland, M. C. Gilmour, R.; Houk, K. N. Importance of Intermolecular Hydrogen Bonding for the
Stereoꢀchemical Control of Allene–Enone (3+2) Annulations Catalyzedby a Bifunctional, Amino Acid Derived
Phosphine Catalyst. Angew. Chem., Int. Ed. 2016, 55, 2022–2027. (b) Bickelhaupt, F. M.; Houk, K. N. Analyzing
Reaction Rates with the Distortion/InteractionꢀActivation Strain Model. Angew. Chem., Int. Ed. 2017, 56, 10070–
10086.
35
(a) Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. Theoretical Studies on the Bifunctionality of Chiral
ThioureaꢀBased Organocatalysts: Competing Routes to C−C Bond Formation. J. Am. Chem. Soc. 2006, 128,
13151–13160. (b) Duarte, F. J. S.; Santos, A. G. Enantioselective Organocatalytic Intramolecular Diels−Alder
Reactions: A Computational Study. J. Org. Chem. 2012, 77, 3252–3261. (c) Aasheim, J. H.; Fliegl, H.; Uggerud, E.;
BongeꢀHansen, T.; Eisenstein, O. Stereoselectivity through a Network of NonꢀClassical CH Weak Interactions: A
Prospective Study of a Bicyclic Organocatalytic Scaffold. New J. Chem. 2014, 38, 5975–5982. (d) Armstrong, A.;
29
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Boto, R. A.; Dingwall, P.; ContrerasꢀGarcía, J.; Harvey, M. J.; Mason, N. J.; Rzepa, H. S. The Houk–List Transition
States for Organocatalytic Mechanisms Revisited. Chem. Sci. 2014, 5, 2057–2071. (e) Simón, L.; Paton, R. S.
Origins of Asymmetric Phosphazene Organocatalysis: Computations Reveal a Common Mechanism for Nitroꢀ and
PhosphoꢀAldol Additions. J. Org. Chem. 2015, 80, 2756–2766. (f) Xue, Y.; Wang, Y.; Cao, Z.; Zhou, J.; Chen, Z.ꢀX.
Computational Insight into the Cooperative Role of NonꢀCovalent Interactions in the azaꢀHenry Reaction
Catalyzed by Quinine Derivatives: Mechanism and Enantioselectivity. Org. Biomol. Chem. 2016, 14, 9588–9597.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
36
(a) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Córdova, A. The Origin of Stereoselectivity in Primary Amino
Acid Catalyzed Intermolecular Aldol Reactions. Angew. Chem., Int. Ed. 2005, 44, 7028–7032. (b) Moran, A.;
Hamilton, A.; Bo, C.; Melchiorre, P. A Mechanistic Rationale for the 9ꢀAmino(9ꢀdeoxy)epi Cinchona Alkaloids
Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones. J. Am. Chem. Soc. 2013, 135, 9091–9098.
(c) Kumari, P.; Barik, S.; Khan, N. H.; Ganguly, B.; Kureshy, R. I.; Abdi, S. H. R.; Bajaj, H. C. The Origin for
Highly Enantioselective Induction of 1ꢀNaphthol to IsatinꢀDerived NꢀBoc Ketimines Catalyzed by Quinine
Thiourea Catalyst: An Experimental and Computational Study. RSC Adv. 2015, 5, 69493–69501. (d) Cheng, G.ꢀJ.;
Zhang, X.; Chung, L. W.; Xu, L.; Wu, Y.ꢀD. Computational Organic Chemistry: Bridging Theory and Experiment
in Establishing the Mechanisms of Chemical Reactions. J. Am. Chem. Soc. 2015, 137, 1706–1725. (e) Monaco, M.
R.; Fazzi, D.; Tsuji, N.; Leutzsch, M.; Liao, S.; Thiel, W.; List, B. The Activation of Carboxylic Acids via
SelfꢀAssembly Asymmetric Organocatalysis: A Combined Experimental and Computational Investigation. J. Am.
Chem. Soc. 2016, 138, 14740–14749.
37
Fang, Y.ꢀQ.; Jacobsen, E. N. Cooperative, Highly Enantioselective Phosphinothiourea Catalysis of Imine–Allene
[3+2] Cycloadditions. J. Am. Chem. Soc. 2008, 130, 5660–5661.
38
(a) Wang, T.; Yu, Z.; Hoon, D. L.; Huang, K.ꢀW.; Lan, Y.; Lu, Y. Highly Enantioselective Construction of
Tertiary Thioethers and Alcohols via PhosphineꢀCatalyzed Asymmetric γꢀAddition Reactions of
5HꢀThiazolꢀ4ꢀOnes and 5HꢀOxazolꢀ4ꢀOnes: Scope and Mechanistic Understandings. Chem. Sci. 2015, 6, 4912–
4922. (b) Wang, T.; Yu, Z.; Hoon, D. L.; Phee, C. Y.; Lan, Y.; Lu, Y. Regiodivergent Enantioselective γꢀAdditions of
Oxazolones to 2,3ꢀButadienoates Catalyzed by Phosphines: Synthesis of α,αꢀDisubstituted αꢀAmino Acids and
N,OꢀAcetal Derivatives. J. Am. Chem. Soc. 2016, 138, 265–271.
39
Johnson, E. R.; Keinan, S.; MoriꢀSánchez, P.; ContrerasꢀGarcía, J.; Cohen, A. J.; Yang, W. Revealing
Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506.
30
ACS Paragon Plus Environment