Regio- and Stereoselective Cascades via Aldol Condensation and 1,3

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Regio- and Stereoselective Cascades via Aldol Condensation and 1,3-Dipolar Cycloaddition for Construction of Functional Pyrrolizidine Derivatives Zhuo-Ya Mao,† Yi-Wen Liu,† Pan Han,† Han-Qing Dong,‡,§ Chang-Mei Si,*,† Bang-Guo Wei,*,† and Guo-Qiang Lin†,‡ †

Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

‡

S Supporting Information *

ABSTRACT: An efficient and step-economical approach to access functionalized pyrrolizidine derivatives by a one-pot tandem sequence, including an aldol condensation and subsequent 1,3-dipolar cycloaddition process, has been developed, starting from acetone, aldehyde, and proline. A number of substituted aromatic aldehydes were amenable to this transformation, and the desired products, racemic 7a−7w and chiral 9a−9m, were obtained with excellent regioselectivities and outstanding diastereoselectivities. Moreover, in situ NMR studies revealed MgSO4 could effectively promote the aldol condensation pathway in this tandem process.

T

he discovery of an efficient reaction or versatile method for divergent skeleton construction is one of the most challenging tasks in organic synthesis.1 As a prime instance, functionalized pyrrolizidine skeletons are a common structure unit in many bioactive alkaloids, azasugars and pharmaceutical agents.2 Typical examples include daphnipaxinin 1, norsecurinine 2, as well as platyphilline 3 (Figure 1). Daphniphyllum alkaloids are

Figure 2. Strategy to pyrrolizidine skeletons by tandem process. Figure 1. Examples of natural products containing pyrrolizidine skeletons.

on catalysis by chiral secondary amines, numerous high quality studies using other variants (chiral enamines, iminium ions, dienamines, and singly occupied molecular orbital enamines) have been reported.11 1,3-Dipolar [3 + 2] cycloaddition is one of the most powerful methods applied to construct highly substituted pyrrolidine for many complex natural products and medicinal molecules.12 The number of publications on [3 + 2] cycloaddition reactions, through either asymmetric organocatalytic or metal-mediated approach, has increased dramatically over the years.13 Among them, azomethine ylides derived from aldehydes and ketones were well documented for pyrrolizidine synthesis.14 Very recently, Liu and co-workers reported 1,3-dipolar cycloaddition reaction of β,γ-unsaturated α-keto esters with an unsaturated azomethine ylide.15 Although α,β-unsaturated carbonyl

neurotoxic and cause depression of voluntary movement as well as respiratory function through the central nervous system.3 Additionally, a few Daphniphyllum alkaloids show potent cytotoxicity against several tumor cell lines.4 Although tremendous effort has been devoted to the construction of a functionalized pyrrolizidine scaffold,5 most synthetic routes require a multistep sequence.6 A more straightforward and efficient approach is still quite limited. In the past years, asymmetric organocatalysis, which is mediated solely by small organic molecules, has undoubtedly become one of the most efficient and reliable methods in modern organic synthesis, and many powerful asymmetric approaches using a cascade process have been achieved to simultaneously form multiple bonds (Figure 2).7 In particular, following the pioneering work by Enders,7a List,8 Jørgensen9 and MacMillan10 © XXXX American Chemical Society

Received: December 29, 2017

A

DOI: 10.1021/acs.orglett.7b04056 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Scheme 1. Reactions with Different Aromatic Aldehydesa−d

compounds did not react under their optimal condition, we envisioned that such substrates could be generated in situ through aldol condensation and undergo subsequent 1,3-dipolar cycloaddition under certain conditions. As a continuation of our interest in developing diverse building blocks for natural products,16 herein we present such a catalytic and step-economical one-pot tandem approach through an aldol condensation and 1,3-dipolar cycloaddition process of aromatic aldehyde, acetone and proline. Our investigation started with a tandem process of aromatic aldehyde 4, acetone 5 and proline 6. When a mixture of benzaldehyde 4a, acetone 5 and proline 6 was stirred for 24 h at room temperature, the desired product 7a was indeed formed, but the isolated yield was only 13% (Table 1, entry 1). Different reaction Table 1. Optimization of Reaction Conditions

entrya 1 2c 3 4 5 6 7 8 9 10

additive

time (h)

yieldb (%)

S-methylisothiourea sulfate PPTS NH4Cl MgSO4 MgCl2 CuSO4

24 24 48 72 48 48 48 48 48 48

13 27 30 31 53 41 30 68 38 41

a

The reactions were performed with benzaldehyde 4a (1.0 mmol), acetone (10 mmol), additive (0.1 mmol) and proline (0.5 mmol) in DMSO (4 mL). bIsolated yield. cThe reaction temperature was 100 °C.

a

The reactions were performed with aldehydes 4 (1.0 mmol), acetone 5 (10 mmol), MgSO4 (0.1 mmol) and proline (0.5 mmol) in DMSO (4 mL) for 48 h. bIsolated yield. cendo/exo > 20:1. ddr was determined by 1H NMR of crude products.

temperatures and time were screened, unfortunately without significant improvement for the yield of 7a (Table 1, entries 2−4). To improve the yield of the reaction, in situ NMR was used for rapid and high flux condition sieves.17 Several organic acids, bases, salts and hydrogen bonded donors were used as additives. The results of in situ NMR showed that organic acids could even prevent the reaction. Interestingly, hydrogen-bonded donors (thiourea, urea, and substituted thioureas) could slightly improve the yield of 7a. To our delight, several salts could promote the reaction. Thus, different additives were examined (see the Supporting Information). As partially shown in Table 1, different salts were used as additives to optimize the reaction conditions (Table 1, entries 5−10). Among them, magnesium sulfate proved to be the most effective additive for this tandem process (up to 68% yield). Next, we turned to investigate the scope and limitation of this tandem 1,3-dipolar cycloaddition. Different aromatic aldehydes were surveyed under the optimal condition, as summarized in Scheme 1. In general, the reactions with most para- and metasubstituted benzaldehydes proceeded smoothly in moderate yields and with excellent diastereoselectivities (7b−m), while several ortho-substituted benzaldehydes led to slightly lower yields of desired products (7n−r). It is worth mentioning that some efforts to improve the yield of 7m turned out to be unobvious, most likely due to the strong electron-withdrawing CF3− group (7m). Several bicyclic aromatic aldehydes, including

α- and β-naphthyl aldehydes, also afforded the desired tandem products (7s,u) with the less hindered β-naphthaldehyde being more efficient in this tandem process. Furan and thiophene formaldehydes were also suitable substrates to give the corresponding products in moderate yields (7t, 7v−w). Alkyl aldehydes were also screened, but the reaction was very messy. In addition, the efforts to examine benzyl and allyl aldehydes turned out to be fruitless. We then started to explore the synthesis of the optically pure pyrrolizidine skeleton using chiral substituted prolines. In this case, a C-4 chiral center was introduced to proline for the purpose of enantioselective induction during the [3 + 2] cycloaddition step. When (2S,4R)-4-hydroxyproline was used, the desired product could be generated, albeit in only 21% yield. After numerous unsuccessful trials in improving the yield, O-silyl-protected (2S,4R)-4-hydroxyproline 8 was applied. Fortunately, the desired product 9a was obtained in 46% yield. The minor isomer from the reaction was not isolated in significant quantities. The scope and limitation of this tandem 1,3-dipolar cycloaddition process were also investigated. As summarized in Scheme 2, the desired products 9b−k were obtained from various substituted benzaldehydes in 38−52% yields. Notably, β-naphthyl, α-thiophene aldehydes could also afford the desired products 9l−m in 45− 48% yields. B

DOI: 10.1021/acs.orglett.7b04056 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Reactions of Different Aromatic Aldehydes with Protected (2S,4R)-4-Hydroxyprolinea,b

Figure 3. Proposed mechanism of the tandem reaction.

In summary, we established a novel and efficient approach for highly regio- and diastereoselective synthesis of functionalized pyrrolizidine derivatives 7a−w and 9a−m through a one-pot approach starting from aromatic aldehydes, acetone and proline or (2S,4R)-4-OTBS-proline in the presence of MgSO4. The reaction underwent a tandem sequence of aldol condensation and 1,3-dipolar cycloaddition process. The mechanism of this tandem process was proposed through in situ NMR experiments, and the results indicated that MgSO4 effectively promoted the aldol condensation pathway in this tandem sequence.

a

The reactions were performed with aldehydes 4 (1.0 mmol), acetone 5 (10 mmol), MgSO4 (0.1 mmol) and 8 (0.5 mmol) in DMSO (4 mL) for 48 h. bIsolated yield.

The relative stereochemistry of compounds 7a−w was unambiguously assigned by X-ray crystallographic analysis from the cocrystal of compound 7a with oxalic acid.18 Attempts to obtain a single crystal for 9a−m were unsuccessful, but fortunately, the deprotected compound 10 could afford a good cocrystal with oxalic acid, allowing for absolute configuration assignments (Scheme 3) for compounds 9a−m.

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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.7b04056. Experimental procedure, characterization of all new compounds, and results of in situ NMR (PDF)

Scheme 3. Transformation from 9i to 10

Accession Codes

CCDC 1585533−1585534 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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A possible mechanism for this tandem reaction was illustrated in Figure 3 on the basis of our in situ NMR studies and the results of previous studies.19 First, enamine d was formed from oxazolidinone species. Next, both aldol addition and aldol condensation pathways occurred competitively to generate g and f, respectively. In addition, in situ NMR studies (see the Supporting Information) confirmed that MgSO4 could promote the aldol condensation pathway to increase the yield of the tandem reaction. Then, iminium salt h, which was generated from the condensation of f with proline, underwent decarboxylation through a fivemembered lactone intermediate to give the unsaturated azomethine ylide20 i. Finally, the 1,3-dipolar cycloaddition reaction of ylide i with α,β-unsaturated ketone f occurred to afford the endo-product (7 or 9). The high diastereoselectivity in forming 7 and 9 can be rationalized by comparing the steric hindrance of competitive conformations in the transition state (see the Supporting Information).

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Bang-Guo Wei: 0000-0003-3470-6741 Present Address §

(H.-Q.D.) Arvinas, Inc., 5 Science Park, New Haven, CT 06511.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21772027, 21472022) and the China Postdoctoral Science C

DOI: 10.1021/acs.orglett.7b04056 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Foundation (KLF301012 to C.-M.S.) for financial support. We also thank Prof. Xun Sun (Fudan University) for helpful suggestions.

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DOI: 10.1021/acs.orglett.7b04056 Org. Lett. XXXX, XXX, XXX−XXX