Assembly of four diverse heterocyclic libraries enabled by prins cyclization, Au-catalyzed enyne cycloisomerization, and automated amide synthesis

Article

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Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins

Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated

Amide Synthesis

Jiayue Cui,^†,‡David I. Chai,^†,‡Christopher Miller,^†Jason Hao,^†Christopher Thomas,^§JingQi Wang,^§

Karl A. Scheidt,^§and Sergey A. Kozmin*^,†

^†Chicago Tri-Institutional Center for Chemical Methods and Library Development, Department of Chemistry, University of Chicago,

Chicago, Illinois 60637, United States

^§Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States

S

* Supporting Information

ABSTRACT: We describe a uniﬁed synthetic strategy for

eﬃcient assembly of four new heterocyclic libraries. The

synthesis began by creating a range of structurally diverse

pyrrolidinones or piperidinones. Such compounds were

obtained in a simple one-ﬂask operation starting with readily

available amines, ketoesters, and unsaturated anhydrides. The

use of tetrahydropyran-containing ketoesters, which were

rapidly assembled by our Prins cyclization protocol, enabled

eﬃcient fusion of pyran and piperidinone cores. A newly

developed Au(I)-catalyzed cycloisomerization of alkyne-

containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic

dienamides. The ﬁnal stage of the process entailed diversiﬁcation of each of the initially produced carboxylic acids using a fully

automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.

several amide-containing libraries.^10,11While small libraries

INTRODUCTION

■

were produced as individual compounds,¹⁰larger libraries were

The amide-bond formation plays a central role in organic

typically generated as compound mixtures presumably due to

synthesis, chemical biology, and pharmaceutical research.¹

the manual nature of the assembly process.¹¹

According to a recent survey, N-acylation of amines represents

As the amide-bond formation continues to play a dominant

the most frequently employed reaction in drug discovery.²

role in organic, bioorganic, and medicinal chemistry, the

Thus, it is not surprising that amide synthesis has been

automation of this important process could greatly improve its

extensively used for assembly of small-molecule libraries

designed to deliver pharmacological probes and drugs.³While

eﬃciency, enabling rapid access to large nonpeptide amide-

containing libraries of individual, pure compounds. Herein, we

early work in this area has relied almost exclusively on solid-

phase synthesis,⁴much of the recent eﬀort has shifted to

report the development of a fully automated, chromatography-

generating nonpeptide small-molecule libraries in solution.⁵

free protocol for parallel amide synthesis in solution, which was

employed for the preparation of four representative hetero-

The most attractive feature of solution-based methods is the

cyclic libraries. The ﬁrst stage of the assembly process entailed

high eﬃciency of monitoring and optimizing chemical

the synthesis of a range of structurally diverse pyrrolidinones or

reactions. Indeed, many innovative strategies have been

developed to enable high-throughput organic synthesis in

piperidinones. Such compounds were obtained in a one-ﬂask

solution, including the use of soluble polymeric supports,⁶

operation starting with readily available amines, ketoesters, and

phase-separation tags,⁷scavenging agents,⁸or automated

unsaturated anhydrides. The use of tetrahydropyran-containing

preparative LCMS methods.⁹Another attractive puriﬁcation

ketoesters, which were rapidly assembled by our Prins

cyclization protocol, enabled eﬃcient fusion of pyran and

tactic is a liquid−liquid extraction, which takes advantage of the

piperidinone cores. To further expand heterocyclic diversity, we

diﬀerences in aqueous solubility of reagents, reactants, and

products under either basic or acidic conditions. This method is

particularly well suited for amide-bond formation and can

completely avoid chromatographic puriﬁcation, use of scaveng-

developed Au(I)-catalyzed cycloisomerization of alkyne-con-

taining enamides to aﬀord a wide range of bicyclic and tricyclic

dienamides. The ﬁnal stage of the parallel assembly process

entailed diversiﬁcation of the initially produced heterocyclic

ing agents or attachment of phase-separation tags. Boger and

co-workers were the ﬁrst to recognize the value of parallel

solution-phase amide synthesis followed by a simple liquid−

liquid extraction, and employed this strategy for preparation of

Received: June 25, 2012

Published: August 3, 2012

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Figure 1. General Synthetic Strategy to Skeletally Diverse Heterocyclic Libraries. The assembly process is divided into two stages. First, a number of

skeletally diverse lactams 7-10 are produced starting with readily available primary amines 1, ketoesters 2 and unsaturated anhydrides 4 or 5. Second,

each of the lactams 7-10 is coupled to amines 11 in a fully automated fashion to deliver the resulting amide-containing heterocyclic libraries 12-15.

Figure 2. Development of an automation platform for solution-phase amide synthesis and liquid−liquid extraction. (A) Synthetic scheme used for

the development of automated amide synthesis and extractive puriﬁcation. Carboxylic acids 7 were manually prepared from primary amines 1,

ketoesters 2, and anhydride 4 as previously described.¹²Automated amide synthesis entailed activation of each carboxylic acid 7 with 1,1′-

carbonyldiimidazole (CDI, 16), followed by treatment of the resulting acyl imidazole 17 with 3 equivalents of amines 11 for 48 h at 20 °C and

washing the resulting chloroform solution with 1.2 M aqueous solution of HCl. (B) Structures and isolated yields of four representative amides,

which were prepared by the above protocol following solvent evaporation. The purity of each compound was established by LCMS analysis and

1

conﬁrmed by H NMR spectroscopy.

cores via a solution-phase amide synthesis, which was readily

performed by a conventional liquid-handling robot. This

automation platform delivered 1872 new heterocyclic com-

pounds, which were obtained with high eﬃciency and excellent

chemical purity without chromatographic puriﬁcation.

could be eﬃciently employed for ﬁnal-stage diversiﬁcation of

such libraries. Such an automation platform would deliver a

large number of individual compounds in high purity without

chromatographic puriﬁcation.

Our general synthetic strategy is depicted in Figure 1. The

assembly process begins with a condensation of primary amines

1 and ketoesters 2 to deliver the corresponding vinylogous

carbamates 3. Subsequent reaction of 3 with maleic anhydride 4

would aﬀord pyrrolidinones 7.¹²A similar transformation

employing itaconic anhydride 5 is expected to give ring-

expanded piperidinones 8.¹³Structural diversity can be readily

introduced into 7 and 8 by selecting a variety of amines 1 and

ketoesters 2. The use of alkyne-containing primary amines (R¹

= propargyl) could further expand skeletal diversity of lactams 7

and 8 via a transition-metal-catalyzed enyne cycloisomeriza-

tion¹⁴to deliver tetrahydro-oxindolizines 9 and hexahydro-

oxoquinolizines 10. The ﬁnal stage of the synthesis would rely

on the development of an automated amide-bond forming

protocol that would convert the initial set of core structures 7−

10 to the ﬁnal amide-containing libraries 12−15, which would

RESULTS AND DISCUSSION

■

Library Design. Our previous work demonstrated that

reactions of vinylogous carbamates with maleic anhydride

delivered a library of functionalized pyrrolidinones, which

yielded two noncompetitive inhibitors of facilitative glucose

transport.^12a,bWhile this library was produced using a short and

eﬃcient reaction sequence, chromatographic puriﬁcation of all

ﬁnal compounds was required in order to ensure their high

chemical purity prior to the biological evaluation.^12a,bBuilding

on this precedent, the objectives of our present study were 2-

fold. First, we aimed to increase the size and skeletal diversity of

newly designed heterocyclic libraries based on ﬁve- and six-

membered lactams. Second, we set out to develop a fully

automated protocol for solution-phase amide synthesis that

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Figure 3. Synthesis of a 216-membered library of bicyclic pyrrolidinones. (A) Two-stage assembly process entailed preparation of nine carboxylic

acids 7 starting with 3 amines 1 and 3 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 3

amines 1. (C) Structures of 3 ketoesters 2. (D) Structures of 24 amines 11.

be produced on 10−20 mg scale and subjected to rigorous

purity analysis. The use of cheminformatics methods would

facilitate selection of the appropriate building blocks at each

stage of the diversiﬁcation process in order to produce all ﬁnal

compounds with favorable physicochemical properties en route

to subsequent identiﬁcation of new pharmacological probes.

Automation of the Solution-Phase Amide Synthesis.

Our initial objective was to develop a general protocol for

eﬃcient, automated amide synthesis in solution that would

employ readily available amide-coupling agents followed by a

simple liquid−liquid extraction to purify ﬁnal amide products

(Figure 2). Such an automation platform was expected to

possess excellent throughput capabilities by avoiding chromato-

graphic puriﬁcation using scavenging agents or attaching and

detaching tags for phase separation. For puriﬁcation, we

intended to employ a single extraction step that would entail

partitioning the reaction mixture between an organic phase and

an acidic aqueous solution. This procedure would eﬃciently

separate the amide-containing product, which would be

collected in the organic phase, from an excess of starting

amine, amide-coupling reagent and other coproducts, which

would all partition into the acidic aqueous layer. In order to

develop and validate this protocol, we prepared several

pyrrolidinone-containing carboxylic acids 7 by reaction of

amines 1 with ketoesters 2, followed by cyclization with maleic

anhydride 4 (Figure 2A). Evaluation of a number of existing

amide-coupling protocols revealed that 1,1′-carbonyldiimida-

zole (CDI, 16) served as the best reagent not only to promote

eﬃcient N-acylation but also to aﬀord highest purity of the

resulting amides following a single liquid−liquid extraction step.

During the optimization studies, the eﬃciency of the initial acyl

separate. Retrieval of the chloroform layer and evaporation

produced several representative amide-containing products

12a−d (Figure 2B) in high eﬃciency. High chemical purity

of each of the products was established independently by

1

LCMS analysis and 500 MHz H NMR spectroscopy. We

found that amide-bond formation and liquid−liquid extraction

could be readily performed using a typical robotic liquid

handler, followed by parallel evaporation. The use of this

protocol can yield 1−100 mg of individual ﬁnal products

depending on the amount of carboxylic acid used for the amide-

coupling step.

Synthesis of a Pyrrolidinone Library. Having developed

an automated amide-coupling protocol, we next examined its

ﬁrst application to a larger set of pyrrolidinone-containing

compounds. Our goal was to prepare a 216-membered library

12 on 20 mg scale starting from 3 primary amines 1, 3

ketoesters 2, and 24 amines 11 (Figure 3). We wanted to

ensure that all reactions would produce ﬁnal products 12 in

high chemical purity without chromatographic puriﬁcation of

any of the ﬁnal compounds. Selection of each of the building

blocks shown in Figure 3B−D was guided by Accelrys Pipeline

Pilot, which enabled virtual enumeration of the target library

and estimation of various molecular properties in silico.

Speciﬁcally, during the design process, we applied appropriate

ﬁlters in order to select building blocks that would produce the

target library 12 with molecular weight below 600 and

calculated logarithmic value of n-octanol/water partition

coeﬃcient (cLogP) within a range of 1−5.¹⁵The distribution

of both parameters for this library is shown in the Supporting

Information (Figure S1).¹⁶

The synthesis began with condensations of three primary

amines 1 (Figure 3B) with three ketoesters 2 (Figure 3C),

followed by reactions of the resulting vinylogous carbamates 3

with maleic anhydride 4 to aﬀord nine pyrrolidinone-containing

carboxylic acids 7. Each of the acids 7 was obtained as a single

diastereomer approximately on a 500 mg scale in a single-ﬂask

operation starting with the corresponding amines 1 and

ketoesters 2. In order to ensure their high chemical purity, all

pyrrolidinone-containing carboxylic acids 7 were puriﬁed by

conventional chromatography. The second stage of the

1

imidazole formation was conveniently monitored by H NMR

spectroscopy. This transformation proceeded to completion

typically within 2−4 h at 20 °C in chloroform using a slight

excess of CDI (1.05 equiv). The resulting acyl imidazole 17 was

next treated with 3 equiv of either primary or secondary amines

11. The excess of amine ensured complete conversion of acyl

imidazole 17 to the corresponding amide 12. The ﬁnal reaction

mixture was treated with a 1.2 M solution of hydrochloric acid.

The two phases were thoroughly mixed and allowed to

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assembly process entailed a fully automated synthesis of the

target library 12 using a set of 24 amines 11 (Figure 3D). To

this end, each acid 7 was ﬁrst treated with a slight excess of CDI

(16) in chloroform at room temperature and divided into 24

equal batches. Upon completion of the acyl imidazole

formation, each batch was treated for 48 h with a solution of

amine 11 in chloroform at the same temperature, followed by

addition of a 1.2 M aqueous solution of HCl. The organic and

aqueous layers were thoroughly mixed and allowed to separate.

The amides 12 were obtained by removal of the chloroform

layer and parallel solvent evaporation. We determined the

yields of all ﬁnal compounds by automated weighing, which

established that 216 N-acylations proceeded with high

eﬃciency with an average isolated yield of 87.2 7.2%. The

high purity of each library member was established using

2c eﬃciently aﬀorded the corresponding pyrrolidinones 8b and

8c (Table 1, entries 2 and 3). The use of furan-containing

primary amine 1d was also tolerated (Table 1, entry 4). High

diastereoselectivity was observed in all cases. Interestingly, the

opposite stereochemical outcome was observed during the

formation of six-membered lactams 8 compared to the

corresponding cyclizations leading to ﬁve-membered 2-

pyrrolidiones 7.

The high level of diastereoselectivity of both reactions can be

rationalized by examining conjugate addition and anhydride-

opening steps (Figure 4). The two initial transition states A and

E have one common feature: they both entail the approach of

unsaturated anhydride, which facilitates subsequent lactam

formation by placing the imine moiety in close spatial proximity

to the carbonyl group of the anhydride for its subsequent

opening. In the case of maleic anhydride, this process predicts

the formation of intermediates B and C and explains the

observed stereochemistry of the product 7. For itaconic

anhydride, similar logic predicts the intermediacy of anhydride

F and N-acyliminium ion G en route to the observed six-

membered lactam 8.

LCMS.¹⁶In addition, we acquired 500 MHz H NMR spectra

1

of 18 randomly selected amides, which independently

conﬁrmed their high diastereomeric and chemical purities.¹⁶

Synthesis of a Piperidinone Library. The reactions of

vinylogous carbamates with maleic anhydride provided eﬃcient

and fully diastereoselective entry into the 2-pyrrolidinone core

7 (Figure 3) via a tandem reaction sequence including

conjugate addition and anhydride opening. We next examined

the construction of ring-expanded 2-piperidinones 8 (Table 1)

Because a number of 2-piperidinones 8 were prepared with

good eﬃciency and high diastereoselectivity (Table 1), we next

employed this process for generating a 768-membered library

13 starting with 8 primary amines 1, 4 ketoesters 2, and 24

amines 11 (Figure 5). Analysis of the enumerated library in

silico identiﬁed structures of 8 commercially available amines 1

(Figure 5B), 4 ketoesters 2 (Figure 5C), and the same set of 24

amines 11 (Figure 5D), which would deliver this chemical

library with favorable molecular weight and a narrow cLogP

distribution (Figure S2 in the Supporting Information). The

synthesis began with parallel reactions of 8 amines 1 with each

of the four ketoesters 2. The resulting vinylogous carbamates 3

were not isolated but directly reacted with itaconic anhydride 5

to give 32 piperidinone-containing carboxylic acids 8. Following

this one-ﬂask protocol, each of the acids 8 was obtained

approximately on a 500 mg scale as a single diastereomer with

good eﬃciency following conventional chromatographic

puriﬁcation in order to ensure their high purity. The ﬁnal

stage entailed CDI-promoted coupling of each of the 32

carboxylic acids 8 with 24 amines 11. This operation was fully

automated and conducted under the same conditions used for

generating library of 2-pyrrolidinones 12. This process

delivered 768 amides 13, which were prepared on a 15−20

mg scale. Parallel LCMS analysis of all library members

established their high chemical purity, which was independently

Table 1. Synthesis of Bicyclic 2-Piperidinones

1

conﬁrmed by obtaining 500 MHz H NMR spectra of 64

randomly selected compounds.¹⁶

Synthesis of a Library of Fused Dihydropyrans and

Piperidinones. Assembly of pyrrolidinones 12 and 2-

piperidinones 13 thus far relied on the use of readily available

carbocyclic ketoesters 2, which limited the extent of their

skeletal diversiﬁcation. We next examined the ability of

tetrahydropyran-containing ketoesters to participate in such

lactam-forming reactions. This process would enable fusion of

oxygen- and nitrogen-containing heterocyclic platforms, ex-

panding both the skeletal and heteroatom diversity of the

resulting libraries while maintaining their favorable physico-

chemical properties. Our previously developed Prins cyclization

of β-hydroxy dioxinones enabled eﬃcient assembly of a range

of highly functionalized tetrahydropyranones.¹⁷Validated

through several applications in the synthesis of complex

polyketide natural products,¹⁸this method could aﬀord a

a

Yields refer to those of isolated compounds following chromato-

b

graphic puriﬁcation. Diastereomeric ratios (dr) were determined by

¹H NMR analysis of unpuriﬁed reaction mixtures.

via the corresponding reaction of vinylogous carbamates 3 with

itaconic anhydride 5. A representative reaction of amine 1a with

ketoester 2a cleanly aﬀorded enamine 3, which was

subsequently treated with anhydride 5 to give piperidinone

8a with high eﬃciency and diastereoselectivity (Table 1, entry

1). The structure of 8a was determined by X-ray crystallog-

raphy.¹⁶Investigation of the scope of this transformation

revealed that both six- and seven-membered ketoesters 2b and

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Figure 4. Proposed explanation of the diastereoselective formation of 2-pyrrolidinones 7 and 2-piperidinones 8. In both cases, the tandem reaction

sequence entails a conjugate addition of the enamine to unsaturated anhydride followed by a ring-opening and a proton transfer. Initial approach of

each anhydride facilitates subsequent lactam formation by placing the reactive imine and carbonyl moieties in close spatial proximity, as shown in

intermediates B and F.

Figure 5. Synthesis of a 768-membered library of bicyclic piperidinones. (A) Two-stage assembly process entailed preparation of 32 carboxylic acids

8 starting with 8 amines 1 and 4 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 8 amines 1.

(C) Structures of 4 ketoesters 2. (D) Structures of 24 amines 11.

variety of 3-carbomethoxy-4-tetrahydropyranones 24 diversiﬁed

at both the C(2) and the C(6) positions (Table 2).

expected piperidinone-containing products 26. The results of

the initial scope study of this transformation are summarized in

Table 3. The four ketoesters 24a−d aﬀorded the corresponding

oxabicyclic piperidinones 26a−d with high eﬃciency as single

observed diastereomers. Excellent diastereoselectivity of this

transformation, which aﬀords products containing four stereo-

genic centers, is particularly noteworthy. Stereochemistry of the

ﬁnal products was determined by extensive NMR analysis and

can be explained by considering a transition state model E

(Figure 4) with the approach of itaconic anhydride 5 expected

to occur opposite to the R²substituent, corresponding to a

sterically more accessible face of the pyran moiety.

Having established eﬃcient and fully diastereoselective access

to dihydropyrans fused with piperidinones, we next examined

the possibility of generating a large library of such heterocyclic

compounds from four tetrahydropyran-containing ketoesters

24a−d and the same two sets of amines 1 and 11, which were

used to prepare library 13. This process would produce 768

compounds starting with 4 ketoesters 24, 8 primary amines 1,

The synthesis began with the Mukaiyama aldol reaction of

silyl dienol ether 19 with aldehyde 20 to give β-hydroxy

dioxinones 21. The next step entailed the Lewis acid promoted

Prins cyclization of dioxinones 21 with aldehydes 22, which

proceeded eﬃciently in all cases. Finally, treatment of

dihydropyrans 23 with methanol at 150 °C aﬀorded four

requisite 3-carbomethoxy-4-tetrahydropyranones 24 with high

diastereoselectivity. Erosion of diastereoselectivity in the ﬁnal

product was observed only in one case at the ﬁnal methanolysis

stage (Table 2, entry 3). However, the major diastereomer 24c

was readily obtained in good overall yield and high

diastereomeric purity by chromatographic puriﬁcation.

We next examined reactions of vinylogous carbamates 25

derived from tetrahydopyran-containing ketoesters 24 with

unsaturated anhydrides 4 and 5. While the reaction of maleic

anhydride 4 with 25 proved low yielding, the corresponding

condensation with itaconic anhydride successfully delivered the

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including molecular weight and cLogP (Figure S3 in the

Supporting Information).

Table 2. Synthesis of Carbomethoxytetrahydropyranones

The synthesis began with reactions of 8 amines 1 with each

of the 4 ketoesters 24, followed by treatment of the resulting

vinylogous carbamates with itaconic anhydride 5. This one-ﬂask

operation successfully delivered 32 expected carboxylic acids

26, which were obtained with good eﬃciency and high purity

following a single parallel chromatographic puriﬁcation. Using

the same automated liquid-handling platform employed for

syntheses of libraries 12 and 13, each of the acids 26 was

activated using CDI (16) and coupled to 24 amines 11,

followed by liquid−liquid extraction and solvent evaporation.

This process successfully delivered the target 768-membered

library 27 on 15−20 mg scale in high eﬃciency and excellent

purity, which was determined by LCMS.¹⁶The NMR analysis

of 64 randomly selected compounds once again conﬁrmed their

high chemical and diastereomeric purity.¹⁶

Development of Au-Catalyzed Enynamide Cyclo-

isomerization. The eﬃcient access to a series of structurally

diverse bicyclic lactams prompted us to further expand their

skeletal diversity by examining the ability of such compounds to

participate in enyne cycloisomerizations in the presence of an

appropriate metal catalyst. Among transition metals that

catalyze enyne cycloisomerizations, Au- and Pt-based com-

plexes are particularly noteworthy for their ability to chemo-

selectively activate the alkyne moiety and provide access to

various reaction topologies depending on the structure of the

starting enyne.¹⁴Such reactions typically proceed under mild

conditions, tolerate a wide variety of commonly used functional

groups, and provide powerful methods for structural

diversiﬁcation in organic synthesis. Despite signiﬁcant advances

in Au- and Pt-catalyzed cycloisomerizations of 1,5-enynes, the

vast majority of such reactions typically aﬀord carbocyclic

products.^14bOnly a few examples of Au-catalyzed syntheses of

nitrogen heterocycles are known. Indeed, we reported a series

of Au(I)-catalyzed double cyclizations that produced a number

of oxygen and nitrogen heterocycles.¹⁹While such reactions

eﬃciently proceeded under mild conditions, they were limited

to the synthesis of several unique heterobicyclic products.¹⁹

Recently, Schaus and co-workers described Au(III)-catalyzed

cycloisomerizations of alkyne-tethered dihydropyrimidones.²⁰

While this new catalytic process yielded a number of

pyridopyrimidones, such reactions were conducted at high

temperatures presumably due to the requirement for the initial

isomerization of a vinylogous imide. Furthermore, only internal

alkynes participated in such cycloisomerizations.²⁰

a

Yields refer to those of isolated compounds following chromato-

b

graphic puriﬁcation. Diastereomeric ratios (dr) were determined by

c

¹H NMR analysis of unpuriﬁed reaction mixtures. Major diastereomer

was obtained in diastereomerically pure form after chromatographic

puriﬁcation.

Table 3. Synthesis of Pyrrolidinones Fused to

Dihydropyrans

Prompted by the lack of general studies of transition-metal-

catalyzed cycloisomerizations of enynes containing stable

enamide fragments, we prepared several potential cyclization

substrates 28a−c by reactions of the corresponding primary

propargyl amines 27a−c with ketoester 2a, followed by

treatment of the resulting vinylogous carbamates with itaconic

anhydride 5 (Table 4). Having examined several commonly

employed transition metal complexes, we found that treatment

of phenyl-substituted enyne 28a with 5 mol % of PPh₃AuCl in

the presence of a number of Ag-based additives produced

cycloisomerization product 29a (Table 1, entries 1−3). The

reaction eﬃciency considerably decreased in the absence of

PPh₃AuCl (Table 4, entry 4). Initially, the best results were

obtained by combining PPh₃AuCl with AgSbF₅in either

dichloromethane or chloroform (Table 4, entries 1 and 5). The

use of acetonitrile as a reaction solvent resulted in a further

increase in eﬃciency and enabled nearly quantitative

a

Yields refer to those of isolated compounds following chromato-

b

graphic puriﬁcation. Diastereomeric ratios (dr) were determined by

¹H NMR analysis of unpuriﬁed reaction mixtures.

and 24 primary and secondary amines 11 (Figure 6). Analysis

of the enumerated library in silico revealed that such

compounds would display favorable molecular properties,

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Figure 6. Synthesis of a 768-membered library of 2-piperidinones fused to dihydropyrans. (A) Assembly process entailed preparation of 32

carboxylic acids 26 starting with 8 amines 1 and 4 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B)

Structures of 8 amines 1. (C) Structures of 4 ketoesters 2. (D) Structures of 24 amines 11.

Table 4. Discovery and Optimization of Enyne Cycloisomerization

a

entry

R¹

enyne

catalyst(s), (mol %)

solvent

product

yield (%)

1

2

Ph

H

28a

28b

28a

28c

Ph₃PAuCl (5), AgSbF₆(10)

Ph₃PAuCl(5),AgBF₄(10)

Ph₃PAuCl(5),AgOTf(10)

AuSbF₆(10)

CH₂Cl₂

CH₂CL₂

CHCl₃

29a

29b

29a

29c

85

75

3

60

4

45

5

Ph₃PAuCL(5),AgSbF₆(10)

Ph₃PAuCl (5), AgSbF₆(10)

Ph₃PAuCl(5),AgSbF₆(10)

(p-CF₃Ph)₃PAuCl (5), AgSbF₆(10)

Cy₃PAuCl (5), AgSbF₆(10)

t-Bu₃PAuCl (5), AgSbF₆(10)

Ph(Me)₂PAuCl (5), AgSbF₆(10)

Et₃PAuCl (5), AgSbF₆(10)

complex 30 (3)

85

6

CH₃CN

95

7

20

8

H

30

9

H

95

10

11

12

13

14

15

16

17

H

95

H

87

H

98

H

95

H

complex 31 (3)

100

H

complex 32 (3)

Ph

Me

complex 31 (3)

a

1

Yields were determined by 500 MHz H NMR analysis of unpuriﬁed reaction mixtures using an internal standard. Each of the products 29 was

subsequently isolated and fully characterized.

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conversion of 28a to 29a (Table 4, entry 6). However, this set

of conditions did not give successful results when applied to

enamide 28b containing a terminal alkyne. Indeed, the

conversion level dropped to 20% (Table 4, entry 7). We next

examined the eﬀect of the various phosphine ligands on the

reaction outcome. While electron deﬁcient phosphines did not

provide much improvement (Table 4, entry 8), the use of

sterically hindered or electron-rich phosphines substantially

improved the eﬃciency of cycloisomerization of 28b to 29b

(Table 4, entries 9−12). Interestingly, a similar trend was

recently attributed to a more eﬃcient protodemetalation step in

the presence of bulky or electron rich phosphines when this

step became turnover limiting.²¹Continuing to explore this

trend, we evaluated a number of cationic gold complexes 30, 31

and 32 containing bulky carbene or phosphine ligands (Table

4, entries 13−15). The best results were obtained using either

31 or 32. In both cases, cycloisomerization of 28b proceeded

with quantitative eﬃciency. In addition, complex 31 proved

superb at promoting cyclizations of 28a and 28c (Table 4,

entries 16 and 17).

Table 5. Au-Catalyzed Cycloisomerizations of Enyne-

Containing 2-Piperidinones

The high eﬃciency of this catalytic system, which operates at

low catalyst loadings at room temperature to promote

cyclizations of enamides containing both terminal and internal

alkynes is highly noteworthy. Furthermore, this reaction

tolerates a number of functional groups present in cyclo-

isomerization substrates 28, including unprotected carboxylic

acids. The latter feature of the reaction is particularly important

in maximizing synthetic eﬃciency of subsequent elaboration of

of cycloisomerization products (vide infra) despite the known

reactivity of carboxylic acids in a number of other Au-catalyzed

reactions.²²

a

Yields were determined by 500 MHz ¹H NMR analysis of unpuriﬁed

reaction mixtures using an internal standard. Each of the products 34

was subsequently isolated and fully characterized.

We next examined the utility of cationic gold-phosphine

complex 31 in promoting cycloisomerizations of other

structurally diverse alkyne-containing enamides 33, which

originated from propargyl amines 27, ketoesters 2, and itaconic

anhydride 5 (Table 5). We found that enynes 33a and 33b

successfully underwent cycloisomerizations to deliver the

corresponding dienamides 34a and 34b in high yields (Table

5, entries 1 and 2). Such transformations further expanded the

skeletal diversity of the tricyclic products that can be eﬃciently

prepared by this approach. Furthermore, acyclic ketoesters 2e

or 2f could be eﬃciently converted to the corresponding

enynes 33c and 33d, which upon treatment with Au complex

31 aﬀorded bicylic dienamides 34c and 34d (Table 5, entries 3

and 4).

Table 6. Au-Catalyzed Cycloisomerizations of Enyne-

Containing 2-Pyrrolidinones

While all enyne cycloisomerization products obtained thus

far contained six-membered 2-piperidinones, we next examined

the ability of this reaction to produce 1,3-dienamides

incorporating ﬁve-membered lactams 36 (Table 6). The

requisite alkyne-containing enamides 35 were prepared by the

same one-pot procedure starting with propargyl amines 27,

ketoesters 2, and maleic anhydride 4. Subjections of enynes 35a

and 35b to the general cycloisomerization protocol cleanly

aﬀorded the expected products 36a and 36b with quantitative

eﬃciency (Table 6, entries 1 and 2). Similarly, cyclo-

isomerizations of enynes 35c and 35d, which were derived

from a seven-membered ketoester 2c, successfully aﬀorded

dienamides 36c and 36d (Table 6, entries 3 and 4). The

structure of tricylic lactam 36d was conﬁrmed by X-ray

crystallography.¹⁶

a

Yields were determined by 500 MHz ¹H NMR analysis of unpuriﬁed

Having established synthetic access to a variety of ﬁve- and

six-membered lactams 34 and 36, we next examined the

preparation of a skeletally diverse chemical library using this

reaction mixtures using an internal standard. Each of the products 36

was subsequently isolated and fully characterized.

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Figure 7. Synthesis of a 120-Membered Library of Tetrahydro-oxo-indolizines and Hexahydro-oxo-quinolizines. (A) Structures of ﬁve enamides

employed for the Au-catalyzed cycloisomerization, followed by alkene hydrogenation. (B) Structures of tetrahydro-oxo-indolizines 37, 38 and 39 and

hexahydro-oxo-quinolizines 40 and 41. (C) Structures of 24 amines 11 used for automated amide syntheis. (D) Final amide-containing library

incorporating ﬁve skeletally diverse lactams.

newly uncovered enyne cycloisomerization and our previously

developed automated amide synthesis protocol. Our initial

studies established that chemical stability of the dienamide

moiety found in 34 and 36 proved to be inadequate. Slow

degradation of such compounds was observed upon their

dissolution in either DMSO or MeOH. We found that this

problem can be solved by partial hydrogenatation of the

dienamide fragment. We next subjected ﬁve enynes shown in

Figure 7A to Au-catalyzed cycloisomerization, followed by

immediate heterogeneous hydrogenation (H₂, Pd/C, EtOH).

This one-pot operation eﬃciently delivered the corresponding

tricyclic lactams 37−41 (Figure 7B) as a result of chemo-

selective hydrogenation of disubstituted alkenes. The structure

of 38 was established by X-ray crystallography.¹⁶Such partially

hydrogenated lactams proved to be stable and were next

diversiﬁed by coupling each of them with the same set of 24

amines 11 (Figure 7C), which were employed for synthesis of

other libraries discussed above. This fully automated process

delivered a 120-membered amide-containing library containing

ﬁve heterotryclic cores (Figure 7D) with favorable distributions

of molecular weight and cLogP (Figure S4 in the Supporting

Information). The library was produced on a 15−20 mg scale

with good eﬃciency and excellent chemical purity, which was

established by LCMS analysis.¹⁶Diastereomeric purity of 10

isomerization of alkyne-containing enamides to provide access

into a wide range of bicyclic and tricyclic dienamides. Such

catalytic processes substantially expanded heterocyclic diversity

of the resulting libraries. For ﬁnal diversiﬁcation of each library,

we developed a fully automated, chromatography-free protocol

for parallel amide synthesis, which was applied to prepare 1870

heterocyclic products with favorable physicochemical proper-

ties. Because of the prominent role played by the amide-bond

formation in high-throughput synthesis, chemical biology, and

medicinal chemistry, the development of this automation

platform represents an important and enabling synthetic

advance that will facilitate access to a variety of new amide-

containing libraries for subsequent biomedical applications.

Results of the expansion of this automation platform to other

commonly employed reactions, as well as the broad biological

evaluation of the four new heterocyclic libraries will be reported

in due course.²³

EXPERIMENTAL PROCEDURES

■

General Procedure A: Synthesis of Pyrrolidinones and

Piperidinones. A solution of ketoester (2 or 24, 5.0 mmol) in

CHCl₃(8.0 mL) was treated with primary amine (1 or 27, 5.0 mmol)

and 4 Å molecular sieves. The reaction mixture was stirred at 70 °C.

1

The completion of the reaction monitored by H NMR spectroscopy,

which typically required 12−18 h. The resulting mixture was treated

with anhydrous MgSO₄, ﬁltered, and concentrated under reduced

pressure to a 20 mL volume. The resulting solution was then treated

with either maleic anhydride (4, 1.1 equiv) or itaconic anhydride (5,

1.1 equiv) and stirred overnight at room temperature. The removal of

the solvent under reduced pressure followed by silica gel chromato-

graphic puriﬁcation aﬀorded pyrrolidinones (7 or 35) or piperidinones

(8, 26, 28, or 34).

Pyrrolidinone-Containing Carboxylic Acid 7a (2-((3SR,3aRS)-

1-Allyl-3a-(ethoxycarbonyl)-2-oxo-2,3,3a,4,5,6-hexahydro-1H-

indol-3-yl)acetic Acid). Compound 7a was prepared according to

general procedure A from primary amine 1a, ketoester 2a, and maleic

anhydride 4: yield 661 mg, 43%; ¹H NMR (500 MHz, CDCl₃) δ 10.18

(s, 1H), 4.94 (dddd, J = 17.5, 10.3, 6.1, 5.1 Hz, 1H), 4.46 (d, J = 17.2

Hz, 1H), 4.37 (d, J = 10.4 Hz, 1H), 4.26 (t, J = 3.8 Hz, 1H), 3.53−3.45

1

randomly selected compounds was further conﬁrmed by H

NMR.¹⁶

CONCLUSIONS

■

We have described a uniﬁed strategy for eﬃcient synthesis of

four new heterocyclic libraries. The ﬁrst stage of the process

entailed creation of a range of skeletally diverse pyrrolidinones

or piperidinones in a single-ﬂask operation starting with readily

available amines, ketoesters and unsaturated anhydrides. In the

course of this investigation, we employed our Lewis acid-

promoted Prins cyclization protocol for eﬃcient fusion of pyran

and piperidinone cores and developed Au(I)-catalyzed cyclo-

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(m, 1H), 3.40−3.28 (m, 2H), 3.15 (dd, J = 16.1, 6.1 Hz, 1H), 2.28

(dd, J = 8.5, 5.7 Hz, 1H), 2.10 (ddd, J = 17.5, 5.7, 1.0 Hz, 1H), 1.79

(dd, J = 9.5, 3.6 Hz, 1H), 1.53 (ddd, J = 17.5, 8.5, 1.0 Hz, 1H), 1.45−

1.36 (m, 1H), 1.36−1.27 (m, 1H), 1.08−0.98 (m, 1H), 0.76−0.63 (m,

2H), 0.43 (t, J = 7.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5,

173.5, 171.4, 138.2, 131.4, 117.9, 102.2, 61.7, 52.2, 47.5, 43.1, 31.7,

30.6, 22.9, 19.7, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₆H₂₂NO₅308.1498, found 308.1498.

1H), 1.37−1.26 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9,

173.1, 171.3, 142.7, 136.8, 132.5, 130.3, 128.7, 104.9, 55.5, 52.3, 48.2,

41.6, 36.1, 32.1, 31.7, 27.7, 27.4, 26.1; MS (ESI) calcd for

C₂₁H₂₄ClNO₅405.13 (M⁺), found 406.23 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7g. Compound 7g

was prepared according to general procedure A from primary amine

1a, ketoester 2c, and maleic anhydride 4: yield 838 mg, 65%; ¹H NMR

(500 MHz, CDCl₃) δ 5.74−5.64 (m, 1H), 5.22−5.11 (m, 2H), 4.89−

4.79 (m, 1H), 4.22−4.10 (m, 4H), 3.02 (t, J = 7.0 Hz, 1H), 2.87−2.77

(m, 1H), 2.62−2.51 (m, 1H), 2.40 (dd, J = 16.9, 7.3 Hz, 1H), 2.10−

2.00 (m, 1H), 2.00−1.86 (m, 1H), 1.76−1.61 (m, 2H), 1.61−1.49 (m,

3H), 1.48−1.30 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 175.4, 173.5, 171.4, 140.5, 130.7, 117.1, 104.0, 61.7,

53.9, 48.2, 42.8, 39.5, 32.8, 27.9, 26.1, 23.1, 22.7, 14.1; MS (ESI) calcd

for C₁₈H₂₅NO₅335.17 (M⁺), found 336.33 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7b. Compound 7b

was prepared according to general procedure A from primary amine

1

1b, ketoester 2a, and maleic anhydride 4: yield 1259 mg, 70%; H

NMR (500 MHz, CDCl₃) δ 7.27−7.22 (m, 1H), 6.88−6.83 (m, 1H),

5.06 (t, J = 3.7 Hz, 1H), 4.79 (d, J = 15.2 Hz, 1H), 4.48 (d, J = 15.1

Hz, 1H), 4.12 (dq, J = 10.8, 7.1 Hz, 1H), 4.03 (dq, J = 10.8, 7.1 Hz,

1H), 3.79 (s, 2H), 3.01 (dd, J = 8.4, 5.8 Hz, 1H), 2.80 (dd, J = 16.5,

8.5 Hz, 1H), 2.59 (dt, J = 12.2, 2.9 Hz, 1H), 2.47 (dd, J = 16.5, 5.9 Hz,

1H), 2.20−2.12 (m, 1H), 2.12−2.03 (m, 1H), 1.83 (ddd, J = 14.6, 6.6,

3.6 Hz, 1H), 1.58−1.40 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 175.8, 173.9, 171.3, 159.1, 138.2, 129.2, 127.9,

113.9, 102.2, 61.6, 55.4, 52.1, 47.5, 43.9, 31.6, 30.6, 22.8, 19.6, 14.2;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₁H₂₆NO₆388.1760,

found 388.1753.

Pyrrolidinone-Containing Carboxylic Acid 7h. Compound 7h

was prepared according to general procedure A from primary amine

1

1b, ketoester 2c, and maleic anhydride 4: yield 1641 mg, 87%; H

NMR (500 MHz, CDCl₃) δ 7.12 (dd, J = 8.4, 1.5 Hz, 2H), 6.85−6.78

(m, 2H), 4.85−4.73 (m, 1H), 4.66 (s, 2H), 4.21−4.05 (m, 2H), 3.76

(s, 3H), 3.08 (t, J = 7.0 Hz, 1H), 2.89 (dd, J = 16.9, 6.5 Hz, 1H), 2.57

(dd, J = 12.9, 6.6 Hz, 1H), 2.49−2.40 (m, 1H), 2.01−1.84 (m, 2H),

1.73−1.62 (m, 1H), 1.61−1.42 (m, 3H), 1.35−1.23 (m, 1H), 1.23−

1.15 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5, 173.8, 171.3,

158.9, 140.3, 128.2, 127.5, 114.0, 104.5, 61.6, 55.3, 53.9, 48.2, 43.6,

39.3, 32.8, 27.8, 25.8, 23.0, 22.6, 14.0; MS (ESI) calcd for C₂₃H₂₉NO₆

415.20 (M⁺), found 416.29 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7c. Compound 7c

was prepared according to general procedure A from primary amine

1

1c, ketoester 2a, and maleic anhydride 4: yield 1319 mg, 50%; H

NMR (500 MHz, CDCl₃) δ 11.21 (s, 1H), 7.24−7.18 (m, 2H), 7.17−

7.10 (m, 2H), 5.02 (t, J = 3.7 Hz, 1H), 4.15−4.02 (m, 2H), 3.85 (ddd,

J = 13.7, 10.6, 6.4 Hz, 1H), 3.38 (ddd, J = 13.8, 10.5, 5.1 Hz, 1H), 2.99

(dd, J = 8.4, 5.8 Hz, 1H), 2.90−2.81 (m, 2H), 2.77 (ddd, J = 13.6, 10.5,

6.4 Hz, 1H), 2.60−2.53 (m, 1H), 2.30 (dd, J = 17.4, 8.4 Hz, 1H), 2.20

(ddd, J = 17.8, 6.6, 4.0 Hz, 1H), 2.14−2.03 (m, 1H), 1.86−1.76 (m,

1H), 1.52−1.41 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 176.0, 173.0, 171.3, 164.1, 138.0, 136.9, 132.2, 130.0,

128.6, 101.1, 77.4, 61.4, 52.2, 47.2, 41.3, 32.0, 31.2, 30.5, 22.7, 19.5,

14.0; MS (ESI) calcd for C₂₁H₂₄ClNO₅405.13 (M⁺), found 406.19

(M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7i. Compound 7i

was prepared according to general procedure A from primary amine

1

1c, ketoester 2c, and maleic anhydride 4: yield 1519 mg, 70%; H

NMR (500 MHz, CDCl₃) δ 7.30−7.23 (m, 2H), 7.19−7.11 (m, 2H),

4.88 (dd, J = 10.6, 7.7 Hz, 1H), 4.23−4.14 (m, 2H), 3.79−3.66 (m,

2H), 2.94 (t, J = 7.0 Hz, 1H), 2.84 (t, J = 7.6 Hz, 2H), 2.77 (dd, J =

16.9, 6.7 Hz, 1H), 2.57 (dd, J = 13.1, 6.2 Hz, 1H), 2.37 (dd, J = 16.9,

7.2 Hz, 1H), 2.15−2.06 (m, 1H), 2.04−1.93 (m, 1H), 1.76−1.64 (m,

3H), 1.64−1.49 (m, 3H), 1.48−1.38 (m, 1H), 1.37−1.29 (m, 1H),

1.26 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.5, 173.4,

171.4, 140.7, 136.7, 132.6, 130.3, 128.8, 103.0, 61.7, 54.0, 48.1, 41.6,

39.7, 32.8, 31.8, 27.9, 26.0, 23.1, 22.6, 14.1; MS (ESI) calcd for

C₂₃H₂₈ClNO₅433.17 (M⁺), found 434.24 (M + H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7d. Compound 7d

was prepared according to general procedure A from primary amine

1

1a, ketoester 2b, and maleic anhydride 4: yield 1076 mg, 65%; H

NMR (500 MHz, CDCl₃) δ 6.41−6.31 (m, 1H), 5.69 (ddt, J = 17.2,

10.3, 5.1 Hz, 1H), 5.25−5.12 (m, 3H), 4.20 (ddt, J = 16.3, 4.9, 1.8 Hz,

1H), 4.03 (ddt, J = 16.4, 5.0, 1.8 Hz, 1H), 3.69 (s, 3H), 3.06 (t, J = 6.9

Hz, 1H), 2.78 (dd, J = 17.0, 6.8 Hz, 1H), 2.53−2.44 (m, 1H), 2.37

(dd, J = 17.0, 7.0 Hz, 1H), 2.26−2.15 (m, 1H), 1.96−1.84 (m, 2H),

1.76−1.62 (m, 2H), 1.62−1.52 (m, 1H), 1.37−1.27 (m, 1H); ¹³C

NMR (126 MHz, CDCl₃) δ 175.7, 173.3, 171.3, 142.7, 130.9, 130.2,

117.2, 105.9, 55.5, 52.3, 48.3, 42.9, 36.1, 32.1, 27.7, 27.4, 26.1; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₆H₂₂NO₅308.1498, found

308.1496.

Piperidinone-Containing Carboxylic Acid 8a (2-((3RS,4aSR)-

1-(3,4-Dimethoxyphenethyl)-4a-(ethoxycarbonyl)-2-oxo-

2,3,4,4a,5,6-hexahydro-1H-cyclopenta[b]pyridin-3-yl)acetic

Acid). Compound 8a (1.59 g, 55%) was obtained according to general

procedure A. ¹H NMR (500 MHz, CDCl₃) δ 6.77 (m, 3H), 5.11 (t, J =

2.5 Hz, 1H), 4.15 (m, 2H), 3.95 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H),

3.68 (m, 1H), 2.79 (m, 4H), 2.67 (m, 1H), 2.50 (m, 2H), 2.34 (m,

2H), 1.86 (dt, J = 12.8, 9.3 Hz, 1H), 1.69 (t, J = 12.8 Hz, 1H), 1.21 (t,

J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 173.9, 169.7,

149.0, 147.7, 140.9, 131.5, 120.7, 112.2, 111.4, 106.8, 61.5, 56.0, 56.0,

54.4, 46.0, 36.9, 36.7, 36.4, 35.7, 32.3, 29.0, 14.2; MS (ESI) calcd for

C₂₃H₂₉NO₇431.2 (M⁺), found 414.3 (M − OH)⁺, 432.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8b. Compound 8b

Pyrrolidinone-Containing Carboxylic Acid 7e. Compound 7e

was prepared according to general procedure A from primary amine

1

1b, ketoester 2b, and maleic anhydride 4: yield 1588 mg, 82%; H

NMR (500 MHz, CDCl₃) δ 7.21−7.14 (m, 2H), 6.89−6.81 (m, 2H),

5.20 (dd, J = 8.8, 4.4 Hz, 1H), 4.78 (d, J = 15.4 Hz, 1H), 4.55 (d, J =

15.4 Hz, 1H), 3.80 (d, J = 1.2 Hz, 3H), 3.66 (s, 3H), 3.04 (dd, J = 9.3,

4.8 Hz, 1H), 2.71 (ddd, J = 16.2, 9.3, 1.2 Hz, 1H), 2.56−2.41 (m, 2H),

2.22−2.09 (m, 1H), 1.95−1.79 (m, 2H), 1.79−1.64 (m, 2H), 1.62−

1.52 (m, 1H), 1.34−1.21 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ

175.6, 173.8, 171.3, 158.9, 142.5, 128.4, 127.6, 114.0, 106.3, 55.4, 55.3,

52.3, 48.4, 43.8, 36.0, 32.0, 27.6, 27.4, 26.1; MS (ESI) calcd for

C₂₁H₂₆NO₆388.1760 (M + H), found 388.1768.

1

(1.12 g, 51%) was obtained according to general procedure A: H

NMR (500 MHz, CDCl₃) δ 5.42 (m, 1H), 5.32 (dd, J = 5.1, 2.8 Hz,

1H), 4.14 (m, 2H), 3.82 (m, 1H), 3.70 (m, 1H), 2.77 (dd, J = 16.2, 6.9

Hz, 1H), 2.67 (m, 1H), 2.52 (dd, J = 16.2, 4.9 Hz, 1H), 2.32 (dd, J =

13.0, 5.7 Hz, 1H), 2.25 (m, 3H), 2.14 (m, 1H), 2.05 (m, 1H), 1.95 (m,

5H), 1.68 (m, 1H), 1.58 (m, 3H), 1.50 (m, 4H), 1.37 (m, 1H), 1.27

(m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

175.3, 173.9, 170.3, 135.8, 135.2, 122.7, 108.1, 61.7, 46.4, 43.2, 37.5,

36.8, 36.1, 34.9, 34.8, 28.6, 25.3, 24.5, 22.9, 22.4, 18.6, 14.3; MS (ESI)

calcd for C₂₂H₃₁NO₅389.2 (M⁺), found 372.3 (M − OH)⁺, 390.3 (M

+ H)⁺.

Pyrrolidinone-Containing Carboxylic Acid 7f. Compound 7f

was prepared according to general procedure A from primary amine

1

1c, ketoester 2b, and maleic anhydride 4: yield 1766 mg, 79%; H

Piperidinone-Containing Carboxylic Acid 8c. Compound 8c

(814 mg, 37%) was obtained according to general procedure A: H

NMR (500 MHz, CDCl₃) δ 7.29 (m, 2H), 7.20 (m, 1H), 7.14 (d, J =

6.7 Hz, 2H), 5.42 (t, J = 7.0 Hz, 1H), 5.17 (d, J = 16.0 Hz, 1H), 4.75

(d, J = 16.1 Hz, 1H), 3.77 (s, 3H), 2.84 (m, 2H), 2.62 (m, 1H), 2.15

(dd, J = 13.2, 4.1 Hz, 1H), 2.05 (m, 2H), 1.93 (m, 2H), 1.69 (m, 3H),

NMR (500 MHz, CDCl₃) δ 7.30−7.24 (m, 2H), 7.20−7.14 (m, 2H),

5.22 (dd, J = 8.9, 4.4 Hz, 1H), 3.79 (ddd, J = 13.8, 9.8, 6.4 Hz, 1H),

3.70 (s, 3H), 3.56 (ddd, J = 13.8, 9.8, 5.6 Hz, 1H), 3.01 (t, J = 6.9 Hz,

1H), 2.86 (ddd, J = 13.5, 9.8, 5.6 Hz, 1H), 2.82−2.72 (m, 2H), 2.49

(ddd, J = 13.6, 4.7, 2.6 Hz, 1H), 2.35 (dd, J = 17.2, 7.2 Hz, 1H), 2.31−

2.22 (m, 1H), 2.01−1.89 (m, 2H), 1.80−1.64 (m, 2H), 1.61−1.53 (m,

1

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1.57 (m, 1H), 1.24 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7,

174.2, 171.1, 140.6, 137.3, 128.6, 126.8, 126.4, 116.1, 52.6, 51.6, 49.5,

39.5, 36.6, 35.6, 35.6, 26.3, 25.3, 24.8; MS (ESI) calcd for C₂₁H₂₅NO₅

371.2 (M⁺), found 354.2 (M − OH)⁺, 372.2 (M + H)⁺.

135.0, 122.9, 107.1, 61.5, 54.3, 43.2, 37.1, 37.0, 36.4, 35.9, 34.6, 29.0,

28.5, 25.3, 23.0, 22.4, 14.2; MS (ESI) calcd for C₂₁H₂₉NO₅375.2

(M⁺), found 358.3 (M − OH)⁺, 376.3 (M + H)⁺, 398.3 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8j. Compound 8j

was prepared according to general procedure A from primary amine 1j,

ketoester 2d, and itaconic anhydride 5: yield 1277 mg, 49%; ¹H NMR

(500 MHz, CDCl₃) δ 7.98 (m, 2H), 7.87 (m, 1H), 7.74 (d, J = 8.2 Hz,

1H), 7.53 (ddd, J = 8.4, 6.8, 1.7 Hz, 1H), 7.49 (td, J = 8.6, 6.9, 1.5 Hz,

1H), 7.35 (d, J = 7.0 Hz, 1H), 5.48 (d, J = 16.4 Hz, 1H), 5.36 (d, J =

16.1 Hz, 1H), 4.87 (dd, J = 3.2, 1.6 Hz, 1H), 4.23 (m, 2H), 4.14 (m,

1H), 3.01 (m, 2H), 2.83 (dd, J = 16.8, 3.9 Hz, 1H), 2.63 (dd, J = 12.7,

5.4 Hz, 1H), 2.36 (m, 2H), 2.22 (m, 1H), 1.95 (m, 2H), 1.24 (t, J =

7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 174.2, 170.3,

141.3, 133.7, 130.8, 130.8, 128.9, 127.4, 126.1, 125.6, 125.5, 122.9,

122.5, 108.6, 61.5, 54.5, 45.9, 37.0, 36.6, 36.2, 35.5, 28.9, 14.2; MS

(ESI) calcd for C₂₄H₂₅NO₅407.2 (M⁺), found 390.2 (M − OH)⁺,

408.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8d. Compound 8b

1

(582 mg, 57%) was obtained according to general procedure A: H

NMR (500 MHz, CDCl₃) δ 7.33 (dd, J = 1.7, 0.8 Hz, 1H), 6.32 (dd, J

= 3.2, 1.9 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 5.51 (t, J = 4.1 Hz, 1H),

5.28 (d, J = 15.8 Hz, 1H), 4.57 (d, J = 15.8 Hz, 1H), 3.65 (s, 3H), 2.77

(dd, J = 16.3, 7.5 Hz, 1H), 2.63 (m, 2H), 2.28 (dd, J = 12.9, 5.7 Hz,

1H), 2.22 (d, J = 13.6 Hz, 1H), 2.00 (d, J = 4.1 Hz, 2H), 1.69 (t, J =

12.9 Hz, 1H), 1.43 (d, J = 13.6 Hz, 1H), 0.97 (s, 3H), 0.83 (s, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 175.1, 174.8, 170.6, 150.8, 141.7,

135.6, 110.7, 109.3, 108.3, 52.8, 47.2, 45.6, 42.6, 38.8, 38.7, 37.3, 36.0,

31.7, 28.7, 25.3; MS (ESI) calcd for C₂₀H₂₅NO₆375.2 (M⁺), found

358.2 (M − OH)⁺, 376.2 (M + H)⁺, 398.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8e. Compound 8e

was prepared according to general procedure A from primary amine

Piperidinone-Containing Carboxylic Acid 8k. Compound 8k

1

was prepared according to general procedure A from primary amine

1d, ketoester 2d, and itaconic anhydride 5: yield 1144 mg, 63%; H

1

1k, ketoester 2d, and itaconic anhydride 5: yield 568 mg, 35%; H

NMR (500 MHz, CDCl₃) δ 5.04 (s, 1H), 4.13 (m, 2H), 3.79 (m, 1H),

3.42 (m, 1H), 2.77 (m, 2H), 2.61 (m, 1H), 2.50 (dd, J = 12.6, 5.2 Hz,

1H), 2.43 (dd, J = 16.1, 9.3 Hz, 1H), 2.31 (dd, J = 12.7, 7.4 Hz, 2H),

1.82 (dt, J = 12.8, 9.2 Hz, 1H), 1.64 (t, J = 12.7 Hz, 1H), 1.53 (m, 2H),

1.21 (m, 15H), 0.83 (t, J = 6.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 176.7, 174.0, 169.9, 140.9, 107.1, 61.5, 54.3, 44.2, 36.9, 36.9, 36.4,

35.9, 31.9, 29.4, 29.3, 29.0, 27.1, 26.5, 22.7, 14.2, 14.2, 14.2; MS (ESI)

calcd for C₂₁H₃₃NO₅379.2 (M⁺), found 362.3 (M − OH)⁺, 380.3 (M

+ H)⁺.

NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 1.9 Hz, 1H), 7.16 (m, 2H),

5.01 (d, J = 16.9 Hz, 1H), 4.86 (d, J = 16.9 Hz, 2H), 4.20 (m, 2H),

2.98 (dd, J = 17.4, 5.3 Hz, 1H), 2.91 (m, 1H), 2.76 (dd, J = 17.0, 4.4

Hz, 1H), 2.56 (dd, J = 12.7, 5.5 Hz, 1H), 2.37 (m, 2H), 2.26 (m, 1H),

1.91 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 177.6, 174.1, 170.2, 141.0, 133.3, 133.2, 132.4, 129.2, 128.4, 127.4,

108.3, 61.7, 54.5, 45.4, 37.1, 36.5, 36.0, 35.4, 29.0, 14.3; MS (ESI)

calcd for C₂₀H₂₁Cl₂NO₅425.1 (M⁺), found 408.2 (M − OH)⁺, 426.2

(M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8f. Compound 8f

Piperidinone-Containing Carboxylic Acid 8l. Compound 8l

was prepared according to general procedure A from primary amine

1

was prepared according to general procedure A from primary amine

1e, ketoester 2d, and itaconic anhydride 5: yield 626 mg, 55%; H

1

1d, ketoester 2a, and itaconic anhydride 5: yield 1018 mg, 88%; H

NMR (500 MHz, CDCl₃) δ 7.25 (m, 5H), 5.00 (m, 2H), 4.84 (m,

1H), 4.14 (m, 2H), 2.91 (m, 2H), 2.81 (m, 1H), 2.56 (dd, J = 12.9, 5.8

Hz, 1H), 2.36 (m, 2H), 2.26 (m, 1H), 1.85 (m, 2H), 1.19 (t, J = 7.0

Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 174.1, 170.2, 141.2,

136.7, 128.4, 127.0, 126.9, 108.2, 61.5, 54.4, 54.4, 47.9, 36.9, 36.5, 36.4,

35.5, 29.0, 14.2, 14.1; MS (ESI) calcd for C₂₀H₂₃NO₅357.2 (M⁺),

found 340.2 (M − OH)⁺, 358.2 (M + H)⁺, 380.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8g. Compound 8g

was prepared according to general procedure A from primary amine 1f,

NMR (500 MHz, CDCl₃) δ 5.25 (dd, J = 5.2, 2.8 Hz, 1H), 4.11 (q, J =

7.1 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 2.76 (dd, J = 16.3, 6.1 Hz, 1H),

2.66 (dq, J = 11.9, 5.8 Hz, 3H), 2.52 (dd, J = 16.3, 5.6 Hz, 1H), 2.30

(dd, J = 12.9, 5.7 Hz, 1H), 2.22 (m, 2H), 2.12 (m, 1H), 1.65 (m, 1H),

1.55 (t, J = 13.0 Hz, 1H), 1.46 (m, 2H), 1.34 (m, 1H), 1.24 (m, 12H),

1.18 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 6.9 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 175.9, 173.9, 169.9, 135.9, 107.8, 61.5, 46.3, 44.0,

37.2, 36.6, 36.1, 34.9, 31.8, 29.3, 29.3, 27.1, 26.7, 24.4, 22.6, 18.5, 14.2,

14.1; MS (ESI) calcd for C₂₂H₃₅NO₅393.3 (M⁺), found 376.3 (M −

OH)⁺, 394.3 (M + H)⁺, 416.3 (M + Na)⁺.

1

ketoester 2d, and itaconic anhydride 5: yield 855 mg, 55%; H NMR

(500 MHz, CDCl₃) δ 6.74 (m, 3H), 5.91 (s, 2H), 5.06 (dd, J = 3.2, 1.8

Hz, 1H), 4.81 (m, 2H), 4.14 (m, 2H), 2.92 (dq, J = 12.8, 5.6 Hz, 1H),

2.81 (dd, J = 5.6, 1.6 Hz, 2H), 2.55 (dd, J = 12.7, 5.6 Hz, 1H), 2.33 (m,

3H), 1.83 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 176.5, 174.0, 170.4, 147.9, 146.7, 141.2, 130.6, 120.5, 108.4,

108.3, 107.8, 101.1, 61.6, 54.5, 47.7, 37.0, 36.6, 36.6, 35.8, 29.1, 14.2;

MS (ESI) calcd for C₂₁H₂₃NO₇401.1 (M⁺), found 402.2 (M + H)⁺,

424.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8m. Compound 8m

was prepared according to general procedure A from primary amine

1

1e, ketoester 2a, and itaconic anhydride 5: yield 858 mg, 79%; H

NMR (500 MHz, CDCl₃) δ 7.30 (m, 2H), 7.21 (m, 3H), 5.39 (d, J =

16.0 Hz, 1H), 5.21 (dd, J = 5.2, 2.8 Hz, 1H), 4.55 (d, J = 16.0 Hz, 1H),

4.18 (q, J = 7.1 Hz, 2H), 3.47 (s, 1H), 2.81 (m, 3H), 2.40 (m, 1H),

2.27 (dt, J = 12.9, 3.4 Hz, 1H), 2.15 (m, 1H), 2.04 (m, 1H), 1.81 (t, J

= 12.8 Hz, 1H), 1.66 (m, 1H), 1.52 (td, J = 13.6, 13.2, 2.8 Hz, 1H),

1.37 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 176.7, 174.2, 170.4, 137.4, 136.9, 128.6, 128.5, 126.7, 126.2, 109.1,

61.6, 48.9, 46.6, 36.5, 36.4, 36.3, 34.8, 24.2, 18.5, 14.3; MS (ESI) calcd

for C₂₁H₂₅NO₅371.2 (M⁺), found 354.2 (M − OH)⁺, 372.2 (M +

H)⁺.

Piperidinone-Containing Carboxylic Acid 8h. Compound 8h

was prepared according to general procedure A from primary amine

1

1g, ketoester 2d, and itaconic anhydride 5: yield 705 mg, 42%; H

NMR (500 MHz, CDCl₃) δ 7.32 (dd, J = 1.8, 0.9 Hz, 1H), 6.28 (m,

1H), 5.27 (t, J = 2.5 Hz, 1H), 4.92 (m, 1H), 4.81 (m, 1H), 4.12 (m,

2H), 2.90 (m, 1H), 2.81 (m, 1H), 2.70 (m, 1H), 2.54 (dd, J = 12.7, 5.6

Hz, 1H), 2.46 (m, 1H), 2.34 (m, 2H), 1.86 (dt, J = 13.2, 9.2 Hz, 1H),

1.71 (t, J = 12.8 Hz, 1H), 1.18 (m, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 176.0, 173.9, 170.3, 150.2, 141.9, 140.9, 110.6, 108.4, 108.3, 61.6,

54.5, 41.2, 37.0, 36.9, 36.5, 35.9, 29.2, 14.2; MS (ESI) calcd for

C₁₈H₂₁NO₆347.1 (M⁺), found 330.2 (M − OH)⁺, 348.2 (M + H)⁺,

370.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8n. Compound 8n

was prepared according to general procedure A from primary amine 1f,

ketoester 2a, and itaconic anhydride 5: yield 1014 mg, 83%; ¹H NMR

(500 MHz, CDCl₃) δ 6.69 (m, 3H), 5.89 (s, 2H), 5.22 (m, 2H), 4.47

(d, J = 15.8 Hz, 1H), 4.16 (m, 2H), 2.78 (m, 3H), 2.36 (dd, J = 12.9,

5.5 Hz, 1H), 2.25 (dt, J = 13.1, 3.3 Hz, 1H), 2.14 (m, 1H), 2.05 (m,

1H), 1.79 (t, J = 13.0 Hz, 1H), 1.64 (dd, J = 14.0, 5.2 Hz, 1H), 1.50

(td, J = 13.6, 13.1, 2.8 Hz, 1H), 1.36 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 176.7, 174.2, 170.3, 147.9, 146.4,

136.8, 131.3, 119.4, 109.0, 108.3, 107.1, 100.9, 61.6, 48.5, 46.6, 36.5,

36.4, 36.3, 34.8, 24.3, 18.5, 14.3; MS (ESI) calcd for C₂₂H₂₅NO₇415.2

(M⁺), found 398.2 (M − OH)⁺, 416.3 (M + H)⁺, 438.2 (M + Na)⁺.

Piperidinone-Containing Carboxylic Acid 8o. Compound 8o

was prepared according to general procedure A from primary amine

Piperidinone-Containing Carboxylic Acid 8i. Compound 8i

was prepared according to general procedure A from primary amine

1

1h, ketoester 2d, and itaconic anhydride 5: yield 571 mg, 47%; H

NMR (500 MHz, CDCl₃) δ 5.41 (t, J = 3.4 Hz, 1H), 5.10 (t, J = 2.4

Hz, 1H), 4.14 (m, 2H), 3.82 (m, 1H), 3.59 (m, 1H), 2.80 (m, 2H),

2.60 (m, 1H), 2.52 (dd, J = 12.3, 5.4 Hz, 1H), 2.46 (m, 1H), 2.34 (m,

2H), 2.19 (m, 1H), 2.11 (m, 1H), 1.95 (m, 4H), 1.85 (dt, J = 12.6, 9.3

Hz, 1H), 1.65 (m, 1H), 1.59 (m, 2H), 1.52 (m, 2H), 1.22 (t, J = 7.1

Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.5, 173.9, 169.9, 140.8,

1

1g, ketoester 2a, and itaconic anhydride 5: yield 583 mg, 55%; H

7445

dx.doi.org/10.1021/jo301061r | J. Org. Chem. 2012, 77, 7435−7470

The Journal of Organic Chemistry

Article

NMR (500 MHz, CDCl₃) δ 7.31 (m, 1H), 6.27 (m, 2H), 5.51 (dd, J =

5.2, 2.8 Hz, 1H), 5.24 (d, J = 15.8 Hz, 1H), 4.54 (d, J = 15.8 Hz, 1H),

4.15 (q, J = 7.1 Hz, 2H), 2.82 (dd, J = 16.1, 5.8 Hz, 1H), 2.75 (dq, J =

12.9, 5.6 Hz, 1H), 2.65 (dd, J = 16.1, 5.3 Hz, 1H), 2.37 (dd, J = 13.0,

5.7 Hz, 1H), 2.25 (m, 2H), 2.13 (m, 1H), 1.66 (m, 2H), 1.50 (td, J =

13.6, 13.1, 2.6 Hz, 1H), 1.38 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 176.2, 174.0, 170.2, 150.9, 141.6, 136.7,

110.6, 109.0, 108.0, 61.7, 46.6, 42.2, 37.0, 36.7, 36.2, 34.9, 24.4, 18.6,

14.3; MS (ESI) calcd for C₁₉H₂₃NO₆361.2 (M⁺), found 344.2 (M −

OH)⁺, 362.2 (M + H)⁺.

1H), 1.78−1.54 (m, 4H), 1.33−1.23 (m, 1H); ¹³C NMR (126 MHz,

CDCl₃) δ 176.1, 174.2, 171.3, 148.0, 146.5, 140.6, 131.2, 119.6, 116.2,

108.4, 107.1, 101.0, 52.7, 51.6, 49.4, 39.6, 36.7, 35.9, 35.6, 26.3, 25.3,

24.9; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₂H₂₆NO₇

416.1709, found 416.1714.

Piperidinone-Containing Carboxylic Acid 8u. Compound 8u

was prepared according to general procedure A from primary amine

1

1g, ketoester 2b, and itaconic anhydride 5: yield 452 mg, 28%; H

NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 1.7, 0.9 Hz, 1H), 6.28 (dd, J

= 3.1, 1.8 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 5.68 (t, J = 7.1 Hz, 1H),

5.08 (d, J = 15.9 Hz, 1H), 4.69 (d, J = 15.9 Hz, 1H), 3.74 (s, 3H), 2.86

(dd, J = 16.7, 6.0 Hz, 1H), 2.76 (dt, J = 6.8, 4.4 Hz, 1H), 2.48 (dd, J =

16.7, 6.4 Hz, 1H), 2.17 (m, 1H), 2.11 (dd, J = 13.2, 4.4 Hz, 1H), 2.00

(m, 2H), 1.78 (m, 2H), 1.64 (m, 2H), 1.27 (m, 1H); ¹³C NMR (126

MHz, CDCl₃) δ 176.6, 174.1, 171.0, 150.8, 141.5, 140.5, 116.3, 110.5,

108.1, 52.6, 51.8, 42.9, 39.5, 36.6, 35.6, 35.6, 26.4, 25.3, 24.9; MS (ESI)

calcd for C₁₉H₂₃NO₆361.2 (M⁺), found 344.2 (M − OH)⁺, 362.2 (M

+ H)⁺.

Piperidinone-Containing Carboxylic Acid 8p. Compound 8p

was prepared according to general procedure A from primary amine 1i,

1

ketoester 2a, and itaconic anhydride 5: yield 914 mg, 58%; H NMR

(500 MHz, CDCl₃) δ 6.76 (m, 3H), 5.33 (dd, J = 5.2, 2.8 Hz, 1H),

4.12 (q, J = 7.0 Hz, 2H), 3.86 (m, 2H), 3.84 (s, 4H), 3.81 (s, 3H), 2.85

(m, 1H), 2.76 (dd, J = 16.0, 5.7 Hz, 1H), 2.69 (m, 2H), 2.62 (dd, J =

16.1, 5.6 Hz, 1H), 2.32 (dd, J = 13.0, 5.6 Hz, 1H), 2.25 (m, 2H), 2.14

(m, 1H), 1.67 (m, 1H), 1.61 (t, J = 12.8 Hz, 1H), 1.48 (td, J = 13.4,

12.9, 2.6 Hz, 1H), 1.38 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 176.1, 173.9, 169.8, 148.9, 147.5, 135.9, 131.7,

120.5, 112.1, 111.3, 107.6, 61.5, 55.9, 55.9, 46.4, 45.6, 36.8, 36.4, 36.1,

34.8, 32.4, 24.4, 18.5, 14.2; MS (ESI) calcd for C₂₄H₃₁NO₇445.2

(M⁺), found 428.3 (M − OH)⁺, 446.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8q. Compound 8q

was prepared according to general procedure A from primary amine 1j,

ketoester 2a, and itaconic anhydride 5: 1040 mg, 84%; ¹H NMR (500

MHz, CDCl₃) δ 7.99 (d, J = 8.2 Hz, 1H), 7.88 (m, 1H), 7.74 (d, J =

8.2 Hz, 1H), 7.51 (m, 3H), 7.33 (d, J = 7.1 Hz, 1H), 5.90 (d, J = 16.7

Hz, 1H), 5.07 (dd, J = 5.1, 2.9 Hz, 1H), 5.02 (d, J = 16.7 Hz, 1H), 4.25

(m, 2H), 3.03 (dd, J = 16.6, 5.1 Hz, 1H), 2.85 (m, 2H), 2.47 (dd, J =

12.9, 5.4 Hz, 1H), 2.31 (dt, J = 13.3, 3.3 Hz, 1H), 2.03 (m, 3H), 1.66

(m, 1H), 1.58 (td, J = 13.5, 2.8 Hz, 1H), 1.40 (m, 1H), 1.31 (t, J = 7.1

Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.1, 174.2, 170.1, 137.0,

133.6, 131.3, 130.3, 128.8, 127.1, 125.9, 125.7, 125.5, 122.4, 122.4,

109.1, 61.6, 47.4, 46.7, 36.3, 36.2, 36.1, 34.7, 24.1, 18.5, 14.3; MS (ESI)

calcd for C₂₅H₂₇NO₅421.2 (M⁺), found 404.3 (M − OH)⁺, 422.3 (M

+ H)⁺.

Piperidinone-Containing Carboxylic Acid 8v. Compound 8v

was prepared according to general procedure A from primary amine

1

1h, ketoester 2b, and itaconic anhydride 5: yield 438 mg, 38%; H

NMR (500 MHz, CDCl₃) δ 5.54 (t, J = 7.2 Hz, 3H), 5.39 (m, 3H),

3.98 (m, 3H), 3.74 (s, 9H), 3.60 (m, 3H), 2.80 (dd, J = 16.3, 6.9 Hz,

3H), 2.68 (m, 3H), 2.37 (dd, J = 16.3, 5.7 Hz, 3H), 2.19 (m, 9H), 2.03

(m, 9H), 1.95 (m, 13H), 1.79 (m, 3H), 1.68 (m, 13H), 1.57 (m, 6H),

1.50 (m, 6H), 1.36 (m, 2H), 1.23 (m, 1H); ¹³C NMR (126 MHz,

CDCl₃) δ 176.1, 174.1, 171.1, 140.2, 135.0, 123.0, 114.9, 52.6, 51.6,

43.3, 39.7, 37.0, 36.2, 35.5, 34.8, 28.4, 26.8, 25.6, 25.3, 25.0, 22.9, 22.4;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₂H₃₂NO₅390.2280,

found 390.2280.

Piperidinone-Containing Carboxylic Acid 8w. Compound 8w

was prepared according to general procedure A from primary amine 1i,

ketoester 2b, and itaconic anhydride 5: yield 1090 mg, 42%; ¹H NMR

(500 MHz, CDCl₃) δ 6.77 (m, 3H), 5.64 (t, J = 7.2 Hz, 1H), 4.06 (m,

1H), 3.88 (s, 3H), 3.85 (s, 4H), 3.76 (s, 3H), 2.85 (dt, J = 9.4, 5.6 Hz,

2H), 2.78 (dd, J = 16.4, 7.1 Hz, 1H), 2.72 (dt, J = 12.6, 6.0 Hz, 1H),

2.40 (dd, J = 15.9, 4.8 Hz, 1H), 2.26 (m, 1H), 2.05 (m, 3H), 1.80 (m,

1H), 1.67 (m, 3H), 1.60 (t, J = 13.3 Hz, 1H), 1.39 (m, 1H), 1.24 (m,

1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 174.0, 170.8, 148.8,

147.5, 140.4, 131.3, 120.6, 114.6, 112.0, 111.2, 77.4, 77.2, 76.9, 55.9,

52.5, 51.5, 46.1, 39.4, 36.7, 35.6, 35.5, 32.4, 26.6, 25.5, 24.9; MS (ESI)

calcd for C₂₄H₃₁NO₇445.2 (M⁺), found 428.2 (M − OH)⁺, 446.2 (M

+ H)⁺.

Piperidinone-Containing Carboxylic Acid 8r. Compound 8r

was prepared according to general procedure A from primary amine

1

1k, ketoester 2a, and itaconic anhydride 5: yield 861 mg, 67%; H

NMR (500 MHz, CDCl₃) δ 7.32 (s, 1H), 7.13 (m, 2H), 5.26 (d, J =

17.1 Hz, 1H), 4.91 (dd, J = 5.1, 2.8 Hz, 1H), 4.56 (d, J = 17.1 Hz, 1H),

4.18 (q, J = 7.1 Hz, 2H), 3.00 (dd, J = 16.9, 5.1 Hz, 1H), 2.69 (m, 2H),

2.35 (dd, J = 12.9, 5.6 Hz, 1H), 2.25 (dt, J = 13.2, 3.2 Hz, 1H), 2.11

(m, 1H), 2.00 (m, 1H), 1.90 (t, J = 12.9 Hz, 1H), 1.64 (m, 1H), 1.51

(td, J = 13.7, 2.8 Hz, 1H), 1.34 (m, 1H), 1.24 (t, J = 7.4 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 177.3, 174.2, 170.3, 136.7, 133.0, 133.0,

132.7, 129.1, 128.3, 127.4, 109.0, 61.8, 46.8, 46.8, 36.2, 36.1, 35.8, 34.8,

24.2, 18.5, 14.4; MS (ESI) calcd for C₂₁H₂₃Cl₂NO₅439.1 (M⁺), found

422.2 (M − OH)⁺, 440.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8x. Compound 8x

was prepared according to general procedure A from primary amine 1j,

1

ketoester 2b, and itaconic anhydride 5: yield 791 mg, 32%; H NMR

(500 MHz, CDCl₃) δ 7.94 (d, J = 8.3 Hz, 1H), 7.88 (m, 1H), 7.74 (d,

J = 8.3 Hz, 1H), 7.52 (m, 2H), 7.43 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.1

Hz, 1H), 5.56 (d, J = 16.4 Hz, 1H), 5.36 (t, J = 7.0 Hz, 1H), 5.27 (d, J

= 16.6 Hz, 1H), 3.81 (s, 3H), 2.89 (m, 2H), 2.71 (m, 1H), 2.20 (dd, J

= 13.2, 4.2 Hz, 1H), 2.03 (m, 3H), 1.89 (m, 1H), 1.69 (m, 3H), 1.57

(m, 1H), 1.24 (m, 1H); MS (ESI) calcd for C₂₅H₂₇NO₅421.2 (M⁺),

found 404.3 (M − OH)⁺, 422.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8s. Compound 8s

was prepared according to general procedure A from primary amine

1

1d, ketoester 2b, and itaconic anhydride 5: yield 443 mg, 38%; H

NMR (500 MHz, CDCl₃) δ 5.54 (t, J = 7.1 Hz, 1H), 3.76 (s, 4H), 3.60

(m, 1H), 2.80 (dd, J = 16.1, 7.5 Hz, 1H), 2.70 (m, 1H), 2.40 (dd, J =

16.1, 5.1 Hz, 1H), 2.23 (m, 1H), 2.05 (m, 3H), 1.79 (m, 1H), 1.70 (m,

4H), 1.56 (m, 2H), 1.40 (m, 1H), 1.26 (m, 11H), 0.86 (t, J = 6.6 Hz,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.3, 174.1, 171.3, 140.3,

115.1, 52.7, 51.6, 51.6, 45.5, 40.0, 37.0, 36.6, 35.6, 31.9, 29.4, 29.4,

27.1, 26.9, 26.5, 25.5, 25.0, 22.8, 14.2; MS (ESI) calcd for C₂₂H₃₅NO₅

393.3 (M⁺), found 376.3 (M − OH)⁺, 394.4 (M + H)⁺, 416.4 (M +

Na)⁺.

Piperidinone-Containing Carboxylic Acid 8y. Compound 8y

was prepared according to general procedure A from primary amine

1

1k, ketoester 2b, and itaconic anhydride 5: yield 1118 mg, 46%; H

NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.4,

2.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.18 (t, J = 6.9 Hz, 1H), 4.98 (d,

J = 17.2 Hz, 1H), 4.86 (d, J = 17.0 Hz, 1H), 3.79 (s, 3H), 2.77 (m,

3H), 2.11 (m, 3H), 1.98 (m, 2H), 1.80 (m, 2H), 1.63 (m, 2H), 1.34

(m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.0, 174.2, 170.8, 140.8,

133.1, 133.0, 129.2, 128.3, 127.5, 115.4, 52.8, 51.7, 47.9, 39.2, 36.9,

35.6, 35.3, 26.1, 25.3, 24.9; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₂₁H₂₄Cl₂NO₅440.1032, found 440.1037.

Piperidinone-Containing Carboxylic Acid 8t. Compound 8t

was prepared according to general procedure A from primary amine 1f,

1

ketoester 2b, and itaconic anhydride 5: yield 595 mg, 33%; H NMR

Piperidinone-Containing Carboxylic Acid 8z. Compound 8z

(500 MHz, CDCl₃) δ 6.74 (d, J = 7.9 Hz, 1H), 6.64 (d, J = 1.7 Hz,

1H), 6.62 (dd, J = 8.0, 1.8 Hz, 1H), 5.92 (d, J = 1.7 Hz, 2H), 5.46 (t, J

= 7.0 Hz, 1H), 5.04 (d, J = 15.8 Hz, 1H), 4.69 (d, J = 15.8 Hz, 1H),

3.77 (s, 3H), 2.88−2.76 (m, 2H), 2.63−2.56 (m, 1H), 2.19−2.07 (m,

2H), 2.07−2.00 (m, 1H), 2.00−1.92 (m, 1H), 1.88 (t, J = 13.2 Hz,

was prepared according to general procedure A from primary amine

1d, ketoester 2e, and itaconic anhydride 5: yield 479 mg, 41%; H

NMR (500 MHz, CDCl₃) δ 5.19 (t, J = 4.1 Hz, 1H), 3.66 (m, 2H),

3.61 (s, 3H), 2.70 (m, 1H), 2.53 (m, 2H), 2.19 (m, 2H), 1.97 (d, J =

4.1 Hz, 2H), 1.59 (m, 2H), 1.47 (m, 1H), 1.38 (d, J = 13.7 Hz, 1H),

1

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1

1.23 (m, 11H), 0.92 (s, 3H), 0.82 (t, J = 6.7 Hz, 3H), 0.79 (s, 3H); ¹³

C

1k, ketoester 2e, and itaconic anhydride 5: yield 944 mg, 77%; H

NMR (126 MHz, CDCl₃) δ 175.6, 175.1, 169.8, 134.9, 107.4, 52.4,

47.2, 45.3, 44.5, 38.7, 38.4, 37.1, 35.9, 31.8, 31.6, 29.3, 29.3, 28.5, 27.2,

26.7, 25.3, 22.6, 14.1, 14.1; MS (ESI) calcd for C₂₃H₃₇NO₅407.3

(M⁺), found 390.3 (M − OH)⁺, 408.3 (M + H)⁺.

NMR (500 MHz, CDCl₃) δ 7.35 (d, J = 1.9 Hz, 1H), 7.15 (m, 2H),

5.41 (d, J = 17.2 Hz, 1H), 4.89 (dd, J = 4.8, 3.2 Hz, 1H), 4.49 (d, J =

17.1 Hz, 1H), 3.71 (s, 3H), 3.09 (dd, J = 17.2, 4.9 Hz, 1H), 2.60 (m,

2H), 2.25 (m, 2H), 1.98 (t, J = 13.0 Hz, 1H), 1.89 (t, J = 4.1 Hz, 2H),

1.48 (d, J = 13.7 Hz, 1H), 0.94 (s, 3H), 0.82 (s, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 177.3, 175.4, 170.1, 136.0, 133.2, 133.0, 132.7, 129.1,

128.3, 127.4, 108.5, 52.7, 47.6, 47.1, 45.6, 38.5, 37.9, 36.1, 35.7, 31.7,

28.6, 25.4; MS (ESI) calcd for C₂₂H₂₅Cl₂NO₅453.1 (M⁺), found 436.2

(M − OH)⁺, 454.2 (M + H)⁺.

Carbomethoxytetrahydropyranone 24a ((2RS,6RS)-Methyl

6-tert-Butyl-2-methyl-4-oxotetrahydro-2H-pyran-3-carboxy-

late). Compound 24a was prepared according to reported

procedures:¹⁷¹H NMR (500 MHz, CDCl₃) δ 3.96 (dd, J = 10.4,

6.0 Hz, 1H), 3.77 (s, 3H), 3.31 (dd, J = 11.8, 2.3 Hz, 1H), 3.17 (dd, J

= 10.4, 0.7 Hz, 1H), 2.45 (dd, J = 13.9, 2.3 Hz, 1H), 2.29 (ddd, J =

13.9, 11.9, 0.9 Hz, 1H), 1.32 (d, J = 6.0 Hz, 3H), 0.93 (s, 9H); ¹³C

NMR (126 MHz, CDCl₃) δ 203.8, 168.9, 84.4, 75.0, 64.6, 52.2, 42.2,

34.4, 25.6, 20.9; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₂H₂₀O₄Na 251.1259, found 251.1267.

Carbomethoxytetrahydropyranone 24b. Compound 24b was

prepared according to reported procedures:¹⁷¹H NMR (500 MHz,

CDCl₃) δ 3.97 (dq, J = 10.4, 6.0 Hz, 1H), 3.76 (s, 3H), 3.43 (ddd, J =

11.5, 7.9, 2.3 Hz, 1H), 3.19 (dd, J = 10.4, 0.8 Hz, 1H), 2.50 (dd, J =

14.2, 2.3 Hz, 1H), 2.27 (ddd, J = 14.2, 11.6, 0.9 Hz, 1H), 1.97 (q, J =

8.3 Hz, 1H), 1.87−1.81 (m, 1H), 1.69−1.51 (m, 6H), 1.45−1.40 (m,

1H), 1.32 (d, J = 6.0 Hz, 3H), 1.21−1.14 (m, 1H); ¹³C NMR (126

MHz, CDCl₃) δ 202.8, 168.8, 81.2, 75.0, 64.6, 52.3, 46.2, 45.5, 29.3,

28.6, 25.62, 25.43, 21.0; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₃H₂₀O₄Na 263.1259, found 263.1266.

Carbomethoxytetrahydropyranone 24c. Compound 24c was

prepared according to reported procedures:¹⁷¹H NMR (500 MHz,

CDCl₃) δ 3.76 (s, 3H), 3.39−3.33 (m, 2H), 3.33−3.27 (m, 1H), 2.46

(dd, J = 14.3, 2.3 Hz, 1H), 2.27−2.22 (m, 1H), 1.79 (dq, J = 13.4, 6.7

Hz, 1H), 0.99−0.93 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.57−0.49 (m,

2H), 0.48−0.43 (m, 1H), 0.40−0.35 (m, 1H); ¹³C NMR (126 MHz,

CDCl₃) δ 203.1, 168.8, 81.6, 81.4, 63.9, 52.2, 44.3, 33.4, 18.5, 18.1,

15.7, 2.9, 2.1; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for

C₁₃H₂₀O₄Na 263.1259, found 263.1258.

Piperidinone-Containing Carboxylic Acid 8aa. Compound 8aa

was prepared according to general procedure A from primary amine

1

1e, ketoester 2e, and itaconic anhydride 5: yield 474 mg, 76%; H

NMR (500 MHz, CDCl₃) δ 7.30 (m, 2H), 7.22 (m, 3H), 5.50 (d, J =

16.1 Hz, 1H), 5.14 (t, J = 4.1 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 3.67

(s, 3H), 2.90 (m, 1H), 2.74 (dd, J = 17.0, 5.2 Hz, 1H), 2.63 (dt, J =

18.5, 5.4 Hz, 1H), 2.29 (dd, J = 12.8, 5.8 Hz, 1H), 2.22 (d, J = 13.5 Hz,

1H), 1.88 (m, 3H), 1.46 (d, J = 13.6 Hz, 1H), 0.94 (s, 3H), 0.82 (s,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.5, 175.4, 170.3, 137.5,

137.5, 136.0, 128.6, 126.8, 126.3, 108.8, 52.6, 49.5, 47.2, 45.6, 38.6,

38.3, 36.5, 36.1, 31.7, 28.6, 25.4; MS (ESI) calcd for C₂₂H₂₇NO₅385.2

(M⁺), found 368.2 (M − OH)⁺, 386.3 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8ab. Compound

8ab was prepared according to general procedure A from primary

amine 1f, ketoester 2e, and itaconic anhydride 5: yield 890 mg, 76%;

¹H NMR (500 MHz, CDCl₃) δ 7.26 (s, 1H), 6.74 (m, 2H), 6.69 (m,

1H), 5.92 (d, J = 1.8 Hz, 2H), 5.34 (d, J = 15.8 Hz, 1H), 5.19 (m, 1H),

4.45 (dd, J = 15.7, 3.4 Hz, 1H), 3.67 (s, 3H), 2.82 (m, 1H), 2.74 (m,

1H), 2.63 (dt, J = 13.1, 5.5 Hz, 1H), 2.28 (dd, J = 12.8, 5.8 Hz, 1H),

2.22 (d, J = 13.6 Hz, 1H), 1.91 (t, J = 3.0 Hz, 2H), 1.82 (td, J = 13.0,

3.0 Hz, 1H), 1.44 (d, J = 13.6 Hz, 1H), 0.94 (s, 3H), 0.81 (s, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 176.0, 175.4, 170.4, 147.9, 146.4, 136.0,

131.4, 119.6, 108.8, 108.4, 107.2, 101.0, 66.0, 52.6, 49.2, 47.2, 45.6,

38.7, 38.3, 36.6, 36.1, 31.7, 28.6, 25.5, 15.3; MS (ESI) calcd for

C₂₃H₂₇NO₇429.2 (M⁺), found 412.2 (M − OH)⁺, 430.2 (M + H)⁺.

Piperidinone-Containing Carboxylic Acid 8ac. Compound 8ac

was prepared according to general procedure A from primary amine

1

1h, ketoester 2e, and itaconic anhydride 5: yield 420 mg, 38%; H

NMR (500 MHz, CDCl₃) δ 5.46 (m, 1H), 5.32 (m, 1H), 3.90 (m,

1H), 3.72 (m, 1H), 3.67 (s, 3H), 2.74 (dd, J = 15.7, 7.3 Hz, 1H), 2.53

(m, 2H), 2.31 (td, J = 12.3, 11.6, 5.6 Hz, 1H), 2.23 (m, 2H), 2.11 (m,

1H), 2.00 (m, 7H), 1.61 (m, 3H), 1.55 (m, 2H), 1.43 (d, J = 13.7 Hz,

1H), 1.21 (m, 1H), 0.97 (s, 3H), 0.84 (s, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 175.3, 175.1, 170.2, 135.2, 134.9, 122.6, 107.7, 52.6, 47.2,

45.3, 43.8, 38.8, 38.5, 37.4, 35.9, 34.8, 31.7, 28.6, 28.6, 25.4, 25.3, 22.9,

22.4; MS (ESI) calcd for C₂₃H₃₃NO₅403.2 (M⁺), found 386.2 (M −

OH)⁺, 404.2 (M + H)⁺.

Carbomethoxytetrahydropyranone 24d. Compound 24d was

prepared according to reported procedures:¹⁷¹H NMR (500 MHz,

CDCl₃) δ 7.37−7.28 (m, 5H), 4.60 (q, J = 9.9 Hz, 2H), 4.04 (dq, J =

10.5, 6.0 Hz, 1H), 3.94−3.89 (m, 1H), 3.77 (s, 3H), 3.60−3.53 (m,

2H), 3.23 (dd, J = 10.5, 0.7 Hz, 1H), 2.53−2.41 (m, 2H), 1.36 (d, J =

6.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 202.1, 168.6, 137.8,

128.6, 127.95, 127.85, 76.1, 75.2, 73.6, 71.9, 64.3, 52.3, 43.4, 20.9;

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₆H₂₀O₅Na 315.1208,

found 315.1211.

Piperidinone-Containing Carboxylic Acid 8ad. Compound

8ad was prepared according to general procedure A from primary

amine 1i, ketoester 2e, and itaconic anhydride 5: yield 570 mg, 46%;

¹H NMR (500 MHz, CDCl₃) δ 6.80 (m, 3H), 5.39 (dd, J = 5.0, 3.2

Hz, 1H), 3.96 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.68 (s, 3H), 2.94

(m, 1H), 2.77 (m, 2H), 2.62 (m, 1H), 2.53 (dd, J = 16.0, 3.4 Hz, 1H),

2.26 (m, 2H), 2.06 (m, 2H), 1.63 (t, J = 13.0 Hz, 1H), 1.45 (d, J = 13.6

Hz, 1H), 1.00 (s, 3H), 0.87 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

175.7, 175.1, 169.8, 148.9, 147.5, 135.0, 131.8, 120.6, 112.1, 111.3,

107.4, 55.9, 55.9, 52.4, 47.1, 46.2, 45.3, 38.7, 38.2, 36.8, 35.9, 32.5,

31.6, 28.5, 25.3; MS (ESI) calcd for C₂₅H₃₃NO₇459.2 (M⁺), found

442.3 (M − OH)⁺, 460.3 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26a (2-((3SR,4aRS,5RS,7RS)-1-Benzyl-7-tert-butyl-4a-

(methoxycarbonyl)-5-methyl-2-oxo-2,3,4,4a,5,7-hexahydro-

1H-pyrano[4,3-b]pyridin-3-yl)acetic Acid). Compound 26a (428

1

mg, 82%) was obtained according to general procedure A: H NMR

(500 MHz, CDCl₃) δ 7.34−7.28 (m, 1H), 7.25−7.20 (m, 1H), 5.43 (s,

1H), 5.27 (d, J = 15.5 Hz, 1H), 4.47 (d, J = 15.5 Hz, 1H), 3.84 (q, J =

6.4 Hz, 1H), 3.72 (s, 1H), 3.59 (s, 3H), 3.14−3.06 (m, 1H), 3.00 (dd,

J = 17.0, 5.3 Hz, 1H), 2.78 (dd, J = 17.0, 5.2 Hz, 1H), 2.47 (dd, J =

12.6, 7.4 Hz, 1H), 1.79 (t, J = 12.6 Hz, 1H), 1.18 (d, J = 6.3 Hz, 3H),

0.73 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 176.4, 172.7, 170.9,

138.3, 137.4, 128.7, 127.2, 127.0, 111.6, 82.1, 74.6, 52.8, 51.4, 49.4,

37.5, 36.5, 34.7, 28.8, 25.5, 16.2; MS (ESI) calcd for C₂₄H₃₁NO₆429.2

(M⁺), found 412.2 (M − OH)⁺, 430.2 (M + H)⁺, 452.2 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26b. Compound 26b (366 mg, 74%) was obtained

Piperidinone-Containing Carboxylic Acid 8ae. Compound 8ae

was prepared according to general procedure A from primary amine 1j,

1

ketoester 2e, and itaconic anhydride 5: yield 715 mg, 60%; H NMR

(500 MHz, CDCl₃) δ 8.00 (d, J = 8.3 Hz, 1H), 7.88 (dd, J = 8.0, 1.5

Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.53 (m, 2H), 7.43 (t, J = 7.7 Hz,

1H), 7.30 (d, J = 7.2 Hz, 1H), 5.99 (d, J = 16.7 Hz, 1H), 5.03 (dd, J =

5.1, 2.9 Hz, 1H), 4.93 (d, J = 16.7 Hz, 1H), 3.74 (s, 3H), 3.05 (m,

1H), 2.73 (m, 2H), 2.36 (dd, J = 12.8, 5.6 Hz, 1H), 2.27 (dd, J = 13.7,

1.9 Hz, 1H), 2.05 (m, 1H), 1.85 (m, 2H), 1.52 (d, J = 13.7 Hz, 1H),

0.95 (s, 3H), 0.85 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.8,

175.6, 170.2, 136.3, 133.8, 131.6, 130.4, 128.9, 127.3, 126.1, 125.8,

125.6, 122.7, 122.6, 109.0, 77.4, 77.2, 76.9, 52.7, 48.3, 47.2, 45.7, 38.5,

38.3, 36.3, 36.2, 31.7, 28.6, 25.4; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₂₆H₃₀NO₅436.2124, found 436.2120.

1

according to general procedure A: H NMR (500 MHz, CDCl₃) δ

5.43 (s, 1H), 5.41−5.38 (m, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.98 (q, J =

6.6 Hz, 1H), 3.82−3.72 (m, 1H), 3.67 (s, 2H), 3.64−3.55 (m, 1H),

3.02−2.91 (m, 1H), 2.75 (dd, J = 16.8, 5.9 Hz, 1H), 2.71−2.63 (m,

1H), 2.38 (dd, J = 12.8, 7.2 Hz, 1H), 2.30−2.20 (m, 1H), 2.06−1.99

(m, 1H), 1.99−1.92 (m, 5H), 1.77−1.66 (m, 2H), 1.66−1.56 (m, 5H),

Piperidinone-Containing Carboxylic Acid 8af. Compound 8af

was prepared according to general procedure A from primary amine

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1.56−1.47 (m, 4H), 1.44−1.34 (m, 1H), 1.34−1.24 (m, 1H), 1.19 (dd,

J = 6.6, 2.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 172.6,

170.5, 170.5, 136.4, 135.0, 123.0, 111.0, 78.1, 74.5, 52.9, 51.3, 44.8,

43.4, 37.9, 37.9, 36.3, 34.9, 29.3, 28.7, 28.6, 28.5, 25.9, 25.8, 25.4, 23.0,

22.4, 16.6; MS (ESI) calcd for C₂₆H₃₇NO₆459.3 (M⁺), found 460.4

(M + H)⁺.

2.70 (dd, J = 17.0, 4.6 Hz, 1H), 2.43 (dd, J = 12.7, 7.5 Hz, 1H), 1.66

(dd, J = 12.7, 10.9 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H), 0.83 (s, 9H); ¹³C

NMR (126 MHz, CDCl₃) δ 177.0, 172.7, 170.4, 150.6, 141.7, 138.1,

111.1, 110.7, 108.6, 82.1, 74.5, 52.8, 51.3, 42.2, 37.4, 36.4, 34.7, 28.5,

25.5, 16.1; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₂H₃₀NO₇

420.2022, found 420.2000.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26h. Compound 26h was prepared according to general

procedure A from primary amine 1h, ketoester 24a, and itaconic

anhydride 5: yield 363 mg, 71%; ¹H NMR (500 MHz, CDCl₃) δ 5.54

(s, 1H), 5.47 (s, 1H), 3.90 (q, J = 6.5 Hz, 1H), 3.84 (s, 1H), 3.77 (ddd,

J = 13.4, 11.3, 5.0 Hz, 1H), 3.68 (s, 3H), 3.62 (ddd, J = 13.5, 11.1, 5.5

Hz, 1H), 3.09−3.01 (m, 1H), 2.77−2.67 (m, 2H), 2.45 (dd, J = 12.7,

7.6 Hz, 1H), 2.31 (td, J = 12.3, 11.3, 5.4 Hz, 1H), 2.07−1.92 (m, 5H),

1.66−1.59 (m, 3H), 1.58−1.51 (m, 2H), 1.19 (d, J = 6.5 Hz, 3H), 0.91

(s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 175.1, 172.5, 170.9, 137.9,

135.0, 123.1, 110.4, 82.2, 74.7, 52.8, 51.4, 44.0, 38.2, 36.3, 35.2, 34.8,

29.1, 28.6, 25.7, 25.4, 23.0, 22.4, 16.2; MS (ESI) calcd for C₂₅H₃₇NO₆

447.3 (M⁺), found 448.3 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26i. Compound 26i was prepared according to general

procedure A from primary amine 1i, ketoester 24a, and itaconic

anhydride 5: yield 460 mg, 80%; ¹H NMR (500 MHz, CDCl₃) δ 6.78

(d, J = 7.9 Hz, 1H), 6.76−6.71 (m, 2H), 5.42 (d, J = 1.5 Hz, 1H), 3.88

(q, J = 6.4 Hz, 2H), 3.86−3.80 (m, 7H), 3.80−3.72 (m, 1H), 3.62 (s,

3H), 3.07−3.00 (m, 1H), 2.90−2.81 (m, 2H), 2.79−2.72 (m, 1H),

2.69 (dd, J = 16.9, 4.9 Hz, 1H), 2.44 (dd, J = 12.7, 7.6 Hz, 1H), 1.63

(dd, J = 12.6, 10.5 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H), 0.85 (s, 9H); ¹³C

NMR (126 MHz, CDCl₃) δ 176.9, 172.5, 170.4, 149.0, 147.6, 138.3,

131.7, 120.6, 111.9, 111.4, 110.3, 82.1, 74.5, 55.9, 55.9, 52.7, 51.4, 47.2,

37.6, 36.4, 34.6, 32.8, 28.5, 25.5, 16.1; MS (ESI) calcd for C₂₇H₃₇NO₈

503.3 (M⁺), found 486.4 (M − OH)⁺, 504.4 (M + H)⁺, 526.4 (M +

Na)⁺.

ylic Acid 26c. Compound 26c (609 mg, 81%) was obtained

1

according to general procedure A: H NMR (500 MHz, CDCl₃) δ

6.77−6.68 (m, 3H), 5.27 (d, J = 1.9 Hz, 1H), 3.91 (dd, J = 6.2, 1.8 Hz,

1H), 3.89−3.82 (m, 1H), 3.81 (s, 3H), 3.81−3.76 (m, 4H), 3.78−3.72

(m, 1H), 3.62 (s, 3H), 3.30 (d, J = 8.0 Hz, 1H), 3.02−2.91 (m, 1H),

2.84−2.71 (m, 4H), 2.48 (dd, J = 12.8, 6.7 Hz, 1H), 1.85 (t, J = 12.1

Hz, 1H), 1.83−1.72 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6

Hz, 3H), 0.48 (d, J = 8.3 Hz, 2H), 0.45−0.36 (m, 1H), 0.18−0.11 (m,

1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 172.7, 170.3, 148.9,

147.5, 136.2, 131.5, 120.6, 111.9, 111.3, 108.9, 81.5, 78.7, 55.8, 55.8,

52.7, 51.6, 45.8, 37.1, 36.4, 33.2, 32.5, 29.8, 18.3, 18.0, 11.7, 3.5, 2.4;

MS (ESI) calcd for C₂₈H₃₇NO₈515.3 (M⁺), found 498.4 (M − OH)⁺,

516.4 (M + H)⁺, 538.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26d. Compound 26d (293 mg, 54%) was obtained

1

according to general procedure A: H NMR (500 MHz, CDCl₃) δ

7.38−7.27 (m, 5H), 6.30 (dd, J = 3.3, 1.8 Hz, 1H), 6.23 (d, J = 3.2 Hz,

1H), 5.58 (d, J = 1.7 Hz, 1H), 4.91 (d, J = 15.7 Hz, 1H), 4.75 (d, J =

15.7 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H),

4.48 (td, J = 6.0, 1.7 Hz, 1H), 4.07 (q, J = 6.5 Hz, 1H), 3.61 (s, 2H),

3.54 (dd, J = 9.9, 6.5 Hz, 1H), 3.40 (dd, J = 9.8, 5.6 Hz, 1H), 3.05−

2.95 (m, 1H), 2.80 (dd, J = 16.9, 5.4 Hz, 1H), 2.72 (dd, J = 16.9, 6.2

Hz, 1H), 2.39 (dd, J = 12.8, 6.7 Hz, 1H), 1.71 (t, J = 12.1 Hz, 1H),

1.21 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.3, 172.4,

170.3, 150.1, 141.8, 138.1, 136.6, 128.5, 128.5, 127.8, 127.8, 127.8,

110.6, 108.8, 108.7, 74.4, 73.5, 73.3, 72.7, 53.0, 51.2, 51.2, 41.0, 37.2,

36.4, 29.2, 16.8; MS (ESI) calcd for C₂₆H₂₉NO₈483.2 (M⁺), found

484.3 (M + H)⁺, 506.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26e. Compound 26e was prepared according to general

procedure A from primary amine 1d, ketoester 24a, and itaconic

anhydride 5: yield 454 mg, 93%; ¹H NMR (500 MHz, CDCl₃) δ 5.46

(s, 1H), 3.88 (q, J = 6.4 Hz, 1H), 3.82 (s, 1H), 3.76−3.68 (m, 1H),

3.65 (s, 3H), 3.48−3.39 (m, 1H), 3.06−2.97 (m, 1H), 2.78 (dd, J =

16.9, 6.0 Hz, 1H), 2.67 (dd, J = 16.9, 5.2 Hz, 1H), 2.41 (dd, J = 12.7,

7.7 Hz, 1H), 1.60 (dd, J = 12.6, 10.7 Hz, 2H), 1.48−1.38 (m, 1H),

1.33−1.18 (m, 12H), 1.15 (d, J = 6.5 Hz, 3H), 0.91−0.81 (m, 12H);

¹³C NMR (126 MHz, CDCl₃) δ 176.8, 172.6, 170.4, 138.0, 110.0, 82.2,

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26j. Compound 26j was prepared according to general

procedure A from primary amine 1j, ketoester 24a, and itaconic

1

anhydride 5: yield 395 mg, 72%; H NMR (500 MHz, CDCl₃) δ

8.04−7.98 (m, 1H), 7.89−7.83 (m, 1H), 7.76 (d, J = 8.2 Hz, 1H),

7.56−7.51 (m, 1H), 7.48 (ddd, J = 8.0, 6.7, 1.2 Hz, 1H), 7.43 (dd, J =

8.2, 7.1 Hz, 1H), 7.36 (dd, J = 7.2, 1.3 Hz, 1H), 5.50 (d, J = 1.4 Hz,

1H), 5.46 (d, J = 16.0 Hz, 1H), 5.26 (d, J = 16.0 Hz, 1H), 3.82 (q, J =

6.4 Hz, 1H), 3.72 (d, J = 1.5 Hz, 1H), 3.28 (s, 3H), 3.21−3.13 (m,

2H), 2.85−2.78 (m, 1H), 2.49 (dd, J = 12.6, 7.2 Hz, 1H), 1.92 (dd, J =

12.7, 10.8 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.77 (s, 9H); ¹³C NMR

(126 MHz, CDCl₃) δ 177.7, 172.7, 170.4, 138.1, 133.8, 131.5, 131.0,

128.8, 127.8, 126.3, 125.7, 125.4, 125.4, 123.2, 111.8, 82.0, 74.5, 52.4,

51.4, 47.0, 37.0, 36.5, 34.6, 28.4, 25.5, 16.1; MS (ESI) calcd for

C₂₈H₃₃NO₆479.2 (M⁺), found 480.4 (M + H)⁺, 502.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26k. Compound 26k was prepared according to general

procedure A from primary amine 1k, ketoester 24a, and itaconic

anhydride 5: yield 468 mg, 82%; ¹H NMR (500 MHz, CDCl₃) δ 7.36

(d, J = 2.0 Hz, 1H), 7.24−7.14 (m, 2H), 5.26 (d, J = 1.5 Hz, 1H), 5.23

(d, J = 16.8 Hz, 1H), 4.48 (d, J = 16.8 Hz, 1H), 3.83 (q, J = 6.4 Hz,

1H), 3.71 (d, J = 1.5 Hz, 1H), 3.68 (s, 3H), 3.22 (dd, J = 17.7, 5.2 Hz,

1H), 3.01 (ddt, J = 11.9, 7.3, 4.6 Hz, 1H), 2.69 (dd, J = 17.7, 4.2 Hz,

1H), 2.43 (dd, J = 12.6, 7.2 Hz, 1H), 1.91 (t, J = 12.1 Hz, 1H), 1.20 (d,

J = 6.4 Hz, 3H), 0.75 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 178.1,

172.7, 170.4, 138.4, 133.3, 133.0, 132.8, 129.2, 129.1, 127.2, 111.2,

82.0, 74.6, 52.9, 51.4, 47.4, 36.3, 36.2, 34.7, 28.1, 25.5, 16.1; MS (ESI)

calcd for C₂₄H₂₉Cl₂NO₆497.1 (M⁺), found 480.3 (M − OH)⁺, 498.3

(M + H)⁺, 520.3 (M + Na)⁺.

74.6, 52.7, 51.4, 44.5, 37.8, 36.3, 34.7, 31.9, 29.3, 29.3, 28.6, 27.2, 26.8,

25.6, 22.7, 16.2, 14.2; MS (ESI) calcd for C₂₅H₄₁NO₆451.3 (M⁺),

found 434.4 (M − OH)⁺, 452.4 (M + H)⁺, 474.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26f. Compound 26f was prepared according to general

procedure A from primary amine 1f, ketoester 24a, and itaconic

1

anhydride 5: yield 431 mg, 77%; H NMR (500 MHz, CDCl₃) δ

6.77−6.72 (m, 2H), 6.70 (dd, J = 7.8, 1.8 Hz, 1H), 5.94−5.90 (m,

2H), 5.49 (d, J = 1.6 Hz, 1H), 5.06 (d, J = 15.3 Hz, 1H), 4.48 (d, J =

15.3 Hz, 1H), 3.85 (q, J = 6.4 Hz, 1H), 3.74 (d, J = 1.5 Hz, 1H), 3.61

(s, 3H), 3.12−3.05 (m, 1H), 2.96 (dd, J = 17.0, 5.4 Hz, 1H), 2.75 (dd,

J = 17.0, 5.3 Hz, 1H), 2.45 (dd, J = 12.6, 7.4 Hz, 1H), 1.76 (dd, J =

12.7, 11.1 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H), 0.78 (s, 9H); ¹³C NMR

(126 MHz, CDCl₃) δ 176.0, 172.6, 170.9, 148.0, 146.7, 138.3, 131.2,

120.4, 111.5, 108.3, 107.9, 101.1, 82.1, 77.4, 77.4, 77.2, 76.9, 74.6, 52.8,

51.4, 49.0, 37.4, 36.5, 34.7, 28.7, 25.6, 16.2; MS (ESI) calcd for

C₂₅H₃₁NO₈473.2 (M⁺), found 474.2 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26g. Compound 26g was prepared according to general

procedure A from primary amine 1g, ketoester 24a, and itaconic

anhydride 5: yield 219 mg, 46%; ¹H NMR (500 MHz, CDCl₃) δ 7.31

(dd, J = 1.7, 0.9 Hz, 1H), 6.30 (dd, J = 3.1, 1.8 Hz, 1H), 6.23 (d, J =

3.1 Hz, 1H), 5.69 (d, J = 1.5 Hz, 1H), 5.07 (d, J = 15.6 Hz, 1H), 4.47

(d, J = 15.6 Hz, 1H), 3.85 (q, J = 6.3 Hz, 1H), 3.79 (d, J = 1.6 Hz,

1H), 3.61 (s, 3H), 3.07−2.99 (m, 1H), 2.86 (dd, J = 17.0, 6.1 Hz, 1H),

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26l. Compound 26l was prepared according to general

procedure A from primary amine 1d, ketoester 24b, and itaconic

anhydride 5: yield 357 mg, 76%; ¹H NMR (500 MHz, CDCl₃) δ 5.37

(d, J = 1.7 Hz, 1H), 4.06 (dd, J = 7.5, 1.6 Hz, 1H), 3.97 (q, J = 6.5 Hz,

1H), 3.77 (ddd, J = 13.6, 10.2, 6.1 Hz, 1H), 3.67 (s, 3H), 3.50−3.40

(m, 1H), 3.00 (ddt, J = 11.1, 7.2, 5.7 Hz, 1H), 2.75 (dd, J = 16.8, 5.7

Hz, 1H), 2.69 (dd, J = 16.9, 6.1 Hz, 1H), 2.39 (dd, J = 12.7, 7.2 Hz,

7448

dx.doi.org/10.1021/jo301061r | J. Org. Chem. 2012, 77, 7435−7470

The Journal of Organic Chemistry

Article

1H), 2.02−1.92 (m, 1H), 1.78−1.34 (m, 12H), 1.33−1.21 (m, 12H),

1.19 (d, J = 6.5 Hz, 3H), 0.86 (t, J = 6.6 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 176.3, 172.6, 170.5, 136.5, 111.1, 78.2, 74.6, 52.8,

51.3, 44.7, 44.0, 37.8, 36.3, 31.9, 29.4, 29.3, 29.1, 28.6, 28.4, 27.2, 26.7,

25.9, 25.8, 22.7, 16.5, 14.2; MS (ESI) calcd for C₂₆H₄₁NO₆463.3

(M⁺), found 446.4 (M − OH)⁺, 464.4 (M + H)⁺, 486.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26m. Compound 26m was prepared according to general

procedure A from primary amine 1e, ketoester 24b, and itaconic

(d, J = 1.4 Hz, 1H), 5.33 (d, J = 16.0 Hz, 1H), 4.01 (dd, J = 6.6, 1.5

Hz, 1H), 3.91 (q, J = 6.5 Hz, 1H), 3.29 (s, 3H), 3.12 (dt, J = 17.6, 4.0

Hz, 1H), 3.07 (d, J = 5.9 Hz, 1H), 2.85 (dd, J = 16.9, 4.3 Hz, 1H), 2.46

(dd, J = 12.6, 6.8 Hz, 1H), 1.98−1.86 (m, 2H), 1.67−1.58 (m, 1H),

1.53−1.38 (m, 5H), 1.31−1.22 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 177.4, 172.7, 170.4, 136.8, 133.8, 131.3,

131.1, 128.8, 127.8, 126.3, 125.7, 125.4, 125.2, 123.1, 112.6, 77.7, 74.5,

52.5, 51.3, 46.4, 44.3, 37.0, 36.5, 28.8, 28.2, 28.1, 25.9, 25.8, 16.4; MS

(ESI) calcd for C₂₉H₃₃NO₆491.2 (M⁺), found 492.4 (M + H)⁺, 514.4

(M + Na)⁺.

1

anhydride 5: yield 368 mg, 68%; H NMR (500 MHz, CDCl₃) δ

7.34−7.28 (m, 2H), 7.26−7.20 (m, 3H), 5.35 (d, J = 1.6 Hz, 1H), 5.15

(d, J = 15.5 Hz, 1H), 4.63 (d, J = 15.5 Hz, 1H), 4.00−3.93 (m, 2H),

3.59 (s, 3H), 3.10−3.03 (m, 1H), 2.90 (dd, J = 16.9, 5.3 Hz, 1H), 2.81

(dd, J = 17.0, 5.7 Hz, 1H), 2.43 (dd, J = 12.7, 6.9 Hz, 1H), 1.92−1.85

(m, 1H), 1.81 (dd, J = 12.7, 11.6 Hz, 1H), 1.69−1.60 (m, 1H), 1.55−

1.37 (m, 5H), 1.32−1.23 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.18−1.11

(m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 175.9, 172.7, 170.9, 137.1,

136.7, 128.7, 127.3, 127.1, 112.2, 77.9, 74.5, 52.9, 51.3, 48.6, 44.5, 37.4,

36.4, 29.2, 28.6, 28.2, 25.9, 25.8, 16.6.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26r. Compound 26r was prepared according to general

procedure A from primary amine 1k, ketoester 24b, and itaconic

1

anhydride 5: yield 360 mg, 56%; H NMR (500 MHz, CDCl₃) δ

7.37−7.33 (m, 1H), 7.16 (s, 2H), 5.16 (d, J = 16.8 Hz, 1H), 5.13 (d, J

= 1.7 Hz, 1H), 4.60 (d, J = 16.7 Hz, 1H), 4.00−3.92 (m, 2H), 3.68 (s,

3H), 3.11 (dd, J = 17.5, 5.5 Hz, 1H), 3.01−2.91 (m, 1H), 2.72 (dd, J =

17.5, 4.4 Hz, 1H), 2.38 (dd, J = 12.7, 6.7 Hz, 1H), 1.93 (t, J = 12.3 Hz,

1H), 1.92−1.82 (m, 1H), 1.66−1.56 (m, 1H), 1.55−1.46 (m, 2H),

1.46−1.38 (m, 4H), 1.32−1.23 (m, 2H), 1.21 (d, J = 6.5 Hz, 3H),

1.19−1.13 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.6, 172.8,

170.3, 136.6, 133.3, 132.9, 132.8, 129.1, 129.1, 129.0, 127.3, 111.5,

77.6, 77.4, 74.4, 53.0, 51.3, 46.4, 44.4, 36.3, 36.2, 28.6, 28.3, 28.1, 25.9,

25.8, 16.6; MS (ESI) calcd for C₂₅H₂₉Cl₂NO₆509.1 (M⁺), found 492.3

(M − OH)⁺, 510.3 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26s. Compound 26s was prepared according to general

procedure A from primary amine 1d, ketoester 24c, and itaconic

anhydride 5: yield 461 mg, 73%; ¹H NMR (500 MHz, CDCl₃) δ 5.30

(d, J = 1.8 Hz, 1H), 3.93 (dd, J = 6.1, 1.7 Hz, 1H), 3.80−3.70 (m, 1H),

3.64 (s, 2H), 3.50−3.40 (m, 1H), 3.31 (d, J = 7.9 Hz, 1H), 3.02−2.92

(m, 1H), 2.73 (dd, J = 16.9, 5.2 Hz, 1H), 2.67 (dd, J = 16.9, 6.4 Hz,

1H), 2.48 (dd, J = 12.8, 6.8 Hz, 1H), 1.87−1.76 (m, 2H), 1.57−1.48

(m, 1H), 1.47−1.39 (m, 1H), 1.27−1.17 (m, 9H), 1.15 (t, J = 7.1 Hz,

1H), 0.90 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.82 (t, J = 6.9

Hz, 3H), 0.52−0.45 (m, 2H), 0.44−0.36 (m, 1H), 0.18−0.11 (m, 1H);

¹³C NMR (126 MHz, CDCl₃) δ 176.6, 172.8, 170.3, 136.2, 108.9, 81.6,

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26n. Compound 26n was prepared according to general

procedure A from primary amine 1f, ketoester 24b, and itaconic

1

anhydride 5: yield 353 mg, 68%; H NMR (500 MHz, CDCl₃) δ

6.77−6.66 (m, 3H), 5.93 (s, 2H), 5.39 (d, J = 1.6 Hz, 1H), 4.97 (d, J =

15.3 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 3.99 (dd, J = 7.3, 1.6 Hz, 1H),

3.96 (q, J = 6.8 Hz, 1H), 3.61 (s, 3H), 3.09−3.01 (m, 1H), 2.88 (dd, J

= 17.0, 5.3 Hz, 1H), 2.79 (dd, J = 16.9, 5.8 Hz, 1H), 2.41 (dd, J = 12.6,

6.9 Hz, 1H), 1.96−1.87 (m, 1H), 1.79 (dd, J = 12.7, 11.6 Hz, 1H),

1.72−1.62 (m, 1H), 1.61−1.41 (m, 5H), 1.34−1.25 (m, 1H), 1.20 (d, J

= 6.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 175.4, 172.7, 171.0,

148.0, 146.8, 136.7, 131.0, 120.5, 112.2, 108.3, 107.9, 101.1, 78.0, 74.5,

52.9, 51.3, 48.3, 44.5, 37.4, 36.4, 29.2, 28.6, 28.3, 25.9, 25.8, 16.6; MS

(ESI) calcd for C₂₆H₃₁NO₈485.2 (M⁺), found 486.2 (M + H)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26o. Compound 26o was prepared according to general

procedure A from primary amine 1g, ketoester 24b, and itaconic

anhydride 5: yield 283 mg, 60%; ¹H NMR (500 MHz, CDCl₃) δ 7.29

(dd, J = 1.7, 0.9 Hz, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (d, J =

3.2 Hz, 1H), 5.56 (d, J = 1.6 Hz, 1H), 4.98 (d, J = 15.6 Hz, 1H), 4.58

(d, J = 15.7 Hz, 1H), 4.03 (d, J = 7.3 Hz, 1H), 3.93 (q, J = 6.5 Hz,

1H), 3.59 (s, 2H), 3.03−2.95 (m, 1H), 2.80 (dd, J = 17.0, 6.2 Hz, 1H),

2.73 (dd, J = 17.1, 4.9 Hz, 1H), 2.39 (dd, J = 12.6, 7.1 Hz, 1H), 1.99−

1.90 (m, 1H), 1.69 (dd, J = 12.7, 11.1 Hz, 3H), 1.58−1.41 (m, 4H),

1.38−1.20 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 176.9, 172.6, 170.3, 150.3, 141.6, 136.7, 111.8, 110.6, 108.5,

78.0, 74.4, 52.8, 51.2, 44.4, 41.5, 37.2, 36.3, 28.8, 28.5, 28.1, 25.8, 25.8,

16.4; MS (ESI) calcd for C₂₃H₂₉NO₇431.2 (M⁺), found 414.3 (M −

OH)⁺, 432.3 (M + H)⁺, 454.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26p. Compound 26p was prepared according to general

procedure A from primary amine 1i, ketoester 24b and itaconic

anhydride 5: yield 457 mg, 73%; ¹H NMR (500 MHz, CDCl₃) δ 6.78

(d, J = 7.9 Hz, 1H), 6.76−6.72 (m, 2H), 5.35 (d, J = 1.6 Hz, 1H), 4.05

(d, J = 7.4 Hz, 1H), 3.98 (q, J = 6.5 Hz, 1H), 3.84 (d, J = 10.2 Hz,

7H), 3.73 (ddd, J = 13.5, 10.4, 5.0 Hz, 1H), 3.64 (s, 3H), 2.98 (dt, J =

12.0, 6.0 Hz, 1H), 2.88−2.81 (m, 1H), 2.80−2.70 (m, 2H), 2.40 (dd, J

= 12.7, 7.1 Hz, 1H), 1.97−1.89 (m, 1H), 1.76−1.63 (m, 2H), 1.63−

1.47 (m, 3H), 1.41−1.34 (m, 1H), 1.32−1.23 (m, 1H), 1.19 (d, J = 6.5

Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 172.6, 170.3, 149.0,

147.6, 136.7, 131.6, 120.6, 111.9, 111.3, 111.0, 78.0, 74.5, 55.9, 55.9,

52.8, 51.3, 46.3, 44.7, 37.5, 36.4, 32.6, 28.9, 28.6, 28.4, 25.8, 25.7, 16.5;

MS (ESI) calcd for C₂₈H₃₇NO₈515.3 (M⁺), found 516.4 (M + H)⁺,

538.4 (M + Na)⁺.

78.8, 52.7, 51.6, 43.5, 37.4, 36.3, 33.2, 31.8, 29.9, 29.3, 29.2, 27.1, 26.5,

22.6, 18.3, 18.0, 14.1, 11.8, 3.4, 2.4; MS (ESI) calcd for C₂₆H₄₁NO₆

463.3 (M⁺), found 446.5 (M − OH)⁺, 464.5 (M + H)⁺, 486.4 (M +

Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26t. Compound 26t was prepared according to general

procedure A from primary amine 1e, ketoester 24c, and itaconic

1

anhydride 5: yield 343 mg, 68%; H NMR (500 MHz, CDCl₃) δ

7.31−7.23 (m, 2H), 7.23−7.16 (m, 3H), 5.28 (d, J = 1.8 Hz, 1H), 5.15

(d, J = 15.7 Hz, 1H), 4.66 (d, J = 15.7 Hz, 1H), 3.83 (dd, J = 6.4, 1.8

Hz, 1H), 3.59 (s, 3H), 3.30 (d, J = 8.1 Hz, 1H), 3.09−2.99 (m, 1H),

2.92 (dd, J = 17.1, 6.1 Hz, 1H), 2.81 (dd, J = 17.1, 4.9 Hz, 1H), 2.50

(dd, J = 12.9, 6.4 Hz, 1H), 2.06 (t, J = 12.4 Hz, 1H), 1.75−1.65 (m,

1H), 0.88−0.83 (m, 1H), 0.81 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.7 Hz,

3H), 0.57−0.50 (m, 1H), 0.50−0.44 (m, 1H), 0.44−0.37 (m, 1H),

0.22−0.13 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.2, 172.9,

170.6, 137.0, 136.0, 128.5, 127.1, 126.8, 109.9, 81.6, 78.6, 52.8, 51.6,

47.9, 36.8, 36.4, 33.2, 29.9, 18.1, 11.9, 3.9, 2.5; MS (ESI) calcd for

C₂₅H₃₁NO₆441.2 (M⁺), found 424.4 (M − OH)⁺, 442.4 (M + H)⁺,

464.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26u. Compound 26u was prepared according to general

procedure A from primary amine 1f, ketoester 24c, and itaconic

1

anhydride 5: yield 361 mg, 66%; H NMR (500 MHz, CDCl₃) δ

6.74−6.64 (m, 3H), 5.89 (s, 2H), 5.32 (d, J = 1.9 Hz, 1H), 4.94 (d, J =

15.5 Hz, 1H), 4.67 (d, J = 15.5 Hz, 1H), 3.85 (dd, J = 6.4, 1.9 Hz, 1H),

3.61 (s, 3H), 3.31 (d, J = 8.2 Hz, 1H), 3.07−2.97 (m, 1H), 2.89 (dd, J

= 17.1, 6.0 Hz, 1H), 2.79 (dd, J = 17.1, 4.9 Hz, 1H), 2.48 (dd, J = 12.9,

6.5 Hz, 1H), 2.02 (t, J = 12.4 Hz, 1H), 1.81−1.68 (m, 1H), 0.85 (d, J =

6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.57−0.44 (m, 2H), 0.44−0.37

(m, 1H), 0.22−0.13 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.0,

172.9, 170.7, 147.9, 146.6, 136.0, 130.9, 120.2, 109.8, 108.2, 107.6,

101.0, 81.6, 78.7, 52.8, 51.6, 47.5, 36.8, 36.4, 33.2, 29.9, 18.3, 18.2,

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26q. Compound 26q was prepared according to general

procedure A from primary amine 1j, ketoester 24b, and itaconic

anhydride 5: yield 379 mg, 63%; ¹H NMR (500 MHz, CDCl₃) δ 8.00

(d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.76 (d, J = 8.2 Hz,

1H), 7.57−7.49 (m, 1H), 7.48 (ddd, J = 8.0, 6.7, 1.2 Hz, 1H), 7.42 (t, J

= 7.7 Hz, 1H), 7.33 (d, J = 7.1 Hz, 1H), 5.40 (d, J = 16.1 Hz, 1H), 5.36

7449

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The Journal of Organic Chemistry

Article

11.9, 3.9, 2.5; MS (ESI) calcd for C₂₆H₃₁NO₈485.2 (M⁺), found 486.4

(M + H)⁺, 508.3 (M + Na)⁺.

7.36−7.23 (m, 5H), 5.34 (d, J = 1.8 Hz, 1H), 4.59 (d, J = 12.2 Hz,

1H), 4.54 (d, J = 12.2 Hz, 1H), 4.49 (td, J = 6.0, 1.7 Hz, 1H), 4.08 (q,

J = 6.6 Hz, 1H), 3.85−3.75 (m, 1H), 3.67 (s, 3H), 3.54 (dd, J = 9.8,

6.4 Hz, 1H), 3.47−3.37 (m, 2H), 3.01−2.91 (m, 1H), 2.76 (dd, J =

16.8, 5.5 Hz, 1H), 2.64 (dd, J = 16.8, 6.2 Hz, 1H), 2.36 (dd, J = 12.7,

6.8 Hz, 1H), 1.64 (t, J = 12.1 Hz, 1H), 1.60−1.51 (m, 1H), 1.49−1.39

(m, 1H), 1.28−1.18 (m, 13H), 0.85 (t, J = 6.9 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 176.3, 172.4, 170.2, 137.9, 136.4, 128.5, 127.8,

127.8, 107.6, 74.4, 73.5, 73.3, 72.6, 52.9, 51.1, 43.6, 37.5, 36.2, 31.8,

29.3, 29.3, 29.2, 27.1, 26.5, 22.7, 16.8, 14.2; MS (ESI) calcd for

C₂₉H₄₁NO₇515.3 (M⁺), found 516.4 (M + H)⁺, 538.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26aa. Compound 26aa was prepared according to general

procedure A from primary amine 1e, ketoester 24d, and itaconic

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26v. Compound 26v was prepared according to general

procedure A from primary amine 1g, ketoester 24c, and itaconic

1

anhydride 5: yield 373 mg, 63%; H NMR (500 MHz, CDCl₃) δ

7.29−7.28 (m, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 6.21 (d, J = 3.2 Hz,

1H), 5.52 (d, J = 1.7 Hz, 1H), 5.00 (d, J = 15.8 Hz, 1H), 4.64 (d, J =

15.8 Hz, 1H), 3.91 (dd, J = 6.0, 1.8 Hz, 1H), 3.61 (s, 3H), 3.30 (d, J =

8.0 Hz, 1H), 3.02 (dq, J = 11.9, 6.0 Hz, 1H), 2.77 (d, J = 5.7 Hz, 2H),

2.51 (dd, J = 12.9, 6.8 Hz, 1H), 1.90 (t, J = 12.2 Hz, 1H), 1.80 (h, J =

6.7 Hz, 1H), 0.89 (d, J = 6.8 Hz, 4H), 0.84 (d, J = 6.6 Hz, 4H), 0.50

(dq, J = 7.6, 4.7 Hz, 2H), 0.44−0.37 (m, 1H), 0.19−0.12 (m, 1H); ¹³C

NMR (126 MHz, CDCl₃) δ 176.8, 172.8, 170.4, 150.4, 141.6, 136.2,

110.6, 109.9, 108.3, 81.5, 78.8, 52.8, 51.6, 41.0, 37.0, 36.4, 33.2, 29.8,

18.1, 18.1, 11.7, 3.5, 2.5; MS (ESI) calcd for C₂₃H₂₉NO₇431.2 (M⁺),

found 432.4 (M + H)⁺, 454.4 (M + Na)⁺.

1

anhydride 5: yield 257 mg, 63%; H NMR (500 MHz, CDCl₃) δ

7.36−7.27 (m, 5H), 7.25−7.19 (m, 5H), 5.39 (s, 1H), 5.00 (d, J = 15.6

Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 4.45 (d,

J = 12.1 Hz, 1H), 4.41 (td, J = 6.1, 1.8 Hz, 1H), 4.10 (q, J = 6.4 Hz,

1H), 3.58 (s, 3H), 3.48 (dd, J = 9.7, 6.3 Hz, 1H), 3.29 (dd, J = 9.8, 5.8

Hz, 1H), 3.09−2.99 (m, 1H), 2.85−2.78 (m, 2H), 2.40 (dd, J = 12.8,

6.5 Hz, 1H), 1.80 (t, J = 12.0 Hz, 1H), 1.20 (d, J = 6.6 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 176.4, 172.6, 170.6, 138.0, 136.8, 136.4,

128.6, 128.5, 128.5, 127.8, 127.8, 127.2, 127.1, 126.6, 108.5, 74.3, 73.5,

73.0, 72.7, 52.9, 51.3, 47.8, 37.0, 36.4, 29.4, 17.0; MS (ESI) calcd for

C₂₈H₃₁NO₇493.2 (M⁺), found 494.3 (M + H)⁺, 516.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26ab. Compound 26ab was prepared according to general

procedure A from primary amine 1f, ketoester 24d, and itaconic

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26w. Compound 26w was prepared according to general

procedure A from primary amine 1h, ketoester 24c, and itaconic

anhydride 5: yield 520 mg, 77%; ¹H NMR (500 MHz, CDCl₃) δ 5.39

(s, 1H), 5.33 (s, 1H), 3.91 (dd, J = 6.0, 1.8 Hz, 1H), 3.74 (ddd, J =

13.0, 10.6, 5.4 Hz, 1H), 3.64 (s, 3H), 3.30 (d, J = 8.0 Hz, 1H), 2.97−

2.87 (m, 1H), 2.74 (dd, J = 16.8, 5.4 Hz, 1H), 2.64 (dd, J = 16.8, 6.3

Hz, 1H), 2.44 (dd, J = 12.9, 6.6 Hz, 1H), 2.23−2.13 (m, 1H), 2.06−

1.97 (m, 1H), 1.95−1.88 (m, 4H), 1.87−1.78 (m, 2H), 1.59−1.52 (m,

2H), 1.52−1.45 (m, 2H), 0.91 (d, J = 6.7 Hz, 4H), 0.88 (d, J = 6.7 Hz,

4H), 0.51−0.46 (m, 2H), 0.44−0.37 (m, 1H), 0.20−0.12 (m, 1H); ¹³C

NMR (126 MHz, CDCl₃) δ 176.5, 172.8, 170.2, 135.9, 134.9, 122.9,

108.5, 81.6, 78.7, 52.7, 51.6, 42.7, 37.2, 36.3, 34.7, 33.3, 29.9, 28.4,

25.2, 22.9, 22.3, 18.4, 18.1, 11.9, 3.7, 2.4; MS (ESI) calcd for

C₂₆H₃₇NO₆459.3 (M⁺), found 460.4 (M + H)⁺, 482.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26x. Compound 26x was prepared according to general

procedure A from primary amine 1j, ketoester 24c, and itaconic

anhydride 5: yield 436 mg, 61%; ¹H NMR (500 MHz, CDCl₃) δ 8.01

(d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.75 (d, J = 8.2 Hz,

1H), 7.53 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.48 (ddd, J = 8.0, 6.8, 1.2

Hz, 1H), 7.45−7.38 (m, 1H), 7.32 (d, J = 7.0 Hz, 1H), 5.42 (d, J =

16.1 Hz, 1H), 5.36 (d, J = 16.0 Hz, 1H), 5.31 (d, J = 1.8 Hz, 1H), 3.86

(dd, J = 5.9, 1.8 Hz, 1H), 3.32 (s, 3H), 3.29 (d, J = 7.8 Hz, 1H), 3.23−

3.13 (m, 1H), 3.04 (dd, J = 17.1, 5.9 Hz, 1H), 2.87 (dd, J = 17.2, 4.8

Hz, 1H), 2.60 (dd, J = 12.9, 6.8 Hz, 1H), 2.12 (t, J = 12.3 Hz, 1H),

1.77−1.66 (m, 1H), 0.95−0.86 (m, 1H), 0.82 (d, J = 6.8 Hz, 3H), 0.73

(d, J = 6.8 Hz, 3H), 0.55−0.45 (m, 2H), 0.47−0.38 (m, 1H), 0.18−

0.11 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 177.3, 172.8, 170.6,

136.3, 133.8, 131.3, 131.1, 128.9, 127.8, 126.4, 125.8, 125.4, 125.0,

123.0, 110.9, 81.5, 78.8, 52.5, 51.7, 45.8, 37.0, 36.6, 33.1, 29.9, 18.2,

17.8, 11.7, 3.3, 2.5; MS (ESI) calcd for C₂₉H₃₃NO₆491.2 (M⁺), found

492.4 (M + H)⁺, 514.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26y. Compound 26y was prepared according to general

procedure A from primary amine 1k, ketoester 24c, and itaconic

anhydride 5: yield 450 mg, 60%; ¹H NMR (500 MHz, CDCl₃) δ 7.36

(d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 (d, J = 8.4 Hz,

1H), 5.14−5.08 (m, 2H), 4.75 (d, J = 16.8 Hz, 1H), 3.82 (dd, J = 6.6,

1.9 Hz, 1H), 3.70 (s, 3H), 3.34 (d, J = 8.1 Hz, 1H), 3.04 (dd, J = 17.1,

5.6 Hz, 1H), 3.01−2.93 (m, 1H), 2.77 (dd, J = 17.1, 4.2 Hz, 1H), 2.47

(dd, J = 12.9, 6.0 Hz, 1H), 2.16 (t, J = 12.5 Hz, 1H), 1.79−1.69 (m,

1H), 0.96−0.87 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz,

3H), 0.61−0.49 (m, 2H), 0.49−0.41 (m, 1H), 0.27−0.18 (m, 1H); ¹³C

NMR (126 MHz, CDCl₃) δ 177.6, 173.0, 170.5, 135.8, 133.4, 133.0,

132.7, 129.2, 128.8, 127.4, 109.5, 81.5, 78.5, 53.0, 51.7, 45.5, 36.3, 36.1,

33.3, 29.7, 18.4, 18.3, 12.0, 4.1, 2.5; MS (ESI) calcd for C₂₅H₂₉Cl₂NO₆

509.1 (M⁺), found 492.3 (M − OH)⁺, 510.3 (M + H)⁺, 532.3 (M +

Na)⁺.

1

anhydride 5: yield 393 mg, 68%; H NMR (500 MHz, CDCl₃) δ

7.37−7.23 (m, 5H), 6.75−6.65 (m, 3H), 5.90 (d, J = 1.4 Hz, 1H), 5.90

(d, J = 1.4 Hz, 1H), 5.37 (d, J = 1.9 Hz, 1H), 4.86 (d, J = 15.6 Hz,

1H), 4.74 (d, J = 15.5 Hz, 1H), 4.51 (q, J = 12.1 Hz, 2H), 4.42 (td, J =

6.1, 1.8 Hz, 1H), 4.10 (q, J = 6.4 Hz, 1H), 3.62 (s, 3H), 3.49 (dd, J =

9.8, 6.4 Hz, 1H), 3.32 (dd, J = 9.8, 5.7 Hz, 1H), 3.05−2.95 (m, 1H),

2.81 (dd, J = 5.7, 2.1 Hz, 2H), 2.37 (dd, J = 12.7, 6.5 Hz, 1H), 1.80 (t,

J = 12.3 Hz, 1H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 176.3, 172.5, 170.6, 147.9, 146.7, 138.0, 136.4, 130.6, 128.5,

128.5, 127.8, 127.8, 127.8, 120.4, 108.5, 108.3, 107.8, 101.1, 74.3, 73.5,

73.1, 72.7, 53.0, 51.2, 47.5, 37.0, 36.4, 29.3, 17.0; MS (ESI) calcd for

C₂₉H₃₁NO₉537.2 (M⁺), found 538.3 (M + H)⁺, 560.2 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26ac. Compound 26ac was prepared according to general

procedure A from primary amine 1h, ketoester 24d, and itaconic

1

anhydride 5: yield 555 mg, 70%; H NMR (500 MHz, CDCl₃) δ

7.37−7.31 (m, 4H), 7.31−7.27 (m, 1H), 5.45−5.41 (m, 1H), 5.40 (d, J

= 1.9 Hz, 1H), 4.61 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H),

4.50 (td, J = 6.1, 1.7 Hz, 1H), 4.11 (q, J = 6.5 Hz, 1H), 3.82 (ddd, J =

13.5, 10.5, 5.2 Hz, 1H), 3.70 (s, 3H), 3.67−3.59 (m, 1H), 3.57 (dd, J =

9.7, 6.4 Hz, 1H), 3.43 (dd, J = 9.7, 5.8 Hz, 1H), 2.99−2.89 (m, 1H),

2.78 (dd, J = 16.7, 6.1 Hz, 1H), 2.63 (dd, J = 16.7, 5.8 Hz, 1H), 2.36

(dd, J = 12.7, 6.7 Hz, 1H), 2.28−2.17 (m, 1H), 2.10−2.00 (m, 1H),

1.99−1.92 (m, 4H), 1.64 (t, J = 11.5 Hz, 1H), 1.61−1.56 (m, 2H),

1.56−1.48 (m, 2H), 1.22 (d, J = 6.5 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 175.9, 172.4, 170.3, 138.0, 136.2, 134.9, 128.6, 127.9, 127.9,

123.0, 107.6, 74.4, 73.5, 73.2, 72.7, 53.0, 51.2, 42.9, 37.6, 36.3, 34.7,

29.5, 28.6, 25.3, 23.0, 22.4, 17.0; MS (ESI) calcd for C₂₉H₃₇NO₇511.3

(M⁺), found 512.3 (M + H)⁺, 534.3 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26ad. Compound 26ad was prepared according to general

procedure A from primary amine 1i, ketoester 24d, and itaconic

1

anhydride 5: yield 339 mg, 53%; H NMR (500 MHz, CDCl₃) δ

7.34−7.28 (m, 4H), 7.28−7.23 (m, 1H), 6.77−6.68 (m, 3H), 5.37 (d, J

= 1.9 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H),

4.50 (td, J = 6.2, 1.9 Hz, 1H), 4.09 (q, J = 6.5 Hz, 1H), 3.97−3.87 (m,

1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78−3.68 (m, 1H), 3.65 (s, 3H), 3.53

(dd, J = 9.7, 6.4 Hz, 1H), 3.38 (dd, J = 9.7, 5.9 Hz, 1H), 3.01−2.91 (m,

1H), 2.88−2.77 (m, 1H), 2.77−2.70 (m, 2H), 2.70−2.64 (m, 1H),

2.37 (dd, J = 12.7, 6.7 Hz, 1H), 1.68 (t, J = 12.1 Hz, 1H), 1.21 (d, J =

6.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 172.4, 170.1,

149.0, 147.6, 137.9, 136.5, 131.4, 128.5, 127.8, 127.8, 120.6, 112.0,

Tetrahydropyran-fused Piperidinone-Containing Carboxylic

Acid 26z. Compound 26z was prepared according to general

procedure A from primary amine 1d, ketoester 24d, and itaconic

1

anhydride 5: yield 351 mg, 65%; H NMR (500 MHz, CDCl₃) δ

7450

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The Journal of Organic Chemistry

Article

111.3, 107.7, 74.4, 73.5, 73.2, 72.6, 55.9, 55.9, 52.9, 51.2, 45.7, 37.2,

36.3, 32.4, 29.2, 16.8; MS (ESI) calcd for C₃₁H₃₇NO₉567.2 (M⁺),

found 568.4 (M + H)⁺, 590.4 (M + Na)⁺.

(1H, dt, J = 13.5, 2.0 Hz), 1.26 (1H, m), 1.15 (3H, t, J = 7.0 Hz); ¹³C

NMR (DMSO-d₆, 125 MHz) δ 173.4, 172.7, 168.3, 136.2, 106.5, 78.4,

75.2, 60.8, 45.9, 36.0, 35.8, 35.7, 33.9, 33.5, 23.7, 18.2, 13.9, 3.1;

HRMS-EI m/z [M]⁺calcd for C₁₈H₂₃NO₅333.1576, found 333.1569

Enynamide 33a (2-((3RS,4aSR)-4a-(Ethoxycarbonyl)-2-oxo-1-

(prop-2-yn-1-yl)-2,3,4,4a,5,6-hexahydro-1H-cyclopenta[b]-

pyridin-3-yl)acetic Acid). Compound 33a was prepared according

to general procedure A from primary amine 27b, ketoester 2d, and

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26ae. Compound 26ae was prepared according to general

procedure A from primary amine 1j, ketoester 24d, and itaconic

anhydride 5: yield 277 mg, 46%; ¹H NMR (500 MHz, CDCl₃) δ 7.97

(d, J = 8.4 Hz, 1H), 7.86 (dd, J = 7.8, 1.8 Hz, 1H), 7.75 (d, J = 8.3 Hz,

1H), 7.56−7.45 (m, 2H), 7.42−7.35 (m, 1H), 7.27 (d, J = 7.1 Hz,

1H), 7.25−7.20 (m, 3H), 7.17−7.11 (m, 2H), 5.45 (d, J = 16.2 Hz,

1H), 5.34 (d, J = 1.8 Hz, 1H), 5.28 (d, J = 16.1 Hz, 1H), 4.45 (d, J =

12.0 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.37 (td, J = 5.5, 3.0 Hz, 1H),

4.04 (q, J = 6.4, 5.8 Hz, 1H), 3.45 (dd, J = 9.8, 6.4 Hz, 1H), 3.29 (s,

3H), 3.28−3.24 (m, 1H), 3.14−3.04 (m, 1H), 2.92 (dd, J = 17.0, 5.7

Hz, 1H), 2.84 (dd, J = 17.0, 5.2 Hz, 1H), 2.42 (dd, J = 12.8, 6.6 Hz,

1H), 1.91 (t, J = 12.3 Hz, 1H), 1.20 (d, J = 6.5 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 176.8, 172.4, 170.3, 137.8, 136.4, 133.8, 131.0,

130.9, 128.8, 128.3, 127.8, 127.7, 127.7, 126.3, 125.7, 125.4, 124.8,

123.0, 108.8, 74.3, 73.3, 73.1, 72.5, 52.5, 51.2, 45.7, 36.7, 36.4, 29.1,

16.8; MS (ESI) calcd for C₃₂H₃₃NO₇543.2 (M⁺), found 544.4 (M +

H)⁺, 566.4 (M + Na)⁺.

Tetrahydropyran-Fused Piperidinone-Containing Carbox-

ylic Acid 26af. Compound 26af was prepared according to general

procedure A from primary amine 1k, ketoester 24d, and itaconic

anhydride 5: yield 392 mg, 62%; ¹H NMR (500 MHz, CDCl₃) δ 7.36

(d, J = 2.1 Hz, 1H), 7.34−7.26 (m, 3H), 7.23−7.20 (m, 2H), 7.16 (dd,

J = 8.4, 2.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.15 (d, J = 1.9 Hz, 1H),

5.08 (d, J = 16.9 Hz, 1H), 4.74 (d, J = 16.9 Hz, 1H), 4.50 (d, J = 12.2

Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.38 (td, J = 5.9, 1.9 Hz, 1H), 4.13

(q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.47 (dd, J = 9.7, 6.4 Hz, 1H), 3.30

(dd, J = 9.7, 5.6 Hz, 1H), 3.03−2.89 (m, 2H), 2.76 (dd, J = 16.8, 4.0

Hz, 1H), 2.36 (dd, J = 12.7, 5.8 Hz, 1H), 1.94 (t, J = 12.3 Hz, 1H),

1.24 (d, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.9, 172.7,

170.3, 137.9, 136.2, 133.4, 133.1, 132.4, 129.3, 128.7, 128.5, 127.8,

127.8, 127.8, 127.4, 108.0, 74.3, 73.5, 72.9, 72.6, 53.1, 51.2, 45.9, 36.4,

36.2, 29.2, 17.1; MS (ESI) calcd for C₂₈H₂₉Cl₂NO₇561.1 (M⁺), found

562.4 (M + H)⁺, 584.3 (M + Na)⁺.

Enynamide 28a (2-((3RS,4aSR)-4a-(Ethoxycarbonyl)-2-oxo-1-

(3-phenylprop-2-yn-1-yl)-1,2,3,4,4a,5,6,7-octahydroquinolin-

3-yl)acetic Acid). Compound 28a was prepared according to general

procedure A from primary amine 27a, ketoester 2a, and itaconic

anhydride 5 (3.16 g, 80%): ¹H NMR (CDCl₃, 500 MHz) δ 7.35 (2H,

m), 7.22−7.19 (3H, m), 5.59 (1H, dd, J = 4.5, 2.5 Hz), 5.02 (1H, d, J =

17.0 Hz), 4.27 (1H, d, J = 17.5 Hz), 4.09 (2H, 7.0 Hz), 2.83 (1H, dd, J

= 16.0, 6.0 Hz), 2.71 (1H, m), 2.48 (1H, dd, J = 16.5, 5.5 Hz), 2.29−

2.10 (3H, m), 1.65 (1H, br), 1.59 (1H, t, J = 13.0 Hz), 1.47 (1H, dt, J

= 14.0, 2.5 Hz), 1.37 (1H, m), 1.15 (3H, t, J = 6.5 Hz); ¹³C NMR

(CDCl₃, 125 MHz) δ 175.6, 173.7, 169.9, 136.0, 131.8, 128.3, 128.2,

122.8, 109.3, 84.3, 83.4, 61.6, 46.4, 37.0, 36.7, 36.2, 35.2, 34.6, 24.3,

18.5, 14.1; HRMS-ESI m/z [M + H]⁺calcd for C₂₃H₂₅NO₅396.1811,

found 396.1818.

1

itaconic anhydride 5 (1.71 g, 56%): H NMR (CDCl₃, 500 MHz) δ

5.28 (1H, s), 4.60 (1H, dd, J = 17.5, 2.5 Hz), 4.36 (1H, dd, J = 17.5,

2.5 Hz), 4.18 (2H, m), 2.91−2.81 (2H, m), 2.70 (1H, dd, J = 6.0, 16.5

Hz), 2.59−2.50 (2H, m), 2.43−2.36 (2H, m), 2.21 (1H, t, J = 2.0 Hz),

1.91 (1H, m), 1.73 (1H, t, J = 12.5 Hz), 1.25 (3H, t, J = 7.0 Hz); ¹³C

NMR (CDCl₃, 125 MHz) δ 176.7, 173.7, 169.3, 140.3, 107.9, 77.9,

71.5, 61.5, 54.2, 36.8, 36.4, 36.3, 35.6, 33.4, 29.0, 14.1; HRMS-ESI m/z

[M + H]⁺calcd for C₁₆H₂₀NO₅306.1341, found 306.1339.

Enynamide 33b. Compound 33b was prepared according to

general procedure A from primary amine 27a, ketoester 2b and

1

itaconic anhydride 5 (1.62 g, 41%): H NMR (CDCl₃, 500 MHz) δ

7.35 (2H, m), 7.22 (3H, m), 5.78 (1H, t, J = 7.0 Hz), 4.86 (1H, d, J =

17.5 Hz), 4.45 (1H, d, J = 17.5 Hz), 3.70 (3H, s), 2.83 (1H, dd, J =

16.5, 6.5 Hz), 2.71 (1H, m), 2.38 (1H, dd, J = 16.5, 6.0 Hz), 2.23 (1H,

m), 2.10−1.98 (4H, m), 1.76−1.61 (5H, m), 1.42−1.34 (1H, m); ¹³C

NMR (CDCl₃, 125 MHz) δ 175.9, 173.9, 170.7, 139.8, 131.8, 128.3,

128.2, 122.7, 116.3, 84.4, 83.4, 52.6, 51.6, 39.5, 36.5, 36.0, 35.7, 35.5,

26.3, 25.3, 24.9; HRMS-EI m/z [M]⁺calcd for C₂₃H₂₅NO₅395.1733,

found 395.1734.

Enynamide 33c. Compound 33c was prepared according to

general procedure A from primary amine 27a, ketoester 2e, and

1

itaconic anhydride 5 (1.85 g, 50%): H NMR (CDCl₃, 500 MHz) δ

7.34 (2H, m), 7.21 (3H, m), 4.95 (1H, d, J = 2.5 Hz), 4.87 (1H, d, J =

17.0 Hz), 4.62 (1H, d, J = 2.5 Hz), 4.53 (1H, d, J = 17.0 Hz), 4.07

(2H, q, J = 7.5 Hz), 2.98 (1H, m), 2.81 (1H, dd, J = 17.0, 5.5 Hz), 2.53

(1H, dd, J = 17.0, 6.5 Hz), 2.29 (1H, dd, J = 13.5, 6.0 Hz), 1.61 (1H, t,

J = 13.0 Hz), 1.43 (3H, s), 1.14 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃,

125 MHz) δ 176.3, 173.6, 170.3, 146.0, 131.8, 128.3, 128.1, 122.7,

96.2, 83.9, 83.4, 61.6, 46.5, 36.5, 36.4, 36.1, 35.4, 24.8, 14.0; HRMS-

ESI m/z [M + H]⁺calcd for C₂₁H₂₄NO₅370.1654, found 370.1652.

Enynamide 33d. Compound 33d was prepared according to

general procedure A from primary amine 27b, ketoester 2f, and

1

itaconic anhydride 5 (1.47 g, 50%): H NMR (CDCl₃, 500 MHz) δ

5.01 (1H, d, J = 2.0 Hz), 4.76 (1H, d, J = 2.0 Hz), 4.62 (1H, dd, J =

17.5, 1.5 Hz), 4.35 (1H, dd, J = 17.5, 1.5 Hz), 4.20 (2H, m), 4.14 (2H,

q, J = 7.0 Hz), 3.14 (1H, m), 2.90 (1H, dd, J = 17.0, 5.5 Hz), 2.61 (1H,

dd, J = 17.0, 6.5 Hz), 2.41−2.25 (5H, m), 2.18−2.12 (1H, m), 1.62

(1H, t, J = 13.0 Hz), 1.27 (3H, dt, J = 7.0, 1.0 Hz), 1.26 (3H, dt, J =

7.0, 1.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 172.7, 172.6, 170.4,

144.4, 97.6, 78.2, 72.0, 72.0, 61.8, 60.7, 49.7, 35.8, 35.7, 34.7, 33.0,

32.9, 29.5, 14.2, 14.0; HRMS-EI m/z [M]⁺calcd for C₁₉H₂₅NO₇

379.1631, found 379.1623.

Enynamide 35a (2-((3SR,3aRS)-3a-(Ethoxycarbonyl)-2-oxo-1-

(prop-2-yn-1-yl)-2,3,3a,4,5,6-hexahydro-1H-indol-3-yl)acetic

Acid). Compound 35a was prepared according to general procedure A

from primary amine 27b, ketoester 2a, and maleic anhydride 4 (2.53 g,

Enynamide 28b. Compound 28b was prepared according to

general procedure A from primary amine 27b, ketoester 2a and

1

itaconic anhydride 5 (3.19 g, quant): H NMR (CDCl₃, 500 MHz) δ

1

5.47 (1H, dd, J = 5.0, 3.0 Hz), 4.80 (1H, dd, J = 17.0, 2.0 Hz), 4.10

(2H, q, J = 7.0 Hz), 4.05 (1H, dd, J = 17.5, 2.5 Hz), 2.81 (1H, dd, J =

16.5, 6.0 Hz), 2.69 (1H, m), 2.53 (1H, dd, J = 6.0 Hz), 2.33 (1H, dd, J

= 13.0, 6.0 Hz), 2.27−2.09 (5H, m), 1.65 (1H, br), 1.59 (1H, t, J =

13.0 Hz), 1.47 (1H, dt, J = 14.0, 2.5 Hz), 1.39−1.29 (1H, m),

1.17(3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.1, 173.7,

169.6, 136.0, 108.8, 78.8, 71.7, 61.6, 46.4, 36.7, 36.6, 36.1, 34.6, 34.2,

24.2, 18.5, 14.1; HRMS-ESI m/z [M + H]⁺calcd for C₁₇H₂₂NO₅

320.1498, found 320.1497.

Enynamide 28c. Compound 28c was prepared according to

general procedure A from primary amine 27c, ketoester 2a and

itaconic anhydride 5 (2.40 g, 72%): ¹H NMR (DMSO-d₆, 500 MHz) δ

5.40 (1H, dd, J = 4.5, 3.0 Hz), 4.66 (1H, dd, J = 17.0, 2.5 Hz), 4.11

(2H, q, J = 7.0 Hz), 4.03 (1H, dd, J = 17.0, 2.0 Hz), 2.65 (1H, dd, J =

16.5, 4.5 Hz), 2.50 (1H, m), 2.42 (1H, dd, J = 16.5, 7.0 Hz), 2.23−2.12

(4H, m), 1.17 (3H, s), 1.70 (1H, s, J = 13.0 Hz), 1.65 (1H, m), 1.51

83%): H NMR (CDCl₃, 500 MHz) δ 5.19 (1H, t, J = 7.5 Hz), 4.23

(2H, dq, J = 17.5, 2.5 Hz), 4.13−4.03 (2H, m), 2.96 (1H, t, J = 7.0

Hz), 2.80 (1H, dd, J = 17.5, 6.5 Hz), 2.54 (1H, m), 2.29 (1H, dd, J =

17.5, 8.0 Hz), 2.22−2.07 (3H, m), 1.81 (1H, m), 1.55−1.42 (2H, m),

1.17 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 172.5,

171.1, 137.3, 102.4, 76.8, 71.7, 61.5, 52.0, 47.3, 31.2, 30.3, 29.6, 22.7,

19.5, 14.0; HRMS-ESI m/z [M + H]⁺calcd for C₁₆H₂₀NO₅306.1341,

found 306.1339.

Enynamide 35b. Compound 35b was prepared according to

general procedure A from primary amine 27a, ketoester 2a, and maleic

anhydride 4 (1.95 g, 51%): ¹H NMR (CDCl₃, 500 MHz) δ 7.33 (2H,

m), 7.25−7.19 (3H, m), 5.28 (1H, t, J = 3.5 Hz), 4.45 (2H, q, J = 11.5

Hz), 4.05 (2H, m), 2.98 (1H, t, J = 7.0 Hz), 2.79 (1H, dd, J = 17.0, 6.5

Hz), 2.53 (1H, m), 2.31 (1H, dd, J = 17.5, 7.5 Hz), 2.22−2.08 (2H,

m), 1.80 (1H, m), 1.56−1.42 (2H, m), 1.13 (3H, t, J = 7.0 Hz); ¹³C

NMR (CDCl₃, 125 MHz) δ 175.5, 172.8, 171.1, 137.4, 131.8, 128.5,

7451

dx.doi.org/10.1021/jo301061r | J. Org. Chem. 2012, 77, 7435−7470

The Journal of Organic Chemistry

Article

128.2, 122.5, 102.7, 83.4, 82.3, 61.5, 52.0, 47.4, 31.3, 30.6, 30.2, 22.8,

19.5, 14.0; HRMS-ESI m/z [M + H]⁺calcd for C₂₂H₂₄NO₅382.1654,

found 382.1647.

Cycloisomerization Product 34a (2-((2RS,9aSR)-9a-(Ethoxy-

carbonyl)-3-oxo-2,3,5,8,9,9a-hexahydro-1H-cyclopenta[ij]-

quinolizin-2-yl)acetic Acid). Compound 34a (98% yield deter-

1

mined by H NMR using mesitylene as an internal standard) was

Enynamide 35c. Compound 35c was prepared according to

general procedure A from primary amine 27b, ketoester 2b, and maleic

anhydride 4 (2.63 g, 86%):¹H NMR (CDCl₃, 500 MHz) δ 5.40 (1H,

dd, J = 9.0, 4.5 Hz), 4.40 (1H, d, J = 17.0 Hz), 4.20 (1H, d, J = 17.0

Hz), 3.71 (3H, s), 3.09 (1H, t, J = 6.5 Hz), 2.80 (1H, dd, J = 17.0, 6.5

Hz), 2.50 (1H, d, J = 11.5 Hz), 2.40−2.27 (2H, m), 2.21 (1H, s),

2.01−1.94 (2H, m), 1.78−1.60 (3H, m), 1.38 (1H, q, J = 12.0 Hz);

¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 172.4, 171.1, 141.7, 106.2, 76.8,

prepared according to the general procedure B: ¹H NMR (CDCl₃, 500

MHz) δ 5.94 (1H, dt, J = 2.0, 10.0 Hz), 5.60 (1H, m), 4.85 (1H, dd, J

= 19.5, 4.5), 4.16−4.28 (3H, m), 2.89 (2H, m), 2.60 (3H, m), 2.37

(2H, m), 1.89 (1H, dt, J = 18.5, 9.0 Hz), 1.67 (1H, t, J = 12.5 Hz), 1.28

(3H, t, J = 6.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.3, 173.7,

168.5, 134.6, 121.2, 120.5, 116.0, 61.6, 53.0, 44.1, 36.6, 36.4, 36.3, 35.0,

29.8, 14.2; HRMS-ESI m/z [M + H]⁺calcd for C₁₆H₂₀NO₅306.1341,

found 306.1343.

71.6, 55.4, 52.3, 48.1, 35.6, 31.6, 30.0, 27.5, 27.2, 26.1; HRMS-EI m/z

Cycloisomerization Product 34b. Compound 34b (75% yield

determined by ¹H NMR using mesitylene as an internal standard) was

prepared according to the general procedure B: ¹H NMR (CDCl₃, 500

MHz) δ 7.37−7.29 (3H, m), 7.18 (2H, m), 5.71 (1H, dd, J = 5.5, 4.5

Hz), 4.86 (1H, dd, J = 15.5, 5.5 Hz), 4.00 (1H, dd, J = 15.5, 4.0 Hz),

3.87 (3H, s), 2.97−2.86 (2H, m), 2.45 (1H, dd, J = 16.0, 6.0 Hz), 2.20

(3H, m), 2.02 (1H, m), 1.86−1.66 (5H, m), 1.35 (1H, m); ¹³C NMR

(CDCl₃, 125 MHz) δ 176.0, 174.0, 171.1, 142.2, 139.1, 136.3, 128.2,

128.1, 127.3, 126.0, 117.2, 52.7, 51.9, 40.2, 40.0, 36.6, 35.7, 35.5, 29.5,

26.6, 25.6; HRMS-EI m/z [M]⁺calcd for C₂₃H₂₅NO₅395.1733, found

395.1736.

Cycloisomerization Product 34c. Compound 34c (90% yield

determined by ¹H NMR using mesitylene as an internal standard) was

prepared according to the general procedure B: ¹H NMR (CDCl₃, 500

MHz) δ 7.42−7.29 (5H, m), 5.88 (1H, m), 5.74 (1H, d, J = 1.5 Hz),

5.05 (1H, dd, J = 18.0, 5.5 Hz), 4.31−4.20 (3H, m), 3.09 (1H, m),

2.95 (1H, dd, J = 16.5, 6.0 Hz), 2.60 (1H, dd, J = 17.0, 6.5 Hz), 2.43

(1H, dd, J = 13.5, 6.0 Hz), 1.73 (1H, t, J = 13.0 Hz), 1.58 (3H, s), 1.29

(3H, t, J = 7.5 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 176.3, 173.6,

169.7, 139.4, 138.5, 134.2, 128.6, 127.7, 125.5, 115.8, 106.7, 61.8, 45.9,

42.8, 36.6, 36.2, 36.2, 24.0, 14.1; HRMS-ESI m/z [M]⁺calcd for

C₂₁H₂₃NO₅369.1576, found 369.1585.

Cycloisomerization Product 34d. Compound 34d (quantitative

yield determined by ¹H NMR using mesitylene as an internal

standard) was prepared according to the general procedure B: ¹H

NMR (CDCl₃, 500 MHz) δ 5.95 (1H, m), 5.68 (1H, m), 5.48 (1H, d,

J = 5.5 Hz), 4.55 (1H, dd, J = 17.5, 4.0 Hz), 4.40 (1H, d, J = 17.5 Hz),

4.22 (2H, m), 4.15 (2H, q, J = 7.0 Hz), 3.13 (1H, m), 2.90 (1H, dd, J

= 17.0, 6.5 Hz), 2.54 (1H, dd, J = 16.5, 6.0 Hz), 2.39 (2H, t, J = 8.0

Hz), 2.31 (2H, m), 2.16−2.10 (1H, m), 1.58 (1H, t, J = 13.0 Hz),

1.30−1.25 (6H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.9, 172.7,

172.6, 170.5, 136.8, 122.2, 120.5, 107.3, 61.9, 60.8, 48.9, 41.6, 36.1,

35.8, 32.9, 32.8, 29.6, 14.2, 14.0; HRMS-EI m/z [M − H]⁺calcd for

C₁₉H₂₄NO₇378.1553, found 378.1558.

[M − H]⁺calcd for C₁₆H₁₈NO₅304.1185, found 304.1179.

Enynamide 35d. Compound 35d was prepared according to

general procedure A from primary amine 27a, ketoester 2b, and maleic

anhydride 4 (1.95 g, 51%): ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (2H,

m), 7.23 (3H, m), 5.42 (1H, dd, J = 8.5 4.0 Hz), 4.55 (1H, d, J = 17.5

Hz), 4.32 (1H, d, J = 17.5 Hz), 3.61 (3H, s), 3.02 (1H, t, J = 7.0 Hz),

2.66 (1H, dd, J = 17.0, 7.5 Hz), 2.41 (1H, d, J = 15.0 Hz), 2.34 (1H,

dd, J = 17.0, 6.5 Hz), 2.24 (1H, m), 1.94−1.84 (2H, m), 1.67 (2H, m),

1.55 (1H, t, J = 13.5 Hz), 1.29 (1H, m); ¹³C NMR (CDCl₃, 125 MHz)

δ 175.1, 172.8, 171.0, 141.6, 131.7, 128.4, 128.3, 122.4, 106.7, 83.4,

82.1, 55.4, 52.3, 48.2, 35.5, 31.6, 30.9, 27.4, 27.2, 26.1; HRMS-ESI m/z

[M + H]⁺calcd for C₂₂H₂₄NO₅382.1654, found 382.1653.

General Procedure B: Au-Catalyzed Enynamide Cyclo-

isomerization. A solution of enyne-containing piperidinones (28 or

33, 5.00 mmol) or pyrrolidinones (35, 5.00 mmol) in CH₃CN (8.2

mL) was treated with JohnPhos-Au-NCMe·SbF₆(31, 0.15 mmol, 3

mol %). The resulting solution was stirred overnight at room

temperature under inert nitrogen atmosphere. Removal of solvent

under reduced pressure aﬀorded crude dienamides (29, 34, or 36),

which were used for subsequent hydrogenation without puriﬁcation.

Cycloisomerization product 29a (2-((2RS,10aSR)-10a-(Ethox-

y c a r b o n y l ) - 3 - o x o - 7 - p h e n y l - 1 , 2 , 3 , 5 , 8 , 9 , 1 0 , 1 0 a -

octahydropyrido[3,2,1-ij]quinolin-2-yl)acetic Acid). Compound

29a was prepared according to general procedure B from enynamide

1

28a (quantative yield by H NMR using mesitylene as an internal

1

standard): H NMR (CDCl₃, 500 MHz) δ 7.34 (3H, m), 7.20 (2H,

m), 5.66 (1H, dd, J = 6.0, 2.5 Hz), 5.22 (1H, dd, J = 17.5, 6.0 Hz), 4.24

(2H, m), 3.88 (1H, d, J = 17.5 Hz), 2.98 (1H, dd, J = 16.5, 6.5 Hz),

2.60 (1H, dd, J = 16.5, 6.0 Hz), 2.34 (1H, d, J = 13.0 Hz), 2.15 (1H,

m), 1.89 (1H, dd, J = 18.0, 4.5 Hz), 1.70 (2H, m), 1.55−1.42 (2H, m),

1.30 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.6, 173.9,

169.3, 139.0, 138.7, 131.3, 128.4, 128.0, 127.3, 118.9, 116.8, 61.8, 46.5,

41.3, 37.3, 36.5, 36.1, 34.3, 27.0, 19.0, 14.2; HRMS-ESI m/z [M + H]⁺

calcd for C₂₃H₂₄NO₅395.1733, found 395.1724.

Cycloisomerization Product 29b. Compound 29b was prepared

according to general procedure B from enynamide 28b (quantative

yield by ¹H NMR using mesitylene as an internal standard): ¹H NMR

(CDCl₃, 500 MHz) δ 5.70 (2H, m), 5.03 (1H, dd, J = 18.0, 5.5 Hz),

4.20 (2H, m), 3.85 (1H, d, J = 18.0 Hz), 2.89 (1H, dd, J = 16.0, 6.0

Hz), 2.77 (1H, m), 2.54 (1H, dd, J = 16.5, 6.5 Hz), 2.39 (1H, dd, J =

13.0, 6.0 Hz), 2.30 (1H, m), 2.19 (2H, m), 1.70 (1H, m), 1.61 (1H, t, J

= 13.0 Hz), 1.47 (2H, m), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃,

125 MHz) δ 175.9, 173.9, 169.1, 129.8, 125.5, 120.4, 115.1, 61.7, 45.7,

42.2, 37.0, 36.0, 35.9, 34.4, 27.3, 18.8, 14.2; HRMS-ESI m/z [M + H]⁺

calcd for C₁₇H₂₂NO₅320.1498, found 320.1506.

Cycloisomerization Product 29c. Compound 29c was prepared

according to general procedure B from enynamide 28c (90% yield by

¹H NMR using mesitylene as an internal standard): ¹H NMR (CDCl₃,

500 MHz) δ 5.49 (1H, m), 5.01 (1H, dd, J = 17.0, 6.0 Hz), 4.21 (2H,

m), 3.70 (1H, dq, J = 17.5, 2.5 Hz), 2.89 (1H, dd, J = 16.5, 7.0 Hz),

2.78 (1H, m), 2.50 (1H, dd, J = 16.0, 5.0 Hz), 2.43 (1H, dd, J = 6.0,

13.0 Hz), 2.33−2.29 (2H, m), 2.23−2.16 (1H, m), 1.86−1.77 (1H,

m), 1.77 (3H, m), 1.60 (1H, t, J = 12.5 Hz), 1.50−1.41 (2H, m), 1.27

(3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 174.8, 173.9,

169.4, 129.0, 117.8, 61.5, 46.0, 40.9, 37.7, 37.0, 35.6, 34.6, 29.7, 27.9,

21.6, 18.9, 14.2; HRMS-EI m/z [M]⁺calcd for C₁₈H₂₃NO₅333.1576,

found 333.1569.

Cycloisomerization Product 36a (2-((1SR,9aRS)-9a-(Ethoxy-

carbonyl)-2-oxo-2,4,7,8,9,9a-hexahydro-1H-pyrrolo[3,2,1-ij]-

quinolin-1-yl)acetic Acid). Compound 36a (quantitative yield

1

determined by H NMR using mesitylene as an internal standard)

was prepared according to the general procedure B: ¹H NMR (CDCl₃,

500 MHz) δ 5.81 (1H, dq, J = 10.0, 1.5 Hz), 5.51 (1H, ddd, J = 9.5,

5.0, 2.0 Hz), 4.72 (1H, dd, J = 17.5, 5.0 Hz), 4.2 (2H, m), 4.1 (1H, d, J

= 17.5), 3.01−2.93 (2H, m), 2.65 (1H, dt, J = 12.5, 3.0 Hz), 2.37 (1H,

dd, J = 17.0, 8.0 Hz), 2.22 (1H, dd, J = 17.5, 6.5 Hz), 2.07 (1H, m),

1.92 (1H, m), 1.57 (1H, m), 1.46 (1H, td, J = 13.0, 2.5 Hz), 1.28 (3H,

t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 175.6, 173.0, 170.7,

133.5, 124.8, 117.9, 109.0, 61.5, 51.8, 47.3, 41.3, 31.3, 30.2, 24.3, 19.8,

13.9; HRMS-ESI m/z [M − H]⁺calcd for C₁₆H₁₈NO₅304.1185,

found 304.1186.

Cycloisomerization Product 36b. Compound 36b (quantitative

yield determined by ¹H NMR using mesitylene as an internal

standard) was prepared according to the general procedure B: ¹H

NMR (CDCl₃, 500 MHz) δ 7.38−7.30 (3H, m), 7.21 (2H, m), 5.41

(1H, dd, J = 5.0, 2.5 Hz), 4.83 (1H, dd, J = 17.5, 5.5 Hz), 4.84 (3H,

m), 3.08 (1H, t, J = 7.5 Hz), 2.96 (1H, dd, J = 17.0, 6.5 Hz), 2.65 (1H,

d, J = 10.5 Hz), 2.43 (1H, dd, J = 17.5, 8.0 Hz), 2.09 (1H, dd, J = 16.5,

6.0 Hz), 1.89 (2H, m), 1.51 (2H, m), 1.32 (3H, 7.0 Hz); ¹³C NMR

(CDCl₃, 125 MHz) δ 175.4, 173.1, 170.8, 138.9, 138.2, 134.1, 128.3,

128.0, 127.3, 116.8, 109.8, 61.8, 52.5, 47.4, 41.2, 31.5, 29.9, 23.9, 20.2,

7452

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14.1; HRMS-ESI m/z [M − H]⁺calcd for C₂₂H₂₂NO₅380.1498,

found 380.1494.

(6H, m), 1.71−1.80 (1H, m), 1.61−1.44 (2H, m), 1.26 (3H, t, J = 7.0

Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 174.6, 172.5, 171.3, 131.4, 111.2,

61.4, 51.4, 48.0, 38.9, 32.0, 30.5, 26.8, 25.4, 20.9, 19.9, 14.1; HRMS-

ESI m/z [M + H]⁺calcd for C₁₆H₂₂NO₅308.1498, found 308.1507.

Tricyclic Carboxylic Acid 41. Compound 41 (645 mg, 70%) was

prepared according to the general procedure C: ¹H NMR (CDCl₃, 500

MHz) δ 3.79 (1H, m), 3.73 (3H, s), 3.30 (1H, m), 2.98 (1H, dd, J =

9.0, 5.5 Hz), 2.68 (1H, dd, J = 16.5, 9.0 Hz), 2.50−2.42 (2H, m),

2.20−2.08 (3H, m), 2.00 (1H, m), 1.93−1.88 (2H, m), 1.78−1.69

(3H, m), 1.59 (1H, dt, J = 13.0, 3.5 Hz), 1.38 (1H, m); ¹³C NMR

(CDCl₃, 125 MHz) δ 173.6, 172.4, 171.2, 134.2, 116.8, 55.4, 52.3,

48.2, 38.8, 35.5, 33.2, 32.4, 29.2, 27.3, 26.7, 20.5; HRMS-ESI m/z

[M]⁺calcd for C₁₆H₂₁NO₅307.1420, found 307.1422.

Cycloisomerization Product 36c. Compound 36c (72% yield

determined by ¹H NMR using mesitylene as an internal standard) was

prepared according to the general procedure B: ¹H NMR (CDCl₃, 500

MHz) δ 5.76 (1H, dt, J = 10.0, 2.0 Hz), 5.46 (1H, m), 4.56 (1H, dd, J

= 18.0, 4.5 Hz), 4.22 (1H, dq, J = 18.0 2.5 Hz), 3.76 (3H, s), 3.05 (1H,

t, J = 6.5 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 2.52 (1H, m), 2.40 (1H,

dd, J = 17.5, 7.0 Hz), 2.21−2.10 (2H, m), 1.94 −1.91 (1H, m), 1.79−

1.74 (1H, m), 1.60−1.70 (2H, m), 1.36−1.45 (1H, m); ¹³C NMR

(CDCl₃, 125 MHz) δ 175.3, 173.1, 170.9, 136.2, 128.2, 116.7, 113.1,

55.8, 52.5, 47.5, 42.0, 35.7, 31.9, 31.9, 27.3, 26.9; HRMS-EI m/z [M −

H]⁺calcd for C₁₆H₁₈NO₅304.1185, found 304.1187.

Cycloisomerization Product 36d. Compound 36d (77% yield

determined by ¹H NMR using mesitylene as an internal standard) was

prepared according to the general procedure B: ¹H NMR (CDCl₃, 500

MHz) δ 7.34 (3H, m), 7.18 (2H, m), 5.40 (1H, dd, J = 5.0, 2.5 Hz),

4.71 (1H, dd, J = 17.5, 5.5 Hz), 4.24 (1H, d, J = 17.0 Hz), 3.79 (3H, s),

3.16 (1H, t, J = 6.5 Hz), 2.84 (1H, dd, J = 17.0, 7.0 Hz), 2.56 (1H, m),

2.43 (1H, 17.0, 7.0 Hz), 2.18 (1H, dd, J = 15.5, 6.5 Hz), 1.94−1.66

(5H, m), 1.40 (1H, m); ¹³C NMR (CDCl₃, 125 MHz) δ 175.5, 173.1,

171.0, 140.3, 139.8, 138.4, 128.2, 127.3, 115.6, 114.2, 56.3, 52.5, 47.8,

41.5, 35.3, 31.8, 28.2, 27.3, 26.7; HRMS-ESI m/z [M − H]⁺calcd for

C₂₂H₂₂NO₅380.1498, found 380.1505.

General Procedure C: Diene Hydrogenations. To a round-

bottom ﬂask was added 10% Pd/C (0.30 mmol, 0.10 equiv) and the

corresponding crude acid solution (prepared from general procedure

B, 3.00 mmol, 1.00 equiv) in EtOH (30.0 mL). The mixture was

stirred overnight at room temperature under H₂atmosphere (1 atm).

The mixture was ﬁltered over Celite and concentrated under reduced

pressure. The product was isolated after puriﬁcation by Combi-ﬂash

column chromatography (DCM:(EtOAc + 1% HCOOH) = 95:5 to

30:70).

Tricyclic Carboxylic Acid 37 (2-((2RS,10aSR)-10a-(ethoxycar-

bonyl)-3-oxo-1,2,3,5,6,7,8,9,10,10a-decahydropyrido[3,2,1-ij]-

quinolin-2-yl)acetic Acid). Compound 37 (771 mg, 80%) was

prepared according to the general procedure C: ¹H NMR (CDCl₃, 500

MHz) δ 4.62 (1H, dt, J = 13.0, 3.5 Hz), 4.24−4.13 (2H, m), 2.97 (1H,

dt, J = 12.0, 2.5 Hz), 2.82 (1H, dd, J = 16.0, 7.5), 2.36 (1H, dd, J =

13.0, 5.5 Hz), 2.27 (1H, m), 2.20−2.13 (1H, m), 2.09 (2H, m), 2.01−

1.90 (2H, m), 1.80−1.71 (2H, m), 1.61 (1H, t, J = 13.0 Hz), 1.54−

1.39 (2H, m), 1.26 (3H, t, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz)

δ 175.1, 173.9, 169.4, 132.1, 130.1, 118.0, 116.2, 61.7, 46.1, 41.4, 37.5,

36.5, 35.9, 34.1, 25.2, 18.8, 18.1, 14.2; HRMS-ESI m/z [M]⁺calcd for

C₁₇H₂₃NO₅321.1576, found 321.1584.

General Procedure D: Automated Library Synthesis. A of

solution of a carboxylic acid (7, 8, 26, or 36, 1.25 mmol) in 25 mL of

CDCl₃was treated with CDI (16, 212.8 mg, 1.31 mmol, 1.05 equiv).

The reaction was stirred at room temperature until NMR indicated

complete conversion of the carboxylic acid to the corresponding

acylimidazole, which typically took 2−4 h. Using a Perkin-Elmer

Multiprobe II liquid handler, the resulting solution was distributed into

24 1-dram glass vials, delivering 0.95 mL of the above solution into

each vial. For reactions involving the coupling with secondary amines,

the glass vials were precharged with imidazole hydrochloride (9.9 mg,

0.095 mmol, 2 equiv). For each vial, a solution of one of the 24 amines

11 (2 M, 2.7 equiv) in 0.065 mL of chloroform was added. The

resulting reaction mixtures were capped and agitated on an orbital

shaker at room temperature for 48 h. The vials were then returned to

the deck of the liquid handler and treated with 1.9 mL of 1.2 N HCl

solution followed by eight cycles of rapid aspiration and dispensing to

ensure thorough mixing. After complete phase separation, which can

be accelerated by centrifugation for 10 min at 500 g (versus ∼2 h

without centrifugation), the bottom layers were retrieved by the liquid

hander and transferred to 24 empty barcoded, preweighed one-dram

vials. The vials containing the product solutions were placed in a

GeneVac centrifugal evaporator to remove solvent, and were weighed

using an automated Mettler Toledo weigher to determine the yield of

each ﬁnal product. Each of the tips used for the above material transfer

was then washed in another vial containing 0.5 mL of MeOH in order

to dissolve the residual material present on the tip, which provided

suﬃcient amount of material for purity analysis of each ﬁnal

compound using LC−MS equipped with an autosampler.

Pyrrolidinone-Containing Amide 12a ((3SR,3aRS)-Ethyl 1-(4-

Methoxybenzyl)-2-oxo-3-(2-oxo-2-(prop-2-yn-1-ylamino)-

ethyl)-2,3,3a,4,5,6-hexahydro-1H-indole-3a-carboxylate).

Compound 12a (18.85 mg, 93%) was prepared according to the

general procedure D: 93% yield; ¹H NMR (500 MHz, CDCl₃) δ

7.25−7.17 (m, 2H), 6.87−6.78 (m, 2H), 4.99 (t, J = 3.7 Hz, 1H), 4.77

(d, J = 15.2 Hz, 1H), 4.44 (d, J = 15.1 Hz, 1H), 4.12−3.95 (m, 3H),

3.78 (s, 3H), 2.99 (dd, J = 7.8, 5.6 Hz, 1H), 2.65 (dd, J = 15.1, 7.8 Hz,

1H), 2.56 (dt, J = 12.4, 3.1 Hz, 1H), 2.26−2.17 (m, 2H), 2.17−2.00

(m, 2H), 1.85−1.74 (m, 1H), 1.57−1.36 (m, 2H), 1.12 (t, J = 7.1 Hz,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.5, 171.4, 170.6, 159.1,

138.2, 129.2, 128.1, 113.9, 102.0, 79.7, 71.5, 61.4, 55.4, 52.3, 48.5, 43.8,

33.4, 30.3, 29.4, 22.9, 19.5, 14.2; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₂₄H₂₉N₂O₅425.2076, found 425.2066.

Tricyclic Carboxylic Acid 38. Compound 38 (645 mg, 70%) was

1

prepared according to the general procedure C: H NMR (CD₃CN,

500 MHz) δ 4.18−4.08 (2H, m), 3.85 (1H, m), 3.56 (1H, br), 3.31−

3.26 (1H, m), 2.73−2.65 (2H, m), 2.57−2.52 (1H, m), 2.48−2.41

(2H, m), 2.29−2.22 (2H, m), 2.09 (2H, m), 1.97 (1H, quintet, J = 2.5

Hz), 1.88−1.78 (3H, m), 1.69 (1H, t, J = 12.5 Hz), 1.21 (3H, t, J = 7.0

Hz); ¹³C NMR (CD₃CN, 125 MHz) δ 174.8, 174.0, 168.6, 133.5,

118.8, 61.3, 53.4, 40.1, 36.4, 35.6, 35.3, 35.2, 32.1, 22.4, 21.3, 13.4;

HRMS-ESI m/z [M + H]⁺calcd for C₁₆H₂₂NO₅308.1498, found

308.1503.

Tricyclic Carboxylic Acid 39. compound 39 (882 mg, 77%) was

prepared according to the general procedure C: ¹H NMR (CDCl₃, 500

MHz) δ 5.19 (1H, t, J = 4.0 Hz), 4.23−4.13 (4H, m), 3.87 (1H, m),

3.65 (1H, m), 3.08 (1H, m), 2.85 (1H, dd, J = 16.0, 7.0 Hz), 2.56 (1H,

dd, J = 16.0, 5.0 Hz), 2.38−2.24 (4H, m), 2.19 (2H, m), 2.14−2.08

(1H, m), 1.81 (2H, m), 1.59 (1H, t, J = 13.0 Hz), 1.28 (6H, m); ¹³C

NMR (CDCl₃, 125 MHz) δ 175.3, 173.0, 172.7, 170.1, 135.8, 109.1,

61.7, 60.8, 48.6, 41.1, 36.8, 35.5, 33.2, 32.3, 29.4, 22.6, 21.5, 14.2, 14.1;

HRMS-ESI m/z [M + H]⁺calcd for C₁₉H₂₈NO₇382.1866, found

382.1864.

Tricyclic Carboxylic Acid 40. Compound 40 (600 mg, 65%) was

prepared according to the general procedure C: ¹H NMR (CDCl₃, 500

MHz) δ 4.22−4.11 (2H, m), 3.90 (1H, m), 3.31 (1H, dt, J = 10.5, 3.5

Hz), 2.96 (1H, t, J = 7.5 Hz), 2.84 (1H, dd, J = 17.0, 7.5 Hz), 2.61

(1H, t, J = 12.0, 2.5 Hz), 2.42 (1H, dd, J = 16.5, 6.5 Hz), 2.21−1.87

Pyrrolidinone-Containing Amide 12b. Compound 12b (18.02

mg, 85%) was prepared according to the general procedure D: H

1

NMR (500 MHz, CDCl₃) δ 7.20−7.11 (m, 2H), 6.87−6.81 (m, 2H),

6.76 (t, J = 5.7 Hz, 1H), 5.08 (dd, J = 8.6, 4.4 Hz, 1H), 4.73 (d, J =

15.4 Hz, 1H), 4.52 (d, J = 15.4 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H),

3.33−3.17 (m, 2H), 3.07 (dd, J = 8.2, 4.8 Hz, 1H), 2.56 (dd, J = 15.0,

8.2 Hz, 1H), 2.50−2.43 (m, 1H), 2.20−2.07 (m, 2H), 1.92−1.82 (m,

1H), 1.82−1.70 (m, 1H), 1.70−1.61 (m, 1H), 1.61−1.45 (m, 3H),

1.41−1.21 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 174.6, 171.5, 170.6, 158.9, 142.5, 128.5, 127.9, 113.9, 105.8,

55.7, 55.4, 52.1, 49.3, 43.8, 39.6, 35.2, 33.9, 31.7, 27.4, 27.2, 26.2, 20.2,

13.9; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₅H₃₅N₂O₅

443.2546, found 443.2538.

Pyrrolidinone-Containing Amide 12c. Compound 12c (19.75

1

mg, 88%) was prepared according to the general procedure D: H

7453

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NMR (500 MHz, CDCl₃) δ 7.30−7.22 (m, 3H), 7.19−7.14 (m, 2H),

7.08 (t, J = 6.2 Hz, 1H), 5.15 (dd, J = 8.7, 4.4 Hz, 1H), 3.76 (ddd, J =

13.6, 10.0, 6.3 Hz, 1H), 3.70 (s, 3H), 3.54 (ddd, J = 13.7, 9.9, 5.5 Hz,

1H), 3.48−3.29 (m, 4H), 3.27−3.15 (m, 2H), 3.14−3.08 (m, 1H),

2.85 (ddd, J = 13.5, 10.1, 5.6 Hz, 1H), 2.77 (ddd, J = 13.5, 10.0, 6.3

Hz, 1H), 2.53 (dd, J = 15.4, 7.3 Hz, 1H), 2.50−2.44 (m, 1H), 2.41 (t, J

= 8.1 Hz, 2H), 2.30−2.18 (m, 1H), 2.12 (dd, J = 15.4, 6.2 Hz, 1H),

2.09−2.00 (m, 2H), 1.99−1.84 (m, 2H), 1.82−1.63 (m, 5H), 1.56

(ddd, J = 13.7, 12.2, 3.4 Hz, 1H), 1.38−1.25 (m, 1H); ¹³C NMR (126

MHz, CDCl₃) δ 175.9, 173.7, 171.5, 170.5, 142.9, 137.2, 132.4, 130.3,

128.7, 103.9, 55.5, 52.3, 48.7, 47.5, 41.5, 39.8, 36.2, 35.5, 33.7, 31.7,

31.1, 27.5, 27.4, 26.6, 26.2, 18.1. MS(ESI) calcd for C₂₈H₃₆ClN₃O₅

529.23 (M⁺), found 530.18 (M + H)⁺.

1H), 4.14−4.06 (m, 2H), 3.97−3.89 (m, 1H), 2.98 (dd, J = 7.6, 5.8

Hz, 1H), 2.63 (dd, J = 15.1, 7.7 Hz, 1H), 2.55 (dt, J = 12.5, 3.0 Hz,

1H), 2.24−2.15 (m, 1H), 2.15−2.05 (m, 1H), 1.87−1.78 (m, 1H),

1.58−1.39 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 173.9, 171.5, 170.5, 141.1, 138.2, 131.6, 126.9, 126.0, 125.1,

117.7, 101.8, 61.5, 52.4, 48.4, 43.0, 38.5, 33.5, 30.3, 22.9, 19.6, 14.2;

MS(ESI) calcd for C₂₁H₂₆N₂O₄S 402.16 (M⁺), found 403.33 (M +

H)⁺.

Pyrrolidinone-Containing Amide 12i. Compound 12i was

prepared according to the general procedure D from carboxylic acid

1

7h and amine 11f: H NMR (500 MHz, CDCl₃) δ 7.15−7.08 (m,

3H), 6.90−6.77 (m, 5H), 4.80 (dd, J = 10.1, 8.2 Hz, 1H), 4.67 (d, J =

15.5 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H),

4.15−4.01 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H), 3.08 (dd,

J = 8.4, 4.6 Hz, 1H), 2.72 (dd, J = 15.2, 8.4 Hz, 1H), 2.58 (ddd, J =

14.6, 6.7, 2.3 Hz, 1H), 2.22 (dd, J = 15.2, 4.6 Hz, 1H), 2.05−1.91 (m,

2H), 1.77−1.49 (m, 3H), 1.39−1.23 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 174.6, 171.5, 170.5, 158.9, 149.2,

148.4, 140.2, 131.1, 128.3, 127.7, 120.1, 114.0, 111.3, 111.2, 104.6,

61.5, 56.0, 56.0, 55.4, 54.6, 48.0, 43.7, 43.6, 37.5, 34.8, 27.8, 26.4, 23.1,

22.5, 14.2; MS(ESI) calcd for C₃₂H₄₀N₂O₇564.28 (M⁺), found 565.4

(M + H)⁺.

Pyrrolidinone-Containing Amide 12d. Compound 12d (22.01

1

mg, 72%) was prepared according to the general procedure D: H

NMR (500 MHz, CDCl₃) δ 7.38−7.20 (m, 6H), 5.71 (ddt, J = 17.3,

10.3, 5.1 Hz, 1H), 5.22−5.15 (m, 3H), 4.86 (t, J = 9.2 Hz, 1H), 4.48

(dd, J = 14.8, 5.9 Hz, 1H), 4.41 (dd, J = 14.8, 5.5 Hz, 2H), 4.19−4.10

(m, 3H), 3.04 (dd, J = 8.4, 4.6 Hz, 1H), 2.71 (dd, J = 15.3, 8.4 Hz,

1H), 2.61 (ddd, J = 14.4, 6.4, 2.2 Hz, 1H), 2.22 (dd, J = 15.3, 4.6 Hz,

1H), 2.07 (ddd, J = 9.1, 6.8, 3.5 Hz, 2H), 1.77−1.57 (m, 5H), 1.54−

1.38 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 174.2, 171.6, 170.6, 140.4, 138.4, 131.0, 128.7, 127.9, 127.4, 117.0,

104.1, 61.5, 54.7, 48.0, 43.9, 42.8, 34.7, 27.8, 26.5, 23.1, 22.6, 14.2;

MS(ESI) calcd for C₂₅H₃₂N₂O₄424.24 (M⁺), found 425.34 (M + H)⁺.

Pyrrolidinone-Containing Amide 12e. Compound 12e was

prepared according to the general procedure D from carboxylic acid 7b

Pyrrolidinone-Containing Amide 12j. Compound 12j was

prepared according to the general procedure D from carboxylic acid

7h and amine 11g: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (t, J = 5.9 Hz,

1H), 7.57−7.48 (m, 3H), 7.47−7.41 (m, 1H), 7.16−7.10 (m, 2H),

6.86−6.79 (m, 2H), 4.83 (dd, J = 10.3, 8.1 Hz, 1H), 4.69 (d, J = 15.4

Hz, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.54 (dd, J = 15.2, 6.0 Hz, 1H),

4.46 (dd, J = 15.2, 5.8 Hz, 1H), 4.17−4.02 (m, 2H), 3.78 (s, 3H), 3.04

(dd, J = 8.8, 4.1 Hz, 1H), 2.77 (dd, J = 15.2, 8.8 Hz, 1H), 2.58 (ddd, J

= 14.7, 6.3, 2.9 Hz, 1H), 2.25 (dd, J = 15.2, 4.1 Hz, 1H), 2.08−1.93

(m, 2H), 1.76−1.49 (m, 5H), 1.43−1.23 (m, 1H), 1.17 (t, J = 7.1 Hz,

3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.7, 171.4, 171.0, 159.0,

140.0, 139.7, 131.2 (q, 4JC−F = 1.3 Hz), 129.2, 128.3, 127.6, 131.0 (q,

²J_C−F= 32.2 Hz), 124.4 (q, ³J_C−F= 3.8 Hz), 124.2 (q, ³J_C−F= 3.8 Hz),

1

and amine 11x: H NMR (500 MHz, CDCl₃) δ 7.33 (td, J = 7.5, 1.5

Hz, 2H), 7.29−7.18 (m, 5H), 6.89−6.82 (m, 2H), 4.98 (d, J = 3.8 Hz,

1H), 4.81 (dd, J = 15.2, 2.9 Hz, 2H), 4.47 (dd, J = 15.2, 7.9 Hz, 1H),

4.16−3.90 (m, 2H), 3.80 (s, 3H), 3.40 (dd, J = 8.6, 4.2 Hz, 1H), 3.22−

3.10 (m, 1H), 3.01 (m, 1H), 2.81−2.59 (m, 2H), 2.33 (ddd, J = 17.0,

8.7, 2.4 Hz, 1H), 2.19−2.01 (m, 2H), 1.96−1.86 (m, 1H), 1.86−1.75

(m, 1H), 1.75−1.43 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (126

MHz, CDCl₃) δ 174.4, 174.4, 172.1, 172.0, 168.6, 168.6, 158.9, 145.4,

145.3, 138.7, 129.2, 129.1, 128.7, 128.5, 126.9, 126.6, 113.9, 113.9,

101.2, 61.1, 61.1, 55.4, 52.5, 52.4, 47.9, 47.9, 46.3, 46.2, 43.7, 43.0,

43.0, 43.0, 43.0, 33.8, 33.7, 33.0, 33.0, 31.0, 30.2, 30.1, 22.9, 22.9, 19.8,

19.8, 14.3, 14.3. MS(ESI) calcd for C₃₂H₃₈N₂O₅530.28 (M⁺), found

531.48 (M + H)⁺.

1

124.2 (q, J_C−F= 273.4 Hz), 114.0, 105.0, 61.5, 55.4, 54.8, 47.9, 43.6,

43.3, 37.1, 34.7, 27.7, 26.5, 23.1, 22.5, 14.2; MS(ESI) calcd for

C₃₁H₃₅F₃N₂O₅572.25 (M⁺), found 573.37 (M + H)⁺.

Pyrrolidinone-Containing Amide 12k. Compound 12k was

prepared according to the general procedure D from carboxylic acid 7i

1

Pyrrolidinone-Containing Amide 12f. Compound 12f was

and amine 11r: H NMR (500 MHz, CDCl₃) δ 7.51 (dd, J = 1.8, 0.9

prepared according to the general procedure D from carboxylic acid

Hz, 1H), 7.29−7.23 (m, 2H), 7.22−7.15 (m, 2H), 7.07 (dd, J = 3.5,

0.9 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.86 (dd, J = 10.7, 7.5 Hz,

1H), 4.23−4.07 (m, 2H), 3.94−3.63 (m, 7H), 3.61−3.48 (m, 2H),

3.48−3.41 (m, 1H), 3.18 (dd, J = 8.3, 4.7 Hz, 1H), 2.92−2.79 (m,

2H), 2.75−2.63 (m, 2H), 2.34 (dd, J = 16.6, 8.4 Hz, 1H), 2.15−2.07

(m, 1H), 2.05−1.94 (m, 1H), 1.81−1.72 (m, 1H), 1.72−1.50 (m, 4H),

1.50−1.39 (m, 1H), 1.40−1.30 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 173.9, 172.2, 169.2, 159.3, 147.7, 144.1,

141.4, 136.8, 132.5, 130.6, 128.7, 117.3, 111.6, 102.2, 61.3, 54.2, 48.7,

45.5, 42.1, 41.3, 39.5, 31.9, 31.8, 28.4, 25.9, 23.2, 23.0, 14.3; MS(ESI)

calcd for C₃₂H₃₈ClN₃O₆595.24 (M⁺), found 596.34 (M + H)⁺.

Pyrrolidinone-Containing Amide 12l. Compound 12l was

prepared according to the general procedure D from carboxylic acid

1

7e and amine 11u. H NMR (500 MHz, CDCl₃) δ 7.20−7.14 (m,

2H), 6.83 (d, J = 8.6 Hz, 2H), 5.05 (dd, J = 8.9, 4.3 Hz, 1H), 4.73 (d, J

= 15.6 Hz, 1H), 4.55 (d, J = 15.5 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H),

3.62−3.57 (m, 1H), 3.57−3.50 (m, 1H), 3.45−3.33 (m, 2H), 2.91 (dd,

J = 16.7, 4.6 Hz, 1H), 2.64−2.56 (m, 1H), 2.31 (dd, J = 16.7, 7.3 Hz,

1H), 2.15−2.05 (m, 1H), 1.92−1.79 (m, 2H), 1.70−1.51 (m, 7H),

1.30−1.18 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3, 172.0,

168.2, 158.7, 143.1, 128.4, 128.3, 128.1, 113.9, 113.8, 104.9, 55.7, 55.2,

51.9, 48.5, 46.5, 43.6, 43.2, 35.8, 30.3, 27.6, 27.4, 26.3, 26.1, 25.5, 24.6;

MS(ESI) calcd for C₂₆H₃₄N₂O₅454.25 (M⁺), found 455.41 (M + H)⁺.

Pyrrolidinone-Containing Amide 12g. Compound 12g was

prepared according to the general procedure D from carboxylic acid 7a

1

and amine 11d: H NMR (500 MHz, CDCl₃) δ 6.73 (t, J = 5.5 Hz,

7i and amine 11o: H NMR (500 MHz, CDCl₃) δ 7.31−7.23 (m,

1H), 5.81−5.69 (m, 1H), 5.27 (d, J = 17.2 Hz, 1H), 5.19 (dd, J = 10.3,

1.5 Hz, 1H), 5.02 (t, J = 3.7 Hz, 1H), 4.28 (dd, J = 15.9, 5.3 Hz, 1H),

4.13 (q, J = 7.1 Hz, 2H), 4.00−3.89 (m, 1H), 3.33−3.18 (m, 2H), 2.97

(dd, J = 7.6, 5.8 Hz, 1H), 2.63−2.52 (m, 2H), 2.27−2.06 (m, 3H),

1.89−1.79 (m, 1H), 1.69−1.58 (m, 1H), 1.57−1.36 (m, 4H), 1.23 (t, J

= 7.1 Hz, 3H), 0.91 (d, J = 6.6 Hz, 6H); ¹³C NMR (126 MHz, CDCl₃)

δ 174.1, 171.6, 170.7, 138.3, 131.6, 117.7, 101.7, 61.4, 52.4, 48.6, 43.0,

38.4, 38.2, 33.6, 30.2, 26.0, 22.9, 22.6, 22.6, 19.6, 14.3; MS(ESI) calcd

for C₂₁H₃₂N₂O₄376.24 (M⁺), found 377.39 (M + H)⁺.

2H), 7.19−7.13 (m, 2H), 6.87 (t, J = 5.5 Hz, 1H), 6.11 (d, J = 3.1 Hz,

1H), 5.90 (dd, J = 3.1, 1.3 Hz, 1H), 4.86 (dd, J = 10.0, 8.3 Hz, 1H),

4.43 (dd, J = 15.4, 5.8 Hz, 1H), 4.36−4.28 (m, 1H), 4.20−4.07 (m,

2H), 3.76 (dt, J = 13.9, 8.0 Hz, 1H), 3.66 (dt, J = 14.1, 7.1 Hz, 1H),

2.96 (dd, J = 8.0, 5.2 Hz, 1H), 2.83 (t, J = 7.7 Hz, 2H), 2.64−2.53 (m,

2H), 2.27 (s, 3H), 2.18−2.03 (m, 3H), 1.71−1.58 (m, 5H), 1.48−1.37

(m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ

174.1, 171.6, 170.3, 151.9, 149.5, 140.7, 136.9, 132.6, 130.4, 128.8,

108.3, 106.4, 103.0, 61.5, 54.7, 47.9, 41.5, 37.8, 37.0, 34.6, 31.8, 27.9,

26.5, 23.1, 22.6, 14.2, 13.7; MS(ESI) calcd for C₂₉H₃₅ClN₂O₅526.22

(M⁺), found 527.33 (M + H)⁺.

Pyrrolidinone-Containing Amide 12h. Compound 12h was

prepared according to the general procedure D from carboxylic acid 7a

1

and amine 11e: H NMR (500 MHz, CDCl₃) δ 7.25−7.17 (m, 2H),

Pyrrolidinone-Containing Amide 12m. Compound 12m was

6.97 (dd, J = 3.4, 1.2 Hz, 1H), 6.93 (dd, J = 5.1, 3.4 Hz, 1H), 5.78−

5.68 (m, 1H), 5.25 (d, J = 17.2 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H),

5.01 (t, J = 3.7 Hz, 1H), 4.67−4.53 (m, 2H), 4.26 (dd, J = 15.8, 5.3 Hz,

prepared according to the general procedure D from carboxylic acid 7g

1

and amine 11m: H NMR (500 MHz, CDCl₃) δ 7.25−7.18 (m, 1H),

7.14 (dd, J = 7.4, 1.8 Hz, 1H), 6.92−6.82 (m, 3H), 6.72 (t, J = 5.5 Hz,

7454

dx.doi.org/10.1021/jo301061r | J. Org. Chem. 2012, 77, 7435−7470

The Journal of Organic Chemistry

Article

1H), 5.72 (ddt, J = 17.2, 10.2, 5.0 Hz, 1H), 5.22−5.14 (m, 2H), 4.84

(dd, J = 10.0, 8.4 Hz, 1H), 4.21−3.99 (m, 3H), 3.83 (s, 4H), 3.60−

3.38 (m, 2H), 3.00 (dd, J = 7.4, 5.7 Hz, 1H), 2.92−2.76 (m, 3H),

2.70−2.53 (m, 2H), 2.16−1.97 (m, 3H), 1.74−1.53 (m, 5H), 1.52−

1.37 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 174.2, 171.7, 170.4, 157.6, 140.6, 131.0, 130.8, 127.9, 127.5, 120.7,

116.9, 110.5, 103.7, 61.4, 55.4, 54.6, 48.0, 42.7, 40.0, 34.7, 30.3, 27.9,

26.4, 23.1, 22.6, 14.2; MS(ESI) calcd for C₂₇H₃₆N₂O₅468.26 (M⁺),

found 469.38 (M + H)⁺.

(t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.5,

170.8, 142.3, 138.2, 137.1, 132.5, 130.2, 128.8, 128.5, 128.4, 125.9,

101.0, 61.5, 52.6, 48.5, 41.5, 39.7, 35.6, 33.5, 32.2, 30.2, 29.2, 28.8,

23.0, 19.7, 14.3; MS(ESI) calcd for C₃₁H₃₇ClN₂O₄536.24 (M⁺), found

537.47 (M + H)⁺.

Piperidinone-Containing Amide 13a ((3RS,4aSR)-Ethyl 1-

Benzyl-3-(2-(4-(furan-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-

2-oxo-2,3,4,4a,5,6-hexahydro-1H-cyclopenta[b]pyridine-4a-

carboxylate). Compound 13a was prepared according to the general

1

procedure D from carboxylic acid 8f and amine 11r: H NMR (500

Pyrrolidinone-Containing Amide 12n. Compound 12n was

MHz, CDCl₃) δ 7.50 (dd, J = 1.7, 0.8 Hz, 1H), 7.29 (d, J = 4.3 Hz,

4H), 7.24−7.18 (m, 1H), 7.04 (dd, J = 3.5, 0.9 Hz, 1H), 6.49 (dd, J =

3.5, 1.8 Hz, 1H), 5.00 (dd, J = 3.2, 1.8 Hz, 1H), 4.95 (d, J = 15.5 Hz,

1H), 4.89 (d, J = 15.5 Hz, 1H), 4.19−4.05 (m, 2H), 3.81 (s, 4H),

3.74−3.63 (m, 2H), 3.57 (t, J = 5.2 Hz, 2H), 2.99−2.90 (m, 2H),

2.79−2.73 (m, 1H), 2.54 (dd, J = 12.7, 5.1 Hz, 1H), 2.44−2.35 (m,

1H), 2.32 (dd, J = 12.7, 7.0 Hz, 1H), 2.25 (ddd, J = 15.4, 8.6, 3.2 Hz,

1H), 2.05−1.98 (m, 1H), 1.91−1.81 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 174.5, 170.7, 169.6, 159.3, 147.7,

144.1, 141.5, 137.2, 128.5, 127.1, 127.0, 127.0, 119.4, 117.2, 111.6,

107.8, 61.4, 54.5, 47.8, 45.5, 43.8, 41.8, 37.0, 36.8, 35.9, 35.1, 29.1,

14.3; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₉H₃₄N₃O₆

520.2448, found 520.2452.

prepared according to the general procedure D from carboxylic acid 7f

and amine 11b: H NMR (500 MHz, CDCl₃) δ 7.31−7.23 (m, 3H),

1

7.22−7.13 (m, 2H), 6.82 (t, J = 5.9 Hz, 1H), 5.18 (dd, J = 8.6, 4.4 Hz,

1H), 3.85−3.71 (m, 1H), 3.68 (s, 3H), 3.60−3.49 (m, 1H), 3.21−3.10

(m, 1H), 3.09−3.01 (m, 1H), 2.98−2.92 (m, 1H), 2.91−2.82 (m, 1H),

2.81−2.74 (m, 1H), 2.54−2.45 (m, 2H), 2.33−2.19 (m, 1H), 2.14 (dd,

J = 15.0, 4.8 Hz, 1H), 2.03−1.84 (m, 2H), 1.84−1.60 (m, 11H), 1.56

(ddd, J = 14.1, 12.3, 3.5 Hz, 1H), 1.51−1.41 (m, 1H), 1.40−1.28 (m,

1H), 1.28−1.09 (m, 4H), 1.00−0.86 (m, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 174.0, 171.4, 170.6, 142.6, 137.0, 132.5, 130.3, 128.8, 104.5,

55.9, 52.2, 49.1, 46.2, 41.6, 38.0, 35.2, 33.8, 31.7, 31.0, 27.4, 27.2, 26.6,

26.2, 26.0; MS(ESI) calcd for C₂₈H₃₇ClN₂O₄500.24 (M⁺), found

501.14 (M + H)⁺.

Piperidinone-Containing Amide 13b. Compound 13b was

Pyrrolidinone-Containing Amide 12o. Compound 12o was

prepared according to the general procedure D from carboxylic acid 8f

prepared according to the general procedure D from carboxylic acid 7d

1

and amine 11m: H NMR (500 MHz, CDCl₃) δ 7.32−7.27 (m, 2H),

and amine 11i: H NMR (500 MHz, CDCl₃) δ 6.97−6.88 (m, 1H),

7.25−7.19 (m, 3H), 7.18 (dd, J = 6.8, 1.4 Hz, 1H), 7.11 (dd, J = 7.4,

1.8 Hz, 1H), 6.90−6.82 (m, 2H), 6.08 (t, J = 5.6 Hz, 1H), 4.98 (dd, J =

3.2, 1.7 Hz, 1H), 4.92−4.86 (m, 2H), 4.19−4.07 (m, 2H), 3.82 (s,

3H), 3.53−3.37 (m, 2H), 2.92−2.85 (m, 1H), 2.78 (t, J = 6.9 Hz, 2H),

2.68 (dd, J = 14.7, 5.6 Hz, 1H), 2.59−2.48 (m, 2H), 2.42−2.29 (m,

2H), 2.24 (ddd, J = 14.9, 8.6, 3.2 Hz, 1H), 1.90−1.82 (m, 2H), 1.19 (t,

J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 170.9, 170.7,

157.6, 141.5, 136.9, 130.7, 128.5, 127.9, 127.5, 127.1, 127.0, 120.7,

110.5, 107.8, 61.4, 55.4, 54.6, 47.8, 39.8, 38.5, 37.5, 37.0, 35.7, 30.4,

29.0, 14.3; MS(ESI) calcd for C₂₉H₃₄N₂O₅490.25 (M⁺), found 491.28

(M + H)⁺, 513.24 (M + Na)⁺.

5.70 (ddt, J = 17.3, 10.3, 5.1 Hz, 1H), 5.21 (ddd, J = 17.3, 1.6 Hz, 1H),

5.16 (ddd, J = 10.3, 1.5 Hz, 1H), 5.12 (dd, J = 8.6, 4.4 Hz, 1H), 4.19

(ddt, J = 16.4, 5.1, 1.8 Hz, 1H), 4.04 (ddt, J = 16.2, 5.2, 1.7 Hz, 1H),

3.67 (s, 3H), 3.02−2.95 (m, 2H), 2.88 (dd, J = 13.4, 6.0 Hz, 1H), 2.54

(dd, J = 15.0, 8.4 Hz, 1H), 2.51−2.45 (m, 1H), 2.25−2.12 (m, 2H),

1.99−1.92 (m, 4H), 1.92−1.83 (m, 1H), 1.82−1.64 (m, 6H), 1.64 (s,

0H), 1.50−1.45 (m, 7H), 1.37−1.24 (m, 1H); ¹³C NMR (126 MHz,

CDCl₃) δ 174.1, 171.4, 170.8, 142.6, 131.2, 117.1, 105.4, 55.7, 52.2,

51.5, 49.3, 42.9, 40.3, 37.1, 35.2, 33.8, 33.8, 28.4, 27.4, 27.2, 26.1;

MS(ESI) calcd for C₂₇H₃₈N₂O₄454.28 (M⁺), found 455.36 (M + H)⁺.

Pyrrolidinone-Containing Amide 12p. Compound 12p was

prepared according to the general procedure D from carboxylic acid 7d

Piperidinone-Containing Amide 13c. Compound 13c was

1

prepared according to the general procedure D from carboxylic acid

and amine 11q: H NMR (500 MHz, CDCl₃) δ 5.69 (ddt, J = 17.2,

1

8g and amine 11e: H NMR (500 MHz, CDCl₃) δ 7.19 (dd, J = 4.8,

10.3, 5.0 Hz, 1H), 5.20 (ddd, J = 17.3, 1.6 Hz, 1H), 5.17−5.09 (m,

2H), 4.20−4.13 (m, 1H), 4.09−4.00 (m, 1H), 3.78−3.59 (m, 9H),

3.58−3.37 (m, 1H), 3.29 (dd, J = 7.0, 5.0 Hz, 1H), 2.83 (dd, J = 16.5,

5.1 Hz, 1H), 2.55 (dd, J = 11.3, 5.0 Hz, 1H), 2.30 (dd, J = 16.5, 6.9 Hz,

1H), 2.24−2.14 (m, 1H), 1.96−1.84 (m, 3H), 1.75−1.65 (m, 3H),

1.65−1.54 (m, 2H), 1.35−1.24 (m, 1H), 1.01−0.95 (m, 2H), 0.81−

0.73 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 173.4, 172.4, 172.2,

171.9, 171.1, 169.0, 142.9, 131.2, 116.7, 105.6, 104.8, 55.6, 52.0, 48.5,

48.2, 45.2, 42.7, 41.9, 41.7, 36.1, 30.1, 27.6, 27.4, 26.1, 11.0, 7.6;

MS(ESI) calcd for C₂₄H₃₃N₃O₅443.24 (M⁺), found 444.35 (M + H)⁺.

Pyrrolidinone-Containing Amide 12q. Compound 12q was

prepared according to the general procedure D from carboxylic acid 7c

1.5 Hz, 1H), 6.95−6.89 (m, 2H), 6.76−6.69 (m, 3H), 5.91 (s, 2H),

5.03 (t, J = 2.3 Hz, 1H), 4.83 (d, J = 15.4 Hz, 1H), 4.70 (d, J = 15.3

Hz, 1H), 4.57 (d, J = 5.5 Hz, 2H), 4.19−4.07 (m, 2H), 3.47 (s, 1H),

2.91 (dq, J = 13.1, 5.4 Hz, 1H), 2.81 (dd, J = 14.6, 5.0 Hz, 1H), 2.56

(ddd, J = 14.4, 7.8, 5.5 Hz, 2H), 2.46−2.31 (m, 2H), 2.27 (ddd, J =

15.3, 8.7, 3.3 Hz, 1H), 1.93−1.81 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 174.1, 170.9, 170.8, 147.9, 146.7,

141.2, 141.1, 130.7, 127.0, 126.0, 125.2, 120.4, 108.2, 107.7, 101.1,

61.5, 54.6, 47.5, 38.4, 38.2, 37.6, 37.0, 35.7, 29.1, 14.2; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₂₆H₂₉N₂O₆S 497.1746, found

497.1740.

1

Piperidinone-Containing Amide 13d. Compound 13d was

and amine 11v: H NMR (500 MHz, CDCl₃) δ 7.30−7.22 (m, 3H),

prepared according to the general procedure D from carboxylic acid 8g

7.17 (dq, J = 9.1, 4.0, 3.3 Hz, 3H), 5.01 (t, J = 3.7 Hz, 1H), 4.13−4.05

(m, 2H), 3.94−3.82 (m, 2H), 3.72 (q, J = 4.0 Hz, 2H), 3.42 (ddd, J =

13.8, 10.4, 4.9 Hz, 1H), 3.28 (dd, J = 8.6, 4.4 Hz, 1H), 2.93−2.72 (m,

3H), 2.66−2.53 (m, 7H), 2.28−2.08 (m, 3H), 1.88−1.80 (m, 1H),

1.60−1.43 (m, 2H), 1.34−1.22 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 173.6, 172.2, 168.8, 138.6, 137.2, 132.4,

130.2, 128.8, 100.6, 61.2, 52.7, 48.4, 47.7, 45.0, 41.4, 32.2, 31.0, 30.2,

27.7, 27.5, 23.0, 19.9, 14.4; MS(ESI) calcd for C₂₅H₃₁ClN₂O₄S 490.17

(M⁺), found 491.28 (M + H)⁺.

1

and amine 11k: H NMR (500 MHz, CDCl₃) δ 7.31−7.26 (m, 2H),

7.24 (td, J = 6.5, 1.7 Hz, 3H), 6.76−6.69 (m, 3H), 5.89 (s, 2H), 5.03

(dd, J = 3.2, 1.8 Hz, 1H), 4.81 (d, J = 15.3 Hz, 1H), 4.69 (d, J = 15.3

Hz, 1H), 4.40 (d, J = 5.6 Hz, 2H), 4.18−4.08 (m, 2H), 3.46 (s, 1H),

2.95−2.88 (m, 1H), 2.83 (dd, J = 14.7, 5.0 Hz, 1H), 2.57 (ddd, J =

14.7, 5.5, 2.6 Hz, 2H), 2.45−2.36 (m, 1H), 2.33 (dd, J = 12.7, 7.0 Hz,

1H), 2.27 (ddd, J = 15.3, 8.7, 3.2 Hz, 1H), 1.92−1.82 (m, 2H), 1.18 (t,

J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.1, 171.2, 170.9,

147.9, 146.7, 141.2, 138.4, 130.6, 128.8, 127.8, 127.5, 120.4, 108.3,

108.2, 107.7, 101.1, 61.5, 54.5, 47.6, 43.7, 38.2, 37.6, 37.0, 35.7, 29.1,

14.2; MS(ESI) calcd for C₂₈H₃₀N₂O₆490.21 (M⁺), found 491.22 (M

+ H)⁺, 513.21 (M + Na)⁺.

Pyrrolidinone-Containing Amide 12r. Compound 12r was

prepared according to the general procedure D from carboxylic acid 7c

1

and amine 11l: H NMR (500 MHz, CDCl₃) δ 7.33−7.23 (m, 5H),

7.22−7.13 (m, 7H), 6.77 (t, J = 5.7 Hz, 1H), 5.05 (t, J = 3.7 Hz, 1H),

4.17−4.06 (m, 2H), 3.88 (ddd, J = 13.8, 10.7, 6.3 Hz, 1H), 3.44 (ddd, J

= 13.8, 10.6, 5.2 Hz, 1H), 3.35−3.19 (m, 3H), 2.98−2.76 (m, 3H),

2.68−2.51 (m, 5H), 2.31−2.20 (m, 1H), 2.21−2.08 (m, 2H), 1.87

(ddt, J = 13.6, 6.5, 3.3 Hz, 1H), 1.74−1.63 (m, 2H), 1.62−1.50 (m,

3H), 1.46 (ddd, J = 15.4, 10.1, 2.9 Hz, 1H), 1.35−1.25 (m, 1H), 1.22

Piperidinone-Containing Amide 13e. Compound 13e was

prepared according to the general procedure D from carboxylic acid 8h

1

and amine 11a: H NMR (500 MHz, CDCl₃) δ 7.33 (d, J = 0.9 Hz,

1H), 6.37 (s, 1H), 6.32−6.29 (m, 1H), 6.28−6.25 (m, 1H), 5.23 (t, J =

2.4 Hz, 1H), 4.94 (d, J = 15.5 Hz, 1H), 4.78 (d, J = 15.7 Hz, 1H),

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4.17−4.08 (m, 2H), 4.05−3.97 (m, 1H), 3.96−3.87 (m, 1H), 3.48 (s,

1H), 2.90−2.82 (m, 1H), 2.75−2.68 (m, 1H), 2.58−2.51 (m, 2H),

2.49−2.40 (m, 1H), 2.38−2.28 (m, 2H), 2.21−2.17 (m, 1H), 1.91−

1.82 (m, 1H), 1.77 (dd, J = 13.5, 12.5 Hz, 1H), 1.21−1.15 (m, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 174.1, 170.8, 170.4, 150.4, 141.9,

141.1, 110.5, 108.2, 108.0, 79.8, 71.5, 61.5, 54.6, 41.2, 38.3, 37.6, 36.9,

35.8, 29.2, 29.1, 14.2; MS(ESI) calcd for C₂₁H₂₄N₂O₅384.17 (M⁺),

found 407.16 (M + Na)⁺.

14.3; MS(ESI) calcd for C₂₇H₃₆N₂O₆484.26 (M⁺), found 485.32 (M

+ H)⁺, 507.31 (M + Na)⁺.

Piperidinone-Containing Amide 13k. Compound 13k was

prepared according to the general procedure D from carboxylic acid 8j

1

and amine : H NMR (500 MHz, CDCl₃) δ 8.03−7.94 (m, 1H),

7.92−7.77 (m, 4H), 7.71 (d, J = 8.1 Hz, 1H), 7.59−7.32 (m, 7H),

7.25−7.20 (m, 1H), 6.29 (t, J = 5.1 Hz, 1H), 5.10 (d, J = 16.5 Hz, 1H),

5.03 (dd, J = 14.4, 6.5 Hz, 1H), 4.75 (d, J = 16.4 Hz, 1H), 4.72−4.65

(m, 2H), 4.18 (dq, J = 11.0, 7.2 Hz, 1H), 4.10 (dq, J = 10.8, 7.1 Hz,

1H), 3.02−2.89 (m, 2H), 2.65 (dd, J = 13.0, 5.5 Hz, 1H), 2.51 (dd, J =

14.0, 4.6 Hz, 1H), 2.39−2.28 (m, 2H), 2.25−2.16 (m, 1H), 2.01 (t, J =

13.0 Hz, 1H), 1.96−1.85 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 174.3, 170.7, 170.5, 140.9, 134.1, 134.0, 133.8,

131.5, 130.9, 130.9, 129.0, 128.8, 128.6, 127.5, 127.0, 126.7, 126.1,

126.1, 125.7, 125.6, 125.6, 123.9, 122.8, 122.6, 108.3, 61.5, 54.5, 45.1,

41.6, 38.3, 38.0, 37.1, 35.5, 29.0, 14.3; MS(ESI) calcd for C₃₅H₃₄N₂O₄

546.25 (M⁺), found 547.28 (M + H)⁺.

Piperidinone-Containing Amide 13f. Compound 13f was

prepared according to the general procedure D from carboxylic acid

1

8h and amine 11n: H NMR (500 MHz, CDCl₃) δ 7.32−7.27 (m,

1H), 6.73 (s, 1H), 6.28 (dd, J = 3.1, 1.8 Hz, 1H), 6.25 (dd, J = 3.3, 1.0

Hz, 1H), 5.16 (dd, J = 3.2, 1.8 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.82

(d, J = 15.6 Hz, 1H), 4.15−4.05 (m, 2H), 3.46 (s, 1H), 3.36 (t, J = 7.1

Hz, 2H), 3.31 (t, J = 6.4 Hz, 2H), 3.21−3.07 (m, 2H), 2.90−2.81 (m,

1H), 2.66−2.55 (m, 2H), 2.49 (dd, J = 12.8, 5.7 Hz, 1H), 2.46−2.35

(m, 5H), 2.34−2.24 (m, 2H), 2.09−1.96 (m, 2H), 1.88−1.73 (m, 2H),

1.69−1.59 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 175.9, 174.2, 171.1, 170.2, 150.7, 141.7, 141.3, 110.5, 107.9,

107.3, 61.4, 54.6, 47.5, 41.1, 39.9, 38.5, 37.2, 37.0, 36.0, 35.9, 31.1,

29.1, 26.7, 18.1, 14.2; MS(ESI) calcd for C₂₅H₃₃N₃O₆471.24 (M⁺),

found 472.25 (M + H)⁺, 494.24 (M + Na)⁺.

Piperidinone-Containing Amide 13l. Compound 13l was

prepared according to the general procedure D from carboxylic acid

8j and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.3 Hz,

1H), 7.90−7.84 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55−7.39 (m,

4H), 5.45 (d, J = 16.4 Hz, 1H), 5.38 (d, J = 16.4 Hz, 1H), 4.84 (dd, J =

3.4, 1.7 Hz, 1H), 4.23−4.15 (m, 1H), 4.14−4.05 (m, 1H), 3.57−3.48

(m, 1H), 3.47−3.38 (m, 3H), 3.03−2.93 (m, 2H), 2.69−2.60 (m, 1H),

2.57 (dd, J = 12.7, 5.4 Hz, 1H), 2.40−2.30 (m, 2H), 2.28−2.15 (m,

2H), 1.99−1.88 (m, 3H), 1.88−1.78 (m, 2H), 1.26−1.19 (m, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 174.7, 171.2, 169.2, 141.8, 133.8, 131.4,

131.0, 128.9, 127.3, 126.0, 125.8, 125.5, 123.5, 122.7, 107.8, 61.3, 54.6,

46.6, 46.0, 45.7, 37.2, 36.8, 36.5, 36.0, 29.1, 26.2, 24.5, 14.3; MS(ESI)

calcd for C₂₈H₃₂N₂O₄460.24 (M⁺), found 461.26 (M + H)⁺, 483.25

(M + Na)⁺.

Piperidinone-Containing Amide 13g. Compound 13g was

prepared according to the general procedure D from carboxylic acid 8i

1

and amine 11f: H NMR (500 MHz, CDCl₃) δ 6.85−6.74 (m, 3H),

5.42−5.37 (m, 1H), 5.06 (t, J = 2.4 Hz, 1H), 4.40 (dd, J = 14.4, 6.0 Hz,

1H), 4.27 (dd, J = 14.6, 5.4 Hz, 1H), 4.19−4.09 (m, 2H), 3.91−3.81

(m, 7H), 3.77 (ddd, J = 13.2, 10.6, 5.8 Hz, 1H), 3.47 (ddd, J = 13.2,

10.7, 5.3 Hz, 1H), 2.85−2.77 (m, 1H), 2.69 (dd, J = 14.6, 4.8 Hz, 1H),

2.61−2.41 (m, 3H), 2.38−2.27 (m, 2H), 2.09 (m, 2H), 2.00−1.89 (m,

4H), 1.85 (dt, J = 13.0, 9.4 Hz, 1H), 1.74 (t, J = 13.0 Hz, 1H), 1.64−

1.56 (m, 2H), 1.56−1.48 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR

(126 MHz, CDCl₃) δ 174.1, 171.1, 170.1, 149.2, 148.4, 141.0, 135.0,

131.2, 122.8, 120.1, 111.2, 111.1, 106.8, 61.5, 56.0, 56.0, 54.4, 43.5,

43.1, 38.7, 37.6, 37.0, 35.9, 34.5, 29.1, 28.6, 25.4, 23.0, 22.4, 14.3;

MS(ESI) calcd for C₃₀H₄₀N₂O₆524.29 (M⁺), found 525.29 (M + H)⁺.

Piperidinone-Containing Amide 13h. Compound 13h was

prepared according to the general procedure D from carboxylic acid 8i

Piperidinone-Containing Amide 13m. Compound 13m was

prepared according to the general procedure D from carboxylic acid 8k

1

and amine 11a: H NMR (500 MHz, CDCl₃) δ 7.40−7.33 (m, 1H),

7.23−7.16 (m, 2H), 6.16 (t, J = 5.4 Hz, 1H), 4.99−4.90 (m, 2H), 4.85

(dd, J = 3.2, 1.7 Hz, 1H), 4.27−4.12 (m, 2H), 4.07−3.94 (m, 2H),

2.95−2.87 (m, 1H), 2.82 (dd, J = 15.1, 5.0 Hz, 1H), 2.60−2.50 (m,

2H), 2.42−2.32 (m, 2H), 2.29−2.21 (m, 1H), 2.20 (t, J = 2.5 Hz, 1H),

1.98 (t, J = 13.0 Hz, 1H), 1.94−1.85 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H);

¹³C NMR (126 MHz, CDCl₃) δ 174.1, 170.8, 170.6, 141.1, 133.3,

133.3, 132.4, 129.2, 128.5, 127.4, 108.1, 79.6, 71.7, 61.6, 54.6, 45.3,

37.8, 37.4, 37.1, 35.6, 29.3, 29.0, 14.4; MS(ESI) calcd for

C₂₃H₂₄Cl₂N₂O₄462.11 (M⁺), found 533.39 (M + H)⁺, 555.38 (M +

Na)⁺.

1

and amine 11s: H NMR (500 MHz, CDCl₃) δ 5.43 (dd, J = 3.3, 1.8

Hz, 1H), 5.07 (t, J = 2.3 Hz, 1H), 4.21−4.08 (m, 4H), 3.88 (ddd, J =

13.3, 10.7, 5.6 Hz, 1H), 3.66−3.31 (m, 9H), 2.85−2.70 (m, 3H),

2.55−2.41 (m, 2H), 2.39−2.26 (m, 3H), 2.25−2.08 (m, 2H), 2.05−

1.92 (m, 4H), 1.91−1.77 (m, 2H), 1.66−1.56 (m, 2H), 1.56−1.48 (m,

2H), 1.32−1.18 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3,

169.7, 169.4, 155.3, 141.1, 135.1, 122.5, 106.0, 61.6, 61.2, 54.2, 45.1,

43.5, 43.0, 41.3, 37.5, 36.9, 36.5, 35.8, 35.2, 34.4, 28.9, 28.4, 25.2, 22.9,

22.3, 14.6, 14.2; MS(ESI) calcd for C₂₈H₄₁N₃O₆515.30 (M⁺), found

516.32 (M + H)⁺, 538.3 (M + Na)⁺.

Piperidinone-Containing Amide 13i. Compound 13i was

prepared according to the general procedure D from carboxylic acid

8a and amine 11l: ¹H NMR (500 MHz, CDCl₃) δ 7.24 (m, 2H), 7.14

(m, 3H), 6.79 (m, 3H), 6.03 (s, 1H), 5.09 (t, J = 2.5 Hz, 1H), 4.16 (q,

J = 7.1 Hz, 2H), 4.01 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.64 (m,

1H), 3.23 (m, 2H), 2.79 (m, 3H), 2.66 (m, 1H), 2.60 (t, J = 7.6 Hz,

2H), 2.55 (dd, J = 13.0, 5.8 Hz, 1H), 2.48 (dd, J = 14.5, 5.3 Hz, 2H),

2.35 (m, 2H), 1.87 (m, 1H), 1.78 (t, J = 13.0 Hz, 1H), 1.60 (m, 2H),

1.50 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 174.2, 171.0, 170.2, 149.1, 147.8, 142.2, 141.1, 131.7, 128.5, 128.4,

125.9, 120.8, 112.3, 111.5, 106.6, 61.5, 56.1, 56.1, 54.5, 45.9, 39.4, 38.5,

37.6, 36.9, 35.8, 35.6, 32.5, 29.4, 29.0, 28.7, 14.3; MS(ESI) calcd for

C₃₃H₄₂N₂O₆562.30 (M⁺), found 563.37 (M + H)⁺.

Piperidinone-Containing Amide 13j. Compound 13j was

prepared according to the general procedure D from carboxylic acid

8a and amine 11w: ¹H NMR (500 MHz, CDCl₃) δ 6.80 (m, 3H), 5.09

(t, J = 2.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.00 (m, 1H), 3.87 (s,

3H), 3.85 (s, 3H), 3.71 (m, 1H), 3.42 (m, 4H), 2.82 (m, 4H), 2.61

(dd, J = 15.9, 2.9 Hz, 1H), 2.49 (m, 2H), 2.35 (m, 2H), 1.90 (m, 6H),

1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.6, 170.5,

169.2, 149.0, 147.6, 141.5, 132.1, 120.7, 112.3, 111.4, 105.8, 61.3, 56.0,

56.0, 54.5, 46.6, 45.9, 45.7, 37.0, 36.6, 36.5, 36.0, 32.4, 29.1, 26.2, 24.5,

Piperidinone-Containing Amide 13n. Compound 13n was

prepared according to the general procedure D from carboxylic acid 8k

1

and amine 11n: H NMR (500 MHz, CDCl₃) δ 7.34 (d, J = 2.1 Hz,

1H), 7.27−7.23 (m, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.74 (t, J = 6.2

Hz, 1H), 4.96−4.88 (m, 2H), 4.79 (dd, J = 3.2, 1.7 Hz, 1H), 4.24−

4.11 (m, 2H), 3.38−3.26 (m, 4H), 3.21−3.11 (m, 2H), 2.92−2.85 (m,

1H), 2.78 (dd, J = 15.4, 5.6 Hz, 1H), 2.58−2.47 (m, 2H), 2.41−2.30

(m, 4H), 2.25−2.17 (m, 1H), 2.06−1.95 (m, 3H), 1.91−1.82 (m, 1H),

1.67−1.59 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz,

CDCl₃) δ 175.9, 174.2, 170.9, 170.8, 141.4, 133.2, 133.1, 132.8, 129.0,

128.8, 127.4, 107.3, 61.5, 54.6, 47.5, 45.2, 39.8, 37.9, 37.1, 37.0, 35.8,

35.8, 31.0, 29.0, 26.6, 18.1, 14.4; MS(ESI) calcd for C₂₇H₃₃Cl₂N₃O₅

549.18 (M⁺), found 550.18 (M + H)⁺.

Piperidinone-Containing Amide 13o. Compound 13o was

prepared according to the general procedure D from carboxylic acid 8l

1

and amine 11a: H NMR (500 MHz, CDCl₃) δ 6.69 (t, J = 5.4 Hz,

1H), 5.25 (dd, J = 5.3, 2.8 Hz, 1H), 4.16 (dd, J = 7.0, 2.0 Hz, 1H), 4.14

(dd, J = 7.1, 1.9 Hz, 1H), 4.05−3.94 (m, 2H), 3.71 (ddd, J = 13.6, 10.5,

5.2 Hz, 1H), 3.64 (ddd, J = 13.7, 10.7, 5.7 Hz, 1H), 2.68−2.59 (m,

2H), 2.56−2.49 (m, 1H), 2.34 (dd, J = 13.1, 5.4 Hz, 1H), 2.31−2.21

(m, 2H), 2.17 (t, J = 2.6 Hz, 1H), 2.16−2.09 (m, 1H), 1.72−1.58 (m,

3H), 1.55−1.45 (m, 2H), 1.43−1.35 (m, 1H), 1.34−1.20 (m, 13H),

0.87 (t, J = 6.6 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.2, 171.0,

170.0, 136.2, 107.3, 79.8, 71.4, 61.6, 46.6, 44.2, 38.8, 37.3, 36.7, 35.0,

32.0, 29.5, 29.4, 29.2, 27.3, 27.0, 24.5, 22.8, 18.7, 14.4, 14.2; MS(ESI)

calcd for C₂₅H₃₈N₂O₄430.28 (M⁺), found 431.29 (M + H)⁺.

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Piperidinone-Containing Amide 13p. Compound 13p was

prepared according to the general procedure D from carboxylic acid 8l

and amine 11o: H NMR (500 MHz, CDCl₃) δ 6.46 (t, J = 5.7 Hz,

35.1, 26.2, 24.5, 24.5, 18.8, 14.4; MS(ESI) calcd for C₂₆H₃₂N₂O₆

468.23 (M⁺), found 469.23 (M + H)⁺, 491.22 (M + Na)⁺.

Piperidinone-Containing Amide 13u. Compound 13u was

1

prepared according to the general procedure D from carboxylic acid 8o

and amine 11g: H NMR (500 MHz, CDCl₃) δ 7.52−7.45 (m, 2H),

1H), 6.04 (d, J = 3.0 Hz, 1H), 5.85 (dd, J = 3.1, 1.3 Hz, 1H), 5.22 (dd,

J = 5.3, 2.8 Hz, 1H), 4.35 (dd, J = 15.5, 5.6 Hz, 1H), 4.29 (dd, J = 15.4,

5.4 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.71−3.58 (m, 2H), 2.70−2.60

(m, 2H), 2.56−2.49 (m, 1H), 2.39−2.32 (m, 1H), 2.31−2.20 (m, 5H),

2.18−2.09 (m, 1H), 1.73−1.64 (m, 2H), 1.62−1.54 (m, 1H), 1.54−

1.34 (m, 3H), 1.33−1.18 (m, 13H), 0.87 (t, J = 6.6 Hz, 3H); ¹³C

NMR (126 MHz, CDCl₃) δ 174.3, 170.9, 169.9, 151.8, 149.7, 136.3,

108.1, 107.1, 106.3, 61.5, 46.6, 44.1, 38.7, 37.4, 36.7, 36.5, 35.0, 32.0,

29.5, 27.3, 26.8, 24.5, 22.8, 18.7, 14.3, 14.2, 13.7; MS(ESI) calcd for

C₂₈H₄₂N₂O₅486.31 (M⁺), found 487.32 (M + H)⁺, 509.3 (M + Na)⁺.

Piperidinone-Containing Amide 13q. Compound 13q was

prepared according to the general procedure D from carboxylic acid

8m and amine 11c: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 8.2,

6.9 Hz, 2H), 7.23−7.17 (m, 3H), 6.38 (t, J = 5.7 Hz, 1H), 5.39 (d, J =

16.0 Hz, 1H), 5.13 (dd, J = 5.2, 2.8 Hz, 1H), 4.54 (d, J = 16.1 Hz, 1H),

4.17 (q, J = 7.1 Hz, 2H), 3.44−3.29 (m, 3H), 3.28 (s, 3H), 3.27−3.20

(m, 1H), 2.79−2.68 (m, 2H), 2.59−2.51 (m, 1H), 2.42 (dd, J = 13.1,

5.3 Hz, 1H), 2.29−2.22 (m, 1H), 2.17−2.08 (m, 1H), 2.06−1.95 (m,

1H), 1.91 (t, J = 13.0 Hz, 1H), 1.76−1.67 (m, 2H), 1.68−1.60 (m,

1H), 1.52 (td, J = 13.6, 2.7 Hz, 1H), 1.40−1.30 (m, 1H), 1.25 (t, J =

7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 170.9, 170.7,

137.7, 137.2, 128.6, 126.8, 126.2, 108.5, 71.4, 61.5, 58.8, 48.8, 46.8,

38.6, 37.8, 37.6, 36.6, 34.9, 29.3, 24.4, 18.7, 14.4; MS(ESI) calcd for

C₂₅H₃₄N₂O₅442.25 (M⁺), found 443.27 (M + H)⁺, 465.23 (M +

Na)⁺.

Piperidinone-Containing Amide 13r. Compound 13r was

prepared according to the general procedure D from carboxylic acid

8m and amine 11n: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (dd, J = 8.2,