DOI: 10.1002/chem.201303307

Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of b-Amino Esters and Anti-HIV Drug DPC 083 Hai-Na Yuan, Shen Li, Jing Nie, Yan Zheng, and Jun-An Ma*[a] Optically active b-amino esters are an important class of molecules in biological systems and organic synthesis.[1] Direct asymmetric Mannich reaction[2] of simple esters with imines provides an ideal approach toward the construction of these useful building-blocks. However, such transformation remains a great challenge due to the high pKa value of the a-proton in carboxylic acid derivatives. In this context, the enantioselective decarboxylative Mannich reaction of malonic acid half esters with imines has emerged as a very important tool for the asymmetric synthesis of optically active b-amino esters.[3] For example, this process generally employs an ester equivalent, such as a malonic acid half oxyester or thioester, to participate in the reaction under very mild conditions and thereby circumvent the problems with strong bases and self-condensation. Catalytic asymmetric decarboxylative Mannich reactions with a wide range of aldimine-based electrophiles have proven to be highly effective.[4–6] However, expansion of the electrophilic acceptors to ketimines for the synthesis of b-amino esters with a quaternary stereogenic center seems to be more challenging, since controlling the ketimine geometry in combination with the p-facial selectivity of electrophilic attack is critical for the stereochemical outcome. Only one recent report by Shibata and co-workers has addressed a decarboxylative addition of malonic acid half thioesters (MAHTs) to ketimines derived from isatins to offer the b-amino thioesters with a maximum of 83 % ee.[7, 8] Obviously, there is still plenty of room for the development of efficient protocols for the enantioselective decarboxylative Mannich reactions with ketimines. Moreover, the asymmetric decarboxylative Mannich reaction using the less reactive malonic acid half oxyesters (MAHOs), which directly leading to b-amino oxyesters, has not been documented yet. Herein, we demonstrate that cyclic trifluoromethylketimines are highly effective substrates for organocatalytic

[a] H.-N. Yuan, Dr. S. Li, Dr. J. Nie, Dr. Y. Zheng, Prof. J.-A. Ma Department of Chemistry, Key Laboratory of Systems Bioengineering (The Ministry of Education), State Synergetic Innovation Center of Chemical Science and Engineering Tianjin University, Tianjin 300072 (P. R. of China) Fax: (+ 86) 22-2740-3475 E-mail: [email protected] Supporting information for this article is available on the WWW under


asymmetric decarboxylative Mannich reaction of MAHOs, providing products in excellent yields and enantioselectivities. The cyclic structure of these ketimines, in which the C=N bond is constrained in the E geometry, appears to be important for the success of the reactions. Furthermore, the potential application of this catalytic asymmetric decarboxylACHTUNGREative Mannich reaction was further exemplified in a highly enantioselective synthesis of the anti-HIV drug DPC 083. We initiated our study from the decarboxylative Mannich condensation of 3-oxo-3-phenoxypropanoic acid (1 a) with cyclic trifluoromethylketimine 2 a in THF at room temperature. The reaction hardly occurs without the use of a catalyst (Table 1, entry 1). Then we focused on the catalytic performance of the saccharide-derived amino-thioureas, developed previously in our laboratory (Figure 1).[9] The amine moiety of the catalyst was found to have a significant effect on the catalytic activity as well as the enantioselectivity: a poor result was attained with catalyst (d, S, S)-Aa bearing a primary amine function (entry 2), whereas remarkable improvement in the yields and enantioselectivities of the Mannich adduct 3 a could be observed when tertiary amine-thiourea catalysts were employed (entries 3–10). Among them, catalyst (d, S, S)-Bd exhibited the best catalytic activity and chiral induction ability (entry 8). Solvent screening revealed that THF remains to be the solvent of choice, and other solvents such as chloroform, dichloromethane, toluene, and 1,4-dioxane diminish the yield and/or enantioselectivity (entries 11–14). The catalyst loading can be reduced to as low as 1 mol % without a significant decrease in the product yield and enantioselectivity, although a prolonged time was required (entries 15 and 16). Reducing the amount of MAHO to 1.5 or even 1.2 equivalents gave comparable results under standard reaction conditions (entries 17 and 18). Interestingly, the catalyst (d, R, R)-C, a diastereoisomer of (d, S, S)-Bd with the opposite configuration on the diamine moiety, could give the Mannich adduct 3 a with the retained configuration in high enantioselectivity as well (entry 19). There is no doubt that the use of catalyst (l, R, R)-D led to the other enantiomer of the b-amino oxyester in comparable yield and ee value (entry 20). These results demonstrated that the reversal of enantioselectivity is directly related to the saccharide moiety of organocatalysts. Under the optimal conditions, the scope of the reaction was explored with a variety of MAHOs 1 and cyclic keti-

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Chem. Eur. J. 2013, 19, 15856 – 15860

COMMUNICATION Table 1. Screening of catalysts and conditions optimization for the decarboxylative Mannich reaction of MAHO 1 a with ketimine 2 a.


Catalyst [mol %]


Time [h]

Yield [%][b]

ee [%][c]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15[d] 16[d] 17[e] 18[f] 19 20

– ACHTUNGRE(d,S,S)-Aa (10) ACHTUNGRE(d,S,S)-Ab (10) ACHTUNGRE(d,S,S)-Ac (10) ACHTUNGRE(d,S,S)-Ba (10) ACHTUNGRE(d,S,S)-Bb (10) ACHTUNGRE(d,S,S)-Bc (10) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,S,S)-Be (10) ACHTUNGRE(d,S,S)-Bf (10) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,S,S)-Bd (5) ACHTUNGRE(d,S,S)-Bd (1) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,S,S)-Bd (10) ACHTUNGRE(d,R,R)-C (10) ACHTUNGRE(l,S,S)-D (10)


96 96 48 48 48 48 48 48 48 48 72 72 48 48 72 96 48 48 48 48

0 28 95 94 97 70 84 99 94 90 65 72 84 93 98 96 98 98 99 97

– 55 (R) 94 (R) 98 (R) 96 (R) 98 (R) 91 (R) 99 (R) 97 (R) 91 (R) 75 (R) 82 (R) 95 (R) 93 (R) 96 (R) 94 (R) 98 (R) 97 (R) 98 (R) 97 (S)

[a] General reaction conditions: 2 a (0.1 mmol), 1 a (0.2 mmol), and catalyst (1–10 mol %) in solvent for the stated time. PMB = para-methoxybenzyl, THF = tetrahydrofuran. [b] Isolated yield. [c] Determined by HPLC analysis on a chiral stationary phase. The absolute configuration was determined by comparison of the optical rotation value of its derivative with the literature data (vide infra). [d] 2 a (0.3 mmol) and 1 a (0.6 mmol) were used; [e] 1.5 equiv of 1 a was used; [f] 1.2 equiv of 1 a was used.

Figure 1. Structures tested.





mines 2 in the presence of 10 mol % (d, S, S)-Bd (Scheme 1). The use of MAHOs with different phenolicester substituents afforded the corresponding b-amino esters 3 a–g in high yields (90–99 %) with excellent enantioselectivities (90–99 % ee). Next studies showed that the decarboxylative Mannich reaction could be extended to a series of cyclic ketimines. The substituents on the aromatic ring of the ketimines had a negligible influence, generating the de-

Chem. Eur. J. 2013, 19, 15856 – 15860

sired adducts 3 h–o in 93–99 % yields and 91–99 % ee. The N-TMB-protected cyclic ketimine (TMB = 2,4,6-trimethylbenzyl) was found to be an equally effective substrate, delivering 3 p in 98 % yield with 99 % ee. A dramatic decrease in enantioselectivity was observed (3 q, 55 % ee) when N-protecting group-free substrate was subjected to the reaction, which indicates the protecting group was indispensable. Good results could also be obtained when the trifluoromethyl group on the quinazolin-2ACHTUNGRE(1 H)-one ring was replaced with an analogous electron-withdrawing difluoromethyl group (3 r in 90 % yield with 92 % ee). However, other substrates that replaced the trifluoromethyl group with a methyl or phenyl group were ineffective in this reaction system. These results indicated that the strong electron-withdrawing di- and trifluoromethyl groups are critical for the reactivity and selectivity of this decarboxylative Mannich reaction.[10] The utility of this decarboxylative Mannich products was demonstrated by the following transformations (Scheme 2). Starting from the adduct (R)-3 i, a simple reduction of the ester moiety with NaBH4, followed by cyclization to the amide nitrogen, gave 5,9b-dihydro-1 H-azetoACHTUNGRE[1,2-c]quinazolin-4ACHTUNGRE(2 H)-one (5) containing an azetidine moiety, which is a key subunit found in a number of bioactive natural products (Scheme 2 a).[11] Our efficient enantioselective decarboxylative Mannich reaction also provides an attractive approach to the anti-HIV drug DPC 083 (Scheme 2 b).[12] Compound (S)-3 a, which was used as the key intermediate for the synthesis of DPC 083, was obtained in 97 % yield with 97 % ee upon the decarboxylative Mannich reaction of MAHO 1 a with ketimine 2 a in the presence of (l, R, R)-D. The enantiopurity of (S)-3 a was further improved to 99 % ee after a single recrystallization from THF. Reduction of the phenol ester group with NaBH4 and powdered anhydrous CaCl2 in methanol yielded the alcohol 6 in 85 % yield with 99 % ee. Subsequently, a simple oxidation using pyridinium chlorochromate (PCC) afforded the corresponding aldehyde 7 in 72 % yield. Treatment of 7 with cyclopropylmagnesium bromide in THF at 0 8C gave the adduct 8 in 81 % yield with a diastereomeric ratio of 1:1. The final product 10 could be easily obtained after dehydration and deprotection of the mixture 8. The optical rotation data of DPC 083 (10) are entirely consistent with those described in the literature.[13] Thus, the determination of the stereochemistry of 10 was used as the basis for the assignment of absolute configuration reported in Table 1 and Scheme 1. To gain some insights into the mechanism, a 19F NMR study was undertaken on the decarboxylative Mannich reaction of MAHO 1 a with ketimine 2 a in the presence of (d, S, S)-Bd in [D8]THF (see the Supporting Information for further details). As shown in Figure 2 a, two new signals at 80.39 and 80.52 ppm could be detected after a few hours, which implied the formation of two diastereoisomers of the addition intermediate 12. Although such proposed intermediate could not be isolated directly, these experimental results provide supportive evidence that nucleophilic addition of MAHOs to the ketimines could occur prior to the

 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


J. -A. Ma et al.

Scheme 1. Scope of the decarboxylative Mannich reaction of MAHOs 1 with cyclic ketimines 2.

Scheme 2. a) Further transformation of the decarboxylative Mannich product. b) Synthesis of anti-HIV drug DCP 083.


 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2013, 19, 15856 – 15860

Enantioselective Decarboxylative Mannich Reaction


Figure 2. a) Stack plot of 19F NMR spectra. (Spectra A, B, and C: 19F NMR spectrum of ketimine 2 a, Mannich product 3 a, and the hydration by-product 11; Spectrum D: 19F NMR spectra of the reaction mixture collected at certain hours). b) Hydrogen-bonding complex between organocatalyst and ketamine; F green, N blue, O red, S yellow. c) Proposed mechanism for the organocatalytic decarboxylative Mannich reaction of MAHOs 1 with cyclic ketimines 2.

decarboxylation step during the decarboxylative Mannich reaction. On the other hand, the interactions between substrate and organocatalyst were probed computationally by examining the bond critical points (BCPs) with Baders atoms in molecules (AIM) analysis.[14] The calculations revealed that the cyclic ketimine was activated and oriented by H-bonding with the NH groups of the organocatalyst.[15] A H p bonding interaction between the aromatic-substituted protecting group on the ketimine substrate and the saccharide moiety of organocatalyst may also play an important role in stabilizing the transition state (Figure 2 b). This is in agreement with the observation that substrate 2 q lacking an aromatic protection group on its nitrogen exhibited only moderate enenatioselectivity in forming product 3 q. Additionally, the tertiary amine moiety of organocatalyst electrostatically bonds to the MAHOs 1 through a salt bridge. From the above analysis and the absolute configurations of the products 3, a transition state (TS) for the reaction of MAHOs 1 with ketimines 2 in the presence of chiral organocatalyst Bd is proposed in Figure 2 c. Because the nucleophile approaches the Si-face of the C=N group, the R enantiomer of the Mannich products 3 is preferentially formed.

The potential application of this catalytic asymmetric decarboxylative Mannich reaction was demonstrated as a key step in a new and efficient asymmetric synthesis of the antiHIV drug DPC 083. Efforts are currently underway to elucidate the mechanistic details and the application of MAHOsderived synthons to other transformations, the results of which will be reported in due course.



In summary, we have developed a highly efficient enantioselective decarboxylative Mannich reaction of MAHOs with cyclic trifluoromethylketimines. With the aid of saccharidederived amino-thiourea catalysts, a series of enantioenriched b-amino oxyesters containing a chiral b-quaternary center were obtained in very high yields and enantioselectivities.

This work was supported by the National Natural Science Foundation of China, and the National Basic Research Program of China (973 Program, 2014CB745100).

Chem. Eur. J. 2013, 19, 15856 – 15860

Experimental Section General procedure for decarboxylative Mannich reactions of malonic acid half oxyesters with ketimines: A mixture of cyclic N-acyl ketimine 2 (0.1 mmol), amino-thiourea catalyst (d, S, S)-Bd (0.01 mmol), and malonic acid half oxyester 1 (0.2 mmol) in THF (1.0 mL) was added into a 10 mL Schlenk flask equipped with a stirring bar. The reaction was then stirred at room temperature for the corresponding time. After completion of the reaction (monitored by TLC), solvent was removed under reduced pressure, the residue was treated with 1 N NaHCO3 (8 mL) and extracted with ethyl acetate (3  10 mL). The combined organic layers were washed with saturated brine (8 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate or ethyl acetate/CH2Cl2) to give the product 3.

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J. -A. Ma et al.

Keywords: asymmetric catalysis · b-amino esters · decarboxylative Mannich reaction · malonic acid half oxyesters · saccharide-derived amino-thioureas

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Received: August 23, 2013 Published online: October 21, 2013

Chem. Eur. J. 2013, 19, 15856 – 15860

Highly enantioselective decarboxylative Mannich reaction of malonic acid half oxyesters with cyclic trifluoromethyl ketimines: synthesis of β-amino esters and anti-HIV drug DPC 083.

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