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#-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation Joel F. Hooper, Sangwon Seo, Fiona R. Truscott, James D. Neuhaus, and Michael C. Willis J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11892 • Publication Date (Web): 15 Jan 2016 Downloaded from http://pubs.acs.org on January 28, 2016
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Journal of the American Chemical Society
α-Amino Aldehydes as Readily Available Chiral Aldehydes for RhCatalyzed Alkyne Hydroacylation Joel F. Hooper,† Sangwon Seo,† Fiona R. Truscott, James D. Neuhaus and Michael C. Willis* Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. ABSTRACT: Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance and with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine and cysteine were successfully employed, as was an enantiomerically enriched α-OMTMaldehyde derived from phenyl lactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine.
INTRODUCTION Alkene and alkyne hydroacylation reactions represent powerful methods for the preparation of ketones and 1 enones, respectively. These processes offer an atom economical and, in many cases, highly efficient method for the construction of carbon-carbon bonds using a variety 2 of transition metal and also non-metal catalysts. Reactions that achieve high levels of regio- and enantioselec3,4 tivity have been developed, and applications to target 5 synthesis are being reported. Despite the advent of a number of non-chelation controlled hydroacylation processes,6-9 the sub-class of intermolecular hydroacylation (HA) reactions that has enjoyed most success, is that based on some form of sub10-14 strate chelation, be it originating from the aldehyde, or 15 alkene or alkyne. A consequence of such a strategy is that the coordinating group needed to achieve the desired reactivity and selectivity is necessarily present in both the substrate and the product. Methods that utilize the coordinating group directly in a subsequent transformation, resulting in “traceless” processes, go someway to address16 ing these limitations. However, a more attractive scenario would be one in which the coordinating group was a simple, useful substituent the presence of which would be desired in the final product. In this context, the ability to exploit a simple amino-group would be appealing. Although aniline-derived benzaldehyde-type substrates have recently been reported as effective substrates for intermo17a 17b lecular HA reactions, by both us, and others, these substrates by their nature are limited to aromatic examples. Alkyl aldehydes featuring amino-substituents are notable by their absence in the HA literature, presumably a consequence of their strong-coordinating ability and basic character. Conversely, these are precisely the prop-
erties that result in amino groups being so prevalent in bioactive molecules.18 The α-amino carbonyl motif is present in a number of 19 medicinal agents and natural products (Scheme 1), and features in intermediates for the synthesis of heterocycles and in particular, enantiomerically enriched amino alco20 hols. To target these important structures we were attracted to the use of naturally occurring α-amino acids as a readily available feedstock for chiral amino aldehydes to use in HA reactions (eq 1, Scheme 1). Although enantiose4 lective HA reactions have been reported, examples of enantioenriched aldehydes being employed as substrates 15a,21 in intermolecular reactions are scarce. Given the mild reaction conditions employed with our recently reported, 22 highly active small-bite-angle catalysts, we were confident that we should be able to maintain the enantiomeric purity of such aldehydes in HA reactions. In this Article we show that it is possible to utilize α-amino-substituted alkyl aldehydes in HA reactions, and describe the application of chiral α-amino aldehydes as effective substrates for the synthesis of synthetically appealing chiral α-amino enones.
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Scheme 1. The α-amino ketone motif in biologically relevant molecules, together with a Rh-catalyzed hydroacylation route exploiting amino acids to access α-amino enones (eq 1). O O
NHMe
F
Cl Ketamine (anaesthetic) O NH 2
S
O
O Effient (antiplatelet)
H N
Ph
O N
CO 2H O O Ph Keto-ACE (hypertension)
Cathinone (amphetamine)
O
O
O R
OH NH 2
R PG
H N
α-amino acids abundant feedstock, chiral, diverse substituents
Me
Me Amfepramone (appetite suppressant)
Me
Me
R
Me
Rh(I) cat.
R
R1 PG
R2 hydroacylation
mild reaction conditions, functional group tolerant
R1 (1) N
R2
α-amino enones valuable synthetic building block
RESULTS AND DISCUSSION We have previously shown that non-chiral α-hydroxy aldehydes could be effectively employed in HA reactions provided that the alcohol was protected as a methylthi23 omethyl (MTM) ether. We postulated that the corresponding MTM-protected amino aldehydes should also be viable HA substrates, with the MTM-group functioning as a simple, removable, chelating-substituent. Using a glycine derivative, we quickly established that both a MTM group and an electron-withdrawing protecting group were necessarily to achieve reactivity (Scheme 2). For example, aldehyde 1a, featuring only a Cbz-protecting group on the amine, was essentially inert in a reaction with 1-octyne and a Rh(I)/dcpm catalyst, delivering only trace quantities of the desired HA adduct (2a). Aldehyde 1b, combining a Cbz-group with a MOM-group on the Natom, was similarly unreactive. For both of these substrates the majority of the starting aldehydes were recovered, suggesting that reductive-decarbonylation generates a non-active Rh-complex. However, aldehydes 3a and 3b, featuring a MTM-group and either a Cbz or Ts group, respectively, delivered the desired enones (4a,b) in good yields. We attribute the success of the MTM-bearing aldehydes to the S-atom both directing the Rh-complex to the aldehyde C-H bond for rapid oxidative addition, and also stabilising the resultant acyl rhodium hydride intermediate towards reductive-decarbonylation.22a,b The corresponding aldehyde bearing only a MTM group, but without an accompanying electron-withdrawing group was unstable and could not be isolated in pure form.
O
C6H13
[Rh(nbd) 2]BF4 (5 mol%) dcpm (5 mol%)
H 1a, R = H 1b, R = MOM
MeS
O
N N
Cbz
R N
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O N
H 3a, R = Cbz 3b, R = Ts
acetone, 55 °C
Cbz
R N
O
C6H13 2a, R = H, traces 2b, R = MOM, traces
[Rh(nbd) 2]BF4 (5 mol%) MeS O C 6H13 dcpm (5 mol%) N R C6H13 acetone, 55 °C 4a, R = Cbz, 92% 4b, R = Ts, 70%
With the key reactivity principle in place, we next explored the scope of the alkyne component in combination with aldehyde 3a (Table 1). In all cases, a catalyst generated from the combination of [Rh(nbd)2]BF4 and the bisphosphine ligand dcpm, was employed. Both linear and branched aliphatic alkynes (entries 1 - 3) as well as carbocyclic alkynes (entries 4 and 5) could be employed. Aromatic alkynes, including a 3-thiophene example, were excellent substrates (entries 6, 7 and 8), giving the enone products in high yields. The exceptional functional group tolerance of this reaction was demonstrated through the use of a ferrrocenyl (entry 9), enyne (entry 10), alkyl iodide (entry 11) and unprotected alcohol (entry 12) substrates, all giving the corresponding products in good yields. Table 1. Alkyne scope in hydroacylation reactions with aldehyde 3a.a
Cbz
MTM O N
R
[Rh(nbd) 2]BF 4 (5 mol%) dcpm (5 mol%)
H
acetone, 55 °C
3a
entry
alkyne
yield
entry
Cbz
alkyne
7
73%
8
80%
9
4
87%
10
5
75%
11
6
99%
12
Ph
2 Me
3
Me
yield
OMe
94%
Me
R
4c-n
Me
1
MTM O N
99%
S
76%
Fe
93% 75% I
3
Me OH
86% 71%
a
Reaction conditions: 3a (1.0 equiv), alkyne (1.5 equiv), [Rh(nbd)2]BF4 (5 mol%), dcpm (5 mol%), acetone, 55 °C.
The reaction between glycine-derived aldehyde 3a and 5-pentynol proceeded smoothly; however, the product isolated was tetrahydrofuran-substituted ketone 4o, resulting from intramolecular conjugate addition of the hydroxyl group into the initially formed enone (equation 2). Scheme 2. Initial evaluation of glycine-derived aldehydes 1a,b and 3a,b in alkyne hydroacylation.
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Having established mild and effective conditions for alkyne hydroacylation using MTM-protected amino aldehydes, we next focused on access to enantiomerically pure substrates. Initial attempts to MTM protect Cbz-leucine methyl ester resulted in racemization (Scheme 3). However, by switching to the Weinreb amide substrate 5a, the MTM-protected product (6a) could be prepared in excellent yield, and following reduction with Dibal-H delivered the aldehyde 7a in 99% yield with an excellent >99:1 enantiomeric ratio. This method was then applied to a variety of amino acid substrates. The aldehydes prepared were typically used without purification, although all of the aldehydes obtained were assayed (HPLC) for enantiopurity, and were shown to possess enantiomeric ratios of at least 98:2. The phenylalanine derived aldehyde (7f) was found to be less chemically stable than the other aldehydes and also to be more labile to racemization; however, with care, an er of 99:1 could be achieved. Scheme 3. Synthesis of the enantiomerically enriched α-amino aldehydes. Me
Me NaHMDS MTM-Cl, NaI
Me O OMe NH
Cbz
Me
Me
DMF
5a Me
Me
O
Me
H N
Teoc
MTM
Boc
N
N Me MTM
H
Cbz
N
O
Dibal-H toluene -78 °C, 99%
Me
MTM
MTM
Cbz
7f, 99:1 er
N
Cbz
Me
Me
Me
O
Me
Me O
MTM
Cbz
Teoc
O
N
MTM
Cbz
Me
Cbz
8g, 89% >99:1 er, 100% es
MTM
7g, 98:2 dr
Cbz
N
Cbz
N
Cbz MTM
7h, >99:1 er
N
O
N
MTM
Me
8j, 60% 98:2 er, 97% es
N
Me
O
8k, 79% 97:3 dr, 98% ds
O S
Cbz
MTM
N
MTM
8l, 67% 98:2 dr, 100% ds
O
With a simple and robust synthesis of MTM-protected α-amino aldehydes established, we next examined the use of these molecules in hydroacylation reactions with various alkynes (Table 2). Starting from leucine, the CbzBoc- and Teoc-protected aldehydes were combined with 1-octyne to give the hydroacylation products in excellent yields and with enantiometic ratios of 99:1 or higher (8ac). These high er values correlate with enantiospecificities (es) in the range of 95-100%.24 The Cbz-leucine substrate was effectively combined with phenylacetylene and a cyclopropyl-alkyne (8d,e). The alanine, valine and phenylalanine derived aldehydes were all combined with 1octyne without incident (8f-h). In addition, the phenylalanine substrate was also partnered with the bulky tBu-
MTM
O C6H13
Me
N Cbz N MTM
SiMe3 Me
N Cbz N MTM
8m, 86% >99:1 er, 100% es Me
Me Me Me
8i, 84% 98.5:1.5 er, 99% es
Me C 6H13 Cbz
N
Cbz
8h, 85% 98.5:1.5 er, 99% es
MTM
MTM
C 6H13 Ph
OH Me
H
Me
MTM
C 6H13 N
O
Cbz
MTM
Ph
MTM
O
8f, 87% >99:1 er, 100% es
O
N
MTM 8c, 90% >99:1 er, 100% es
7e, >99:1 er
O
C6H13 N
Boc
8e, 84% 99:1 er, 99% es
Ph
C 6H13 N
N
O
Me
O H
N
MTM 8b, 96% >99:1 er, 100% es Me Me O
8d, 73% 99:1 er, 99% es
MTM
H
Cbz
O
C6H13
N
Me
Me
Me
O
N
R3 R2 MTM 8a-n
N
PG
O
Me
H N
7d, >99:1 er
Me Cbz
Me
H
O
Me
O
Ph
Me
7a, >99:1 er
7c, >99:1 er
7b, >99:1 er
acetone, 55 °C, 3 h
R2
MTM
R1
7
Me Me
O
H N
H N
[Rh(nbd) 2]BF4 (5 mol%) dcpm (5 mol%)
R3
MTM 8a, 82% 99:1 er, 98% es
6a
Me
PG
50:50 er
OMe
Cbz
O
O R1
Cbz
MTM
Me
NaHMDS OMe MTM-Cl, NaI N DMF, 88% Me
NH
Cbz
Me
O
O OMe
Cbz
Table 2. Hydroacylation reactions of amino acid derived enantiomerically enriched aldehydes.a
C 6H13
Me
N
substituted alkyne, as well as propargyl alcohol, while maintaining high er vaues (8i,j). The hydroxyl-substituted enone 8j, derived from phenylalanine and propargyl alcohol, has the connectivity and carbon back-bone featured in Keto-ACE (Scheme 1). Employing an isoleucine-derived aldehyde, hydroacylation was achieved with 1-octyne, as well as a 3-thiophene-substituted alkyne (8k,l). The functional group tolerance of this reaction was further demonstrated by the use of the N-methyltryptophan aldehyde, giving the enantiopure hydroacylation products with alkyl and TMS-substituted alkynes (8m,n). Pleasingly, the reaction was also compatible with internal alkynes, furnishing the expected products in good yields and as single regioisomers (8o,p). Unfortunately, alkenes and allenes show only poor reactivity with this class of aldehyde.
8n, 82% 99:1 er, 99% es Me
Me O
Me O
Et Et Cbz MTM 8o, 92% 98:2 er, 96% es N
a
Me MTM 8p, 73% 97:3 er, 95% es, >20:1 rr Cbz
N
Reaction conditions: aldehyde (1.0 equiv), alkyne (1.5 equiv), [Rh(nbd)2]BF4 (5 mol%), dcpm (5 mol%), acetone, 55 °C, 3 h. es values were calculated using raw HPLC data, rather than the rounded er values reported above.
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In addition to employing amino aldehyde substrates bearing a MTM group, we were also able to exploit the chelating ability of S-methyl cysteine, and methioninederived aldehydes, 9 and 10, respectively (Scheme 4). In both cases, hydroacylation of the MTM-free aldehydes was achieved using the dcpm-derived catalyst in combination with octyne. The methionine-derived substrate required a higher catalyst loading (10 mol%). This reduced reactivity is consistent with our previous report of aliphatic γ-substituted thiomethyl-aldehydes, and again suggests that the MTM-bearing substrates benefit from a conformational arrangement that promotes chelation.23 Following on from this, the MTM-protected α-hydroxy aldehyde 11, derived from phenyl lactic acid, delivered the hydroacylation adduct 14 in excellent yield as a single enantiomer. Scheme 4. Hydroacylation of cysteine, methionine and phenyl lactate derived aldehydes. O
MeS NH
Cbz 9, >99:1 er
H +
NH Cbz 10, >99:1 er
H +
H + OMTM
11, >99:1 er
MeS
acetone, 55 °C, 3 h
C6H13
Cbz
[Rh(nbd) 2]BF4 (10 mol%) MeS C 6H13 dcpm (10 mol%) acetone, 55 °C, 3 h
NH
O C6H13 Cbz
NH
13, 63% 97:3 er, 94% es
O Ph
O
12, 75% 99:1 er, 98% es
O MeS
C 6H13
[Rh(nbd) 2]BF4 (5 mol%) dcpm (5 mol%)
C 6H13
[Rh(nbd) 2]BF 4 (5 mol%) dcpm (5 mol%) acetone, 55 °C, 3 h
O Ph
C 6H13 OMTM 14, 79% >99:1 er, 100% es
The variation possible in the identity of the electronwithdrawing groups on the nitrogen atom of the amino aldehydes allows flexibility with regard to N-deprotection strategies and corresponding reagent choice; three example transformations are shown below (Scheme 5). Treatment of the Cbz-protected hydroacylation product 8a with BF3.OEt2 allowed for the selective removal of the MTM group (15a). Alternatively, the carbamate could be removed in the presence of the MTM group by treating the Teoc-derivative with TBAF (8b → 15b). The use of a Boc group allowed for a double deprotection; treatment with AgNO3 and then TFA delivered the ammonium trifluoroacetate salt (8c → 15c). Importantly, enantiomeric ratios were conserved throughout these protecting group manipulations.
Scheme 5. Example deprotection possibilities for hydroacylation products.
Me
Me O
Me C6H13
Cbz
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N
BF 3.OEt 2 CH 2Cl 2
Cbz 15a, 83%, 98.5:1.5 er, 99% es Me
Me O C 6H13
Teoc
Me
N
MTM 8c
Me O C6H13
MTM 15b, 85%, >99:1 er, 100% es
MTM 8b AgNO3 2,6-lutidine THF/H2O C6H13
Boc
TBAF THF
HN
Me O
N
C 6H13 NH
MTM 8a
Me
Me O
then TFA
Me
Me O C6H13 NH 3+ CF 3CO 2-
15c, 95%, >99:1 er, 100% es
As a demonstration of the utility of the MTM-directed hydroacylation reactions of enantiomerically enriched αamino aldehydes, we applied this method to a short enantio and diastereoselective synthesis of the natural product sphingosine (Scheme 6). The key MTM/Cbz-protected, serine-derived amino aldehyde 16 was available as before, by Dibal-H reduction of the corresponding Weinreb amide in good yield and with a 99:1 er. Hydroacylation of 16 proceeded smoothly on a gram scale using only 2 mol% catalyst loading, affording enone 17 in 94% yield with no loss in the enantiopurity (99:1). Selective MTM deprotection was achieved by first converting to the hydroxymethyl group (AgNO3, 2,6-lutidine, THF/H2O, rt), and its subsequent thermal decomposition (reflux in toluene) to provide carbamate 18 (98:2 er). Literature precedent25 using LiAl(OtBu)3H allowed excellent antidiastereoselective reduction of ketone 18 to alcohol 19 in good yield. Finally, treating 19 with NaOH and heating in MeOH/H2O led to one-pot TBS and Cbz deprotection, and afforded sphingosine 20. The MTM-directed hydroacylation not only established an efficient and competitive route to this natural product, but the mild reaction conditions also allowed the straightforward preparation of several tagged-derivatives. For example, hydroacylation of aldehyde 16 with functionalized alkynes afforded fluorophore 21a,26a electrochemically active organometallic 21b26b and alkyne 21c (suitable for Huisgen cycloaddition chemistry),26c in good yields.
Scheme 6. Application to the synthesis of sphingosine (20), together with the preparation of example tagged derivatives (21a-c).
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O
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
TBSO
H
O
N Cbz MTM 17, 94%, 99:1 er, 100% es
acetone, 55 °C
N Cbz MTM 16, 99:1 er
C13H 27
TBSO
(1.3 g scale)
AgNO3, 2,6-lutidine THF/H2O, rt OH
ACKNOWLEDGMENT
then tol. 120 °C
TBSO
C13H 27
C13H 27
TBSO
EtOH, -78 oC
NH Cbz 19, 93%, >99:1 dr
NH Cbz 18, 91%, 98:2 er, 98% es
NaOH MeOH/H 2O, 80 oC OH HO
C13H 27
20 (sphingosine), 97%
NH 2 O O
TBSO
O
O
11
Cbz
N
MTM 21a, 84%, 97:3 er, 97% es Me
TBSO
O
O
a H
O
TBSO
N Cbz MTM 16, 99:1 er
11
Fe N Cbz MTM 21b, 76%, 98.5:1.5 er, 99% es O TBSO Cbz
11
N
MTM
21c, 49%, 97:3 er, 96% es a
Reagents: [Rh(nbd)2]BF4 (2 mol%), dcpm (2 mol%), and appropriately tagged terminal alkyne (1.5 equiv).
CONCLUSIONS In conclusion, we have developed a Rh(I)-catalyzed MTM-directed hydroacylation of alkynes using enantiomerically enriched α-amino aldehydes. The reaction is highly functional group tolerant, delivering a wide range of α-amino enones in excellent yields and with almost complete retention of enantiopurities. This transformation has been used for the crucial C–C bond-forming step in a concise synthesis of the natural product sphingosine. MTM-Free aldehydes derived from S-methyl cysteine, and methionine, could also be employed in efficient intermolecular alkyne HA reactions. The demonstration of N-MTM groups functioning as efficient chelating units provides an additional synthetically useful motif to exploit in intermolecular HA reactions.
ASSOCIATED CONTENT Supporting Information Experimental procedures and supporting characterization data and spectra (pdf). “This material is available free of charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION Corresponding Author
This work was supported by the EPSRC.
REFERENCES
O LiAl(OtBu) 3H
*
[email protected] † . These authors contributed equally to this work
1. (a) Willis, M. C.; Chem. Rev. 2010, 110, 725. (b) Jun, C.-H.; Jo, E.-A.; Park, J.-W. Eur. J. Org. Chem. 2007, 1869. 2. Selected examples: (a) Schedler, M.; Wang, D.-S.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52, 2585. (b) Bugaut, X.; Liu, F.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 8130. 3. Intermolecular examples: (a) Jun, C.-H.; Lee, H.; Hong, J.-B.; Kwon, B.-I. Angew. Chem. Int. Ed. 2002, 41, 2146. (b) González-Rodríguez, C.; Pawley, R. J.; Chaplin, A. B.; Thompson, A. L.; Weller, A. S.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50, 5134. (c) Zhang, H.-J.; Bolm, C. Org. Lett. 2011, 13, 3900. (d) Chen, Q.-A.; Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc. 2015, 137, 3157. 4. Intermolecular examples: (a) Stemmler, R. T.; Bolm, C. Adv. Synth. Catal. 2007, 349, 1185. (b) Osborne, J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008, 130, 17232. (c) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552. (d) Inui, Y.; Tanaka, M.; Imai, M.; Tanaka, K.; Suemune, H. Chem. Pharm. Bull. 2009, 57, 1158. (e) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16330. (f) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16354. 5. von Delius, M.; Le, C. M.; Dong, V. M. J. Am. Chem. Soc. 2012, 134, 15022. 6. For a review, see: Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202. 7. Rh-catalysis: (a) Marder, T. B.; Roe, D. C.; Milstein, D. Organometallics 1988, 7, 1451. (b) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082. 8. Ru-catalysis: (a) Kondo, T.; Akazome, M.; Tsuji, Y.; Watanabe, Y. J. Org. Chem. 1990, 55, 1286. (b) Omura, S.; Fukuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094. (c) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14120. (d) Williams, V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J. Tetrahedron, 2009, 65, 5024. See also ref 3e. 9. Co-catalysis: (a) Lenges, C. P.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1998, 120, 6965. (b) Chen, Q.-A.; Kim, D. K.; Dong, V. M. J. Am. Chem. Soc. 2014, 136, 3772. 10. O-Chelation: (a) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org. Chem. 1997, 62, 4564. (b) Imai, M.; Tanaka, M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2004, 69, 1144. (c) Murphy, S. K.; Petrone, D. A.; Coulter, M. M.; Dong, V. M. Org. Lett. 2011, 13, 6216. 11. S-Chelation: (a) Willis, M. C.; McNally, S. J.; Beswick, P. J. Angew. Chem. Int. Ed. 2004, 43, 340. (b) Willis, M. C.; Woodward, R. L. J. Am. Chem. Soc. 2005, 127, 18012. (c) Willis, M. C.; Randell-Sly, H. E.; Woodward, R. L.; McNally, S. J.; Currie, G. S. J. Org. Chem. 2006, 71, 5291. (d) Lenden, P.; Entwistle, D. A.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50, 10657. For an intramolecular example, see: (e) Bendorf, H. D.; Colella, C. M.; Dixon, E. C.; Marchetti, M.; Matukonis, A. N.; Musselman, J. D.; Tiley, T. A. Tetrahedron Lett. 2002, 43, 7031. 12. N-Chelation: (a) Suggs, J. W. J. Am. Chem. Soc. 1978, 100, 640. For in situ generated N-chelation: (b) Jun, C.-H.; Lee, D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem. Int. Ed. 2000, 39, 3070; and ref 3a.
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13. P-Chelation: Lee, H.; Jun, C.-H. Bull. Korean Chem. Soc. 1995, 16, 66. 14. C-Chelation: Lochow, C. F.; Miller, R. G. J. Am. Chem. Soc. 1976, 98, 1281. 15. (a) Murphy, S. K.; Bruch, A.; Dong, V. M. Angew. Chem. Int. Ed. 2014, 53, 2455. (b) Murphy, S. K.; Bruch, A.; Dong, V. M. Chem. Sci. 2015, 6, 174. See also, refs 4c,d,e, 5, and 10b. 16. (a) Hooper, J. F.; Chaplin, A. B.; González-Rodríguez, C.; Thompson, A. L.; Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 2906. (b) Hooper, J. F.; Young, R. D.; Weller, A. S.; Willis, M. C. Chem. Eur. J. 2013, 19, 3125. (c) Hooper, J. F.; Young, R. D.; Pernik, I.; Weller, A. S.; Willis, M. C. Chem. Sci. 2013, 4, 1568. 17. (a) Castaing, M; Wason, S. L.; Estepa, B.; Hooper, J. F.; Willis, M. C. Angew. Chem. Int. Ed. 2013, 52, 13280. (b) Zhang, T.; Qi, Z.; Zhang, X.; Wu, L.; Li, X. Chem. Eur. J. 2014, 20, 3283. For a related intramolecular ketone hydroacylation, see: (c) Khan, H. A.; Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2, 407. 18. Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061. 19. For example: (a) Meltzer, P. C.; Butler, D.; Deschamps, J. R.; Madras, B. K. J. Med. Chem. 2006, 49, 1420. (b) Nchinda, A. T.; Chibale, K.; Redelinghuys, P.; Sturrock, E. D. Bioorg. Med.
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Chem. Lett. 2006, 16, 4612. (c) Jamora, C.; Iravani, M. Am. J. Ther. 2010, 17, 511. 20. For example: (a) Bouteiller, C.; Becerril-Ortega, J.; Marchand, P.; Nicole, O.; Barré, L.; Buisson, A.; Perrio, C. Org. Biomol. Chem., 2010, 8, 1111. (b) Zhang, J.; Wang,Y.-Q.; Wang, X.-W.; Li, W.-D. Z. J. Org. Chem. 2013, 78, 6154. 21. Kim, G.; Lee, E.-j, Tetrahedron Asym. 2001, 12, 2073. 22. (a) Chaplin, A. B.; Hooper, J. F.; Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 4885. (b) Pernik, I.; Hooper, J. F.; Chaplin, A. B.; Weller, A. S.; Willis, M. C. ACS Catal. 2012, 2, 2779. (c) Prades, A.; Fernández, M.; Pike, S. D.; Willis, M. C.; Weller, A. S. Angew. Chem. Int. Ed. 2015, 54, 8520. 23. Parsons, S. R.; Hooper, J. F.; Willis, M. C. Org. Lett. 2011, 13, 998. 24 Denmark, S. E.; Vogler, T.; Chem. Eur. J. 2009, 15, 11737. 25. (a) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045. (b) Yang H.; Liebeskind, L. S. Org. Lett. 2007, 9, 2993. 26. (a) Giepmans, B. N. G.; Adams, S. R.; Ellisman, M. H.; Tsien, R. Y. Science 2006, 312, 217. (b) Marsh, B. J.; Hampton, L.; Goggins, S.; Frost, C. G. New. J. Chem. 2014, 38, 5260. (c) Kolb, H. C.; Sharpless, K. B. Drug Disc. Today 2003, 8, 1128.
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