Indium-mediated addition of γ-substituted allylic halides to N-aryl α-imino esters: Diastereoselective production of β,β′- disubstituted α-amino acid derivatives with two contiguous stereocenters

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DOI: 10.1002/ejoc.201200254

Indium-Mediated Addition of γ-Substituted Allylic Halides to N-Aryl α-Imino

Esters. Diastereoselective Production of β,βЈ-Disubstituted α-Amino Acid

Derivatives with Two Contiguous Stereocenters

Nayyar Ahmad Aslam,^[a]Vadla Rajkumar,^[a]Chennakesava Reddy,^[a]Makoto Yasuda,^[b]

Akio Baba,^[b]and Srinivasarao Arulananda Babu*^[a]

Keywords: Synthetic methods / Allylation / Indium / Amino acids / Diastereoselectivity

Chelation-controlled Barbier-type indium-mediated addition

the resulting γ,δ-unsaturated β,βЈ-disubstituted N-aryl amino

of γ-substituted allylic halides to N-aryl (including N-PMP)

acid derivatives followed by ring closing metathesis (RCM)

α-imino- and N-acylhydrazono esters and highly diastereo- led to the synthesis of 2,3-disubstituted N-aryltetrahydropyr-

selective tailoring of functionalized γ,δ-unsaturated β,βЈ-di-

substituted N-aryl α-amino acid derivatives, bearing two

contiguous stereocenters is reported. Further N-allylation of

idine derivatives bearing two contiguous stereocenters. The

stereochemistry of the key products was unequivocally es-

tablished from X-ray structure analyses.

Introduction

α-imino esters by Jørgensen et al.,^[6a](b) γ-substituted allyl-

trichlorosilanes to α-hydrazono esters by Kobayashi et

al.,^[6b](c) sulfonimidoyl-substituted bis(allyl)titanium com-

plexes to N-sulfonyl α-imino esters by Gais et al.,^[6c,6d](d) α-

methylallylboronate to N-acylhyrazones and crotylboronate

addition to glyoxylic acid by Kobayashi et al.^[6e,6f]and (e) γ-

substituted allylmetals to oxime ethers by Ricci et al.^[6g]and

Hanessian et al.^[6h]and ketimine derived from trifluoropy-

ruvate by Zhang et al.^[6i]Notably, in some of these versatile

methods there is a need for prior preparation of α- and/

or γ-substituted allylmetals and some of the reagents are

relatively expensive.

In recent years, indium-mediated Barbier-type stereo-

selective allylation of carbonyl (C=O) and imino (C=N)

functionalities have attracted the attention of many syn-

thetic chemists.^[7]This method has the advantage of involv-

ing the direct use of indium powder and allylic halides Ϫ

thereby avoiding the requirement for prior preparation of

allylic reagents Ϫ and the reactions can be accomplished in

aqueous media. The indium-mediated nonstereoselective as

well as stereoselective additions of simple allylic halides to

C=N bond systems (aldimines, ketimines, hydrazones, ox-

imes, and sulfonimines) have been well-studied.^[8,9]How-

ever, there exists only a limited number of reports on the

indium-mediated stereoselective addition of γ-substituted

allylic halides to C=N bond systems such as oxime

ethers,^[10]sulfonimines,^[11]acylhydrazones,^[12]and imines de-

rived from alkyl as well as arylamines,^[13]leading to homo-

allylic amines with two contiguous stereocenters.

Isoleucine (natural) and alloisoleucine^[1a](unnatural) are

γ,δ-hydrogenated versions of the γ,δ-unsaturated β,βЈ-di-

substituted α-amino acids, bearing two contiguous ste-

reocenters. The β,βЈ-disubstituted α-amino acids and γ- or

δ-hydroxy β,βЈ-disubstituted α-amino acids form the core

or subunits in various important natural products, for ex-

ample, nikkomycin B,^[1b]4-hydroxyisoleucine,^[1c]lysobac-

tin^[1d]and halipeptin A.^[1e]The inclusion of β,βЈ-disubsti-

tuted α-amino acids into peptides provides conformational

rigidity, enhanced activity, and resistance towards proteoly-

sis.^[2,3]Due to this biological importance and because of

their value as synthetic building blocks, various excellent

enantio- and stereoselective methods^[3,4]have been devel-

oped for the synthesis of β,βЈ-disubstituted α-amino acid

and γ,δ-unsaturated β,βЈ-disubstituted α-amino acid deriva-

tives. Among the available methods,^[3,4]stereoselective ad-

dition of α- and/or γ-substituted allyl metals to the C=N

bond^[4–6]of α-imino esters is one of the direct methods used

to obtain the unnatural γ,δ-unsaturated β,βЈ-disubstituted

α-amino acid derivatives having two contiguous stereocen-

ters. In this regard, to the best of our knowledge, there ex-

ists only a few significant reports,^[6]such as the stereoselec-

tive addition of (a) γ-substituted allylstannanes to N-tosyl

[a] Department of Chemical Sciences, Indian Institute of Science

Education and Research (IISER) Mohali, Knowledge City,

Sector 81, SAS Nagar, Mohali,

Manauli P. O., Punjab, 140306, India

Fax: +91-172-2240266

E-mail: sababu@iisermohali.ac.in

In spite of the encouraging developments on the indium-

mediated stereoselective addition of allylic halides to C=N

systems, a survey of the literature indicated that the theme

of indium-based addition of simple as well as γ-substituted

[b] Department of Applied Chemistry, Graduate School of

Engineering, Osaka University,

2–1 Yamadaoka, Suita, Osaka 565-0871, Japan

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200254.

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allylic reagents to C=N bond systems affording the γ,δ-un- two contiguous stereogenic centers and the synthesis of

saturated amino acid derivatives is an interesting and highly functionalized γ,δ-unsaturated β,βЈ-disubstituted N-

emerging topic of study.^[14,15]Recently, Kang and co- aryl α-amino acid derivatives having more than one stereo-

workers^[16]have reported the indium-mediated addition of center, as illustrated in Scheme 1. Control of the stereo-

γ,γЈ-dimethyl allylindium to N-aryl α-imino esters for the centers during the addition of γ-substituted allylmetals to

synthesis of γ,δ-unsaturated β,βЈ-dimethyl N-aryl α-amino the C=N bond of N-aryl α-imino esters leading to dia-

acid derivatives bearing only one chiral center.

stereomers demands either a cyclic/rigid TS or a chelation-

We envisaged that addition of the γ-substituted allylin- controlled TS. These two conditions require strong coordi-

diums to α-imino esters would enable the construction of nation acceptance and high nucleophilicity in the organo-

Scheme 1. Theme of this work: Barbier-type addition of γ-substituted allylindium compounds to N-aryl α-imino esters.

Table 1. Optimization of the addition of 2a to 1a.

[a] Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), metal (0.75 mmol). Isolated yields are given. [b] THF dried with activated molecu-

lar seives was used. In other cases, THF dried with sodium was used. [c] The reaction was carried out at 80 °C. [d] The reaction was

carried out at –10 to 0 °C. [e] The reaction was carried out at 5 °C. [f] Indium powder was added in three portions (each portion was

added after a 4 h interval).

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β,βЈ-Disubstituted α-Amino Acid Derivatives

metallic reagents. Strikingly, the N-aryl α-amino acids form the mixture was stirred at room temp. for 2 h; this gave the

the core framework in various medicinal agents.^[17]Hence, product 3a in a 42% yield (ds 98:2, Table 1, entry 1). Pro-

the development of new protocols for the synthesis of N- longing the reaction time to 12 h resulted the formation of

aryl α-amino acid derivatives will be highly beneficial product 3a in 48% yield (Table 1, entry 2). The cinnamyl-

(Scheme 1).

ation of 1a in anhydrous tetrahydrofuran (THF) gave the

We herein report the direct Barbier-type indium-medi- product 3a in a 52% yield (Table 1, entry 3). In anhydrous

ated addition of various γ-substituted allylic halides to N- THF, increasing or lowering the reaction temperature did

aryl (including N-PMP) α-imino- and α-hydrazono esters. not alter the yield (Table 1, entries 4 and 5). We then em-

Our procedure has led to the highly diastereoselective pro- ployed a DMF/H₂O mixture, which also furnished the

duction of γ,δ-unsaturated β,βЈ-disubstituted N-aryl α- product 3a (47%, Table 1, entry 6). Next, various THF/

amino acid derivatives and 2,3-disubstituted N-aryltetrahy- H₂O combinations were tested (Table 1, entries 7–10).

dropyridine derivatives bearing two contiguous stereocen- THF/water combinations were also found to promote the

ters.

stereoselective formation of the syn isomer 3a, bearing two

contiguous stereocenters. At ambient temperature, 64%

yield of the syn isomer 3a^[18a](ds 98:2) was obtained for a

12 h reaction time (Table 1, entry 10). The reaction in THF/

Results and Discussion

At the outset, to a mixture of α-imino ester 1a and cinn- water at 80 °C gave only 38% yield of the product 3a

amyl bromide (2a, E geometry) in anhydrous N,N-dimethyl- (Table 1, entry 11). The reaction in THF/water at 5 °C

formamide (DMF), was added indium metal powder and yielded a slight increment in yield of 3a (67%; Table 1, en-

Table 2. Stereoselective cinnamylation of 1b–i.^[18a]

[a] Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), metal (0.75 mmol). Isolated yields are given.

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try 12). Portionwise addition of indium powder to the reac- mediated cinnamylation of α-imino esters prepared from

tion in THF/water at ambient temperature also gave only anilines with electron-withdrawing or -donating groups fur-

63% of the product 3a (Table 1, entry 13). Significantly, nished the respective α-amino acid derivatives 3b–g (syn iso-

small amounts of water in THF or small amounts of THF mers, ds 98:2; Table 2, entries 1–6). The cinnamylation of

in water gave the product 3a in 66 and 50% yields, respec- 1h, obtained from α-naphthylamine, gave the syn isomer 3h

tively (Table 1, entries 14 and 15). Inclusion of various addi- (Table 2, entry 7). The reaction of 2a with α-hydrazono es-

tives did not improve the yield of 3a (Table 1, entries 16 and ter 1i afforded the α-amino acid derivative 3i with moderate

17). Employing Zn dust afforded low yields, and Sn powder diastereoselectivity (ds 75:25; Table 2, entry 8).

failed to yield the product 3a in good yields (Table 1, entries

The exclusive formation of the syn products 3a–i^[18a,18e]

18–21). Hence, indium metal powder and THF/water sys- in the cinnamylation of α-imino esters 1a–i could be ex-

tem were established as the best choice for the diastereo- plained by a chelation TS in aqueous media (Model B, Fig-

selective production of 3a (syn isomer) bearing two contigu- ure 1). The allylindium compounds are tolerant to water^[7]

ous stereocenters.

and, in these reactions, the aqueous media contributes to

The scope of the Barbier-type cinnamylation was tested the rapid quenching of the transient indium amide, formed

by using various α-imino esters 1b–i (Table 2). The indium- after the addition of allylindium; furthermore, the very high

Scheme 2. One-pot multicomponent reactions. Reagents and conditions: 6a (0.5 mmol), 6b–d (0.5 mmol), 2a (1.25 mmol), In (0.75 mmol).

Isolated yields are given.

Table 3. Stereoselective addition of 2b to 1.^[18a]

[a] Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), metal (0.75 mmol). Isolated yields are given. [b] This reaction was carried out

using Zn dust (2 mmol) instead of In.

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β,βЈ-Disubstituted α-Amino Acid Derivatives

stereoselectivity observed revealed that the addition process

was kinetically controlled. In the transition state, involve-

ment of both the indium(III) species as well as indium(I)

species is possible, as proposed in various reports. The for-

mation of two discrete species from cinnamyl bromide and

indium in [D₈]THF/D₂O was observed (see NMR spectra

1

of the Supporting Information in reference^[7i]) in H NMR

studies by various groups,^[19a–19i]including us, and the ad-

dition of a carbonyl compound to both the species revealed

that one species was more reactive than the other species.

The nature of the active indium species remains elusive be-

cause of its fleeting character.^{[7a,7j,19a–19i]}Recent reports

Figure 1. Plausible transition states for the observed diastereoselec-

tivity.

Table 4. Stereoselective crotylation of α-imino ester 1.^[18a]

[a] Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), metal (0.75 mmol). Isolated yields are given. [b] Reaction time was 6 h. [c] Reac-

tion time was 2 h. [d] The products 11d and 11i were isolated as a mixture of diastereomers.

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strongly suggest the involvement of an In^IIIspecies in the is essential for the high diastereoselectivity,^[7i,19e,19f]might

TS (proposed by Singaram,^[19a]Baba^{[7r,19b–19f]}and Koszi- favor a low-valent indium species.

nowski^[19g]); however, in the present reactions, the involve-

The direct indium-mediated three-component one-pot

reaction of ethyl glyoxalate (6a), amines 6b–d and cinnamyl

ment of an In^Ispecies (proposed by Chan^[19h]and Hilt^[19i]

)

is also very likely, as a chelation-controlled/rigid TS, which bromide (2a) was then performed. The one-pot indium-me-

Scheme 3. Stereoselective geranylation of α-imino ester 1. Reagents and conditions: 1 (1 mmol), 2d (2 mmol), NaI (2 mmol), In (1.5 mmol).

Isolated yields are given.

Table 5. Stereoselective crotylation of α-imino esters 1j–l.^[18a]

[a] Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), metal (0.75 mmol). Isolated yields are given.

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diated cinnamylation in aqueous media exclusively afforded indium afforded the product 11l in anhydrous THF, as well

the respective α-amino acid derivatives 3a, 3c, and 3f (syn as in THF/water mixture (Table 5, entries 4 and 5). In these

isomers, ds 98:2, Scheme 2).

We then focused our attention on the optimization of bly due to the involvement of a less rigid cyclic TS species.

the Barbier-type indium-mediated direct addition of cyclo- The scope of this method is delineated in Scheme 4. The

cases, a moderate diastereoselectivity was observed, proba-

hexenyl bromide (2b, Z geometry) to the α-imino esters 1a, hydrogenation of a representative compound 11e led to the

1e, and 1g (Table 3). In contrast to the cinnamyl bromide synthesis of a novel N-aryl alloisoleucine derivative 15. The

case, the indium-mediated addition of 2b to 1a in aqueous hydrolysis of compounds 3a and 3c gave the respective un-

media failed to give the products 7/8 (Table 3, entries 1 natural β,βЈ-disubstituted N-aryl α-amino acids 16a and

and 2), perhaps because the cyclohexenylindium was un- 16b. Reduction of the ester group of the representative com-

stable in aqueous media.^[7i]However, a smooth reaction of pounds 3b, 3c, and 14b afforded the respective novel δ,ω-

the α-imino ester 1a and 2b in anhydrous THF furnished unsaturated γ,γЈ-disubstituted N-aryl β-amino alcohols

the α-amino acid derivative 7a (anti isomer) bearing two 17a–c, bearing two contiguous stereocenters.^[18d]

contiguous stereocenters (ds 98:2, Table 3, entry 3). The

indium-mediated one-pot treatment of cyclohexenyl brom-

ide (2b), 4-bromo aniline, and ethyl glyoxalate in THF also

afforded the product 7a in a 44% yield (Table 3, entry 5).

Similarly, the α-imino esters 1e and 1g also reacted with 2b

to furnish the anti isomers 7b and 7c, respectively (Table 3,

entries 6 and 7). The exclusive formation of anti products

7a–c could be accounted for by a chelation TS (Model C,

Figure 1).

The reactivity pattern of the crotyl bromide (2c, E geom-

etry) with α-imino esters was subsequently investigated

(Table 4). The reaction of crotylindium with 1a in THF/

water (1:1) was optimized to afford the syn isomer of the α-

amino acid derivative 11a (61%, ds 98:2, Table 4, entries 1

and 2). Similarly, the product 11b was obtained in a 60%

yield (Table 4, entry 3). Changing the ratio of the THF/

water did not improve the yield of 11b (Table 4, entries 4

and 5). The indium-mediated crotylation of 1b–d gave the

respective products 11c–e (Table 4, entries 6–9). Although

the yield of 11d was high in DMF, a somewhat lower dia-

stereoselectivity was observed (ds 75:25). The crotylation of

α-imino esters 1f–h furnished the respective syn isomers

11f–h (Table 4, entries 10–13). Successful addition of crotyl-

indium to the α-hydrazono ester 1i gave the product 11i

(65%) with reasonably good diastereoselectivity (ds 75:25,

Table 4, entry 14). The exclusive formation of syn products

11a–i in these reactions could be accounted for by a chela-

tion TS (Model B, Figure 1).

Next, we studied the reaction of geranyl bromide (2d, E

Scheme 4. Scope and generality. Reagents and conditions: (a) H₂

geometry) with α-hydrazono- and α-imino esters

(1 atm), Pd/C (10 mol-%), THF, room temp.; (b) 1 m Aq. KOH,

MeOH, reflux, 48 h; (c) LiAlH₄(2 equiv.), THF, 0 °C to room

(Scheme 3). The α-hydrazono ester 1i and α-imino esters 1a,

1d, and 1g underwent stereoselective geranylation to give temp., 12 h.

the respective β,βЈ-disubstituted α-amino acid derivatives 13

and 14a–c (ds 90:10), bearing a terpene unit and two contig-

Finally, we were interested in extending the utility of this

uous stereocenters (including an all carbon quaternary cen- synthetic protocol and constructing 2,3-disubstituted N-

ter).^[18c]

aryltetrahydropyridine derivatives bearing two contiguous

Subsequently, the addition of crotyl bromide (2c, E stereocenters (Scheme 5). N-Allylation of γ,δ-unsaturated

geometry) to hydrazono esters 1j–l, prepared from ethyl β,βЈ-disubstituted N-aryl α-amino acid derivatives 3b, 3d, 3f

benzoylformate and methyl pyruvate, was studied (Table 5). and 11a, 11d, and 11e, obtained from the stereoselective cinn-

The reaction of crotylindium with N,N-diphenyl hydrazono amylation and crotylation of the α-imino esters 1, respec-

esters 1j and 1k in anhydrous THF or THF/water (1:1) did tively, gave the products 18a–f. The reaction of 18a–f in the

not afford any product (Table 5, entries 1–3) and the start- presence of a catalytic amount of Grubb’s 2nd generation cat-

ing materials 1j and 1k were recovered. This was perhaps alyst^[20a–d]successfully afforded, the 2,3-disubstituted N-aryl-

due to their low reactivity with crotyl indium. Treatment of tetrahydropyridine derivatives 19a–f, bearing two contiguous

acylhydrazone derived from methyl pyruvate 1l with crotyl- stereocenters, in very good yields. Next, the hydrogenation of

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Scheme 5.^[18d]Scope and generality. Reagents and conditions: (a) K₂CO₃(3 equiv.), NaI (0.1 equiv.), allyl bromide (6 equiv.), MeCN, reflux,

24–48 h; (b) Grubb’s 2nd generation catalyst (0.05–0.1 equiv.), CH₂Cl₂, room temp., overnight; (c) H₂(1 atm), Pd/C (10 mol-%), THF,

room temp.; (d) 1 m aq. KOH, MeOH, 90–95 °C, 48 h.

TMS as an internal or external standard. Column chromatography

was carried out on silica gel (100–200 mesh) or neutral Al₂O₃. Re-

actions were conducted in anhydrous solvent under nitrogen atmo-

sphere where required. Solutions were dried using anhydrous so-

dium sulfate. Reagents were added to the reaction flask by using a

syringe. Thin layer chromatography (TLC) was performed on silica

plates or neutral Al₂O₃and components were visualized by obser-

vation under iodine. Isolated yields of all the products are reported

(yields were not optimized). Ratios of diastereomers were deter-

a representative compound 19b led to the synthesis of 2,3-

disubstituted N-aryl piperidine derivative 20a. Hydrolysis

of 19f gave 3-methyl-1-(p-tolyl)-1,2,3,6-tetrahydropyridine-2-

carboxylic acid (20b)^[19j](N-aryl Baikiain analogue^[19k]).

Conclusions

A highly diastereoselective C–C bond formation synthetic

protocol was established by using the direct Barbier-type

indium-mediated addition of various γ-substituted allylic

1

mined from the H and ¹³C NMR spectra of either crude reaction

mixtures or after isolation; in all the reactions, only the major dia-

stereomer was isolated in pure form. The ratio of diastereoselectiv-

halides to N-aryl α-imino esters and α-hydrazono esters. ity (ds 98:2) refers to the predominant presence of the major dia-

stereomer and rarely, traces of the corresponding minor isomer in

the NMR spectrum of the crude reaction mixture. After the column

purification, we did not observe any minor diastereomer.

Production of γ,δ-unsaturated β,βЈ-disubstituted N-aryl (in-

cluding N-PMP) α-amino acid derivatives bearing two con-

tiguous stereocenters, with remarkable diastereoselectivity,

was accomplished. Furthermore, the synthetic utility of this

protocol has been illustrated by efficiently constructing

various 2,3-disubstituted N-aryltetrahydropyridine, 2,3-di-

substituted N-aryl piperidine, and N-aryl Baikiain deriva-

tives, bearing two contiguous stereocenters.

Procedure A. Indium-Mediated Addition of Cinnamyl Bromide (2a)

to α-Imino Esters 1: To a vigorously stirring solution of α-imino

ester 1^[20e](0.5 mmol, 1 equiv.) and E-cinnamyl bromide (2a;

1.25 mmol, 2.5 equiv.) in THF (3 mL) and H₂O (3 mL), was added

indium powder (0.75 mmol, 1.5 equiv.). The mixture was stirred

vigorously for 12 h at room temp., then transferred to a separating

funnel and extracted with EtOAc (3ϫ15 mL). The combined or-

ganic layers were dried with anhydrous Na₂SO₄, then the solvent

was evaporated under vacuum. Purification of the resulting crude

reaction mixture by column chromatography on neutral alumina

or silica gel (EtOAc/hexane) gave the product 3 (see Tables 1 and

2 for individual entries).

Experimental Section

General: Melting points are uncorrected. IR spectra were recorded

as thin films or KBr pellets. ¹H and ¹³C NMR spectra were re-

corded with 400 and 100 MHz spectrometers, respectively, with

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Procedure B. One-Pot Synthesis of N-Aryl α-Amino Esters (3a, 3c,

and 3f): Ethyl glyoxylate 6a (0.6 mmol, 1.2 equiv.) and the respec-

tive amine 6b–d (0.5 mmol, 1 equiv.) were dissolved in THF (2 mL)

and stirred for 15 min at room temp. To the resulting solution, E-

cinnamyl bromide (2a; 1.25 mmol, 2.5 equiv.), THF (1 mL) and

H₂O (3 mL) were added. Indium powder (0.75 mmol, 1.5 equiv.)

was added while stirring the reaction mixture vigorously, and stir-

ring was continued for 12 h at room temp. After this period, the

reaction mixture was transferred to a separating funnel and ex-

tracted with EtOAc (3ϫ15 mL). The combined organic layers were

dried with anhydrous Na₂SO₄, then the solvent was evaporated un-

der vacuum. Purification of the resulting crude reaction mixture by

column chromatography on neutral alumina (EtOAc/hexane) gave

the products (3a, 3c, and 3f) (see Scheme 2 for individual entries).

the N-aryl alloisolucine derivative 15 (Scheme 4). Compound 19b

(0.15 mmol, 1 equiv.) was hydrogenated in anhydrous THF (2 mL)

using Pd-C (10 mol-%) and the contents were stirred under H₂

(1 atm) at room temp. to afford the product 20a (Scheme 5).

Procedure G. Hydrolysis^[22]of the N-Aryl α-Amino Esters 3a,c and

the Synthesis of Unnatural N-Aryl α-Amino Acids 16a,b: The respec-

tive N-aryl α-amino ester 3a,c (0.5 mmol, 1 equiv.) was hydrolyzed

by heating to reflux with 1 m aq. potassium hydroxide (3 mL) and

methanol (1 mL) for 48 h. After this period the reaction mixture

was cooled to room temp., transferred to a separating flask, and

washed with CH₂Cl₂(2ϫ10 mL). To the reaction mixture was

added aq. HCl dropwise and the solid products were filtered to

afford the corresponding N-aryl α-amino acids 16a,b (Scheme 4).

Compound 19f (0.2 mmol, 1 equiv.) was hydrolyzed by heating to

reflux with 1 m aq. potassium hydroxide (2 mL) and methanol

(0.05 mL) for 48 h to afford the product 20b (Scheme 5).

Procedure H. Reduction^[23]of N-Aryl α-Amino Esters 3/14 to N-Aryl

β-Amino Alcohols 17: A dry flask was charged with anhydrous THF

(4 mL) and the respective N-aryl α-amino ester 3b, 3c or 14b

(0.5 mmol) under a nitrogen atmosphere, at 0 °C. To this solution

was added LiAlH₄(1 mmol) in portions and the mixture was

stirred overnight at room temp. EtOH (few drops) and water (1–

2 mL) were then added sequentially and the resulting white suspen-

sion was filtered through a Celite pad and rinsed with THF

(20 mL). The filtrate was dried with anhydrous Na₂SO₄, the solvent

was removed by rotary evaporation, and the product was purified

by column chromatography on silica gel (EtOAc/hexane) to afford

the respective N-aryl α-amino alcohols 17a–c (Scheme 4).

Procedure C. Indium-Mediated Addition of Cyclohexenyl Bromide

(2b) to α-Imino Esters 1: To a vigorously stirring solution of α-

imino ester 1 (0.5 mmol, 1 equiv.) and Z-cyclohexenyl bromide (2b;

1.25 mmol, 2.5 equiv.) in THF (3 mL), was added indium powder

(0.75 mmol, 1.5 equiv.). The mixture was stirred vigorously for 12 h

at room temp. under a nitrogen atmosphere. After this period,

water (10 mL) was added to the reaction mixture, which was then

transferred to a separating funnel and extracted with EtOAc

(3ϫ15 mL). The combined organic layers were dried with anhy-

drous Na₂SO₄and the solvent was then evaporated under vacuum.

Purification of the resulting crude reaction mixture by column

chromatography on neutral alumina (EtOAc/hexane) gave the

product 7 (see Table 3 for individual entries).

Procedure D. Indium-Mediated Addition of Crotyl Bromide (2c) to

α-Imino Esters 1: To a vigorously stirring solution of α-imino ester

1 (0.5 mmol, 1 equiv.) and E-crotyl bromide (2c; 1.25 mmol,

2.5 equiv.) in THF (3 mL) and H₂O (3 mL) was added indium pow-

der (0.75 mmol, 1.5 equiv.). The mixture was stirred vigorously for

12 h at room temp., then transferred to a separating funnel and

extracted with EtOAc (3ϫ15 mL). The combined organic layers

were dried with anhydrous Na₂SO₄, then the solvent was then evap-

orated under vacuum. Purification of the resulting crude reaction

mixture by column chromatography on neutral alumina or silica

gel (EtOAc/hexane) gave the product 11 (see Table 4 and Table 5

for individual entries).

Procedure I. N-Allylation of γ,δ-Unsaturated β,βЈ-Disubstituted N-

Aryl α-Amino Acid Derivatives 3b,d,f and 11a,d,e: To the respective

N-aryl α-amino ester 3b,d,f and 11a,d,e (1 mmol, 1 equiv.) in

MeCN (5 mL) was added allyl bromide (6 equiv.), NaI (0.1 equiv.),

and activated K₂CO₃(3 equiv.). The resulting reaction mixture was

heated to reflux for 24–48 h. After completion of the reaction as

indicated by the TLC, the reaction mixture was cooled to room

temp., water (5–6 mL) was added, and the resulting reaction was

transferred to a separating flask and extracted with EtOAc

(3ϫ15 mL). The combined organic layers were dried with anhy-

drous Na₂SO₄and the solvent was evaporated under vacuum. Puri-

fication of the resulting crude reaction mixture by column

chromatography on silica gel (EtOAc/hexane) gave the products

18a–f (see Scheme 5 for individual entries).

Procedure E. Indium-Mediated Addition of Geranyl Bromide (2d) to

α-Imino Esters 1: To a vigorously stirring solution of α-imino ester

1 (1 mmol, 1 equiv.) in anhydrous DMF (2 mL) was sequentially

added indium powder (1.5 mmol, 1.5 equiv.), sodium iodide

(2 mmol, 2 equiv.), and E-geranyl bromide (2d; 2 mmol, 2 equiv.).

The mixture was stirred vigorously for 12–24 h at room temp. under

a nitrogen atmosphere, then water (5–10 mL) was added. The re-

sulting reaction mixture was transferred to a separating funnel and

extracted with EtOAc (3ϫ15 mL). The combined organic layers

were dried with anhydrous Na₂SO₄, then the solvent was evapo-

rated under vacuum. Purification of the resulting crude reaction

mixture by column chromatography on neutral alumina (EtOAc/

hexane as eluent) gave the products 13 and 14 [major dia-

stereomers, see Scheme 3 for individual entries].

Procedure J. Synthesis of 19a–f by RCM of Compounds 18a–f: To

the respective compounds 18a–f (0.5 mmol, 1 equiv.) in anhydrous

CH₂Cl₂(2 mL) was added Grubb’s 2nd generation catalyst (0.05–

0.1 equiv.), and the resulting reaction mixture was stirred overnight

at room temp. After completion of the reaction as indicated by the

TLC, the reaction mixture was subjected to rotary evaporation.

Purification of the resulting crude reaction mixture by column

chromatography on silica gel (EtOAc/hexane) gave the products

19a–f (see Scheme 5 for individual entries).

(2R,3R)-Ethyl

2-[(4-Bromophenyl)amino]-3-phenylpent-4-enoate

(3a): Following the general procedure A as described above, 3a was

obtained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexane, 2:98) as a colorless solid; yield 66%; m.p.

Procedure F. Hydrogenation^[21]of N-Aryl α-Amino Esters 11e to N-

Aryl Alloisolucine Derivative 15: A dry flask containing N-aryl α-

amino ester 11e (0.5 mmol, 1 equiv.) in anhydrous THF (4 mL) was

charged with Pd-C (10 mol-%) and the contents were stirred under

89–91 °C (Hexane/EtOAc). IR (KBr): ν = 3363, 2958, 1725, 1594,

˜

1181, 700 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.32 (t, J =

H₂(1 atm) at room temp. After disappearance of starting material 6.9 Hz, 2 H), 7.26–7.19 (m, 5 H), 6.46 (d, J = 8.8 Hz, 2 H), 6.18–

(reaction monitored by TLC) the reaction mixture was filtered

through a Celite pad and rinsed with EtOAc (20 mL). The solvent

was removed by rotary evaporation and the product was purified

by column chromatography on silica gel (EtOAc/hexane) to afford

6.09 (m, 1 H), 5.22–5.17 (m, 2 H), 4.29 (t, J = 8.4 Hz, 1 H), 4.14–

4.06 (m, 2 H), 4.02 (d, J = 8.4 Hz, 1 H), 3.78 (t, J = 8.4 Hz, 1 H),

1.17 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

172.4, 145.8, 139.1, 136.6, 132.0, 128.8, 128.0, 127.3, 118.0, 115.4,

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FULL PAPER

110.3, 61.2, 61.1, 53.0, 14.2 ppm. HRMS (ESI): calcd. for

(%) = 310 (5) [M + 1]⁺, 237 (22), 236 (100), 220 (12), 192 (22), 118

C₁₉H₂₀BrNO₂Na [M + Na]⁺396.0575; found 396.0570. Along with (88). HRMS (ESI): calcd. for C₂₀H₂₃NO₂Na [M + Na]⁺332.1626;

the main product 3a, minor products such as 5a (5%), 5b (12%)

and 5c (8%) were also observed (in all other cases, only the dia-

stereoisomer 3 was isolated in pure form). See the Supporting In-

formation for the structures of 5a–c.

found 332.1626.

Ethyl (2R,3R)-2-[(4-Methoxyphenyl)amino]-3-phenylpent-4-enoate

(3d): Following the general procedure A as described above, 3d was

obtained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexanes, 3:97) as a colorless solid; yield 60%; m.p.

4-Bromo-N,N-dicinnamylaniline (5a):^[18b,24]Obtained after column

chromatography (EtOAc/hexanes, 0.5:99.5) as a colorless solid;

74–76 °C (Hexane/EtOAc). IR (KBr): ν = 3361, 2955, 1727, 1520,

˜

1238, 1187 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.29 (t, J =

8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 3 H), 6.70 (d, J = 8.9 Hz, 2 H),

6.54 (d, J = 8.9 Hz, 2 H), 6.16–6.10 (m, 1 H), 5.20–5.14 (m, 2 H),

4.24 (d, J = 7.3 Hz, 1 H), 4.10–4.04 (m, 2 H), 3.77–3.71 (m, 1 H),

3.68 (s, 3 H), 3.38 (s, 1 H), 1.14 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 173.0, 152.9, 140.9, 139.6, 137.0, 128.7,

128.0, 127.2, 117.7, 115.5, 114.8, 62.6, 60.9, 55.7, 53.2, 14.2 ppm.

MS (CI): m/z (%) = 326 (10) [M + 1]⁺, 253 (22), 252 (98), 208 (20),

134 (100), 122 (30). HRMS (ESI): calcd. for C₂₀H₂₃NO₃Na [M +

Na]⁺348.1576; found 348.1568.

yield 5%; m.p. 96–98 °C. IR (KBr): ν = 2923, 1588, 1494, 967,

˜

1

732 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.34–7.19 (m, 12 H),

6.65 (d, J = 9.0 Hz, 2 H), 6.49 (d, J = 15.9 Hz, 2 H), 6.21 (td, J₁

= 15.9, J₂= 5.0 Hz, 2 H), 4.08 (d, J = 5.0 Hz, 4 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 147.8, 136.7, 131.9, 131.4, 128.6, 127.6,

126.4, 125.2, 114.3, 108.5, 52.4 ppm. MS (CI): m/z (%) = 406 (85)

[M + 3]⁺, 404 (100) [M + 1]⁺.

4-Bromo-N-cinnamylaniline (5b):^[18b,24,25]Obtained after column

chromatography (EtOAc/hexanes, 1:99) as a colorless solid; yield

12%; m.p. 75–77 °C. IR (KBr): ν = 3401, 2926, 1591, 1492, 969,

˜

746 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.21 (m, 7 H),

6.59 (d, J = 15.9 Hz, 1 H), 6.52 (d, J = 8.8 Hz, 2 H), 6.27 (td, J₁

= 15.9, J₂= 4.4 Hz, 1 H), 3.89 (d, J = 4.4 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 147.0, 136.7, 132.0, 131.7, 128.6, 127.7,

126.4, 126.3, 114.6, 109.2, 46.1 ppm. MS (CI): m/z (%) = 288 (100)

[M + 1]⁺, 286 (90), 210 (10), 208 (13).

Ethyl

(2R,3R)-2-[(4-Chlorophenyl)amino]-3-phenylpent-4-enoate

(3e): Following the general procedure A as described above, 3e was

obtained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexane, 2:98) as a colorless solid; yield 65%; m.p.

86–87 °C (Hexane/EtOAc). IR (KBr): ν = 3364, 2960, 1726, 1602,

˜

1516, 1180, 820 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.34–7.31

1

Ethyl 2-Hydroxy-3-phenylpent-4-enoate (5c):^[26]Obtained after col-

(m, 2 H), 7.30–7.22 (m, 3 H), 7.07 (d, J = 8.9 Hz, 2 H), 6.51 (d, J

= 8.9 Hz, 2 H), 6.18–6.09 (m, 1 H), 5.23–5.18 (m, 2 H), 4.31–4.27

(m, 1 H), 4.14–4.07 (m, 2 H), 4.0 (d, J = 8.5 Hz, 1 H), 3.79 (d, J

= 8.5 Hz, 1 H), 1.17 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 172.4, 145.3, 139.1, 136.7, 129.1, 128.8, 128.0, 127.4,

123.2, 118.0, 114.9, 61.4, 61.1, 53.1, 14.2 ppm. MS (CI): m/z (%) =

330 (3) [M + 1]⁺, 258 (30), 257 (15), 256 (100), 140 (50), 138 (100).

HRMS (ESI): calcd. for C₁₉H₂₀ClNO₂Na [M + Na]⁺352.1080;

found 352.1072.

umn chromatography (EtOAc/hexanes, 4:96) as a colorless liquid;

yield 8%. IR (neat): ν = 3459, 2979, 1731, 1494, 1257 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 7.33–7.22 (m, 5 H), 6.26–6.17 (m, 1

H), 5.22 (d, J = 7.5 Hz, 1 H), 5.19 (s, 1 H), 4.50 (d, J = 4.1 Hz, 1

H), 4.13 (q, J = 7.1 Hz, 2 H), 3.77 (dd, J₁= 7.5, J₂= 4.1 Hz, 1 H),

2.69 (s, 1 H), 1.21 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 173.3, 138.3, 137.4, 128.8, 128.4, 127.3, 117.0, 74.0,

61.7, 53.4, 14.2 ppm. MS (CI): m/z (%) = 221 (35) [M + 1]⁺, 203

(60), 175 (35), 157 (37). This compound was isolated as a mixture

of diastereomers; the NMR data refer to the major isomer.

Ethyl (2R,3R)-2-[(3,4-Dimethylphenyl)amino]-3-phenylpent-4-enoate

(3f): Following the general procedure A as described above, 3f was

obtained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexane, 2:98) as a colorless solid; yield 70%; m.p.

Ethyl (2R,3R)-3-Phenyl-2-(phenylamino)pent-4-enoate (3b): Follow-

ing the general procedure A as described above, 3b was obtained

after purification by neutral alumina column chromatography

68–70 °C. IR (KBr): ν = 3353, 2919, 1722, 1617, 1518, 1320,

˜

1

1185 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.30 (t, J = 8.4 Hz,

(EtOAc/hexane, 2:98) as a colorless oil; yield 71%. IR (CH Cl ): ν

˜

2

= 3388, 2980, 1734, 1602, 1506, 1181 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 7.31 (t, J = 6.5 Hz, 2 H), 7.23 (d, J = 6.5 Hz, 3 H),

7.12 (t, J = 7.5 Hz, 2 H), 6.71 (t, J = 7.5 Hz, 1 H), 6.59 (d, J =

7.5 Hz, 2 H), 6.20–6.11 (m, 1 H), 5.22–5.16 (m, 2 H), 4.34 (t, J =

8.5 Hz, 1 H), 4.14–4.05 (m, 2 H), 4.0 (d, J = 8.5 Hz, 1 H), 3.79 (t, J

= 8.5 Hz, 1 H), 1.16 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 172.7, 146.7, 139.4, 136.9, 129.3, 128.8, 128.0, 127.3,

118.6, 117.8, 113.8, 61.3, 61.0, 53.2, 14.2 ppm. MS (CI): m/z (%) =

296 (5) [M + 1]⁺, 223 (20), 222 (100), 180 (20), 178 (22), 104 (80).

HRMS (ESI): calcd. for C₁₉H₂₁NO₂Na [M + Na]⁺318.1470; found

318.1460.

2 H), 7.24–7.20 (m, 3 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.41 (s, 1 H),

6.36 (d, J = 8.0 Hz, 1 H), 6.19–6.10 (m, 1 H), 5.21–5.15 (m, 2 H),

4.30 (d, J = 8.0 Hz, 1 H), 4.14–4.04 (m, 2 H), 3.84 (s, 1 H), 3.77

(t, J = 8.0 Hz, 1 H), 2.13 (s, 3 H), 2.10 (s, 3 H), 1.16 (t, J = 7.1 Hz,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.9, 144.8, 139.5,

137.3, 137.0, 130.3, 128.7, 128.0, 127.2, 126.6, 117.7, 115.7, 111.1,

61.5, 60.9, 53.2, 20.0, 18.7, 14.2 ppm. MS (CI): m/z (%) = 324 (5)

[M + 1]⁺, 323 (5) [M]⁺, 250 (5), 206 (100), 132 (80), 105 (20).

HRMS (ESI): calcd. for C₂₁H₂₅NO₂Na [M + Na]⁺346.1782; found

346.1769.

Ethyl (2R,3R)-2-[(3,4-Dichlorophenyl)amino]-3-phenylpent-4-enoate

(3g): Following the general procedure A as described above, 3g was

obtained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexane, 2:98) as a colorless solid; yield 57%; m.p.

Ethyl (2R,3R)-3-Phenyl-2-(p-tolylamino)pent-4-enoate (3c): Follow-

ing the general procedure A as described above, 3c was obtained

after purification by neutral alumina column chromatography

(EtOAc/hexanes, 2:98) as a colorless solid; yield 65%; m.p. 67–

70–72 °C. IR (KBr): ν = 3358, 2909, 1726, 1598, 1476, 1188,

˜

1

69 °C. IR (KBr): ν = 3359, 2911, 1724, 1619, 1524, 1181 cm^–1. H

701 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.26 (m, 2 H),

˜

NMR (400 MHz, CDCl₃): δ = 7.30 (t, J = 7.6 Hz, 2 H), 7.23 (d, J 7.25–7.18 (m, 3 H), 7.12 (d, J = 8.7 Hz, 1 H), 6.64 (d, J = 2.7 Hz,

= 7.6 Hz, 3 H), 6.93 (d, J = 8.4 Hz, 2 H), 6.51 (d, J = 8.4 Hz, 2 1 H), 6.39 (dd, J₁= 8.7, J₂= 2.7 Hz, 1 H), 6.15–6.06 (m, 1 H),

H), 6.19–6.10 (m, 1 H), 5.22–5.15 (m, 2 H), 4.30 (d, J = 7.2 Hz, 1 5.22–5.17 (m, 2 H), 4.26–4.22 (m, 1 H), 4.15–4.03 (m, 3 H), 3.76

H), 4.12–4.04 (m, 2 H), 3.88 (s, 1 H), 3.77 (t, J = 7.2 Hz, 1 H), 2.19

(t, J = 8.3 Hz, 1 H), 1.17 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR

(s, 3 H), 1.15 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, (100 MHz, CDCl₃): δ = 172.1, 146.2, 138.8, 136.4, 132.8, 130.6,

CDCl₃): δ = 173.0, 144.5, 139.5, 137.0, 129.8, 128.8, 128.0, 127.8,

127.2, 117.8, 114.0, 61.7, 60.9, 53.2, 20.4, 14.2 ppm. MS (CI): m/z

129.0, 127.9, 127.5, 121.1, 118.2, 114.9, 113.3, 61.3, 61.0, 53.0,

14.2 ppm. MS (CI): m/z (%) = 366 (65) [M + 3]⁺, 365 (25) [M +

10

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β,βЈ-Disubstituted α-Amino Acid Derivatives

2]⁺, 364 (100) [M + 1]⁺, 292 (45), 290 (70), 246 (15). HRMS (ESI):

122.7, 114.6, 61.1, 60.7, 38.7, 26.4, 25.0, 21.6, 14.3 ppm. MS (CI):

calcd. for C₁₉H₁₉Cl₂NO₂Na [M + Na]⁺386.0691; found 386.0685. m/z (%) = 296 (30) [M + 3]⁺, 295 (15) [M + 2]⁺, 294 (100) [M +

1]⁺, 280 (30), 220 (40), 212 (25). HRMS (ESI): calcd. for

Ethyl

(2R,3R)-2-(Naphthalen-1-ylamino)-3-phenylpent-4-enoate

C₁₆H₂₀ClNO₂Na [M + Na]⁺316.1080; found 316.1084.

(3h): Following the general procedure A as described above, 3h was

obtained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexane, 1:99) as a brown solid; yield 50%; m.p. 77–

Ethyl (R)-2-[(R)-Cyclohex-2-en-1-yl]-2-[(3,4-dichlorophenyl)amino]-

acetate (7c): Following the general procedure C as described above,

7c was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 3:97) as a colorless solid; yield

79 °C. IR (KBr): ν = 3419, 2979, 1732, 1582, 1528, 1483, 1179 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 7.6 Hz, 1 H), 7.64

(d, J = 7.6 Hz, 1 H), 7.43–7.23 (m, 9 H), 6.61 (d, J = 7.6 Hz, 1 H),

6.30–6.21 (m, 1 H), 5.30–5.23 (m, 2 H), 4.75 (d, J = 7.6 Hz, 1 H),

4.50 (t, J = 7.6 Hz, 1 H), 4.19–4.06 (m, 2 H), 3.96 (t, J = 7.6 Hz,

1 H), 1.16 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 172.8, 142.0, 139.4, 136.7, 134.3, 128.9, 128.6, 128.0, 127.4,

126.3, 125.8, 124.9, 123.8, 120.0, 118.6, 118.1, 105.6, 61.1, 61.1,

53.3, 14.2 ppm. MS (CI): m/z (%) = 347 (25) [M + 2]⁺, 346 (100)

[M + 1]⁺, 272 (65), 228 (15), 143 (10). HRMS (ESI): calcd. for

C₂₃H₂₃NO₂Na [M + Na]⁺368.1626; found 368.1620.

45%; m.p. 73–75 °C. IR (KBr): ν = 3356, 2932, 1724, 1599, 1476,

˜

1186, 853 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.17 (d, J =

8.7 Hz, 1 H), 6.68 (d, J = 2.7 Hz, 1 H), 6.44 (dd, J₁= 8.7, J₂

=

2.7 Hz, 1 H), 5.94–5.91 (m, 1 H), 5.61 (dd, J₁= 10.2, J₂= 1.3 Hz,

1 H), 4.20 (q, J = 7.1 Hz, 3 H), 3.88 (dd, J₁= 9.6, J₂= 5.1 Hz, 1

H), 2.69 (s, 1 H), 2.03–2.00 (m, 2 H), 1.82–1.79 (m, 2 H), 1.56–1.51

(m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 172.8, 146.8, 132.8, 131.7, 130.6, 125.3, 120.6, 114.6,

113.0, 61.3, 60.4, 38.6, 26.4, 24.9, 21.5, 14.3 ppm. MS (CI): m/z (%)

= 330 (60) [M + 3]⁺, 329 (15) [M + 2]⁺, 328 (100) [M + 1]⁺, 255

(20), 254 (37), 246 (14). HRMS (ESI): calcd. for C₁₆H₁₉Cl₂NO₂Na

[M + Na]⁺350.0691; found 350.0679.

Ethyl (2R,3R)-2-(2-Benzoylhydrazinyl)-3-phenylpent-4-enoate (3i):

Following the general procedure A as described above, 3i (major,

syn isomer) was obtained after purification by silica column

chromatography (EtOAc/hexane, 18:82) as a colorless solid; yield

Ethyl

(2R,3S)-2-[(4-Bromophenyl)amino]-3-methylpent-4-enoate

(11a): Following the general procedure D as described above, 11a

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 2:98) as a colorless liquid; yield

71%; m.p. 105–107 °C (Hexane/EtOAc). IR (KBr): ν = 3362, 2987,

˜

1726, 1664, 1463, 1202 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

7.81 (d, J = 4.8 Hz, 1 H), 7.67 (d, J = 7.1 Hz, 2 H), 7.50 (t, J =

7.1 Hz, 1 H), 7.42–7.25 (m, 7 H), 6.12–6.03 (m, 1 H), 5.18–5.12 (m,

2 H), 4.89 (s, 1 H), 4.24–4.15 (m, 3 H), 3.74 (t, J = 8.4 Hz, 1 H),

1.22 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

172.0, 167.3, 138.8, 137.2, 132.5, 132.0, 128.9, 128.7, 128.4, 127.5,

126.9, 117.3, 66.8, 61.1, 51.9, 14.2 ppm. MS (CI): m/z (%) = 340

(25) [M + 2]⁺, 339 (100) [M + 1]⁺, 290 (5), 265 (25). HRMS (ESI):

calcd. for C₂₀H₂₂N₂O₃Na [M + Na]⁺361.1528; found 361.1532.

Only a fraction of the major isomer was obtained in the pure form,

3i refers to the major (syn) isomer, which was characterized by the

X-ray structure analysis. The minor isomer could not be separated

from the major isomer.

61%. IR (neat): ν = 3387, 2979, 1731, 1595, 1502, 1193, 674 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 8.8 Hz, 2 H), 6.50

(d, J = 8.8 Hz, 2 H), 5.79–5.70 (m, 1 H), 5.15–5.09 (m, 2 H), 4.20–

4.13 (m, 3 H), 3.93 (dd, J₁= 9.5, J₂= 5.6 Hz, 1 H), 2.65 (q, J =

6.9 Hz, 1 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.14 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.5, 146.0, 138.9,

132.0, 116.7, 115.3, 110.0, 61.1, 61.0, 41.3, 16.4, 14.3 ppm. MS

(CI): m/z (%) = 313 (10) [M + 2]⁺, 311 (10) [M]⁺, 258 (100), 256

(100), 240 (10), 238 (10), 184 (75), 182 (75), 159 (10). HRMS (ESI):

calcd. for C₁₄H₁₈BrNO₂Na [M + Na]⁺334.0419; found 334.0410.

Along with the diastereomer 11a, minor products such as 9 (11%)

and 10 (5%) were also observed^[18b](In all other cases, only the

diastereomer 11 was isolated in pure form). See the Supporting

Information for the structures of 9 and 10.

Ethyl (R)-2-[(4-Bromophenyl)amino]-2-[(R)-cyclohex-2-en-1-yl]acet-

ate (7a): Following the general procedure C as described above, 7a

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 3:97) as a colorless solid; yield

4-Bromo-N,N-bis[(E)-but-2-en-1-yl]aniline (9): Obtained after puri-

fication by chromatography (EtOAc/hexanes, 0.5:99.5) as a color-

50%; m.p. 79–81 °C (EtOAc). IR (KBr): ν = 3350, 2929, 1725,

˜

1

less liquid; yield 11%; IR (neat): ν = 2917, 1593, 1503, 1225,

1594, 1516, 1487, 1184, 677 cm^–1. H NMR (400 MHz, CDCl₃): δ

˜

1

805 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.24 (d, J = 8.9 Hz, 2

= 7.22 (d, J = 8.9 Hz, 2 H), 6.48 (d, J = 8.9 Hz, 2 H), 5.92–5.89

(m, 1 H), 5.63 (dd, J₁= 10.2, J₂= 1.6 Hz, 1 H), 4.2–4.1 (m, 3 H),

3.89 (dd, J₁= 9.7, J₂= 5.2 Hz, 1 H), 2.67 (s, 1 H), 2.02–1.99 (m,

2 H), 1.81–1.78 (m, 2 H), 1.55–1.51 (m, 2 H), 1.24 (t, J = 7.1 Hz,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 146.3, 132.0,

131.4, 125.7, 115.0, 109.8, 61.1, 60.6, 38.7, 26.4, 25.0, 21.6,

14.3 ppm. MS (CI): m/z (%) = 340 (98) [M + 3]⁺, 339 (15) [M +

2]⁺, 338 (100) [M + 1]⁺, 266 (50), 264 (52), 258 (10), 182 (5). HRMS

(ESI): calcd. for C₁₆H₂₀BrNO₂Na [M + Na]⁺360.0575; found

360.0567.

H), 6.55 (d, J = 8.9 Hz, 2 H), 5.60–5.54 (m, 2 H), 5.47–5.41 (m, 2

H), 3.79 (d, J = 3.5 Hz, 4 H), 1.69 (d, J = 6.2 Hz, 6 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 147.8, 131.6, 127.3, 126.3, 113.9,

107.6, 51.9, 17.7 ppm. MS (CI): m/z (%) = 281(100) [M + 2]⁺, 279

(100) [M]⁺, 266 (20), 264 (20), 227 (80), 225 (80), 145 (40), 130 (50).

(E)-4-Bromo-N-(but-2-en-1-yl)aniline (10): Obtained after purifica-

tion by chromatography (EtOAc/hexane, 1:99) as a colorless liquid;

yield 5%; IR (neat): ν = 3400, 2925, 1593, 1490, 807 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 9.0 Hz, 2 H), 6.48 (d,

J = 9.0 Hz, 2 H), 5.75–5.66 (m, 1 H), 5.59–5.51 (m, 1 H), 3.72 (s,

1 H), 3.64 (d, J = 5.8 Hz, 2 H), 1.70 (d, J = 6.3 Hz, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 147.2, 131.9, 128.3, 127.5, 114.5,

108.9, 45.9, 17.8 ppm. MS (CI): m/z (%) = 227 (100) [M + 2]⁺, 225

(100) [M]⁺, 211 (45), 209 (45), 173 (55), 171 (55), 130 (80).

Ethyl (R)-2-[(4-Chlorophenyl)amino]-2-[(R)-cyclohex-2-en-1-yl]acet-

ate (7b): Following the general procedure C as described above, 7b

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 3:97) as a colorless solid; yield

45%; m.p. 78–80 °C. IR (KBr): ν = 3384, 2933, 1731, 1600, 1503,

˜

1179, 815 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.11 (d, J =

8.8 Hz, 2 H), 6.53 (d, J = 8.8 Hz, 2 H), 5.93–5.90 (m, 1 H), 5.64

(dd, J₁= 10.1, J₂= 1.6 Hz, 1 H), 4.21–4.10 (m, 3 H), 3.90 (dd, J₁

= 9.8, J₂= 5.2 Hz, 1 H), 2.68 (s, 1 H), 2.03–2.00 (m, 2 H), 1.83–

1.79 (m, 2 H), 1.61–1.52 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H) ppm.

Ethyl

(2R,3S)-2-[(4-Chlorophenyl)amino]-3-methylpent-4-enoate

(11b): Following the general procedure D as described above, 11b

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 2:98) as a colorless liquid; yield

60%. IR (neat): ν = 3388, 2980, 1731, 1600, 1504, 1193, 678 cm^–1.

˜

¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 145.9, 131.4, 129.1, 125.7, ¹H NMR (400 MHz, CDCl₃): δ = 7.10 (d, J = 8.9 Hz, 2 H), 6.54

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S. A. Babu et al.

FULL PAPER

(d, J = 8.9 Hz, 2 H), 5.79–5.70 (m, 1 H), 5.15–5.09 (m, 2 H), 4.20– 2]⁺, 302 (100) [M + 1]⁺, 248 (15), 246 (25), 230 (30), 230 (30), 228

4.14 (m, 3 H), 3.93 (dd, J₁= 9.5, J₂= 5.6 Hz, 1 H), 2.65 (q, J = (45), 174 (7), 172 (11). HRMS (ESI): calcd. for C₁₄H₁₇Cl₂NO₂Na

6.9 Hz, 1 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.15 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.6, 145.6, 138.9,

129.1, 123.0, 116.7, 114.8, 61.1, 61.0, 41.3, 16.4, 14.3 ppm. MS

(CI): m/z (%) = 269 (12) [M + 2]⁺, 268 (30) [M + 1]⁺, 267 (17)

[M]⁺, 214 (35), 212 (100), 194 (15), 140 (25), 138 (85). HRMS

(ESI): calcd. for C₁₄H₁₈ClNO₂Na [M + Na]⁺290.0923; found

290.0916.

[M + Na]⁺324.0534; found 324.0525.

Ethyl (2R,3S)-2-[(3,4-Dimethylphenyl)amino]-3-methylpent-4-enoate

(11g): Following the general procedure D as described above, 11g

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexanes, 2:98) as a colorless liquid; yield

48%. IR (neat): ν = 3384, 2978, 1732, 1619, 1512, 1191 cm^–1. H

1

˜

NMR (400 MHz, CDCl₃): δ = 6.90 (d, J = 8.0 Hz, 1 H), 6.45 (d,

J = 2.4 Hz, 1 H), 6.38 (dd, J₁= 8.0, J₂= 2.4 Hz, 1 H), 5.81–5.72

(m, 1 H), 5.13–5.06 (m, 2 H), 4.18–4.11 (m, 2 H), 3.99–3.91 (m, 2

H), 2.63 (q, J = 6.9 Hz, 1 H), 2.16 (s, 3 H), 2.12 (s, 3 H), 1.23 (t,

J = 7.1 Hz, 3 H), 1.14 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 173.1, 145.1, 139.3, 137.3, 130.3, 126.4,

116.3, 115.7, 111.1, 61.4, 60.8, 41.4, 20.0, 18.7, 16.5, 14.3 ppm. MS

(CI): m/z (%) = 262 (100) [M + 1]⁺, 206 (15), 188 (40), 132 (5).

HRMS (ESI): calcd. for C₁₆H₂₃NO₂Na [M + Na]⁺284.1626; found

284.1618.

Ethyl (2R,3S)-3-Methyl-2-(phenylamino)pent-4-enoate (11c): Fol-

lowing the general procedure D as described above, 11c was ob-

tained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexanes, 2:98) as a colorless liquid; yield 54%. IR

1

(CH Cl ): ν = 3387, 2979, 1732, 1603, 1505, 1191 cm^–1. H NMR

˜

2

(400 MHz, CDCl₃): δ = 7.17 (t, J = 7.3 Hz, 2 H), 6.74 (t, J =

7.3 Hz, 1 H), 6.64 (d, J = 7.3 Hz, 2 H), 5.84–5.75 (m, 1 H), 5.17–

5.10 (m, 2 H), 4.21–4.14 (m, 3 H), 4.0 (s, 1 H), 2.68 (q, J = 6.9 Hz,

1 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 172.9, 147.0, 139.2, 129.3, 118.4,

116.4, 113.7, 61.1, 60.9, 41.4, 16.5, 14.3 ppm. MS (CI): m/z (%) =

235 (10) [M + 2]⁺, 234 (65) [M + 1]⁺, 178 (30), 161 (12), 160 (100).

HRMS (ESI): calcd. for C₁₄H₁₉NO₂Na [M + Na]⁺256.1313; found

256.1301.

Ethyl

(2R,3S)-3-Methyl-2-(naphthalen-1-ylamino)pent-4-enoate

(11h): Following the general procedure D as described above, 11h

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 2:98) as a brownish red solid;

yield 40%; m.p. 89–91 °C. IR (KBr): ν = 3369, 2963, 1719, 1581,

˜

Ethyl (2R,3S)-2-[(4-Methoxyphenyl)amino]-3-methylpent-4-enoate

(11d): Following the general procedure D as described above, 11d

was obtained after purification by neutral alumina column

1

1530, 1193 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.86 (dd, J₁=

6.0, J₂= 3.3 Hz, 1 H), 7.77 (dd, J₁= 6.0, J₂= 3.3 Hz, 1 H), 7.46–

7.43 (m, 2 H), 7.31–7.24 (m, 2 H), 6.56 (d, J = 7.2 Hz, 1 H), 5.89–

5.80 (m, 1 H), 5.24–5.15 (m, 2 H), 4.95 (d, J = 8.7 Hz, 1 H), 4.21–

4.14 (m, 3 H), 2.82 (q, J = 6.9 Hz, 1 H), 1.27–1.24 (m, 6 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 172.9, 142.1, 139.2, 134.4, 128.6,

126.4, 125.8, 124.9, 123.8, 120.1, 118.3, 116.7, 105.4, 61.0, 60.8,

41.5, 16.8, 14.3 ppm. MS (CI): m/z (%) = 284 (100) [M + 1]⁺, 228

(15), 210 (40), 154 (5), 143 (10). HRMS (ESI): calcd. for

C₁₈H₂₁NO₂Na [M + Na]⁺306.1470; found 306.1460.

chromatography (EtOAc/hexanes, 3:97) as a colorless liquid; yield

1

59%. IR (neat): ν = 3375, 2979, 1732, 1514, 1240, 1037 cm^–1. H

˜

NMR (400 MHz, CDCl₃): δ = 6.75 (d, J = 8.9 Hz, 2 H), 6.60 (d,

J = 8.9 Hz, 2 H), 5.82–5.73 (m, 1 H), 5.15–5.08 (m, 2 H), 4.17–

4.11 (m, 2 H), 3.89 (s, 2 H), 3.73 (s, 3 H), 2.64 (s, 1 H), 1.22 (t, J

= 7.1 Hz, 3 H), 1.15 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 173.2, 152.8, 141.1, 139.3, 116.4, 115.4,

114.8, 62.3, 60.8, 55.7, 41.4, 16.5, 14.3 ppm. MS (CI): m/z (%) =

263 (20) [M]⁺, 208 (70), 134 (100), 77 (10). HRMS (ESI): calcd. for

C₁₅H₂₁NO₃Na [M + Na]⁺286.1419; found 286.1410.

Ethyl

(2R,3S)-2-(2-Benzoylhydrazinyl)-3-methylpent-4-enoate

(11i):^[6b,6e]Following the general procedure D as described above,

11i was obtained as a mixture of diastereomers (ds 75:25) after

purification by silica gel column chromatography (EtOAc/hexane,

Ethyl (2R,3S)-3-Methyl-2-(p-tolylamino)pent-4-enoate (11e): Fol-

lowing the general procedure D as described above, 11e was ob-

tained after purification by neutral alumina column chromatog-

raphy (EtOAc/hexane, 2:98) as a colorless liquid; yield 59%. IR

12:88) as a colorless oil; yield 65%. IR (neat): ν = 3289, 2979, 1731,

˜

1

1643, 1462, 1202 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.08 (s,

(neat): ν = 3376, 2979, 1728, 1514, 1230, 1020 cm^–1. ¹H NMR

1 H), 7.74 (d, J = 7.4 Hz, 2 H), 7.51 (t, J = 7.4 Hz, 1 H), 7.43 (t,

J = 7.4 Hz, 2 H), 6.01–5.80 (m, 1 H), 5.23–5.09 (m, 3 H), 4.29–

4.17 (m, 2 H), 3.78 (d, J = 4.0 Hz, 1 H), 2.80 (q, J = 7.0 Hz, 1 H),

1.29 (t, J = 7.1 Hz, 3 H), 1.16 (d, J = 7.0 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 172.3, 166.9, 138.9, 132.6, 131.9, 128.7,

126.9, 116.2, 66.7, 61.0, 38.8, 14.5, 14.3 ppm. MS (CI): m/z (%) =

278 (15) [M + 2]⁺, 277 (100) [M + 1]⁺, 259 (5), 203 (25). HRMS

(ESI): calcd. for C₁₅H₂₀N₂O₃Na [M + Na]⁺299.1371; found

˜

(400 MHz, CDCl₃): δ = 6.95 (d, J = 8.0 Hz, 2 H), 6.53 (d, J =

8.0 Hz, 2 H), 5.80–5.71 (m, 1 H), 5.13–5.06 (m, 2 H), 4.12 (q, J =

7.1 Hz, 2 H), 4.00 (s, 1 H), 3.92 (d, J = 5.4 Hz, 1 H), 2.63 (q, J =

6.9 Hz, 1 H), 2.20 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.13 (d, J =

6.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 144.7,

139.3, 129.8, 127.6, 116.4, 113.9, 61.5, 60.8, 41.4, 20.4, 16.5,

14.3 ppm. MS (CI): m/z (%) = 249 (16) [M + 2]⁺, 248 (100) [M +

1]⁺, 216 (55), 192 (10), 174 (6).

1

299.1365. H and ¹³C NMR spectroscopic data given here refer to

the major isomer of 11i.

Ethyl (2R,3S)-2-[(3,4-Dichlorophenyl)amino]-3-methylpent-4-enoate

(11f): Following the general procedure D as described above, 11f

was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 2:98) as a colorless liquid; yield

Methyl (2R,3S)-2-(2-Benzoylhydrazinyl)-2,3-dimethylpent-4-enoate

(11l):^[6e]Following the general procedure as described D above, 11l

was obtained as a mixture of diastereomers after purification by

silica gel column chromatography (EtOAc/hexane, 12:88) as a col-

49%. IR (neat): ν = 3401, 2980, 1731, 1599, 1494, 1133, 675 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 7.17 (d, J = 8.7 Hz, 1 H), 6.69

(d, J = 2.7 Hz, 1 H), 6.45 (dd, J₁= 8.7, J₂= 2.7 Hz, 1 H), 5.77–

orless solid; yield 63%. IR (KBr): ν = 3283, 2950, 1731, 1644, 1450,

˜

1260, 1130 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.87 (br. s, 1

5.68 (m, 1 H), 5.15–5.10 (m, 2 H), 4.25 (d, J = 9.4 Hz, 1 H), 4.18 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.44–7.33 (m, 3 H), 5.81–5.72 (m, 1

(q, J = 7.1 Hz, 2 H), 3.90 (dd, J₁= 9.4, J₂= 5.6 Hz, 1 H), 2.65 (q,

J = 6.9 Hz, 1 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.14 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.2, 146.4, 138.6,

132.8, 130.7, 120.8, 116.9, 114.8, 113.3, 61.2, 60.7, 41.2, 16.3,

14.3 ppm. MS (CI): m/z (%) = 304 (60) [M + 3]⁺, 303 (15) [M +

H), 5.11–5.03 (m, 2 H), 3.67 (s, 3 H), 2.66–2.57 (m, 1 H), 1.29 (s,

3 H), 1.03 (d, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 175.3, 166.6, 137.7, 132.8, 131.7, 128.7, 126.9, 117.7, 67.8, 52.2,

44.1, 18.7, 14.9 ppm. MS (CI): m/z (%) = 277 (100) [M + 1]⁺, 246

(1). ¹H and ¹³C NMR spectroscopic data given here refer to the

12

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β,βЈ-Disubstituted α-Amino Acid Derivatives

major diastereomer of 11l (the NMR was recorded for the mixture

purification by silica gel column chromatography (EtOAc/hexane,

of diastereomers).

2:98) as a colorless liquid; yield 80%. IR (neat): ν = 3376, 2979,

˜

1728, 1514, 1230, 1020 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

6.95 (d, J = 8.4 Hz, 2 H), 6.55 (d, J = 8.4 Hz, 2 H), 4.14 (q, J =

7.1 Hz, 2 H), 3.95 (s, 2 H), 2.21 (s, 3 H), 1.90–1.87 (m, 1 H), 1.57–

1.50 (m, 1 H), 1.31–1.26 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3 H), 0.98

(d, J = 6.9 Hz, 3 H), 0.94 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 174.1, 145.3, 129.8, 127.4, 113.9, 61.2, 60.8,

38.0, 26.2, 20.4, 15.0, 14.3, 11.8 ppm. MS (CI): m/z (%) = 251 (16)

[M + 2]⁺, 250 (100) [M + 1]⁺, 176 (10). HRMS (ESI): calcd. for

C₁₅H₂₄NO₂[M + H]⁺250. 1807; found 250.1791.

Ethyl (2R,3S)-2-(2-Benzoylhydrazinyl)-3,7-dimethyl-3-vinyloct-6-en-

oate (13): Following the general procedure E as described above,

13 was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexane, 5:95) as a colorless oil; yield 80%. IR (neat):

ν = 3295, 2975, 1730, 1638, 1447, 1192 cm^–1. H NMR (400 MHz,

1

˜

CDCl₃): δ = 7.95 (s, 1 H), 7.71 (d, J = 7.2 Hz, 2 H), 7.49 (t, J =

7.2 Hz, 1 H), 7.40 (t, J = 7.2 Hz, 2 H), 5.94–5.87 (m, 1 H), 5.17–

5.04 (m, 4 H), 4.23–4.14 (m, 2 H), 3.60 (s, 1 H), 1.98–1.92 (m, 2

H), 1.66 (s, 3 H), 1.58 (s, 3 H), 1.58–1.46 (m, 2 H), 1.24 (t, J =

7.1 Hz, 3 H), 1.20 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 172.2, 167.1, 142.1, 132.7, 131.8, 131.5, 128.6, 126.9, 124.3, 114.6,

71.2, 60.8, 42.9, 37.7, 25.7, 22.5, 19.0, 17.6, 14.2 ppm. HRMS

(ESI): calcd. for C₂₁H₃₁N₂O₃[M + H]⁺359.2335; found 359.2352.

(2R,3R)-3-Phenyl-2-(p-tolylamino)pent-4-enoic Acid (16a): Follow-

ing the general procedure G as described above, 16a was obtained

as a yellowish white solid; yield 55%; m.p. 116–118 °C. IR (KBr):

ν = 3247, 3134, 2604–2361, 1709, 1544, 1509, 1246 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃+ [D₆]DMSO): δ = 7.27 (d, J = 4.3 Hz, 4 H),

7.22–7.19 (m, 1 H), 6.99 (d, J = 8.2 Hz, 2 H), 6.84 (d, J = 8.2 Hz,

2 H), 6.22–6.16 (m, 1 H), 5.69 (br. s, 2 H), 5.28–5.19 (m, 2 H), 4.28

(d, J = 7.0 Hz, 1 H), 4.02 (t, J = 7.0 Hz, 1 H), 2.22 (s, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃+ [D₆]DMSO): δ = 177.1, 144.1,

141.1, 134.9, 134.5, 133.4, 132.9, 131.9, 128.1, 123.1, 121.8, 68.7,

56.4, 25.3 ppm. MS (CI): m/z (%) = 282 (45) [M + 1]⁺, 236 (100),

207 (10).

Ethyl (2R,3S)-2-[(4-Bromophenyl)amino]-3,7-dimethyl-3-vinyloct-6-

enoate (14a): Following the general procedure E as described above,

14a was obtained after purification by neutral alumina column

chromatography (EtOAc/hexane, 1:99) as a colorless oil; yield 55%.

IR (neat): ν = 3390, 2926, 1731, 1595, 1496, 1180, 813 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 7.22 (d, J = 8.9 Hz, 2 H), 6.49 (d,

J = 8.9 Hz, 2 H), 5.93–5.86 (m, 1 H), 5.27 (dd, J₁= 10.6, J₂

=

1.2 Hz, 1 H), 5.12 (dd, J₁= 16.2, J₂= 1.2 Hz, 1 H), 5.08–5.02 (m,

1 H), 4.16–4.10 (m, 3 H), 3.81 (d, J = 10.6 Hz, 1 H), 2.03–1.95 (m,

1 H), 1.91–1.86 (m, 1 H), 1.67 (s, 3 H), 1.58 (s, 3 H), 1.58–1.52 (m,

1 H), 1.39–1.32 (m, 1 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.16 (s, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 172.5, 146.3, 141.5,

132.0, 131.7, 124.1, 116.1, 115.3, 109.9, 64.0, 60.8, 43.6, 38.4, 25.7,

22.6, 18.9, 17.6, 14.3 ppm. HRMS (ESI): calcd. for

C₂₀H₂₈BrNO₂Na [M + Na]⁺416.1201; found 416.1183.

(2R,3R)-2-[(4-Bromophenyl)amino]-3-phenylpent-4-enoic Acid (16b):

Following the general procedure G as described above, 16b was

obtained as a colorless solid; yield 65%; m.p. 100–102 °C. IR

(KBr): ν = 3571, 3378, 3079–2549, 1713, 1595, 1502, 1273,

˜

702 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.20 (m, 7 H),

6.46 (d, J = 8.9 Hz, 2 H), 6.16–6.07 (m, 1 H), 5.23–5.18 (m, 2 H),

5.01 (br. s, 2 H), 4.29 (d, J = 7.5 Hz, 1 H), 3.82 (t, J = 7.5 Hz, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.1, 145.7, 138.7,

136.7, 132.0, 128.9, 128.1, 127.5, 118.0, 115.4, 110.5, 61.3,

52.7 ppm. MS (CI): m/z (%) = 348 (45) [M + 2]⁺, 346 (50) [M]⁺,

302 (95), 300 (100), 206 (11).

Ethyl (2R,3S)-2-[(4-Methoxyphenyl)amino]-3,7-dimethyl-3-vinyloct-

6-enoate (14b): Following the general procedure E as described

above, 14b was obtained after purification by neutral alumina col-

umn chromatography (EtOAc/hexane, 1:99) as a colorless oil; yield

1

61%. IR (neat): ν = 3397, 2927, 1731, 1514, 1240, 1039 cm^–1. H

˜

NMR (400 MHz, CDCl₃): δ = 6.74 (d, J = 8.7 Hz, 2 H), 6.59 (d,

(2R,3R)-3-Phenyl-2-(p-tolylamino)pent-4-en-1-ol (17a): Following

the general procedure H as described above, 17a was obtained after

purification by silica gel column chromatography (EtOAc/hexane,

J = 8.7 Hz, 2 H), 5.95–5.87 (m, 1 H), 5.24 (dd, J₁= 10.2, J₂

=

1.2 Hz, 1 H), 5.13–5.05 (m, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.86

(s, 1 H), 3.79 (s, 1 H), 3.72 (s, 3 H), 2.05–1.85 (m, 3 H), 1.67 (s, 3

H), 1.58 (s, 3 H), 1.41–1.32 (m, 1 H), 1.19 (t, J = 7.1 Hz, 6 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 152.7, 141.9, 141.4, 131.6,

124.3, 115.6, 115.3, 114.8, 65.4, 60.5, 55.7, 43.5, 38.5, 25.7, 22.7,

18.8, 17.6, 14.3 ppm. HRMS (ESI): calcd. for C₂₁H₃₂NO₃[M +

H]⁺346.2382; found 346.2369.

6:94) as a colorless liquid; yield 65%. IR (neat): ν = 3399, 2922,

˜

1

1616, 1519, 1039 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.34 (t,

J = 7.6 Hz, 2 H), 7.26 (m, 3 H), 7.01 (d, J = 8.2 Hz, 2 H), 6.59 (d,

J = 8.2 Hz, 2 H), 6.18–6.09 (m, 1 H), 5.23–5.19 (m, 2 H), 3.82–

3.77 (m, 2 H), 3.72–3.68 (m, 1 H), 3.64–3.60 (m, 1 H), 2.27 (s, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 140.6, 137.5,

129.9, 128.7, 128.0, 127.8, 126.9, 117.8, 114.6, 61.8, 59.5, 52.0,

20.4 ppm. MS (CI): m/z (%) = 269 (20) [M + 2]⁺, 268 (100) [M +

1]⁺, 250 (4), 236 (5), 150 (9). HRMS (ESI): calcd. for C₁₈H₂₁NONa

[M + Na]⁺290.1521; found 290.1534.

Ethyl

(2R,3S)-2-[(3,4-Dichlorophenyl)amino]-3,7-dimethyl-3-vin-

yloct-6-enoate (14c): Following the general procedure E as de-

scribed above, 14c was obtained after purification by neutral alu-

mina column chromatography (EtOAc/hexane, 1:99) as a colorless

oil; yield 55%. IR (neat): ν = 3391, 2926, 1731, 1599, 1494, 1132,

˜

(2R,3R)-3-Phenyl-2-(phenylamino)pent-4-en-1-ol (17b): Following

the general procedure H as described above, 17b was obtained after

purification by silica gel column chromatography (EtOAc/hexane,

1

678 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.17 (d, J = 8.7 Hz, 1

H), 6.70 (d, J = 2.7 Hz, 1 H), 6.45 (dd, J₁= 8.7, J₂= 2.7 Hz, 1 H),

5.93–5.86 (m, 1 H), 5.27 (dd, J₁= 10.5, J₂= 1.2 Hz, 1 H), 5.12

(dd, J₁= 17.4, J₂= 1.2 Hz, 1 H), 5.08–5.02 (m, 1 H), 4.16–4.10

(m, 3 H), 3.79 (d, J = 10.5 Hz, 1 H), 2.05–1.87 (m, 2 H), 1.68 (s, 3

H), 1.59 (s, 3 H), 1.58–1.51 (m, 1 H), 1.40–1.33 (m, 1 H), 1.26 (t,

J = 7.1 Hz, 3 H), 1.17 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 172.2, 146.8, 141.3, 132.8, 131.8, 130.7, 124.0, 120.8, 116.4,

114.8, 113.3, 63.8, 60.9, 43.6, 38.4, 25.7, 22.6, 18.9, 17.6, 14.3 ppm.

HRMS (ESI): calcd. for C₂₀H₂₇Cl₂NO₂Na [M + Na]⁺406.1317;

found 406.1307.

6:94) as a colorless liquid; yield 60%. IR (neat): ν = 3400, 2926,

˜

1600, 1503, 1316, 1040 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

7.33 (t, J = 7.2 Hz, 2 H), 7.28–7.24 (m, 3 H), 7.18 (t, J = 8.2 Hz,

2 H), 6.76 (t, J = 7.2 Hz, 1 H), 6.14 (d, J = 7.2 Hz, 2 H), 6.18–6.09

(m, 1 H), 5.23–5.19 (m, 2 H), 3.86–3.79 (m, 2 H), 3.72–3.68 (m, 1

H), 3.64 (dd, J₁= 10.9, J₂= 5.2 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 147.5, 140.5, 137.6, 129.4, 128.8, 128.0,

126.9, 118.4, 117.7, 114.3, 62.0, 59.1, 52.1 ppm. MS (CI): m/z (%)

= 255 (20) [M + 2]⁺, 254 (100) [M + 1]⁺, 236 (4), 222 (5). HRMS

(ESI): calcd. for C₁₇H₁₉NONa [M + Na]⁺276.1364; found

276.1371.

Ethyl (2R,3S)-3-Methyl-2-(p-tolylamino)pentanoate (15): Following

the general procedure F as described above, 15 was obtained after

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S. A. Babu et al.

(2R,3S)-2-[(4-Methoxyphenyl)amino]-3,7-dimethyl-3-vinyloct-6-en- J = 9.1 Hz, 2 H), 5.77–5.67 (m, 2 H), 5.16–5.03 (m, 4 H), 4.11–

FULL PAPER

1-ol (17c): Following the general procedure H as described above,

17c was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexanes, 5:95) as a colorless liquid; yield 80%. IR

4.00 (m, 5 H), 2.94–2.84 (m, 1 H), 1.19 (t, J = 7.1 Hz, 3 H), 1.00

(d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.9,

147.9, 139.4, 134.8, 131.7, 116.5, 116.4, 116.3, 110.0, 66.6, 60.6,

(neat): ν = 3399, 2925, 1620, 1513, 1239, 1041 cm^–1. ¹H NMR 48.5, 38.6, 17.2, 14.2 ppm. MS (CI): m/z (%) = 353 (95) [M + 2]⁺,

˜

(400 MHz, CDCl₃): δ = 6.75 (d, J = 9.0 Hz, 2 H), 6.65 (d, J =

9.0 Hz, 2 H), 5.84–5.77 (m, 1 H), 5.24 (dd, J₁= 9.5, J₂= 1.3 Hz,

1 H), 5.08 (dd, J₁= 16.2, J₂= 1.3 Hz, 1 H), 5.05–4.95 (m, 1 H),

3.82–3.78 (m, 1 H), 3.74 (s, 3 H), 3.40 (t, J = 9.0 Hz, 1 H), 3.31–

3.27 (m, 1 H), 1.93–1.81 (m, 2 H), 1.65 (s, 3 H), 1.55 (s, 3 H), 1.48–

1.33 (m, 2 H), 0.94 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 152.3, 143.7, 143.0, 131.6, 124.3, 115.6, 115.2, 115.0, 64.2, 62.0,

55.8, 45.0, 38.8, 25.7, 22.6, 19.4, 17.6 ppm. HRMS (ESI): calcd. for

C₁₉H₂₉NO₂Na [M + Na]⁺326.2096; found 326.2101.

352 (100) [M + 1]⁺, 274 (10), 246 (15), 172 (5).

Ethyl (2R,3S)-2-[Allyl(4-methoxyphenyl)amino]-3-methylpent-4-eno-

ate (18e): Following the general procedure I as described above,

18e was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexanes, 2.5:97.5) as a colorless liquid; yield 75%.

IR (neat): ν = 2980, 1731, 1513, 1243, 1039 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 6.86 (d, J = 9.2 Hz, 2 H), 6.79 (d, J =

9.2 Hz, 2 H), 5.78–5.67 (m, 2 H), 5.18–5.01 (m, 4 H), 4.07 (q, J =

7.1 Hz, 2 H), 4.00–3.88 (m, 3 H), 3.74 (s, 3 H), 2.91–2.81 (m, 1 H),

1.18 (t, J = 7.1 Hz, 3 H), 1.08 (d, J = 6.7 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 171.4, 152.9, 143.2, 139.9, 136.0, 118.2,

116.2, 116.0, 114.3, 68.6, 60.2, 55.5, 49.1, 38.6, 17.3, 14.3 ppm. MS

(CI): m/z (%) = 304 (100) [M + 1]⁺, 262 (4), 208 (6).

(2R,3R)-Ethyl 2-[Allyl(3,4-dimethylphenyl)amino]-3-phenylpent-4-

enoate (18a): Following the general procedure I as described above,

18a was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexanes, 1.5:98.5) as a colorless liquid; yield 81%.

1

IR (neat): ν = 2922, 1732, 1614, 1505, 1154, 1029 cm^–1. H NMR

˜

Ethyl (2R,3S)-2-[Allyl(p-tolyl)amino]-3-methylpent-4-enoate (18f):

Following the general procedure I as described above, 18f was ob-

tained after purification by silica gel column chromatography

(EtOAc/hexanes, 1.5:98.5) as a colorless liquid; yield 90%. IR

(400 MHz, CDCl₃): δ = 7.23–7.19 (m, 2 H), 7.16–7.12 (m, 3 H),

6.88 (d, J = 8.3 Hz, 1 H), 6.55 (d, J = 2.6 Hz, 1 H), 6.50 (dd, J₁=

8.3, J₂= 2.6 Hz, 1 H), 5.96–5.87 (m, 1 H), 5.39–5.30 (m, 1 H),

5.13–5.03 (m, 2 H), 4.91–4.85 (m, 2 H), 4.66 (d, J = 11.0 Hz, 1 H),

4.13 (q, J = 7.1 Hz, 2 H), 4.02 (dd, J₁= 11.0, J₂= 8.4 Hz, 1 H),

3.87–3.85 (m, 2 H), 2.15 (s, 3 H), 2.11 (s, 3 H), 1.23 (t, J = 7.1 Hz,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.5, 146.8, 139.9,

138.4, 136.7, 136.1, 129.8, 128.4, 128.3, 126.7, 126.5, 117.4, 116.9,

115.8, 113.3, 65.6, 60.6, 51.0, 48.4, 20.3, 18.7, 14.3 ppm. MS (CI):

m/z (%) = 364 (100) [M + 1]⁺, 336 (5), 206 (5).

(neat): ν = 2980, 1731, 1513, 1243, 1039 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = 7.01 (d, J = 8.4 Hz, 2 H), 6.79 (d, J = 8.4 Hz, 2 H),

5.79–5.68 (m, 2 H), 5.17–5.01 (m, 4 H), 4.09–3.94 (m, 5 H), 2.91–

2.85 (m, 1 H), 2.23 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.03 (d, J =

6.7 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.4, 146.8,

139.8, 135.7, 129.5, 127.4, 116.1, 116.0, 115.3, 67.0, 60.4, 48.5, 38.8,

20.3, 17.3, 14.3 ppm. MS (CI): m/z (%) = 289 (20) [M + 2]⁺, 288

(100) [M + 1]⁺.

Ethyl (2R,3R)-2-[Allyl(4-methoxyphenyl)amino]-3-phenylpent-4-eno-

ate (18b): Following the general procedure I as described above,

18b was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexanes, 2.5:97.5) as a colorless oil; yield 65%. IR

Ethyl

(2R,3R)-1-(3,4-Dimethylphenyl)-3-phenyl-1,2,3,6-tetra-

hydropyridine-2-carboxylate (19a): Following the general procedure

J as described above, 19a was obtained after purification by silica

gel column chromatography (EtOAc/hexanes, 2:98) as a yellow

(neat): ν = 2929, 1731, 1680, 1513, 1244, 1039 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 7.24–7.20 (m, 2 H), 7.17–7.12 (m, 3 H),

6.68 (d, J = 1.1 Hz, 4 H), 5.94–5.86 (m, 1 H), 5.39–5.29 (m, 1 H),

5.12–5.02 (m, 2 H), 4.91–4.85 (m, 2 H), 4.50 (d, J = 11.2 Hz, 1 H),

4.14 (q, J = 7.1 Hz, 2 H), 3.99 (dd, J₁= 11.2, J₂= 8.2 Hz, 1 H),

3.81 (d, J = 5.4 Hz, 2 H), 3.70 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.3, 153.1, 142.7,

140.0, 138.2, 135.9, 128.4, 128.3, 126.7, 118.9, 116.9, 116.1, 114.0,

67.5, 60.5, 55.5, 50.8, 49.0, 14.3 ppm. MS (CI): m/z (%) = 366 (100)

[M + 1]⁺, 208 (15), 163 (5).

semisolid; yield 91%. IR (neat): ν = 2922, 1732, 1615, 1512,

˜

1

1024 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.34–7.22 (m, 5 H),

7.00 (d, J = 8.3 Hz, 1 H), 6.75 (s, 1 H), 6.70 (d, J = 8.3 Hz, 1 H),

6.14 (dd, J₁= 10.3, J₂= 2.8 Hz, 1 H), 5.94 (dd, J₁= 10.3, J₂

=

1.7 Hz, 1 H), 4.74 (d, J = 6.9 Hz, 1 H), 4.13 (br. s, 1 H), 4.05 (br.

s, 2 H), 3.73–3.69 (m, 1 H), 3.54–3.49 (m, 1 H), 2.21 (s, 3 H), 2.15

(s, 3 H), 0.74 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 171.1, 147.3, 140.2, 137.3, 130.4, 128.5, 128.4, 127.2,

127.1, 126.5, 124.1, 116.0, 111.9, 60.6, 59.8, 45.6, 43.6, 20.4, 18.7,

13.7 ppm. HRMS (ESI): calcd. for C₂₂H₂₆NO₂[M + H]⁺336.1964;

found 336.1968.

Ethyl (2R,3R)-2-[Allyl(phenyl)amino]-3-phenylpent-4-enoate (18c):

Following the general procedure I as described above, 18c was ob-

tained after purification by silica gel column chromatography

(EtOAc/hexanes, 1.5:98.5) as a colorless liquid; yield 64%. IR

Ethyl (2R,3R)-1-(4-Methoxyphenyl)-3-phenyl-1,2,3,6-tetrahydropyr-

idine-2-carboxylate (19b): Following the general procedure J as de-

scribed above, 19b was obtained after purification by silica gel col-

umn chromatography (EtOAc/hexanes, 3:97) as a colorless solid;

(neat): ν = 2981, 1732, 1598, 1504, 1163, 1026 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 7.23–7.10 (m, 7 H), 6.76–6.70 (m, 3 H),

5.97–5.88 (m, 1 H), 5.42–5.34 (m, 1 H), 5.16–5.06 (m, 2 H), 4.94–

4.89 (m, 2 H), 4.74 (d, J = 11.1 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2

H), 4.07 (dd, J₁= 11.1, J₂= 8.3 Hz, 1 H), 3.92–3.89 (m, 2 H), 1.24

(t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.3,

148.6, 139.7, 138.2, 135.6, 128.7, 128.5, 128.2, 126.8, 118.3, 117.0,

116.0, 115.4, 65.3, 60.7, 50.9, 48.3, 14.3 ppm. MS (CI): m/z (%) =

336 (100) [M + 1]⁺, 262 (5), 246 (5).

yield 75%; m.p. 67–69 °C. IR (KBr): ν = 2983, 1723, 1514, 1184,

˜

1

1040 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.36–7.31 (m, 2 H),

7.29–7.25 (m, 3 H), 6.93 (d, J = 9.2 Hz, 2 H), 6.84 (d, J = 9.2 Hz,

2 H), 6.16 (dd, J₁= 10.3, J₂= 3.7 Hz, 1 H), 5.96 (dd, J₁= 10.3, J₂

= 2.2 Hz, 1 H), 4.68 (d, J = 6.9 Hz, 1 H), 4.18–3.94 (m, 3 H), 3.76

(s, 3 H), 3.73–3.65 (m, 1 H), 3.58–3.50 (m, 1 H), 0.73 (t, J = 7.1 Hz,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 153.2, 143.4,

140.1, 128.5, 128.4, 127.2, 126.4, 124.2, 116.4, 114.7, 61.6, 59.7,

55.6, 46.0, 43.7, 13.6 ppm. MS (CI): m/z (%) = 338 (100) [M +

1]⁺, 278 (7), 208 (10), 246 (10). HRMS (ESI): calcd. for C₂₁H₂₄NO₃

[M + H]⁺338.1756; found 338.1773.

Ethyl (2R,3S)-2-[Allyl(4-bromophenyl)amino]-3-methylpent-4-enoate

(18d): Following the general procedure I as described above, 18d

was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexanes, 1.5:98.5) as a colorless liquid; yield 69%.

IR (neat): ν = 2979, 1732, 1589, 1495, 1242, 1027, 670 cm^–1. ¹H

Ethyl (2R,3R)-1,3-Diphenyl-1,2,3,6-tetrahydropyridine-2-carboxyl-

ate (19c): Following the general procedure J as described above,

˜

NMR (400 MHz, CDCl₃): δ = 7.27 (d, J = 9.1 Hz, 2 H), 6.74 (d,

14

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β,βЈ-Disubstituted α-Amino Acid Derivatives

19c was obtained after purification by silica gel column chromatog-

44.3, 25.6, 23.4, 13.7 ppm. MS (CI): m/z (%) = 340 (100) [M +

raphy (EtOAc/hexanes, 2:98) as a colorless solid; yield 95%; m.p.

1]⁺, 288 (10).

83–84 °C. IR (KBr): ν = 2977, 1734, 1599, 1502, 1292, 1026 cm^–1.

˜

(2R,3S)-3-Methyl-1-(p-tolyl)-1,2,3,6-tetrahydropyridine-2-carbox-

ylic Acid (20b): Following the general procedure G as described

above, 20b was obtained (as a mixture of diastereomers, ds

¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.23 (m, 7 H), 6.94 (d, J =

8.1 Hz, 2 H), 6.81 (t, J = 8.1 Hz, 1 H), 6.16 (dd, J₁= 10.1, J₂=

2.8 Hz, 1 H), 5.97 (dd, J₁= 10.1, J₂= 2.1 Hz, 1 H), 4.79 (d, J =

6.9 Hz, 1 H), 4.13–4.02 (m, 3 H), 3.73–3.66 (m, 1 H), 3.57–3.49 (m,

1 H), 0.74 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 171.0, 149.0, 140.0, 129.3, 128.5, 128.4, 127.2, 126.3, 124.0,

119.0, 114.1, 60.2, 59.9, 45.3, 43.5, 13.6 ppm. HRMS (ESI): calcd.

for C₂₀H₂₂NO₂[M + H]⁺308.1651; found 308.1663.

80:20)^[19j]as a semisolid; yield 90%. IR (CDCl ): ν = 3543–2852,

˜

3

1714, 1518, 1215, 1037 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

9.65 (br. s, 1 H), 7.03 (d, J = 8.1 Hz, 2 H), 6.72 (d, J = 8.1 Hz, 2

H), 5.82–5.71 (m, 2 H), 4.33 (s, 1 H), 3.87–3.76 (m, 2 H), 2.87 (br.

s, 1 H), 2.23 (s, 3 H), 1.20 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 178.2, 147.9, 129.8, 127.8, 126.9, 124.0,

113.7, 60.9, 45.1, 33.3, 20.3, 17.4 ppm. MS (CI): m/z (%) = 232

(100) [M + 1]⁺, 200 (50), 188 (70), 120 (5). NMR spectroscopic

data given here refers to the major diastereomer.

Ethyl (2R,3S)-1-(4-Bromophenyl)-3-methyl-1,2,3,6-tetrahydropyr-

idine-2-carboxylate (19d): Following the general procedure J as de-

scribed above, 19d was obtained after purification by silica gel col-

umn chromatography (EtOAc/hexanes, 2:98) as an orange oil; yield

Supporting Information (see footnote on the first page of this arti-

cle): X-ray structures, copies of ¹H and ¹³C NMR spectra of all

compounds.

84%. IR (neat): ν = 2977, 1732, 1590, 1494, 1022, 692 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 7.33 (d, J = 9.2 Hz, 2 H), 6.76 (d,

J = 9.2 Hz, 2 H), 5.88 (dd, J₁= 10.2, J₂= 3.1 Hz, 1 H), 5.58 (dd,

J₁= 10.2, J₂= 2.2 Hz, 1 H), 4.51 (d, J = 6.6 Hz, 1 H), 4.08 (q, J

= 7.1 Hz, 2 H), 3.95–3.79 (m, 2 H), 2.91–2.86 (m, 1 H), 1.91–1.14

(m, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.3, 148.1,

131.9, 126.8, 123.9, 115.2, 110.6, 60.4, 59.0, 45.4, 32.0, 17.4,

14.4 ppm. MS (CI): m/z (%) = 325 (95) [M + 2]⁺, 324 (100) [M +

1]⁺, 246 (30), 172 (10). HRMS (ESI): calcd. for C₁₅H₁₉NO₂Br [M

+ H]⁺324.0599; found 324.0594.

Acknowledgments

This work was funded by the Department of Science and Technol-

ogy (DST), New Delhi (Fast Track Young Scientist Scheme). We

thank the staff of the NMR and X-ray facilities of IISER-Mohali

and Mr. K. Maheswararao for help in solving the X-ray structures.

N. A. A., V. R., and C. R. thank the Indian Institute of Science

Education and Research Mohali (IISER-M) and the Council of

Scientific and the Industrial Research (CSIR)/University Grants

Commission (UGC), New Delhi for fellowships. The authors thank

IICT-Hyderabad, CDRI-Lucknow and NIPER-Mohali for provid-

ing HRMS and LCMS data.

Ethyl (2R,3S)-1-(4-Methoxyphenyl)-3-methyl-1,2,3,6-tetrahydropyr-

idine-2-carboxylate (19e): Following the general procedure as de-

scribed above, 19e was obtained after purification by silica gel col-

umn chromatography (EtOAc/hexanes, 3:97) as a brown solid; yield

76%; m.p. 55–57 °C. IR (KBr): ν = 2961, 1727, 1514, 1171,

˜

1

1032 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.88–6.81 (m, 4 H),

5.88 (dd, J₁= 10.1, J₂= 3.1 Hz, 1 H), 5.56 (dd, J₁= 10.1, J₂

=

2.1 Hz, 1 H), 4.45 (d, J = 6.6 Hz, 1 H), 4.05 (q, J = 7.1 Hz, 2 H),

3.89–3.85 (m, 2 H), 3.75 (s, 3 H), 2.91 (br. s, 1 H), 1.16 (t, J =

7.1 Hz, 3 H), 1.11 (d, J = 7.5 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 171.7, 152.9, 143.6, 126.8, 124.4, 115.8, 114.6, 60.3,

60.1, 55.6, 46.0, 32.2, 17.4, 14.4 ppm. HRMS (ESI): calcd. for

C₁₆H₂₂NO₃[M + H]⁺276.1600; found 276.1613.

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Ethyl

(2R,3S)-3-Methyl-1-(p-tolyl)-1,2,3,6-tetrahydropyridine-2-

carboxylate (19f): Following the general procedure J as described

above, 19f was obtained after purification by silica gel column

chromatography (EtOAc/hexanes, 2:98) as a colorless oil; yield

1

60%. IR (neat): ν = 2976, 1738, 1519, 1450, 1156, 1023 cm^–1. H

˜

NMR (400 MHz, CDCl₃): δ = 7.05 (d, J = 8.6 Hz, 2 H), 6.81 (d,

J = 8.6 Hz, 2 H), 5.88 (dd, J₁= 10.1, J₂= 3.1 Hz, 1 H), 5.56 (dd,

J₁= 10.1, J₂= 2.1 Hz, 1 H), 4.53 (d, J = 6.6 Hz, 1 H), 4.06 (q, J

= 7.1 Hz, 2 H), 3.97–3.84 (m, 2 H), 2.89 (br. s, 1 H), 2.24 (s, 3 H),

1.16 (t, J = 7.1 Hz, 3 H), 1.12 (d, J = 7.6 Hz, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 171.7, 147.0, 129.8, 127.8, 126.8, 124.4,

113.9, 60.1, 59.4, 45.6, 32.1, 20.3, 17.4, 14.4 ppm. HRMS (ESI):

calcd. for C₁₆H₂₂NO₂[M + H]⁺260.1651; found 260.1663.

Ethyl (2R,3R)-1-(4-Methoxyphenyl)-3-phenylpiperidine-2-carboxyl-

ate (20a): Following the general procedure F as described above,

20a was obtained after purification by silica gel column chromatog-

raphy (EtOAc/hexanes, 4:96) as a colorless oil; yield 54%. IR

(neat): ν = 2930, 1727, 1602, 1512, 1148, 1037 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 7.24–7.13 (m, 5 H), 6.87 (d, J = 9.0 Hz, 2

H), 6.72 (d, J = 9.0 Hz, 2 H), 4.44 (d, J = 5.6 Hz, 1 H), 3.66 (s, 3

H), 3.64–3.52 (m, 3 H), 3.26–3.23 (m, 2 H), 2.30–2.19 (m, 1 H),

2.01–1.97 (m, 1 H), 1.79–1.73 (m, 1 H), 1.17 (s, 1 H), 0.62 (t, J =

7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.4, 153.6,

144.5, 141.5, 128.3, 127.8, 126.9, 118.3, 114.3, 65.6, 59.4, 55.5, 44.6,

Eur. J. Org. Chem. 0000, 0–0

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S. A. Babu et al.

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1

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16

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β,βЈ-Disubstituted α-Amino Acid Derivatives

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Received: March 2, 2012

Published Online: ᭿

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S. A. Babu et al.

FULL PAPER

Diastereoselective Allylation

N. A. Aslam, V. Rajkumar, C. Reddy,

M. Yasuda, A. Baba,

S. A. Babu* ..................................... 1–18

Indium-Mediated Addition of γ-Substi-

tuted Allylic Halides to N-Aryl α-Imino

Esters. Diastereoselective Production of

β,βЈ-Disubstituted α-Amino Acid Deriva-

tives with Two Contiguous Stereocenters

Highly diastereoselective C–C bond forma-

tion through Barbier-type indium-me-

diated addition of γ-substituted allylic hal-

ides to N-aryl α-imino and α-hydrazono es-

ters was established. Diastereoselective pro-

duction of γ,δ-unsaturated β,βЈ-disubsti-

tuted N-aryl (including N-PMP) α-amino

acid- and 2,3-disubstituted N-aryltetra-

hydropyridine derivatives bearing two con-

tiguous stereocenters was accomplished.

Keywords: Synthetic methods / Allylation /

Indium / Amino acids / Diastereoselectivity

18

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Article Doi

Indium-mediated addition of γ-substituted allylic halides to N-aryl α-imino esters: Diastereoselective production of β,β′- disubstituted α-amino acid derivatives with two contiguous stereocenters

DOI: 10.1002/ejoc.201200254

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