Note Cite This: J. Org. Chem. 2018, 83, 12903−12910
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Reformatsky Reaction to Alkynyl N-tert-Butanesulfinyl Imines: Lewis Acid Controlled Stereodivergent Synthesis of β‑Alkynyl-β-Amino Acids Luis Fernández-Sánchez, José A. Fernández-Salas,* M. Carmen Maestro,* and Jose L. García Ruano Departamento de Química Orgánica (módulo-1), Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain
J. Org. Chem. 2018.83:12903-12910. Downloaded from pubs.acs.org by REGIS UNIV on 10/19/18. For personal use only.
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ABSTRACT: A highly diastereoselective Refortmatsky reaction to N-tert-butanesulfinyl propargylaldimines and ketimines is presented. The reaction proceeded with excellent yields and diastereoselectivities provided by the sulfinyl group in the presence of Me3Al. The use of TBSOTf as a Lewis acid promoter switched the sense of the stereoinduction. Thus, this methodology allowed the stereodivergent asymmetric synthesis of β-alkynyl β-amino acid derivatives, from the same sulfinyl configuration, by simply changing the Lewis acid promoter. of related γ,δ-alkynyl-β-amino acids10 inaccessible following this strategy. To circumvent this limitation, the use of alkynyl imines or their precursors11 as substrates in Mannich-type stereoselective reactions has emerged in recent decades.12 Snapper and Hoveyda described an efficient silver-catalyzed asymmetric Mannich reaction with chiral ligands of silyl ketene acetal to N-ortho-methoxyphenyl alkynyl imine.12a However, the ortho-methoxyphenyl directing group is difficult to remove, requiring an oxidative procedure incompatible with many functional groups. The diastereoselective synthesis of β-alkynyl β-amino acids has also been addressed using a chiral auxiliary in either the imine ((S)-phenylglycinol)12c or the nucleophile (chiral phenol derivative).12d Both methods only disclosed the reactivity of one α,β-alkynyl imine, and a multistep oxidative cleavage protocol for the amino acid deliverance is required. Recently, Maruoka and co-workers have followed a similar approach pursuing the synthesis of very challenging chiral αtertiary amines by using alkynyl sulfinyl ketimines as platforms, though β-amino acids synthesis is not compatible with this methodology (Scheme 1A).13 Taking all these precedents into consideration, the development of an efficient and general method for the asymmetric synthesis of β-alkynyl β-amino acid derivatives would be highly desirable. Great progress in the field of asymmetric synthesis over the past decades has allowed high control over the selectivity of a given reaction. However, access to the opposite diastereoisomer is not usually possible by using the same set of starting materials under similar reaction conditions. Thus, development of new methodologies that allow access to both stereoisomers by using the same configuration of the starting materials is highly desirable.5f,14 Herein, we describe a Reformatsky reaction to readily accessible N-sulfinyl alkynyl imines as chiral templates. Facile
T
he development of efficient and practical strategies for the stereoselective construction of privileged structures is an ongoing objective and still holds a preferred position in organic chemistry research.1 β-Amino acids constitute a fundamental class of building blocks for the synthesis of significant molecules with interesting pharmacological applications, showing hypoglycemic and antiketogenic properties as well as antibacterial and antifungal activities.2 Besides their intrinsic relevance, β-amino acids are precursors for β-lactams, which are important building blocks present in a large number of antibiotics.3 On the other hand, the corresponding β-peptides display a high tendency toward the formation of stable secondary structures of notable biological transcendence.4 Moreover, β-amino acids have been widely used in modern organic chemistry as chiral templates for asymmetric synthesis.2a Therefore, several groups have focused their attention on the development of efficient methods for the asymmetric synthesis of β-amino acids.2a,5 Addition to imines,5 including N-sulfinyl imines,6 of ester enolates or silyl ketene acetals5d,f,g and Reformatsky-type reagents,7 has been the approach of choice to face this challenge. Although significant efforts have been devoted to the synthesis of β-amino acids, a number of challenges in connection with its substrate generality still persist, the synthesis of challenging γ,δalkynyl-β-amino acid derivatives being one of them. Propargyl β-amino acids are a special class of nonproteinogenic amino acids. In addition to potentially changing biological properties, these amino acids are key intermediates for interesting compounds with pharmacological activity, such as Xemilofiban, which has proven to be a platelet aggregation inhibitor that can prevent ischemia, heart attacks, and other major adverse cardiac events.8 In this regard, asymmetric synthesis of propargylamines has been well established,9 featuring the alkynylation of imines as the preferred approach. Despite remarkable progress, the enolizable moiety makes the synthesis © 2018 American Chemical Society
Received: July 26, 2018 Published: September 14, 2018 12903
DOI: 10.1021/acs.joc.8b01918 J. Org. Chem. 2018, 83, 12903−12910
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The Journal of Organic Chemistry
diastereoisomer (entry 10). TMSOTf reverses the selectivity of the reaction, leading to the R-configured isomer with reasonably high stereocontrol (entry 11). To our delight, when a more sterically hindered silyl derivative was used, the diastereoselectivity was improved up to 7:93, since the facial discrimination increased as well (entry 12). After optimizing the reaction conditions, we studied the scope of the reaction regarding the synthesis of the S isomer. The results were summarized in Table 2. First, a different
Scheme 1. Previous Work (A), Present Work (B)
Table 2. Highly Diastereoselective Reformastky Reaction to Alkynyl N-Sulfinyl Imines: AlMe3a sulfinyl cleavage would lead to the synthesis of enantiopure βalkynyl β-amino acid derivatives. This straightforward approach gives access to both stereoisomers of the desired γ,δ-alkynyl β-amino acids using the same configuration at the sulfur atom of the sulfinyl group. This stereodivergent approach relies on the use of different Lewis acids (Scheme 1B), which efficiently switches the reactivity of the imine. We began our studies investigating the Reformatsky reaction of the α-bromo ester derivative 2a and the alkynyl N-sulfinyl imine bearing a phenyl ring 1a as a model substrate (Table 1). After optimizing the amount of the Reformatsky reagent (2a) and the temperature (entries 1−6), the reaction showed good efficiency when carried out at −10 °C in the presence of 4 equiv of the α-bromo ester (entry 6). At −40 °C the reaction did not take place and the starting imine was recovered (entry 7). Gratifyingly, in the presence of AlMe3 at −78 °C,15 the desired γ,δ-alkynyl-β-amino ester derivative 3a was obtained with complete diastereoselectivity (>98:2) in 88% isolated yield (entry 9). With the aim of developing a new stereodivergent procedure, which would allow us to synthesize both enantiomers of the corresponding alkynyl β-amino acid derivative starting from the same configuration at the sulfinyl group, we used a highly oxophilic Lewis acid which could potentially modify the transition state through which the reaction takes place. Consequently, when the reaction was performed in the presence of BF3·OEt2, a compound with the S configuration (3a) was still obtained as the major
a
All reactions were carried out with 1 (0.1 mmol), 2a (0.4 mmol), Zn (0.4 mmol), and AlMe3 (0.11 mmol) in 0.25 mL of THF. The diastereomeric ratio was determined by 1H NMR. Isolated yields.
Table 1. Reformatsky Reaction with Alkynyl Sulfinyl Imines: Optimizationa
entry
Lewis acids (equiv)
2a (equiv)
T (°C)
t (h)
convb,c (%)
d.r.b (3a:3a′)
1 2d 3 4 5 6 7 8 9 10 11 12
− − − − − − − Cu(OTf)2 (1.1) AlMe3 (1.1) BF3·OEt3 (2.1) TMSOTf (2.1) TBSOTf (2.1)
2.5 2 2.5 3.5 3.5 4 4 4 4 4 4 4
rt 0 0 0 −10 −10 −40 rt −78 rt −78 −78
1.25 15 4 20 5 5 18 22 3 22 6 6
100 (75) − 90 100 (72) 20 100 (84) − − 100 (88) 100 (80) 65 (62) 100 (86)
87:13 − − 90:10 − 91:9 − − >98:2 86:14 14:86 7:93
a
All reactions were carried out with 1a (0.1 mmol) and Zn (0.4 mmol) in 0.25 mL of THF. bDetermined by 1H NMR. cIsolated yield of the major diastereoisomer in brackets. dReaction carried out with 2 equiv of Zn. 12904
DOI: 10.1021/acs.joc.8b01918 J. Org. Chem. 2018, 83, 12903−12910
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The Journal of Organic Chemistry
yields and very good diastereoselectivities. No reaction was observed with methyl ketimine 1h. We propose that the Reformatsky reaction proceeded via a chairlike transition state17 where both the bulky tert-butyl ester group and the substituent in the sulfinyl imine could occupy equatorial positions. The reaction with aldimines (E isomer) and ketimines (Z isomer) takes place through a common transition state, although the E/Z isomeric distribution of the starting imine should be considered. Me3Al would be simply acting as a Lewis acid, enhancing the reactivity of the imine.18 In this context, Me3Al could also be involved in differentiating the two Me3Al imine isomer reaction rates, which are in rapid equilibrium.13a,17a,19 Highly oxophilic Lewis acid (R3SiOTf) could potentially coordinate to the oxygen atom of the sulfinyl group, disengaging the six-membered chairlike transition state. Thus, the reaction would take place under nonchelation control. The tert-butyl group of the sulfinyl group would direct the approach of the nucleophile to the less hindered re-face of the imine, leading to the opposite configuration (R) at the carbon atom that bears the amino group (Scheme 2).
substitution in the aryl unit was considered. Arenes bearing an electron-rich (OMe) and an electron-deficient group (CO2Me) as well as a bromo group in both the ortho and para position were well tolerated, and the desired products were obtained with complete diastereoselectivity and from good to excellent yields (3b−3e; Table 2). Aliphatic alkynyl imine 1f led to the β-amino ester product in high yield, and only one diastereomer was observed (3f). Similarly, imine 1g, bearing a TMS-substituted alkyne, underwent an efficient Reformatsky reaction to give versatile product 3g. In addition to sulfinyl aldimines, the corresponding less reactive and challenging ketimines proved to be suitable substrates in the Me3Al-promoted Reformatsky reaction. Thus, differently substituted aryl and alkyl terminus acetylene ketimines led to the desired β-amino ester with an α-tertiary amine moiety with complete diastereoselectivity (3h−3k). It should be noted that chiral α-tertiary amines are fundamental and recurrent motifs in naturally occurring and synthetic bioactive compounds, and their synthesis still stands as an important challenge in organic chemistry.13a To the best of our knowledge, the synthesis of such β-alkynyl β-tertiary amino acid derivatives has never been described. The absolute configuration of the asymmetric centers of 3g were unequivocally assigned as (Rs,S) by X-ray crystallographic analysis.16 We then studied the Reformatsky reaction to alkynyl Nsulfinyl imines mediated by TBSOTf in order to evaluate the scope of the reaction (Table 3). Regarding the aldimines, these
Scheme 2. Proposed Transition States for AlMe3- and R3SiOTf-Mediated Reformatsky Reactions
Table 3. Highly Diastereoselective Reformastky Reaction to Alkynyl N-Sulfinyl Imines: TBSOTfa
As mentioned above, apart from the high stereoinduction provided, the tert-butane sulfinyl group is an easily removable auxiliary (Scheme 3). Treatment of sulfinamides 3a and 3f Scheme 3. Sulfinyl Group Cleavage: Synthesis of β-Alkynyl β-Amino Esters and β-Amino Acids
with HCl in methanol allows the efficient deprotection to the amino ester (4a and 4f) in high yields without erosion in the enantiomeric purity, whereas deliverance of the optically pure β-alkynyl β-amino acid (5a and 5f) was efficiently accomplished in the presence of H2O. In conclusion, we have described a highly diastereoselective Reformatsky reaction to enantiopure alkynyl N-sulfinylimines. The methodology tolerates a reasonably high range of aldimines and ketimines bearing differently substituted alkynyl groups. In addition, by simply changing the Lewis acid promoter, the reactivity switched and allowed selective preparation of both epimers from N-sulfinylimines with the same configuration at the sulfur atom. Finally, the sulfinyl
a
All reactions were carried out with 1 (0.1 mmol), 2a (0.4 mmol), Zn (0.4 mmol), and TBSOTf (0.21 mmol) in 0.25 mL of THF. The diastereomeric ratio was determined by 1H NMR. Isolated yields of the major diastereoisomer.
new reaction conditions tolerated electron-rich (OMe) and electron-deficient groups (CO2Me) as well as a bromo substituent in both the ortho and para position of the phenyl group, leading to the desired β-amino ester products in good yields and diastereoselectivities (3a′−e′). Imines bearing alkyl and TMS substituted alkynes underwent an efficient Reformatsky reaction, to give adducts 3f′ and 3g′ in good 12905
DOI: 10.1021/acs.joc.8b01918 J. Org. Chem. 2018, 83, 12903−12910
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The Journal of Organic Chemistry
6.90−6.87 (m, 2H), 3.83 (s, 3H), 1.25 (s, 9H). 13C NMR (CDCl3): δ 161.4, 147.9, 134.6, 114.4, 113.2, 101.2, 85.3, 58.3, 55.4, 22.6. IR (NaCl): 2983, 2961, 2868, 2846, 2197, 1603, 1560, 1509, 1459, 1296, 1174, 1085, 1033 cm−1. MS (ESI+) m/z (%): 549 (2M + Na)+ (60), 286 (M + Na)+ (8), 264 (M + 1)+ (52), 208 (100), 180 (18), 139 (36). HRMS: m/z calcd for C14H18NO2S [M + H]+, 264.1052; found, 264.1060. (RS,E)-Ethyl 4-[3-(tert-Butylsulfinylimino)prop-1-ynyl]benzoate (1c). Following the general procedure A, ethyl 4-(3-oxoprop-1-yn-1yl)benzoate (3 mmol) gave 1c (631 mg, 2.07 mmol, 69% yield). Eluent: n-hexane/AcOEt (6/1). [α]20D −154.1 (c 0.85, CHCl3); 1H NMR (CDCl3): δ 8.04 (s, 1H), 8.06−8.04 (m, 2H), 7.65−7.62 (m, 2H), 4.39 (c, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.26 (s, 9H). 13 C NMR (CDCl3): δ 165.6, 147.5, 132.4, 132.4, 131.8, 129.6, 125.2, 98.5, 87.4, 61.4, 58.6, 22.6, 14.3. IR (NaCl): 2981, 2929, 2870, 2206, 1721, 1564, 1274, 1176, 1092 cm−1. MS (ESI+) m/z (%): 633 (2M + Na)+ (55), 306 (M + 1)+ (69), 250 (100), 187 (9). HRMS: m/z calcd for C16H20NO3S [M + H]+, 306.1158; found, 306.1165. (R S ,E)-N-[3-(4-Bromophenyl)prop-2-ynylidene]-2-methylpropane-2-sulfinamide (1d). Following the general procedure A, ethyl 3-(4-bromophenyl)propiolaldehyde (3 mmol) gave 1d (758 mg, 2.43 mmol, 81% yield). Eluent: n-hexane/AcOEt (5/1). [α]20D −130.6 (c 0.96, CHCl3). 1H NMR (CDCl3): δ 8.00 (s, 1H), 7.54− 7.50 (m, 2H), 7.45−7.41 (m, 2H), 1.25 (s, 9H). 13C NMR (CDCl3): δ 147, 133.9, 132.0, 125.1, 119.8, 98.7, 86.4, 58.5, 22.6. IR (NaCl): 2961, 2926, 2868, 2205, 1562, 1486, 1179, 1090, 1011 cm−1. MS (ESI +) m/z (%) 647 (2M + Na)+ (28), 314 (M + 3)+ (66), 312 (M + 1)+ (64), 258 (100), 256 (100). HRMS: m/z calcd for C13H14BrNOS [M + H]+, 312.0052; found, 312.0036. (R S ,E)-N-[3-(2-Bromophenyl)prop-2-ynylidene]-2-methylpropane-2-sulfinamide (1e). Following the general procedure A, 3(2-bromophenyl)propiolaldehyde (3 mmol) gave 1e (727 mg, 2.34 mmol, 78% yield). Eluent: n-hexane/AcOEt (5/1); [α]20D −171.1 (c 1.03, CHCl3). 1H NMR (CDCl3): δ 8.08 (s, 1H), 7.64−7.58 (m, 2H), 7.34−7.24 (m, 2H), 1.26 (s, 9H). 13C NMR (CDCl3): δ 147.6, 134.4, 132.8, 131.4, 127.2, 126.4, 123.3, 97.8, 89.1, 58.6, 22.6. IR (NaCl): 2961, 2926, 2867, 2206, 1561, 1470, 1179, 1090 cm−1. MS (ESI+) m/ z (%): 647 (2M + Na)+ (16), 312 (M + 1)+ (53), 258 (100), 256 (100); HRMS: m/z calcd for C13H14BrNOS [M + H]+, 312.0052; found, 312.0045. (RS,E)-2-Methyl-N-(oct-2-ynylidene)propane-2-sulfinamide (1f). Following the general procedure A, oct-2-ynal (3 mmol) gave 1f (361 mg, 1.59 mmol, 53% yield). Eluent: n-hexane/AcOEt (6/1). The spectroscopic data are in accordance with the literature.20 (RS,E)-2-Methyl-N-[3-(trimethylsilyl)prop-2-ynylidene]propane-2sulfinamide (1g). Following the general procedure A, 3(trimethylsilyl)propiolaldehyde (3 mmol) gave 1g (543 mg, 2.37 mmol, 79% yield). Eluent: n-hexane/AcOEt (from 7/1 to 3/1). [α]20D −268.9 (c 0.85, CHCl3); 1H NMR (CDCl3): δ 7.78 (s, 1H), 1.22 (s, 9H), 0.25 (s, 9H). 13C NMR (CDCl3): δ 148.4, 108.4, 100.3, 59.0, 23.2, 0.0. IR (NaCl): 2962, 2928, 2902, 2869, 2202, 1563, 1365, 1250, 1098, 1070 cm−1. MS (ESI+) m/z (%): 545 (68), 481 (2M+ + Na) (16), 284 (26), 252 (M + Na)+ (22), 230 (M + 1)+ (46), 174 (100), 156 (15). HRMS: m/z calcd for C10H20NOSSi [M + H]+, 230.1029; found, 230.1021. (RS,Z)-2-methyl-N-(4-phenylbut-3-yn-2-ylidene)propane-2-sulfinamide (1h).13a Following the general procedure B, 4-phenylbut-3yn-2-one (0.43 mmol) gave 1h (80 mg, 0.3225 mmol, 75% yield) as a mixture of isomers Z/E (93:7). Eluent: n-hexane/AcOEt (5/1). [α]20D −208.3 (c 0.70, CHCl3). 1H NMR (CDCl3): δ 7.57−7.54 (m, 2H), 7.46−7.35 (m, 3H), 2.46 (s, 3H), 1.27 (s, 9H); 13C NMR (CDCl3): δ 162.1, 132.5, 130.5, 128.6, 120.7, 102.2, 84.2, 56.9, 29.4, 22.2. IR (NaCl): 2982, 2926, 2865, 2209, 2158, 1563, 1365, 1178, 1081 cm−1. MS (ESI+) m/z (%): 517 (2M+ + Na) (90), 270 (M + Na)+ (17), 248 (M + 1)+ (23), 192 (100). HRMS: m/z calcd for C14H18NOS [M + H]+, 248.1103; found, 248.1108. (R S,Z)-N-[4-(2-Methoxyphenyl)but-3-yn-2-ylidene]-2-methylpropane-2-sulfinamide (1i). Following the general procedure B, 4(2-methoxyphenyl)but-3-yn-2-one (0.43 mmol) gave 1h (103 mg, 0.37 mmol, 86% yield). Eluent: n-hexane/AcOEt (from 4/1 to 3/1).
group can be easily removed, leading to the desired enantiomerically pure β-alkynyl β-amino acids.
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EXPERIMENTAL SECTION
General Considerations. All solvents were dried using activated 4 Å molecular sieves and stored under nitrogen. 4 Å molecular sieves, with a 1.6−2.5 mm particle size, were activated by microwave (700 W) (3 × 60 s) and subsequent cycles of vacuum/nitrogen. For thin layer chromatography (TLC) silica gel plates with a fluorescence indicator (254 nm) were used, and compounds were visualized by irradiation with UV light and/or by treatment with a solution of potassium permanganate in water followed by heating. Flash column chromatography was performed using silica gel (230−400 mesh) and compressed air. Hexane, ethyl acetate, dichloromethane, and diethyl ether for flash chromatography were acquired from commercial sources and were used without previous purification. Optical rotation was recorded in cells with a 10 cm path length; the specific solvents and concentrations (in g/100 mL) are indicated. NMR spectra were acquired on a Bruker Avance 300 MHz spectrometer, running at 300, 75, and 282 MHz for 1H, 13C, and 19F respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3, 7.26 ppm for 1H NMR and 77.2 ppm for 13C NMR respectively). 13C NMR spectra were acquired on a broad band decoupled mode. The following abbreviations are used to describe peak patterns when appropriate: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra (MS) were obtained by ESI ionization mode. High resolution mass spectra (HRMS) were performed by ESI ionization mode using a time-of-flight (TOF) mass analyzer, as indicated for each compound. Zn, dust;
