Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

Accepted Manuscript

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements

of N,N-diallyl allylic ammonium ylides

Thomas H. West, Stéphanie S.M. Spoehrle, Andrew D. Smith

PII:

S0040-4020(17)30097-2

10.1016/j.tet.2017.01.062

TET 28432

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 25 August 2016

Revised Date: 5 December 2016

Accepted Date: 26 January 2017

Please cite this article as: West TH, Spoehrle SSM, Smith AD, Isothiourea-catalysed chemo- and

enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides, Tetrahedron

(2017), doi: 10.1016/j.tet.2017.01.062.

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Graphical Abstract

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Isothiourea-catalysed chemo- and

enantioselective [2,3]-sigmatropic

rearrangements of N,N-diallyl allylic

ammonium ylides

Leave this area blank for abstract info.

Thomas H. West, Stéphanie S. M. Spoehrle and Andrew D. Smith

EaStCHEM, School of Chemistry, University of St Andrews, UK. KY16 9ST

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements

of N,N-diallyl allylic ammonium ylides

Thomas H. West, Stéphanie S. M. Spoehrle and Andrew D. Smith

^aEaStCHEM, School of Chemistry, University of St Andrews, UK. KY16 9ST

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

The isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangement of N,N-

diallyl allylic ammonium ylides is explored as a key part of a route to free functionalised α-

amino esters and piperidines. The [2,3]-sigmatropic rearrangement proceeds with excellent

diastereo- and enantiocontrol (>95:5 dr, up to 97% ee), with the resultant N,N-diallyl α-amino

esters undergoing either mono- or bis-N-allyl deprotection. Bis-N-allyl deprotection leads to free

α-amino esters, while the mono-deprotection strategy has been utilised in the synthesis of a

target functionalised piperidine.

Available online

Keywords:

[2,3]-rearrangement

Isothiourea catalysis

allylic ammonium ylides

enantioselective catalysis

α-amino esters

.

———

Corresponding author. Tel.: +44 (0)1334 463896; e-mail: ads10@st-andrews.ac.uk

2

Tetrahedron

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1. Introduction

N,N-diallyl substituents were considered to allow N-deprotection

under standard laboratory conditions. Sweeney and Coldham

have independently utilized N,N-diallyl groups in the synthesis of

α-amino acids, via base mediated [2,3]-rearrangement and

subsequent N-deprotection.⁹Notable previous work by Tambar

has shown that treatment of N-methyl-N-allyl amine 9 with

cinnamyl carbonate 10 in the presence of Pd₂(dba)₃·CHCl₃, P(2-

furyl)₃and Cs₂CO₃gave ammonium ylide 11, bearing a

stereogenic nitrogen.⁵[2,3]-Rearrangement of ammonium ylide

11 proceeded through the N-cinnamyl unit and the N-allyl unit,

resulting in non-chemoselective [2,3]-rearrangement to give a 4:1

mixture of N-cinnamyl rearranged product 12 and N-allyl

rearranged product 13 in a combined 78% yield (Scheme 2a).⁵

We report herein that isothiourea-mediated catalysis of N,N-

diallyl allylic ammonium ylides proceeds chemoselectively,

generating N,N-diallyl amino esters 15 with high diastereo- and

enantiocontrol that can be readily bis-deprotected to generate free

α-amino esters (Scheme 2b). Mono-N-allyl deprotection,

followed by metathesis, leads to valuable piperidine building

blocks.

[2,3]-Sigmatropic rearrangements are concerted symmetry

allowed processes that proceed through a five-membered, six-

electron transition state with an envelope conformation.

Stereoselective [2,3]-sigmatropic rearrangements have found

great utility in organic synthesis,¹with their ability to form

carbon-carbon bonds through well-defined and predictable

transition states under often mild reaction conditions making

them attractive for the synthesis of highly functionalised

molecular building blocks.²

In this context, the [2,3]-rearrangement of allylic ammonium

ylides leads to the formation of substituted α-amino acid

derivatives. Initially investigated by Ollis,³only limited variants

of this process that use a sub-stoichiometric amount of a catalyst

in the formation of the reactive ylide have been explored to

date.^1eThe most common approach utilizes an intermediate metal

carbenoid to generate the reactive ylide intermediate as shown by

Doyle (Scheme 1a),⁴yet catalytic enantioselective variants have

remained elusive.^1bIn 2011, Tambar and co-workers⁵reported

an alternative strategy in the catalytic [2,3]-rearrangements of

allylic ammonium ylides through Pd-catalysed allylic substitution

of allylic carbonates 5 with tertiary amino esters 4 and in situ

rearrangement (Scheme 1b). This process generates

functionalized α-amino esters 6 with high diastereocontrol but in

racemic form.⁵Building upon this work, we demonstrated an

isothiourea-promoted^6,7

catalytic

enantioselective

[2,3]-

rearrangement of allylic ammonium ylides, leading to a range of

α-amino acid derivatives 8 bearing either N,N-dimethyl or cyclic-

N-alkyl substituents (Scheme 1c).⁸This process allows for the

synthesis of a variety of α-amino ester derivatives and the

incorporation of pharmacological relevant amine motifs such as

the morpholine unit, although the preparation of free α-amino

esters was not possible as suitable N-substituents amenable to

facile deprotection were not incorporated.

Scheme 2: Proposed chemoselective [2,3]-rearrangement of

N,N-diallyl allylic ammonium ylides.

2. Results and Discussion

Initial Studies and Optimisation

To avoid any potential chemoselectivity issues initial studies

probed the use of N,N-dibenzyl substituents in the isothiourea-

catalysed [2,3]-rearrangement methodology. Treatment of N,N-

dibenzyl cinnamyl amine 16 with 4-nitrophenyl bromoacetate 17

resulted in no ammonium salt formation, presumably due to the

sterically hindered N,N-dibenzyl substituent. To reduce the steric

bulk around the N-substituent, an N-methyl-N-benzyl substitution

was employed 18. While the corresponding ammonium salt could

not be isolated, in situ ammonium salt formation and subsequent

[2,3]-rearrangement gave, after treatment with sodium

methoxide, N-methyl-N-benzyl-α-amino ester 20 in good yield

Scheme 1: Catalytic stereoselective [2,3]-rearrangements of

allylic ammonium ylides

In this manuscript this limitation is addressed through the

application of this methodology to N-substituents amenable to

either mono- or bis-N-deprotection. At the onset of these

investigations, the use of N,N-dibenzyl, N-methyl-N-allyl-, and

3

(76%) but modest stereocontrol (80:20 dr, 76% ee). The modest

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stereocontrol is likely to be due to the formation of a stereogenic

nitrogen within the presumed ammonium salt and (+)-BTM

bound-diastereoisomeric ammonium ylides within the [2,3]-

rearrangement step. Due to the low sterecontrol achieved with an

unsymmetrical

N,N-substituent,

symmetrical

N,N-diallyl

substitution was investigated. Treatment of N,N-diallyl cinnamyl

amine with 4-nitrophenyl bromoacetate 17 gave the

corresponding quaternary ammonium salt 21 in 50% isolated

yield (Scheme 3). Isothiourea-promoted rearrangement of 21,

followed by addition of sodium ethoxide, resulted in

chemoselective [2,3]-rearrangement to give N,N-diallyl-α-amino

ester 22 in excellent yield (91%) and good stereocontrol (92:8 dr,

87% ee).

Entry^a

1

2

Additive (mol%)

HOBt (20)

-

NBu₄OPNP (100)

HOBt (100)

Yield(%)^b

dr^c

92:8

89:11

88:12

94:6

ee (%)^d

87

91

81

77

82

76

74

97

3

4

5^e

>95:5

^aReactions performed on 0.24 mmol scale, ^bIsolated yield after flash column

chromatography, combined yield of mixture of diastereomers, ^cDetermined

by ¹H NMR of crude material, ^dDetermined by HPLC analysis on chiral

stationary phase, ^ePerformed on 2.11 mmol scale.

Table 1: Reaction additive optimization.

The relative and absolute configuration within 22 was

assigned by analogy to that previously unambiguously

determined on an N,N-dimethyl substituted analogue. This

configurational outcome is consistent with a Lewis base mediated

mechanism involving enantioselective [2,3]-rearrangement that

occurs through a BTM-bound intermediate ylide 24 via an endo-

type pre-transition state assembly such as 25. In this arrangement

the carbonyl oxygen preferentially adopts a coplanar and syn-

orientation to the S atom within the isothiouronium ion, allowing

a stabilizing electrostatic or non-bonding O-S interaction (n_Oto

σ*_C-S).^10,11The stereodirecting C(2)-phenyl unit within BTM

adopts a pseudoaxial position to minimize 1,2-steric interactions,

with rearrangement occurring anti to this substituent. A π-cation

interaction between the allylic C(3)-phenyl substituent and the

acyl ammonium ion provides an additional interaction that is

essential for high stereocontrol (Figure 1).

^aIsolated yield, ^bIsolated as a mixture of diastereoisomers, ^cDetermined by

¹H NMR analysis of crude material, ^dDetermined by HPLC analysis on chiral

stationary phase.

Scheme 3: Evaluation of alternative N-substituents.

Figure 1: Stereochemical Rationale.

Further optimisation was performed to improve the

stereocontrol of the process (Table 1). The requirement for the

HOBt co-catalyst was examined, with rearrangement in the

absence of HOBt resulting in reduced product yield and

stereocontrol (81%, 89:11 dr, 76% ee, entry 2, table 1). The use

of a stoichiometric amount of NBu₄OPNP as an additive also

resulted in a loss in both diastereo- and enantiocontrol (88:12 dr,

74% ee, entry 3). However, the use of stoichiometric HOBt as an

additive resulted in a dramatic enhancement in enantiocontrol

(82%, 94:6 dr, 97% ee, entry 4, table 1). In this process, we

postulate that HOBt aids catalyst turnover from an acyl

ammonium intermediate after [2,3]-rearrangement, although the

reason for enhanced enantiocontrol is not clear and is the subject

of ongoing mechanistic investigations. These optimized

conditions were taken forward to examine the substrate scope of

the reaction. Notably this process could be readily performed on

a reasonable laboratory scale without erosion of stereocontrol,

with 479 mg (1.60 mmol) of ethyl ester 22 (76% isolated yield)

being generated from 1.0 g of N,N-diallyl ammonium salt 21

(entry 5).

Reaction Scope and N,N-diallyl deprotection

With these optimised conditions in hand, the scope of in situ

nucleophilic derivatization was examined. The [2,3]-

rearrangement of N,N-diallyl ammonium salt 21 could be

derivatised in situ using pyrrolidine or LiAlH₄to give amide 27

and amino-alcohol 28 respectively in excellent yield and

stereocontrol (Scheme 4). However, using 100 mol% HOBt in the

catalysis followed by derivatization with benzylamine to give 29,

produced inseparable unidentified allyl-derived side products.

However, the use of a catalytic amount of HOBt (20 mol %)

allowed the isolation of benzyl amide 29 in excellent yield with

good levels of stereocontrol (92:8 dr, 84% ee).

4

Tetrahedron

ACCEPTED MANUSCRIPT

With a range of N,N-diallyl ethyl esters in hand, efforts were

turned to removal of the N,N-diallyl groups to synthesise a range

of α-amino esters. Utilising the Pd-catalysed deallylation

chemistry developed by Bernard and co-workers¹²treatment of

22

bis(diphenylphosphino)butane) (10 mol%) and thiosalicylic acid

(5.0 equiv.) in THF at 60 °C followed by aq. 1 HCl allowed

with

Pd(dba)₂

(10

mol%),

dppb

(1,4

M

facile isolation of the desired free amine 36 as its hydrochloride

salt,¹³in excellent yield and without erosion of stereochemical

purity, without the need for flash column chromatography. This

was applied to a small range of N,N-diallyl rearrangement

products 31-33 giving the desired deallylation products 37-39 in

good to excellent yield without erosion of diastereo- or

enantiopurity (Scheme 6).¹⁴The relative and absolute

configurations of the bis-deallylated products was confirmed

through derivatization of 36 to the known corresponding N-

acetamide.¹⁵

^aIsolated yield after flash column chromatography, combined yield of mixture

of diastereomers ^bDetermined by ¹H NMR of crude material, ^cDetermined by

HPLC analysis on chiral stationary phase ^dReaction performed using HOBt

(20 mol%).

Scheme 4: Scope of in situ nucleophilic derivatization.

Variation of the C(3)-substituent within the N,N-diallyl

ammonium salt 15 was next investigated. Electron-neutral and

electron-withdrawing aromatic substituents could be well

tolerated giving ethyl esters 31, 32 and 34 in excellent yield and

good to excellent stereocontrol. Incorporation of a sterically

demanding ortho-substituent in the C(3)-aryl group was well

tolerated giving 33 in good yield and stereocontrol (Scheme 5).

^aIsolated yield, ^bDetermined by ¹H NMR analysis, ^cDetermined by HPLC

analysis on chiral stationary phase after filtration through K₂CO₃plug, ^d

^cDetermined by HPLC analysis on chiral stationary phase after N-Boc

protection.

Scheme 6: Scope of N,N-deallylation of [2,3]-rearrangement

products, ^aEnantiopurity determined after N-Boc protection.

Application to piperidine synthesis

To further demonstrate the synthetic utility of this [2,3]-

rearrangement process, it was postulated that

a highly

functionalised piperdine architecture could be accessed through

selective mono-N-allyl deprotection, followed by ring-closing

metathesis and hydrogenation. Piperidine core structures are

ubiquitous among bioactive molecules,¹⁶with an analysis of

launched drugs within the integrity database showing 320

registered drugs that contain piperidines.¹⁷For example, the

piperidine motif is central to Merck’s factor XIa inhibitor 40.¹⁸

To showcase the utility of this [2,3]-rearrangement methodology

we next targeted the preparation of the (2S,3S)-piperidine 2-

carboxylate 41 that maps directly to this core structure.

^aIsolated yield after flash column chromatography, combined yield of mixture

of diastereomers ^bDetermined by ¹H NMR of crude material, ^cDetermined by

HPLC analysis on chiral stationary phase, ^dEnantiopurity determined after

N,N-deallylation and N-Boc protection.

Scheme 5: Scope of C(3)-substituent. ^aEnantiopurity

determined after N,N-deallylation and N-Boc protection.

Figure 2: Merck Factor XIa inhibitor and target (2S,3S)-

piperidine 2-carboxylate 41

5

Mono-deallylation of 22 following Bernard’s methodology,¹²

through treatment with Pd(dba)₂(10 mol %), dppb (10 mol %),

thiosalicylic acid (1.2 equiv.) in THF at 60 °C, gave 42 in modest

yield (46% yield) but with retention of diastereomeric purity.

Subsequent N-benzyl protection to give 43, followed by

treatment with Hoveyda-Grubbs 2^ndgeneration catalyst (HG-II)

(5 mol%) in the presence of p-toluenesulfonic acid¹⁹(1.5 equiv.)

in toluene at 80 °C gave ring-closed product 44 in good yield and

as a single diastereoisomer after purification. Finally, treatment

of 44 with Pd/C and H₂resulted in hydrogenation and

hydrogenolysis to give functionalised piperidine 45 in good yield

and with excellent levels of stereocontrol (>95:5 dr, 94% ee).

CO₂(s)/acetone bath, respectively. Analytical thin layer

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chromatography was performed on pre-coated aluminium plates

(Kieselgel 60 F₂₅₄silica). Plates were visualised under UV light

(254 nm) or by staining with either phosphomolybdic acid or

KMnO₄followed by heating. Flash column chromatography was

performed on Kieselgel 60 silica in the solvent system stated.

Melting points were recorded on an Electrothermal 9100 melting

point apparatus, dec refers to decomposition. Optical rotations

were measured on

a Perkin Elmer Precisely/Model-341

polarimeter operating at the sodium D line with a 100 mm path

cell at 20 °C. HPLC analyses were obtained on a Shimadzu

HPLC consisting of a DGU-20A5 degasser, LC-20AT liquid

chromatography

SIL-20AHT

autosampler,

CMB-20A

communications bus module, SPD-M20A diode array detector

and a CTO-20A column oven that allows the temperature to be

set from 25-40 °C. Separation was achieved using a Chiralcel OJ-

H, or Chiralpak AD-H, AS-H, IA, IB, and ID columns. The

columns were flushed with 40% IPA/hexane for 15 mins before

switching to the indicated solvent mixtures, as this ensured

reproducibility of chromatograms. Infrared spectra (ν_max) were

recorded on a Shimadzu IRAffinity-1 Fourier transform IR

spectrophotometer using either thin film or solid using Pike

MIRacle ATR accessory. Analysis was carried out using

Shimadzu IRsolution v1.50 and only characteristic peaks are

reported. ¹H, ¹³C{¹H}, ¹⁹F{¹H} and ¹⁹F NMR spectra were

acquired on either a Bruker Avance 300 {δ_H(300 MHz), δ_C(75

MHz), δ_F(282 MHz)}, a Bruker Avance II 400 {δ_H(400 MHz),

δ_C(100 MHz), δ_F(376 MHz)}, a Bruker Ultrashield 500 {δ_H(500

MHz), δ_C(126 MHz), δ_F(471 MHz)}, a Bruker Ascend 400 {δ_H

400 MHz, δ_C(100 MHz), δ_F(471 MHz)} or a Bruker Avace III

700 {δ_H(700 MHz), δ_C(179 MHz), δ_F(659 MHz)} spectrometer

at ambient temperature (unless otherwise stated) in the deuterated

solvent stated. Chemical shifts, δ, are quoted in parts per million

(ppm) and are referenced to the residual solvent peak. Coupling

constants, J, are quoted in Hertz (Hz) to the nearest 0.1 Hz. The

following abbreviations are used: s, singlet; d, doublet; t, triplet;

q, quartet; dd, doublet of doublets; ddd, doublet of doublet of

doublets; dt, doublet of triplets; ddt, doublet of doublets of

triplets; dtt, doublet of triplets of triplets; dq, doublet of quartets;

td, triplet of doublets; tdd, triplet of triplets of doublets; tt, triplet

of triplets; m, multiplet; br, broad; and apt, apparent. Mass

spectrometry (HRMS) data were acquired by electrospray

ionisation (ESI), electron impact (EI), chemical ionisation (CI),

atmospheric pressure chemical ionisation (APCI) or nanospray

ionisation (NSI) at the EPSRC UK National Mass Spectrometry

Facility at Swansea University.

^aIsolated yield, ^bDetermined by ¹H NMR analysis after flash coloumn

chromatography, ^cDetermined by HPLC analysis on chiral stationary phase.

Scheme 7: Mono-N-deallylation and synthesis of a target

functionalized (2S,3S) piperidine motif.

3. Conclusions

The

isothiourea-catalysed

enantioselective

[2,3]-

rearrangement of N,N-diallyl cinnamic ammonium ylides

proceeds chemoselectivity and with excellent enantioselectivity.

The use of stoichiometric HOBt allowed excellent levels of

diastereo- and enantiocontrol to be achieved (up to >95:5 dr, up

to 97% ee). The substrate scope of this process has been

examined across a small number of different aryl and nucleophile

variations. The N,N-diallyl substituents can be readily removed to

generate the parent free α-amino ester, and this methodology has

been applied to the synthesis of a functionalised target piperdine

motif.

Isothiourea Catalysts; (+)-BTM and (±)-BTM were synthesised

according to literature procedures.²⁰Allylic Alcohols 4-

nitrocinnamyl

alcohol,

4-bromocinnamyl

alcohol,

2-

bromocinnamyl alcohol and 4-fluorocinnamyl alcohol were

synthesised according to previously reported procedure.⁶

Authentic racemic samples of the [2,3]-rearrangement products

22, 27-29 and 31-34 were synthesised using (±)-BTM.

(E)-N,N-Dibenzyl-3-phenylprop-2-en-1-amine 16

4. Experimental Section

A solution of N,N-dibenzylamine (6.1 mL, 31.7 mmol, 2.5

equiv.) in THF (12.5 mL) was treated dropwise with a solution of

cinnamyl bromide (2.5 g, 12.7 mmol, 1.0 equiv.) in THF (26 mL)

over 10 mins at rt. The resulting mixture for stirred for 16 h, aq. 1

Reactions were performed in flame-dried glassware under an N₂

atmosphere unless otherwise stated. Anhydrous CH₂Cl₂and Et₂O

were obtained from an MBraun SPS-800 system, MeCN was

HPLC grade stored over 4 Å MS. All other solvents and

commercial reagents were used as received without further

purification unless otherwise stated. Room temperature (rt) refers

to 20-25 °C. Temperatures of 0 °C, −20 °C and −78 °C were

obtained using ice/water bath, an immersion cooler and

M

NaOH (30 mL) was added and the mixture stirred for a further

5 min, Et₂O (30 mL) was then added, the layers separated and the

aqueous layer extracted with Et₂O (2 × 50 mL). The combined

organic layers were washed with brine (50 mL) dried over

6

Tetrahedron

MgSO₄and concentrated in vacuo, the resulting residue was

128.9 (ArCH), 138.8 (C(4)H), 139.4 (ArC), 141.1 (ArC), 170.6

ACCEPTED MANUSCRIPT

purified by flash column chromatography (5-20% EtOAc/PE) to

give the title product as a yellow oil (4.23 g, quant., >98:2 E:Z);

¹H NMR (500 MHz, CDCl₃) δ_H3.24 (2H, dd, J 6.5, 1.5, C(1)H₂),

3.64 (4H, s, PhCH₂), 6.24-6.38 (1H, m, C(2)H), 6.54 (1H, d, J

16.0, C(3)H), 7.14-7.49 (15H, m, ArH); data consistent with

literature.²¹

(C=O); HRMS (ESI⁺) C₂₀H₂₄O₂N⁺[M+H]⁺found: 310.1794,

requires: 310.1802 (−2.6 ppm).

General Procedure A: Synthesis of N,N-diallylamines from

Allylic Alcohols

A solution of allylic alcohol (1.0 equiv.) in Et₂O (0.33

M) was

(E)-N-Benzyl-N-methyl-3-phenylprop-2-en-1-amine 18

cooled to 0 °C and treated with PBr₃(0.4 equiv.) and stirred for 1

h, the reaction was quenched by the dropwise addition of aq. sat.

NaHCO₃(equal volume), the mixture was allowed to warm to rt.

The layers were then separated, the aqueous layer extracted with

Et₂O (2 × equal volume), the combined organic layers washed

with brine, dried over MgSO₄and concentrated in vacuo. The

A solution of N-benzyl-N-methylamine (8.2 mL, 63.5 mmol, 2.5

equiv.) in THF (26 mL) was treated dropwise with a solution of

cinnamyl bromide (5.0 g, 25.4 mmol, 1.0 equiv.) in THF (50 mL)

over 10 mins at rt. The resulting mixture was stirred for a further

15 mins, aq. 1

M

NaOH (50 mL) added and the mixture stirred

residue was dissolved in THF (0.5

diallylamine (2.5 equiv.) in THF (2.5

M

) and added to N,N-

for a further 5 min, Et₂O (50 mL) was then added, the layers

separated and the aqueous layer extracted with Et₂O (2 × 50 mL).

The combined organic layers were washed with brine (50 mL)

dried over MgSO₄and concentrated in vacuo, the resulting

residue was purified by flash column chromatography (5-20%

EtOAc/PE) to give the title product as an orange oil (5.2 g, 86%,

M with respect to N,N-

diallylamine) via dropping funnel , upon completion the dropping

funnel was rinsed with THF (half volume) and the reaction was

stirred at rt for 15 min. The reaction was treated with aq. 1 M

NaOH (equal volume) and stirred for 15 min, then Et₂O (equal

volume) was added, the layers separated and the aqueous layer

extracted with Et₂O (2 × equal volume). The combined organic

layers were washed with brine, dried over MgSO₄then

concentrated in vacuo, N,N-diallyl allylic amines were used

without further purification.

1

98:2 E:Z); H NMR (500 MHz, CDCl₃) δ_H2.28 (3H, s, NCH₃),

3.23 (2H, dd, J 6.7, 1.5, C(1)H₂), 3.58 (2H, s, PhCH₂), 6.36 (1H,

dt, J 15.9, 6.7, C(2)H), 6.57 (1H, dd, J 15.9, 1.5, C(3)H), 7.20-

7.47 (10H, m, ArH); data consistent with literature.²²

Methyl

(2S,3S)-2-(benzyl(methyl)amino)-3-phenylpent-4-

General Procedure B: Synthesis of N,N diallyl allylic

enoate 20

ammonium salts

A solution of 4-nitrophenyl-2-bromoacetate (63 mg, 0.24 mmol,

1.0 equiv.) and (E)-N-Benzyl-N-methyl-3-phenylprop-2-en-1-

amine (60 mg, 0.252 mmol, 1.05 equiv.) in MeCN (1.75 mL) was

stirred for 24 h at rt, then cooled to −20 °C and a solution of (+)-

BTM (12 mg, 0.048 mmol, 0.2 equiv.), HOBt (6.4 mg, 0.048

mmol, 0.2 equiv.) and iPr₂NH (47 µL, 0.34 mmol, 1.4 equiv.) in

MeCN (1.75 mL) was added and the reaction sitrred for 24 h at

A solution of N,N-diallyl amine (1.0 equiv.) in MeCN (1 M) was

treated with 4-nitrophenyl bromoacetate (1.2 equiv.) and the

reaction mixture was stirred for 16 h. Et₂O (5 × volume) was

added and the mixture stirred for 1-16 h, the precipitate was

filtered and dried in vacuo to give the salts. Ammonium salts

were used directly or recrystallized from MeCN/Et₂O if required.

−20 °C, then quenched with NaOMe (1

0.72 mmol, 3.0 equiv.) and stirred at rt for 1 h. Aq. 1

(10 mL) was added and the mixture extracted with CH₂Cl₂(3 ×

20 mL), the combined organic layers were washed with aq. 1

M

in MeOH, 0.72 mL,

Amine Synthesis

M

NaOH

(E)-N,N-Diallyl-3-phenylprop-2-en-1-amine 46

M

NaOH (2 × 20 mL), then brine (20 mL), dried over MgSO₄and

concentration in vacuo. Crude dr 80:20, the residue was purified

by flash column chromatography (5% EtOAc/PE) to give the title

product as a colourless oil (56 mg, 76%, 80:20 dr); Chiralpak OJ-

H (0.5% IPA/hexane, flow rate 1.5 mL/min, 211 nm, 40 °C) t_R

Major 9.5 min, Minor 6.9 min, 76% ee; [α]^ꢁ_ꢀ^ꢂ−5.7 (c 1, CHCl₃);

υ_max(film, cm⁻¹) 2949, 1728, 1452, 1254, 1190, 1146, 1026, 984,

A solution of cinnamyl bromide (25.0 g, 126.9 mmol, 1.0 equiv.)

in THF (250 mL) was added dropwise to a solution of N,N-

diallylamine (39.1 mL, 317.0 mmol, 2.5 equiv.) in THF (125 mL)

dropwise over 10 min at rt. The resulting solution was stirred at rt

for a further 15 min. aq. 1

M NaOH (200 mL) was then added and

the mixture stirred for a further 5 min, Et₂O (200 mL) was then

added, the layers separated and the aqueous layer extracted with

Et₂O (2 × 200 mL). The combined organic layers were washed

with brine (200 mL) dried over MgSO₄and concentrated in

vacuo, the resulting residue was purified by high vacuum

distillation to give the title product as a colourless liquid (25.2 g,

93%); bp 136-138 °C @ 1mmbar; υ_max(film, cm⁻¹) 2800, 1641,

1494, 1448, 1417, 1352, 1119, 995, 964, 916, 873; ¹H NMR (500

MHz, CDCl₃) δ_H3.17 (4H, d, J 6.5, diallyl-C(1)H₂), 3.28 (2H, d,

J 6.7, C(1)H₂), 5.13-5.27 (4H, m, diallyl-C(3)H₂), 5.92 (2H, ddt,

J 16.8, 10.2, 6.5, diallyl-C(2)H), 6.29 (1H, dt, J 15.8, 6.7,

C(2)H), 6.54 (1H, d, J 15.8, C(3)H), 7.22-7.44 (5H, m, ArH);

¹³C{¹H} NMR (75 MHz, CDCl₃) δ_C55.8 (C(1)H₂), 56.6 (diallyl-

C(1)H₂), 117.7 (diallyl-C(5)H₂), 126.3 (ArC(2,6)H), 127.3

(ArC(4)H), 127.4 (C(2)H), 128.6 (ArC(3,5)H), 132.7 (C(3)H),

135.6 (diallyl-C(2)H), 137.1 (ArC(1)); HRMS (ESI⁺) C₁₅H₂₀N⁺

[M+H]⁺found: 214.1590, requires: 214.1590 (−0.1 ppm).

1

918; Major (Syn) diastereoisomer; H NMR (500 MHz, CDCl₃)

δ_H2.15 (3H, s, NCH₃), 3.39 (1H, d, J 13.7, PhCHH), 3.70 (1H, d,

J 11.8, C(2)H), 3.75 (1H, d, J 13.7, PhCHH), 3.77 (3H, s, OCH₃),

3.87 (1H, dd, J 11.8, 8.3, C(3)H), 4.94-5.12 (2H, m, C(5)H₂),

5.85 (1H, ddd, J 17.1, 10.2, 8.3, C(4)H), 6.69-6.86 (2H, m, ArH),

7.10-7.21 (5H, m, ArH), 7.22-7.40 (3H, m, ArH); ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ_C38.1 (NCH₃), 50.2 (C(3)H), 51.0 (C(2)H),

58.2 (PhCH₂), 69.4 (OCH₃), 116.7 (C(5)H₂), 126.6 (ArCH),

126.9 (ArCH), 128.1 (ArCH), 128.5 (ArCH), 128.5 (ArCH),

128.7 (ArCH), 138.8 (C(4)H), 139.2 (ArC), 140.7 (ArC), 171.4

(C=O); Minor (Anti) diastereoisomer; ¹H NMR (500 MHz,

CDCl₃) δ_H2.29 (3H, s, NCH₃), 3.48 (3H, s, OCH₃), 3.51 (1H, d, J

13.6, PhCHH), 3.68 (1H, d, J 11.6, C(2)H)), 3.75 (1H, d, J 13.6

PhCHH), 3.83-3.94 (1H, m, C(3)H), 5.04-5.10 (2H, m, C(5)H₂),

6.20 (1H, ddd, J 17.2, 10.2, 8.2, C(4)H), 6.69-6.86 (2H, m, ArH),

7.10-7.21 (5H, m, ArH), 7.22-7.40 (3H, m, ArH); ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ_C38.1 (NCH₃), 49.6 (C(3)H), 50.8 (C(2)H),

58.3 (PhCH₂), 70.5 (OCH₃), 116.1 (C(5)H₂), 126.9 (ArCH),

127.1 (ArCH), 128.4 (ArCH), 128.4 (ArCH), 128.7 (ArCH),

(E)-N,N-diallyl-3-(4-nitrophenyl)prop-2-en-1-amine 47

7

Following general procedure A, 4-nitrocinnamyl alcohol (2.86 g,

15.98 mmol, 1.0 equiv.) was reacted with PBr₃(601 µL, 6.39

mmol, 0.4 equiv.) in Et₂O (48 mL), then with N,N-diallylamine

(4.93 mL, 40 mmol, 2.5 equiv.) in THF (32 mL) to give the title

product as an orange oil (2.63 g, 64%) was used without further

purification; υ_max(film, cm⁻¹) 2978, 1595, 1512, 1339, 1109, 968,

used without further purification; υ_max(film, cm⁻¹) 2918, 2803,

1

ACCEPTED MANUSCRIPT

1603, 1508, 1227, 1157, 1119, 966, 917, 841; H NMR (400

MHz, CDCl₃) δ_H3.13 (4H, dt, J 6.5, 1.3, diallyl-C(1)H₂), 3.23

(2H, dd, J 6.7, 1.4, C(1)H₂), 5.12-5.28 (4H, m, diallyl-C(3)H₂),

5.88 (2H, ddt, J 16.8, 10.2, 6.5, diallyl-C(2)H), 6.17 (1H, dt, J

15.8, 6.7, C(2)H), 6.47 (1H, dt, J 15.8, 1.4, C(2)H), 6.89-7.07

(2H, m, Ar(3,5)H), 7.28-7.37 (2H, m, Ar(2,6)H); ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ_F−114.9 (ArF); ¹³C{¹H} NMR (100 Mz,

CDCl₃) δ_C55.7 (C(1)H₂), 56.6 (diallyl-C(1)H₂), 115.4 (d, J_CF

21.5, ArC(3,5)H), 117.9 (diallyl-C(3)H₂), 127.0 (C(2)H), 127.7

(d, J_CF7.8, ArC(2,6)H), 131.5 (C(3)H), 131.9 (d, J_CF2.9,

1

918, 858; H NMR (400 MHz, CDCl₃) δ_H3.14 (4H, d, J 6.5,

diallyl-C(1)H₂), 3.28 (2H, dd, J 6.3, 1.4, C(1)H₂), 5.12-5.25 (4H,

m, diallyl-C(3)H₂), 5.88 (2H, ddt, J 16.8, 10.2, 6.5, diallyl-

C(2)H), 6.45 (1H, dt, J 15.9, 6.3, C(2)H), 6.59 (1H, d, J 15.9,

C(3)H), 7.48 (2H, d, J 8.8, Ar(2,6)H), 8.17 (2H, d, J 8.8,

Ar(3,5)H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ_C55.5 (C(1)H₂),

56.8 (diallyl-C(1)H₂), 117.9 (diallyl-C(3)H₂), 124.0 (ArC(3,5)H),

126.7 (ArC(2,6)H), 130.3 (C(2)H), 133.1 (C(3)H, 135.3 (diallyl-

C(2)H), 143.6 (ArC(1)), 146.8 (ArC(4)-NO₂); HRMS (ESI⁺)

2

3

4

1

ArC(1)), 135.4 (diallyl-C(2)H), 162.2 (d, J_CF247, ArC(4)-F);

HRMS (ESI⁺) C₁₅H₁₉NF⁺[M+H]⁺found: 232.1494, requires:

232.1502 (−3.5 ppm).

+

C₁₅H₁₉O₂N₂[M+H]⁺found: 259.1440, requires: 259.1447 (−2.7

(E)-N,N-Diallyl-N-(2-(4-nitrophenoxy)-2-oxoethyl)-3-

ppm).

phenylprop-2-en-1-ammonium bromide 21

(E)-N,N-diallyl-3-(4-bromophenyl)prop-2-en-1-amine 48

Following general procedure B: (E)-N,N-diallyl-3-(phenyl)prop-

2-en-1-amine (5.0 g, 23.47 mmol, 1.0 equiv.) was reacted with 4-

nitrophenyl bromoacetate (7.32 g, 28.17 mmol, 1.2 equiv.) in

MeCN (23.5 mL) to give the title product as a white solid (5.54

g, 50%); mp 128 °C (dec.); υ_max(film, cm⁻¹) 2945, 1771, 1616,

Following general procedure A, 4-bromocinnamyl alcohol (1.62

g, 7.59 mmol, 1.0 equiv.) was reacted with PBr₃(286 µL, 3.04

mmol, 0.4 equiv.) in Et₂O (24 mL), then with N,N-diallylamine

(2.53 mL, 18.97 mmol, 2.5 equiv.) in THF (16 mL) to give the

title product as a pale yellow oil (0.99 g, 45%) was used without

further purification; υ_max(film, cm⁻¹) 2976, 1487, 1400, 1072,

1

1591, 1528, 1452, 1346, 1996, 166, 1142, 988, 937, 883; H

NMR (500 MHz, d₆-DMSO) δ_H4.27 (4H, d, J 7.3, diallyl-

C(1)H₂), 4.37 (2H, d, J 7.4, C(1)H₂), 4.73 (2H, s, COCH₂), 5.57-

5.89 (4H, m, diallyl-C(3)H₂), 6.24 (2H, ddt, J 17.3, 10.0, 7.3,

diallyl-C(2)H), 6.60 (1H, dt, J 15.5, 7.4, C(2)H), 7.03 (1H, d, J

15.5, C(3)H), 7.34-7.46 (3H, m, ArH), 7.49 (2H, d, J 9.1,

Ar(3,5)H), 7.56-7.68 (2H, m, ArH), 8.37 (2H, d, J 9.1,

Ar(2,6)H); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ_C56.2

(COCH₂), 62.3 (diallyl-C(1)H₂), 62.5 (C(1)H₂), 115.7 (C(2)H),

123.0 (ArC(2,6)H), 125.4 (ArC(3,5)H), 125.6 (diallyl-C(3)H₂),

1

1009, 968, 918; H NMR (400 MHz, CDCl₃) δ_H3.12 (4H, dt, J

6.5, 1.3, diallyl-C(1)H₂), 3.22 (2H, dd, J 6.6, 1.4, C(1)H₂), 5.09-

5.25 (4H, m, diallyl-C(3)H₂), 5.87 (2H, ddt, J 16.8, 10.2, 6.5,

diallyl-C(2)H), 6.25 (1H, dt, J 15.9, 6.6, C(2)H), 6.45 (dt, J 15.9,

1.4, C(3)H), 7.23 (2H, d, J 8.5, Ar(2,6)H), 7.42 (2H, d, J 8.5,

Ar(3,5)H); ¹³C{¹H} NMR (100 Mz, CDCl₃) δ_C55.8 (C(1)H₂),

56.8 (diallyl-C(1)H₂), 117.9 (diallyl-C(3)H₂), 121.2 (ArC(4)-Br),

127.9 (ArC(2,6)H), 128.5 (C(2)H), 131.5 (C(3)H), 131.8

(ArC(3,5)H), 135.6 (diallyl-C(2)H), 136.2 (ArC(1)); HRMS

(ESI⁺) C₁₅H₁₉N⁷⁹Br⁺[M+H]⁺found: 292.0694, requires:

292.0701 (−2.4 ppm).

127.4

(C(3)ArC(2,6)H),

128.6

(diallyl-C(2)H),

128.8

(C(3)ArC(3,5)H), 129.2 (C(3)ArC(4)H), 135.1 (C(3)ArC(1)),

141.6 (C(3)H), 145.7 (ArC(1)-O), 153.7 (ArC(4)-NO₂), 163.3

+

(C=O); HRMS (ESI⁺) C₂₃H₂₅O₄N₂[M]⁺found: 393.1801,

requires: 393.1809 (−2.0 ppm).

(E)-N,N-diallyl-3-(2-bromophenyl)prop-2-en-1-amine 49

(E)-N,N-Diallyl-N-(2-(4-nitrophenoxy)-2-oxoethyl)-3-(4-

Following general procedure A, 2-bromocinnamyl alcohol (1.36

g, 6.37 mmol, 1.0 equiv.) was reacted with PBr₃(240 µL, 2.55

mmol, 0.4 equiv.) in Et₂O (20 mL), then with N,N-diallylamine

(1.96 mL, 15.93 mmol, 2.5 equiv.) in THF (13 mL) to give the

title product as a pale yellow oil (1.10 g, 59%) was used without

further purification; υ_max(film, cm⁻¹) 2976, 1643, 1466, 1435,

nitrophenyl)prop-2-en-1-ammonium bromide 51

Following general procedure B: (E)-N,N-diallyl-3-(4-

nitrophenyl)prop-2-en-1-amine (1.0 g, 3.88 mmol, 1.0 equiv.)

was reacted with 4-nitrophenyl bromoacetate (1.21 g, 4.66 mmol,

1.2 equiv.) in MeCN (4 mL) to give the title product as a white

solid (0.55 g, 28%) after recrystallization from MeCN; mp 142

°C (dec.); υ_max(film, cm⁻¹) 2945, 1773, 1593, 1516, 1452, 1343,

1197, 1167, 1069, 1012, 951, 880; ¹H NMR (500 MHz, d₆-

DMSO) δ_H4.30 (4H, d, J 7.3, diallyl-C(1)H₂), 4.43 (2H, d, J 7.4,

C(1)H₂), 4.77 (2H, s, COCH₂), 5.71-5.84 (4H, m, diallyl-C(3)H₂),

6.24 (2H, ddt, diallyl-C(2)H), 6.87 (1H, dt, J 15.5, 7.4, C(2)H),

7.17 (1H, d, J 15.5, C(3)H), 7.51 (2H, d, J 9.1, Ar(2,6)H), 7.92

(2H, d, J 8.9, C(3)Ar(2,6)H), 8.29 (2H, d, J 8.9, C(3)Ar(3,5)H),

8.38 (2H, d, J 9.1, Ar(3,5)H); ¹³C{¹H} NMR (126 MHz, d₆-

DMSO) δ_C56.3 (COCH₂), 61.9 (C(1)H₂), 62.5 (diallyl-C(1)H₂),

120.9 (C(2)H), 123.0 (ArC(2,6)H), 123.9 (ArC(3,5)H), 125.3

(diallyl-C(2)H), 125.6 (ArC(3,5)H), 128.5 (ArC(2,6)H), 128.8

(diallyl-C(3)H₂), 139.1 (C(3)H), 141.7 (C(3)ArC(4)-NO₂), 145.7

(ArC(1)-O), 147.4 (C(3)ArC(1)), 153.7 (ArC(4)-NO₂), 163.2

1

1256, 1113, 1047, 1022, 966, 918; H NMR (400 MHz, CDCl₃)

δ_H3.15 (4H, dt, J 6.5, 1.3, diallyl-C(1)H₂), 3.29 (2H, dd, J 6.7,

1.5, C(1)H₂), 5.11-5.27 (4H, m, diallyl-C(3)H₂), 5.89 (2H, ddt, J

16.8, 10.2, 6.5, diallyl-C(2)H), 6.19 (1H, dt, J 15.8, 6.7, C(2)H),

6.86 (1H, d, J 15.8, C(3)H), 7.08 (1H, td, J 7.7, 1.6, Ar(6)H),

7.19-7.32 (1H, m, Ar(5)H), 7.53 (2H, td, J 8.0, 1.6, Ar(3,4)H);

¹³C{¹H} NMR (100 Mz, CDCl₃) δ_C55.7 (C(1)H₂), 56.7 (diallyl-

C(1)H₂), 118.0 (diallyl-C(3)H₂), 123.5 (ArC(2)-Br), 127.2

(ArC(4)H), 127.6 (ArC(5)H), 128.8 (ArC(6)H), 130.6 (C(2)H),

131.6 (C(2)H), 133.0 (ArC(3)H), 135.6 (diallyl-C(2)H), 137.2

(ArC(1)); HRMS (ESI⁺) C₁₅H₁₉N⁷⁹Br⁺[M+H]⁺found: 292.0694,

requires: 292.0701 (−2.4 ppm).

(E)-N,N-diallyl-3-(4-fluorophenyl)prop-2-en-1-amine 50

+

(C=O); HRMS (ESI⁺) C₂₃H₂₄O₆N₃[M]⁺found: 438.1651,

Following general procedure A, 4-fluorocinnamyl alcohol (1.36

g, 6.37 mmol, 1.0 equiv.) was reacted with PBr₃(240 µL, 2.55

mmol, 0.4 equiv.) in Et₂O (20 mL), then with N,N-diallylamine

(1.96 mL, 15.93 mmol, 2.5 equiv.) in THF (13 mL) to give the

title product as a pale yellow oil (1.10 g, 59%, 96:4 E:Z) was

requires: 438.1660 (−2.1 ppm).

(E)-N,N-Diallyl-3-(2-bromophenyl)-N-(2-(4-nitrophenoxy)-2-

oxoethyl)prop-2-en-1-ammonium bromide 52

8

Tetrahedron

Following general procedure B: (E)-N,N-diallyl-3-(2-

(ArC(2,6)H), 131.7 (ArC(3,5)H), 134.4 (C(3)ArC(1)), 140.2

ACCEPTED MANUSCRIPT

bromophenyl)prop-2-en-1-amine (1.1 g, 3.77 mmol, 1.0 equiv.)

was reacted with 4-nitrophenyl bromoacetate (1.18 g, 4.53 mmol,

1.2 equiv.) in MeCN (4 mL) to give the title product as a white

solid (0.80 g, 39%) after recrystallization from MeCN; mp 98 °C

(dec.); υ_max(film, cm⁻¹) 2954, 1773, 1525, 1348, 1201, 1168,

(C(3)H), 145.7 (ArC(1)-O), 153.7 (ArC(4)-NO₂), 163.3 (C=O);

HRMS (ESI⁺) C₂₃H₂₄O₄N₂₇₉Br⁺[M]⁺found: 471.0904, requires:

471.0914 (−2.1 ppm).

[2,3]-Rearrangement Products

1

1066, 1022, 943, 858; H NMR (400 MHz, d₆-DMSO) δ_H4.31

(4H, d, J 7.2, diallyl-C(1)H₂), 4.46 (2H, d, J 7.4, C(1)H₂), 4.79

(2H, s, COCH₂), 5.65.-5.84 (4H, m, diallyl-C(3)H₂), 6.24 (2H,

ddd, J 17.0, 9.8, 5.3, diallyl-C(2)H), 6.62 (1H, dt, J 15.3, 7.4,

C(2)H), 7.24 (1H, d, J 15.3, C(3)H), 7.33 (1H, t, J 7.6, Ar(4)H),

7.47 (1H, t, J 7.7, Ar(5)H), 7.52 (2H, d, J 8.9, ArC(2,6)H), 7.69

(1H, d, J 8.0, Ar(6)H), 7.96 (1H, d, J 7.8, Ar(3)H), 8.37 (2H, d, J

8.9, ArC(3,5)H); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ_C56.2

(COCH₂), 62.0 (C(1)H₂), 62.4 (diallyl-C(1)H₂), 119.5 (C(2)H),

123.0 (ArC(2,6)H), 123.3 (C(3)ArC(2)-Br), 125.4 (ArC(3,5)H),

General Procedure C: Catalytic asymmetric [2,3]-

rearrangement of N,N-diallyl ammonium salts and subsequent

nucleophilic quench

A flame dried Schlenk flask was charged with a solution of (+)-

BTM (0.2 equiv.), HOBt (1.0 equiv.), iPr₂NH (1.4 equiv.) and

MeCN (0.07

M) and cooled to −20 °C and stirred for 5 mins. The

solution was treated with the requisite ammonium salt (1.0

equiv.) and stirred for a further 16 h, after which the

corresponding nucleophile (2.0 - 5.0 equiv.) was added and the

reaction allowed to warm to rt and stirred for the time stated. The

125.6

(diallyl-C(3)H₂),

128.1

(C(3)ArC(4)H),

128.6

(C(3)ArC(6)H), 128.6 (diallyl-C(2)H), 130.9 (C(3)ArC(5)H),

132.9 (C(3)ArC(3)H), 134.8 (C(3)ArC(1)), 139.4 (C(3)H), 145.7

(ArC(1)-O), 153.7 (ArC(4)-NO₂), 163.2 (C=O); HRMS (ESI⁺)

C₂₃H₂₄O₄N₂⁷⁹Br⁺[M]⁺found: 471.0904, requires: 471.0914 (−2.1

ppm).

reaction was quenched with aq. 1

extracted with CH₂Cl₂(3 × equal volume). The combined organic

layers were washed with aq. 1 NaOH (2 × equal volume),

M NaOH (equal volume) and

M

brine (equal volume), dried over MgSO₄and concentrated in

1

vacuo. The residue was analysed by H NMR to determine dr,

(E)-N,N-Diallyl-3-(4-fluorophenyl)-N-(2-(4-nitrophenoxy)-2-

oxoethyl)prop-2-en-1-ammonium bromide 53

then purified by flash column chromatography to give the

rearranged product.

Following general procedure B: (E)-N,N-diallyl-3-(4-

fluorophenyl)prop-2-en-1-amine (1.0 g, 4.33 mmol, 1.0 equiv.)

was reacted with 4-nitrophenyl bromoacetate (1.35 g, 5.19 mmol,

1.2 equiv.) in MeCN (4.3 mL) to give the title product as a white

solid (1.23 g, 58%); mp 132 °C (dec.); υ_max(film, cm⁻¹) 2945,

Ethyl (2S,3S)-2-(diallylamino)-3-phenylpent-4-enoate 22

Following general procedure C, (E)-N,N-diallyl-N-(2-(4-

nitrophenoxy)-2-oxoethyl)-3-phenylprop-2-en-1-ammonium

bromide (1.0 g, 2.11 mmol, 1.0 equiv.) was reacted with (+)-

BTM (107 mg, 0.42 mmol, 0.2 equiv.), HOBt (285 mg, 2.11

mmol, 1.0 equiv.) and iPr₂NH (413 µL, 2.95 mmol, 1.4 equiv.) in

1

1771, 1591, 1528, 1348, 1200, 1159, 1141, 988, 939, 837; H

NMR (500 MHz, d₆-DMSO) δ_H4.28 (4H, d, J 7.3, diallyl-

C(1)H₂), 4.36 (2H, d, J 7.5, C(1)H₂), 4.75 (2H, s, COCH₂), 5.71-

5.82 (4H, m, diallyl-C(3)H₂), 6.24 (2H, ddt, J 17.3, 10.1, 7.2,

diallyl-C(2)H), 6.56 (1H, dt, J 15.5, 7.5, C(2)H), 7.02 (1H, d, J

15.5, C(3)H), 7.27 (2H, t, J 8.8, Ar(3,5)H), 7.50 (2H, d, J 9.1,

Ar(2,6)H), 7.71 (2H, dd, J 8.7, 5.7, Ar(2,6)H), 8.37 (2H, d, J 9.1,

Ar(3,5)H); ¹⁹F NMR (476 MHz, d₆-DMSO) δ_F−112.1 (ddt, J

14.4, 9.0, 5.6, ArF); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ_C

56.2 (COCH₂), 62.2 (diallyl-C(1)H₂), 62.4 (C(1)H₂), 115.6 (d,

²J_CF21.4, ArC(3,5)H) + C(2)H), 123.0 (ArC(2,6)H), 125.4

(ArC(3,5)H), 125.6 (diallyl-C(3)H), 128.6 (diallyl-C(2)H), 129.6

MeCN (30 mL), then quenched with NaOEt (1

M in EtOH, 10.6

mL, 10.6 mmol, 5.0 equiv.) and stirred for a further 24 h at rt.

Crude dr >95:5. The residue was purified by flash column

chromatography on silica gel (5% EtOAc/hexanes) to give the

title product (479 mg, 76%, >95:5 dr) as a colourless oil; HPLC

analysis, Chiralpak AD-H (0.5% IPA/hexane, flow rate 1.5

mL/min, 211 nm, 40 °C) t_RMajor 3.2 min, Minor 3.7 min, 97%

ee; [α]^ꢁ_ꢀ^ꢂ+18.8 (c 1, CHCl₃); υ_max(film, cm⁻¹) 2980, 1726, 1640,

1

1445, 1417, 1246, 1152, 995, 916; H NMR (500 MHz, CDCl₃)

δ_H1.33 (3H, t, J 7.1, OCH₂CH₃), 2.83 (2H, dd, J 14.5,8.3,

NCHH), 3.37 (2H, ddt, J 14.5, 4.1, 1.9, NCHH), 3.76-3.85 (2H,

m, C(2)H + C(3)H), 4.14-4.30 (2H, OCH₂CH₃), 4.88-5.16 (6H,

m, C(5)H₂+ diallyl-C(3)H₂), 5.34-5.37 (2H, m, diallyl-C(2)H),

5.92 (1H, dddd, J 17.1, 10.2, 7.0, 0.9, C(4)H), 7.13-7.19 (2H, m,

ArH), 7.20-7.26 (1H, m, ArH), 7.26-7.35 (2H, m, ArH); ¹³C{¹H}

NMR (179 MHz, CDCl₃) δ_C14.7 (OCH₂CH₃), 50.4 (C(3)H), 53.2

(NCH₂), 60.1 (OCH₂CH₃), 65.4 (C(2)H), 116.7 (C(5)H₂), 117.2

(diallyl-C(3)H₂), 126.5 (ArC(4)H), 128.3 (ArC(2,6)H), 128.5

(ArC(3,5)H), 128.5 (ArC(2,6)H), 136.4 (diallyl-C(2)H), 138.7

(C(4)H), 141.0 (ArC(1)), 171.5 (C=O); HRMS (ESI⁺)

C₁₉H₂₆O₂N⁺[M+H]⁺found: 300.1948, requires: 300.1958 (−3.4

ppm).

3

4

(d, J_CF8.2, ArC(2,6)H), 131.8 (d, J_CF3.1, ArC(1)), 140.4

1

(C(3)H), 145.7 (ArC(1)-O)), 153.7 (ArC(4)-NO₂), 162.5 (d, J_CF

247, ArC(4)-F), 163.3 (C=O); HRMS (ESI⁺) C₂₃H₂₄O₄N₂F⁺[M]⁺

found: 411.1708, requires: 411.1715 (−1.7 ppm).

(E)-N,N-Diallyl-3-(4-bromophenyl)-N-(2-(4-nitrophenoxy)-2-

oxoethyl)prop-2-en-1-ammonium bromide 54

Following general procedure B: (E)-N,N-diallyl-3-(4-

bromophenyl)prop-2-en-1-amine (0.99 g, 3.39 mmol, 1.0 equiv.)

was reacted with 4-nitrophenyl bromoacetate (1.06 g, 4.06 mmol,

1.2 equiv.) in MeCN (4 mL) to give the title product as a white

solid (1.12 g, 60%); mp 126 °C (dec.); υ_max(film, cm⁻¹) 2943,

1771, 1591, 1526, 1487, 1450, 1346, 1198, 1167, 1142, 939, 883;

¹H NMR (500 MHz, d₆-DMSO) δ_H4.26 (4H, d, J 7.3, diallyl-

C(1)H₂), 4.35 (2H, d, J 7.4, C(1)H₂), 4.73 (2H, s, COCH₂), 5.68-

5.85 (4H, m, diallyl-C(3)H₂), 6.12-6.31 (2H, m, diallyl-C(2)H),

6.63 (1H, dt, J 15.5, 7.4, C(2)H), 6.99 (1H, d, J 15.5, C(3)H),

7.49 (2H, d, J 9.1, Ar(2,6)H), 7.55-7.66 (4H, m, Ar(2,3,5,6)H),

8.36 (2H, d, J 9.1, Ar(3,5)H); ¹³C {¹H} NMR (126 MHz, d₆-

DMSO) δ_C56.2 (COCH₂), 62.3 (C(1)H₂), 62.3 (diallyl-C(1)H₂),

116.8 (C(2)H), 122.4 (ArC(4)-Br), 123.0 (ArC(2,6)H), 125.4

(ArC(3,5)H), 125.6 (diallyl-C(3)H₂), 128.7 (diallyl-C(2)H), 129.5

(2S,3S)-N-Benzyl-2-(diallylamino)-3-phenylpent-4-enamide

29

Following general procedure C, (E)-N,N-diallyl-N-(2-(4-

nitrophenoxy)-2-oxoethyl)-3-phenylprop-2-en-1-ammonium

bromide (114 mg, 0.24 mmol, 1.0 equiv.) was reacted with (+)-

BTM (12 mg, 0.048 mmol, 0.2 equiv.), HOBt (6.4 mg, 0.048

mmol, 0.2 equiv.) and iPr₂NH (47 µL, 0.34 mmol, 1.4 equiv.) in

MeCN (3.5 mL), then quenched with BnNH₂(131 µL, 1.20

mmol, 5.0 equiv.) and stirred for a further 24 h. Crude dr 93:7.

9

The residue was purified by flash column chromatography on

silica gel (0-2% Et₂O/CH₂Cl₂) to give the title product (85 mg,

98%, 92:8 dr) as a colourless oil; HPLC analysis, Chiralpak OJ-H

(5% IPA/hexane, flow rate 1.5 mL/min, 211 nm, 40 °C) t_RMajor

6.2 min, Minor 5.2 min, 84% ee; [α]^ꢁ_ꢀ^ꢂ+53.1 (c 1.0, CHCl₃); υ_max

(film, cm⁻¹) 3296, 2928, 1631, 1506, 1452, 1334, 1246, 1120,

87%, >95:5 dr) as a colourless oil; HPLC analysis, Chiralpak

ACCEPTED MANUSCRIPT

AD-H (5% IPA/hexane, flow rate 1.5 mL/min, 211 nm, 40 °C) t_R

Major 3.8 min, Minor 5.9 min, 98% ee; [α]^ꢁ_ꢀ^ꢂ+134.0 (c 1,

CHCl₃); υ_max(film, cm⁻¹) 2974, 1629, 1429, 1420, 1157, 991; H

1

NMR (700 MHz, CDCl₃) δ_H1.76-1.93 (4H, m, C(3ʹ + 4ʹ)H₂),

2.96 (2H, dd, J 15.1, 7.9, NCHH), 3.36-3.45 (3H, m, NCHH

+C(2ʹ)HH), 3.49 (2H, t, J 6.9, C(5ʹ)H₂), 3.58 (1H, dt, J 9.8, 6.5,

C(2ʹ)HH), 3.82-3.98 (2H, m, C(2)H + C(3)H), 4.84-5.09 (6H, m,

C(5)H₂+ diallyl-C(3)H₂), 5.41 (2H, dddd, J 17.1, 10.2, 7.9, 4.2,

diallyl-C(2)H), 5.90 (1H, ddd, J 17.0, 10.1, 7.7, C(4)H), 7.21

(3H, tt, J 8.2, 1.5, ArH), 7.30 (2H, dd, J 8.6, 6.6, ArH); ¹³C{¹H}

NMR (179 MHz, CDCl₃) δ_C24.4 (C(4ʹ)H₂), 26.4 (C(3ʹ)H₂), 45.4

(C(5ʹ)H₂), 51.3 (C(3)H), 53.3 (diallyl-C(1)H₂), 63.5 (C(2)H),

116.1 (diallyl-C(3)H₂), 116.9 (C(5)H₂), 126.4 (ArC(4)H), 128.3

(ArC(2,6)H), 128.8 (ArC(3,5)H), 137.9 (diallyl-C(2)H), 138.7

(C(4)H), 141.4 (ArC(1)), 171.0 (C=O); HRMS (ESI⁺)

1

912; H NMR (500 MHz, CDCl₃) δ_H2.92 (2H, dd, J 14.6, 8.0,

NCHH), 3.38-3.46 (2H, m, NCHH), 3.51 (1H, d, J 9.9, C(2)H),

3.94-4.02 (1H, m, C(3)H), 4.51 (2H, dd, J 5.6, 2.9, PhCH₂), 4.93-

5.16 (6H, m, C(5)H₂+ diallyl-CH₂), 5.45 (2H, dddd, J 16.8, 10.5,

8.0, 4.4, diallyl-C(1)H), 5.95-6.06 (2H, m, C(4)H + NH), 7.14-

7.34 (10H, m, ArH); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ_C43.4

(PhCH₂), 49.7 (C(3)H), 53.5 (diallyl-C(1)H₂), 66.7 (C(2)H),

117.0 (C(5)H₂+ diallyl-C(3)H₂), 126.4 (C(3)Ar(C(4)H), 127.7

(Ar(C(4)H), 128.2 (C(3)Ar(C(2,6)H), 128.3 (Ar(C(2,6)H), 128.6

(C(3)Ar(C(3,5)H), 128.8 (Ar(C(3,5)H), 137.1 (diallyl-C(2)H),

138.4 (C(3)ArC(1)), 139.0 (C(4)H), 141.5 (Ar(C(1)), 170.2

(C=O); HRMS (NSI⁺) C₂₄H₂₉N₂O⁺[M+H]⁺found: 361.2277,

requires 361.2274 (+0.8 ppm).

C₂₁H₂₉ON₂[M+H]⁺found: 325.2265, requires: 325.2274 (−2.8

+

ppm).

Ethyl

(2S,3S)-3-(2-bromophenyl)-2-(diallylamino)pent-4-

(2S,3S)-2-(Diallylamino)-3-phenylpent-4-en-1-ol 28

enoate 33

Following general procedure C, with slight modification (E)-

N,N-diallyl-N-(2-(4-nitrophenoxy)-2-oxoethyl)-3-phenylprop-2-

en-1-ammonium bromide (114 mg, 0.24 mmol, 1.0 equiv.) was

reacted with (+)-BTM (12 mg, 0.048 mmol, 0.2 equiv.), HOBt

(32 mg, 0.24 mmol, 1.0 equiv.) and iPr₂NH (47 µL, 0.34 mmol,

1.4 equiv.) in MeCN, then concentrated in vacuo and the solvent

switched to THF (3.5 mL, 2 cycles). The solution was cooled to 0

Following general procedure C, (E)-N,N-diallyl-3-(2-

bromophenyl)-N-(2-(4-nitrophenoxy)-2-oxoethyl)prop-2-en-1-

ammonium bromide (0.3 g, 0.54 mmol, 1.0 equiv.) was reacted

with (+)-BTM (27 mg, 0.11 mmol, 0.2 equiv.), HOBt (73 mg,

0.54 mmol, 1.0 equiv.) and iPr₂NH (105 µL, 0.76 mmol, 1.4

equiv.) in MeCN (7.7 mL), then quenched with NaOEt (1

M in

EtOH, 2.70 mL, 2.70 mmol, 5.0 equiv.) and stirred for a further

24 h at rt. Crude dr 92:8. The residue was purified by flash

column chromatography on silica gel (5% EtOAc/hexanes) to

give the title product (173 mg, 85%, 92:8 dr) as a colourless oil;

Enantiopurity determined after derivatisation to 38 and N-Boc

protection 92% ee; [α]^ꢁ_ꢀ^ꢂ+ 9.6 (c 1, CHCl₃); υ_max(film, cm⁻¹)

°C and treated with LiAlH₄(1.0

2.0 equiv.) dropwise. The reaction was stirred for 1 h, quenched

by the addition of aq. 1 KOH (10 mL) and extracted with

EtOAc (3 × 20 mL). The combined organic layers were washed

with aq. 1 KOH (2 × 10 mL), dried over MgSO₄then

M in THF, 0.48 mL, 0.48 mmol,

M

1

concentrated in vacuo. Crude dr >95:5. The residue was purified

by flash coloumn chromatography on silica gel (0-10%

Et₂O/CH₂Cl₂) to give the title product (54 mg, 88%, >95:5 dr) as

2980, 1728, 1638, 1472, 1244, 1177, 1153, 1020, 918; H NMR

(500 MHz, CDCl₃) δ_H1.32 (3H, t, J 7.1, OCH₂CH₃), 2.79 2H, dd,

J 14.4, 8.5, NCHH), 3.38 (2H, ddt, J 14.4, 4.0, 1.9, NCHH), 3.85

(1H, d, J 11.6, C(2)H), 4.14-4.29 (2H, m, OCH₂CH₃), 4.47 (1H,

dd, J 11.6, 8.0, C(3)H), 4.93-5.17 (6H, m, C(5)H₂+ diallyl-

C(3)H₂), 5.40 (2H, dddd, J 17.3, 11.3, 8.5, 4.0, diallyl-C(2)H),

5.75 (1H, ddd, J 17.6, 10.1, 8.0, C(4)H), 7.05 (1H, ddd, J 8.1,

7.2, 1.7, ArC(4)H), 7.15 (1H, dd, J 7.7, 1.7, ArC(5)H), 7.28 (1H,

dd, J 7.7, 1.3, ArC(6)H), 7.53 (1H, dd, J 8.0, 1.3, ArC(3)H);

¹³C{¹H} NMR (126 MHz, CDCl₃) δ_C14.8 (OCH₂CH₃), 48.5

(C(3)H), 53.3 (NCH₂), 60.2 (OCH₂CH₃), 65.1 (C(2)H), 117.3

(diallyl-C(3)H₂), 117.6 (C(5)H₂), 125.3 (ArC(2)-Br), 127.2

(ArC(5)H, 127.8 (ArC(4)H), 129.7 (ArC(6)H, 132.9 (ArC(3)H),

136.2 (diallyl-C(2)H), 137.3 (C(4)H), 139.8 (ArC(1)), 171.2

(C=O); HRMS (ESI⁺) C₁₉H₂₅O₂NBr⁺[M+H]⁺found: 378.1052,

requires: 378.1063 (−2.9 ppm).

a

colourless oil; HPLC analysis, Chiralpak OJ-H (0.5%

IPA/hexane, flow rate 1.5 mL/min, 211 nm, 40 °C) t_RMajor 5.5

min, Minor 4.5 min, 96% ee; [α]^ꢁ_ꢀ^ꢂ+27.3 (c 1.0, CHCl₃); υ_max

1

(film, cm⁻¹) 3420, 2924, 1601, 1415, 1265, 1045, 991, 914; H

NMR (400 MHz, CDCl₃) δ_H2.70 (2H, dd, J 14.1, 8.0, NCHH),

3.23 (2H, ddt, J 14.1, 4.4, 1.7, NCHH), 3.30 (1H, app. t, J 10.0,

CHHOH), 3.37 (1H, td, J 9.5, 9.0, 4.1, C(2)H), 3.47 (1H, t, J 9.5,

C(3)H), 3.63 (1H, dd, J 10.0, 4.1, CHHOH), 4.84-5.11 (6H, m,

diallyl-C(3)H₂+ C(5)H₂), 5.64 (2H, dddd, 17.2, 10.2, 8.0, 4.8,

diallyl-C(2)H), 5.79-6.01 (1H, m, C(4)H), 7.21-7.34 (5H, m,

ArH); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ_C51.4 (C(3)H), 52.6

(diallyl-C(1)H₂), 60.3 (C(1)H₂), 62.2 (C(2)H), 115.8 (C(5)H₂),

117.4 (diallyl-C(3)H₂), 126.9 (ArC(4)H), 128.2 (ArC(2,6)H),

128.8 (ArC(3,5)H), 137.0 (diallyl-C(2)H), 138.9 (C(4)H), 143.0

(ArC(1)); HRMS (NSI⁺) C₁₇H₂₄NO⁺[M+H]⁺found: 258.1853,

requires 258.1852 (+0.4 ppm).

Ethyl (2S,3S)-2-(diallylamino)-3-(4-nitrophenyl)pent-4-enoate

32

(2S,3S)-2-(Diallylamino)-3-phenyl-1-(pyrrolidin-1-yl)pent-4-

en-1-one 27

Following general procedure C, (E)-N,N-diallyl-3-(4-

nitrophenyl)-N-(2-(4-nitrophenoxy)-2-oxoethyl)prop-2-en-1-

ammonium bromide (0.2 g, 0.39 mmol, 1.0 equiv.) was reacted

with (+)-BTM (20 mg, 0.08 mmol, 0.2 equiv.), HOBt (53 mg,

0.39 mmol, 1.0 equiv.) and iPr₂NH (76 µL, 0.55 mmol, 1.4

Following general procedure C, (E)-N,N-diallyl-N-(2-(4-

nitrophenoxy)-2-oxoethyl)-3-phenylprop-2-en-1-ammonium

bromide (114 mg, 0.24 mmol, 1.0 equiv.) was reacted with (+)-

BTM (12 mg, 0.048 mmol, 0.2 equiv.), HOBt (32 mg, 0.24

mmol, 1.0 equiv.) and iPr₂NH (47 µL, 0.34 mmol, 1.4 equiv.) in

MeCN (3.5 mL), then quenched with pyrrolidine (100 µL, 1.20

mmol, 5.0 equiv.) and stirred for a further 24 h at rt. Crude dr

>95:5. The residue was purified by flash column chromatography

on silica gel (0-5% Et₂O/CH₂Cl₂) to give the title product (68 mg,

equiv.) in MeCN (5.6 mL), then quenched with NaOEt (1

M in

EtOH, 1.95 mL, 1.95 mmol, 5.0 equiv.) and stirred for a further

24 h at rt. Crude dr 90:10. The residue was purified by flash

column chromatography on silica gel (5% EtOAc/hexanes) to

give the title product (92 mg, 69%, 90:10 dr) as a yellow oil;

Enantiopurity determined after derivatisation to 39 and N-Boc

protection, 96% ee; [α]^ꢁ_ꢀ^ꢂ+54.7 (c 1, CHCl₃); υ_max(film, cm⁻¹)

10

Tetrahedron

2980, 1724, 1518, 1343, 1155, 920, 854; ¹H NMR (500 MHz,

ddd, J 17.1, 10.2, 7.6, C(4)H), 6.98 (2H, t, J 8.7, Ar(3,5)H), 7.09

ACCEPTED MANUSCRIPT

CDCl₃) δ_H1.34 (3H, t, J 7.1, OCH₂CH₃), 2.81 (2H, dd, J 14.4,

8.4, NCHH), 3.35 (2H, ddt, J 14.4, 4.0, 1.9, NCHH), 3.82 (1H, d,

J 11.7, C(2)H), 3.98 (1H, dd, J 11.7, 7.9, C(3)H), 4.24 (2H, dddd,

J 18.0, 10.8, 7.1, 3.7, OCH₂CH₃), 4.98-5.16 (6H, m, C(5)H₂+

diallyl-C(3)H₂), 5.36 (2H, dddd, J 16.9, 10.3, 8.3, 4.1, diallyl-

C(2)H), 5.86 (1H, ddd, J 17.0, 10.3, 7.9, C(4)H), 7.33 (2H, d, J

8.8, Ar(2,6)H), 8.19 (2H, d, J 8.8, Ar(3,5)H); ¹³C{¹H} NMR (126

MHz, CDCl₃) δ_C14.7 (OCH₂CH₃), 50.1 (C(3)H), 53.1 (NCH₂),

60.4 (OCH₂CH₃), 64.9 (C(2)H), 117.9 (diallyl-C(3)H₂), 118.2

(C(5)H₂), 123.6 (ArC(3,5)H), 129.4 (ArC(2,6)H), 135.6 (diallyl-

C(2)H), 137.1 (C(4)H), 146.7 (ArC(1)), 149.1 (ArC(4)-NO₂),

(2H, ddt, 8.3, 5.2, 2.5, Ar(2,6)H); ¹⁹F{¹H} NMR (272 MHz,

CDCl₃) δ_F−116.9 (ArF); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ_C

14.7 (OCH₂CH₃), 49.5 (C(3)H), 53.1 (NCH₂), 60.2 (OCH₂CH₃),

2

65.3 (C(2)H), 115.1 (d, J_CF21.2, ArC(3,5)H), 116.8 (C(5)H₂),

3

117.4 (diallyl-C(3)H₂), 129.9 (d, J_CF7.8, ArC(2,6)H), 136.2

(diallyl-C(2)H), 136.7 (d, ⁴J_CF3.2, ArC(1)), 138.5 (C(4)H), 161.6

1

(d, J_CF244, ArC-F), 171.3 (C=O); HRMS (ESI⁺) C₁₉H₂₅O₂NF⁺

[M+H]⁺found: 318.1854, requires: 318.1864 (−3.1 ppm).

Deallylation of Products

170.6 (C=O); HRMS (ESI⁺) C₁₉H₂₅O₄N₂[M+H]⁺found:

General Procedure D: Bis-deallylation of α-N,N diallyl amino

+

345.1802, requires: 345.1809 (−2.0 ppm).

esters

Ethyl

enoate 34

(2S,3S)-3-(4-bromophenyl)-2-(diallylamino)pent-4-

A flamed dried Schlenk tube was charged with Pd(dba)₂(0.1

equiv.), dppb (0.1 equiv.) and thiosalicyclic acid (5.0 equiv.)

under Ar. A solution of N,N-diallyl amino ester (1.0 equiv.) in

Following general procedure C, (E)-N,N-diallyl-3-(4-

bromophenyl)-N-(2-(4-nitrophenoxy)-2-oxoethyl)prop-2-en-1-

ammonium bromide (400 mg, 0.73 mmol, 1.0 equiv.) was reacted

with (+)-BTM (37 mg, 0.15 mmol, 0.2 equiv.), HOBt (99 mg,

0.73 mmol, 1.0 equiv.) and iPr₂NH (142 µL, 1.02 mmol, 1.4

degassed THF (0.1

heated to 60 °C under Ar for 3 h. Once complete the reaction was

cooled to rt and aq. 1 HCl and EtOAc added, the layers

separated and the aqueous layer washed with EtOAc (2 × equal

volume). The aqueous layer was then concentrated in vacuo to

give the pure α-amino ester hydrochloride salt.

M) was added and the resulting mixture

M

equiv.) in MeCN (10.4 mL), then quenched with NaOEt (1

M in

EtOH, 3.65 mL, 3.65 mmol, 5.0 equiv.) and stirred for a further

24 h at rt. Crude dr 90:10. The residue was purified by flash

column chromatography on silica gel (5% EtOAc/hexanes) to

give the title product (213 mg, 77%, 91:9 dr) as a yellow oil;

HPLC analysis, Chiralpak AD-H (0.5% IPA/hexane, flow rate

1.5 mL/min, 211 nm, 40 °C) t_RMajor 3.2 min, Minor 3.9 min,

96% ee; [α]^ꢁ_ꢀ^ꢂ+40.5 (c 1, CHCl₃); υ_max(film, cm⁻¹) 2980, 1726,

General Procedure E: N-Boc protection of α-amino ester

hydrochloride salts

A solution of α-amino ester hydrochloride salt (1.0 equiv.) in

CH₂Cl₂(0.07

M) was treated with NEt₃(3.0 equiv.) and Boc₂O

(5.0 equiv.) and stirred for 16 h at room temperature. The

resulting mixture was concentrated in vacuo, dissolved in MeOH

(3 × equal volume) and treated with 4-DMAP (0.1 equiv.) and

stirred for 3 h. Once complete the solution was concentrated in

vacuo, dissolved in EtOAc (5 × equal volume) washed with aq. 1

1

1489, 1173, 1153, 1011, 918; H NMR (500 MHz, CDCl₃) δ_H

1.30 (3H, t, J 7.1, OCH₂CH₃), 2.79 (2H, dd, J 14.4, 8.4, NCHH),

3.33 (2H, ddt, J 14.4, 4.1, 1.9, NCHH), 3.67-3.81 (2H, m, C(2)H

+ C(3)H), 4.13-4.26 (2H, m, OCH₂CH₃), 4.96-5.09 (6H, m,

C(5)H₂+ diallyl-C(3)H₂), 5.38 (2H, dddd, J 16.5, 10.8, 8.4, 4.1,

diallyl-C(2)H), 5.83 (1H, ddd, J 17.0, 10.2, 7.7, C(4)H), 7.02

(2H, d, J 8.4, Ar(2,6)H), 7.41 (2H, d, J 8.4, Ar(3,5)H); ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ_C14.7 (OCH₂CH₃), 49.7 (C(3)H), 53.1

(NCH₂), 60.2 (OCH₂CH₃), 65.1 (C(2)H), 117.1 (C(5)H₂), 117.5

(diallyl-C(3)H₂), 120.0 (ArC-Br), 130.3 (ArC(2,6)H), 131.3

(ArC(3,5)H), 136.1 (diallyl-C(2)H), 138.1 (C(4)H), 140.1

(ArC(1)), 171.2 (C=O); HRMS (ESI⁺) C₁₉H₂₅O₂NBr⁺[M+H]⁺

found: 378.1054, requires: 378.1063 (−2.4 ppm).

M

HCl (equal volume) and brine (equal volume), dried over

MgSO₄and concentrated in vacuo to give the N-Boc α-amino

ester.

Ethyl (2S,3S)-2-amino-3-phenylpent-4-enoate hydrochloride

36

Following general procedure D, Pd(dba)₂(19 mg, 0.033 mmol,

0.1 equiv), dppb (14 mg, 0.033 mmol, 0.1 equiv.), thiosalicyclic

acid (254 mg, 1.65 mmol, 5.0 equiv.) and ethyl (2S,3S)-2-

(diallylamino)-3-phenylpent-4-enoate (100 mg, 0.33 mmol, 1.0

equiv.) were reacted in THF (3.3 mL) to give the title product as

a colourless gum (65 mg, 77%, >95:5 dr); The corresponding free

amine was prepared for HPLC analysis by dissolution in HPLC

iPrOH and filtration through a pipette plug of K₂CO₃; HPLC

analysis, Chiralpak AS-H (5% IPA/hexane, flow rate 1.5

mL/min, 211 nm, 40 °C) t_RMajor 3.5 min, Minor 4.0 min, 94%

ee; [α]^ꢁ_ꢀ^ꢂ+59.2 (c 1, MeOH); υ_max(film, cm⁻¹) 3375, 2870, 1736,

1587, 1495, 1219, 1043, 993, 858; ¹H NMR (400 MHz, d₄-

MeOH) δ_H1.24 (3H, t, J 7.1, OCH₂CH₃), 3.88 (1H, t, J 8.4,

C(3)H), 4.23 (2H, q, J 7.1, OCH₂CH₃), 4.36 (1H, d, J 8.4,

C(2)H), 5.20-5.33 (2H, m, C(5)H₂), 6.13 (1H, ddd, J 17.2, 9.9,

9.1, C(4)H), 7.28-7.47 (5H, m, ArH); ¹³C{¹H} (126 MHz, d₄-

MeOH) δ_C14.3 (OCH₂CH₃), 52.9 (C(3)H), 58.0 (C(2)H), 63.4

(OCH₂CH₃), 119.9 (C(5)H), 129.2 (ArC(4)H), 129.2

(ArC(3,5)H), 1303 (ArC(2,6)H), 136.1 (C(4)H), 138.7 (ArC(1)),

169.4 (C=O); HRMS (ESI⁺) C₁₃H₁₈O₂N⁺[M]⁺found: 220.1327,

requires: 220.1332 (−2.3 ppm).

Ethyl

(2S,3S)-2-(diallylamino)-3-(4-fluorophenyl)pent-4-

enoate 31

Following general procedure C, (E)-N,N-diallyl-3-(4-

nitrophenyl)-N-(2-(4-fluorophenoxy)-2-oxoethyl)prop-2-en-1-

ammonium bromide (400 mg, 0.82 mmol, 1.0 equiv.) was reacted

with (+)-BTM (40 mg, 0.16 mmol, 0.2 equiv.), HOBt (111 mg,

0.82 mmol, 1.0 equiv.) and iPr₂NH (160 µL, 1.15 mmol, 1.4

equiv.) in MeCN (12 mL), then quenched with NaOEt (1

M in

EtOH, 4.10 mL, 4.10 mmol, 5.0 equiv.) and stirred for a further

24 h at rt. Crude dr 94:6. The residue was purified by flash

column chromatography on silica gel (5% EtOAc/hexanes) to

give the title product (222 mg, 85%, 95:5 dr) as a colourless oil;

HPLC analysis, Chiralpak AD-H (0.5% IPA/hexane, flow rate

1.5 mL/min, 211 nm, 40 °C) t_RMajor 3.3 min, Minor 4.3 min,

96% ee; [α]^ꢁ_ꢀ^ꢂ+14.8 (c 1, CHCl₃); υ_max(film, cm⁻¹) 2980, 1726,

1508, 1223, 1157, 918, 829; ¹H NMR (300 MHz, CDCl₃) δ_H1.30

(3H, t, J 7.1, OCH₂CH₃), 2.79 (2H, dd, J 14.5, 8.3, NCHH), 3.34

(2H, ddt, J 14.5, 4.0, 1.9, NCHH), 3.65-3.84 (2H, m, C(2)H +

C(3)H), 4.09-4.34 (2H, m, OCH₂CH₃), 4.86-5.14 (6H, m, C(5)H₂

+ diallyl-C(3)H₂), 5.26-5.50 (2H, m, diallyl-C(2)H), 5.85 (1H,

Ethyl (2S,3S)-2-acetamido-3-phenylpent-4-enoate 55

11

A

solution of ethyl (2S,3S)-2-amino-3-phenylpent-4-enoate

(ArC(2,6)H), 130.6 (ArC(3,5)H), 134.6 (C(4)H), 146.4

ACCEPTED MANUSCRIPT

hydrochloride (276 mg, 1.08 mmol, 1.0 equiv.) in dry CH₂Cl₂(6

mL) was treated with Et₃N (300 µL, 2.15 mmol, 2.0 equiv.) and

acetic anhydride (200 µL, 2.12 mmol, 2.0 equiv.) and stirred for

16 h at room temperature. The reaction mixture was then diluted

by the addition of EtOAc (50 mL). The resulting solution was

washed with brine (20 mL), dried over MgSO₄and concentrated

(ArC(1)), 149.1 (ArC(4)-NO₂), 169.0 (C=O); HRMS (ESI⁺)

C₁₃H₁₇O₄N₂[M]⁺found: 265.1176, requires: 265.1183 (−2.6

+

pm).

Ethyl

hydrochloride 37

(2S,3S)-2-amino-3-(4-fluorophenyl)pent-4-enoate

in vacuo. The crude residue was purified by Biotage^®Isolera^TM

4

[SNAP Ultra 25 g, 75 mL/min, PE:EtOAc (90:10 1 CV, 90:10 to

40:60 10 CV, 40:60 1 CV)] to give the title product as a white

solid (273 mg, 97%, >95:5 dr); HPLC analysis, Chiralpak AD-H

(10% IPA/hexane, flow rate 0.7 mL/min, 211 nm, 30 °C) t_R

Minor 10.0 min, Major 12.2 min, 95% ee; [α]^ꢁ_ꢀ^ꢂ+89.8 (c 1,

CHCl₃), lit.¹⁵[α]_ꢀ^ꢁꢂ+77.3 (c 0.98, CHCl₃); mp: 64-66 °C; ¹H

NMR (400 MHz, CDCl₃) δ_H1.21 (3H, t, J 7.1, OCH₂CH₃), 1.93

(3H, s, C(O)CH₃), 3.82 (1H, t, J 7.4, C(3)H), 4.13 (2H, q, J 7.1,

OCH₂CH₃), 4.98 (1H, dd, J 8.7, 6.6, C(2)H), 5.15 – 5.23 (2H, m,

C(5)H₂), 5.72 (1H, d, J 8.7, NH), 6.01 – 6.12 (1H, m, C(4)H),

7.18 – 7.34 (5H, ArH); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ_C14.2

(OCH₂CH₃), 23.3 (C(O)CH₃), 52.3 (C(3)H), 55.9 (C(2)H), 61.4

(OCH₂CH₃), 117.9 (C(5)H₂), 127.5 (ArC(4)H), 128.2 (ArCH),

128.8 (ArCH), 136.3 (C(4)H), 138.9 (ArC(1)), 169.8 (C=O

ester), 171.4 (NHC=O). Data consistent with literature.¹⁵

Following general procedure D, Pd(dba)₂(9.2 mg, 0.016 mmol,

0.1 equiv), dppb (12.8 mg, 0.016 mmol, 0.1 equiv.),

thiosalicyclic acid (122 mg, 0.75 mmol, 5.0 equiv.) and ethyl

(2S,3S)-3-(4-fluorophenyl)-2-(diallylamino)pent-4-enoate

(50

mg, 0.16 mmol, 1.0 equiv., 94:6 dr) were reacted in THF (1.5

mL) to give the title product as a oily yellow solid (46 mg,

quant., 92:8 dr); Enantiopurity determined after N-Boc

protection, 94% ee; [α]^ꢁ_ꢀ^ꢂ+40.8 (c 1, CHCl₃); υ_max(film, cm⁻¹)

1

3397, 2864, 1736, 1603, 1508, 1223, 1014, 934, 836; H NMR

(400 MHz, d₄-MeOH) δ_H1.26 (3H, t, J 7.1, OCH₂CH₃), 3.86 (1H,

t, J 8.4, C(3)H), 4.24 (2H, q, J 7.1, OCH₂CH₃), 4.35 (1H, d, J 8.4,

C(2)H), 5.21-5.31 (2H, m, C(5)H₂), 6.11 (1H, ddd, J 16.8, 10.3,

9.0, C(4)H), 7.14 (2H, t, J 8.8, Ar(3,5)H), 7.38 (2H, dd, J 8.8,

5.2, Ar(2,6)H); ¹⁹F{¹H} NMR (376, d₄-MeOH) δ_F−116.2 (ArF);

¹³C{¹H} NMR (126 MHz, d₄-MeOH) δ_C14.3 (OCH₂CH₃), 52.2

2

(C(3)H), 58.0 (C(2)H), 63.5 (OCH₂CH₃), 117.1 (d, J_CF21.8,

3

ArC(3,5)H), 120.0 (C(5)H₂), 131.2 (d, J_CF8.2, ArC(2,6)H),

Ethyl

(2S,3S)-2-amino-3-(2-bromophenyl)pent-4-enoate

4

1

134.8 (d, J_CF3.3, ArC(1)), 135.9 (C(4)H), 163.9 (d, J_CF246,

ArC(4)-F), 169.4 (C=O); HRMS (ESI⁺) C₁₃H₁₇O₂NF⁺[M]⁺

found: 238.1232, requires: 238.1238 (−2.5 ppm).

hydrochloride 38

Following general procedure D, Pd(dba)₂(16 mg, 0.027 mmol,

0.1 equiv), dppb (12 mg, 0.027 mmol, 0.1 equiv.), thiosalicyclic

acid (203 mg, 1.32 mmol, 5.0 equiv.) and ethyl (2S,3S)-3-(2-

bromophenyl)-2-(diallylamino)pent-4-enoate (100 mg, 0.27

mmol, 1.0 equiv., 93:7 dr) were reacted in THF (2.7 mL) to give

the title product as a colourless gum (44 mg, 49%, 93:7 dr);

Enantiopurity determined after N-Boc protection, 92% ee;

[α]_ꢀ^ꢁꢂ+23.1 (c 1, MeOH); υ_max(film, cm⁻¹) 3350, 2982, 1736,

1470, 1242, 1219, 1022, 939, 854;¹H NMR (500 MHz, d₄-

MeOH) δ_H1.17 (3H, t, J 7.2, OCH₂CH₃), 4.19 (2H, qd, J 7.2, 4.2,

OCH₂CH₃), 4.36 (1H, dd, J 9.4, 7.2, C(3)H), 4.47 (1H, d, J 7.2,

C(2)H), 5.29-5.43 (2H, m, C(5)H₂), 6.13 (1H, ddd, J 16.7, 10.2,

9.4, C(4)H), 7.26 (1H, ddd, J 8.0, 5.0, 4.0, Ar(5)H), 7.42 (1H, dd,

J 4.0, 0.7, Ar(4)H), 7.68 (1H, dt, J 8.0, 0.9, Ar(6)H); ¹³C{¹H}

NMR (179 MHz, d₄-MeOH) δ_C14.2 (OCH₂CH₃), 51.5 (C(3)H),

56.3 (C(2)H), 63.6 (OCH₂CH₃), 121.9 (C(5)H₂), 125.4 (ArC(2)-

Br), 129.4 (ArC(5)H), 130.7 (ArC(4)H), 130.8 (ArC(6)H), 133.9

(ArC(3)H), 134.8 (C(4)H), 138.0 (ArC(1)), 169.0 (C=O); HRMS

(ESI⁺) C₁₃H₁₇O₂N⁷⁹Br⁺[M]⁺found: 298.0434, requires: 298.0437

(−1.0 ppm).

Ethyl

(2S,3S)-3-(2-bromophenyl)-2-((tert-

butoxycarbonyl)amino)pent-4-enoate 56

Following general procedure D ethyl (2S,3S)-2-amino-3-(2-

bromophenyl)pent-4-enoate hydrochloride (48 mg, 0.14 mmol,

1.0 equiv.), NEt₃(58 µL, 0.42 mmol, 3.0 equiv.) and Boc₂O (153

mg, 0.7 mmol, 5.0 equiv.) were reacted in CH₂Cl₂(2 mL) to give

the title product as a yellow oil (40 mg, 72%, 88:12 dr); HPLC

analysis, Chiralpak AD-H (2% IPA/hexane, flow rate 1.5

mL/min, 211 nm, 40 °C) t_RMajor 12.4 min, Minor 9.4 min, 92%

ee; [α]^ꢁ_ꢀ^ꢂ+38.4 (c 1, CHCl₃); υ_m₁_ax(film, cm⁻¹) 3345, 2930, 1717,

1506, 1368, 1161, 1022, 930; H NMR (500 MHz, CDCl₃) δ_H

1.20 (3H, t, J 7.1, OCH₂CH₃), 1.33 (9H, s, C(CH₃)₃), 4.06-4.18

(2H, m, OCH₂CH₃), 4.26 (1H, t, J 8.9, C(3)H), 4.68 (1H, t, J 8.9,

C(2)H), 4.95 (1H, d, J 9.3, NH), 5.13-5.24 (2H, m, C(5)H₂), 6.01

(1H, ddd, J 16.9, 10.2, 8.6, C(4)H), 7.03-7.15 (1H, m, ArH),

7.25-7.34 (2H, m, ArH), 7.56 (1H, d, J 8.0, ArH); ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ_C14.1 (OCH₂CH₃), 28.2 (C(CH₃)₃), 51.2

(C(3)H), 56.8 (C(2)H), 61.2 (OCH₂CH₃), 80.0 (C(CH₃)₃), 118.6

(C(5)H₂), 125.1 (ArC(2)-Br), 127.6 (ArC(5)H), 128.6 (ArC(4)H),

129.2 (ArC(6)H), 133.1 (ArC(3)H), 135.5 (C(4)H), 138.4

(ArC(1)), 154.9 (NC=O), 171.5 (C=O); HRMS (ESI⁺)

C₁₈H₂₄O₄NBrNa⁺[M+Na]⁺found: 420.0773, requires: 420.0781

(−1.9 ppm).

Ethyl

(2S,3S)-2-amino-3-(4-nitrophenyl)pent-4-enoate

hydrochloride 39

Following general procedure D, Pd(dba)₂(8.4 mg, 0.015 mmol,

0.1 equiv), dppb (6.4 mg, 0.015 mmol, 0.1 equiv.), thiosalicyclic

acid (116 mg, 0.75 mmol, 5.0 equiv.) and ethyl (2S,3S)-3-(4-

nitrophenyl)-2-(diallylamino)pent-4-enoate (50 mg, 0.15 mmol,

1.0 equiv., 90:10 dr) were reacted in THF (1.5 mL) to give the

title product as a colourless gum (24 mg, 53%, 88:12 dr);

Enantiopurity determined after N-Boc protection, 96% ee; [α]_ꢀ^ꢁꢂ

+93.6 (c 0.25, MeOH); υ_max(film, cm⁻¹) 3377, 2905, 1740, 1520,

Ethyl

(2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-

fluorophenyl)pent-4-enoate 57

Following general procedure D ethyl (2S,3S)-2-amino-3-(4-

fluorophenyl)pent-4-enoate hydrochloride (46 mg, 0.16 mmol,

1.0 equiv.), NEt₃(67 µL, 0.48 mmol, 3.0 equiv.) and Boc₂O (174

mg, 0.8 mmol, 5.0 equiv.) were reacted in CH₂Cl₂(2.3 mL) to

give the title product as a colourless oil (24 mg, 45%, >95:5 dr);

HPLC analysis, Chiralpak AD-H (5% IPA/hexane, flow rate 1.5

mL/min, 211 nm, 40 °C) t_RMajor 7.4 min, Minor 5.6 min, 94%

ee; [α]^ꢁ_ꢀ^ꢂ+44.7 (c 1, CHCl₃); υ_max(film, cm⁻¹) 3367, 2980, 2929,

1

1346, 1225, 1111, 1014, 852; H NMR (500 MHz, d₄-MeOH) δ_H

1.24 (3H, t, J 7.1, OCH₂CH₃), 3.99-4.08 (1H, m, C(3)H), 4.25

(2H, q, J 7.1, OCH₂CH₃), 4.51 (1H, d, J 7.9, C(2)H), 5.24-5.40

(2H, m, C(5)H₂), 6.14 (1H, ddd, J 16.7, 103, 9.2, C(4)H), 7.64

(2H, d, J 8.7, Ar(2,6)H), 8.28 (2H, d, J 8.7 Ar(3,5)H); ¹³C{¹H}

NMR (126 MHz, d₄-MeOH) δ_C14.3 (OCH₂CH₃), 52.5 (C(3)H),

57.6 (C(2)H), 63.7 (OCH₂CH₃), 121.5 (C(5)H₂), 125.2

1

1715, 1510, 1357, 1224, 1161, 1024, 835; H NMR (400 MHz,

12

Tetrahedron

CDCl₃) δ_H1.23 (3H, J 7.1, OCH₂CH₃), 1.40 (9H, s, C(CH₃)₃),

(C(4)H), 140.3 (ArC(1)), 173.9 (C=O); HRMS (ESI⁺)

ACCEPTE

D

MANUSCRIPT

3.79 (1H, t, J 7.5, C(3)H), 4.14 (2H, qd, J 7.1, 1.1, OCH₂CH₃),

4.59-4.71 (1H, m, C(2)H), 4.88 (1H, d, J 9.2, NH), 5.11-5.27

(2H, m, C(5)H₂), 6.07 (1H, ddd, J 16.9, 10.3, 8.3, C(4)H), 7.03

(2H, t, J 8.7, Ar(3,5)H), 7.19 (2H, dd, J 8.7, 5.4, Ar(2,6)H);

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ_F−115.5 (ArF); ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ_C14.3 (OCH₂CH₃), 28.4 (C(CH₃)₃),

51.8 (C(3)H), 57.5 (C(2)H), 61.4 (OCH₂CH₃), 80.2 (C(CH₃)₃),

C₁₆H₂₂O₂N⁺[M+H]⁺found: 260.1638, requires: 260.1645 (−2.7

ppm).

Ethyl (2S,3S)-2-(allyl(benzyl)amino)-3-phenylpent-4-enoate

43

A solution of ethyl (2S,3S)-2-(allylamino)-3-phenylpent-4-enoate

(202 mg, 0.78 mmol, 1.0 equiv.) in MeCN (11.2 mL), was treated

with K₂CO₃(215 mg, 1.56 mmol, 2.0 equiv.), KI (26 mg, 0.156

mmol, 0.2 equiv.), and benzyl bromide (140 µL, 1.17 mmol, 1.5

equiv.), the resulting solution was heated at reflux for 16 h. Once

2

3

115.6 (d, J_CF21.3, ArC(3,5)H), 118.0 (C(5)H₂), 130.0 (d, J_CF

7.9, ArC(2,6)H), 134.8 (d, J_CF2.4, ArC(1)), 136.4 (C(4)H),

3

1

155.3 (NC=O), 162.1 (d, J_CF246, ArC(4)-F), 171.5 (C=O);

HRMS (ESI⁺) C₁₈H₂₄O₄NFNa⁺[M+Na]⁺found: 360.1575,

requires: 360.1582 (−1.9 ppm).

complete the reaction was cooled to rt, and aq. 1

M NaOH (20

mL) and CH₂Cl₂(20 mL) added, the layers separated and the

aqueous layer extracted with CH₂Cl₂(2 × 20 mL). The combined

organic layers were washed with brine (50 mL), dried over

MgSO₄and concentrated in vacuo. The residue was purified by

flash column chromatography (1-10% EtOAc/PE) to give the title

product as a colourless oil (233 mg, 86%, 94:6 dr); [α]^ꢁ_ꢀ^ꢂ−6.1 (c

1, CHCl₃); υ_max(film, cm⁻¹) 2978, 1726, 1495, 1454, 1248, 1173,

1153, 1136, 1028, 970; ¹H NMR (500 MHz, CDCl₃) δ_H1.35 (3H,

t, J 7.1, OCH₂CH₃), 2.82 (1H, dd, J 14.2, 8.7, NCHH), 3.27 (1H,

d, J 14.1, PhCHH), 3.31 (1H, ddt, J 14.2, 4.0, 1.9, NCHH), 3.73

(1H, d, J 11.6, C(2)H), 3.86 (1H, dd, J 11.6, 8.1, C(3)H), 3.95

(1H, d, J 14.1, PhCHH), 4.18-4.32 (2H, m, OCH₂CH₃), 4.94-5.11

(4H, m, C(5)H₂+ NCH₂CHCH₂), 5.47 (1H, dddd, J 17.0, 10.3,

8.7, 4.0, NCH₂CH), 5.83 (1H, ddd, J 17.0, 10.2, 8.1, C(4)H),

6.69-6.84 (2H, m, ArH), 7.03-7.08 (2H, m, ArH), 7.10-7.18 (3H,

m, ArH), 7.22-7.32 (3H, m, ArH); ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ_C14.8 (OCH₂CH₃), 50.3 (C(3)H), 53.4 (NCH₂), 54.0

(PhCH₂), 60.1 (OCH₂CH₃), 65.1 (C(2)H), 116.7 (C(5)H₂), 117.7

(NCH₂CHCH₂), 126.6 (ArCH), 126.8 (ArCH), 128.0 (ArCH),

128.4 (ArCH), 128.7 (ArCH), 128.9 (ArCH), 136.2 (NCH₂CH),

138.7 (C(4)H), 139.3 (C(3)ArC(1)), 140.7 (ArC(1)), 171.3

(C=O); HRMS (ESI⁺) C₂₃H₂₈O₂N⁺[M+H]⁺found: 350.2106,

requires: 350.2115 (−2.6 ppm).

Ethyl

(2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-

nitrophenyl)pent-4-enoate 58

Following general procedure D ethyl (2S,3S)-2-amino-3-(4-

nitrophenyl)pent-4-enoate hydrochloride (24 mg, 0.08 mmol, 1.0

equiv.), NEt₃(33 µL, 0.24 mmol, 3.0 equiv.) and Boc₂O (87 mg,

0.40 mmol, 5.0 equiv.) were reacted in CH₂Cl₂(1.1 mL) to give

the title product as a colourless oil (22 mg, 76%);

HPLC analysis, Chiralpak IB (1% IPA/hexane, flow rate 1.5

mL/min, 211 nm, 40 °C) t_RMajor 10.0 min, Minor 8.7 min, 96%

ee; [α]^ꢁ_ꢀ^ꢂ+52.7 (c 1, CHCl₃); υ_max(film, cm⁻¹) 3360, 2980, 1736,

1715, 1522, 1346, 1163, 1024, 855;¹H NMR (500 MHz, CDCl₃)

δ_H1.21 (3H, t, J 7.1, OCH₂CH₃), 1.37 (9H, s, C(CH₃)₃), 3.88 (1H,

t, J 7.8, C(3)H), 4.13 (2H, qd, J 7.1, 1.3, OCH₂CH₃), 4.71 (1H, t,

J 7.8, C(2)H), 4.96 (1H, d, J 9.2, NH), 5.10-5.33 (2H, m,

C(5)H₂), 6.05 (1H, ddd, J 16.9, 10.2, 8.5, C(4)H), 7.41 (2H, d, J

8.6, Ar(2,6)H), 8.18 (2H, d, J 8.6, Ar(3,5)H); ¹³C{¹H} NMR (126

MHz, CDCl₃) δ_C14.3 (OCH₂CH₃), 28.3 (C(CH₃)₃), 52.8 (C(3)H),

57.4 (C(2)H), 61.7 (OCH₂CH₃), 80.5 (C(CH₃)₃), 119.5 (C(5)H₂),

123.8 (ArC(2,6)H), 129.4 (ArC(3,5)H), 134.9 (C(4)H), 147.1

(ArC(1)), 147.2 (ArC(4)-NO₂), 155.2 (NC=O), 171.0 (C=O);

HRMS (ESI⁺) C₁₈H₂₄O₆N₂Na⁺[M+Na]⁺found: 387.1521,

requires: 387.1532 (−1.4 ppm).

Ethyl (2S,3S)-1-benzyl-3-phenyl-1,2,3,6-tetrahydropyridine-

Ethyl (2S,3S)-2-(allylamino)-3-phenylpent-4-enoate 42

2-carboxylate 44

A flame dried two-necked flask was charged with Pd(dba)₂(58

mg, 0.1 mmol, 0.1 equiv.), dppb (43 mg, 0.1 mmol, 0.1 equiv.)

and thiosalicylic acid (184 mg, 1.2 mmol, 1.2 equiv.). A solution

of ethyl (2S,3S)-2-(diallylamino)-3-phenylpent-4-enoate (300

mg, 1.0 mmol, 1.0 equiv.) in degassed THF (10 mL) was added

via syringe. The resulting solution was heated at reflux for 16 h,

once complete the reaction was cooled to rt and treated with aq. 1

A two-neck flask equipped with a reflux condenser with charged

with p-TsOH (191 mg, 1.01 mmol, 1.5 equiv.) followed by a

solution of ethyl (2S,3S)-2-(allyl(benzyl)amino)-3-phenylpent-4-

enoate (233 mg, 0.67 mmol, 1.0 equiv., 94:6 dr) in degassed

PhMe (67 mL), the solution was heated to 80 °C and stirred until

full dissolution. After which the reaction was treated with

Hoveyda-Grubbs 2^ndgeneration catalyst (21 mg, 0.034 mmol, 5

mol%) and the reaction mixture stirred at 80 °C for 16 h. Once

complete by TLC, the reaction was cooled to rt and concentrated

M

HCl (20 mL) and EtOAc (20 mL). The layer separated and the

organic layer extracted with aq. 1 HCl (2 × 20 mL). The

combined aqueous layers were basified to ~pH 14 with aq. 2

M

in vacuo, CH₂Cl₂(50 mL) and aq. 1 M NaOH (50 mL) were

NaOH, then extracted with EtOAc (5 × 30 mL), the organics

combined, washed with brine (50 mL), dried over MgSO₄and

concentrated in vacuo. The residue was purified by flash column

chromatography (5% EtOAc/PE) to give the title product as a

colourless oil (118 mg, 46%); [α]^ꢁ_ꢀ^ꢂ+56.9 (c 1, CHCl₃); υ_max

(film, cm⁻¹) 3335, 2980, 1728, 1640, 1454, 1178, 1152, 1024,

added the layers separated and the aqueous layer extracted with

CH₂Cl₂(2 × 50 mL). The combined organic layers were washed

with brine (50 mL) dried over MgSO₄and concentrated in vacuo.

The residue was purified by Biotage^®Isolera^TM4 [SNAP Ultra

10 g,36 mL/min, PE:EtOAc (99:1 1 CV, 99:1 to 90:10 10 CV,

80:20 2 CV)] to give the title product as a yellow oil (161 mg,

75%, 92:8 dr); [α]_ꢀ^ꢁꢂ−127.1 (c 1, CHCl₃); υ_max(film, cm⁻¹) 2978,

1

993, 918; H NMR (500 MHz, CDCl₃) δ_H1.21 (3H, t, J 7.1,

1

OCH₂CH₃), 3.05 (1H, ddt, J 14.0, 6.5, 1.4, NCHH), 3.23 (1H,

ddt, J 14.0, 5.6, 1.4, NCHH), 3.57-3.65 (2H, m, C(2)H + C(3)H),

4.13 (2H, qd, J 7.1, 3.8, OCH₂CH₃), 5.01-5.19 (4H, m, C(5)H₂+

NCH₂CHCH₂), 5.74 (1H, dddd, J 16.9, 10.2, 6.5, 5.7, NCH₂CH),

6.03-6.17 (1H, m, C(4)H), 7.19-7.25 (3H, m, ArH), 7.27-7.33

(2H, m, ArH); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ_C14.3

(OCH₂CH₃), 50.9 (NCH₂), 53.6 (C(3)H), 60.7 (OCH₂CH₃), 65.3

(C(2)H), 116.9 (C(5)H), 117.2 (NCH₂CHCH₂), 127.1 (ArC(4)H),

128.2 (ArC(2,6)H), 128.7 (ArC(3,5)H), 136.2 (NCH₂CH), 137.6

1728, 1493, 1452, 1177, 1144, 1029, 845; H NMR (500 MHz,

CDCl₃) δ_H0.81 (3H, t, J 7.1, OCH₂CH₃), 3.26 (1H, ddt, J 17.0,

4.4, 2.4, NCHH), 3.57 (1H, ddt, J 17.0, 3.8, 2.4, NCHH), 3.62-

3.81 (4H, m, OCH₂CH₃+ C(3)H + PhCHH), 3.84, (1H, d, J 6.9,

PhCHH), 4.00-4.08 (1H, m, C(2)H), 5.85 (1H, dq, J 10.2, 2.4,

C(5)H), 5.99 (1H, ddt, J 10.2, 4.1, 2.5, C(4)H), 7.15-7.24 (3H, m,

ArH), 7.25-7.31 (3H, m, ArH), 7.31-7.39 (4H, m, ArH); ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ_C13.9 (OCH₂CH₃), 44.1 (C(2)H), 48.6

(NCH₂), 59.5 (PhCH₂), 60.2 (OCH₂CH₃), 64.7 (C(3)H), 124.9

13

Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc.,

2006, 128, 6536-6537. c) Kobayashi, M.; Okamoto, S.

Tetrahedron Lett. 2006, 47, 4347-4350. d) Joannesse, C.;

(C(5)H), 126.9 (C(4)H), 127.0 (ArC(4)H), 127.4 (ArC(4)H),

128.3 (ArCH), 128.5 (ArCH), 128.7 (ArCH), 129.0 (ArCH),

138.2 (ArC(1)), 140.4 (ArC(1)), 170.7 (C=O); HRMS (ESI⁺)

C₂₁H₂₄O₂N⁺[M+H]⁺found: 322.1795, reuiqres: 322.1802 (−2.2

ppm).

ACCEPTED MANUSCRIPT

Johnston, C. P.; Concellón, C; Simal, C.; Philp, D.; Smith, A. D.

Angew. Chem. Int. Ed. 2009, 48, 8914-8918. For recent reviews,

see: e) Morrill, L. C.; Smith, A. D. Chem. Soc. Rev., 2014, 43,

6214-6226. f) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem.

Soc. Rev. 2012, 41, 2109-2121. g) Merad, J.; Pons, J.-M.; Chuzel,

O.; Bressy, C. Eur. J. Org. Chem., DOI: 10.1002/ejoc.201600399

7. For selected examples of isothiourea-catalysed processes from this

laboratory see a) Simal, C; Lebl, T.; Slawin, A. M. Z.; Smith, A.

D. Angew. Chem. Int. Ed. 2012, 51, 3653-3657. b) Morrill, L. C.;

Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.; Smith, A. D.

Chem. Sci. 2013, 4, 4146-4155. c) Stark, D. G.; Morrill, L. C.;

Yeh, P.-P.; Slawin, A. M. Z.; O'Riordan, T. J. C.; Smith, A. D.;

Angew. Chem. Int. Ed. 2013, 52, 11642-11646. d) Yeh, P.-P.;

Daniels, D. S. B.; Fallan, C.; Gould, E.; Simal, C.; Taylor, J. E.;

Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem., 2015, 13,

2177-2191

Ethyl (2S,3S)-3-phenylpiperidine-2-carboxylate 45

A

solution of ethyl (2S,3S)-1-benzyl-3-phenyl-1,2,3,6-

tetrahydropyridine-2-carboxylate (143 mg, 0.45 mmol, 1.0

equiv., 92:8 dr) in EtOAc (4.5 mL) was treated with AcOH (27

µL, 0.45 mmol, 1.0 equiv.) and Pd/C (47 mg, 10% wt., 0.045

mmol, 0.1 equiv.). The resulting suspension was degassed with

H₂for 15 min, then left stirring under an atmosphere of H₂

(balloon, 1 atm) for 48 h at rt. The reaction was diluted with

EtOAc (30 mL), filtered through Celite^®(eluent EtOAc), washed

with aq. sat. NaHCO₃(30 mL), dried over MgSO₄and

concentrated in vacuo. The crude residue was purified by flash

column chromatography (10-15% Et₂O/CH₂Cl₂) to give the

product as a colourless oil (63 mg, 60%, >95:5 dr); HPLC

analysis, Chiralpak AS-H (1% IPA/hexane, flow rate 1.5

mL/min, 211 nm, 40 °C) t_RMajor 3.7 min, Minor 3.4 min, 94%

ee; [α]^ꢁ_ꢀ^ꢂ+11.0 (c 1, CHCl₃); υ_max(film, cm⁻¹) 3348, 2932, 1728,

8. West,T. H.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D. J.

Am. Chem. Soc. 2014, 136, 4476-4479.

9. (a) Workman, J. A.; Gaarrido, N. P.; Sanҫon, J.; Roberts, E.;

Wessel, H. P.; Sweeney, J. B. J. Am. Chem. Soc. 2005, 127, 1066-

1067 (b) Arboré, A. P. A.; Cane-Honeysett, D. J.; Coldham, I.;

Middleton, M. L. Synlett 2000, 236-238.

10. For the initial postulate of 1,5-S•••O interactions as a control

element in isothiourea catalysis see (a) Birman, V. B.; Li, X.; Han,

Z. Org. Lett., 2007, 9, 37-40. For other manuscripts of interest see

(b) Abbasov, M. E.; Hudson, B. M.; Tantillo, D. J.; Romo, D. J.

Am. Chem. Soc., 2014, 136, 4492-4495. (c) Liu, P.; Yang, X.;

Birman, V. B.; Houk, K. N. Org. Lett., 2012, 14, 3288–3291. (d).

Robinson, E. R. T.; Walden, D. M.; Fallan, C.; Greenhalgh, M. D.;

Cheong, P. H.-Y.; Smith, A. D. Chem. Sci. 2016,. DOI:

10.1039/C6SC00940A. Romo and Tantillo (ref 9b) have probed

the nature of 1,5-S•••O interactions of α,β-unsaturated acyl

ammonium species with NBO and postulate this interaction is due

to a number of orbital interactions. In particular, unfavorable n_S

σ*_C-H/σ_C-Hinteractions disfavor alternative conformations with an

O-C-N-C dihedral angle of 180°.

11. See the following publications for a selection of discussions on the

origin of this interaction: (a) Zhang, X.; Gong, Z.; Li, J.; Lu, T. J.

Chem. Inf. Model., 2015, 55, 2138-2153; (b) Ángyán, J. G.;

Kucsman, Á.; Poirier, R. A.; Csizmadia, I. G. J. Mol. Struct.:

Theochem 1985, 123, 189−201; (c) Murray, J. S.; Lane, P.;

Politzer, P.; Int. J. Quantum Chem. 2008, 108, 2770−2781; (d)

Iwaoka, M.; Takemoto, S.; Tomoda, S.; J. Am. Chem. Soc. 2002,

124, 10613−10620; (e). Brameld, K. A.; Kuhn, B.; Reuter, D. C.;

Stahl, M. J. Chem. Inf. Model., 2008, 48, 1-24.

1

1493, 1452, 1370, 1246, 1200, 1179, 1128, 1032, 862; H NMR

(500 MHz, CDCl₃) δ_H0.94 (3H, t, J 7.1, OCH₂CH₃), 1.52 (1H,

ddp, J 14.5, 7.3, 3.8, C(6)HH), 1.78 (1H, dddt, J 12.8, 9.0, 7.7,

3.7, C(6)HH), 1.89 (1H, ddt, J 13.2, 8.8, 4.3, C(5)HH), 1.98 (1H,

br. s, NH), 2.11 (1H, dtd, J 13.6, 7.1, 3.7, C(5)HH), 2.82 (1H,

ddd, J 11.6, 7.9, 3.6, C(4)HH), 3.20-3.34 (2H, m, C(3)H +

C(4)HH), 3.82 (1H, d, J 4.5, C(2)H), 3.92 (2H, qd, J 7.1, 3.0,

OCH₂CH₃), 7.12-7.21 (1H, m, Ar(4)H), 7.22-7.31 (2H, m,

Ar(2,6)H), 7.40-7.48 (2H, m, Ar(3,5)H); ¹³C{¹H} NMR (126

MHz, CDCl₃) δ_C14.0 (OCH₂CH₃), 23.3 (C(6)H₂), 28.9 (C(5)H₂),

42.2 (C(3)H), 44.5 (C(4)H₂), 60.3 (OCH₂CH₃), 61.5 (C(2)H),

126.3 (ArC(4)H), 128.1 (ArC(2,6)H), 128.7 (ArC(3,5)H), 142.7

(ArC(1)), 172.7 (C=O); HRMS (ESI⁺) C₁₄H₂₀O₂N⁺[M+H] found:

234.1483, requires: 234.1489 (−2.6 ppm).

Acknowledgments

The research leading to these results (T.H.W.) has received

funding from the ERC under the European Union's Seventh

12. Lemaire-Audoire, S.; Savignac, M.; Genêt, J. P.; Bernard, J.-M.

Tetrahedron Lett. 1995, 36, 1267-1270.

Framework Programme (FP7/2007-2013)

/

E.R.C. grant

13. Duthion, B.; Pardo, D. G.; Cossy, J. Org. Lett. 2010, 12, 4620-

4623.

agreement n° 279850 and the European Union (Marie Curie ITN

“SubiCat” PITN-GA-2013-607044) (S. S. M. S.).²³A.D.S. thanks

the Royal Society for a Wolfson Research Merit Award. We also

thank the EPSRC UK National Mass Spectrometry Facility at

Swansea University.

14. For recent methodology for the synthesis of α-amino-β-aryl amino

acids see: (a) Zhang, X.; He, G.; Chen, G. Org. Biomol, Chem.,

2016, 14, 5511-5515. (b) He, F.-S.; Jin, J.-H.; Yang, Z.-T.; Yu, X.;

Fossey, J. S.; Deng, W.-P., ACS Catal. 2016, 6, 652-656. (c) He,

Z.-T; Zhao, Y.-S.; Tian, P.; Wang, C.-C.; Dong, H.-Q.; Lin, G.-Q.

Org. Lett. 2014, 16, 1426-1429. (d) Gilfillan, L.; Artschwager, R.;

Harkiss, A. H.; Liskamp, R. M.; Sutherland, A. Org. Biomol.

Chem. 2015, 13, 4514-4523. (e) He, J.; Li, S.; Deng, Y.; Fu, H.;

Laforteza, B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q Science,

2014, 343 1216-1220.

15. Liu, M.; Shen, A.; Sun, X.-W.; Deng, F.; Xu, M.-H.; Lin, G.-Q.

Chem. Commun. 2010, 46, 8460-8462.

16. (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,

6752-6756. (b) Meanwell, N. A. Chem. Res. Toxicol. 2011, 24,

1420-1456. (c) McGrath, N. A.; Brichacek, M.; Njardarson, J. T.

J. Chem. Educ. 2010, 87, 1348-1349.

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14

Tetrahedron

ACCEPTED MANUSCRIPT

20. Daniels, D. S. B.; Smith, S. R.; Lebl, T.; Shapland, P.; Smith,

A. D. Synthesis 2015, 47, 34-41.

Supplementary Material

21. Emayavaramban, B.; Roy, M.; Sundararaju, B. Chem. Eur. J.

2016, 22, 3952-3955.

22. Blart, E.; Genȇt, J. P.; Safi, M.; Savignac, M.; Sinou, D.

Tetrahedron 1994, 50, 505-514.

23. The data underpinning this publication can be found at DOI:

http://dx.doi.org/10.17630/f522b48d-ed02-42b3-a161-

54687ea5af57

Supplementary material containing HPLC traces and NMR

spectra of all novel compounds can be found in Supplementary

Material.

Article Doi

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

DOI: 10.1016/j.tet.2017.01.062

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Authors:

Article abstract of DOI:10.1016/j.tet.2017.01.062

Full text of DOI:10.1016/j.tet.2017.01.062

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