Letter pubs.acs.org/OrgLett
Highly Enantioselective Synthesis of syn-β-Hydroxy α‑Dibenzylamino Esters via DKR Asymmetric Transfer Hydrogenation and Gram-Scale Preparation of Droxidopa Guodong Sun,†,§ Zihong Zhou,† Zhonghua Luo,† Hailong Wang,† Lei Chen,† Yongbo Xu,† Shun Li,† Weilin Jian,† Jiebin Zeng,† Benquan Hu,† Xiaodong Han,† Yicao Lin,† and Zhongqing Wang*,†,§ †
HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P.R. China State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd, Dongguan 523871, P.R. China
§
S Supporting Information *
ABSTRACT: A highly efficient preparation of enantiomerically pure syn aryl β-hydroxy α-dibenzylamino esters is reported. The outcome was achieved via dynamic kinetic resolution and asymmetric transfer hydrogenation of aryl αdibenzylamino β-keto esters. The desired products were obtained in high yields (up to 98%) with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (up to >99% ee). Furthermore, this method was applied for the gram-scale preparation of droxidopa. hiral aryl β-hydroxy α-amino acids and derivatives are important structural motifs in many pharmaceutical molecules. For example, aryl β-hydroxy α-amino acids are found in droxidopa1 and a BMS drug candidate,2 in addition to chloramphenicol,3 thiamphemicol,4 florenicol,5 and all their corresponding derivatives (Figure 1). Furthermore, chiral aryl β-hydroxy α-amino acids are also found in natural products such as cyclomarins6 and ustiloxins.7
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drawbacks such as high pressure and air-sensitive catalysts being required. DKR asymmetric transfer hydrogenation (DKRATH) with hydrogen donors instead of hydrogen gas is more attractive because of its low cost and operational simplicity. In this field, several groups have recently described the reduction of these related compounds in their N-monoprotected forms10a−d or hydrochloride salts10e,f through Ru-catalyzed DKR-ATH. Nevertheless, anti diastereomers are often obtained as the major products (Scheme 1, previous work). For the Scheme 1. Previous Reports of the Synthesis of Aryl βHydroxy α-Amino Esters and This Work
Figure 1. Examples of chiral pharmaceuticals derived from aryl βhydroxy α-amino acids and derivatives.
Because of the great importance of aryl β-hydroxy α-amino acids, much effort has been devoted to developing asymmetric methods to prepare these useful compounds.8 Among these methods, asymmetric hydrogenation via dynamic kinetic resolution (DKR) of racemic aryl α-amino β-keto esters is regarded as a powerful synthetic method. The method for DKR asymmetric hydrogenation (DKR-AH) of racemic aryl α-amino β-keto esters with chiral ruthenium catalysts was first reported by Noyori in 1989.9a It provided the syn-aryl β-hydroxy αamino esters with high diastereo- and enantioselectivities and has thus been developed further since then. However, the AH of related compounds9 remains problematic due to some © XXXX American Chemical Society
synthesis of the syn diastereomers, successful results are rarely reported,11 and these generally proceed either with poor enantioselectivities or diastereoselectivities. Therefore, an asymmetric synthesis of syn-aryl β-hydroxy α-amino acids with high diastereo- and enantioselectivities is still challenging and highly desirable. Received: July 4, 2017
A
DOI: 10.1021/acs.orglett.7b01982 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Previously, Guanti et al.12 reported a practical method to prepare syn-β-hydroxy α-amino esters by reduction of αdibenzylamino β-keto esters with NaBH4, but the method provided only racemic products, although the diastereoselectivities were perfect (up to >99:1 dr). In light of this, we envisaged that an asymmetric method for the reduction of aryl αdibenzylamino β-keto esters with Ru-catalyzed DKR-ATH could be developed to prepare enantiomerically pure syn aryl βhydroxy α-dibenzylamino esters (Scheme 1, this work). Our initial investigation was carried out using HCOOH/ Et3N as hydrogen donor, with 5a as the model prochiral substrate in DCM at reflux. Thus, a series of catalysts (Table 1,
oxo-tethered Ru(II) catalyst (R,R)-CAT05 developed by Ikariya and co-workers. 1 5 Surprisingly, the chiral Cp*MTfDPEN catalysts (M = Rh or Ir, Table 1, entries 6 and 7) both showed no catalytic activities for this reaction. Subsequently, the influence of the base on the activity of this DKR asymmetric transfer hydrogenation was evaluated. The secondary amine diethylamine proved to be the optimal base and could significantly shorten the reaction time (full conversion in 24 h, Table 1, entry 9), while other bases could not play such a role (Table 1, entries 8, 10, and 11). Most importantly, it was observed that 91% conversion could be achieved using only 5 mol % catalyst without decreasing the stereoselectivity or prolonging the reaction time (Table 1, entry 12). Hence, the optimized reaction conditions use oxo-tethered Ru(II) catalyst (R,R)-CAT05 as the catalyst in a mixture of HCOOH and diethylamine (5:2, 3 equiv, as the hydrogen donor) in DCM at reflux (40 °C) for 24 h. With the optimized conditions in hand, a wide range of substrates were used in the reaction. The results are summarized in Scheme 2. Substrates with electron-donating
Table 1. Optimization of the Reaction Conditions for the DKR-ATH of 5aa
Scheme 2. DKR-ATH of Aryl α-Dibenzylamino β-Keto Esters 5a−l Catalyzed by (R,R)-CAT05a
entry
catalyst
base
convb (%)
drc (syn/anti)
eed (%)
1 2 3 4 5 6 7 8 9e 10 11 12f
(R,R)-CAT01 (R,R)-CAT02 (R,R)-CAT03 (R,R)-CAT04 (R,R)-CAT05 (R,R)-CAT06 (R,R)-CAT07 (R,R)-CAT05 (R,R)-CAT05 (R,R)-CAT05 (R,R)-CAT05 (R,R)-CAT05
Et3N Et3N Et3N Et3N Et3N Et3N Et3N DIPEA Et2NH i Pr2NH t BuNH2 Et2NH
19 36 32 97 97 trace trace 91 >99 99 99 91
ND ND ND >20:1 >20:1 ND ND >20:1 >20:1 >20:1 >20:1 >20:1
83 92 92 99 >99 ND ND >99 >99 >99 >99 >99
a
Reaction conditions: 5a (1.67 mmol), HCO2H/base (5:2) (3 equiv), DCM(8.0 mL) at reflux (40 °C) for 40 h. bDetermined by HPLC. c Determined by 1H NMR. dDetermined by chiral HPLC using a CHIRALPAK IA column. e24 h. f5.0 mol % of (R,R)-CAT05 was used. ND= not detected.
a General conditions: 10 mol % of (R,R)-CAT05, substrates 5a−l (1.67 mmol), HCOOH (5.01 mmol), and Et2NH (2.00 mmol) were stirred at 40 °C in DCM for 24 h. Isolated yields after column chromatography18 were reported, dr ratios were determined by 1H NMR of the crude reaction mixture, and only a single diastereomer was visible for most of the products; ee values were determined by a CHIRALPAK IA column. bReaction time 15 h. cReaction time 48 h. d 5.0 mol % of (R,R)-CAT05 was used.
(R,R)-CAT01 to (R,R)-CAT07) were screened under these conditions. The Ru(II) catalyst (R,R)-CAT01 afforded the desired product 6a in low conversion (19%, Table 1, entry 1). (R,R)-CAT02 and (R,R)-CAT03 both showed a moderate conversion (>30%, Table 1, entries 2 and 3). Notably, a Ru(II) catalyst (R,R)-CAT04, containing a trifluoromethanesulfonyl group on the nitrogen atom, exhibited a higher catalytic activity and afforded 6a in 97% conversion with >20:1 dr and 99% ee (Table 1, entry 4). These above results indicated that the sulfonyl function on the sulfonamide group may affect the reactivity or stereoselectivity.13 As previously reported, “tethered” Ru (II) catalysts showed better activity and stereoselectivities in the ATH reaction due to their better rigidity.14 Indeed, the best result (97% conversion, >20:1 dr and >99% ee, Table 1, entry 5) was provided by the unique
(5a, 5b, 5d, 5g, 5h, and 5l) or electron-withdrawing (5c, 5f, and 5i) substituents all gave excellent stereoselectivity (>20:1 dr and >99% ee) and good-to-excellent yields (78−98%) under the optimized conditions. In particular, the substrate 5f afforded the desired product 6f in 98% isolated yield, with >20:1 dr and 99.9% ee within 24 h. However, analysis of the electronic effect displayed that the substrates with electron-withdrawing substituents (5c and 5i, 15 h) at the para-position converted B
DOI: 10.1021/acs.orglett.7b01982 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters faster than those with electron-donating substituents (5g and 5h, 48 h). Furthermore, this method was also successfully applied to heteroaromatic substrates, such as 5j and 5k, which showed good yields and stereoselectivities too. The lower enantioselectivity of 5k might be due to the weak CH/π interaction between the pyridine ring and η6-arene ligand of the Ru catalyst.16 Only the syn diastereomers17 were obtained in all the above cases. It was believed that the dibenzyl substituents at the nitrogen atom may play a key role on the stereoselectivity. To test this idea, the diallylamino derivative 5e was synthesized and subjected to the reaction. As expected, 6e was obtained with lower dr and ee value (13:1 dr, 96% ee). In order to demonstrate the practicality of this method, the further application for the synthesis of Droxidopa was performed as follows (Scheme 3) . The DKR-ATH reaction
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Guodong Sun: 0000-0003-3785-7641 Zihong Zhou: 0000-0002-9905-6957 Zhongqing Wang: 0000-0001-5194-4157 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the State Key Laboratory of Anti-Infective Drug Development (Sunshine Lake Pharma Co., Ltd.), (No. 2015DQ780357). We thank Zeping Zhan and Guozhu Liu (HEC Pharm Co., Inc.) for NMR assistance and Lina Zhu and Baolei Luan (HEC pharm Co., Inc.) for HPLC and optical rotation assistance.
Scheme 3. Gram-Scale Synthesis of Droxidopa
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REFERENCES
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of 5a on a 10 g scale was complete in 39 h by using only 5.0 mol % of (R,R)-CAT05 and gave the desired product 6a in 99% isolated yield. Subsequent hydrolysis of optically pure 6a using LiOH as the base afforded the product 7 in 92% yield without loss of the enantiomeric excess. Deprotection of all four benzyl groups of 7 could be achieved in one step by catalytic hydrogenation under 1 atm of H2 at room temperature, which furnished Droxidopa hydrochloride in almost quantitative yield. Finally, droxidopa was isolated by adjusting the pH value to 4−5 with Et3N, and the yield was up to 90%. The absolute configuration of droxidopa was confirmed as (2S,3R) by comparison with the known standard optical rotation.19 In summary, we have developed an efficient asymmetric synthesis of enantiomeric pure syn-aryl β-hydroxy α-dibenzylamino esters via DKR asymmetric transfer hydrogenation. Our results showed perfect diastereoselectivity and excellent enantioselectivity (dr >20:1 and up to >99% ee) on varieties of aryl α-dibenzylamino β-keto esters. The dibenzyl substituents at the nitrogen atom not only play a key role in the stereochemical outcome of the reaction but also are easily removed to release the free amino group under mild conditions. This method is therefore an alternative to DKR-AH, yet a complementary addition to DKR-ATH and has already shown its potential in applications for the synthesis of useful chiral bioactive compounds.
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Experimental details and characterization data for all new compounds (PDF)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01982. C
DOI: 10.1021/acs.orglett.7b01982 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters (f) Llopis, Q.; Fér ard, C.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. Synthesis 2016, 48, 3357. (11) Bourdon, L. H.; Fairfax, D. J.; Martin, G. S.; Mathison, C. J.; Zhichkin, P. Tetrahedron: Asymmetry 2004, 15, 3485. (12) Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C. Tetrahedron 1988, 44, 3671. (13) The sulfonyl function on the sulfonamide group may affect the catalytic activities of the Ru−RSO2DPEN catalysts. See: Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskowski, C. Chem. Commun. 2001, 2572. (14) (a) Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986. (b) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127, 7318. (c) Parekh, V.; Ramsden, J. A.; Wills, M. Catal. Sci. Technol. 2012, 2, 406. (d) Nedden, H. G.; ZanottiGerosa, A.; Wills, M. Chem. Rec. 2016, 16, 2623. (15) (a) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito, T.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960. (b) Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2016, 138, 10084. (16) Wang, B.; Zhou, H.; Lu, G.; Liu, Q.; Jiang, X. Org. Lett. 2017, 19, 2094. (17) The syn and anti diastereomers can be distinguished in the NMR spectrum. (18) During purification via chromatography, the self-disproportionation of enantiomers phenomenon (SDE) was considered at first. However as all of the eluted fractions, earlier and later, were collected for the measurements of the enantiomeric excess, the SDE, even if it happened, would not affect the experimental results. (19) The known standard optical rotation was from the 17th edition (March 7, 2016) official monographs: α20 D : −38 to −43 (after drying, 0.1 g, 0.1 mol/L hydrochloric acid TS, 20 mL, 100 mm). See: http:// jpdb.nihs.go.jp/jp17e/.
D
DOI: 10.1021/acs.orglett.7b01982 Org. Lett. XXXX, XXX, XXX−XXX
