Isothiourea-mediated asymmetric functionalization of 3-alkenoic acids

Article

pubs.acs.org/joc

Isothiourea-Mediated Asymmetric Functionalization of 3‑Alkenoic

Acids

Louis C. Morrill, Samuel M. Smith, Alexandra M. Z. Slawin, and Andrew D. Smith*

EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, U.K.

S

* Supporting Information

ABSTRACT: Isothiourea HBTM-2.1 promotes the catalytic asymmetric α-functionalization of 3-alkenoic acids through formal

[2 + 2] cycloadditions with N-tosyl aldimines and formal [4 + 2] cycloadditions with either 4-aryltriﬂuoromethyl enones or N-

aryl-N-aroyl diazenes, providing useful synthetic building blocks in good yield and with excellent enantiocontrol (up to >99% ee).

Stereodeﬁned products are amenable to further synthetic elaboration through manipulation of the oleﬁnic functionality.

Scheme 1. Generation and Utility of C1-Ammonium

Dienolates

INTRODUCTION

■

The organocatalytic generation of dienolates or their dienamine

equivalents is an increasingly popular area of research.¹These

intermediates have powerful synthetic potential due to their

ability to react regio- and enantioselectively through either α- or

γ-positions, allowing rapid access to diverse molecular scaﬀolds.

In particular, recent research has demonstrated the ability of

ammonium and azolium dienolates to participate in asymmetric

transformations.²⁻¹¹For example, Peters²and Ye³have

accessed cinchona alkaloid and norephedrine derived C1-

ammonium dienolates from α,β-unsaturated acid chloride

starting materials and applied these toward the synthesis of a

range of stereodeﬁned products (Scheme 1). C1-Ammonium

dienolate 1 may form either via initial dehydrohalogenation to

form vinyl ketene 2, which is intercepted by the Lewis base, or

from initial attack of the Lewis base to form α,β-acyl

ammonium 3 followed by γ-deprotonation. To the best of

our knowledge, all catalytically generated β,β-disubstituted C1-

ammonium dienolates documented in the literature react to

give γ-functionalized products.

C1-Azolium dienolates have also received considerable

attention within the past two years. For example, Ye

demonstrated that α,β-unsaturated acid chlorides 4, in the

presence of an N-heterocyclic carbene (NHC) and base, aﬀord

C1-azolium dienolates 5 that react via the γ-center in

asymmetric formal [4 + 2] cycloadditions with 2π electrophiles

(Scheme 2a).⁴Chi subsequently disclosed the ability to access

the same dienolate via both enals 6 (in presence of a

stoichiometric oxidant)^5,6and α,β-unsaturated esters 7

(Scheme 2b,c).⁷Alternatively, enals bearing an α-bromo

leaving group such as 8 have also been demonstrated as

suitable azolium dienolate precursors (Scheme 2d).⁸In

examples a−d, each process is postulated to involve γ-

deprotonation of the corresponding β,β-disubstituted-α,β-acyl

azolium intermediate to generate the corresponding dienolate,

often depicted in both (E)- and (Z)-conﬁgurations, followed by

γ-functionalization of the resulting azolium dienolate.⁹Alter-

natively, aldehydes that contain a γ-leaving group such as 9 have

been used to access C1-azolium dienolates 10 (Scheme 2e).

Interestingly, these dienolates give α-functionalization via

Received: November 22, 2013

Published: January 16, 2014

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Scheme 2. Generation and Utility of C1-Azolium Dienolates

Scheme 3. Proposed Asymmetric Transformations of 3-

Alkenoic Acids via Either α- or γ-Functionalization

observed. Encouraged by Ye’s report demonstrating diazo-

dicarboxylates as suitable reaction partners with C1-ammonium

dienolates,^3aalong with both Ye and Chi who showed that

triﬂuoromethyl ketones are suitable partners in [4 + 2]

cycloadditions with C1-azolium dienolates,^4,5these 2π

components were evaluated. Following our report in the

previous manuscript, we also evaluated N-tosyl aldimines as 2π

electrophiles.¹⁹Using 3-methylbut-3-enoic acid 14 or 2-

(cyclopent-1-en-1-yl)acetic acid 15 with pivaloyl chloride as

activating agent, achiral DHPB 17 (3,4-dihydro-2H-pyrimido-

[2,1-b]benzothiazole) as catalyst, and triﬂuoromethyl ketone 18

as the 2π electrophile,²⁰no distinguishable cycloaddition

products were observed (Table 1). Under the same reaction

conditions, (E)-4-phenylbut-3-enoic acid 16 reacted with

triﬂuoromethyl ketone 18, giving solely the [2 + 2]

cycloaddition product β-lactone 21 (60:40 dr anti:syn) derived

from α-functionalization²¹in 71% combined yield, while

reaction with N-tosyl aldimine 19 gave β-lactam 22 (83:17 dr

anti:syn) in 68% yield (anti diastereoisomer).²²⁻²⁴Unfortu-

nately, diazodicarboxylate 20 proved incompatible with this

system, giving no distinguishable product despite full

consumption of 20.

Encouraged by the promising diastereoselectivities observed

in the reaction with N-tosyl aldimine 19, further optimization

studies focused upon ﬁnding a suitable asymmetric variant.

Screening of a range of isothiourea catalysts and C(4)-

substituted alkenoic acids revealed that chiral isothiourea

HBTM-2.1 23 eﬃciently promotes the formal [2 + 2]

cycloaddition of (E)-pent-3-enoic acid 24 and imine 25 at rt,

aﬀording β-lactam 26 in moderate diastereoselectivity (68:32 dr

anti:syn), with each separable diastereoisomer isolated in good

yield (53% anti, 27% syn) and enantioselectivity (anti 79% ee,

syn 72% ee) (Table 2). Lowering the temperature to −78 °C

resulted in similar diastereoselectivity (71:29 dr anti:syn) but

with each separable diastereoisomer formed in excellent

enantioselectivity (anti 97% ee, syn > 99% ee).²⁵

ﬂuorination with NFSI, and γ-functionalization in the formal [4

+ 2] cycloaddition with diazodicarboxylates 11, aﬀording esters

12¹⁰and lactams 13,¹¹respectively.

Building upon the elegant nucleophile-catalyzed aldol-

lactonization (NCAL) reaction developed by Romo,¹²we

have recently shown that isothioureas^13,14can generate

ammonium enolates¹⁵in situ from carboxylic acids that

subsequently undergo a range of intra- and intermolecular

Michael addition-lactonization/lactamization reactions to gen-

erate stereodeﬁned products.¹⁶Although powerful, the success

of the intermolecular processes often relies upon using

arylacetic acids as starting materials,^17,18which constitutes a

limitation of this organocatalytic strategy. To broaden the

substrate scope of such processes, the use of 3-alkenoic acids

would allow access to extended ammonium dienolates that

could give rise to either α- or γ-functionalized products in a

stereodeﬁned manner (Scheme 3). In this manuscript, a range

of 3-alkenoic acids are shown to act as suitable precursors to

isothiourea-derived ammonium dienolates that react in a variety

of formal [2 + 2] and [4 + 2] cycloadditions. In contrast to

previously accessed C1-ammonium dienolates formed via γ-

deprotonation, these ammonium dienolates are formed via α-

deprotonation and provide exclusively α-functionalized prod-

ucts. This strategy introduces an additional exocyclic oleﬁn

functional handle, allowing for further product functionalization

into useful synthetic building blocks.

RESULTS AND DISCUSSION

■

Generation of Isothiourea Derived Ammonium Dien-

olates and Reaction with 2π Electrophiles. Initial studies

probed the ability of isothioureas to generate an ammonium

dienolate from a 3-alkenoic acid, with subsequent reaction with

a reactive 2π component used to test if α- or γ-selectivity is

The absolute conﬁguration of syn-β-lactam 27 was conﬁrmed

unambiguously by X-ray crystallography as (3S,4S),²⁶while that

of the anti-β-lactam 26 was conﬁrmed by an epimerization

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Table 1. Initial Studies

a

b

1

Determined by H NMR spectroscopic analysis of the crude reaction mixture. Isolated yield (≥95:5 dr).

experiment (Scheme 4). Treatment of syn-β-lactam (3S,4S)-27

(>99:1 dr, >99% ee) using iPr₂NEt at rt for 16 h gave a (58:42

syn:anti) mixture comprising of syn-β-lactam (3S,4S)-27 (96%

ee) and anti-β-lactam (3R,4S)-26 (96% ee) as determined by

Chiral HPLC. The absolute conﬁguration of the anti-β-lactam

formed by epimerization is opposite to that observed

experimentally in the catalytic process. Assuming epimerization

Table 2. Formal [2 + 2] Cycloaddition Using N-Tosyl

Aldimine 25

Scheme 4. Epimerization Experiment

a

b

c

entry T (°C) dr (anti:syn) yield (% anti, syn) ee (% anti, syn)

1

2

23

68:32

71:29

53, 27

53, 11

79, 72

−78

97, >99

a

Determined by ¹H NMR spectroscopic analysis of the crude reaction

mixture. Isolated yield (≥95:5 dr). Determined by chiral HPLC

analysis.

b

c

a

Determined by ¹H NMR spectroscopic analysis of the crude reaction

b

mixture. Determined by HPLC analysis.

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occurs solely at C(3), this allows the absolute conﬁguration of

the anti-β-lactam formed in Table 2 to be assigned (3S,4R).²⁷

The generality of this protocol was next investigated by

variation of both the acid and aldimine components (Table 3).

both diastereoisomers being formed in exquisite enantioselec-

tivity (>99% ee).²⁹

[4 + 2] Cycloadditions of Isothiourea Derived

Ammonium Dienolates with 4π Electrophiles. Having

established the propensity of these ammonium dienolates to

react at the α-position with 2π electrophiles, their ability to

partake in formal [4 + 2] cycloadditions with electron-deﬁcient

4π Michael acceptors was investigated. HBTM-2.1 23

eﬃciently catalyzes the reaction between (E)-pent-3-enoic

and (E)-1,1,1-triﬂuoro-4-phenyl-3-buten-2-one in only 5 min at

rt, giving δ-lactone 36 in 80% yield with good diastereose-

lectivity (88:12 dr) and excellent enantioselectivity (96%

ee).³⁰⁻³²The reaction proceeds eﬃciently using (E)-3-

hexenoic acid, giving δ-lactone 37, although when using (E)-

styrylacetic acid the reaction has to be carried out at −78 °C to

prevent product decomposition and gives the major diaster-

eoisomer of δ-lactone 38 in reduced enantioselectivity (60%

ee). Heteroaryl and 4-bromophenyl substituted triﬂuoromethyl

enones are also tolerated giving δ-lactones 39 and 40 in good

yields and high diastereo- and enantioselectivity (Table 4).

Table 3. Formal [2 + 2] Cycloaddition Scope

Table 4. Formal [4 + 2] Cycloadditions with 4-

Aryltriﬂuoromethyl Enones

a

Determined by ¹H NMR spectroscopic analysis of the crude reaction

b

c

mixture. Isolated yield (≥95:5 dr). Determined by chiral HPLC

analysis. Isolated yield (92:8 dr). Isolated yield (88:12 dr).

d

e

a

Determined by ¹H NMR spectroscopic analysis of the crude reaction

b

c

mixture. Isolated yield (88:12 dr). Determined by HPLC analysis.

d

e

f

Within the aldimine, electron-donating and -withdrawing

groups can be incorporated provided the reactions are carried

out at rt.²⁸4-OMe substituted β-lactam 28 is formed in good

diastereo- and enantioselectivity, while incorporation of the 4-

CF₃group results in a signiﬁcant reduction in enantioselectivity

(44% ee). Heteroaryl substituents (2-furyl) and extended

aromatics (2-naphthyl) are tolerated within the aldimine, giving

β-lactams 30 and 31 in modest diastereoselectivity with the

major (anti) diastereoisomer formed in excellent ee (95 and

97%, respectively). In cases where the minor (syn) diaster-

eoisomer can be isolated, it is always formed in excellent

enantioselectivity (>96% ee). Both the 4-position substituent

and the conﬁguration within the acid component can also be

varied; for example, (E)-4-ethyl, (E)-4-isopropyl, and (E)-4-

benzyl alkenoic acids give the corresponding β-lactams 32−34

in high yields and good diastereo- and enantioselectivities.

Finally, (Z)-pent-3-enoic acid was used as a starting material,

giving the usual α-functionalization under the reaction

conditions, but generating β-lactam 35 with negligible

diastereoselectivity at −78 °C (43:57 dr, anti:syn), despite

Isolated yield (93:7 dr). Isolated yield (≥95:5 dr). Isolated yield

(84:16 dr).

The generality of this asymmetric Michael addition-

lactonization process was next investigated using N-aryl-N-

aroyldiazenes as Michael acceptors, followed by in situ ring-

opening of the intermediate 1,3,4-oxadiazin-6-one formal [4 +

2] cycloaddition adduct with MeOH. Examples including the

use of 3-alkenoic acids bearing 4-alkyl (Me, Et, iPr), 4-benzyl

and 4-phenyl substituents, in addition to (E)- and (Z)-alkene

conﬁgurations are all readily incorporated giving, after in situ

ring-opening with methanol,³³a range of hydrazides 41−46 in

high yields (71−85%) and excellent enantioselectivity (91−

99% ee) (Table 5).^34,35Diazenes bearing electron deﬁcient (4-

FC₆H₄) and heteroaryl (2-furyl) N-aroyl substituents are also

tolerated, giving products 47 and 48 in excellent ee.

Having developed a highly enantioselective route to

hydrazides 41−48, their potential for further elaboration

through functionalization of the oleﬁn was probed. Treatment

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Table 5. Formal [4 + 2] Cycloaddition/Ring-Opening with

N-Aryl-N-aroyldiazenes

Scheme 5. Conversion of Hydrazide 41 to Lactones 49 and

50

a

b

Isolated yield. Determined by HPLC analysis.

of hydrazide 41 under Upjohn dihydroxylation conditions,

followed by acid-catalyzed cyclization, gave a 70:30 mixture of

separable diastereomeric 5-membered lactones 49 and 50 in

85% combined yield, both in 99% ee (Scheme 5).³⁶These

interesting aza-sugar derivatives structurally resemble the

cyclized form of (+)-polyoxamic acid, indicating their potential

biological signiﬁcance.

a

Determined by ¹H NMR spectroscopic analysis of the crude reaction

b

c

mixture. Isolated yield (>98:2 dr). Determined by HPLC analysis.

We propose that the catalytic cycle for these transformations

proceeds via initial N-acylation of HBTM-2.1 23 with the

preformed mixed anhydride to form the corresponding acyl

ammonium ion. α-Deprotonation generates the (Z,E)-enolate

(from the (E)-alkenoic acid), which undergoes stereoselective

Michael addition via α-functionalization with electron-deﬁcient

4π Michael acceptors, followed by intramolecular cyclization, to

generate the corresponding heterocyclic species (Figure 1).

The sense of stereoinduction in these transformations is

consistent with our previous rationale.^16a,cWe tentatively assign

the origin of the observed α-functionalization in these processes

to preferential reaction via the assumed s-trans (Z,E)-dienolate

conformation 51, in preference to the s-cis (Z,E)-dienolate

conformation 52 that is presumably necessary to participate in

γ-functionalization.

CONCLUSION

■

Isothiourea-mediated functionalization of 3-alkenoic acids

occurs regioselectively, giving products derived from α-

functionalization of an intermediate ammonium enolate in a

range of formal [2 + 2] and [4 + 2] cycloadditions. Formal [2 +

2] cycloadditions with N-tosyl aldimines proceed readily using

HBTM-2.1 (10 mol %) with moderate diastereocontrol (up to

87:13 dr) and excellent enantiocontrol (up to >99% ee).

Formal [4 + 2] cycloadditions with either 4-aryl-triﬂuorome-

thylenones or N-aryl-N-aroyldiazenes are also catalyzed by

HBTM-2.1 (1−5 mol %), with products obtained in high

Figure 1. Proposed mechanism of asymmetric heterocycle formation.

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give acid 3-methylbut-3-enoic acid 14 as a colorless oil (1.50 g, 76%):

bp 88−90 °C (20 mmHg); {lit.³⁸bp 67−70 °C (10 mmHg)}; δ_H(500

MHz, CDCl₃) 1.87 (3H, s, CH₃), 3.11 (2H, s, CH₂), 4.92 (1H, s, 

CHH), 4.99 (1H, s, CHH). Data are in accordance with the

literature.³⁸

diastereo- and enantiocontrol (up to 95:5 dr, up to 99% ee).

The simple, two-step elaboration of stereodeﬁned hydrazides

into aza-sugar analogues without erosion of enantiopurity has

also been demonstrated. Current research from this laboratory

is directed toward developing alternative applications of

isothioureas in asymmetric catalysis.

Ethyl 2-cyclopentylideneacetate 63. Following a literature

procedure,³⁹to a suspension of 60% NaH in mineral oil (1.23 g, 51.4

mmol) in Et₂O (120 mL) at 0 °C was added ethyl 2-

(diethoxyphosphoryl)acetate (10.2 mL, 51.4 mmol), and the reaction

mixture was stirred for 5 min at 0 °C. A solution of cyclopentanone

(4.42 mL, 50.0 mmol) in Et₂O (10 mL) was added, and the reaction

mixture was allowed to stir at rt for 4 h. The reaction mixture was

diluted with water and extracted with Et₂O (×3). The combined

organic extracts were dried (MgSO₄), ﬁltered, and concentrated in

vacuo. Chromatographic puriﬁcation (eluent Et₂O:petrol 10:90) gave

ethyl 2-cyclopentylideneacetate 63 as a colorless oil (7.00 g, 91%): δ_H

(500 MHz, CDCl₃) 1.30 (3H, t, J 7.1, CH₃), 1.68 (2H, quintet, J 6.8,

CH₂), 1.77 (2H, quintet, J 7.0, CH₂), 2.44−2.47 (2H, m, CH₂C),

2.78−2.81 (2H, m, CH₂C), 4.17 (2H, q, J 7.1, CH₂CH₃), 5.82 (1H,

quintet, J 2.2, CH). Data are in accordance with the literature.³⁹

Ethyl 2-(cyclopent-1-en-1-yl)acetate 64. Following a literature

procedure,⁴⁰to a solution of DIPA (5.82 mL, 41.2 mmol) in THF (80

mL) at 0 °C was added 2.5 M n-BuLi (16.5 mL, 41.2 mmol), and the

reaction mixture was stirred at that temperature for 30 min. The

reaction mixture was cooled to −78 °C, and a solution of ethyl 2-

(cyclopent-1-en-1-yl)acetate 63 (5.88 g, 38.2 mmol) in THF (25 mL)

was added dropwise over 15 min before stirring for a further 20 min.

The reaction mixture was quenched by addition of sat. aq. NH₄Cl, and

the reaction mixture was warmed to rt before being poured into water

and extracted with Et₂O (×3). The combined organic extracts were

dried (MgSO₄), ﬁltered, and concentrated in vacuo to give ethyl 2-

(cyclopent-1-en-1-yl)acetate 64 as a light yellow oil (5.68 g, 97%): δ_H

(500 MHz, CDCl₃) 1.29 (3H, t, J 7.1, CH₃), 1.93 (2H, quintet, J 7.5,

CH₂), 2.33−2.38 (4H, m, CH₂and CH₂), 3.14 (2H, s, CH₂CO₂Et),

4.17 (2H, q, J 7.1, CH₂CH₃), 5.55−5.57 (1H, m, CH). Data are in

accordance with the literature.⁴⁰

2-(Cyclopent-1-en-1-yl)acetic acid 15. Following a literature

procedure,⁴¹a solution of ethyl 2-(cyclopent-1-en-1-yl)acetate 64

(4.15 g, 27.0 mmol) in 0.5 M KOH (80.8 mL, 40.4 mmol) was heated

at reﬂux for 16 h. Once cooled to rt the reaction mixture was extracted

with Et₂O (×3). The combined organic extracts were dried (MgSO₄),

ﬁltered, and concentrated in vacuo. Recrystallization from petrol gave

2-(cyclopent-1-en-1-yl)acetic acid 15 as a white solid (2.74 g, 59%):

mp 44−46 °C; {lit.⁴¹mp 48−51 °C}; δ_H(300 MHz, CDCl₃) 1.90−

2.00 (2H, m, CH₂), 2.37−2.42 (4H, m, CH₂and CH₂), 3.21 (2H, s,

CH₂CO₂H), 5.63 (1H, m, CH). Data are in accordance with the

literature.⁴¹

(E)-5-Methylhex-3-enoic acid 65. Following a literature

procedure,⁴²a solution of piperidine (39.5 μL, 0.40 mmol) and acetic

acid (22.9 μL, 0.40 mmol) in DMSO (1 mL) was stirred at rt for 5

min, after which time a solution of malonic acid (4.16 g, 40.0 mmol)

and isovaleraldehyde (4.29 mL, 40.0 mmol) in DMSO (20 mL) was

added. The reaction mixture was stirred at rt for 20 min and then at

100 °C for 16 h. Once cooled to rt, the reaction mixture was diluted

with H₂O and extracted with Et₂O (×3). The combined organic

fractions were washed with H₂O, dried (MgSO₄), ﬁltered, and

concentrated in vacuo. Chromatographic puriﬁcation (eluent

Et₂O:petrol 30:70) gave (E)-5-methylhex-3-enoic acid 65 as a

colorless oil (2.93 g, 57%): δ_H(400 MHz, CDCl₃) 0.99 (6H, d, J

6.8, CH(CH₃)₂), 2.26−2.34 (1H, m, C(5)H), 3.07 (2H, dt, J 6.6, 0.9,

C(2)H₂), 5.47 (1H, dtd, J 15.4, 6.7, 1.1, C(3)H), 5.54−5.60 (1H, m,

C(4)H). Data are in accordance with the literature.⁴²

EXPERIMENTAL SECTION

■

General Information. Reactions involving moisture-sensitive

reagents were carried out under an argon atmosphere using standard

vacuum line techniques in addition to dry solvents. In these cases, all

glassware used was ﬂame-dried and cooled under a vacuum.

For moisture-sensitive reactions, solvents (THF, CH₂Cl₂, toluene,

hexane, and Et₂O) were obtained anhydrous and puriﬁed by an

alumina column. Petrol is deﬁned as petroleum ether 40−60 °C. All

other solvents and commercial reagents were used as supplied without

further puriﬁcation unless stated otherwise. Room temperature (rt)

refers to 20−25 °C, with temperatures of 0 and −78 °C obtained using

1

ice/water and CO₂(s)/acetone baths, respectively. H NMR spectra

were acquired at 300, 400, or 500 MHz, ¹³C{¹H} NMR spectra were

acquired at 75, 100, or 125 MHz, and ¹⁹F{¹H} NMR spectra were

acquired at 282, 376, or 471 MHz. Chemical shifts are quoted in parts

per million (ppm) relative to the residual solvent peak. Coupling

constants, J, are quoted in Hertz (Hz). NMR peak assignments were

conﬁrmed using 2D ¹H correlated spectroscopy (COSY), 2D ¹H

nuclear Overhauser eﬀect spectroscopy (NOESY), 2D ¹H−¹³C

heteronuclear multiple-bond correlation spectroscopy (HMBC), and

1

2D H−¹³C heteronuclear single quantum coherence (HSQC) where

necessary. Infrared spectra were recorded as thin ﬁlms using an

attenuated total reﬂectance (ATR) accessory. Mass spectrometry (m/

z) data was acquired using electrospray ionization (ESI), electron

impact (EI), chemical ionization (CI), atmospheric solids analysis

probe (ASAP), atmospheric pressure chemical ionization (APCI), or

nanospray ionization (NSI) using a time-of-ﬂight (TOF) mass

analyzer. Optical rotations were recorded with a path length of 1

dm and concentrations, c, are quoted in g/100 mL. All chiral high-

performance liquid chromatography (HPLC) traces were compared

with an authentic racemic trace. Racemic compounds were prepared

using general procedure A, employing either DHPB 17 or

( )-HBTM-2.1 23 as catalyst.

Isothiourea Catalysts Used. DHPB 17, HBTM-2.1 ( )-23 and

HBTM-2.1 (2S,3R)-23 were made to literature procedures.^16d

N-Tosyl Aldimines Used. 4-Methyl-N-[(1E)-phenylmethylidene]-

benzene-1-sulfonamide 19, 4-methyl-N-[(1E)-4-(bromophenyl)-

methylidene]benzene-1-sulfonamide 25, 4-methyl-N-[(1E)-4-

(methoxyphenyl)methylidene]benzene-1-sulfonamide 53, 4-methyl-

N-[(1E)-4-(triﬂuoromethylphenyl)methylidene]benzene-1-sulfona-

mide 54, N-[(1E)-furan-2-ylmethylidene]-4-methylbenzene-1-sulfona-

mide 55, and 4-methyl-N-[(1E)-naphthalen-2-ylmethylidene]benzene-

1-sulfonamide 56 were made according to literature procedures.³⁷

Triﬂuoromethyl Enones Used. (E)-1,1,1-Triﬂuoro-4-phenyl-3-

buten-2-one 57, (E)-1,1,1-triﬂuoro-4-(4-bromophenyl)-3-buten-2-one

58, and (E)-1,1,1-triﬂuoro-4-(2-thienyl)-3-buten-2-one 59 were made

according to literature procedures.^16d

N-Aryl-N-aroyldiazenes Used. (NE)-N-(Phenylimino)-

benzamide 60, (NE)-4-ﬂuoro-N-(phenylimino)benzamide 61, and

(NE)-N-(phenylimino)furan-2-carboxamide 62 were made according

to literature procedures.^16c

Carboxylic Acids Used. (E)-4-Phenylbut-3-enoic acid 16, (E)-

pent-3-enoic acid 24, and (E)-hex-3-enoic acid 81 were used as

purchased.

3-Methylbut-3-enoic acid 14. Following a literature procedure,³⁸

to a solution of 3-methylbut-3-en-1-ol (2.00 mL, 19.8 mmol) in

acetone (100 mL) at 0 °C was added 2.68 M Jones’ reagent (10.4 mL,

27.7 mmol), and the reaction mixture was stirred at 0 °C for 1 h. The

reaction mixture was washed with 2 M NaOH, and then the aqueous

layer was acidiﬁed with conc HCl and extracted with Et₂O (×3). The

combined organic extracts were dried (MgSO₄), ﬁltered, and

concentrated in vacuo. The residual oil was puriﬁed by distillation to

(E)-5-Phenylpent-3-enoic acid 66. Following a literature

procedure,⁴²a solution of piperidine (39.5 μL, 0.40 mmol) and acetic

acid (22.9 μL, 0.40 mmol) in DMSO (1 mL) was stirred at rt for 5

min, after which time a solution of malonic acid (4.16 g, 40.0 mmol)

and 3-phenylpropionaldehyde (5.28 mL, 40.0 mmol) in DMSO (20

mL) was added. The reaction mixture was stirred at rt for 20 min and

then at 100 °C for 16 h. Once cooled to rt, the reaction mixture was

diluted with H₂O and extracted with Et₂O (×3). The combined

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organic fractions were washed with H₂O, dried (MgSO₄), ﬁltered, and

concentrated in vacuo. Chromatographic puriﬁcation (eluent

Et₂O:petrol 25:75) gave (E)-5-phenylpent-3-enoic acid 66 as a

colorless oil (4.15 g, 59%): δ_H(400 MHz, CDCl₃) 3.13 (2H, dq, J

6.8, 1.1, C(5)H₂), 3.40 (2H, d, J 6.7, C(2)H₂), 5.63 (1H, dtt, J 15.3,

6.9, 1.4, C(3)H), 5.77 (1H, dtt, J 15.3, 6.7, 1.3, C(4)H), 7.18−7.23

(3H, m, Ar(2,6)H and Ar(4)H), 7.28−7.32 (2H, m, Ar(3,5)H). Data

are in accordance with the literature.⁴³

(diethoxyphosphoryl)acetate (10.1 mL, 51.0 mmol) dropwise over

30 min, and the reaction mixture was stirred for 30 min at rt. A

solution of 1,2-diphenylethanone (10 g, 51.0 mmol) in THF (20 mL)

was added dropwise, and the reaction mixture was allowed to stir at rt

for 4 h. The reaction mixture was diluted with water and extracted with

Et₂O (×3). The combined organic extracts were dried (MgSO₄),

ﬁltered, and concentrated in vacuo. Chromatographic puriﬁcation

(eluent Et₂O:petrol 5:95) gave (E)-ethyl 3,4-diphenylbut-2-enoate 71

as a colorless oil (2.35 g, 17%): δ_H(300 MHz, CDCl₃) 1.35 (3H, t, J

7.1, CH₂CH₃), 4.27 (2H, q, J 7.1, CH₂CH₃), 4.55 (2H, s, CH₂Ph),

6.29 (1H, d, CH), 7.14−7.27 (5H, m, ArH), 7.33−7.36 (3H, m,

ArH), 7.42−7.48 (2H, m, ArH). Data are in accordance with the

literature.⁴⁸

(E)-3,4-Diphenylbut-2-enoic acid 72. Following a literature

procedure,⁴¹a solution of (E)-ethyl 3,4-diphenylbut-2-enoate 71 (2.35

g, 8.84 mmol) in 0.5 M KOH (26.8 mL, 13.3 mmol) was heated at

reﬂux for 16 h. Once cooled to rt the reaction mixture was extracted

with Et₂O (×3). The reaction mixture was treated with 1 M H₂SO₄

until acidic and extracted with Et₂O (×3). The combined organic

extracts were dried (MgSO₄), ﬁltered, and concentrated in vacuo.

Chromatographic puriﬁcation (eluent Et₂O:petrol 25:75) gave (E)-

3,4-diphenylbut-2-enoic acid 72 as a white solid (210 mg, 10%): mp

122−124 °C; {lit.⁴⁹mp 138−139 °C}; δ_H(300 MHz, CDCl₃) 4.59

(2H, s, CH₂Ph), 6.34 (1H, s, CH), 7.18−7.29 (5H, m, ArH), 7.34−

7.39 (3H, m, ArH), 7.46−7.49 (2H, m, ArH). Data are in accordance

with the literature.⁴⁹

General Procedure A: Isothiourea-Catalyzed Intermolecular

Reactions. To a solution of acid (1−2 equiv) in CH₂Cl₂(∼1 mL per

0.2 mmol of acid) were added iPr₂NEt (1.5 equiv based upon acid)

and activating agent (1.5 equiv based upon acid) at rt. The reaction

mixture was allowed to stir at rt for 10 min. The requisite isothiourea

(1−10 mol %), Michael acceptor/ketone/imine (1 equiv), and

iPr₂NEt (2.5 equiv) were then added at the required temperature.

The reaction mixture was stirred at the required temperature until

complete by TLC. The reaction mixture was subsequently quenched

by addition of HCl (1 M in H₂O). The reaction mixture was poured

into H₂O and extracted with CH₂Cl₂(×3). The combined organics

were dried (MgSO₄), ﬁltered, and concentrated in vacuo to give the

crude reaction mixture.

(Z)-Pent-3-en-1-ol 67. Following a literature procedure,⁴⁴

Lindlar’s catalyst (5% on CaCO₃, Pb poisoned, 900 mg (45 mg Pd),

0.43 mmol) was degassed in a RB ﬂask. Quinoline (0.72 mL, 6.04

mmol), Et₂O (150 mL) and pent-3-yn-1-ol (2.74 mL, 29.7 mmol)

were added, and a balloon of H₂gas was appended to the reaction

ﬂask. H₂gas was bubbled through the reaction mixture at rt for 20 h.

The reaction mixture was ﬁltered through Celite and concentrated in

vacuo, and the residual oil was puriﬁed by distillation to give alcohol

(Z)-pent-3-en-1-ol 67 (94:6 (Z):(E)) as a colorless oil (1.64 g, 64%):

bp 140−141 °C (760 mmHg); {lit.⁴⁴bp 140 °C (760 mmHg)}; Data

for (Z)-isomer δ_H(500 MHz, CDCl₃) 1.65−1.68 (3H, m, CH₃),

2.32−2.37 (2H, m, C(2)H₂), 3.66 (2H, q, J 6.2, C(1)H₂), 5.37−5.43

(1H, m, C(4)H), 5.62−5.68 (1H, m, C(3)H); Selected data for (E)-

isomer δ_H(500 MHz, CDCl₃) 1.68−1.70 (3H, m, CH₃), 2.23−2.28

(2H, m, C(2)H₂). Data are in accordance with the literature.⁴⁴

(Z)-Pent-3-enoic acid 68. Following a literature procedure,⁴⁴to

K₂Cr₂O₇(56.1 mg, 0.19 mmol), HNO₃(343 mg, 3.81 mmol) and

NaIO₄(8.97 g, 42.0 mmol) in H₂O (25 mL) was added a solution of

(Z)-pent-3-en-1-ol 67 (1.64 g, 19.1 mmol) in MeCN (50 mL) at 0 °C.

The reaction mixture was stirred at 0 °C for 8 h followed by rt for 16

h. The inorganic salts were ﬁltered and washed with Et₂O. H₂O was

added, and the reaction mixture was extracted with Et₂O (×3). The

combined organic fractions were dried (MgSO₄), ﬁltered, and

concentrated in vacuo. The residual oil was puriﬁed by distillation to

give (Z)-pent-3-enoic acid 68 (94:6 (Z):(E)) as a colorless oil (0.69 g,

36%): bp 100−102 °C (22 mmHg); {lit.⁴⁴bp 100 °C (20 mmHg)};

Data for (Z)-isomer δ_H(500 MHz, CDCl₃) 1.64 (3H, dt, J 6.8, 0.8,

CH₃), 3.14 (2H, dd, J 7.2, 0.4, C(2)H₂), 3.66 (2H, q, J 6.2, C(1)H₂),

5.56 (1H, dtq, J 10.7, 7.1, 1.8, C(3)H), 5.66−5.73 (1H, m, C(4)H);

Selected data for (E)-isomer δ_H(500 MHz, CDCl₃) 1.70 (3H, dt, J

6.3, 1.3, CH₃), 3.06 (2H, dt, J 6.7, 1.2, C(2)H₂). Data are in

accordance with the literature.⁴⁴

(3S,4S)-4-Phenyl-3-[(E)-2-phenylethynyl]-4-(triﬂuoromethyl)-

oxetan-2-one 21 and (3S,4R)-4-Phenyl-3-[(E)-2-phenylethynyl]-

4-(triﬂuoromethyl)oxetan-2-one 73. Following general procedure

A, (E)-4-phenylbut-3-enoic acid 16 (259 mg, 1.60 mmol), iPr₂NEt

(0.42 mL, 2.40 mmol) and pivaloyl chloride (296 μL, 2.40 mmol) in

CH₂Cl₂(10 mL), DHPB 17 (15.2 mg, 0.08 mmol, 10 mol %), 2,2,2-

triﬂuoro-1-phenylethan-1-one 18 (109 μL, 0.80 mmol) and iPr₂NEt

(0.35 mL, 2.00 mmol) for 1.5 h at rt gave crude lactones 21 and 73

(60:40 dr). Chromatographic puriﬁcation (eluent Et₂O:petrol

2.5:97.5) gave lactone 21 (>98:2 dr) as a white solid (110 mg,

43%) and lactone 73 (>98:2 dr) as a white solid (73.4 mg, 29%).

Following general procedure A, (E)-4-phenylbut-3-enoic acid 16

(259 mg, 1.60 mmol), iPr₂NEt (0.42 mL, 2.40 mmol) and pivaloyl

chloride (296 μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-2.1

(2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %), 2,2,2-triﬂuoro-1-

phenylethan-1-one 18 (109 μL, 0.80 mmol) and iPr₂NEt (0.35 mL,

2.00 mmol) for 1.5 h at −78 °C gave crude lactones (3S,4S)-21 and

(3R,4R)-73 (65:35 dr). Chromatographic puriﬁcation (eluent

Et₂O:petrol 2.5:97.5) gave lactone (3S,4S)-21 (>98:2 dr) as a white

solid (98.3 mg, 39%) and lactone (3R,4R)-73 (>98:2 dr) as a white

solid (52.6 mg, 21%):

(E)-Ethyl 3-phenylbut-2-enoate 69. Following a literature

procedure,⁴⁵to a suspension of 60% NaH in mineral oil (1.00 g,

41.6 mmol) in THF (35 mL) at 0 °C was added ethyl 2-

(diethoxyphosphoryl)acetate (8.26 mL, 41.6 mmol) dropwise over

30 min, and the reaction mixture was stirred for 30 min at rt. A

solution of acetophenone (4.85 mL, 41.6 mmol) in THF (15 mL) was

added dropwise, and the reaction mixture was allowed to stir at rt for 4

h. The reaction mixture was diluted with water and extracted with

Et₂O (×3). The combined organic extracts were dried (MgSO₄),

ﬁltered, and concentrated in vacuo. Chromatographic puriﬁcation

(eluent Et₂O:petrol 5:95) gave (E)-ethyl 3-phenylbut-2-enoate 69 as a

colorless oil (2.35 g, 30%): δ_H(500 MHz, CDCl₃) 1.35 (3H, t, J 7.1,

CH₂CH₃), 2.61 (3H, d, J 1.3, CH₃), 4.25 (2H, q, J 7.1, CH₂CH₃), 6.16

(1H, q, J 1.2, CH), 7.38−7.42 (3H, m, ArH), 7.50−7.52 (2H, m,

ArH). Data are in accordance with the literature.⁴⁵

(E)-3-Phenylbut-2-enoic acid 70. Following a literature

procedure,⁴¹a solution of (E)-ethyl 3-phenylbut-2-enoate 69 (2.35

g, 12.4 mmol) in 0.5 M KOH (37.1 mL, 18.6 mmol) was heated at

reﬂux for 16 h. Once cooled to rt the reaction mixture was extracted

with Et₂O (×3). The reaction mixture was treated with 1 M H₂SO₄

until acidic and extracted with Et₂O (×3). The combined organic

extracts were dried (MgSO₄), ﬁltered, and concentrated in vacuo.

Recrystallization from Et₂O gave (E)-3-phenylbut-2-enoic acid 70 as a

white solid (1.39 g, 70%): mp 94−96 °C; {lit.⁴⁶mp 95−97 °C}; δ_H

(500 MHz, CDCl₃) 2.64 (3H, d, J 1.2, CH₃), 6.21 (1H, q, J 1.2, 

CH), 7.41−7.44 (3H, m, ArH), 7.51−7.54 (2H, m, ArH). Data are in

accordance with the literature.⁴⁷

Data for lactone (3S,4S)-21: mp 66−67 °C; [α]²_D⁰−14.8 (c 0.5,

CH₂Cl₂); Chiral HPLC Chiralcel OD-H (0.5% IPA:hexane, ﬂow rate 1

mL min⁻¹, 211 nm, 30 °C) t_R(3R,4R) 9.6 min, t_R(3S,4S) 12.6 min,

79% ee; ν_max(ATR)/cm⁻¹3080, 3030 (C−H), 1847 (CO), 1698;

δ_H(400 MHz, CDCl₃) 4.95−4.98 (1H, m, C(3)H), 5.64 (1H, dd, J

15.7, 9.4, PhCHCH), 6.71 (1H, d, J 15.7, PhCHCH), 7.20−7.23

(2H, m, ArH), 7.27−7.31 (3H, m, ArH), 7.46−7.49 (5H, m, ArH); δ_C

(100 MHz, CDCl₃) 60.9 (C(3)), 79.5 (q, J 32.8, C(4)), 116.1

(PhCHCH), 123.6 (q, J 280, CF₃), 126.9 (ArC), 127.3 (ArC), 128.8

(ArC), 128.8 (ArC), 128.9 (4ry ArC), 129.0 (ArC), 130.1 (ArC), 135.3

(E)-Ethyl 3,4-diphenylbut-2-enoate 71. Following a literature

procedure,⁴⁵to a suspension of 60% NaH in mineral oil (2.04 g, 51.0

mmol) in THF (50 mL) at 0 °C was added ethyl 2-

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(C(4)ArC(1), 138.4 (PhCHCH), 165.9 (C(2)O); δ_F(376 MHz,

CDCl₃) −78.7 (CF₃); m/z (APCI⁺) 319 ([M + H]⁺, 100%); HRMS

(APCI⁺) C₁₈H₁₄F₃O₂⁺([M + H]⁺) requires 319.0940, found 319.0940

(−0.1 ppm).

(C(2)O); m/z (NSI) 404 ([M + H]⁺, 70%); HRMS (NSI)

C₂₄H₂₂NO₃S⁺([M + H]⁺) requires 404.1314, found 404.1313 (−0.2

ppm).

(3S,4R)-4-(4-Bromophenyl)-1-[(4-methylbenzene)sulfonyl]-

3-[(1E)-prop-1-en-1-yl]azetidin-2-one 26 and (3S,4S)-4-(4-Bro-

mophenyl)-1-[(4-methylbenzene)sulfonyl]-3-[(1E)-prop-1-en-

1-yl]azetidin-2-one 27. Following general procedure A, (E)-pent-3-

enoic acid 24 (162 μL, 1.60 mmol), iPr₂NEt (420 μL, 2.40 mmol) and

pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-

2.1 (2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %), imine 25 (270 mg,

0.80 mmol) and iPr₂NEt (348 μL, 2.00 mmol) for 1.5 h at rt gave

crude lactams (3S,4R)-26 and (3S,4S)-27 (68:32 dr). Chromato-

graphic puriﬁcation (eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-

26 (>98:2 dr) as a colorless oil (177 mg, 53%) and lactam (3S,4S)-27

(>98:2 dr) as a white solid (91 mg, 27%).

Data for lactam (3S,4R)-26: Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 220 nm, 30 °C) t_R(3S,4R) 18.6

min, t_R(3R,4S) 47.0 min, 79% ee; ν_max(ATR)/cm⁻¹3032, 2965 (C−

H), 1794 (CO), 1595, 1366 (SO), 1169 (SO); δ_H(400 MHz,

CDCl₃) 1.68 (3H, ddd, J 6.5, 1.6, 0.8 Hz, CH₃CHCH), 2.44 (3H, s,

ArCH₃), 3.64 (1H, ddt, J 8.0, 3.3, 0.9 Hz, C(3)H), 4.70 (1H, d, J 3.3

Hz, C(4)H), 5.38−5.45 (1H, m, CH₃CHCH), 5.62−5.69 (1H, m,

CH₃CHCH), 7.07−7.11 (2H, m, ArH), 7.26−7.29 (2H, m,

SO₂Ar(3,5)H), 7.40−7.43 (2H, m, ArH), 7.64−7.67 (2H, m,

SO₂Ar(2,6)H); δ_C(125 MHz, CDCl₃) 18.2 (CH₃CHCH), 21.8

(ArCH₃), 62.8 (C(3)), 63.4 (C(4)), 121.0 (CH₃CHCH), 123.0

(C(4)ArC(4)), 127.6 (ArC), 128.2 (ArC), 130.0 (ArC), 132.1 (ArC),

133.1 (CH₃CHCH)), 135.1 (4ry ArC), 135.5 (4ry ArC), 145.5

(C(4)ArC(1)), 165.4 (C(2)O); m/z (APCI) 420 ([M + H]⁺, 98%);

HRMS (APCI) C₁₉H₁₈BrNO₃S⁺([M + H]⁺) requires 420.0264, found

420.0266 (+0.6 ppm).

Data for lactam (3S,4S)-27: mp 92−94 °C; Chiral HPLC Chiralpak

AD-H (10% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C)

t_R(3S,4S) 20.9 min, t_R(3R,4R) 23.0 min, 72% ee; ν_max(ATR)/cm⁻¹

2941, 2926, (C−H), 1786 (CO), 1487, 1368 (SO), 1125 (S

O); δ_H(400 MHz, CDCl₃) 1.51 (3H, ddd, J 6.6, 1.7, 1.0 Hz,

CH₃CHCH), 2.46 (3H, s, ArCH₃), 4.16 (1H, ddt, J 7.8, 6.7, 1.1,

C(3)H), 4.78 (1H, ddq, J 15.3, 7.7, 1.7 Hz, CH₃CHCH), 5.17 (1H,

d, J 6.7 Hz, C(4)H), 5.69 (1H, dqd, J 15.3, 6.6, 1.3 Hz, CH₃CH

CH), 6.97−7.00 (2H, m, ArH), 7.31−7.33 (2H, m, SO₂Ar(3,5)H),

7.40−7.42 (2H, m, ArH), 7.75−7.77 (2H, m, SO₂Ar(2,6)H); δ_C(125

MHz, CDCl₃) 18.2 (CH₃CHCH), 21.9 (ArCH₃), 58.3 (C(3)), 61.1

(C(4)), 119.4 (CH₃CHCH), 122.7 (C(4)ArC(4)), 127.7 (ArC),

129.1 (ArC), 130.1 (ArC), 131.7 (ArC), 133.2 (4ry ArC), 133.9

(CH₃CHCH)), 135.6 (4ry ArC), 145.7 (C(4)ArC(1)), 165.4

(C(2)O); m/z (NSI) 420 ([M + H]⁺, 100%); HRMS (NSI)

C₁₉H₁₈BrNO₃S⁺([M + H]⁺) requires 420.0264, found 420.0263

(−0.1 ppm).

Data for lactone (3S,4R)-73: mp 110−112 °C; [α]²_D⁰−93.0 (c 0.5,

CH₂Cl₂); Chiral HPLC Chiralcel OD-H (2% IPA:hexane, ﬂow rate 1

mL min⁻¹, 211 nm, 30 °C) t_R(3R,4S) 13.1 min, t_R(3S,4R) 14.9 min,

77% ee; ν_max(ATR)/cm⁻¹3080, 2944 (C−H), 1834 (CO), 1692;

δ_H(400 MHz, CDCl₃) 4.77 (1H, d, J 8.7, C(3)H), 6.38−6.47 (1H, m,

PhCHCH), 6.83−6.88 (1H, m, PhCHCH), 7.34−7.50 (9H, m,

ArH); δ_C(100 MHz, CDCl₃) 64.9 (C(3)), 79.6 (q, J 30.1, C(4)),

115.1 (PhCHCH), 123.3 (q, J 281, CF₃), 126.3 (ArC), 127.1 (ArC),

128.9 (ArC), 128.9 (ArC), 129.1 (ArC), 130.2 (ArC), 132.9 (4ry ArC),

135.4 (C(4)ArC(1)), 139.0 (PhCHCH), 165.9 (C(2)O); δ_F(376

MHz, CDCl₃) −74.2 (CF₃); m/z (APCI⁺) 319 ([M + H]⁺, 100%);

+

HRMS (APCI⁺) C₁₈H₁₄F₃O₂([M + H]⁺) requires 319.0940, found

319.0941 (+0.2 ppm).

(3S,4R)-1-[(4-Methylbenzene)sulfonyl]-4-phenyl-3-[(E)-2-

phenylethenyl]azetidin-2-one 22. Following general procedure A,

(E)-4-phenylbut-3-enoic acid 16 (259 mg, 1.60 mmol), iPr₂NEt (0.42

mL, 2.40 mmol) and pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂

(10 mL), DHPB 17 (15.2 mg, 0.08 mmol, 10 mol %), imine 19 (207

mg, 0.80 mmol) (109 μL, 0.80 mmol) and iPr₂NEt (0.35 mL, 2.00

mmol) for 1.5 h at rt gave crude lactam 22 (83:17 dr).

Chromatographic puriﬁcation (eluent Et₂O:petrol 20:80) gave lactam

22 (>98:2 dr) as a white solid (219 mg, 68%).

Following general procedure A, (E)-4-phenylbut-3-enoic acid 16

(260 mg, 1.60 mmol), iPr₂NEt (420 μL, 2.40 mmol) and pivaloyl

chloride (296 μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-2.1

(2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %), imine 19 (207 mg, 0.80

mmol) and iPr₂NEt (348 μL, 2.00 mmol) for 1.5 h at rt gave crude

lactam (3S,4R)-22 (85:15 dr). Chromatographic puriﬁcation (eluent

Et₂O:petrol 20:80) gave lactam (3S,4R)-22 (>98:2 dr) as a white solid

(125 mg, 39%): mp 137−139 °C; [α]²_D⁰+9.8 (c 0.5, CH₂Cl₂); Chiral

HPLC Chiralpak AD-H (10% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211

nm, 30 °C) t_R(3S,4R) 24.4 min, t_R(3R,4S) 40.9 min, 72% ee; ν_max

(ATR)/cm⁻¹3024, 2924 (C−H), 1790 (CO), 1450, 1359 (SO),

1165 (SO); Data for major diastereoisomer δ_H(300 MHz, CDCl₃)

2.44 (3H, s, CH₃), 3.91 (1H, ddd, J 8.0, 3.3, 1.1 Hz, C(3)H), 4.90 (1H,

d, J 3.3 Hz, C(4)H), 6.16 (1H, dd, J 15.9, 8.0 Hz, PhCHCH), 6.53

(1H, dd, J 15.9, 1.1 Hz, PhCHCH), 7.24−7.36 (12H, m, ArH),

7.65−7.69 (2H, m, SO₂Ar(2,6)H); δ_C(100 MHz, CDCl₃) 21.8 (CH₃),

62.9 (C(3)), 64.3 (C(4)), 119.3 (HCCHPh), 126.6 (ArC), 126.8

(ArC), 127.7 (ArC), 128.4 (ArC), 128.8 (ArC), 129.1 (ArC), 129.1

(ArC), 130.0 (ArC), 135.8 (HCCHPh), 135.8 (4ry ArC), 135.8 (4ry

ArC), 135.8 (4ry ArC), 145.4 (C(4)ArC(1)), 165.2 (C(2)O); m/z

(NSI) 404 ([M + H]⁺, 65%); HRMS (NSI) C₂₄H₂₂NO₃S⁺([M +

H]⁺) requires 404.1315, found 404.1313 (−0.5 ppm).

Reaction carried out for 1.5 h at −78 °C gave crude lactams

(3S,4R)-26:(3S,4S)-27 (71:29 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-26 (>98:2 dr) as a

colorless oil (179 mg, 53%) with identical spectroscopic properties as

before in 97% ee; [α]²_D⁰0.6 (c 0.5, CH₂Cl₂) and lactam (3S,4S)-27

(>98:2 dr) as a white solid (35.6 mg, 11%) with identical

spectroscopic properties as before in >99% ee; [α]²_D⁰−14.6 (c 0.5,

CH₂Cl₂).

(3S,4R)-4-(4-Methoxyphenyl)-1-[(4-methylbenzene)-

sulfonyl]-3-[(1E)-prop-1-en-1-yl]azetidin-2-one 28. Following

general procedure A, (E)-pent-3-enoic acid 24 (162 μL, 1.60

mmol), iPr₂NEt (420 μL, 2.40 mmol) and pivaloyl chloride (296

μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-2.1 (2S,3R)-23 (24.6 mg,

0.08 mmol, 10 mol %), imine 53 (231 mg, 0.80 mmol) and iPr₂NEt

(348 μL, 2.00 mmol) for 1.5 h at rt gave crude lactam (3S,4R)-28

(80:20 dr). Chromatographic puriﬁcation (eluent Et₂O:petrol 30:70)

gave lactam (3S,4R)-28 (96:4 dr) as a yellow oil (220 mg, 74%): [α]_D²⁰

−11.2 (c 0.5, CH₂Cl₂); Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4R) 17.6

min, t_R(3R,4S) 53.0 min, 86% ee; ν_max(ATR)/cm⁻¹2966 (C−H),

1790 (CO), 1612, 1516, 1364 (SO), 1167 (SO); Data for

major diastereomer δ_H(500 MHz, CDCl₃) 1.68 (3H, ddd, J 6.5, 1.6,

(3S,4S)-1-[(4-Methylbenzene)sulfonyl]-4-phenyl-3-[(E)-2-

phenylethenyl]azetidin-2-one 74. Following general procedure A,

(E)-4-phenylbut-3-enoic acid 16 (260 mg, 1.60 mmol), iPr₂NEt (420

μL, 2.40 mmol) and pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂

(10 mL), HBTM-2.1 (2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %),

imine 19 (207 mg, 0.80 mmol) and iPr₂NEt (348 μL, 2.00 mmol) for

2.5 h at −78 °C gave crude lactam (3S,4S)-74 (83:17 dr).

Chromatographic puriﬁcation (eluent Et₂O:petrol 20:80) gave lactam

(3S,4S)-74 (>98:2 dr) as a white solid (136 mg, 42%): mp 127−129

°C; [α]²_D⁰−6.4 (c 0.5, CH₂Cl₂); Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4S) 23.0 min,

t_R(3R,4R) 46.8 min, 16% ee; ν_max(ATR)/cm⁻¹3024, 2924 (C−H),

1790 (CO), 1450, 1359 (SO), 1165 (SO); Data for major

diastereoisomer δ_H(500 MHz, CDCl₃) 2.48 (3H, s, CH₃), 4.40−4.42

(1H, m, C(3)H), 5.38 (1H, d, J 6.7 Hz, C(4)H), 5.49 (1H, dd, J 15.9,

7.3 Hz, PhCHCH), 6.61 (1H, d, J 15.8 Hz, PhCHCH), 7.06−

7.07 (2H, m, ArH), 7.16−7.24 (5H, m, ArH), 7.28−7.34 (5H, m, Ar-

H), 7.80 (2H, d, J 8.4 Hz, SO₂Ar(2,6)H); δ_C(100 MHz, CDCl₃) 21.9

(CH₃), 58.1 (C(4)), 61.8 (C(3)), 118.4 (HCCHPh), 126.5 (C(4)

ArC(2,6)), 127.5 (ArC), 127.8 (ArC), 128.2 (ArC), 128.6 (ArC), 128.6

(ArC), 128.9 (ArC), 130.0 (ArC), 133.7 (4ry ArC), 135.8 (4ry ArC),

135.9 (HCCHPh), 136.1 (4ry ArC), 145.5 (C(4)ArC(1)), 165.0

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0.8 Hz, CH₃CHCH), 2.42 (3H, s, ArCH₃), 3.67 (1H, ddt, J 8.0, 3.3,

0.9 Hz, C(3)H), 3.80 (3H, s, OCH₃), 4.73 (1H, d, J 3.3 Hz, C(4)H),

5.43 (1H, ddq, J 15.3, 8.0, 1.6 Hz, CH₃CHCH), 5.63−5.70 (1H, m,

CH₃CHCH), 6.80−6.81 (2H, m, C(4)Ar(3,5)H), 7.12−7.14 (2H,

m, C(4)Ar(2,6)H), 7.24 (2H, d, J 8.6 Hz, SO₂Ar(3,5)H), 7.60−7.61

(2H, m, SO₂Ar(2,6)H); δ_C(125 MHz, CDCl₃) 18.2 (CH₃CHCH),

21.8 (ArCH₃), 55.5 (OCH₃), 62.6 (C(3)), 64.0 (C(4)), 114.3 (C(4)

ArC(3,5)), 121.4 (CH₃CHCH), 127.6 (SO₂ArC(2,6)), 127.8 (C(4)

ArC(1)), 128.2 (C(4)ArC(2,6)), 129.8 (SO₂ArC(3,5)), 132.6

(CH₃CHCH)), 135.9 (SO₂ArC(1)), 145.1 (SO₂ArC(4)), 160.2

(C(4)ArC(4)), 165.9 (C(2)O); m/z (ESI) 394 ([M + Na]⁺, 80%);

HRMS (ESI) C₂₀H₂₁NNaO₄S⁺([M + Na]⁺) requires 394.1089, found

394.1075 (−2.2 ppm).

48%) with identical spectroscopic properties as before in 95% ee; [α]_D²⁰

−6.4 (c 0.5, CH₂Cl₂).

(3S,4R)-1-[(4-Methylbenzene)sulfonyl]-4-(naphthalen-2-yl)-

3-[(1E)-prop-1-en-1-yl]azetidin-2-one 31 and (3S,4S)-1-[(4-

Methylbenzene)sulfonyl]-4-(naphthalen-2-yl)-3-[(1E)-prop-1-

en-1-yl]azetidin-2-one 75. Following general procedure A, (E)-

pent-3-enoic acid 24 (162 μL, 1.60 mmol), iPr₂NEt (420 μL, 2.40

mmol) and pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂(10

mL), HBTM-2.1 (2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %), imine

56 (247 mg, 0.80 mmol) and iPr₂NEt (348 μL, 2.00 mmol) for 1.5 h

at rt gave crude lactams (3S,4R)-31 and (3S,4S)-75 (67:33 dr).

Chromatographic puriﬁcation (eluent Et₂O:petrol 20:80) gave lactam

(3S,4R)-31 (>98:2 dr) as a colorless oil (188 mg, 60%) and lactam

(3S,4S)-75 (94:6 dr) as a colorless oil (96 mg, 31%).

(3S,4R)-1-[(4-Methylbenzene)sulfonyl]-3-[(1E)-prop-1-en-1-

yl]-4-[4-(triﬂuoromethyl)phenyl]azetidin-2-one 29. Following

general procedure A, (E)-pent-3-enoic acid 24 (162 μL, 1.60

mmol), iPr₂NEt (420 μL, 2.40 mmol) and pivaloyl chloride (296

μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-2.1 (2S,3R)-23 (24.6 mg,

0.08 mmol, 10 mol %), imine 54 (262 mg, 0.80 mmol) and iPr₂NEt

(348 μL, 2.00 mmol) for 1.5 h at rt gave crude lactam (3S,4R)-29

(87:13 dr). Chromatographic puriﬁcation (eluent Et₂O:petrol 20:80)

gave lactam (3S,4R)-29 (>98:2 dr) as a colorless oil (151 mg, 46%):

[α]²_D⁰+1.0 (c 0.5, CH₂Cl₂); Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4R) 20.3

min, t_R(3R,4S) 48.4 min, 44% ee; ν_max(ATR)/cm⁻¹2970 (C−H),

1796 (CO), 1597, 1323 (SO), 1165 (SO); Data for major

diastereomer δ_H(400 MHz, CDCl₃) 1.69 (3H, ddd, J 6.5, 1.6, 0.8 Hz,

CH₃CHCH), 2.44 (3H, s, ArCH₃), 3.67 (1H, ddt, J 8.0, 3.3, 0.9 Hz,

C(3)H), 4.79 (1H, d, J 3.3 Hz, C(4)H), 5.39−5.46 (1H, m, CH₃CH

CH), 5.64−5.73 (1H, m, CH₃CHCH), 7.25−7.28 (2H, m,

SO₂Ar(3,5)H), 7.35 (2H, d, J 8.3 Hz, C(4)Ar(3,5)H), 7.55 (2H, d,

J 8.1 Hz, C(4)Ar(2,6)H), 7.65−7.68 (2H, m, SO₂Ar(2,6)H); δ_C(125

MHz, CDCl₃) 18.2 (CH₃CHCH), 21.8 (ArCH₃), 63.0 (C(3) or

C(4)), 63.2 (C(3) or C(4)), 120.8 (CH₃CHCH), 123.9 (q, J 271

Hz, CF₃), 125.9 (q, J 3.5 Hz, C(4)ArC(3,5)), 126.9 (C(4)ArC(2,6)),

127.6 (SO₂ArC(2,6)), 130.0 (SO₂ArC(3,5)), 131.2 (q, J 32.5 Hz, C(4)

ArC(4)), 133.4 (CH₃CHCH), 135.4 (SO₂ArC(1)), 140.2 (C(4)

ArC(1)), 145.7 (SO₂ArC(4)), 165.2 (C(2)O); δ_F(376 MHz,

CDCl₃) −63.3 (CF₃); m/z (NSI) 410 ([M + H]⁺, 15%); HRMS

(NSI) C₂₀H₁₉F₃NO₃S⁺([M + H]⁺) requires 410.1032, found

410.1030 (−0.5 ppm).

(3S,3R)-4-(Furan-2-yl)-1-[(4-methylbenzene)sulfonyl]-3-

[(1E)-prop-1-en-1-yl]azetidin-2-one 30. Following general proce-

dure A, (E)-pent-3-enoic acid 24 (162 μL, 1.60 mmol), iPr₂NEt (420

μL, 2.40 mmol) and pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂

(10 mL), HBTM-2.1 (2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %),

imine 55 (199 mg, 0.80 mmol) and iPr₂NEt (348 μL, 2.00 mmol) for

1.5 h at rt gave crude lactam (3S,4R)-30 (73:27 dr). Chromatographic

puriﬁcation (eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-30 (95:5

dr) as a white solid (171 mg, 65%): mp 137−139 °C; Chiral HPLC

Chiralpak AD-H (10% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30

°C) t_R(3S,4R) 11.6 min, t_R(3R,4S) 13.4 min, 45% ee; ν_max(ATR)/

cm⁻¹2976 (C−H), 1788 (CO), 1595, 1362 (SO), 1165 (SO);

Data for major diastereoisomer δ_H(400 MHz, CDCl₃) 1.71 (3H, ddd,

J 6.5, 1.6, 0.9 Hz, CH₃CHCH), 2.42 (3H, s, ArCH₃), 4.00−4.03

(1H, m, C(3)H), 4.86−4.87 (1H, m, C(4)H), 5.45−5.52 (1H, m,

CH₃CHCH), 5.71−5.80 (1H, m, CH₃CHCH), 6.35 (1H, dd, J

3.3, 1.9 Hz, C(4)ArC(4)H), 6.50 (1H, dd, J 3.3, 0.7 Hz, C(4)ArC(3)

H), 7.20 (1H, dt, J 1.0, 0.5 Hz, C(4)ArC(5)H), 7.22−7.24 (2H, m,

SO₂Ar(3,5)H), 7.52−7.55 (2H, m, SO₂Ar(2,6)H); δ_C(125 MHz,

CDCl₃) 18.2 (CH₃CHCH), 21.8 (ArCH₃), 56.7 (C(3)), 58.7

(C(4)), 110.9 (C(4)ArC), 112.0 (C(4)ArC), 121.1 (CH₃CHCH),

127.4 (SO₂ArC(2,6)), 129.8 (SO₂ArC(3,5)), 133.0 (CH₃CHCH)),

135.7 (C(4)ArC(1)), 143.5 (C(4)ArC(5)), 145.0 (SO₂ArC(1)), 147.6

(SO₂ArC(4)), 164.9 (C(2)O); m/z (APCI) 332 ([M + H]⁺, 100%);

HRMS (APCI) C₁₇H₁₈NO₄S⁺([M + H]⁺) requires 332.0951, found

332.0954 (+0.9 ppm).

Data for lactam (3S,4R)-31: Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4R) 17.1

min, t_R(3R,4S) 37.0 min, 81% ee; ν_max(ATR)/cm⁻¹2972 (C−H),

1792 (CO), 1699, 1364 (SO), 1167 (SO); δ_H(500 MHz,

CDCl₃) 1.71 (3H, ddd, J 6.5, 1.5, 0.7 Hz, CH₃CHCH), 2.38 (3H, s,

ArCH₃), 3.77 (1H, ddd, J 7.9, 2.4, 0.8 Hz, C(3)H), 4.95 (1H, d, J 3.3

Hz, C(4)H), 5.48−5.53 (1H, m, CH₃CHCH), 5.68−5.72 (1H, m,

CH₃CHCH), 7.14−7.16 (2H, m, SO₂Ar(3,5)H), 7.23 (1H, dd, J

8.5, 1.8 Hz, C(4)ArH), 7.49−7.53 (2H, m, ArH), 7.60−7.63 (2H, m,

SO₂Ar(2,6)H), 7.70−7.72 (1H, m, C(4)Ar(1)H), 7.74 (1H, d, J 8.5,

C(4)ArH), 7.81−7.84 (1H, m, C(4)ArH); δ_C(125 MHz, CDCl₃) 18.2

(CH₃CHCH), 21.7 (ArCH₃), 62.9 (C(3)), 64.4 (C(4)), 121.3

(CH₃CHCH), 123.3 (ArC), 126.6 (ArC), 126.7 (ArC), 126.8

(ArC), 127.6 (SO₂ArC(2,6)), 127.8 (ArC), 128.1 (ArC), 129.0 (ArC),

129.8 (SO₂ArC(3.5)), 132.9 (CH₃CHCH)), 133.0 (4ry ArC), 133.1

(4ry ArC), 133.5 (4ry ArC), 135.7 (4ry ArC), 145.4 (C(4)ArC(1)),

165.7 (C(2)O); m/z (APCI) 392 ([M + H]⁺, 26%); HRMS

(APCI) C₂₃H₂₂NO₃S⁺([M + H]⁺) requires 392.1315, found 392.1318

(+0.8 ppm).

Data for lactam (3S,4S)-75: Chiral HPLC Chiralcel OD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4S) 19.2 min,

t_R(3R,4R) 25.0 min, 81% ee; ν_max(ATR)/cm⁻¹2972 (C−H), 1790

(CO), 1597, 1364 (SO), 1169 (SO); δ_H(400 MHz, CDCl₃)

1.43 (3H, ddd, J 6.6, 1.7, 1.0 Hz, CH₃CHCH), 2.43 (3H, s, ArCH₃),

4.26 (1H, ddq, J 7.8, 6.8, 1.0, C(3)H), 4.84 (1H, ddq, J 15.3, 7.8, 1.7

Hz, CH₃CHCH), 5.42 (1H, d, J 6.7 Hz, C(4)H), 5.66−5.75 (1H,

m, CH₃CHCH), 7.13 (1H, dd, J 8.5, 1.9 Hz, C(4)ArH), 7.24−7.27

(2H, m, SO₂Ar(3,5)H), 7.48−7.52 (2H, m, ArH), 7.55 (1H, dd, J 1.2,

0.5, C(4)Ar(1)H), 7.66−7.68 (1H, m, C(4)ArH), 7.72−7.77 (3H, m,

ArH), 7.81−7.84 (1H, m, C(4)ArH); δ_C(100 MHz, CDCl₃) 18.1

(CH₃CHCH), 21.8 (ArCH₃), 58.6 (C(3)), 62.0 (C(4)), 119.7

(CH₃CHCH), 124.8 (ArC), 126.6 (ArC), 126.6 (ArC), 127.1

(ArC), 127.8 (ArC), 127.8 (SO₂ArC(2,6)), 128.1 (ArC), 128.3 (ArC),

130.0 (SO₂ArC(3,5)), 131.5 (4ry ArC), 133.0 (4ry ArC), 133.4 (4ry

ArC), 133.6 (CH₃CHCH), 135.9 (4ry ArC), 145.4 (C(4)ArC(1)),

165.7 (C(2)O); m/z (APCI) 392 ([M + H]⁺, 83%); HRMS

(APCI) C₂₃H₂₂NO₃S⁺([M + H]⁺) requires 392.1315, found 392.1316

(+0.3 ppm).

Reaction carried out for 1.5 h at −78 °C gave crude lactams

(3S,4R)-31:(3S,4S)-75 (76:24 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-31 (>98:2 dr) as a

colorless oil (201 mg, 64%) with identical spectroscopic properties as

before in 97% ee; [α]²_D⁰−10.6 (c 0.5, CH₂Cl₂) and lactam (3S,4S)-75

(95:5 dr) as a colorless oil (69.0 mg, 22%) with identical spectroscopic

properties as before in 99% ee; [α]²_D⁰+0.6 (c 0.5, CH₂Cl₂).

(3S,4R)-3-[(1E)-But-1-en-1-yl]-1-[(4-methylbenzene)-

sulfonyl]-4-phenylazetidin-2-one 32 and (3S,4S)-3-[(1E)-But-1-

en-1-yl]-1-[(4-methylbenzene)sulfonyl]-4-phenylazetidin-2-

one 76. Following general procedure A, (E)-hex-3-enoic acid 81 (190

μL, 1.60 mmol), iPr₂NEt (420 μL, 2.40 mmol) and pivaloyl chloride

(296 μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-2.1 (2S,3R)-23

(24.6 mg, 0.08 mmol, 10 mol %), imine 19 (207 mg, 0.80 mmol) and

iPr₂NEt (348 μL, 2.00 mmol) for 1.5 h at rt gave crude lactams

(3S,4R)-32 and (3S,4S)-76 (84:16 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-32 (>98:2 dr) as a

Reaction carried out for 1.5 h at −78 °C gave crude lactam (3S,4R)-

30 (63:37 dr). Chromatographic puriﬁcation (eluent Et₂O:petrol

20:80) gave lactam (3S,4R)-30 (95:5 dr) as a white solid (126 mg,

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colorless oil (158 mg, 55%) and lactam (3S,4S)-76 (98:2 dr) as a white

solid (22 mg, 8%).

Reaction carried out for 1.5 h at −78 °C gave crude lactam (3S,4R)-

33 (79:21 dr). Chromatographic puriﬁcation (eluent Et₂O:petrol

15:85) gave lactam (3S,4R)-33 (>98:2 dr) as a colorless oil (185 mg,

63%) with identical spectroscopic properties as before in 97% ee; [α]_D²⁰

+1.6 (c 0.5, CH₂Cl₂).

(3S,4R)-1-[(4-Methylbenzene)sulfonyl]-4-phenyl-3-[(1E)-3-

phenylprop-1-en-1-yl]azetidin-2-one 34 and (3S,4S)-1-[(4-

Methylbenzene)sulfonyl]-4-phenyl-3-[(1E)-3-phenylprop-1-en-

1-yl]azetidin-2-one 77. Following general procedure A, (E)-5-

phenylpent-3-enoic acid 66 (282 mg, 1.60 mmol), iPr₂NEt (420 μL,

2.40 mmol) and pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂(10

mL), HBTM-2.1 (2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %), imine

19 (207 mg, 0.80 mmol) and iPr₂NEt (348 μL, 2.00 mmol) for 1.5 h

at rt gave crude lactams (3S,4R)-34 and (3S,4S)-77 (72:28 dr).

Chromatographic puriﬁcation (eluent Et₂O:petrol 25:75) gave lactam

(3S,4R)-34 (>98:2 dr) as a colorless oil (197 mg, 59%) and lactam

(3S,4S)-77 (95:5 dr) as a colorless oil (61 mg, 18%).

Data for lactam (3S,4R)-34: Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4R) 18.4

min, t_R(3R,4S) 25.3 min, 62% ee; ν_max(ATR)/cm⁻¹3028 (C−H),

1792 (CO), 1597, 1364 (SO), 1169 (SO); Data for major

diastereoisomer δ_H(500 MHz, CDCl₃) 2.42 (3H, s, ArCH₃), 3.37

(2H, d. J 6.7 Hz, PhCH₂), 3.76 (1H, ddd, J 7.7, 3.3, 0.9 Hz, C(3)H),

4.81 (1H, d, J 3.3 Hz, C(4)H), 5.51 (1H, ddt, J 15.4, 7.7, 1.5 Hz,

BnCHCH), 5.84 (1H, dtd, J 15.3, 6.7, 1.2 Hz, BnCHCH), 7.12−

7.14 (2H, m, ArH), 7.20−7.23 (5H, m, ArH), 7.28−7.35 (5H, m,

ArH), 7.62−7.64 (2H, m, SO₂(2,6)H); δ_C(125 MHz, CDCl₃) 21.8

(ArCH₃), 38.9 (PhCH₂CHCH), 62.3 (C(3)), 64.1 (C(4)), 121.4

(BnCHCH), 126.4 (ArC), 126.7 (ArC), 127.5 (ArC), 128.6 (ArC),

128.6 (ArC), 128.9 (ArC), 129.1 (C(4)ArC(4)), 129.8 (SO₂ArC(3,5)),

135.7 (4ry ArC), 135.8 (4ry ArC), 136.1 (BnCHCH), 139.0

(SO₂ArC(1)), 145.2 (C(4)ArC(1)), 165.4 (C(2)O); m/z (NSI)

418 ([M + H]⁺, 20%); HRMS (NSI) C₂₅H₂₄NO₃S⁺([M + H]⁺)

requires 418.1471, found 418.1467 (−1.1 ppm).

Data for lactam (3S,4S)-77: Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4S) 14.4 min,

t_R(3R,4R) 26.7 min, 39% ee; ν_max(ATR)/cm⁻¹3028, 2924 (C−H),

1788 (CO), 1595, 1359 (SO), 1167 (SO); Data for minor

diastereoisomer δ_H(500 MHz, CDCl₃) 2.45 (3H, s, ArCH₃), 3.12

(2H, d. J 6.7 Hz, PhCH₂), 4.18−4.21 (1H, m, C(3)H), 4.85 (1H, ddt, J

15.4, 7.7, 1.5 Hz, BnCHCH), 5.26 (1H, d, J 6.7 Hz, C(4)H), 5.78

(1H, dtd, J 15.4, 6.8, 1.2, BnCHCH), 6.76−6.79 (2H, m, ArH),

7.08−7.23 (5H, m, ArH), 7.27−7.35 (5H, m, ArH), 7.77−7.79 (2H,

m, SO₂(2,6)H); δ_C(125 MHz, CDCl₃) 21.9 (ArCH₃), 38.9 (PhCH₂),

58.1 (C(3)), 61.8 (C(4)), 120.4 (BnCHCH), 126.2 (ArC), 127.4

(ArC), 127.8 (ArC), 128.4 (ArC), 128.6 (ArC), 128.7 (ArC), 128.7

(ArC), 130.0 (SO₂ArC(3,5)), 134.0 (4ry ArC), 135.7 (4ry ArC), 136.8

(BnCHCH), 138.9 (SO₂ArC(1)), 145.5 (C(4)ArC(1)), 165.4

(C(2)O); m/z (NSI) 418 ([M + H]⁺, 28%); HRMS (NSI)

C₂₅H₂₄NO₃S⁺([M + H]⁺) requires 418.1471, found 418.1459 (−3.0

ppm).

Data for lactam (3S,4R)-32: Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4R) 11.5

min, t_R(3R,4S) 17.8 min, 81% ee; ν_max(ATR)/cm⁻¹2967 (C−H),

1794 (CO), 1699, 1366 (SO), 1169 (SO); Data for major

diastereomer δ_H(500 MHz, CDCl₃) 0.95 (3H, t, J 7.5 Hz, CH₂CH₃),

2.00−2.07 (2H, m, CH₂CH₃), 2.42 (3H, s, ArCH₃), 3.70 (1H, ddt, J

7.8, 2.4, 0.9 Hz, C(3)H), 4.77 (1H, d, J 3.3 Hz, C(4)H), 5.42 (1H, ddt,

J 15.4, 7.8, 1.6 Hz, EtCHCH), 5.70 (1H, dtd, J 15.4, 6.3, 1.1 Hz,

EtCHCH), 7.21−7.25 (4H, m, ArH), 7.27−7.34 (3H, m, ArH),

7.62−7.64 (2H, m, SO₂Ar(2,6)H); δ_C(125 MHz, CDCl₃) 13.1

(CH₂CH₃), 21.8 (ArCH₃), 25.6 (CH₂CH₃), 62.6 (C(3) or C(4)), 64.2

(C(3) or C(4)), 119.1 (EtCHCH), 126.7 (C(4)ArC(2,6)), 127.6

(SO₂ArC(2,6)), 128.9 (C(4)ArC(3,5)), 129.0 (C(4)ArC(4)), 129.9

(SO₂ArC(3.5)), 135.7 (4ry ArC), 136.0 (4ry ArC), 139.3 (EtCH

CH)), 145.2 (C(4)ArC(1)), 165.8 (C(2)O); m/z (NSI) 356 ([M +

H]⁺, 37%); HRMS (NSI) C₂₀H₂₂NO₃S⁺([M + H]⁺) requires

356.1315, found 356.1316 (+0.3 ppm).

Data for lactam (3S,4S)-76: mp 85−87 °C; Chiral HPLC Chiralpak

AD-H (10% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C)

t_R(3S,4S) 14.9 min, t_R(3R,4R) 27.9 min, 74% ee; ν_max(ATR)/cm⁻¹

2967 (C−H), 1788 (CO), 1456, 1368 (SO), 1171 (SO); Data

for major diastereomer δ_H(500 MHz, CDCl₃) 0.72 (3H, t, J 7.4 Hz,

CH₃CH₂), 1.78−1.84 (2H, m, CH₃CH₂), 2.45 (3H, s, ArCH₃), 4.16

(1H, ddd, J 7.6, 6.7, 1.0, C(3)H), 4.76 (1H, ddt, J 15.5, 7.6, 1.6 Hz,

EtCHCH), 5.24 (1H, d, J 6.7 Hz, C(4)H), 5.69 (1H, dtd, J 15.5,

6.4, 1.2 Hz, EtCHCH), 7.08−7.11 (2H, m, ArH), 7.25−7.31 (5H,

m, ArH), 7.76−7.78 (2H, m, SO₂Ar(2,6)H); δ_C(100 MHz, CDCl₃)

13.1 (CH₃CH₂), 21.8 (ArCH₃), 25.6 (CH₃CH₂), 58.2 (C(3), 61.8

(C(4)), 117.7 (EtCHCH), 127.5 (C(4)ArC(2,6)), 127.8

(SO₂ArC(2,6)), 128.4 (C(4)ArC(3,5)), 128.6 (C(4)ArC(4)), 130.0

(SO₂ArC(3.5)), 134.0 (4ry ArC), 135.8 (4ry ArC), 140.0 (EtCH

CH)), 145.4 (C(4)ArC(1)), 165.7 (C(2)O); m/z (NSI) 356 ([M +

H]⁺, 39%); HRMS (NSI) C₂₀H₂₂NO₃S⁺([M + H]⁺) requires

356.1315, found 356.1316 (+0.3 ppm).

Reaction carried out for 1.5 h at −78 °C gave crude lactams

(3S,4R)-32:(3S,4S)-76 (82:18 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-32 (>98:2 dr) as a

colorless oil (189 mg, 67%) with identical spectroscopic properties as

before in 98% ee; [α]²_D⁰+2.4 (c 0.5, CH₂Cl₂) and lactam (3S,4S)-76

(98:2 dr) as a white solid (47.0 mg, 16%) with identical spectroscopic

properties as before in >99% ee; [α]²_D⁰−9.3 (c 0.5, CH₂Cl₂).

(3S,4R)-1-[(4-Methylbenzene)sulfonyl]-3-[(1E)-3-methylbut-

1-en-1-yl]-4-phenylazetidin-2-one 33. Following general proce-

dure A, (E)-5-methylhex-3-enoic acid 65 (205 mg, 1.60 mmol),

iPr₂NEt (420 μL, 2.40 mmol) and pivaloyl chloride (296 μL, 2.40

mmol) in CH₂Cl₂(10 mL), HBTM-2.1 (2S,3R)-23 (24.6 mg, 0.08

mmol, 10 mol %), imine 19 (207 mg, 0.80 mmol) and iPr₂NEt (348

μL, 2.00 mmol) for 1.5 h at rt gave crude lactam (3S,4R)-33 (73:27

dr). Chromatographic puriﬁcation (eluent Et₂O:petrol 15:85) gave

lactam (3S,4R)-33 (>98:2 dr) as a colorless solid (155 mg, 53%):

Chiral HPLC Chiralpak AD-H (10% IPA:hexane, ﬂow rate 1 mL

min⁻¹, 220 nm, 30 °C) t_R(3S,4R) 9.9 min, t_R(3R,4S) 14.4 min, 82% ee;

ν_max(ATR)/cm⁻¹2961 (C−H), 1794 (CO), 1597, 1435, 1366

(SO), 1169 (SO); Data for major diastereomer δ_H(500 MHz,

CDCl₃) 0.95 (6H, d, J 6.8 Hz, CH(CH₃)₂), 2.23−2.30 (1H, m,

CH(CH₃)₂), 2.42 (3H, s, ArCH₃), 3.68−3.70 (1H, m, C(3)H), 4.77

(1H, d, J 3.3 Hz, C(4)H), 5.38 (1H, ddd, J 15.5, 7.7, 1.4 Hz, iPrCH

CH), 5.62 (1H, ddd, J 15.5, 6.5, 1.1 Hz, iPrCHCH), 7.21−7.25

(4H, m, ArH), 7.27−7.34 (3H, m, ArH), 7.62−7.64 (2H, m,

SO₂Ar(2,6)H); δ_C(125 MHz, CDCl₃) 21.8 (ArCH₃), 22.0 (CH-

(CH₃)₂), 31.2 (CH(CH₃)₂), 62.5 (C(3)), 64.3 (C(4)), 117.3

(iPrCHCH), 126.7 (C(4)ArC(2,6)), 127.6 (SO₂ArC(2,6)), 128.9

(C(4)ArC(3,5)), 129.0 (C(4)ArC(4)), 129.8 (SO₂ArC(3,5)), 135.7

(4ry ArC), 136.0 (4ry ArC), 144.4 (iPrCHCH), 145.2 (C(4)

ArC(1)), 165.8 (C(2)O); m/z (NSI) 370 ([M + H]⁺, 32%); HRMS

(NSI) C₂₁H₂₄NO₃S⁺([M + H]⁺) requires 370.1471, found 370.1472

(+0.2 ppm).

Reaction carried out for 1.5 h at −78 °C gave crude lactams

(3S,4R)-34:(3S,4S)-77 (72:28 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 25:75) gave lactam (3S,4R)-34 (>98:2 dr) as a

colorless oil (189 mg, 57%) with identical spectroscopic properties as

before in 95% ee; [α]²_D⁰+0.8 (c 0.5, CH₂Cl₂) and lactam (3S,4S)-77

(95:5 dr) as a colorless oil (53.0 mg, 16%) with identical spectroscopic

properties as before in 97% ee; [α]²_D⁰−6.8 (c 0.5, CH₂Cl₂).

(3S,4R)-1-[(4-Methylbenzene)sulfonyl]-4-phenyl-3-[(1Z)-

prop-1-en-1-yl]azetidin-2-one 35 and (3S,4S)-1-[(4-

Methylbenzene)sulfonyl]-4-phenyl-3-[(1Z)-prop-1-en-1-yl]-

azetidin-2-one 78. Following general procedure A, (Z)-pent-3-enoic

acid 68 (160 mg, 1.60 mmol), iPr₂NEt (420 μL, 2.40 mmol) and

pivaloyl chloride (296 μL, 2.40 mmol) in CH₂Cl₂(10 mL), HBTM-

2.1 (2S,3R)-23 (24.6 mg, 0.08 mmol, 10 mol %), imine 19 (207 mg,

0.80 mmol) and iPr₂NEt (348 μL, 2.00 mmol) for 1.5 h at rt gave

crude lactams (3S,4R)-35 and (3S,4S)-78 (48:52 dr). Chromato-

graphic puriﬁcation (eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-

35 (92:8 dr) as a colorless oil (89 mg, 33%) and lactam (3S,4S)-78

(88:12 dr) as a white solid (97 mg, 36%).

1649

dx.doi.org/10.1021/jo402591v | J. Org. Chem. 2014, 79, 1640−1655

The Journal of Organic Chemistry

Article

+

Data for lactam (3S,4R)-35: Chiral HPLC Chiralpak AD-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3R,4S) 14.5

min, t_R(3S,4R) 16.0 min, 92% ee; ν_max(ATR)/cm⁻¹3030, 2967 (C−

H), 1788 (CO), 1456, 1362 (SO), 1167 (SO); Data for major

diastereoisomer δ_H(500 MHz, CDCl₃) 1.51 (3H, dd, J 6.9, 1.8 Hz,

CH₃CHCH), 2.43 (3H, s, ArCH₃), 4.00−4.02 (1H, m, C(3)H),

4.75 (1H, d, J 3.2 Hz, C(4)H), 5.44 (1H, ddq, J 10.6, 8.8, 1.8 Hz,

CH₃CHCH), 5.78 (1H, dqd, J 10.7, 6.9, 1.4 Hz, CH₃CHCH),

7.23−7.25 (4H, m, ArH), 7.28−7.35 (3H, m, ArH), 7.62−7.65 (2H,

m, SO₂Ar(2,6)H); δ_C(125 MHz, CDCl₃) 14.0 (CH₃CHCH), 21.8

(ArCH₃), 58.2 (C(3)), 64.4 (C(4)), 120.5 (CH₃CHCH), 126.7

(C(4)ArC(3,5)), 127.6 (SO₂ArC(3,5)), 128.9 (SO₂ArC(2,6)), 129.1

(C(4)ArC(4)), 129.9 (C(4)ArC(2,6)), 132.1 (CH₃CHCH), 135.7

(4ry ArC), 136.0 (4ry ArC), 145.3 (C(4)ArC(1)), 165.9 (C(2)O);

m/z (NSI) 342 ([M + H]⁺, 42%); HRMS (NSI) C₁₉H₂₀NO₃S⁺([M +

H]⁺) requires 342.1158, found 342.1159 (+0.2 ppm).

Data for lactam (3S,4S)-78: mp 83−85 °C; Chiral HPLC Chiralcel

OD-H (10% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C)

t_R(3S,4S) 12.0 min, t_R(3R,4R) 15.8 min, 98% ee; ν_max(ATR)/cm⁻¹

3032, 2922 (C−H), 1788 (CO), 1458, 1354 (SO), 1165 (S

O); Data for minor diastereoisomer δ_H(500 MHz, CDCl₃) 1.55−1.57

(3H, m, CH₃CHCH), 2.46 (3H, s, ArCH₃), 4.47−4.50 (1H, m,

C(3)H), 4.89−4.94 (1H, m, CH₃CHCH), 5.31 (1H, d, J 6.8 Hz,

C(4)H), 5.54 (1H, dqd, J 10.8, 6.9, 1.5 Hz, CH₃CHCH), 7.09−7.11

(2H, m, ArH), 7.23−7.34 (5H, m, ArH), 7.76−7.78 (2H, m,

SO₂Ar(2,6)H); δ_C(125 MHz, CDCl₃) 13.9 (CH₃CHCH), 21.9

(ArCH₃), 53.7 (C(3)), 61.8 (C(4)), 118.6 (CH₃CHCH), 127.4

(C(4)ArC(3,5)), 127.8 (SO₂ArC(3,5)), 128.5 (SO₂ArC(2,6)), 128.7

(C(4)ArC(4)), 130.0 (C(4)ArC(2,6)), 132.1 (CH₃CHCH), 134.0

(4ry ArC), 135.7 (4ry ArC), 145.4 (C(4)ArC(1)), 165.9 (C(2)O);

m/z (NSI) 342 ([M + H]⁺, 30%); HRMS (NSI) C₁₉H₂₀NO₃S⁺([M +

H]⁺) requires 342.1158, found 342.1160 (+0.5 ppm).

HRMS (NSI⁺) C₁₅H₁₇F₃NO₂([M + NH₄]⁺) requires 300.1206,

found 300.1206 (+0.0 ppm).

(3S,4R)-4-Phenyl-3-((E)-but-1-en-1-yl)-6-(triﬂuoromethyl)-

3,4-dihydro-2H-pyran-2-one 37. Following general procedure A,

(E)-hex-3-enoic acid 81 (47.4 μL, 0.40 mmol), iPr₂NEt (104 μL, 0.60

mmol) and pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL),

HBTM-2.1 (2S,3R)-23 (6.16 mg, 0.02 mmol, 5 mol %), (E)-1,1,1-

triﬂuoro-4-phenyl-3-buten-2-one 57 (80.0 mg, 0.40 mmol) and

iPr₂NEt (174 μL, 1.0 mmol) for 5 min at rt gave crude lactone

(3S,4R)-37 (90:10 dr). Chromatographic puriﬁcation (eluent

Et₂O:petrol 3:97) gave lactone (3S,4R)-37 (93:7 dr) as a colorless

oil (98.7 mg, 83%): [α]_D²⁰−191.0 (c 0.5, CH₂Cl₂); Chiral HPLC

Chiralcel OD-H (1% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30

°C) major diastereoisomer t_R(3S,4R) 8.9 min, t_R(3R,4S) 12.4 min,

96% ee; minor diastereoisomer t_R9.9 min, t_R14.4 min, 12% ee; ν_max

(ATR)/cm⁻¹3065, 2968 (C−H), 1786 (CO), 1699; Data for major

diastereoisomer δ_H(500 MHz, CDCl₃) 0.92 (3H, t, J 7.5, CH₃), 2.00−

2.06 (2H, m, CH₂CH₃), 3.42 (1H, t, J 7.1, C(3)H), 3.71−3.74 (1H, m,

C(4)H), 5.41−5.45 (1H, m, C(3)CHCHCH₂CH₃or C(3)CH

CHCH₂CH₃), 5.49−5.54 (1H, m, C(3)CHCHCH₂CH₃or

C(3)CHCHCH₂CH₃), 6.10 (1H, d, J 4.6, C(5)H), 7.14−7.16

(2H, m, C(4)Ar(2,6)H), 7.31−7.40 (3H, m, C(4)Ar(3,5)H and

C(4)Ar(4)H); δ_C(125 MHz, CDCl₃) 13.2 (CH₃), 25.6 (CH₂CH₃),

43.3 (C(4)), 49.9 (C(3)), 109.7 (q, J 3.5, C(5)), 118.5 (q, J 270, CF₃),

121.6 (C(3)CHCHCH₂CH₃), 127.5 (ArC), 128.1 (ArC), 129.2

(ArC), 138.7 (4ry C(4)ArC(1)), 138.8 (C(3)CHCHCH₂CH₃),

140.8 (q, J 37.9, C(6)), 166.2 (C(2)); δ_F(376 MHz, CDCl₃) −72.6

(CF₃); Selected data or minor diastereoisomer δ_H(500 MHz, CDCl₃)

3.63 (1H, t, J 7.7, C(3)H), 3.87−3.90 (1H, m, C(4)H), 5.10 (1H, ddt,

J 15.5, 8.5, 1.6, C(3)CHCHCH₂CH₃), 5.70 (1H, dt, J 15.4, 6.4,

C(3)CHCHCH₂CH₃), 6.23 (1H, d, J 5.7, C(5)H), 7.11 (2H, d, J

8.0, Ar(2,6)H); δ_C(125 MHz, CDCl₃) 43.0 (C(4)), 47.6 (C(3)),

110.7 (q, J 3.5, C(5)), 120.5 (C(3)CHCHCH₂CH₃), 128.2 (ArC),

128.2 (ArC), 129.0 (ArC), 138.9 (C(3)CHCHCH₂CH₃), 166.6

(C(2)); δ_F(376 MHz, CDCl₃) −72.6 (CF₃); m/z (NSI⁺) 297 ([M +

Reaction carried out for 1.5 h at −78 °C gave crude lactams

(3S,4R)-35:(3S,4S)-78 (43:57 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 20:80) gave lactam (3S,4R)-35 (92:8 dr) as a

colorless oil (58 mg, 21%) with identical spectroscopic properties as

before in 99% ee; [α]²_D⁰+4.2 (c 0.5, CH₂Cl₂) and lactam (3S,4S)-78

(88:12 dr) as a white solid (99.0 mg, 36%) with identical spectroscopic

properties as before in 99% ee; [α]²_D⁰−14.2 (c 0.5, CH₂Cl₂).

+

H]⁺, 20%); HRMS (NSI⁺) C₁₆H₁₆F₃O₂([M + H]⁺) requires

297.1097, found 297.1101 (+1.4 ppm).

(3S,4R)-4-Phenyl-3-((E)-styryl)-6-(triﬂuoromethyl)-3,4-dihy-

dro-2H-pyran-2-one 38. Following general procedure A, (E)-4-

phenylbut-3-enoic acid 16 (64.9 mg, 0.40 mmol), iPr₂NEt (104 μL,

0.60 mmol) and pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2

mL), HBTM-2.1 (2S,3R)-23 (6.16 mg, 0.02 mmol, 5 mol %), (E)-

1,1,1-triﬂuoro-4-phenyl-3-buten-2-one 57 (80.0 mg, 0.40 mmol) and

iPr₂NEt (174 μL, 1.0 mmol) for 5 min at −78 °C gave crude lactone

(3S,4R)-38 (95:5 dr). Chromatographic puriﬁcation (eluent

Et₂O:petrol 7.5:92.5) gave lactone (3S,4R)-38 (95:5 dr) as a colorless

oil (113 mg, 82%): [α]_D²⁰−159.6 (c 0.5, CH₂Cl₂); Chiral HPLC

Chiralpak IB (5% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C)

major diastereoisomer t_R(3R,4S) 12.3 min, t_R(3S,4R) 13.9 min, 60%

ee; minor diastereoisomer t_R8.00 min, t_R10.6 min, 52% ee; ν_max

(ATR)/cm⁻¹3063, 3030 (C−H), 1782 (CO), 1699, 1601; Data for

major diastereoisomer δ_H(500 MHz, CDCl₃) 3.65 (1H, t, J 7.6, C(3)

H), 3.85−3.90 (1H, m, C(4)H), 6.15−6.20 (2H, m, C(5)H and

C(3)CHCHPh), 6.36 (1H, d, J 15.9, C(3)CHCHPh), 7.21 (2H,

d, J 7.5, ArH), 7.28−7.42 (8H, m, ArH); δ_C(125 MHz, CDCl₃) 43.3

(C(4)), 50.0 (C(3)), 109.9 (q, J 3.3, C(5)), 118.5 (q, J 270, CF₃),

122.0 (C(3)CHCHPh), 126.6 (ArC), 127.5 (ArC), 128.3 (ArC),

128.4 (ArC), 128.7 (ArC), 129.4 (ArC), 135.7 (C(3)CHCHPh),

135.8 (4ry ArC), 138.5 (4ry ArC), 141.0 (q, J 38.0, C(6)), 165.6

(C(2)); δ_F(376 MHz, CDCl₃) −72.6 (CF₃); Selected data for minor

diastereoisomer δ_H(500 MHz, CDCl₃) 3.99 (1H, t, J 6.2, C(4)H),

5.84 (1H, dd, J 16.0, 8.6, C(3)CHCHPh), 6.30 (1H, d, J 5.9, C(5)

H), 6.59 (1H, d, J 16.0, C(3)CHCHPh), 7.16 (2H, d, J 7.6, ArH);

δ_C(125 MHz, CDCl₃) 47.9 (C(3)), 110.7 (q, J 3.4, C(5)), 121.4

(C(3)CHCHPh), 128.2 (ArC), 128.5 (ArC), 129.3 (ArC), 135.4

(C(3)CHCHPh), 166.2 (C(2)); δ_F(376 MHz, CDCl₃) −72.7

(CF₃); m/z (NSI⁺) 345 ([M + H]⁺, 15%); HRMS (NSI⁺)

(3S,4R)-4-Phenyl-3-((E)-prop-1-en-1-yl)-6-(triﬂuoromethyl)-

3,4-dihydro-2H-pyran-2-one 36. Following general procedure A,

(E)-pent-3-enoic acid 24 (40.6 μL, 0.40 mmol), iPr₂NEt (104 μL, 0.60

mmol) and pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL),

HBTM-2.1 (2S,3R)-23 (6.16 mg, 0.02 mmol, 5 mol %), (E)-1,1,1-

triﬂuoro-4-phenyl-3-buten-2-one 57 (80.0 mg, 0.40 mmol) and

iPr₂NEt (174 μL, 1.0 mmol) for 5 min at rt gave crude lactone

(3S,4R)-36 (88:12 dr). Chromatographic puriﬁcation (eluent

Et₂O:petrol 4:96) gave lactone (3S,4R)-36 (88:12 dr) as a colorless

oil (89.8 mg, 80%): [α]_D²⁰−212.4 (c 0.5, CH₂Cl₂); Chiral HPLC

Chiralcel OD-H (1% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30

°C) major diastereoisomer t_R(3S,4R) 9.7 min, t_R(3R,4S) 13.2 min,

96% ee; minor diastereoisomer t_R10.7 min, t_R14.8 min, 15% ee; ν_max

(ATR)/cm⁻¹3060, 3027 (C−H), 1784 (CO), 1699; Data for major

diastereoisomer δ_H(500 MHz, CDCl₃) 1.68 (3H, t, J, 5.9, CH₃), 3.43

(1H, t, J 6.9, C(3)H), 3.70−3.75 (1H, m, C(4)H), 5.44−5.56 (2H, m,

C(3)CHCHCH₃and C(3)CHCHCH₃), 6.09 (1H, d, J 4.5, C(5)

H), 7.11 (2H, d, J 7.8, C(4)Ar(2,6)H), 7.31−7.40 (3H, m,

C(4)Ar(3,5)H and C(4)Ar(4)H); δ_C(75 MHz, CDCl₃) 18.1

(CH₃), 43.2 (C(4)), 49.9 (C(3)), 109.7 (q, J 3.5, C(5)), 118.5 (q, J

270, CF₃), 123.8 (C(3)CHCHCH₃), 127.4 (ArC), 128.1 (ArC),

129.2 (ArC), 132.1 (C(3)CHCHCH₃), 138.7 (4ry C(4)ArC(1)),

140.8 (q, J 37.9, C(6)), 166.1 (C(2)); δ_F(376 MHz, CDCl₃) −72.6

(CF₃); Selected data or minor diastereoisomer δ_H(500 MHz, CDCl₃)

3.63 (1H, t, J 7.8, C(3)H), 3.86−3.88 (1H, m, C(4)H), 5.13 (1H, dd, J

15.4, 8.6, C(3)CHCHCH₃), 5.69 (1H, dq, J 14.7, 7.1, C(3)CH

CHCH₃), 6.23 (1H, d, J 5.7, C(5)H), 7.11 (2H, d, J 7.7, Ar(2,6)H); δ_C

(75 MHz, CDCl₃) 18.0 (CH₃), 43.0 (C(4)), 47.7 (C(3)), 110.8 (q, J

3.5, C(5)), 122.6 (C(3)CHCHCH₃), 128.2 (ArC), 128.3 (ArC),

129.1 (ArC), 132.2 (C(3)CHCHCH₃), 166.6 (C(2)); δ_F(376

MHz, CDCl₃) −72.7 (CF₃); m/z (NSI⁺) 300 ([M + NH₄]⁺, 100%);

C₂₀H₁₆F₃O₂([M + H]⁺) requires 345.1097, found 345.1098 (+0.3

+

ppm).

1650

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The Journal of Organic Chemistry

Article

(3S,4R)-4-(4-Bromophenyl)-3-((E)-prop-1-en-1-yl)-6-(triﬂuor-

omethyl)-3,4-dihydro-2H-pyran-2-one 39. Following general

procedure A, (E)-pent-3-enoic acid 24 (40.6 μL, 0.40 mmol), iPr₂NEt

(104 μL, 0.60 mmol) and pivaloyl chloride (74.0 μL, 0.60 mmol) in

CH₂Cl₂(2 mL), HBTM-2.1 (2S,3R)-23 (6.16 mg, 0.02 mmol, 5 mol

%), (E)-1,1,1-triﬂuoro-4-(4-bromophenyl)-3-buten-2-one 58 (112 mg,

0.40 mmol) and iPr₂NEt (174 μL, 1.0 mmol) for 5 min at rt gave

crude lactone (3S,4R)-39 (80:20 dr). Chromatographic puriﬁcation

(eluent Et₂O:petrol 3:97) gave lactone (3S,4R)-39 (95:5 dr) as a

colorless oil (105 mg, 73%): [α]²_D⁰−201.0 (c 0.5, CH₂Cl₂); Chiral

HPLC Chiralcel OD-H (1% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211

nm, 30 °C) major diastereoisomer t_R(3R,4S) 10.1 min, t_R(3S,4R) 11.8

min, 92% ee; minor diastereoisomer t_R9.3 min, t_R12.8 min, 90% ee;

ν_max(ATR)/cm⁻¹2987 (C−H), 1786 (CO), 1753, 1660; Data for

major diastereoisomer δ_H(500 MHz, CDCl₃) 1.69 (3H, t, J, 6.4, CH₃),

3.37 (1H, t, J 7.4, C(3)H), 3.68−3.71 (1H, m, C(4)H), 5.43 (1H, ddd,

J 15.3, 7.5, 1.3, C(3)CHCHCH₃), 5.52 (1H, dq, J 15.4, 6.3,

C(3)CHCHCH₃), 6.03 (1H, d, J 4.4, C(5)H), 7.02−7.04 (2H, m,

C(4)Ar(3,5)H), 7.50−7.52 (2H, m, C(4)Ar(2,6)H); δ_C(125 MHz,

CDCl₃) 18.1 (CH₃), 42.7 (C(4)), 49.7 (C(3)), 109.2 (q, J 3.5, C(5)),

118.4 (q, J 270, CF₃), 122.1 (C(4)ArC(4)), 123.4 (C(3)CH

CHCH₃), 129.1 (C(4)ArC(3,5)), 132.3 (C(4)ArC(2,6)), 132.6

(C(3)CHCHCH₃), 137.7 (4ry C(4)ArC(1)), 141.1 (q, J 38,

C(6)), 165.8 (C(2)); δ_F(376 MHz, CDCl₃) −72.7 (CF₃); Selected

data or minor diastereoisomer δ_H(500 MHz, CDCl₃) 3.62 (1H, t, J

7.8, C(3)H), 3.82−3.85 (1H, m, C(4)H), 5.09−5.14 (1H, m,

C(3)CHCHCH₃), 5.65−5.72 (1H, m, C(3)CHCHCH₃), 6.18

(1H, d, J 5.7, C(5)H); δ_C(75 MHz, CDCl₃) 18.0 (CH₃), 44.4 (C(4)),

47.4 (C(3)); δ_F(376 MHz, CDCl₃) −72.8 (CF₃); m/z (NSI⁺) 378

stirring for 1 h at rt gave after chromatographic puriﬁcation (eluent

Et₂O:petrol 40:60) a rotameric mixture (ratio 95:5) of (2R)-41 as a

white solid (105 mg, 80%): mp 108−110 °C; [α]²_D⁰−67.0 (c 0.5,

CH₂Cl₂); Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow rate 1 mL

min⁻¹, 211 nm, 30 °C) t_R(2S) 13.2 min, t_R(2R) 17.3 min, 96% ee; ν_max

(ATR)/cm⁻¹3350 (N−H), 2949 (C−H), 1721 (CO), 1698 (C

O), 1597; Data for major rotamer δ_H(500 MHz, CDCl₃) 1.72 (3H, d,

J 4.7, CH₃CH), 3.78 (3H, s, OCH₃), 5.25−5.26 (1H, m, C(2)H),

5.79−5.89 (2H, m, CHCHCH₃and CHCHCH₃), 6.94−6.97

(3H, m, NAr(2,6)H and NAr(4)H), 7.27−7.30 (2H, m, NAr(3,5)H),

7.50 (2H, t, J 7.6, C(O)Ar(3,5)H), 7.58 (1H, t, J 7.4, C(O)Ar(4)H),

7.86−7.88 (2H, m, C(O)Ar(2,6)H), 8.64 (1H, s, NH); δ_C(125 MHz,

CDCl₃) 18.2 (CH₃CH), 52.4 (OCH₃), 64.6 (C(2)), 114.7

(NArC(2,6)), 121.5 (NArC(4)), 123.6 (CHCHCH₃), 127.2

(C(O)ArC(2,6)), 128.8 (C(O)ArC(3,5)), 129.4 (NArC(3,5)), 132.0

(C(O)ArC(4) or CHCHCH₃), 132.3 (C(O)ArC(4)) or CH

CHCH₃), 133.0 (4ry C(O)ArC(1)), 148.1 (NArC(1)), 167.4

(NHCO), 173.3 (MeOCO); Selected data for minor rotamer

δ_H(500 MHz, CDCl₃) 1.65 (3H, d, J 5.9, CH₃CH), 3.67 (3H, s,

OCH₃), 4.97 (1H, d, J 7.1, C(2)H); δ_C(125 MHz, CDCl₃) 18.1

(CH₃CH), 52.3 (OCH₃), 65.8 (C(2)), 115.0 (NArC(2,6)); m/z

+

(NSI⁺) 325 ([M + H]⁺, 100%); HRMS (NSI⁺) C₁₉H₂₁N₂O₃([M +

H]⁺) requires 325.1547, found 325.1548 (+0.4 ppm).

(2R)-(E)-Methyl 2-(2-benzoyl-1-phenylhydrazinyl)hex-3-

enoate 42. Following general procedure A, (E)-hex-3-enoic acid 81

(47.4 μL, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol) and pivaloyl

chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL), HBTM-2.1

(2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-(phenylimino)-

benzamide 60 (84.0 mg, 0.40 mmol) and iPr₂NEt (174 μL, 1.00

mmol) for 15 min at rt, followed by addition of MeOH (2 mL) and

stirring for 1 h at rt gave after chromatographic puriﬁcation (eluent

Et₂O:petrol 40:60) a rotameric mixture (ratio 95:5) of (2R)-42 as a

white solid (115 mg, 85%): mp 98−100 °C; [α]²_D⁰−54.8 (c 0.5,

CH₂Cl₂); Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow rate 1 mL

min⁻¹, 211 nm, 30 °C) t_R(2S) 11.3 min, t_R(2R) 15.6 min, 99% ee; ν_max

(ATR)/cm⁻¹3352 (N−H), 2990 (C−H), 1721 (CO), 1688 (C

O), 1597, 1508; Data for major rotamer δ_H(500 MHz, CDCl₃) 0.90

(3H, t, J 7.4, CH₃CH₂), 2.03−2.09 (2H, m, CH₃CH₂) 3.78 (3H, s,

OCH₃), 5.26−5.27 (1H, m, C(2)H), 5.77−5.88 (2H, m, CH

CHCH₂CH₃and CHCHCH₂CH₃), 6.93−6.97 (3H, m, NAr(2,6)H

and NAr(4)H), 7.26−7.29 (2H, m, NAr(3,5)H), 7.47−7.50 (2H, m,

C(O)Ar(3,5)H), 7.55−7.58 (1H, m, C(O)Ar(4)H), 7.85−7.87 (2H,

m, C(O)Ar(2,6)H), 8.62 (1H, s, NH); δ_C(125 MHz, CDCl₃) 13.1

(CH₃CH₂), 25.6 (CH₃CH₂), 52.4 (OCH₃), 64.5 (C(2)), 114.7

(NArC(2,6)), 121.6 (NArC(4) or CHCHCH₂CH₃), 121.7

(NArC(4) or CHCHCH₂CH₃), 127.3 (C(O)ArC(2,6)), 128.9

(C(O)ArC(3,5)), 129.4 (NArC(3,5)), 132.1 (C(O)ArC(4)), 133.1

(C(O)ArC(1)), 138.8 (CHCHCH₂CH₃), 148.2 (NArC(1)), 167.4

(NHCO), 173.4 (MeOCO); Selected data for minor rotamer δ_H

(500 MHz, CDCl₃) 3.67 (3H, s, OCH₃), 4.99−5.00 (1H, m, C(2)H);

δ_C(125 MHz, CDCl₃) 12.5 (CH₃CH₂), 52.3 (OCH₃), 66.1 (C(2)),

115.1 (NArC(2,6)), 141.1 (CHCHCH₂CH₃), 148.7 (NArC(1)),

167.4 (NHCO), 173.4 (MeOCO); m/z (NSI⁺) 339 ([M + H]⁺,

+

([M + NH₄]⁺, 56%); HRMS (NSI⁺) C₁₅H₁₆⁷⁸BrF₃NO₂([M +

NH₄]⁺) requires 378.0311, found 378.0311 (+0.0 ppm).

(3S,4R)-4-(Thiophen-2-yl)-3-((E)-prop-1-en-1-yl)-6-(triﬂuoro-

methyl)-3,4-dihydro-2H-pyran-2-one 40. Following general pro-

cedure A, (E)-pent-3-enoic acid 24 (40.6 μL, 0.40 mmol), iPr₂NEt

(104 μL, 0.60 mmol) and pivaloyl chloride (74.0 μL, 0.60 mmol) in

CH₂Cl₂(2 mL), HBTM-2.1 (2S,3R)-23 (6.16 mg, 0.02 mmol, 5 mol

%), (E)-1,1,1-triﬂuoro-4-(2-thienyl)-3-buten-2-one 59 (82.4 mg, 0.40

mmol) and iPr₂NEt (174 μL, 1.0 mmol) for 5 min at rt gave crude

lactone (3S,4R)-40 (84:16 dr). Chromatographic puriﬁcation (eluent

Et₂O:petrol 4:96) gave lactone (3S,4R)-40 (84:16 dr) as a colorless oil

(95.8 mg, 83%): [α]²_D⁰−187.0 (c 0.5, CH₂Cl₂); Chiral HPLC

Chiralpak AS-H (0.5% IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30

°C) major diastereoisomer t_R(3S,4R) 14.1 min, t_R(3R,4S) 16.1 min,

93% ee; ν_max(ATR)/cm⁻¹2998 (C−H), 1784 (CO), 1699, 1674;

Data for major diastereoisomer δ_H(300 MHz, CDCl₃) 1.72−1.74

(3H, m, CH₃), 3.55 (1H, td, J 6.7, 0.7, C(3)H), 4.00−4.04 (1H, m,

C(4)H), 5.47 (1H, ddq, J 15.4, 8.4, 1.7, C(3)CHCHCH₃), 5.63−

5.75 (1H, m, C(3)CHCHCH₃), 6.16 (1H, d, J 5.0, C(5)H), 6.89−

6.90 (1H, m, ArH), 6.98−7.03 (1H, m, ArH), 7.27−7.30 (1H, m,

ArH); δ_C(125 MHz, CDCl₃) 18.1 (CH₃), 38.2 (C(4)), 50.6 (C(3)),

109.2 (q, J 3.5, C(5)), 118.4 (q, J 270, CF₃), 123.2 (C(3)CH

CHCH₃), 125.4 (ArC), 125.4 (ArC), 127.4 (ArC), 132.4 (C(3)CH

CHCH₃), 140.7 (q, J 37.9, C(6)), 141.2 (C(4)ArC(1)), 165.5 (C(2));

δ_F(376 MHz, CDCl₃) −72.4 (CF₃); Selected data or minor

diastereoisomer δ_H(500 MHz, CDCl₃) 3.64 (1H, t, J 7.5, C(3)H),

4.13−4.18 (1H, m, C(4)H), 5.35 (1H, ddq, J 15.4, 8.4, 1.7, C(3)CH

CHCH₃), 6.28 (1H, d, J 5.8, C(5)H); δ_C(75 MHz, CDCl₃) 18.1

(CH₃), 38.0 (C(4)), 48.0 (C(3)), 110.7 (q, J 3.5, C(5)), 122.5 (C(3)

CHCHCH₃), 125.7 (ArC), 126.3 (ArC), 127.4 (ArC), 132.7

(C(3)CHCHCH₃), 166.2 (C(2)); δ_F(376 MHz, CDCl₃) −72.6

(CF₃); m/z (APCI⁺) 289 ([M + H]⁺, 100%); HRMS (APCI⁺)

C₁₃H₁₂F₃O₂S⁺([M + H]⁺) requires 289.0505, found 289.0507 (+0.8

ppm).

+

100%); HRMS (NSI⁺) C₂₀H₂₃N₂O₃([M + H]⁺) requires 339.1703,

found 339.1708 (+1.4 ppm).

(2R)-(E)-Methyl 2-(2-benzoyl-1-phenylhydrazinyl)-5-methyl-

hex-3-enoate 43. Following general procedure A, (E)-5-methylhex-

3-enoic acid 65 (51.2 mg, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol)

and pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL),

HBTM-2.1 (2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-

(phenylimino)benzamide 60 (84.0 mg, 0.40 mmol) and iPr₂NEt (174

μL, 1.00 mmol) for 15 min at rt, followed by addition of MeOH (2

mL) and stirring for 1 h at rt gave after chromatographic puriﬁcation

(eluent Et₂O:petrol 40:60) a rotameric mixture (ratio 95:5) of (2R)-

43 as a white solid (104 mg, 74%): mp 128−130 °C; [α]²_D⁰−66.6 (c

0.5, CH₂Cl₂); Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow rate 1

mL min⁻¹, 211 nm, 30 °C) t_R(2S) 14.5 min, t_R(2R) 19.0 min, 99% ee;

ν_max(ATR)/cm⁻¹3326 (N−H), 2988 (C−H), 1719 (CO Ester),

1678 (CO Amide), 1597, 1506; Data for major rotamer δ_H(500

MHz, CDCl₃) 0.89 (3H, t, J 6.8, CH(CH₃)CH₃), 0.92 (3H, t, J 6.8,

(2R)-(E)-Methyl 2-(2-benzoyl-1-phenylhydrazinyl)pent-3-

enoate 41. Following general procedure A, (E)-pent-3-enoic acid

24 (40.6 μL, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol) and pivaloyl

chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL), HBTM-2.1

(2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-(phenylimino)-

benzamide 60 (84.0 mg, 0.40 mmol) and iPr₂NEt (174 μL, 1.00

mmol) for 15 min at rt, followed by addition of MeOH (2 mL) and

1651

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The Journal of Organic Chemistry

Article

CH(CH₃)CH₃), 2.27−2.34 (1H, m, CH(CH₃)CH₃), 3.78 (3H, s,

OCH₃), 5.27−5.28 (1H, m, C(2)H), 5.72−5.80 (2H, m, CH

CHCH(CH₃)CH₃and CHCHCH(CH₃)CH₃), 6.93−6.97 (3H, m,

NAr(2,6)H and NAr(4)H), 7.26−7.30 (2H, m, NAr(3,5)H), 7.46−

7.49 (2H, m, C(O)Ar(3,5)H), 7.54−7.58 (1H, m, C(O)Ar(4)H),

7.85−7.88 (2H, m, C(O)Ar(2,6)H), 8.64 (1H, s, NH); δ_C(100 MHz,

CDCl₃) 21.8 (CH(CH₃)CH₃), 22.0 (CH(CH₃)CH₃), 31.1

(CH(CH₃)CH₃), 52.3 (OCH₃), 64.4 (C(2)), 114.8 (NArC(2,6)),

120.0 (CHCHCH(CH₃)CH₃), 121.5 (NArC(4)), 127.3 (C(O)

ArC(2,6)), 128.8 (C(O)ArC(3,5)), 129.4 (NArC(3,5)), 132.1 (C(O)

ArC(4)), 133.0 (C(O)ArC(1)), 143.9 (CHCHCH(CH₃)CH₃),

148.2 (NArC(1)), 167.3 (NHCO), 173.4 (MeOCO); Selected

data for minor rotamer δ_H(500 MHz, CDCl₃) 3.66 (3H, s, OCH₃),

5.01 (1H, d, J 7.0, C(2)H); δ_C(100 MHz, CDCl₃) 21.4

(CH(CH₃)CH₃), 21.5 (CH(CH₃)CH₃), 31.1 (CH(CH₃)CH₃), 52.2

(OCH₃), 66.3 (C(2)), 115.2 (NArC(2,6)), 146.1 (CH

CHCH₂CH₃), 148.8 (NArC(1)), 172.0 (MeOCO); m/z (NSI⁺)

(CH₃), 64.9 (C(2)), 114.8 (NArC(2,6)), 121.7 (NArC(4)), 122.1

(CHCHPh), 126.8 (CHArC(4)), 127.2 (C(O)ArC(2,6)), 128.3

(ArC), 128.7 (ArC), 128.8 (C(O)ArC(3,5)), 129.5 NArC(3,5)), 132.1

(C(O)ArC(4)), 133.0 (C(O)ArC(1)), 135.0 (CHCHPh), 135.9

(CHArC(1)), 148.0 (NArC(1)), 167.6 (NHCO), 172.8

(MeOCO); Selected data for minor rotamer δ_H(500 MHz,

CDCl₃) 3.73 (3H, s, CH₃), 5.21 (1H, d, J 7.2, C(2)H), 6.02 (1H, dd, J

16.1, 7.2, CHCHPh), 7.98 (1H, s, NH); δ_C(125 MHz, CDCl₃) 52.5

(CH₃), 66.1 (C(2)), 115.1 (NArC(2,6)), 137.5 (CHCHPh); m/z

+

(NSI⁺) 387 ([M + H]⁺, 100%); HRMS (NSI⁺) C₂₄H₂₃N₂O₃([M +

H]⁺) requires 387.1703, found 387.1704 (−0.2 ppm).

(2R)-(Z)-Methyl 2-(2-benzoyl-1-phenylhydrazinyl)pent-3-

enoate 46. Following general procedure A, (Z)-pent-3-enoic acid

68 (40.0 mg, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol) and pivaloyl

chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL), HBTM-2.1

(2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-(phenylimino)-

benzamide 60 (84.0 mg, 0.40 mmol) and iPr₂NEt (174 μL, 1.00

mmol) for 15 min at rt, followed by addition of MeOH (2 mL) and

stirring for 1 h at rt gave after chromatographic puriﬁcation (eluent

Et₂O:petrol 50:50) a rotameric mixture (ratio 95:5) of (2R)-46 (94:6

(Z):(E)) as a colorless oil (93.7 mg, 72%): [α]²_D⁰−76.8 (c 0.5,

CH₂Cl₂); Chiral HPLC Chiralpak AD-H (20% IPA:hexane, ﬂow rate 1

mL min⁻¹, 220 nm, 30 °C) t_R(2S) 19.1 min, t_R(2R) 23.6 min, 99% ee;

ν_max(ATR)/cm⁻¹3291 (N−H), 2953 (C−H), 1732 (CO Ester),

1674 (CO Amide), 1599; Data for major isomer (Z) and major

rotamer δ_H(400 MHz, CDCl₃) 1.88 (3H, dd, J 7.0, 1.8, CH₃CH),

3.75 (3H, s, OCH₃), 5.48 (1H, d, J 8.2, C(2)H), 5.61−5.67 (1H, m,

CHCHCH₃), 5.91 (1H, dqd, J 10.7, 7.0, 1.0, CHCHCH₃), 6.93−

6.99 (3H, m, NAr(2,6)H and NAr(4)H), 7.26−7.30 (2H, m, NAr(3,5)

H), 7.46−7.51 (2H, m, C(O)Ar(3,5)H), 7.54−7.59 (1H, m,

C(O)Ar(4)H), 7.88−7.91 (2H, m, C(O)Ar(2,6)H), 8.67 (1H, s,

NH); δ_C(100 MHz, CDCl₃) 14.1 (CH₃CH), 52.6 (OCH₃), 59.8

(C(2)), 114.7 (NArC(2,6)), 121.6 (NArC(4)), 121.7 (CHCHCH₃),

127.4 (C(O)ArC(2,6)), 128.9 (C(O)ArC(3,5)), 129.5 (NArC(3,5)),

132.2 (C(O)ArC(4), 132.7 (CHCHCH₃), 132.8 (C(O)ArC(1)),

148.3 (NArC(1)), 167.0 (NHCO), 173.6 (MeOCO); m/z

+

353 ([M + H]⁺, 100%); HRMS (NSI⁺) C₂₁H₂₅N₂O₃([M + H]⁺)

requires 353.1860, found 353.1862 (+0.7 ppm).

(2R)-(E)-Methyl 2-(2-benzoyl-1-phenylhydrazinyl)-5-phenyl-

pent-3-enoate 44. Following general procedure A, (E)-5-phenyl-

pent-3-enoic acid 66 (70.4 mg, 0.40 mmol), iPr₂NEt (104 μL, 0.60

mmol) and pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL),

HBTM-2.1 (2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-

(phenylimino)benzamide 60 (84.0 mg, 0.40 mmol) and iPr₂NEt (174

μL, 1.00 mmol) for 15 min at rt, followed by addition of MeOH (2

mL) and stirring for 1 h at rt gave after chromatographic puriﬁcation

(eluent Et₂O:petrol 50:50) a rotameric mixture (ratio 96:4) of (2R)-

44 as a white solid (123 mg, 77%): mp 136−138 °C; [α]²_D⁰−70.8 (c

0.5, CH₂Cl₂); Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow rate 1

mL min⁻¹, 220 nm, 30 °C) t_R(2S) 28.5 min, t_R(2R) 41.2 min, 99% ee;

ν_max(ATR)/cm⁻¹3323 (N−H), 2890 (C−H), 1730 (CO Ester),

1686 (CO Amide), 1599, 1514; Data for major rotamer δ_H(500

MHz, CDCl₃) 3.41 (2H, d, J 6.1, CHHPh and CHHPh), 3.78 (3H, s,

OCH₃), 5.34−5.35 (1H, m, C(2)H), 5.89−6.00 (2H, m, CHCHBn

and CHCHBn), 6.96−6.99 (3H, m, NAr(2,6)H and NAr(4)H),

7.05−7.03 (CH₂Ar(2,6)H), 7.12−7.15 (CH₂Ar(3,5)H and CH₂Ar(4)

H), 7.28−7.32 (2H, m, NAr(3,5)H), 7.48−7.51 (2H, m, C(O)Ar(3,5)

H), 7.58−7.62 (1H, m, C(O)Ar(4)H), 7.85−7.86 (2H, m, C(O)Ar-

(2,6)H), 8.68 (1H, s, NH); δ_C(100 MHz, CDCl₃) 38.9 (CH₂Ph), 52.4

(OCH₃), 64.5 (C(2)), 114.7 (NArC(2,6)), 121.6 (NArC(4)), 124.1

(CHCHBn), 126.2 (CH₂ArC(4)), 127.3 (C(O)ArC(2,6)), 128.4

(ArC), 128.6 (ArC), 128.8 (C(O)ArC(3,5)), 129.4 (NArC(3,5)),

132.1 (C(O)ArC(4)), 132.8 (C(O)ArC(1)), 135.7 (CHCHBn),

138.9 (CH₂ArC(1)), 148.1 (NArC(1)), 167.1 (NHCO), 173.1

(MeOCO); Selected data for minor rotamer δ_H(500 MHz, CDCl₃)

3.67 (3H, s, OCH₃), 5.06−5.08 (1H, m, C(2)H); δ_C(100 MHz,

CDCl₃) 38.8 (CH₂Ph), 52.3 (OCH₃), 66.2 (C(2)), 115.2

(NArC(2,6)), 148.7 (NArC(1)); m/z (NSI⁺) 401 ([M + H]⁺,

+

(NSI⁺) 325 ([M + H]⁺, 100%); HRMS (NSI⁺) C₁₉H₂₁N₂O₃([M +

H]⁺) requires 325.1547, found 325.1548 (+0.4 ppm).

(2R)-(E)-Methyl 2-(2-(4-ﬂuorobenzoyl)-1-phenylhydrazinyl)-

pent-3-enoate 47. Following general procedure A, (E)-pent-3-

enoic acid 24 (40.6 μL, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol) and

pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL), HBTM-2.1

(2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-4-ﬂuoro-N-

(phenylimino)benzamide 61 (91.2 mg, 0.40 mmol) and iPr₂NEt (174

μL, 1.00 mmol) for 15 min at rt, followed by addition of MeOH (2

mL) and stirring for 1 h at rt gave after chromatographic puriﬁcation

(eluent Et₂O:petrol 40:60) a rotameric mixture (ratio 92:8) of (2R)-

47 as a white solid (109 mg, 79%): mp 102−104 °C; [α]²_D⁰−57.8 (c

0.5, CH₂Cl₂); Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow rate 1

mL min⁻¹, 211 nm, 30 °C) t_R(2S) 13.2 min, t_R(2R) 17.1 min, 99% ee;

ν_max(ATR)/cm⁻¹3522 (N−H), 2951 (C−H), 1751 (CO), 1661

(CO), 1599; Data for major rotamer δ_H(500 MHz, CDCl₃) 1.68−

1.69 (3H, m, CH₃CH), 3.76 (3H, s, OCH₃), 5.21−5.22 (1H, m,

C(2)H), 5.74−5.84 (2H, m, CHCHCH₃and CHCHCH₃),

6.91−6.95 (3H, m, NAr(2,6)H and NAr(4)H), 7.13−7.17 (2H, t, J

8.4, NAr(3,5)H), 7.24−7.27 (2H, m, C(O)Ar(3,5)H), 7.84−7.87 (2H,

m, C(O)Ar(2,6)H), 8.60 (1H, s, NH); δ_C(125 MHz, CDCl₃) 18.2

(CH₃CH), 52.4 (OCH₃), 64.6 (C(2)), 114.8 (NArC(2,6)), 116.0

(d, J 21.8, C(O)ArC(3,5)), 121.7 (NArC(4)), 123.7 (CHCHCH₃),

129.2 (d, J 3.5, C(O)ArC(1)), 129.5 (NArC(3,5)), 129.7 (d, J 8.7,

C(O)ArC(2,6)), 132.4 (CHCHCH₃), 148.1 (NArC(1)), 165.2 (d, J

252, C(O)ArC(4)), 166.4 (NHCO), 173.4 (MeOCO); δ_F(376

MHz, CDCl₃) −107.6 (ArF); Selected data for minor rotamer δ_H(500

MHz, CDCl₃) 1.61−1.62 (3H, m, CH₃CH), 3.65 (3H, s, OCH₃),

4.95 (1H, d, J 7.3, C(2)H), 7.36 (2H, dd, J 8.8, 7.4, C(O)Ar(3,5)H),

7.58−7.61 (2H, C(O)Ar(2,6)H); δ_C(125 MHz, CDCl₃) 18.2

(CH₃CH), 52.4 (OCH₃), 66.0 (C(2)), 114.8 (NArC(2,6)); δ_F

(376 MHz, CDCl₃) −108.8 (ArF); m/z (NSI⁺) 343 ([M + H]⁺,

100%); HRMS (NSI⁺) C₁₉H₂₀FN₂O₃⁺([M + H]⁺) requires 343.1452,

found 343.1458 (+1.6 ppm).

+

100%); HRMS (NSI⁺) C₂₅H₂₅N₂O₃([M + H]⁺) requires 401.1860,

found 401.1859 (−0.2 ppm).

(2R)-(E)-Methyl 2-(2-benzoyl-1-phenylhydrazinyl)-4-phenyl-

but-3-enoate 45. Following general procedure A, (E)-4-phenylbut-3-

enoic acid 16 (64.9 mg, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol)

and pivaloyl chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL),

HBTM-2.1 (2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-

(phenylimino)benzamide 60 (84.0 mg, 0.40 mmol) and iPr₂NEt (174

μL, 1.00 mmol) for 15 min at rt, followed by addition of MeOH (2

mL) and stirring for 1 h at rt gave after chromatographic puriﬁcation

(eluent Et₂O:petrol 40:60) a rotameric mixture (ratio 95:5) of (2R)-

45 as an oﬀ-white solid (109 mg, 71%): mp 116−118 °C; [α]²_D⁰−19.6

(c 0.25, CH₂Cl₂); Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow

rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(2S) 22.0 min, t_R(2R) 27.9 min,

91% ee; ν_max(ATR)/cm⁻¹3325 (N−H), 3057, 2959 (C−H), 1728

(CO), 1693 (CO), 1599; Data for major rotamer δ_H(500 MHz,

CDCl₃) 3.84 (3H, s, CH₃), 5.50 (1H, d, J 5.1, C(2)H), 6.54 (1H, dd, J

16.3, 5.7, CHCHPh), 6.76 (1H, d, J 16.3, CHCHPh), 6.99−7.04

(3H, m, ArH), 7.24−7.41 (7H, m, ArH), 7.44 (2H, t, J 8.7,

C(O)Ar(3,5)H), 7.54 (1H, t, J 7.4, C(O)Ar(4)H), 7.83 (2H, d, J 7.4,

C(O)Ar(2,6)H), 8.72 (1H, s, NH); δ_C(125 MHz, CDCl₃) 52.6

1652

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Article

(2R)-(E)-Methyl 2-(2-(furan-2-yl)-1-phenylhydrazinyl)pent-3-

enoate 48. Following general procedure A, (E)-pent-3-enoic acid 24

(40.6 μL, 0.40 mmol), iPr₂NEt (104 μL, 0.60 mmol) and pivaloyl

chloride (74.0 μL, 0.60 mmol) in CH₂Cl₂(2 mL), HBTM-2.1

(2S,3R)-23 (1.23 mg, 0.004 mmol, 1 mol %), (NE)-N-(phenylimino)-

furan-2-carboxamide 62 (80.0 mg, 0.40 mmol) and iPr₂NEt (174 μL,

1.00 mmol) for 15 min at rt, followed by addition of MeOH (2 mL)

and stirring for 1 h at rt gave after chromatographic puriﬁcation

(eluent Et₂O:petrol 50:50) a rotameric mixture (ratio 94:6) of (2R)-

48 as a colorless oil (109 mg, 87%): [α]²_D⁰−82.4 (c 0.5, CH₂Cl₂);

Chiral HPLC Chiralpak IB (5% IPA:hexane, ﬂow rate 1 mL min⁻¹,

211 nm, 30 °C) t_R(2S) 16.0 min, t_R(2R) 22.2 min, 99% ee; ν_max

(ATR)/cm⁻¹3335 (N−H), 2953 (C−H), 1730 (CO), 1688 (C

O), 1589; Data for major rotamer δ_H(500 MHz, CDCl₃) 1.70 (3H, dt,

J 6.4, 1.3, CH₃CH), 3.76 (3H, s, OCH₃), 5.20−5.21 (1H, m, C(2)

H), 5.75 (1H, ddq, J 15.6, 6.0, 1.5, CHCHCH₃), 5.74 (1H, dqd, J

15.6, 6.4, 1.2, CHCHCH₃), 6.56 (1H, dd, J 3.5, 1.8, C(O)Ar(4)H),

6.92−6.95 (3H, m, NAr(2,6)H and NAr(4)H), 7.24−7.27 (3H, m,

NAr(3,5)H and C(O)Ar(3)H), 7.52 (1H, dd, J 1.7, 0.8, C(O)Ar(5)

H), 8.75 (1H, s, NH); δ_C(125 MHz, CDCl₃) 18.2 (CH₃CH), 52.4

(OCH₃), 64.7 (C(2)), 112.2 (C(O)ArC(4)), 114.8 (NArC(2,6)),

115.9 (C(O)ArC(3)), 121.6 (NArC(4)), 123.3 (CHCHCH₃), 129.4

(NArC(3,5)), 132.8 (CHCHCH₃), 144.7 (C(O)ArC(5)), 146.6

(C(O)ArC(2)), 148.1 (NArC(1)), 158.2 (NHCO), 173.0

(MeOCO); Selected data for minor rotamer δ_H(500 MHz,

CDCl₃) 3.69 (3H, s, OCH₃), 5.10 (1H, d, J 7.1, C(2)H), 6.38 (1H, dd,

J 3.5, 1.7, C(O)Ar(3)H); δ_C(125 MHz, CDCl₃) 18.1 (CH₃CH),

52.4 (OCH₃), 65.5 (C(2)), 111.6 (C(O)ArC(4)), 115.0 (NArC(2,6)),

129.8 (NArC(3,5)), 145.6 (C(O)ArC(5)); m/z (NSI⁺) 315 ([M +

Minor diastereoisomer. Chromatographic puriﬁcation (eluent

Et₂O:petrol 60:40 to 100% Et₂O) gave lactone (3R,4S,5S)-50

(>99:1 dr) as a white solid (0.28 g, 25%): mp 110−112 °C; [α]_D²⁰

−266.4 (c 0.5, CH₂Cl₂); Chiral HPLC Chiralpak IA (40% IPA:hexane,

ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4R,5R) 8.9 min,

t_R(3R,4S,5S) 14.8 min, 99% ee; ν_max(ATR)/cm⁻¹3238 (N−H and

O−H), 2938 (C−H), 1776 (lactone CO), 1668 (amide CO),

1597, 1510; δ_H(500 MHz, CDCl₃) 1.51 (3H, d, J 6.3, CH₃), 4.61−

4.65 (2H, m, C(4)H and C(5)H), 4.76 (1H, d, J 4.3, C(3)H), 4.95

(1H, s, OH), 6.88 (2H, d, J 8.0, NAr(2,6)H), 6.97 (1H, t, J 7.4,

NAr(4)H), 7.30 (2H, tt, J 7.2, 1.8, NAr(3,5)H), 7.48−7.51 (2H, m,

C(O)Ar(3,5)H), 7.58−7.62 (1H, m, C(O)Ar(4)H), 7.89−7.91 (2H,

m, C(O)Ar(2,6)H), 8.92 (1H, s, NH); δ_C(125 MHz, CDCl₃) 13.9

(CH₃), 67.7 (C(3)), 70.3 (C(4)), 79.4 (C(5)), 113.0 (NArC(2,6)),

121.5 (NArC(4)), 127.6 (ArC), 129.1 (ArC), 129.8 (ArC), 131.4 (C

OArC(1)), 133.1 (COArC(4)), 147.3 (NArC(1)), 168.9 (NHC

O), 172.0 (MeOCO); m/z (NSI⁺) 327 ([M + H]⁺, 100%); HRMS

+

(NSI⁺) C₁₈H₁₉N₂O₄([M + H]⁺) requires 327.1339, found 327.1346

(+2.0 ppm).

(3R,4R,5R)-4-Hydroxy-5-methyl-2-(phenylamino)-

dihydrofuran-2(3H)-one 79. To a solution of lactone (3R,4R,5R)-

49 (65.2 g, 0.20 mmol) in MeOH (2 mL) at −78 °C was added SmI₂

(0.1 M in THF, 6.00 mL, 0.60 mmol), and the reaction mixture was

stirred at −78 °C for 10 min, after which time it was quenched by

addition of sat. aq. NaHCO₃. The reaction mixture was extracted with

EtOAc (×3), and the combined organic fractions were dried (MgSO₄),

ﬁltered, and concentrated in vacuo. Chromatographic puriﬁcation

(eluent Et₂O:petrol 60:40) gave lactone (3R,4R,5R)-79 as a colorless

oil (29.0 mg, 70%): [α]²_D⁰+18.0 (c 0.1, CH₂Cl₂); ν_max(ATR)/cm⁻¹

3381 (N−H or O−H), 2986 (C−H), 1761 (CO), 1603, 1499; δ_H

(500 MHz, CDCl₃) 1.45 (3H, d, J 6.8, CH₃), 2.74 (1H, d, J 4.9, OH or

NH), 4.13 (1H, s, OH or NH), 4.18−4.19 (1H, m, C(3)H), 4.41 (1H,

td, J 7.0, 4.8, C(4)H), 4.73 (1H, app. quintet, J 6.7, C(5)H), 6.80−6.85

(3H, m, NAr(2,6)H and NAr(4)H), 7.19−7.23 (2H, m, NAr(3,5)H);

δ_C(125 MHz, CDCl₃) 14.7 (CH₃), 59.6 (C(3)), 74.9 (C(4)), 77.4

(C(5)), 114.1 (NArC(2,6)), 119.6 (NArC(4)), 129.6 (NArC(3,5)),

146.8 (NArC(1)), 174.2 (CO); m/z (NSI⁺) 208 ([M + H]⁺, 100%);

+

H]⁺, 100%); HRMS (NSI⁺) C₁₇H₁₉N₂O₄([M + H]⁺) requires

315.1339, found 315.1335 (−1.4 ppm).

(3R,4R,5R)-N′-(4-Hydroxy-5-methyl-2-oxooxolan-3-yl)-N′-

phenylbenzohydrazide amine 49 and (3R,4S,5S)-N′-(4-Hy-

droxy-5-methyl-2-oxooxolan-3-yl)-N′-phenylbenzohydrazide

amine 50. To a solution of hydrazide (2R)-41 (1.12 g, 3.44 mmol) in

acetone:water (9:1, 40 mL) was added 2,6-lutidine (0.80 mL, 6.88

mmol), N-methylmorpholine-N-oxide (0.60 g, 5.16 mmol) and OsO₄

(4 wt % in H₂O, 0.44 mL, 0.07 mmol), and the reaction mixture was

stirred at rt for 5 h, after which time it was quenched by addition of sat.

aq. Na₂S₂O₃. The reaction mixture was extracted with EtOAc (×3),

and the combined organic fractions were washed with HCl (2 M in

H₂O), dried (MgSO₄), ﬁltered, and concentrated in vacuo to give a

mixture of crude diols (2R,3R,4R)-49 and (2R,3S,4S)-50, which were

used directly in the next reaction without puriﬁcation. The crude

reaction mixture was dissolved in CH₂Cl₂(50 mL) and treated with p-

toluenesulfonic acid (0.65 g, 3.44 mmol). The reaction mixture was

stirred at rt for 2 h before being quenched by addition of H₂O. The

reaction mixture was extracted with CH₂Cl₂(×3), and the combined

organic fractions were dried (MgSO₄), ﬁltered, and concentrated in

vacuo to give crude lactones (3R,4R,5R)-49 and (3R,4S,5S)-50 (70:30

dr).

+

HRMS (NSI⁺) C₁₁H₁₄NO₃([M + H]⁺) requires 208.0968, found

208.0968 (−0.1 ppm).

(3R,4S,5S)-4-Hydroxy-5-methyl-2-(phenylamino)-

dihydrofuran-2(3H)-one 80. To a solution of lactone (3R,4S,5S)-50

(65.2 g, 0.20 mmol) in MeOH (2 mL) at −78 °C was added SmI₂(0.1

M in THF, 6.00 mL, 0.60 mmol), and the reaction mixture was stirred

at −78 °C for 10 min, after which time it was quenched by addition of

sat. aq. NaHCO₃. The reaction mixture was extracted with EtOAc

(×3), and the combined organic fractions were dried (MgSO₄),

ﬁltered, and concentrated in vacuo. Chromatographic puriﬁcation

(eluent Et₂O:petrol 60:40) gave lactone (3R,4S,5S)-80 as a colorless

oil (31.4 mg, 76%): [α]²_D⁰−98.0 (c 0.1, CH₂Cl₂); ν_max(ATR)/cm⁻¹

3389 (N−H or O−H), 2982 (C−H), 1761 (CO), 1603, 1506; δ_H

(400 MHz, CDCl₃) 1.47 (3H, d, J 6.5, CH₃), 2.76 (1H, br s, OH or

NH), 4.08 (1H, d, J 4.4, C(3)H), 4.40 (1H, dd, J 4.4, 2.9, C(4)H),

4.58 (1H, qd, J 6.5, 2.9, C(5)H), 6.67−6.70 (2H, m, NAr(2,6)H), 6.84

(1H, tt, J 7.4, 1.0, NAr(4)H), 7.16−7.21 (2H, m, NAr(3,5)H); δ_C(100

MHz, CDCl₃) 13.8 (CH₃), 60.4 (C(3)), 69.8 (C(4)), 78.6 (C(5)),

114.2 (NArC(2,6)), 120.5 (NArC(4)), 129.6 (NArC(3,5)), 146.0

(NArC(1)), 174.6 (CO); m/z (NSI⁺) 208 ([M + H]⁺, 100%);

Major diastereoisomer. Chromatographic puriﬁcation (eluent

Et₂O:petrol 60:40 to 100% Et₂O) gave lactone (3R,4R,5R)-49

(>99:1 dr) as a white solid (0.59 g, 53%): mp 58−60 °C; [α]_D²⁰

+37.0 (c 0.5, CH₂Cl₂); Chiral HPLC Chiralcel OJ-H (10%

IPA:hexane, ﬂow rate 1 mL min⁻¹, 211 nm, 30 °C) t_R(3S,4S,5S)

13.5 min, t_R(3R,4R,5R) 19.3 min, 99% ee; ν_max(ATR)/cm⁻¹3306

(N−H and O−H), 2980 (C−H), 1767 (lactone CO), 1661 (amide

CO), 1597; δ_H(500 MHz, CDCl₃) 1.44 (3H, d, J 6.3, CH₃), 4.73−

4.79 (3H, m, C(3)H_,C(4)H and C(5)H), 5.02 (1H, br s, OH), 6.93−

6.96 (3H, m, NAr(2,6)H and NAr(4)H), 7.24 (2H, td, J 9.1, 1.7,

NAr(3,5)H), 7.43−7.46 (2H, m, C(O)Ar(3,5)H), 7.58 (1H, tt, J 7.5,

1.4, C(O)Ar(4)H), 7.79−7.81 (2H, m, C(O)Ar(2,6)H), 8.58 (1H, br

s, NH); δ_C(125 MHz, CDCl₃) 14.9 (CH₃), 66.8 (C(3)), 69.3 (C(4)),

77.3 (C(5)), 114.7 (NArC(2,6)), 121.7 (NArC(4)), 127.6 (ArC),

129.0 (ArC), 129.5 (ArC), 131.4 (COArC(1)), 133.0 (C

OArC(4)), 148.0 (NArC(1)), 168.8 (NHCO), 172.0 (MeOC

+

HRMS (NSI⁺) C₁₁H₁₄NO₃([M + H]⁺) requires 208.0968, found

208.0968 (−0.1 ppm).

ASSOCIATED CONTENT

■

S

* Supporting Information

β-Lactam epimerization studies, assignments of aza-sugar

relative conﬁgurations, X-ray structural data, spectral and

HPLC data for all new compounds are provided. This material

is available free of charge via the Internet at http://pubs.acs.org.

+

O); m/z (NSI⁺) 327 ([M + H]⁺, 86%); HRMS (NSI⁺) C₁₈H₁₉N₂O₄

([M + H]⁺) requires 327.1339, found 327.1345 (+1.7 ppm).

1653

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The Journal of Organic Chemistry

Article

(13) For a recent review detailing the use of isothioureas in

nucleophilic catalysis, see Taylor, J. E.; Bull, S. D.; Williams, J. M. J.

Chem. Soc. Rev. 2012, 14, 2109−2121.

(14) For pioneering work demonstrating the utility of isothioureas as

eﬃcient O-acyl transfer agents, see: (a) Birman, V. B.; Li, X. Org. Lett.

2006, 8, 1351−1354. (b) Kobayashi, M.; Okamoto, S. Tetrahedron

Lett. 2006, 47, 4347−4350.

(15) For an excellent review of ammonium enolate chemistry, see

Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596−5605.

(16) For examples, see: (a) Belmessieri, D.; Morrill, L. C.; Simal, C.;

Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714−

2720. (b) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Angew.

Chem., Int. Ed. 2012, 51, 3653−3657. (c) Morrill, L. C.; Lebl, T.;

Slawin, A. M. Z.; Smith, A. D. Chem. Sci. 2012, 3, 2088−2093.

(d) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.;

Smith, A. D. Chem. Sci. 2013, 4, 4146−4155. (e) Belmessieri, D.;

Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2013, 15,

3472−3475. (f) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; O’Riordan, T. J.

Angew. Chem., Int. Ed. 2013, 52, 11642−11646.

(17) In ref 16c, using speciﬁc reaction conditions, selected

nonarylacetic acids could be used, namely, (thiophenyl)acetic acid,

methoxyacetic acid, and 3-phenylpropionic acid, when a highly reactive

N-aryl-N-aroyldiazene Michael acceptor was used.

(18) For a recent report from our research group detailing the use of

2-arylacetic anhydrides as ammonium enolate precusors, see Morrill, L.

C.; Ledingham, L. A.; Couturier, J.-P.; Bickel, J.; Harper, A. D.; Fallan,

C.; Smith, A. D. Org. Biomol. Chem. 2013, 12, 624−636.

(19) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.; Slawin, A. M.

Z.; Smith, A. D. J. Org. Chem. 2014, DOI: 10.1021/jo402590m.

(20) All experiments were carried out under air using bench grade

solvents as standard.

(21) Other carboxylic acid starting materials, namely, (E)-3-

phenylbut-2-enoic acid 70 and (E)-3,4-diphenylbut-2-enoic acid 72,

were tested to attempt to access ammonium dienolates, which react at

the γ-position, but none were successful.

(22) The relative conﬁgurations of β-lactones (anti 21, syn 73) and β-

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X-ray crystallography. Crystallographic data for all diastereoisomers

21, 22, 73, and 74 have been deposited with the Cambridge

Crystalographic Data Centre as supplementary publication numbers

CCDC 968689, 968690, 968692, and 968693.

(23) Although we describe these reactions as formal [2 + 2]

cycloadditions, they may also be considered as intermolecular enolate-

imine cyclization reactions or Gilman−Speeter reactions. For

representative examples, see: (a) Hiroki, F.; Kanai, M.; Kambara, T.;

Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 2060−2061.

(b) Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara,

T.; Nomura, Y.; Kanai, M.; Koga, K. Chem. Commun. 1999, 715−716.

(c) Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron 1999, 55,

11219−11228. (d) Kambara, T.; Tomioka, K. Chem. Pharm. Bull.

2000, 48, 1577−1580. (e) Evans, C. D.; Mahon, M. R.; Andrews, P.

C.; Muir, J.; Bull, S. D. Org. Lett. 2011, 13, 6276−6279. For the

Gilman−Speeter reaction, see: (f) Gilman, H.; Speeter, M. J. Am.

Chem. Soc. 1943, 65, 2255−2256.

(24) For selected alternative methods for accessing β-lactams bearing

an oleﬁn at C(3), see: (a) Torii, S.; Okumoto, H.; Sadakane, M.; Hai,

A. K. M. A.; Tanaka, H. Tetrahedron Lett. 1993, 34, 6553−6556.

(b) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.;

Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626−6635. (c) Fontana, F.;

Tron, G. C.; Barbero, N.; Ferrini, S.; Thomas, S. P.; Aggarwal, V. K.

Chem. Commun. 2010, 46, 267−269. (d) Xia, P.; Qian, B.; Huang, H.

Tetrahedron Lett. 2012, 53, 1613−1616. For discussions regarding the

biological importance of the β-lactam motif, see: (e) Morin, R. B.;

Gorman, M. Chemistry and Biology of Beta-Lactam Antibiotics;

Academic Press: Waltham, MA, 1982. (f) Jastrzebski, J. T. B. H.;

VanKoten, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.

R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; pp

623−658. (g) Zhang, T. Y.; Hatfield, L. D. In Comprehensive

AUTHOR INFORMATION

Corresponding Author

*E-mail: ads10@st-andrews.ac.uk.

Notes

■

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the Royal Society for a University Research

Fellowship (A.D.S.) and The Carnegie Trust for the

Universities of Scotland (L.C.M.) for funding. The research

leading to these results has received funding from the European

Research Council under the European Union’s Seventh

Framework Programme (FP7/2007-2013)/ERC Grant Agree-

ment No. 279850. We also thank the EPSRC National Mass

Spectrometry Service Centre (Swansea).

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dx.doi.org/10.1021/jo402591v | J. Org. Chem. 2014, 79, 1640−1655

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Isothiourea-mediated asymmetric functionalization of 3-alkenoic acids

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