Substituent Effects on the Reactivity of Cyclic ... - ACS Publications

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Cite This: J. Org. Chem. 2017, 82, 13250−13255

Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates Claudio D. Navo,† Nuria Mazo,† Alberto Avenoza, Jesús H. Busto, Jesús M. Peregrina, and Gonzalo Jiménez-Osés* Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain S Supporting Information *

ABSTRACT: The reactivity of cyclic tertiary sulfamidates derived from α-methylisoserine strongly depends on the substitution at the C and N termini. These substrates are one of the very few examples able to undergo nucleophilic ring opening at a quaternary carbon with complete inversion of the configuration, as demonstrated both experimentally and computationally. When the sulfonamide is unprotected, the characteristic ring-opening reaction is completely silenced, which explains that the majority of the ring-opening reactions reported in the literature invoke Nalkyl or N-carbonyl-protected sulfamidates. Accumulation of negative charge at the NSO3 moiety in the transition state, especially when the sulfonamide NH is deprotonated, drastically raises the activation barrier for the nucleophilic attack. On the other hand, ester groups at the carboxylic position favor ring opening, whereas amides allow competition between the substitution and elimination pathways. Using pyridine as a nucleophilic probe, we have demonstrated both experimentally and computationally that a proper selection of the substitution scheme can enhance the synthetic scope of α-methylisoserine-derived sulfamidates, switching off and on the nucleophilic ring-opening in a controlled manner. This is particularly convenient for hybrid α/β-peptide synthesis, as demonstrated recently by our group.

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INTRODUCTION Five-membered cyclic sulfamidates are well-known heterocyclic electrophiles, which attract a great deal of interest in organic synthesis due to their high versatility and their easy enantiomeric synthesis.1−3 These systems can undergo ringopening reactions with a wide range of nucleophiles and are profusely used in the asymmetric synthesis of natural products4−8 or different molecules with biological activities.9−16 Our interest has been focused on sulfamidates derived from αmethylisoserine, which unambiguously undergo bimolecular nucleophilic substitutions (SN2) with sulfur, nitrogen and oxygen nucleophiles,17−23 with total inversion of the configuration17,19 of the quaternary center and preserving the enantiomeric excess of the starting sulfamidate. These hindered sulfamidates are also able to react with soft neutral nucleophiles such as pyridines under pseudo-first-order conditions, to afford chiral, quaternary cationic β2,2-amino acids.21,24 A survey of the literature revealed that the great majority of the reported ring-opening reactions of five-membered sulfamidates,25−34 including metal-catalyzed variants,35−37 involved N-protected substrates, which are known to be usually more reactive than their unprotected analogues.38 A notable exception is the ring-opening reaction of sulfamidates derived from L-serine described by a seminal report by Halcomb and co-worker, which ring-opened small NH-unprotected peptides bearing sulfamidates with thiocarbohydrates in aqueous conditions.39 This is relevant since one of the most practical and elegant syntheses of sulfamidatesthe metal-catalyzed insertion of nitrenes into C−H bonds40,41efficiently provide NH-unprotected materials, which require additional Nprotection to enable subsequent ring-opening reactions. This © 2017 American Chemical Society

common behavior, despite being widely reported, remains unexplained. Our own experience22 led us to the frequent observation that N-unprotected substrates never reacted to any extent either through substitution or elimination under typical SN2 conditions (i.e., in a polar aprotic solvent) (Scheme 1). In fact, these N-unprotected sulfamidates were commonly obtained by the undesired deprotection of the methyl carbamate or acetyl groups when hard nucleophiles such as alkoxides and amines were used. Besides the influence of the N terminus, we have reported quite dramatic changes in the chemoselectivity of the competitive ring-opening (SN2) and bimolecular elimination (E2) reactions depending on the protecting group at the C terminus (esters favor SN2 while amides favor E2)17,22 (Scheme 1). On a similar note, the very frequent competitive elimination on serine-derived sulfamidates observed with basic nucleophiles such as alkoxides can be partially suppressed by using serine sulfamidate carboxylic acids.30 Intrigued by this special reactivity of five-membered sulfamidates, we combined quantum mechanical and ringopening experiments using pyridine as a nucleophile, with the goal of rationalizing such remarkable substituent effects.

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RESULTS AND DISCUSSION Experimental Assays. As electrophiles, we considered combinations of N−H, N−COMe, and N−CO2Me (for the N Received: September 17, 2017 Published: November 17, 2017 13250

DOI: 10.1021/acs.joc.7b02352 J. Org. Chem. 2017, 82, 13250−13255

Article

The Journal of Organic Chemistry Scheme 1. Ring-Opening and Elimination Reactions of αMethylisoserine-Derived Tertiary Sulfamidatesa

ring-opening (83%) and elimination (17%) products 8 and 9, respectively.24 Different distributions of SN2 and E2 products had been previously observed with amide-substituted tertiary sulfamidates. Of note, the terminal alkene α′-methylidene-βalanine was observed as the sole elimination product, strongly suggesting a E2 mechanism since only the β-hydrogens at the tertiary methyl group can arrange in an “anti” disposition with respect to the leaving OSO2N group. This reactivity was previously described by our research group using basic nucleophiles, such as fluoride or phenoxides.17 The pseudofirst-order kinetics of both the ring-opening and elimination reactions of sulfamidate 4 in pyridine-d5 were analyzed by 1H NMR spectroscopy (Figure 1). A competitive 4 → 8′ (SN2) vs

a

When the terminal N is protected as a carbamate, both reaction channels are accessible, the elimination pathway being suppressed when the terminal C is protected as an ester (refs 17, 21, and 22). On the other hand, when the terminal N is unprotected, both reactions are disallowed (refs 22 and 24).

terminus) and CO2Me and CONHMe (for the C terminus) protection schemes (sulfamidates 1−5, see Table 1) prepared Table 1. Tertiary Sulfamidates (Sulf) Chosen for the Experimental and Computational Study of Substituents Effectsa

Figure 1. Pseudo-first-order kinetics for the ring-opening (SN2) and elimination (E2) reactions of sulfamidate 4 in pyridine-d5 at 60 °C.

Sulf

R1

R2

temp (°C)

time (h)

SN2 (%)b

E2 (%)b

1 2 3 4 5

OMe OMe OMe NHMe NHMe

COMe CO2Me H COMe H

25 25 60 60 60

12 12 24 16 24

6 (>99) 7 (>99) n.d. 8 (83) n.d.

n.d. n.d. n.d. 9 (17) n.d.

4 → 9′ (E2) profile was clearly observed, without detecting any intermediate or transient species. The experimental activation barrier for the pseudo-first-order nucleophilic ring opening of 4 at 60 °C was estimated to be ΔG‡ = 20 kcal mol−1. On the other hand, N-unprotected compounds 3 and 5 were completely unreactive. In both cases, starting materials were fully recovered after prolonged heating (24 h at 60 °C), irrespective of the protecting group at the C terminus. Therefore, we demonstrated that the reactivity at the quaternary center (either substitution or elimination) can be completely switched on or off just by adding or removing a carbonyl group at the sulfonamide nitrogen, and the significant influence of the substitution at both the N and C termini in the reactivity of tertiary sulfamidates. Computational Analysis. The experimental observations described above were satisfactorily explained by quantum mechanical (QM) calculations performed at the PCM/M062X/6-31+G(d,p) level (see Computational Methods). It should be taken into account that because of the very low reaction rates observed under second-order conditions (i.e., using equimolar amounts of sulfamidate and pyridine), it was necessary to carry out the reactions under pseudo-first-order conditions using pyridine as a solvent. Hence, the calculated second-order activation free energies cannot be directly related to the experimental pseudo-first-order reaction rates. Instead, computed activation enthalpies give a better representation of the experimental reaction rates. Hence, the activation enthalpy

Reaction conditions: (i) Pyridine, 25−60 °C, 12−24 h, (ii) 20% H2SO4 (aq.)/CH2Cl2 (1:1), 25 °C, 1 h. bYield measured by 1H NMR in the reaction mixtures. n.d.: not detected. a

following previously reported methodologies.17,21,23 N−COMe (acetamide) and CONHMe (methyl amide) groups were used to simulate the behavior of the sulfamidate in a peptide context.23,24 Pyridine was chosen as the nucleophilic probe since it is a slightly basic, neutral nucleophile amenable for both experiments and computations. Because of the limited nucleophilicity of pyridine, ringopening reactions were carried out under pseudo-first-order conditions by dissolving the sulfamidates in pyridine (0.1 M) followed by an acidic workup with aqueous 20% H2SO4 (see Experimental Section and Table 1). Compounds 1 and 2 bearing a methyl ester at the C terminus showed higher reactivity and yielded exclusively the ring-opening products 6 and 7, respectively, after 12 h at room temperature. Amidesubstituted compound 4, though, needed 60 °C and 16 h to achieve high substrate conversions and yielded a mixture of the 13251


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The Journal of Organic Chemistry

Figure 2. Lowest energy structures for the reactants (top row) and transition structures (TS) of the concerted ring-opening (SN2, middle row) and elimination (E2, bottom row) reactions calculated for sulfamidates 1−5 with M06-2X/6-31+G(d,p). Activation enthalpies (ΔH‡) and free energies (ΔG‡) are expressed in kcal mol−1 and calculated from the lowest energy conformers. The torsion angle χ around the ester or amide groups (see Figure 3 for definition) is also represented. Distances are in angstrom.

calculated for the ring opening of sulfamidate 4 at 60 °C (ΔH‡calc = 22 kcal mol−1) is in line with the experimentally measured activation barrier at the same temperature (ΔG‡exp = 20 kcal mol−1) As can be seen in Figure 2, the SN2-type ring-opening was calculated to be the dominant pathway for ester-substituted sulfamidates 1 and 2, for which elimination was disfavored by at least 5 kcal mol−1. This is remarkable since the β-hydrogens are more accessible than the more hindered quaternary carbon. Conversely, the computed chemoselectivity decreases significantly for amide-substituted sulfamidate 4, for which the activation barriers of the SN2 and E2 pathways are virtually identical. It should be mentioned that when Weinreb amides (N(OMe)Me) are used as C-substituents, the E2 reaction is dominant.17 Hence, our calculations reproduce the observed trend that ring-opening and elimination become competitive with amide groups at the C terminal position, as opposed to esters.17,22,24 The reason for this reduced chemoselectivity is that the activation energy of the SN2 pathway in 4 increases 3−4 kcal mol−1 with respect to those calculated for 1 and 2, in agreement with the smaller reaction rates observed experimentally for 4, while the E2 pathway becomes ∼2 kcal mol−1 more accessible.

The origin of the reduced propensity of amide sulfamidate 4 toward nucleophilic ring-opening is not easily attributable to electronic or inductive effects; in fact, the atomic partial charge at the quaternary carbon in the less reactive sulfamidate 4 is slightly more positive (qNBO = +0.18 e−) than that in compound 1 bearing an ester group (qNBO = +0.16 e−). Instead, a higher distortion of the amide moiety with respect to the ester upon planarization of the quaternary carbon seems to impose an important energy penalty while the geometry of the reactant is distorted into that of the SN2 transition structure (TS). Figure 3 shows the calculated torsion profiles around the Cα−CO bonds for both sulfamidates 1 and 4, and clearly reveals the higher barrier associated with the rotation of the more polarized amide group, which requires ∼4 kcal mol−1 to distort into the TS geometry. The origin of this higher rotational barrier in 4 is likely due to the loss of hydrogen bonding between the amide NH and the sulfamidate leaving O atom, with respect to the lowest energy conformation of the reactant. On the other hand, the less polarized ester group has a greater ability to adopt the geometry of the transition state, with a smaller penalty of only 1.5 kcal mol−1. Since the E2-type elimination happens at a less congested position, the corresponding transition structures are less sensitive to the capacity of each C-substituent (ester or 13252


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Regarding the dramatic substituent effects observed at the Nterminal position, the absence of a carbonyl group in sulfamidates 3 and 5 raises the calculated activation barriers for both ring-opening and elimination by ∼3 kcal mol−1, slowing down the reaction ∼100 times in agreement with the experimental observations. This deactivation is even stronger if a pyridine molecule is hydrogen-bonded to the sulfonamide N−H, which is expected to better represent the experimental conditions. Thus, the activation barrier for the ring-opening reaction from the 5·py complex increases 4 kcal mol−1 with respect to the unsolvated sulfamidate 5, further slowing the reaction rate ∼500 times (Figure 4). The totally deprotonated form of this sulfamidate, 5′, is even more unreactive, with a much higher (14 kcal mol−1) calculated activation barrier that translates into millions-fold lower reaction rates (Figure 4). From the experimental view, such partial or total deprotonation of the sulfonamide N−H by the surrounding pyridine is likely to occur, as inferred from the 1H NMR titration experiments performed on 5 (see Supporting Information). In the absence of pyridine, the NH signal appears as a pseudotriplet due to its weak coupling to the adjacent CH2 hydrogens, whose signals appear as two doublets of doublets. Upon addition of only 0.1 equiv of pyridine, the NH··H2C coupling vanishes and the NH signal shifts downfield ∼1 ppm as a broad singlet. The addition of increasing amounts of pyridine caused further broadening and downfield shift of the NH signal, which finally disappears. Our interpretation of these computational results is that, on the one hand, the absence of a carbonyl group precludes the delocalization of the partial negative charge generated in the NSO3 moiety upon Cα−O bond cleavage. This loss of thermodynamic force is revealed by the later character of the

Figure 3. Potential energy scan around the torsion angle χ in sulfamidates 1 and 4, calculated with M06-2X/6-31+G(d,p). Substitution of the ester group at the C terminus in 1 by the primary amide in 4 significantly increases the energy penalty associated with the rotation of this angle due to the nucleophilic attack at the quaternary carbon (SN2) and, to a lesser extent, to the E2 elimination reaction. The value of the torsion angle χ in the fully optimized transition structures for the SN2 and E2 pathways (Figure 2) are marked with arrows.

amide) to distort. Thus, rotation around the Cα−CO bond is minimal for 4-TSE2, imposing no energy penalty with respect to the reactants’ geometry. The maintenance of a hydrogen bond between the amide N−H and the sulfamidate Cα−O in 4-TSE2, which is lost in 4-TSSN2 due to the more severe rotation of the Cα−CO bond in the latter, is likely another source of the lower difference between the SN2 and E2 pathways in 4 with respect to 1.

Figure 4. Summary of substituent effects on the calculated activation barriers (ΔG‡, in kcal mol−1) for the ring-opening reaction of αmethylisoserine-derived sulfamidates. Substitution of amides by esters at the C terminus, and protonation/protection at the N terminus progressively accelerates the reaction, as reflected on the computed relative second-order reaction rates (k2′). 13253



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nucleophilic ring-opening and elimination transition structures (i.e., shorter N···C forming bonds and longer C···O breaking bonds). On the other hand, accumulation of additional electron density on the same NSO3 moiety either by partial or full deprotonation of the N−H group strongly disfavors charge transfer from pyridine to the breaking C−OSO2N bond at the transition state.

*E-mail: [email protected] (G.J.-O.). ORCID

Jesús H. Busto: 0000-0003-4403-4790 Jesús M. Peregrina: 0000-0003-3778-7065 Gonzalo Jiménez-Osés: 0000-0003-0105-4337 Author Contributions

CONCLUSIONS An explanation of the special reactivity of tertiary αmethylisoserine-derived sulfamidates has been proposed, combining experiments and theoretical calculations. The most important conclusion derived from this study is that their reactivity can be modulated by changing the substituents attached to the N- or the C-terminal positions. While the N terminus acts as a switch, triggering (with N-carbonyl groups) or killing (with N−H) reactivity at the quaternary center, the C terminus allows fine-tuning chemoselectivity (SN2 vs E2). Using non-nucleophilic or hindered bases would afford βelimination, but with nonbasic nucleophiles would undergo substitution. This fact is very useful for the synthesis of peptides incorporating this scaffold since further transformations can be performed without undesired ring-opening reactions, and activating the ring-opening pathway when needed.24 EXPERIMENTAL SECTION

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ASSOCIATED CONTENT

AUTHOR INFORMATION

Corresponding Author

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Article

†

C.D.N and N. M. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to MINECO/FEDER (CTQ2015-67727-R and UNLR13-4E-1931 to J.M.P., CTQ2015-70524-R and RYC2013-14706 to G.J.O., and predoctoral fellowships to C.D.N. and N.M.). We also thank CESGA, BiFi (Memento cluster), and UR (Beronia cluster) for supercomputer support.

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REFERENCES

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Ring-Opening Reactions. Sulfamidates 1−5 (50 mg, ∼0.20 mmol) are dissolved in pyridine (2 mL, ∼0.1 M) and stirred at 25 and 60 °C for 12−24 h. After concentration, the resulting crude is dissolved in a mixture of CH2Cl2 and 20% H2SO4 aqueous solution (1:1, 2 mL) and allowed to react for 1 h at room temperature. Finally, extraction with CHCl3/iPrOH (3:1) yielded the crude reaction mixtures that were analyzed through 1H NMR (400 MHz) spectroscopy. Computational Methods. Full geometry optimizations were carried out with Gaussian 0942 using the M06-2X hybrid functional43 and 6-31+G(d,p) basis set with ultrafine integration grids. Bulk solvent effects in pyridine were considered implicitly through the IEF-PCM polarizable continuum model.44 The possibility of different conformations was considered for all structures. All stationary points were characterized by a frequency analysis performed at the same level used in the geometry optimizations from which thermal corrections were obtained at 333.15 K. The quasiharmonic approximation reported by Truhlar and co-workers was used to replace the harmonic oscillator approximation for the calculation of the vibrational contribution to enthalpy and entropy.45 Scaled frequencies were not considered. Massweighted intrinsic reaction coordinate calculations were carried out by using the Gonzalez and Schlegel scheme46,47 to ensure that the TSs indeed connected the appropriate reactants and products. Gibbs free energies (ΔG) of the lowest energy conformers were used for the discussion on the relative stabilities of the considered structures, unless otherwise stated. Cartesian coordinates, electronic energies, entropies, enthalpies, Gibbs free energies, and lowest frequencies of the calculated structures are available as Supporting Information.

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02352. Additional figures, Cartesian coordinates, electronic energies, entropies, enthalpies, Gibbs free energies, and lowest frequencies of the calculated structures (PDF) 13254


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