Letter pubs.acs.org/OrgLett
Temperature-Dependent Enantio- and Diastereodivergent Synthesis of Amino Acids with One or Multiple Chiral Centers Shiming Fan, Shouxin Liu,* Sufang Zhu, Juan Feng, Zhiwei Zhang, and Jing Huang State Key Laboratory Base, Hebei Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, No. 70 Yuhua East Road, Shijiazhuang 050018, China S Supporting Information *
ABSTRACT: A general and facile methodology for temperature-dependent enantiodivergent and diastereodivergent synthesis of amino acids with one or multiple chiral centers was developed. Camphor-based tricyclic iminolactones attack electrophiles from the endo face at low temperature (−78 to −40 °C) and from the exo face at high temperature (−10 to 25 °C).
S
Scheme 1
tereodivergent reaction is an efficient way to access all optically active stereoisomers of target chiral molecules, which are highly important and valuable in drug discovery.1 Asymmetric catalysis is a powerful and practical method for achieving stereodivergence.2 Enantiodivergent processes can be achieved by selecting between a pair of enantiomeric catalysts. However, diastereodivergent processes that generate chiral molecules with multiple stereogenic centers in a single step are much more challenging. A diastereochemical switch generally requires the use of distinct chiral catalysts3 or ligands,4 the use of stereodivergent dual catalysis,2d,5 the addition of different Lewis acids,6 and change in structure of starting material.7 Recently, an approach involving changing the reaction conditions, including solvent and temperature,8 or using light9 to tune the functions of a single catalyst for simply achieving enantio- and diastereodivergence has been developed. Aside from asymmetric catalysis, using a chiral auxiliary is another selection for stereodivergent synthesis.10 Xu’s group developed a method for the preparation of optically active αamino acids by using hydroxycamphor as chiral auxiliary.11 Tricyclic iminolactone 1 or 2 prepared from glycine and chiral auxiliary hydroxycamphor attacked electrophiles from the endo face because of low steric hindrance. The synthesis of (S)-amino acid used chiral auxiliary 3-hydroxycamphor, whereas the synthesis of non-proteinogenic (R)-amino acid must use another chiral auxiliary, 2-hydroxycamphor. Here, we investigated an approach for changing the reaction temperature to realize stereodivergent reaction using one chiral auxiliary for the synthesis of amino acid stereoisomers with one or multiple chiral centers (Scheme 1). Initially, alkylation of tricyclic iminolactone 1 with benzyl chloride was tested (Table 1, entries 1−4). The orientation of iminolactone alkylation strongly depended on reaction temperature. The reaction was endo alkylation when the reaction temperature was −78 to −40 °C, and only endo-product 3a was obtained. As temperature increased, the content of endo-product © 2017 American Chemical Society
3a decreased, whereas exo-product 4a increased (Table 1, entries 2 and 3). At 25 °C, only the exo-product 4a was obtained (Table 1, entry 4). The attempt was also successful at 25 °C with KOt-Bu as the base. Two stereoisomers of phenylalanine were obtained after subsequent removal of the auxiliary. To evaluate the generality of the reaction, alkylation of tricyclic iminolactones 1 and 2 with benzyl chloride, allyl bromide, and iodomethane were conducted (Table 1, entries 5−12). All reactions yielded endoproducts using LDA as base at low temperature (−78 to −60 °C), whereas exo-products were obtained in good yield and excellent dr (>99:1) using LDA or KOt-Bu as base at room temperature. The results exhibit that the enantiodivergent synthesis of (S)- and (R)-amino acids with one chiral center can be realized using only one chiral auxiliary by varying reaction temperature. We conducted quantum chemical calculations to explain the result of a stereoselective alkylation reaction controlled by temperature. The geometries of products endo-3a and exo-4a were optimized by Gaussian 03 at the B3LYP/6-31++g(d,p) level without restriction. The results showed that the structure of exo4a was more stable than that of endo-3a, with an energy difference Received: July 26, 2017 Published: August 15, 2017 4660
DOI: 10.1021/acs.orglett.7b02296 Org. Lett. 2017, 19, 4660−4663
Letter
Organic Letters Table 1. Enantiodivergent Synthesis of (R)- and (S)-Amino Acids
entry
substrate
E
temp (°C)
product
yield (%)a
endo/exob
1 2 3 4 5 6 7 8 9 10 11 12
1 1 1 1 1 1 1 1 2 2 2 2
a a a a b b c c a a b b
−78 to − 40 −40 −20 25 −78 to − 60 25 −78 to − 60 25 −78 to − 40 25 −78 to − 60 25
3a 3a+4a 3a+4a 4a 3b 4b 3c 4c 5a 6a 5b 6b
85 86 89 81, 76c 89 87, 84c 72 68, 65c 80 73, 72c 82 78, 71c
>99:1 3:2 1:2 99:1 99:1 99:1 99:1 99:1 60:40 99:1 >99:1
35
2:1
eletrophilicity of CC in t-butyl tiglate decreased significantly due to α-methyl of tiglate compared with t-butyl crotonate. To improve the reactivity of CC, we applied a strategy of changing the ester group and selected substituted benzyl tiglate as the Michael reaction acceptor to rerun the reaction. The results showed that the introduction of electron-withdrawing groups from the benzene ring was available to increase the reactivity of ester and resulted in a good yield. However, reaction stereoselectivity strongly depended on the position of the substitution groups at the benzene ring and reaction temperature (Table 4, entries 2−8). The o-position substituent was more favorable for asymmetric Michael addition. Presumably, the stereoselectivity should be affected by camphor and ester groups collectively. The space distance of the o-position substituent and camphor is closer than m- and p-substituents, which shows a stronger stereocontrol effect. When 2,6-dichlorobenzyl tiglate reacted with iminolactone 1, the reaction did not deliver the desired result at low temperature (≤−20 °C) (Table 4, entry 6). As temperature increased successively, two exo-Michael adducts 18 and 19 were obtained. Notably, at −10 °C, the reaction produced predominantly exo-Michael adduct 18 with a 18/19 ratio of 85:15, and the configuration of 18 is (5R,14R,15S) (Table 4, entry 7); however, at 25 °C, the reaction predominantly yielded another exo-Michael adduct 19 with a 18/19 ratio of 10:90, and the configuration of 19 is (5R,14S,15R) (Table 4, entry 8). The absolute configurations of products 18 and 19 were ascertained by X-ray crystallography.12 Products 9a, 11, 13, 15, 16a, 18, and 19 were hydrolyzed with 4−6 N HCl solution at 70 to 80 °C to obtain the corresponding amino acids. Optically pure amino acids were obtained successfully in good yields (>70%) and excellent enantiomeric and/or diastereomeric excesses (>99% ee/de). The syntheses of non-proteinogenic amino acids, including (2R,3R,4S)-3-methyl glutamic acid 23, (2R,3S,4R)-3,4-dimethyl glutamic acid 24, and (2R,3S,4S,5S)-multisubstituted proline 25, were first reported.
a
Yield of isolated product. bEstimated by the yield of isolated product. c Reaction did not occur.
which could be hydrolyzed to form the spirocyclic amino acid, as a proline derivative. The absolute configuration of 15a was confirmed by X-ray crystallography. At 25 °C, optically pure exoMichael adduct 16a ((5S,14S)-isomer) was obtained as the major product (Table 3, entry 4). Compared with the structure of tricyclic iminolactone 1, the imine of 2 lacks the steric hindrance protection of the methyl group at the bridgehead C8. Thus, the intermediate carbanion C15 attacks imino C7 easily. Another main reason for formation of compound 15 should be that the orientation of addition keeps away from the cis-1,4 stereointeraction of methyl at C14 and the marked H of intermediate 15 in boat configuration. To prevent cyclization, ethyl crotonate was replaced with t-butyl crotonate to enhance the steric hindrance effects of the ester group, but only spirocyclic product 15b was obtained (Table 3, entries 5 and 6). From the structure of product 15, the ester group R is far away from the camphor structure. Thus, increasing the size of the ester group cannot hinder the addition occurrence. Using LiHMDS and DBU as bases of the reaction was also examined, but the attempts were unsuccessful (Table 3, entries 7 and 8). On the basis of the results of Michael reaction of tricyclic iminolactone 1 with crotonate esters, we conducted the reaction of tricyclic iminolactone 1 to tiglate. In principle, the Michael reaction can form eight diastereoisomeric products, where three 4662
DOI: 10.1021/acs.orglett.7b02296 Org. Lett. 2017, 19, 4660−4663
Organic Letters
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The recovered chiral auxiliary was recycled to prepare tricyclic iminolactone (Table 5).
a
substrate
product
yield (%)a
configure
[α]D20
1 2 3 4 5 6 7
9a 11 13 16a 18 19 15
20 21 22 23 24 25 26
79 82 76 79 72 81 86
2S,3S 2S,3R 2R,3R 2S,3S 2R,3R,4S 2R,3S,4R 2R,3S,4S,5S
+20 +21.8 −37.2 +37.8 −26.8 −30.5 −54.3
Yield of isolated product.
In summary, we developed a novel and practical method for the enantiodivergent and diastereodivergent synthesis of amino acid stereoisomers with one or multiple chiral centers. The reaction orientation of tricyclic iminolactone is found to be strongly dependent on reaction temperature. Highly stereoselective construction of multiple chiral centers was completed by a diastereodivergent Michael addition in a single operation. The structure of the ester group is another crucial factor that influences the Michael reaction rate and stereoselectivity. Extensions of this strategy with other chiral compounds are in progress in our laboratory.
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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/acs.orglett.7b02296. Synthetic procedures and NMR data (PDF) X-ray data for compounds 8a, 9a, 13c, 15a, 18, 19 (ZIP)
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REFERENCES
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Table 5. Synthesis of Non-proteinogenic Amino Acids
entry
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shouxin Liu: 0000-0003-4104-2971 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was from the National Basic Research Program of China (2011CB512007, 2012CB723501), the National Natural Science Foundation of China (30472074, 30873139), the Hebei Natural Science Foundation (12966737D, 10276406D6), and the Department of Education of Hebei Province Fund (QN2017065, BJ2017059). 4663
DOI: 10.1021/acs.orglett.7b02296 Org. Lett. 2017, 19, 4660−4663
