Development of diamidophosphite ligands and their application to the palladium-catalyzed vinyl-substituted trimethylenemethane asymmetric [3 + 2] cycloaddition

Article abstract of DOI:10.1021/ja305717r

A palladium-catalyzed asymmetric [3 + 2] cycloaddition of a vinyl-substituted trimethylenemethane (TMM) donor with α,β- unsaturated acyl imidazoles is described. A newly designed bisdiamidophosphite ligand derived from (S,S)-trans-1,2-cyclohexanediamine a

Full text of DOI:10.1021/ja305717r

Subscriber access provided by FONDREN LIBRARY, RICE UNIVERSITY
Communication
Development of Diamidophosphite Ligands and their
Application to the Palladium-catalyzed Vinyl-substituted
Trimethylenemethane Asymmetric [3+2] Cycloaddition
Barry M. Trost, and Tom M. Lam
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja305717r • Publication Date (Web): 20 Jun 2012
Downloaded from http://pubs.acs.org on June 27, 2012
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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 4
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Development of Diamidophosphite Ligands and their Applica-
tion to the Palladium-catalyzed Vinyl-substituted Tri-
methylenemethane Asymmetric [3+2] Cycloaddition
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
Barry M. Trost* and Tom M. Lam
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
Supporting Information Placeholder
R'
ABSTRACT: A palladium-catalyzed asymmetric [3+2] cy-
cloaddition of a vinyl-substituted trimethylenemethane (TMM)
donor with α,β-unsaturated acyl imidazoles is described. A
newly designed bisdiamidophosphite ligand derived from
(S,S)-trans-1,2-cyclohexanediamine and (2R,4R)-pentanediol
has been instrumental for the development of this process.
This transformation generates tetrasubstituted cyclopentanes
bearing three contiguous stereocenters in high yields, with
good diastereo- and enantioselectivity.
R'
R''
Pd(0), ligand
AcO
TMS
EWG
(1)
R''
R''
R'
EWG
not observed
EWG
observed
We were attracted to the use of acyl imidazoles8 as ester sur-
rogates due to their synthetic utility along with their tunability
to impart yield and selectivity.9 In our initial ligand screen,
however, L1, which has performed well in our previous stud-
ies of the parent and cyano-TMM donor, led to only 33% yield
of the desired product with low levels of diastereo- and enan-
tioselectivity.
Scheme 1. Initial Ligand Screena
Cycloadditions remain powerful transformations in the syn-
thesis of functionalized ring systems, achieving high levels of
complexity and multiple bond formations in a single reaction.
To that end, the palladium-catalyzed trimethylenemethane
reaction has shown broad application in the formation of vari-
ous five-, seven-and nine-membered ring systems.1 Recently,
the development of chiral phosphoramidite ligands has al-
lowed our group to conduct these same reactions asymmetri-
cally, generating various carbocycles,2 tetrahydrofurans,3 and
pyrrolidines4 in good yields and selectivities.
O
5 mol% Pd(dba)2
ligand
N
AcO
TMS
Ph
Ph
N
Ph
Dioxane, 60 ºC
N
Ph
1
2a
3a
O
N
Ph
Ph
Ph
O
P
O
N
P
N
N
N
N
N
O
O
P
P
OBn
N
Due to the success of this process, we were eager to expand
the donor scope of the transformation to substituted TMM
donors. The placement of a substituent on the TMM species
generates an additional stereocenter, forming tetrasubstituted
cyclopentanes containing three contiguous stereocenters. The
well recognized importance of cyclopentane5 derived struc-
tures possessing important biological activity encourages the
development of more facile asymmetric methods. The racemic
variant of the substituted TMM reaction was first disclosed in
1985,6 where various substituents, including vinyl, phenyl,
acetoxy, and cyano groups formed five membered rings as a
single regioisomer (eq 1). To date, only the cyano-TMM donor
has been rendered asymmetric.7 The difficulty in expanding
the donor scope of the reaction lies in the loss of reactivity and
selectivity whenever substitution other than cyano is used.
Designing a ligand that would enable a broader tolerance of
substituents is then required. Herein, we describe the devel-
opment of such a ligand family and illustrate the process using
the vinyl-substituted TMM donor because of its potential ver-
satility for further synthetic elaboration. Such a substitution
also raises the question of the effect of ligands on regioselec-
tivity which could lead to [5+2] cycloadditions.
Ph
Ph
Ph
L1
33% y
2.2 : 1 dr
L2
L3
>97% y
4.4 : 1 dr
-7% ee
69% y
6.8 : 1 dr
57% ee
14% ee
Ph
N
Ph
Ph
N
Ph
N
Me
P
Me
Me
P
Me
N
O
O
P
O
O P
N
N
N
N
Ph
Ph
Ph
Ph
L4
L5
39% y
5.6 : 1 dr
-6% ee
84% y
9.3 : 1 dr
87% ee
a
All reactions were conducted for 18 h at 0.5 M in dioxane with
2.0 equiv of 1, 5% Pd(dba)2, and 10% (for L1 and L2) or 8% (for
L3, L4 and L5) ligand. Yields are combined isolated values; ee’s
were determined by HPLC with a chiral stationary phase column.
To increase the reactivity of the catalyst system, we investi-
gated diamidophosphites as a new ligand system for the
asymmetric TMM reaction. In earlier studies, we noted that
the use of a phosphorus triamide significantly accelerated the
cycloaddition compared to a phosphite,10 presumably by in-
creasing the nucleophilicity of the palladium-TMM complex.
The substitution of one oxygen atom in the phosphoramidites
for a nitrogen atom in the diamidophosphites should also in-
crease the electron density on the phosphorus center, which
ACS Paragon Plus Environment

Journal of the American Chemical Society
would hopefully increase the efficacy of the palladium-
catalyzed TMM reaction.
Page 2 of 4
Table 1. Selected Optimization Studiesa
1
2
3
4
5
6
7
8
9
Diamidophosphite ligands are an emerging class of ligands
in asymmetric transition metal catalysis. These ligands have
been applied to a limited range of asymmetric transition metal-
catalyzed transformations, such as hydrovinylation, conjugate
addition, and hydrogenation of substituted enoates.11 Di-
amidophosphites have had limited success in palladium-
catalyzed asymmetric allylic alkylations.12 Quite interestingly,
Pfaltz and co-workers have developed a bisdiamidophosphite
O
5 mol% Pd source
8 mol% L4
N
AcO
TMS
Ph
Ph
Ph
solvent, 60 ºC
N
N
Ph
1
2a
3a
O
N
entry
Pd
solvent
Dioxane
DME
% yield
84
dr
% ee
87
1
2
3
4
5
6
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
9.3:1
3:1
ligand
based
on
sulfonamides
of
trans-1,2-
80
83
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
cyclohexanediamine and trans-1,2-stilbenediamines which led
to a novel mass-spectroscopy study of palladium-catalyzed
kinetic resolution of quasienantiomeric allyl species.12d
DCE
58
4.4:1
6.9:1
3.3:1
8.3:1
87
Toluene
THF
76
82
67
10
Scheme 2. Synthesis of Diamidophosphite Ligands
CpPd(η3-C3H5) Dioxane
97
83
Ph
BnOH (1 eq)
Et3N
N
a
L2
77% yield
Ph
All reactions were conducted for 18 h at 0.5 M in solvent with
P
OBn
Ph
N
P
N
Ph
N
NH
PCl3, Et3N
2.0 equiv of 1, 5% palladium precatalyst, and 8% L4. Yields are
combined isolated values; ee’s were determined by HPLC with a
chiral stationary phase column.
Ph
Ph
Cl
PhH, 0 ºC - rt
NH
Ph
Ph
Et3N
N
N
N
P
N
4
P
O
O
HO
OH
With the optimized conditions in hand, we explored the
substrate scope of the reaction (Scheme 3).15 Ortho-, meta-and
para-substituents performed well in this transformation,
providing products 3b-d in good yields and selectivities. The
highest selectivity was observed in the case of the p-methoxy
substrate, where 3b was isolated with 11:1 dr and 90% ee.
Aryl chlorides were tolerated under the reaction conditions,
along with electron-deficient aromatic rings. Five-membered
heterocycles performed well, although with slightly reduced
enantioselectivity. Importantly, nonaromatic groups were
compatible with the reaction conditions. Unsaturated side-
chains such as styrenyl and alkynyl groups could also be used
in this transformation, with good regioselectivity for the α,β-
unsaturated products.16
L3
45% yield
(0.5 eq)
Ph
Ph
In the design of our diamidophosphites, we pursued ligand
structures that contained N-aryl motifs. We believed that the
proximity of the aryl group to the phosphorus atom is im-
portant in enhancing the chiral space about the metal center.13
Our synthesis begins with the Buchwald-Hartwig amination of
commercially available (S,S)-trans-1,2-cyclohexane diamine
with bromobenzene according to literature procedure, giving 4
(Scheme 2).14 Treatment of diamine 4 with phosphorus tri-
chloride in the presence of triethylamine generates the P-
chlorodiazaphospholidine, which after filtration of the tri-
ethylammonium salts under argon is reacted with an equiva-
lent of benzyl alcohol and triethylamine.12b The desired di-
amidophosphite ligand L2 is isolated in good yields. Substitu-
tion of the benzyl alcohol for an alkyl diol in the final step of
the ligand synthesis provided a dimeric diamidophosphite
ligand L3, which could potentially be bidentate.
Scheme 3. Palladium-catalyzed [3+2] Reactions with Vinyl-
TMM Donora
5 mol% CpPd(! 3-C3H5)
O
8 mol% L4
With the new synthesized ligands in hand, we tested their
ability to perform the TMM cycloaddition (Scheme 1). Grati-
fyingly, using L2, we were able to isolate the cycloaddition
product in >97% yield as a single regioisomer. While the en-
antioselectivity remained low, employment of L3 led to a
jump from -7% to 57% ee. The clear dependence of the ligand
system on the propanediol tether encouraged us to place a
chiral element on the diol backbone in order to further define
the chiral space generated by the ligand. Ligands L4 and L5
were thus synthesized using commercially available (2R,4R)-
pentanediol and (2S,4S)-pentanediol, respectively. In the case
of ligand L4, the cycloadduct was isolated in 84% yield, 9.3:1
dr and 87% ee. Both yield and selectivity dropped with ligand
L5.
N
AcO
TMS
R
Ph
N
R
N
Dioxane, 60 ºC
Ph
1
2
3
O
N
MeO
OMe
3d
Cl
OMe
3c
3a
3b
3e
97% y
8.3:1 dr
83% ee
91% y
11:1 dr
90% ee
>97% y
5:1 dr
87% ee
91% y
3:1 dr
87% ee
77% y
3.6:1 dr
86% ee
O
S
Ph
O2N
N
3f
3g
90%y
7.9:1 dr
84% ee
3h
3i
3j
88% y
3.8:1 dr
85% ee
92% y
8.5:1 dr
80% ee
86% y
5:1 dr
81% ee
59% y
8.4:1 dr
83% ee
Following our ligand screen, we performed a solvent and
palladium precatalyst screen (Table 1). Various solvents were
tested but showed reduced yields and selectivities. Interesting-
ly, THF led to a marked reduction in enantioselectivity with
only 10% ee. Toluene, which has been successful in other
TMM reactions, also led to diminished yield and selectivity.
Switching from Pd(dba)2 to CpPd(η3- C3H5) resulted in nearly
quantitative yield with only slight erosion of selectivity. These
conditions were selected as our standard conditions.
Ph
TIPSO
Me
TIPS
Ph
3k
67% y
4:1 dr
3l
97% y
11.3:1 dr
82% ee
3m
3n
72% y
6:1 dr
95% y
3:1 dr
87% ee
75% ee
81% ee
a
All reactions were conducted for 18 h at 0.5 M in dioxane with
2.0 equiv of 1, 5% CpPd(η3- C3H5), and 8% L4. Yields are com-
ACS Paragon Plus Environment

Page 3 of 4
Journal of the American Chemical Society
bined isolated values; ee’s were determined by HPLC with a chi-
ral stationary phase column.
the X-ray crystal structures and Johnson-Matthey for generous
gifts of palladium salts
1
2
3
4
5
6
7
8
9
These cycloadducts are highly versatile as chiral building
blocks. The flexibility of the acyl imidazole group allows for
easy manipulation to various functionalities.8 Additionally, the
proximal nature of the alkene and alkyne in 3l-n led us to in-
vestigate ruthenium-catalyzed ring closing metathesis strate-
gies toward the synthesis of tricyclic systems.17 We posited
that substitution of the imidazole with an alkyl chain bearing a
terminal alkene would generate a triene-yne system, upon
which exposure to Grubbs’ catalyst would first effect an enyne
metathesis reaction followed by second ring closure by the
pendant alkene. To test this, activation of the imidazole with
methyl triflate and subsequent alkylation with homoallyl-
magnesium bromide resulted in the triene-yne 5 in 68% yield
(Scheme 4).8c Using 10 mol% of Hoveyda-Grubbs II catalyst
in benzene at reflux performed the desired ring closure to give
6 in 57% yield. This product possesses three chemically dif-
ferentiated olefins with three stereocenters set during the
TMM cycloaddition. The 5,5,7-fused tricylic ring system of 6
also resembles the carbocyclic core of the Daphnyphyllum
alkaloids.18
REFERENCES
(1) (a) Trost, B. M. Pure Appl. Chem. 1988, 60, 1615. (b)
Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
(c) Chan, D. M. T. Recent Advances in Palladium-Catalyzed
Cycloadditions Involving Trimethylenemethane and its Ana-
logs. In Cycloaddition Reactions in Organic Synthesis, 1st
ed.; Kobayashi, S.,Jorgensen, K. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2002; pp 57-83.
(2) (a) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schwörer,
U. J. Am. Chem. Soc. 2006, 128, 13328. (b) Trost, B. M.;
Bringley, D. A.; Seng, P. S. Org. Lett. 2012, 14, 234.
(3) Trost, B. M.; Bringley, D. A.; Silverman, S. M. J. Am. Chem.
Soc. 2011, 133, 7664.
(4) (a) Trost. B. M.: Silverman, S. M.; Stambuli, J. P. J. Am.
Chem. Soc. 2007, 129, 12398. (b) Trost, B. M.; Silverman, S.
M. J. Am. Chem. Soc. 2010, 132, 8238. (c) Trost, B. M.; Sil-
verman, S. M. J. Am. Chem. Soc. 2012, 134, 4941.
(5) (a) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem.
Rev. 2007, 107, 3286. (b) Mehta, G.; Srikrishna, A. Chem.
Rev. 1997, 97, 671.
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) Trost, B. M.; Nanninga, T. N.; Satoh, T. J. Am. Chem. Soc.
1985, 107, 721.
Scheme 4. Further Functionalization of Cycloadduct 3n
(7) (a) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem.
Soc. 2007, 129, 12396. (b) Trost, B. M.; Silverman, S. M.;
Stambuli, J. P. J. Am. Chem. Soc. 2011, 133, 19483.
(8) (a) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.;
Xu, R. J. Am. Chem. Soc. 2007, 129, 10029. (b) Evans, D.
A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249-2252. (c) Trost,
B. M.; Lehr, K.; Michaelis, D. J.; Xu, J.; Buckl, A. J. Am.
Chem. Soc. 2010, 132, 8915.
(9) Acyl pyrroles and various ester derivatives gave lower yield
and selectivity of the desired cycloadduct.
(10) Unpublished results.
(11) See Ayora, I.; Ceder, R. M.; Espinel, M.; Muller, G.; Roca-
mora, M.; Serrano, M. Organometallics, 2011, 30, 115 and
references therein.
(12) (a) Delapierre, G.; Brunel, J. M.; Constantieux, T.; Buono, G.
Tet. Asymm. 2001, 12, 1345. (b) Tsarev, V. N.; Lyubimov, S.
E.; Shiryaev, A. A.; Zheglov, S. V.; Bondarev, O. G.; Da-
vankov, V. A.; Kabro, A. A.; Moiseev, S. K.; Kalinin, V. N.;
Gavrilov, K. N. Eur. J. Org. Chem. 2004, 2214. (c) Hilgraf,
R.; Pfaltz, A. Adv. Synth. Catal. 2005, 347, 61. (d) Markert,
C.; Rösel, P.; Pfaltz, A. J. Am. Chem. Soc. 2008, 130, 3234.
(e) Gavrilov, K. N.; Zheglov, S. V.; Rastorguev, E. A.;
Groshkin, N. N.; Maksimova, M. G.; Benetsky, E. B.; Da-
vankov, V. A.; Reetz, M. T. Adv. Synth. Catal. 2010, 352,
2599.
H
1) 4Å MS, MeOTf
MeCN
TIPSO
10 mol% HGII
PhH, reflux
3n
81% ee
H
2) THF, -78 ºC
BrMg
H
TIPSO
O
O
6
5
57% yield
79% ee
68% yield
In summary, a palladium-catalyzed vinyl-substituted TMM
asymmetric cycloaddition has been achieved. Tetrasubstituted
cyclopentanes bearing three contiguous stereocenters are syn-
thesized in good yields with good regio-, diastereo- and enan-
tioselectivity. The realization of this process was due to the
development of new bisdiamidophosphite ligands based on
(S,S)-trans-1,2-cyclohexane diamine and (2R,4R)-pentanediol.
These newly synthesized bisdiamidophosphite ligands bearing
N-phenyl substituents represent a class of ligands not previ-
ously examined, allowing reactivity and selectivity that has not
been observed prior to this work. Furthermore, these cycload-
ducts bearing a 1,4-diene and acyl imidazole have been subse-
quently functionalized, displaying the synthetic utility of such
products. Expansion of the scope of the reaction in both donor
and acceptor complexity is currently underway and will be
reported in due course.
(13) Preliminary studies utilizing N-alkyl substituents on the lig-
and structure were less promising, resulting in lower yield and
selectivity.
(14) Aoyama, H.; Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obora,
Y.; Tsuji, Y. J. Am. Chem. Soc. 2005, 127, 10474.
(15) All products were isolated as a single regioisomer. The abso-
lute and relative stereochemistry of the product was deter-
mined by the crystal structure of 3e (see Supporting Infor-
mation). All other products were assigned by analogy.
(16) 26% of the γ,δ-cycloadduct was observed in the case of 3j.
For 3k-n, only the α,β-cycloadduct was observed.
(17) See Mori, M. Adv. Synth. Catal. 2007, 349, 121 and refer-
ences therein.
(18) Li, C.-S.; Di, Y.-T.; Mu, S.-Z.; He, H.-P.; Zhang, Q.; Fang,
X.; Zhang, Y.; Li, S.-L.; Lu, Y.; Gong, Y.-Q.; Hao, X.-J. J.
Nat. Prod. 2008, 71, 1202.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental details, com-
pound characterization data, and spectra. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
ACKNOWLEDGMENT
We thank the NSF for their generous support of our programs.
We thank Dr. Allen Oliver from the University of Notre Dame for
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 4
1
2
3
4
5
6
7
8
9
Ph
N
Ph
N
CpPd(! 3-C3H5)
L4
Me
P
Me
O
AcO
TMS
N
R
O
O P
Ph
N
R
N
N
N
Dioxane, 60 ºC
Ph
O
Ph
Ph
L4
N
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
14 examples
3:1 - 11:1 dr
75 - 90% ee
ACS Paragon Plus Environment