Zn-ProPhenol Catalyzed Enantio- and Diastereoselective Direct

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Zn-ProPhenol Catalyzed Enantio- and Diastereoselective Direct Vinylogous Mannich Reactions Between #,#- and #,#-Butenolides and Aldimines Barry M. Trost, Elumalai Gnanamani, Jacob S. Tracy, and Christopher Kalnmals J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11361 • Publication Date (Web): 03 Dec 2017 Downloaded from http://pubs.acs.org on December 3, 2017

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Journal of the American Chemical Society

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, Christopher A. Kalnmals Department of Chemistry, Stanford University, Stanford, California 94305 Supporting Information Placeholder ABSTRACT: We report a Zn-‐ProPhenol catalyzed reaction between butenolides and imines to obtain tetrasubstituted vinylogous Mannich products in good yield and diastereose-‐ lectivity with excellent enantioselectivity (97 to >99.5% ee). Notably, both α,β-‐ and β,γ-‐butenolides 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.

Nitrogen-‐containing butenolides are common motifs in a variety of natural products and pharmaceutical compounds, 1 and are also useful synthetic intermediates. For example, (-‐)-‐ securinine is a GABAA antagonist, and its analogs have been 2 studied for their anticancer properties. Rugulovasines A and 3 B exhibit hypotensive properties, and a nitrogen-‐containing butenolide was employed as a key synthetic intermediate in 4 the preparation of an NK1 receptor antagonist.

Figure 1. Nitrogen-‐containing biologically important targets.

butenolides

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 re-‐ sulted in complete loss of reactivity (eq. 2). Shibasaki has reported excellent work on the related addition of bu-‐ tenolides lacking substitution at the 5-‐position into both 6 aldimines and ketimines. A non-‐direct vinylogous Mannich reaction of butenolides was reported earlier by Martin and Lopez and later improved 7,8 upon by Hoveyda and Snapper (eq. 3). Both reports re-‐ quire pre-‐activation of the butenolide as the siloxyfuran as well as cryogenic reaction temperatures. In each of these non-‐direct 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

in

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 bu-‐ tenolides used as nucleophiles in a direct asymmetric Man-‐ nich reaction. In this report by Feng et al, α-‐angelica lactone is shown to couple with aldimines via a chiral Sc(III) catalyst 5 (eq. 1). While high selectivities are observed, the imine cou-‐ pling partner required a specialized N-‐aryl protecting group

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tolerated at the 5-‐position and is limited to methyl. In this work, we disclose the first direct vinylogous Mannich reac-‐ tion 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).

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Scheme 1. Scope of imines with α-‐angelica lactonea-‐d

Our group has demonstrated that Zn-‐ProPhenol complex-‐ 9 es are useful for a variety of asymmetric transformations, 10 including a number of Mannich reactions. Due to the limi-‐ tations of existing methods for vinylogous Mannich reactions involving butenolides (vide supra), we wondered if ProPhenol could overcome these issues. Initial results proved surpris-‐ ingly promising. Using α-‐angelica lactone and 10 mol% Zn-‐ ProPhenol 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 diox-‐ ane, 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 subse-‐ quent reactions.

Table 1. Optimization of the reaction conditions

a

Reaction Conditions: 1 equiv of lactone, 1.2 equiv of imine, b 10 mol% of Zn-‐ProPhenol at rt in solvent (0.3 M) for 8 h. c Isolated yields are given. ee was determined using HPLC d 1 analysis. dr was determined by crude H NMR .

and 99% ee and 2-‐furyl imine 1i afforded similar results, giv-‐ ing 3i in 51% yield and 99% ee.

b

c

d

entry

solvent

yield

ee

dr

1

Toluene

64

94

>30:1

2

DCM

65

98

>30:1

3

THF

79

>99.5

>30:1

4

Ether

61

98

>30:1

5

Dioxane

16

34

4:1

a

Reaction Conditions: 1 equiv of lactone, 1.2 equiv of imine, b 10 mol% of Zn-‐ProPhenol at rt in solvent (0.3 M) for 8 h. c Isolated yields are given. ee was determined using HPLC d 1 analysis. dr was determined by crude H NMR. With optimized conditions in hand, a variety of imines were evaluated (Scheme 1). Substitution at the ortho-‐, meta-‐ and para-‐ positions 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. 1-‐ and 2-‐Naphthyl imines gave 3e and 3f in 98% ee and >99.5% ee, respectively, with nearly identical yields. In-‐ troducing 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

During our initial optimization, we observed that β-‐ angelica lactone afforded the same results as α-‐angelica lac-‐ tone, 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 sub-‐ strates of this type were unreactive in previously reported vinylogous Mannich reactions (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. 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 >99.5% ee, respectively, with good yields. Nota-‐ bly, only a single diastereomer is observed despite the pres-‐ ence of a highly epimerizable alpha proton. α,β-‐butenolides with sterically demanding alkyl substituents at the 5-‐position gave incomplete conversion (2c and 2d), but still afforded excellent selectivities in 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 im-‐ proved 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).


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Journal of the American Chemical Society Scheme 2. Scope of α,β-‐ and β,γ-‐ butenolidesa-‐d

In addition to providing high-‐value products in near-‐ perfect enantioselectivity, this reaction can be easily per-‐ formed on gram scale at decreased catalyst loading without impacting yield or selectivity (eq. 5). Using 2 mol% Zn-‐ ProPhenol, α-‐angelica lactone reacted with benzene 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 10 loading.

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 over-‐ b c night. Isolated yields are given. ee was determined using d 1 19 HPLC analysis. dr was determined by crude H NMR or F e NMR. 20 mol % dinuclear zinc-‐ProPhenol used. We further expanded the scope of the reaction to included phenyl-‐ and thiophenyl-‐substituted butenolides. Unlike 2c and 2d, which had bulky alkyl groups at the 5-‐positon, 5-‐aryl butenolides gave full conversion under the optimized condi-‐ tion. α-‐Phenyl-‐β-‐angelica lactone gave 3af in 60% yield with 98% ee, and the analogous thiophenyl-‐substituted com-‐ pound 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 con-‐ figuration of our vinylogous Mannich products, we obtained a crystal structure of 3ah. The configuration was determined to be (S,S), which corresponds to the syn-‐ Mannich adduct. The stereochemistry of all other products was assigned by analogy.

Figure 2. ORTEP diagram of 3ah.

Through judicious choice of the reaction conditions, we were able to effect a variety of selective reduc-‐ tion/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 condi-‐ tions, deprotection of the Cbz group was accompanied by reduction of the enoate double bond, followed by spontane-‐ ous cyclization to lactam 5b in 73% yield, an impressive re-‐ sult for three transformations in one pot. This result is par-‐ ticularly noteworthy, since the 2-‐alkyl-‐3-‐hydroxy piperidine unit is present in a variety of biologically active targets, such as neurokinin substance P receptor antagonist L-‐733,060 11 (6).

Scheme 3. Selective reductions of Mannich products.

This reduction-‐lactamization cascade could provide rapid access to similar compounds, as well as analogs with tertiary alcohols at the 3-‐position. Finally, treatment of 3b with 12 NaBH4 and NiCl2 selectively reduced the butenolide alkene to give saturated lactone 7b while leaving the Cbz group in-‐ tact.



Scheme 4. Further derivatizations of Mannich prod-‐ ucts.

A Mannich product with an appropriately tethered cin-‐ namate ester was treated with Cs2CO3 to afford isoindoline 8g via an intramolecular aza-‐Michael addition reaction 13 14 (Scheme 4). Given the biologically importance and recent 15 interest in the synthesis of isoindoline derivatives, this transformation is particularly notable. Additionally, our products can be further elaborated using cross-‐coupling chemistry, as demonstrated by the Sonogashira reaction per-‐ formed on 3ae.

Scheme 5. Proposed mechanism.

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tions between the right hand diphenylprolinol unit and the bulk of the ring system. In conclusion, our Zn-‐ProPhenol system efficiently cata-‐ lyzes the direct addition of a variety of substituted bu-‐ tenolides to various imines with excellent enantio-‐ (up to >99.5% ee) and diastereoselectivity (up to >30:1 dr). Addi-‐ tionally, this method overcomes many of the hurdles associ-‐ ated with using butenolides as nucleophiles in vinylogous Mannich reactions. This is the first report of such a process 16 that does not require chelating aromatic imines. 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.

ASSOCIATED CONTENT Supporting Information Experimental procedures, characterization data, NMR spec-‐ tra for 3a-‐3i, 3ab-‐3ah, 3db-‐3dd, 4b, 5b, 7b, 8g, and 9ae, and crystallographic data. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *E-‐mail: [email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We thank the NSF (CHE-‐1360634) and the NIH (GM-‐033049) for financial support of our programs. We also acknowledge Prof. Allen Oliver (University of Notre Dame) for X-‐ray crys-‐ tallographic analysis.

REFERENCES

Based on the configuration of our vinylogous Mannich products, we propose the following mechanism. 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 Man-‐ nich 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 ob-‐ served diastereoselectivity, we propose that the butenolide favors the conformation shown to minimize steric interac-‐

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Graphical diagram:



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Zn-ProPhenol Catalyzed Enantio- and Diastereoselective Direct

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