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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
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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 Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States Supporting Information Placeholder R'
ABSTRACT: 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 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.
Cycloadditions remain powerful transformations in the synthesis 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 various five-, seven-and nine-membered ring systems.1 Recently, the development of chiral phosphoramidite ligands has allowed our group to conduct these same reactions asymmetrically, generating various carbocycles,2 tetrahydrofurans,3 and pyrrolidines4 in good yields and selectivities. 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 structures 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 development of such a ligand family and illustrate the process using the vinyl-substituted TMM donor because of its potential versatility for further synthetic elaboration. Such a substitution also raises the question of the effect of ligands on regioselectivity which could lead to [5+2] cycloadditions.
R' AcO
TMS
Pd(0), ligand
EWG
R''
(1)
R''
R''
R'
EWG not observed
EWG observed
We were attracted to the use of acyl imidazoles8 as ester surrogates 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 studies of the parent and cyano-TMM donor, led to only 33% yield of the desired product with low levels of diastereo- and enantioselectivity. Scheme 1. Initial Ligand Screena O TMS
AcO
N
Ph
1
2a
Ph
5 mol% Pd(dba)2 ligand
3a
Ph O P N O
N
L1 33% y 2.2 : 1 dr 14% ee
N
Me Ph
Ph Me N N
P O
Ph
O P
L4 84% y 9.3 : 1 dr 87% ee
N
N
P O
N
N
Ph
Ph
L2 >97% y 4.4 : 1 dr -7% ee
O
Ph
Ph
P OBn
Ph N
Ph
Dioxane, 60 ºC
N
O P
N Ph
L3 69% y 6.8 : 1 dr 57% ee Me Ph
Ph Me
N
N
N
N
Ph
Ph
P O
O P
L5 39% y 5.6 : 1 dr -6% ee
N N Ph
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 investigated 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 increasing 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 increase the electron density on the phosphorus center, which
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would hopefully increase the efficacy of the palladiumcatalyzed TMM reaction. 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 metalcatalyzed transformations, such as hydrovinylation, conjugate addition, and hydrogenation of substituted enoates.11 Diamidophosphites have had limited success in palladiumcatalyzed asymmetric allylic alkylations.12 Quite interestingly, Pfaltz and co-workers have developed a bisdiamidophosphite ligand based on sulfonamides of trans-1,2cyclohexanediamine and trans-1,2-stilbenediamines which led to a novel mass-spectroscopy study of palladium-catalyzed kinetic resolution of quasienantiomeric allyl species.12d Scheme 2. Synthesis of Diamidophosphite Ligands BnOH (1 eq) Ph NH NH Ph
PCl3, Et3N PhH, 0 ºC - rt
Ph N P Cl N Ph
Et3N Et3N
Ph N P OBn N Ph
Ph
Ph N
4 HO
OH
(0.5 eq)
L2 77% yield
P O
N
O P N L3 Ph Ph 45% yield
N
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 important 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 trichloride in the presence of triethylamine generates the Pchlorodiazaphospholidine, which after filtration of the triethylammonium salts under argon is reacted with an equivalent of benzyl alcohol and triethylamine.12b The desired diamidophosphite ligand L2 is isolated in good yields. Substitution 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. With the new synthesized ligands in hand, we tested their ability to perform the TMM cycloaddition (Scheme 1). Gratifyingly, using L2, we were able to isolate the cycloaddition product in >97% yield as a single regioisomer. While the enantioselectivity 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. Following our ligand screen, we performed a solvent and palladium precatalyst screen (Table 1). Various solvents were tested but showed reduced yields and selectivities. Interestingly, 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.
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Table 1. Selected Optimization Studiesa O AcO
TMS 1
5 mol% Pd source 8 mol% L4
N
Ph 2a
Ph
3a
entry
Pd
solvent
1
Pd(dba)2
2
Pd(dba)2
3
Ph N
Ph
solvent, 60 ºC
N
O
N
% yield
dr
% ee
Dioxane
84
9.3:1
87
DME
80
3:1
83
Pd(dba)2
DCE
58
4.4:1
87
4
Pd(dba)2
Toluene
76
6.9:1
82
5
Pd(dba)2
THF
67
3.3:1
10
6
CpPd(η3-C3H5)
Dioxane
97
8.3:1
83
a
All reactions were conducted for 18 h at 0.5 M in solvent with 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.
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 sidechains such as styrenyl and alkynyl groups could also be used in this transformation, with good regioselectivity for the α,βunsaturated products.16 Scheme 3. Palladium-catalyzed [3+2] Reactions with VinylTMM Donora 5 mol% CpPd(! 3-C3H5) 8 mol% L4
O AcO
TMS
N
R
1
2
Ph
N
MeO 3a 97% y 8.3:1 dr 83% ee
O2N 3f 88% y 3.8:1 dr 85% ee
3g 90%y 7.9:1 dr 84% ee
Me
a
TIPS 3l 97% y 11.3:1 dr 82% ee
N
Cl 3e 77% y 3.6:1 dr 86% ee
O Ph
3h 92% y 8.5:1 dr 80% ee
3i 86% y 5:1 dr 81% ee
Ph 3k 67% y 4:1 dr 75% ee
O
3d 91% y 3:1 dr 87% ee
S
N
3
OMe
OMe 3c >97% y 5:1 dr 87% ee
3b 91% y 11:1 dr 90% ee
Ph N
R
Dioxane, 60 ºC
3j 59% y 8.4:1 dr 83% ee
TIPSO
Ph 3m 95% y 3:1 dr 87% ee
3n 72% y 6:1 dr 81% ee
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-
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bined isolated values; ee’s were determined by HPLC with a chiral stationary phase column.
the X-ray crystal structures and Johnson-Matthey for generous gifts of palladium salts
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 investigate ruthenium-catalyzed ring closing metathesis strategies 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 homoallylmagnesium 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 differentiated 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 Scheme 4. Further Functionalization of Cycloadduct 3n
REFERENCES
1) 4Å MS, MeOTf MeCN 3n 81% ee 2) THF, -78 ºC BrMg
10 mol% HGII TIPSO
PhH, reflux O 5 68% yield
TIPSO
H
H
H O
6 57% yield 79% ee
In summary, a palladium-catalyzed vinyl-substituted TMM asymmetric cycloaddition has been achieved. Tetrasubstituted cyclopentanes bearing three contiguous stereocenters are synthesized in good yields with good regio-, diastereo- and enantioselectivity. 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 previously examined, allowing reactivity and selectivity that has not been observed prior to this work. Furthermore, these cycloadducts bearing a 1,4-diene and acyl imidazole have been subsequently 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.
ASSOCIATED CONTENT Supporting Information. Detailed experimental details, compound characterization data, and spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected] ACKNOWLEDGMENT
(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 Analogs. 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.; Silverman, 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. (6) Trost, B. M.; Nanninga, T. N.; Satoh, T. J. Am. Chem. Soc. 1985, 107, 721. (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.; Rocamora, 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.; Davankov, 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.; Davankov, V. A.; Reetz, M. T. Adv. Synth. Catal. 2010, 352, 2599. (13) Preliminary studies utilizing N-alkyl substituents on the ligand 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 absolute and relative stereochemistry of the product was determined by the crystal structure of 3e (see Supporting Information). 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 references 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.
We thank the NSF for their generous support of our programs. We thank Dr. Allen Oliver from the University of Notre Dame for
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O AcO
TMS
N
R Ph
N
N Ph N
R Dioxane, 60 ºC
Me Ph
Ph Me
CpPd(! 3-C3H5) L4
O
N
N
P O
Ph
O P
L4
N N Ph
14 examples 3:1 - 11:1 dr 75 - 90% ee
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