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Catalytic Enantioselective Synthesis of Amino Skipped Diynes Paulo H. S. Paioti, Khalil A. Abboud, and Aaron Aponick J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13387 • Publication Date (Web): 08 Feb 2016 Downloaded from http://pubs.acs.org on February 8, 2016
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Catalytic Enantioselective Synthesis of Amino Skipped Diynes Paulo H. S. Paioti,† Khalil A. Abboud,‡ and Aaron Aponick*,† †
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
‡
Center for X-Ray Crystallography, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
Supporting Information Placeholder
ABSTRACT: The Cu-catalyzed synthesis of non-racemic 3-amino skipped diynes via an enantiodetermining C-C bond formation is described using StackPhos as ligand. Despite challenging issues of reactivity and stereoselectivity inherent to these chiral skipped diynes, the reaction tolerates an extremely broad substrate scope with respect to all components and provides the title compounds in excellent enantiomeric excess. The alkyne moieties are demonstrated here to be useful synthetic handles and 3-amino skipped diynes are convenient building blocks for enantioselective synthesis. Natural products assembled by biosynthetic pathways involving hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machinery can possess interesting structures and exhibit potent biological activities.1 Utilizing a combination of the PKS/NRPS modules permits the direct fusion of polyketides and peptides but also facilitates the construction of heterocycles to yield important classes of compounds such as β-lactams (e.g. nocardicins)2 and oxazoles (e.g., rhizoxin)3 among many others.4 Recently, several linear mono- and polyamines exhibiting broad spectrum antibiotic activity have been isolated including the zeamines,5 fabclavines,6 and taveuniamides,7 but their stereochemistry remains unassigned (Figure 1). NH2
NH2
NH2
( )5
R
( )5
1, R= C5H11, zeamines 2, R= CH3, fabclavines
NH2
( )5 Cl
OH
( )5
Cl
R1=
O N R1 H peptides
NHAc NR2 R1
Cl
3, taveuniamide F R2
Commom structural motif Unknown stereochemistry No chemical synthesis
NHAc Me 4 isolated from Microcoleus lyngbyaceus
plete structural assignment of these natural products. Chiral, non-racemic amines are exceedingly important compounds that find use in a myriad of research areas and commercial settings.8 They are often obtained by resolution or chiral auxiliary chemistry9 and catalytic enantioselective methods for their preparation have proven challenging,10 especially when the stereocenter bears two nearly equivalent alkyl groups,11 as observed in 3 and 4.12,13 Recently, very nice examples of enantioselective intermolecular hydroamination have appeared.14 These reactions employ symmetrical olefin starting materials12 or directing groups15 to control regioselectivity. An alternative bond construction would involve CC bond formation, and we envisioned that this may provide a complementary method with a different substrate scope, facilitating the inclusion of groups such as π-bonds that would be useful for further functionalization. In this vein, we sought to prepare 3-amino-1,4-diynes16 by acetylide addition for maximal synthetic flexibility in the positions adjoining the stereogenic center. This would be an extremely demanding reaction with respect to both reactivity and stereoselectivity as many problematic side reactions could be envisioned and the differences between the groups are quite distal from the reaction center with no α-branching to augment selectivity (Figure 2). Herein we report a convergent, highly enantioselective synthesis of versatile, chiral 3-amino skipped diyne building blocks. R3 R1
N
R4
While nature utilizes hybrid PKS/NRPS assembly lines to iteratively build up these structures by stereoselectively introducing the primary amine moieties with concurrent removal of ancillary functional groups, the enantioselective chemical synthesis of stereocenters bearing two highly similar groups is a formidable challenge complicating the com-
N
R4
R1
R2
electronically sterically biased biased Various Synthetic Methods
R3
Me
Figure 1. Linear mono- and polyamine natural products.
R3
R1
N
R4 R2
no bias (R1 similar to R2) Extremely Challenging
R3
N
R2
R1
R4 Potential Complexity-Building Bond Disconnections
5
R2
• Alkynes would provide a versatile synthetic handle • No steric bias to facilitate enantiodetermining bond forming event • Electronically unbiased systems needed for synthetic purposes • Enantioselective synthesis unknown
Figure 2. Chiral 3-amino skipped diynes.
At the outset, considering the large body of literature reporting the addition of nucleophiles to imines and iminium ions, the enantioselective synthesis of diynes 5 by C-C bond formation would be problematic.17 The anticipated difficul-
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ties included addition to the highly electrophilic β-position,18 enamine formation, racemization of the product under the reaction conditions through a highly stabilized carbocation,19 or by the well-known base-catalyzed 1,4-diyne/1-allen-4-yne equilibrium.20 In the racemic sense, the reactivity problems were overcome by generating the electrophile by ionization of N,X-acetals;21 however, few examples incorporate two different alkyne moieties and the stoichiometric activators employed would likely racemize the products of an enantioselective variant. We surmised that all of these issues could be overcome if a catalytic enantioselective reaction employing extremely mild conditions could be developed. To test this hypothesis, ynal 6a, dibenzylamine 7a, and TMS-acetylene 8a were allowed to react in toluene at 0° C for 24h in the presence of 5 mol % of CuBr and 5.5 mol % rac-StackPhos.22 Under these conditions, the diyne 9a was isolated in 20% yield and the remainder of the material was unreacted aldehyde (Table 1, entry 1). This result demonstrated the desired reactivity, but substantial optimization was needed. Employing dichloromethane as solvent, the yield improved to 94% (entry 2). A control reaction without ligand furnished only trace amount of product (entry 3), and with 99% ee (S)-StackPhos, 9a was isolated in 73% yield and 95% ee (entry 4). The yield improved to 85% at ambient temperature and under these conditions 9a was isolated in 94% ee (entry 5), effectively demonstrating that the products could be obtained in both high chemical and optical yield.23
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lates proved to be most reactive, generating the unsaturated GABA analogue 9k 25 in 1h (entries 11, 12), all forming products in high ee’s. Remarkably, changing the alkyne substituents results in only small changes in enantioselectivity. It is possible that having two similar groups may present general practical difficulties for forming stereocenters; but here, since the structural permutations are remote, the scope can be greatly expanded due to spatially diminished steric and electronic perturbations. Table 2. Reaction scope studies. O + HNR2 7a-e + H R1
6a-f
CuBr (5.0 mol%) (S)-StackPhos (5.5 mol%)
R2 8a-f
entry
product, yield
H + Ph
6a
TMS
96
10d
solvent, T, MS 4Å, 24h
Ph
9a
TMS
94
11f 12f,g
yield (%)
ee (%)
1b
PhMe
20
2b
CH2Cl2
5
-
73
95
85
94
c
CH2Cl2
4d
CH2Cl2
5d
CH2Cl2
rt
9k, 93% 9k, 96%
9c, 77%
S
9d, 72%
TMS
96c
N
13
95 TMS
9l, 69%
O NBn2
95 9e, 73%
14
TIPS
9f, 72%
9m, 62% TMS N
96
TMS
c
15
6
Me TsHN
d
TIPS
90
9n, 63%
NBn2 NO2
d
90
N
Ph
NBn2
Ph
N
95
16
Me
Me
d
95h TMS
9o,91%
9g, 86%
Br
NBn2 Me
NO2
7d
a
CuBr (5.0 mol %), ligand (5.5 mol %) brac-StackPhos. c Without ligand. d Ligand = (S)-StackPhos (99% ee).
With optimal conditions established, the scope of the reaction was studied and it was found that this enantioselective transformation is versatile and robust, tolerating different aldehydes, alkynes, and amines. The aromatic group could be substituted (Table 2, entries 1,2) or be heteroaromatic (entry 3), leading to products in 96% ee, 94% ee, and 96% ee, respectively. Reversing the position of the silyl and aryl groups led to the preparation of compound 9e in 95% ee (entry 4). After desilylation 9a and 9e are enantiomers, although both were formed using the same enantiomer of the ligand.24 Two silyl groups or two aromatics could be incorporated (entries 5, 6), aliphatic groups were also well tolerated on both reaction components (entries 7-10), and propio-
O
82 86
O
Ph
5
94
OMe
Ph
NBn2
3
82
NBn2
2
TMS
temp.
Me 9j, 86%
Ph
solvent
0 °C 0 °C 0 °C 0 °C
Me
NBn2
MeO
eea (%)
product, yield
9b, 79%
Br
NBn2
entrya
3
entry
CuBr, StackPhos TMS 8a
R2
9b-p
NBn2
1b
TIPS
+
ee (%)
NBn2
4 O
R1
CH2Cl2, 0°C, MS 4Å, 24h a
Table 1. Optimization studies. HNBn2, 7a
NR2
Ph
96
N
17d
TsHN
84
Ph
9h, 64%
9p, 61% Ph
NBn2
8d 9e,f
Me Ph
86 89
9i, 85% 9i, 65%
N F5
Ph N PPh2
(S)-StackPhos a
b
Determined by chiral HPLC. Absolute stereochemistry determined by Xray crystallography. See SI for full details. cDetermined after desilylation. d Reaction time = 3h. eReaction time = 6h. f Reaction time = 1h. g Reaction temp = -25 °C. hDetermined after Pauson-Khand reaction (Scheme 2).
The aforementioned examples all employed dibenzylamine, but it would be synthetically useful to incorporate other secondary amines, especially compounds with two different amine substituents. To evaluate the reaction scope to
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this end, morpholine, piperidone and amines with different substituents were used. With the symmetric amines, 9l and 9m were isolated in 95% and 90% ee, respectively (entries 13, 14). More challenging, unsymmetrical secondary amines could also be employed in highly enantioselective reactions (entries 15-17), which is exceptionally uncommon and extremely useful.17 As described above, the substrate scope is broad and tolerates different reaction partners by essentially exchanging the groups on the alkyne. This offers flexibility in much the same way as cross coupling reactions where the halide and organometallic can be interchanged to produce a new pair of reactants.26 During studies on the reaction scope, it was observed that synthesis of 9q completely failed when the ynal was osubstituted with a sulfonamide moiety (Scheme 1A). Reaction of 6g with dibenzylamine and phenylacetylene under the standard conditions resulted in an intractable mixture as the aldehyde appears unstable to the reaction conditions.27 However, if the alkyne substituents are exchanged, the reaction proceeds smoothly, delivering ent -9q, in 92% yield and 90% ee (Scheme 1B). Although this alternative substrate pair leads to the enantiomeric product, this is not limiting as both enantiomers of the ligand are available.22 NBn2
O
A.
HNBn2 7a +
CuBr, (S)-StackPhos
H +
Ph
TsHN 6g
8b
B.
Ph
6a
H + TsHN
9q
CuBr, (S)-StackPhos CH2Cl2, MS 4Å 0 °C, 3h
8f
NBn2
K2CO3
Ph
MeCN, 70°C 6h, 67%
TsHN ent-9q
TsN
Ph
10 90% ee
90% ee
B. Chemoselective Pauson-Khand Reaction N Me
( )3
Me
Co2(CO)8 CyNH2 TMS
9o
PhMe, 70°C 2h, 46%
H N Me
O Me
( )3
TMS
11
95% ee
95% ee, dr >20:1
C. Orthogonal Diyne Functionalization NBn2 TIPS
TMS
9f
NBn2
K2CO3 THF : MeOH 92%
TIPS
13
12
I
CuI, PdCl2(PPh3)2 Et3N, rt, 1h 90%
96% ee
96% ee
F
NBn2
NBn2 TBAF, H2O THF, rt, 12h 67% F
15
96% ee
TIPS
D. Synthesis of Chiral Remote Amines Me NBn2 H2, (Ph3P)3RhCl Me
14
Me
THF : MeOH rt, 24h, 80%
9j
F
96% ee
NBn2
Me
16 H2, Pd(OH)2/C MeOH, rt, 7h, 88%
NBn2
+
TsHN
A. Synthesis of 2-methanamine indoles NBn2
0%, complex mixture
HNBn2, 7a O
Ph
CH2Cl2, MS 4Å 0 °C, 3h
potential building block for diversity-oriented synthesis,32 and 15 after further functionalization.33
Ph
TsHN
Me
NHAc
Me
ent-9q
4
92%, 90% ee
isolated from Microcoleus lyngbyaceus
Scheme 1. Alternative reaction partners. The newly synthesized amines offer many positions for further functionalization and should be highly useful synthons. Examples of the synthetic utility are included in Scheme 2. The 2-substituted indole 10 was prepared via hydroamination of ent -9q using K2CO3 without loss of ee (Scheme 2A). Non-racemic C2-methanamine substituted indole is an important natural product motif28 that is found in lead compounds broadly utilized in medicinal chemistry,29 but these compounds are difficult to prepare without C3 substituents.30 The substituents on the nitrogen can also be utilized, which is especially useful when two different groups are present. Chemoselective Pauson-Khand reaction of 9o generates the heterocycle 11 as a single diastereomer (Scheme 2B).31 The N-allyl group reacts preferentially with the alkyl substituted alkyne and no reaction involving the silyl substituted alkyne is observed. The silyl substituents can be removed and different substituents appended, although broad substrate scope may preclude the need for this (Scheme 2C). The amine 9f was desilylated to form 13, a
AcCl Et3N DCM, rt, 2h, 88%
Me
NH2
Me
17
Scheme 2. Versatility of 3-amino skipped diynes. Additionally, the simple natural product 4 34 (Figure 1), which was isolated from marine cyanobacteria Microcoleus lyngbyaceus,34 was prepared in a straightforward manner. Starting from diyne 9j, 16 and 17 were prepared after simple reduction of the acetylenes using Wilkinson’s catalyst and cleavage of the benzyl groups (Scheme 2D). The free amine 17 was then acylated to complete the synthesis of the 4. To date, none of the taveuniamides have been prepared in enantioenriched form, but these and the polyamines should be accessible using this methodology to establish the challenging stereocenters. In summary, we have disclosed the first enantioselective preparation of amino skipped diynes, a class of chiral molecules with minimal differences in two of the substituents rendering them chiral. Despite this challenging issue and potential reactivity issues, a Cu(I)-StackPhos catalyzed C-C bond formation proved to be rapid and high yielding under very mild conditions while tolerating an exceptionally broad substrate scope. Due to the unique structural features of
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chiral 3-amino skipped diynes, we believe these building blocks will find application in a variety of areas and to this end we have demonstrated several preliminary applications. The method should enable the synthesis of more complex primary amine and polyamine natural products. These studies, as well as detailed mechanistic investigations are ongoing in our laboratories and will be reported in due course. ASSOCIATED CONTENT Supporting Information. Experimental procedures and spectral data for all new compounds. Crystallographic data for ent-9b (CIF). This material is available free of charge via the Internet at http://pubs.acs.org AUTHOR INFORMATION Corresponding Author
*[email protected] Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT We thank the National Science Foundation (CHE-1362498) and the University of Florida for their generous support of our programs. REFERENCES (1) Fisch, K. M. RSC Adv. 2013, 3, 18228. Boettger, D.; Hertweck, C. ChemBioChem 2013, 14, 28. (2) Gaudelli, N. M.; D. H. Long, D. H.; Townsend, C. A. Nature, 2015, 520, 383. (3) (a) Partida-Martinez, L. P.; Hertweck, C. Nature 2005, 437, 88. (b) Partida-Martinez, L. P.; Hertweck, C. ChemBioChem 2007, 8, 41. (4) Pang, B.; Wang, M.; Liu, W. Nat. Prod. Rep. 2015, DOI: 10.1039/C5NP00095E. (5) Wu, J.; Zhang, H-B.; Xu, J-L.; Cox, R.J.; Simpson, T. J.; Zhang, LH. Chem.Commun. 2010, 46, 333. (6) Fuchs, S. W.; Grundmann, F.; Kurz, M.; Kaiser, M.; Bode, H. B. ChemBioChem 2014, 15, 512. (7) (a) Tan, L. T. Phytochemistry 2007, 68, 954. (b) Williamson, R. T.; Singh, I. P.; Gerwick, W. H. Tetrahedron 2004, 60, 7025. (8) For chiral amines in pharmaceuticals see: (a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348. In natural products: (b) Fattorusso, E.; Taglialatela-Scafati, O. Modern Alkaloids: Structure, Isolation, Synthesis and Biology (Wiley, 2008). In catalysis: (c) Zhou, Q-L. Privileged Chiral Ligands and Catalysts (Wiley, 2011). (d) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis (Springer, 1999). In materials science and polymers: (e) Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3. Levine, M.; Kenesky, C. S.; Zheng, S.; Quinn, J.; Breslow, R. Tetrahedron Lett. 2008, 49, 5746. In bioconjugates: (f) Romanini, D. W.; Francis, M. B. Bioconjugate Chem. 2008, 19, 153. (g) Morales, A. R.; Schafer-Hales, K. J.; Marcus, A. I.; Belfield, K. D. Bioconjugate Chem. 2008, 19, 2559. (9) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (b) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77. (10) (a) Li, W.; Zhang, X. Stereoselective Formation of Amines (Springer, 2014). (b) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley, 2010).
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(11 ) The catalytic enantioselective synthesis of diarylmethylamines has been extensively explored. For a review see: (a) Schmidt, F.; Stemmler, R.T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454. For recent leading references see: (b) Chu, L.; Wang, X.-C.; Moore, C.E.; Rheingold, A.L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 16344. (c) Zhao, G.-Z.; Sipos, G.; Salvador, A.; Ou, A.; Gao, P.; Skelton, B.W.; Dorta, R. Adv. Synth. Catal. DOI: 10.1002/adsc.201500975 and references cited therein.
(12) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62. (13) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (14) Pirnot, M. T.; Wang, M-T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2016, 55, 48. (15) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2016, 55, 776. (16) Enantioselective preparation of skipped diynes is scarce: (a)Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. (b) Tedeschi, C.; Saccavini, C.; Maurette, L.; Soleilhavoup, M.; Chauvin, R. J. Organomet. Chem. 2003, 670, 151. (17) (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (b) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790. (c) Zhao, C.; Seidel, D. J. Am. Chem. Soc. 2015, 137, 4650. (d) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437. (e) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763. (18) (a) Zhou, L.; Jiang, H.-F.; Li, C.-J. Adv. Synth. Catal. 2008, 350, 2226. (b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (c) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328. (d) Knopfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054. (19) Naredla, R. R.; Klumpp, D. A. Chem. Rev. 2013, 113, 6905. (20) (a) Mathai, I. M.; Taniguchi, H.; Miller, S. I. J. Am. Chem. Soc. 1967, 89, 115. (b) Gensler, W. J.; Casella, J., Jr. J. Am. Chem. Soc. 1958, 80, 1376. (21) For racemic synthesis of 3-amino skipped diynes see: (a) Gommermann, N.; Koradin, C.; Knochel, P. Synthesis 2002, 14, 2143. (b) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968. (c) Korbad, B. L.; Lee S-H. Eur. J. Org. Chem. 2014, 5089. Yao, B.; Zhang, Y.; Li, Y. J. Org. Chem. 2010, 75, 4554. (22) (a) Cardoso, F. S. P.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2013, 135, 14548. (b) Pappoppula, M., Cardoso, F. S. P.; Garrett, B. O.; Aponick, A. Angew. Chem. Int. Ed. 2015, 54, 15202. (c) Pappoppula, M., Aponick, A. Angew. Chem. Int. Ed. 2015, 54, 15827. (23) Differences in reactivity are observed when rac-ligand is employed. The mechanistic underpinnings for this are under investigation and will be reported in due course. See Supporting Information for further details. (24)(a) Braga, A. L.; Lüdtke, D. S.; Vargas, F.; Paixão, M. W. A. Chem. Commun. 2005, 19, 2512. Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976. (b) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444. (25) (a) Kudirka, R.; Devine, S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew. Chem. Int. Ed. 2009, 48, 3677. (b) Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281. (26) Prieto, M.; Zurita, E., Rosa, E.; Munoz, L.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 2004, 69, 6812. (27) (a) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gomez-Bengoa, E.; Garcia, J. M. J. Am. Chem. Soc. 2004, 126, 9188. (b) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (28) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (29)(a) Yoshihiro, B.; Ryoma, H.; Ryosuke, T. WO2009110520 (A1), September 11, 2009. (b) Gurmit, G.; Vibbha, O. WO2008059238 (A1), May 22, 2008. (30) (a) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012, 134, 17474. (b) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009,
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74, 7052. (c) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086. (d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558. (31) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J. 2003, 9, 2797.
CuBr (S)-StackPhos
O +
HNR2 + H
R1 R1,
R2
= Alkyl, Aryl, Silyl, Propiolate
(32) Burke, M.D.; Schreiber, S.L. Angew. Chem. Int. Ed. 2004, 43, 46. (33) (a) Beal, D. M.; Jones, L. H. Angew. Chem. Int. Ed. 2012, 51, 6320. (b) Yin, H.; Hamilton, A. D. Angew. Chem. Int. Ed. 2005, 44, 4130. (34) (a) Tan, L. T. Phytochemistry 2007, 68, 954. (b) Orsini, M. A.; Pannell, L. K.; Erickson, K. L. J. Nat. Prod. 2001, 64, 572.
R2
CH2Cl2, MS 4Å
NR2 R1
R1, R2: No steric or electronic bias required R2
Up to 96% ee
R2: Can be same or different groups
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Communication
Catalytic Enantioselective Synthesis of Amino Skipped Diynes Paulo H. S. Paioti, Khalil A. Abboud, and Aaron Aponick J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13387 • Publication Date (Web): 08 Feb 2016 Downloaded from http://pubs.acs.org on February 8, 2016
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Catalytic Enantioselective Synthesis of Amino Skipped Diynes Paulo H. S. Paioti,† Khalil A. Abboud,‡ and Aaron Aponick*,† †
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
‡
Center for X-Ray Crystallography, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
Supporting Information Placeholder
ABSTRACT: The Cu-catalyzed synthesis of non-racemic 3-amino skipped diynes via an enantiodetermining C-C bond formation is described using StackPhos as ligand. Despite challenging issues of reactivity and stereoselectivity inherent to these chiral skipped diynes, the reaction tolerates an extremely broad substrate scope with respect to all components and provides the title compounds in excellent enantiomeric excess. The alkyne moieties are demonstrated here to be useful synthetic handles and 3-amino skipped diynes are convenient building blocks for enantioselective synthesis. Natural products assembled by biosynthetic pathways involving hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machinery can possess interesting structures and exhibit potent biological activities.1 Utilizing a combination of the PKS/NRPS modules permits the direct fusion of polyketides and peptides but also facilitates the construction of heterocycles to yield important classes of compounds such as β-lactams (e.g. nocardicins)2 and oxazoles (e.g., rhizoxin)3 among many others.4 Recently, several linear mono- and polyamines exhibiting broad spectrum antibiotic activity have been isolated including the zeamines,5 fabclavines,6 and taveuniamides,7 but their stereochemistry remains unassigned (Figure 1). NH2
NH2
NH2
( )5
R
( )5
1, R= C5H11, zeamines 2, R= CH3, fabclavines
NH2
( )5 Cl
OH
( )5
Cl
R1=
O N R1 H peptides
NHAc NR2 R1
Cl
3, taveuniamide F R2
Commom structural motif Unknown stereochemistry No chemical synthesis
NHAc Me 4 isolated from Microcoleus lyngbyaceus
plete structural assignment of these natural products. Chiral, non-racemic amines are exceedingly important compounds that find use in a myriad of research areas and commercial settings.8 They are often obtained by resolution or chiral auxiliary chemistry9 and catalytic enantioselective methods for their preparation have proven challenging,10 especially when the stereocenter bears two nearly equivalent alkyl groups,11 as observed in 3 and 4.12,13 Recently, very nice examples of enantioselective intermolecular hydroamination have appeared.14 These reactions employ symmetrical olefin starting materials12 or directing groups15 to control regioselectivity. An alternative bond construction would involve CC bond formation, and we envisioned that this may provide a complementary method with a different substrate scope, facilitating the inclusion of groups such as π-bonds that would be useful for further functionalization. In this vein, we sought to prepare 3-amino-1,4-diynes16 by acetylide addition for maximal synthetic flexibility in the positions adjoining the stereogenic center. This would be an extremely demanding reaction with respect to both reactivity and stereoselectivity as many problematic side reactions could be envisioned and the differences between the groups are quite distal from the reaction center with no α-branching to augment selectivity (Figure 2). Herein we report a convergent, highly enantioselective synthesis of versatile, chiral 3-amino skipped diyne building blocks. R3 R1
N
R4
While nature utilizes hybrid PKS/NRPS assembly lines to iteratively build up these structures by stereoselectively introducing the primary amine moieties with concurrent removal of ancillary functional groups, the enantioselective chemical synthesis of stereocenters bearing two highly similar groups is a formidable challenge complicating the com-
N
R4
R1
R2
electronically sterically biased biased Various Synthetic Methods
R3
Me
Figure 1. Linear mono- and polyamine natural products.
R3
R1
N
R4 R2
no bias (R1 similar to R2) Extremely Challenging
R3
N
R2
R1
R4 Potential Complexity-Building Bond Disconnections
5
R2
• Alkynes would provide a versatile synthetic handle • No steric bias to facilitate enantiodetermining bond forming event • Electronically unbiased systems needed for synthetic purposes • Enantioselective synthesis unknown
Figure 2. Chiral 3-amino skipped diynes.
At the outset, considering the large body of literature reporting the addition of nucleophiles to imines and iminium ions, the enantioselective synthesis of diynes 5 by C-C bond formation would be problematic.17 The anticipated difficul-
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ties included addition to the highly electrophilic β-position,18 enamine formation, racemization of the product under the reaction conditions through a highly stabilized carbocation,19 or by the well-known base-catalyzed 1,4-diyne/1-allen-4-yne equilibrium.20 In the racemic sense, the reactivity problems were overcome by generating the electrophile by ionization of N,X-acetals;21 however, few examples incorporate two different alkyne moieties and the stoichiometric activators employed would likely racemize the products of an enantioselective variant. We surmised that all of these issues could be overcome if a catalytic enantioselective reaction employing extremely mild conditions could be developed. To test this hypothesis, ynal 6a, dibenzylamine 7a, and TMS-acetylene 8a were allowed to react in toluene at 0° C for 24h in the presence of 5 mol % of CuBr and 5.5 mol % rac-StackPhos.22 Under these conditions, the diyne 9a was isolated in 20% yield and the remainder of the material was unreacted aldehyde (Table 1, entry 1). This result demonstrated the desired reactivity, but substantial optimization was needed. Employing dichloromethane as solvent, the yield improved to 94% (entry 2). A control reaction without ligand furnished only trace amount of product (entry 3), and with 99% ee (S)-StackPhos, 9a was isolated in 73% yield and 95% ee (entry 4). The yield improved to 85% at ambient temperature and under these conditions 9a was isolated in 94% ee (entry 5), effectively demonstrating that the products could be obtained in both high chemical and optical yield.23
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lates proved to be most reactive, generating the unsaturated GABA analogue 9k 25 in 1h (entries 11, 12), all forming products in high ee’s. Remarkably, changing the alkyne substituents results in only small changes in enantioselectivity. It is possible that having two similar groups may present general practical difficulties for forming stereocenters; but here, since the structural permutations are remote, the scope can be greatly expanded due to spatially diminished steric and electronic perturbations. Table 2. Reaction scope studies. O + HNR2 7a-e + H R1
6a-f
CuBr (5.0 mol%) (S)-StackPhos (5.5 mol%)
R2 8a-f
entry
product, yield
H + Ph
6a
TMS
96
10d
solvent, T, MS 4Å, 24h
Ph
9a
TMS
94
11f 12f,g
yield (%)
ee (%)
1b
PhMe
20
2b
CH2Cl2
5
-
73
95
85
94
c
CH2Cl2
4d
CH2Cl2
5d
CH2Cl2
rt
9k, 93% 9k, 96%
9c, 77%
S
9d, 72%
TMS
96c
N
13
95 TMS
9l, 69%
O NBn2
95 9e, 73%
14
TIPS
9f, 72%
9m, 62% TMS N
96
TMS
c
15
6
Me TsHN
d
TIPS
90
9n, 63%
NBn2 NO2
d
90
N
Ph
NBn2
Ph
N
95
16
Me
Me
d
95h TMS
9o,91%
9g, 86%
Br
NBn2 Me
NO2
7d
a
CuBr (5.0 mol %), ligand (5.5 mol %) brac-StackPhos. c Without ligand. d Ligand = (S)-StackPhos (99% ee).
With optimal conditions established, the scope of the reaction was studied and it was found that this enantioselective transformation is versatile and robust, tolerating different aldehydes, alkynes, and amines. The aromatic group could be substituted (Table 2, entries 1,2) or be heteroaromatic (entry 3), leading to products in 96% ee, 94% ee, and 96% ee, respectively. Reversing the position of the silyl and aryl groups led to the preparation of compound 9e in 95% ee (entry 4). After desilylation 9a and 9e are enantiomers, although both were formed using the same enantiomer of the ligand.24 Two silyl groups or two aromatics could be incorporated (entries 5, 6), aliphatic groups were also well tolerated on both reaction components (entries 7-10), and propio-
O
82 86
O
Ph
5
94
OMe
Ph
NBn2
3
82
NBn2
2
TMS
temp.
Me 9j, 86%
Ph
solvent
0 °C 0 °C 0 °C 0 °C
Me
NBn2
MeO
eea (%)
product, yield
9b, 79%
Br
NBn2
entrya
3
entry
CuBr, StackPhos TMS 8a
R2
9b-p
NBn2
1b
TIPS
+
ee (%)
NBn2
4 O
R1
CH2Cl2, 0°C, MS 4Å, 24h a
Table 1. Optimization studies. HNBn2, 7a
NR2
Ph
96
N
17d
TsHN
84
Ph
9h, 64%
9p, 61% Ph
NBn2
8d 9e,f
Me Ph
86 89
9i, 85% 9i, 65%
N F5
Ph N PPh2
(S)-StackPhos a
b
Determined by chiral HPLC. Absolute stereochemistry determined by Xray crystallography. See SI for full details. cDetermined after desilylation. d Reaction time = 3h. eReaction time = 6h. f Reaction time = 1h. g Reaction temp = -25 °C. hDetermined after Pauson-Khand reaction (Scheme 2).
The aforementioned examples all employed dibenzylamine, but it would be synthetically useful to incorporate other secondary amines, especially compounds with two different amine substituents. To evaluate the reaction scope to
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this end, morpholine, piperidone and amines with different substituents were used. With the symmetric amines, 9l and 9m were isolated in 95% and 90% ee, respectively (entries 13, 14). More challenging, unsymmetrical secondary amines could also be employed in highly enantioselective reactions (entries 15-17), which is exceptionally uncommon and extremely useful.17 As described above, the substrate scope is broad and tolerates different reaction partners by essentially exchanging the groups on the alkyne. This offers flexibility in much the same way as cross coupling reactions where the halide and organometallic can be interchanged to produce a new pair of reactants.26 During studies on the reaction scope, it was observed that synthesis of 9q completely failed when the ynal was osubstituted with a sulfonamide moiety (Scheme 1A). Reaction of 6g with dibenzylamine and phenylacetylene under the standard conditions resulted in an intractable mixture as the aldehyde appears unstable to the reaction conditions.27 However, if the alkyne substituents are exchanged, the reaction proceeds smoothly, delivering ent -9q, in 92% yield and 90% ee (Scheme 1B). Although this alternative substrate pair leads to the enantiomeric product, this is not limiting as both enantiomers of the ligand are available.22 NBn2
O
A.
HNBn2 7a +
CuBr, (S)-StackPhos
H +
Ph
TsHN 6g
8b
B.
Ph
6a
H + TsHN
9q
CuBr, (S)-StackPhos CH2Cl2, MS 4Å 0 °C, 3h
8f
NBn2
K2CO3
Ph
MeCN, 70°C 6h, 67%
TsHN ent-9q
TsN
Ph
10 90% ee
90% ee
B. Chemoselective Pauson-Khand Reaction N Me
( )3
Me
Co2(CO)8 CyNH2 TMS
9o
PhMe, 70°C 2h, 46%
H N Me
O Me
( )3
TMS
11
95% ee
95% ee, dr >20:1
C. Orthogonal Diyne Functionalization NBn2 TIPS
TMS
9f
NBn2
K2CO3 THF : MeOH 92%
TIPS
13
12
I
CuI, PdCl2(PPh3)2 Et3N, rt, 1h 90%
96% ee
96% ee
F
NBn2
NBn2 TBAF, H2O THF, rt, 12h 67% F
15
96% ee
TIPS
D. Synthesis of Chiral Remote Amines Me NBn2 H2, (Ph3P)3RhCl Me
14
Me
THF : MeOH rt, 24h, 80%
9j
F
96% ee
NBn2
Me
16 H2, Pd(OH)2/C MeOH, rt, 7h, 88%
NBn2
+
TsHN
A. Synthesis of 2-methanamine indoles NBn2
0%, complex mixture
HNBn2, 7a O
Ph
CH2Cl2, MS 4Å 0 °C, 3h
potential building block for diversity-oriented synthesis,32 and 15 after further functionalization.33
Ph
TsHN
Me
NHAc
Me
ent-9q
4
92%, 90% ee
isolated from Microcoleus lyngbyaceus
Scheme 1. Alternative reaction partners. The newly synthesized amines offer many positions for further functionalization and should be highly useful synthons. Examples of the synthetic utility are included in Scheme 2. The 2-substituted indole 10 was prepared via hydroamination of ent -9q using K2CO3 without loss of ee (Scheme 2A). Non-racemic C2-methanamine substituted indole is an important natural product motif28 that is found in lead compounds broadly utilized in medicinal chemistry,29 but these compounds are difficult to prepare without C3 substituents.30 The substituents on the nitrogen can also be utilized, which is especially useful when two different groups are present. Chemoselective Pauson-Khand reaction of 9o generates the heterocycle 11 as a single diastereomer (Scheme 2B).31 The N-allyl group reacts preferentially with the alkyl substituted alkyne and no reaction involving the silyl substituted alkyne is observed. The silyl substituents can be removed and different substituents appended, although broad substrate scope may preclude the need for this (Scheme 2C). The amine 9f was desilylated to form 13, a
AcCl Et3N DCM, rt, 2h, 88%
Me
NH2
Me
17
Scheme 2. Versatility of 3-amino skipped diynes. Additionally, the simple natural product 4 34 (Figure 1), which was isolated from marine cyanobacteria Microcoleus lyngbyaceus,34 was prepared in a straightforward manner. Starting from diyne 9j, 16 and 17 were prepared after simple reduction of the acetylenes using Wilkinson’s catalyst and cleavage of the benzyl groups (Scheme 2D). The free amine 17 was then acylated to complete the synthesis of the 4. To date, none of the taveuniamides have been prepared in enantioenriched form, but these and the polyamines should be accessible using this methodology to establish the challenging stereocenters. In summary, we have disclosed the first enantioselective preparation of amino skipped diynes, a class of chiral molecules with minimal differences in two of the substituents rendering them chiral. Despite this challenging issue and potential reactivity issues, a Cu(I)-StackPhos catalyzed C-C bond formation proved to be rapid and high yielding under very mild conditions while tolerating an exceptionally broad substrate scope. Due to the unique structural features of
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chiral 3-amino skipped diynes, we believe these building blocks will find application in a variety of areas and to this end we have demonstrated several preliminary applications. The method should enable the synthesis of more complex primary amine and polyamine natural products. These studies, as well as detailed mechanistic investigations are ongoing in our laboratories and will be reported in due course. ASSOCIATED CONTENT Supporting Information. Experimental procedures and spectral data for all new compounds. Crystallographic data for ent-9b (CIF). This material is available free of charge via the Internet at http://pubs.acs.org AUTHOR INFORMATION Corresponding Author
*[email protected] Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT We thank the National Science Foundation (CHE-1362498) and the University of Florida for their generous support of our programs. REFERENCES (1) Fisch, K. M. RSC Adv. 2013, 3, 18228. Boettger, D.; Hertweck, C. ChemBioChem 2013, 14, 28. (2) Gaudelli, N. M.; D. H. Long, D. H.; Townsend, C. A. Nature, 2015, 520, 383. (3) (a) Partida-Martinez, L. P.; Hertweck, C. Nature 2005, 437, 88. (b) Partida-Martinez, L. P.; Hertweck, C. ChemBioChem 2007, 8, 41. (4) Pang, B.; Wang, M.; Liu, W. Nat. Prod. Rep. 2015, DOI: 10.1039/C5NP00095E. (5) Wu, J.; Zhang, H-B.; Xu, J-L.; Cox, R.J.; Simpson, T. J.; Zhang, LH. Chem.Commun. 2010, 46, 333. (6) Fuchs, S. W.; Grundmann, F.; Kurz, M.; Kaiser, M.; Bode, H. B. ChemBioChem 2014, 15, 512. (7) (a) Tan, L. T. Phytochemistry 2007, 68, 954. (b) Williamson, R. T.; Singh, I. P.; Gerwick, W. H. Tetrahedron 2004, 60, 7025. (8) For chiral amines in pharmaceuticals see: (a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348. In natural products: (b) Fattorusso, E.; Taglialatela-Scafati, O. Modern Alkaloids: Structure, Isolation, Synthesis and Biology (Wiley, 2008). In catalysis: (c) Zhou, Q-L. Privileged Chiral Ligands and Catalysts (Wiley, 2011). (d) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis (Springer, 1999). In materials science and polymers: (e) Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3. Levine, M.; Kenesky, C. S.; Zheng, S.; Quinn, J.; Breslow, R. Tetrahedron Lett. 2008, 49, 5746. In bioconjugates: (f) Romanini, D. W.; Francis, M. B. Bioconjugate Chem. 2008, 19, 153. (g) Morales, A. R.; Schafer-Hales, K. J.; Marcus, A. I.; Belfield, K. D. Bioconjugate Chem. 2008, 19, 2559. (9) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (b) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77. (10) (a) Li, W.; Zhang, X. Stereoselective Formation of Amines (Springer, 2014). (b) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley, 2010).
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(11 ) The catalytic enantioselective synthesis of diarylmethylamines has been extensively explored. For a review see: (a) Schmidt, F.; Stemmler, R.T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454. For recent leading references see: (b) Chu, L.; Wang, X.-C.; Moore, C.E.; Rheingold, A.L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 16344. (c) Zhao, G.-Z.; Sipos, G.; Salvador, A.; Ou, A.; Gao, P.; Skelton, B.W.; Dorta, R. Adv. Synth. Catal. DOI: 10.1002/adsc.201500975 and references cited therein.
(12) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62. (13) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (14) Pirnot, M. T.; Wang, M-T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2016, 55, 48. (15) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2016, 55, 776. (16) Enantioselective preparation of skipped diynes is scarce: (a)Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. (b) Tedeschi, C.; Saccavini, C.; Maurette, L.; Soleilhavoup, M.; Chauvin, R. J. Organomet. Chem. 2003, 670, 151. (17) (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (b) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790. (c) Zhao, C.; Seidel, D. J. Am. Chem. Soc. 2015, 137, 4650. (d) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437. (e) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763. (18) (a) Zhou, L.; Jiang, H.-F.; Li, C.-J. Adv. Synth. Catal. 2008, 350, 2226. (b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (c) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328. (d) Knopfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054. (19) Naredla, R. R.; Klumpp, D. A. Chem. Rev. 2013, 113, 6905. (20) (a) Mathai, I. M.; Taniguchi, H.; Miller, S. I. J. Am. Chem. Soc. 1967, 89, 115. (b) Gensler, W. J.; Casella, J., Jr. J. Am. Chem. Soc. 1958, 80, 1376. (21) For racemic synthesis of 3-amino skipped diynes see: (a) Gommermann, N.; Koradin, C.; Knochel, P. Synthesis 2002, 14, 2143. (b) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968. (c) Korbad, B. L.; Lee S-H. Eur. J. Org. Chem. 2014, 5089. Yao, B.; Zhang, Y.; Li, Y. J. Org. Chem. 2010, 75, 4554. (22) (a) Cardoso, F. S. P.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2013, 135, 14548. (b) Pappoppula, M., Cardoso, F. S. P.; Garrett, B. O.; Aponick, A. Angew. Chem. Int. Ed. 2015, 54, 15202. (c) Pappoppula, M., Aponick, A. Angew. Chem. Int. Ed. 2015, 54, 15827. (23) Differences in reactivity are observed when rac-ligand is employed. The mechanistic underpinnings for this are under investigation and will be reported in due course. See Supporting Information for further details. (24)(a) Braga, A. L.; Lüdtke, D. S.; Vargas, F.; Paixão, M. W. A. Chem. Commun. 2005, 19, 2512. Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976. (b) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444. (25) (a) Kudirka, R.; Devine, S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew. Chem. Int. Ed. 2009, 48, 3677. (b) Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281. (26) Prieto, M.; Zurita, E., Rosa, E.; Munoz, L.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 2004, 69, 6812. (27) (a) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gomez-Bengoa, E.; Garcia, J. M. J. Am. Chem. Soc. 2004, 126, 9188. (b) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (28) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (29)(a) Yoshihiro, B.; Ryoma, H.; Ryosuke, T. WO2009110520 (A1), September 11, 2009. (b) Gurmit, G.; Vibbha, O. WO2008059238 (A1), May 22, 2008. (30) (a) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012, 134, 17474. (b) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009,
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74, 7052. (c) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086. (d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558. (31) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J. 2003, 9, 2797.
CuBr (S)-StackPhos
O +
HNR2 + H
R1 R1,
R2
= Alkyl, Aryl, Silyl, Propiolate
(32) Burke, M.D.; Schreiber, S.L. Angew. Chem. Int. Ed. 2004, 43, 46. (33) (a) Beal, D. M.; Jones, L. H. Angew. Chem. Int. Ed. 2012, 51, 6320. (b) Yin, H.; Hamilton, A. D. Angew. Chem. Int. Ed. 2005, 44, 4130. (34) (a) Tan, L. T. Phytochemistry 2007, 68, 954. (b) Orsini, M. A.; Pannell, L. K.; Erickson, K. L. J. Nat. Prod. 2001, 64, 572.
R2
CH2Cl2, MS 4Å
NR2 R1
R1, R2: No steric or electronic bias required R2
Up to 96% ee
R2: Can be same or different groups
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