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Cite This: J. Am. Chem. Soc. 2017, 139, 18198−18201
Zn-ProPhenol Catalyzed Enantio- and Diastereoselective Direct Vinylogous Mannich Reactions between α,β- and β,γ-Butenolides and Aldimines Barry M. Trost,* Elumalai Gnanamani, Jacob S. Tracy, and Christopher A. Kalnmals Department of Chemistry, Stanford University, Stanford, California 94305, United States S Supporting Information *
ABSTRACT: We report a Zn-ProPhenol catalyzed reaction between butenolides and imines to obtain tetrasubstituted vinylogous Mannich products in good yield and diastereoselectivity with excellent enantioselectivity (97 to >99.5% ee). Notably, both α,β- and β,γbutenolides can be utilized as nucleophiles in this transformation. The imine partner bears the synthetically versatile N-Cbz group, avoiding the use of the specialized aryl directing groups previously required in related work. Additionally, the reaction can be performed on gram scale with reduced catalyst loading as low as 2 mol %. The functional group-rich products can be further elaborated using a variety of methods.
N
itrogen-containing butenolides are common motifs in a variety of natural products and pharmaceutical compounds, and are also useful synthetic intermediates.1 For example, (−)-securinine is a GABAA antagonist, and its analogs have been studied for their anticancer properties.2 Rugulovasines A and B exhibit hypotensive properties,3 and a nitrogencontaining butenolide was employed as a key synthetic intermediate in the preparation of an NK1 receptor antagonist (Figure 1).4 selectivities are observed, the imine coupling partner required a specialized N-aryl protecting group bearing an ortho- hydroxyl group and the report was limited to only a single butenolide. In fact, simply switching from α-angelica lactone to the regioisomeric β-angelica lactone resulted in complete loss of reactivity (eq 2). Shibasaki has reported excellent work on the related addition of butenolides lacking substitution at the 5position into both aldimines and ketimines.6 A nondirect vinylogous Mannich reaction of butenolides was reported earlier by Martin and Lopez and later improved upon by Hoveyda and Snapper (eq 3).7,8 Both reports require preactivation of the butenolide as the siloxyfuran as well as cryogenic reaction temperatures. In each of these nondirect Mannich reactions, an N-aryl imine bearing a chelating functional group on the aromatic ring was required to obtain good enantioselectivities. Additionally, the scope of the butenolide partner is limited; substitution is only tolerated at the 5-position and is limited to methyl. In this work, we disclose
Figure 1. Nitrogen-containing butenolides in biologically important targets.
Given the prevalence of butenolides in bioactive targets and their utility as synthetic intermediates, it is surprising that there is only one reported example of 5-substituted butenolides used as nucleophiles in a direct asymmetric Mannich reaction. In this report by Feng et al., α-angelica lactone is shown to couple with aldimines via a chiral Sc(III) catalyst (eq 1).5 While high © 2017 American Chemical Society
Received: October 31, 2017 Published: December 3, 2017 18198
DOI: 10.1021/jacs.7b11361 J. Am. Chem. Soc. 2017, 139, 18198−18201
Communication
Journal of the American Chemical Society
Scheme 1. Scope of Imines with α-Angelica Lactonea−d
the first direct vinylogous Mannich reaction which utilizes easily deprotected N-Cbz imines and both α,β- and β,γ-butenolides bearing a variety of substituents and substitution patterns (eq 4). Our group has demonstrated that Zn-ProPhenol complexes are useful for a variety of asymmetric transformations,9 including a number of Mannich reactions.10 Due to the limitations of existing methods for vinylogous Mannich reactions involving butenolides (vide supra), we wondered if ProPhenol could overcome these issues. Initial results proved surprisingly promising. Using α-angelica lactone and 10 mol % ZnProPhenol in toluene afforded the desired product 3a in 64% yield and 94% ee. Various solvents were screened to further improve upon these results and with the exception of dioxane, all of the solvents examined afforded Mannich adduct 3a in excellent enantioselectivity and >30:1 dr. THF gave the best result (79% yield, >99.5% ee) and was used for all subsequent reactions (Table 1). Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 1 equiv of lactone, 1.2 equiv of imine, 10 mol % of Zn-ProPhenol at rt in solvent (0.3 M) for 8 h. bIsolated yields are given. cee was determined using HPLC analysis. ddr was determined by crude 1H NMR.
entry
solvent
yieldb
eec
drd
1 2 3 4 5
toluene DCM THF ether dioxane
64 65 79 61 16
94 98 >99.5 98 34
>30:1 >30:1 >30:1 >30:1 4:1
(vide supra). Additionally, due to conjugation with the carbonyl group, α,β-butenolides are more easily synthesized and stored than the analogous β,γ- compounds (Scheme 2). Under our optimized conditions, we are pleased to report that a variety of nucleophiles can be utilized. Commercially available furanone 2b reacted with both electron-deficient (1a) and electron-rich (1d) imines, affording 3ab and 3db in >99.5% and 99% ee, respectively, with good yields. Notably, only a single diastereomer is observed despite the presence of a highly epimerizable α-proton. α,β-butenolides with sterically demanding alkyl substituents at the 5-position gave incomplete conversion (2c and 2d), but still afforded excellent selectivities and good yields. (Trimethylsilyl)methyl butenolide 2c reacted with 1d to form 3dc in >99% ee and 15:1 dr. Poor conversion for these bulky substrates could be improved by doubling the catalyst loading, with 3ac being formed in 69% yield, 99.5% ee, and 16:1 dr when 20 mol % catalyst was used. An isobutyl group (2d) was also tolerated, and 3ad and 3dd were obtained with excellent ee and slightly reduced dr. Introducing a bromo substituent adjacent to the nucleophilic site had no deleterious effects on reactivity or selectivity, and 3ae was obtained in 74% yield with excellent enantio- (>99.5%) and diastereoselectivity (18:1). We further expanded the scope of the reaction to include phenyl- and thienyl-substituted butenolides. Unlike 2c and 2d, which had bulky alkyl groups at the 5-positon, 5-aryl butenolides gave full conversion under the optimized conditions. 5-Phenyl angelica lactone gave 3af in 60% yield with 98% ee, and the analogous thienyl-substituted compound gave 3ag in 62% yield and 97% ee with 3:1 dr. Finally, bicyclo[4.3.0] lactone 2h gave excellent results with 4-fluorophenyl imine 1a, producing 3ah in 85% yield and >99.5% ee. To unambiguously determine the absolute configuration of our vinylogous Mannich products, we obtained a crystal structure of 3ah (Figure 2). The configuration was determined to be (S,S), which corresponds to the synMannich adduct. The stereochemistry of all other products was assigned by analogy.
a
Reaction conditions: 1 equiv of lactone, 1.2 equiv of imine, 10 mol % of Zn-ProPhenol at rt in solvent (0.3 M) for 8 h. bIsolated yields are given. cee was determined using HPLC analysis. ddr was determined by crude 1H NMR.
With optimized conditions in hand, a variety of imines were evaluated (Scheme 1). Substitution at the ortho-, meta- and parapositions is well tolerated and has little impact on the yield, regio-, diastereo-, or enantioselectivity. Phenyl imine 1b produced the corresponding vinylogous Mannich adduct 3b in 76% yield with >99.5 ee, and tolyl imine 1c afforded the desired product in 75% yield and >99.5 ee. Surprisingly, the less electrophilic 4-methoxy imine 1d also gave excellent results, affording 3d in 91% yield and >99.5% ee. With 1- and 2Naphthyl imines, 3e and 3f were obtained in 98% ee and >99.5% ee, respectively, with nearly identical yields. Introducing a sterically demanding substituent at the ortho- position had no effect on the course of the reaction, yielding 3g in 76% yield and 99% ee. Notably, heteroaryl imines were also well tolerated; thiophene 3h was obtained in 69% yield and 99% ee and 2-furyl imine 1i afforded similar results, giving 3i in 51% yield and 99% ee. During our initial optimization, we observed that β-angelica lactone afforded the same results as α-angelica lactone, albeit with slightly longer reaction times. Given this result, we were curious to see whether other α,β-butenolides would participate in the reaction, particularly since substrates of this type were unreactive in previously reported vinylogous Mannich reactions 18199
DOI: 10.1021/jacs.7b11361 J. Am. Chem. Soc. 2017, 139, 18198−18201
Communication
Journal of the American Chemical Society Scheme 2. Scope of α,β- and β,γ-Butenolidesa−d
Through judicious choice of the reaction conditions, we were able to effect a variety of selective reduction/deprotection reactions on adduct 3b. Treatment of 3b with catalytic palladium and 1,4-cyclohexadiene removed the Cbz group, liberating free amine 4b in 52% yield without reducing the enoate alkene. Under hydrogenation conditions, deprotection of the Cbz group was accompanied by reduction of the enoate double bond, followed by spontaneous cyclization to lactam 5b in 73% yield−an impressive result for three transformations in one pot. This result is particularly noteworthy, since the 2-alkyl3-hydroxy piperidine unit is present in a variety of biologically active targets, such as neurokinin substance P receptor antagonist L-733,060 (6) (Scheme 3).11 This reductionScheme 3. Selective Reductions of Mannich Products
lactamization cascade could provide rapid access to similar compounds, as well as analogs with tertiary alcohols at the 3position. Finally, treatment of 3b with NaBH4 and NiCl212 selectively reduced the butenolide alkene to give saturated lactone 7b while leaving the Cbz group intact. A Mannich product with an appropriately tethered cinnamate ester was treated with Cs2CO3 to afford isoindoline 8g via an intramolecular aza-Michael addition reaction (Scheme 4).13
a
Reaction conditions: 1 equiv of lactone, 1.2 equiv of imine, 10 mol % of Zn-ProPhenol at rt in solvent (0.3 M) for overnight. bIsolated yields are given. cee was determined using HPLC analysis. ddr was determined by crude 1H NMR or 19F NMR. eTwenty mol % dinuclear zinc-ProPhenol used.
Scheme 4. Further Derivatizations of Mannich Products
Figure 2. ORTEP diagram of 3ah.
In addition to providing high-value products in near-perfect enantioselectivity, this reaction can be easily performed on gram scale at decreased catalyst loading without impacting yield or selectivity (eq 5). Using 2 mol % Zn-ProPhenol, α-angelica Given their biological importance14 and recent interest in the synthesis of isoindoline derivatives,15 this transformation is particularly notable. Additionally, our products can be further elaborated using cross-coupling chemistry, as demonstrated by the Sonogashira reaction performed on 3ae. Based on the configuration of our vinylogous Mannich products, we propose the following mechanism (Scheme 5). Following generation of the dinuclear metal−ligand complex (I) from ProPhenol and diethylzinc, coordination and deprotonation of the butenolide occurs to generate zinc dienolate II. Based on previous studies on other Zn-ProPhenol catalyzed Mannich reactions, we propose two-point binding of the imine, giving rise to complex III, which directs the addition of the butenolide to the re face of the imine. To explain the observed
lactone reacted with phenyl imine 1b to afford 3b in 79% yield and >99.5% ee. As with the small scale reaction, the product was obtained with >30:1 dr. It is worth noting that the ProPhenol catalyst can be recovered after the reaction, further reducing the effective catalyst loading.10 18200
DOI: 10.1021/jacs.7b11361 J. Am. Chem. Soc. 2017, 139, 18198−18201
Communication
Journal of the American Chemical Society Notes
Scheme 5. Proposed Mechanism
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the NSF (CHE-1360634) and the NIH (GM033049) for financial support of our programs. We also acknowledge Prof. Allen Oliver (University of Notre Dame) for X-ray crystallographic analysis.
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diastereoselectivity, we propose that the butenolide favors the conformation shown to minimize steric interactions between the right-hand diphenylprolinol unit and the bulk of the ring system. In conclusion, our Zn-ProPhenol system efficiently catalyzes the direct addition of a variety of substituted butenolides to various imines with excellent enantio- (up to >99.5% ee) and diastereoselectivity (up to >30:1 dr). Additionally, this method overcomes many of the hurdles associated with using butenolides as nucleophiles in vinylogous Mannich reactions. This is the first report of such a process that does not require chelating aromatic imines.16 The benzyl carbamates in our products can be easily cleaved to unmask the free amines. Furthermore, a broad range of nucleophiles are employed for the first time; both nonactivated α,β- and β,γ-butenolides are viable reaction partners, and alkyl, aryl, and halogen substitution is tolerated. The Mannich adducts we obtain are densely functionalized, and can be further elaborated into a variety of potentially interesting molecules.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b11361. Experimental procedures, characterization data, NMR spectra for 3a−3i, 3ab−3ah, 3db−3dd, 4b, 5b, 7b, 8g, and 9ae (PDF) Data for 3ah (CIF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Barry M. Trost: 0000-0001-7369-9121 Jacob S. Tracy: 0000-0001-9261-7865 18201
DOI: 10.1021/jacs.7b11361 J. Am. Chem. Soc. 2017, 139, 18198−18201
