Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic Stereoselective Reactions of β-Lactams with Aldehydes: The Effect of the N-Methylimidazole Ligand

Article

pubs.acs.org/joc

Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic

Stereoselective Reactions of β‑Lactams with Aldehydes: The Eﬀect

of the N‑Methylimidazole Ligand

́

Paulina Plata, Urszula Klimczak, and Bartosz K. Zambron*

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw 01-224, Poland

S

* Supporting Information

ABSTRACT: The application of the N-methylimidazole (N-MI) ligand

in the Pd(0)/InI-promoted allylations of aldehydes with β-lactam-derived

organoindiums enables the reaction of azetidin-2-ones with diversely

substituted allyl moieties, inert under previously reported conditions. As a

result, allylations and crotylations of a variety of aromatic and aliphatic

aldehydes with previously unavailable chiral ε-amido-allylindiums bearing

α-, β-, or γ-substituted allyl fragments were developed. The reactions

occur under thermodynamic control with a highly eﬃcient remote 1,5- or

1,4,5-stereocontrol to aﬀord a diversity of (3Z)-2,5-anti-2,6-syn- or (3Z)-

2,5-syn-2,6-anti-substituted enediols, aminoalcohols, and homoallylic

alcohols in moderate to high yields and with an excellent diastereose-

lectivity. A detailed study on the eﬀect of the β-lactam and aldehyde

structures and chirality on the yield and stereochemistry in the products

was carried out.

synthesis have been developed, which makes them readily

INTRODUCTION

■

available in both enantiomeric forms in an excellent optical

purity.⁷Thus, these reactive four-membered azacycles are

widely used intermediates for the asymmetric synthesis of

diverse classes of organic compounds such as α- and β-amino

acids or biologically active alkaloids.⁸It is noteworthy that the

vast majority of reports concerning the application of β-lactams

as building blocks deal with stereoselective ring-opening

reactions upon treatment with various types of nucleophiles.

In contrast, the reactions of β-lactams with electrophiles,

including their umpolung by Pd(0)/InI methodology to enable

the reaction with aldehydes developed by our group, are

rare.^3,8,9

Since our previous study was limited to only cis-substituted

β-lactams bearing bulky substituents (OTIPS, i-Pr) at the C3

carbon of the azetidin-2-one ring,³further elaboration of the

chemistry presented and advanced study of the eﬀect of the β-

lactam structure and conﬁguration on the reaction outcome

was a matter of interest. Importantly, in the course of our

previous study, it appeared that the developed reaction

conditions could be applied only to β-lactams bearing an

unsubstituted vinyl moiety, which constituted a serious

limitation for their general use. Bearing in mind that the

possibility of application of the substrates with an elaborated

allyl fragment might lead to desired enediols or homoallylic

alcohols with an additional stereogenic center, substituents or

functional groups in their structure led us to a deeper

The reaction of allylmetal reagents with carbonyl compounds

is one of the most eﬀective C−C bond formation methods in

organic synthesis.¹Among many reagents, the nontoxic, water-

tolerant allylindiums generated in situ by reductive trans-

metalation of π-allylpalladium(II) complexes, providing high

yields and often an excellent selectivity under mild reaction

conditions, constitute a very interesting alternative.²Recently,

we have demonstrated that readily available 4-vinylazetidin-2-

ones bearing strongly electron-withdrawing groups attached to

the nitrogen atom can undergo “umpolung” upon treatment

with InI and catalytic amounts of a Pd(0) catalyst.³As a result

of this process, nucleophilic ε-amido-allylindiums are gen-

erated, which are able to react regio- and stereoselectively with

a variety of aromatic and aliphatic aldehydes to aﬀord

semiprotected (3Z)-2,6-anti-enediols or homoallylic alcohols

in a high yield with a very eﬃcient acyclic remote 1,5-

stereocontrol.^3aDue to the presence of numerous functional

groups in their structure, including an easily modiﬁable N-Ts-

carboxamide function⁴and internal (3Z)-substituted double

bond, enediols obtained in this manner could serve in the

asymmetric synthesis of a variety of heterocycles, as well as

linear derivatives such as challenging 1,5-polyols subunits.⁵It

should be pointed out that achieving high levels of remote

asymmetric induction remains a nontrivial task in current

organic synthesis and that developing methodology for new

stereoselective entries to linear and cyclic organic compounds

with distant stereogenic centers is of high importance.⁶

Due to the well-known antibiotic activity of β-lactams, a

great number of successful methods for their asymmetric

Received: September 10, 2018

Published: November 9, 2018

A

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Table 1. Pd(PPh₃)₄/InI-Mediated Crotylation of Benzaldehyde with β-Lactam 1-Derived ε-Amido-allylindium: Optimization

of the Reaction Conditions

a

b

a

b

entry

solvent

additive (x equiv)

time (h)

conversion (%)

2a yield (%) (dr)

2b yield (%) (dr)

1

2

3

4

5

6

7

8

THF/HMPA (3:1)

THF

24

1

3

1

24

<10

53

nd

22 (98:2)

6 (96:4)

23 (97:3)

64 (98:2)

83 (98:2)

17 (95:5)

39 (96:4)

29 (76:10:8:6)

32 (68:16:9:7)

54 (81:10:5:4)

12 (48:19:27:6)

14 (39:32:25:4)

33 (69:14:9:8)

13 (75:9:14:2)

c

d

e

THF

65

100

f

g

h

i

N-MI (2)

100

64

j

i

THF/EtOH (9:1)

N-MI (2)

j

THF/EtOH (9:1)

j

i

THF/HMPA (9:1)

N-MI (2)

56

a

b

c

d

1

Isolated yields. Assayed by H NMR integration. Reaction performed at reﬂux. No further conversion was observed within the next 2 h (¹H

e

f

1

NMR). The formation of 12% of β-elimination products was observed in the crude mixture H NMR spectra. 10 mol % Pd(PPh₃)₄was used.

g

h

i

The formation of 18% of β-elimination products was observed in the crude mixture ¹H NMR spectra. 2.2 equiv of InI was used. N-

j

Methylimidazole. 3 equiv of InI was used.

examination of the transformation. As a result of this study,

alternative reaction conditions were developed where the

generated in situ InI·N-methylimidazole complex was applied,

allowing a signiﬁcant reaction scope expansion. To the best of

our knowledge, the use of an N-ligand in the Pd/InI-induced

allylations and crotylations has not been reported previously.

phenantroline) and phenol were carried out. As a result of

this study, it was established that the addition of 2 equiv of N-

methylimidazole with respect to β-lactam is very eﬀective and

superior to other additives tested. Under these conditions, full

conversion of azetidin-2-one 1 was observed within 3 h and the

desired (3Z)-2,5-syn-2,6-anti-enediol 2a was obtained in 64%

yield, with a signiﬁcantly higher 84:16 (Z/E)-selectivity and

very eﬀective remote 1,4,5-stereocontol (dr (Z) = 98:2, Table

1, entry 5). A series of additional experiments with the use of

DMPU, DMF, DMSO, NMI, and EtOH as polar cosolvents let

us establish that the addition of 10% v/v of anhydrous EtOH is

optimal. Using this method, full conversion of model β-lactam

1 was observed within just 1 h and the desired (Z)-substituted

enediol 2a was obtained in 83% yield, with a high (Z/E)- and

excellent 2,5-syn-2,6-anti-stereoselectivity (dr (Z/E) = 89:11,

dr (Z) = 98:2, Table 1, entry 6). On the other hand, (E)-

enediol 2b was isolated in 14% yield as an inseparable mixture

of four diastereomers in a 39:32:25:4 ratio. Since further study

revealed that the formation of small quantities of complicated

mixtures of all four isomeric (E)-enediols is general in cases

where the β-lactam-bearing α-substituted vinyl fragment is

employed, in the further investigation, these products were not

isolated nor characterized. It should be pointed out that both

the addition of N-methylimidazole and the replacement of

HMPA with EtOH is crucial to obtain high yields and

selectivities of (Z)-substituted products since experiments in

the absence of N-MI in a 9:1 THF/EtOH mixture (Table 1,

entry 7) or with this ligand in a THF/HMPA mixture (Table

1, entry 8) led to far worse results.

The exact nature of the N-methylimidazole (N-MI) eﬀect on

the reactivity of β-lactams was not investigated. At this stage,

we assume that N-MI coordinates to the amphiphilic (due to

two vacant p orbitals and a lone electron pair¹³) InI, enhancing

its solubility in moderately polar solvents as well as

nucleophilicity, which is manifested as an increased overall

reaction rate. This eﬀect might result from the acceleration of

the Pd-to-In transmetalation step involving electrophilic π-

allylpalladium(II) complex I and N-methylimidazole-activated

InI and/or the subsequent crotylation of benzaldehyde with ε-

amido-organoindium IIb generated in this manner, which

could also be more reactive in comparison to intermediate IIa

RESULTS AND DISCUSSION

■

As a model β-lactam, racemic N-Ts-4-(E)-propenylazetidin-2-

one 1, readily accessible in three steps from commercially

available substrates, was chosen and benzaldehyde was used as

a model electrophile (Table 1).¹⁰As reported, the application

of our previously developed conditions (2 equiv of

benzaldehyde, 2 equiv of InI, and 5 mol % Pd(PPh₃)₄in a

3:1 THF/HMPA mixture at 25 °C) to the β-lactam 1 resulted

in less than 10% of its conversion within 1 h, whereas no

further progress was observed during the next 23 h (Table 1,

entry 1).^3aWe realized that this is most likely due to the

instability of InI in polar aprotic solvents including HMPA, in

which it readily disproportionates,¹¹preventing full conversion

of the less active, as compared to β-lactams bearing an

unsubstituted vinyl moiety, (E)-propenyl-β-lactam 1. Indeed,

the removal of HMPA from the reaction conditions in the next

attempt led to a signiﬁcantly higher 53% conversion, but the

result was still not satisfactory in terms of yield and product

distribution (51% yield, Z/E = 43:57, Table 1, entry 2).

Carrying out the reaction at reﬂux (Table 1, entry 3),

increasing the catalyst loading to 10 mol % (Table 1, entry 4),

and all attempts of replacing Pd(PPh₃)₄with other Pd catalysts

used in similar Pd/InI-induced allylations (Pd(dba)₂, Pd-

(dppf)Cl₂·CH₂Cl₂, Pd₂(dba)₃·CHCl₃, Pd(OAc)₂, or Pd-

(PPh₃)₄with the addition of PPh₃, P(o-furyl)₃, P(i-Pr)₃, or

LiBr in diﬀerent ratios)²failed since in all cases a serious

reduction in yield or Z/E-selectivity was observed. Since it has

been reported that the tertiary amine or phenol additive has a

beneﬁcial eﬀect on the reaction rate in related palladium-to-

boron transmetalation,¹²a series of experiments using diﬀerent

amines (NEt₃, DIPEA, quinuclidine, DABCO, DMAP, quinine,

cinchonidine, pyridine, 2,6-lutidine, quinoline, isoquinoline,

imidazole, N-methylimidazole, phenanthridine, and 1,10-

B

DOI: 10.1021/acs.joc.8b02333

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The Journal of Organic Chemistry

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Scheme 1. Possible Eﬀect of the N-Methylimidazole Ligand on the Pd(PPh₃)₄/InI-Mediated Crotylations of Aldehydes with β-

Lactam-Derived ε-Amido-allylindiums

Scheme 2. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Aromatic and Aliphatic Aldehydes with β-Lactam 1-Derived ε-

Amido-allylindium: The Eﬀect of Aldehyde Structure

a

b

c

Isolated yields. Assayed by ¹H NMR integration. Enantioenriched β-lactam (+)-1 (98:2 dr according to ¹H NMR; >99% ee according to chiral

d

e

1

HPLC) was applied. Determined by chiral HPLC analysis. Additionally, 30% of β-elimination products according to the crude H NMR

integration.

due to its altered aggregation state in solution and/or increased

nucleophilicity of the attached allylic ligand in the presence of

the coordinated electron-donating N-MI (Scheme 1). How-

ever, the eﬀect of N-methylimidazole on the stereochemical

course of the process resulting in a signiﬁcantly higher (Z)-

selectivity remains unclear, which is detailed in further

paragraphs. In most reports on coordination chemistry of

indium(I), reactions of indium(I) halides with bases (ligands)

cause its redox disproportionation.^11,13However, besides the

number of reports on quite stable achiral In(I) complexes with

no synthetic application,¹³there are remarkable examples of

InI complexes able to catalyze allylations and crotylations of

hydrazones, with organoindiums derived from allyl boro-

nates.¹⁴Although we observed an increased rate of

disproportionation of InI in the presence of N-methylimida-

zole, especially in the THF/HMPA mixtures, the generated in

situ complex proved to be stable enough to enable an overall

crotylation process to proceed when THF or a THF/EtOH

mixture was employed.

To further explore our methodology, a variety of aromatic

and aliphatic aldehydes were subjected to the reaction with β-

lactam 1 under optimized conditions, in order to determine the

aldehyde eﬀect on the crotylation outcome (Scheme 2). All of

the reactions involving aromatic aldehydes, electron-rich or

C

DOI: 10.1021/acs.joc.8b02333

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The Journal of Organic Chemistry

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Scheme 3. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 1- and 15−17-Derived ε-Amido-

allylindiums: The Eﬀect of β-Lactam Conﬁguration

a

b

1

Isolated yield. Assayed by H NMR integration.

-deﬁcient, including heteroaromatic furfural and thiophene-2-

carbaldehyde aﬀorded (3Z)-enediols as major products in high

77−87% yields and with an excellent, ≥95:5, 2,5-syn-2,6-

antiselectivity (Scheme 2, structures 2a, (−)-2a, 3−7). Also

reactions with aliphatic aldehydes, primary or secondary

including 4-hydroxybutyric aldehyde containing an unpro-

tected hydroxyl group, proceeded very eﬀectively, delivering

the corresponding products in a high yield and with the same

highly eﬃcient remote 1,4,5-asymmetric induction (68−81%

yield, ≥95:5 dr Scheme 2, structures 8−12). Only in the case

of tertiary pivalaldehyde, the yield of the corresponding (3Z)-

2,5-syn-2,6-antienediol 13 was signiﬁcantly reduced, most likely

due to severe steric hindrance. The rate of the reaction and the

stereoselectivity remained high (43% yield, dr 95:5, Scheme 2,

structure 13). Even in the case of α,β-unsaturated 3-methylbut-

2-enal,^3awhich was incompatible in our previous study, the

corresponding adduct was obtained in a good yield with the

same excellent level of diastereoselectivity (74% yield, 95:5 dr,

Scheme 2, structure 14). Importantly, when the enantioen-

riched N-Ts-4-(E)-propenylazetidin-2-one (−)-1 (>99% ee

according to HPLC¹⁰) was combined with benzaldehyde or

isobutyric aldehyde under our standard conditions, the

corresponding (3Z)-2,5-syn-2,6-antienediols (−)-2a and

(−)-11a were obtained in high yields with the same excellent

enantiomeric excess, which was proved by chiral HPLC

analysis.¹⁰These examples demonstrate that the developed

method can be applied in asymmetric synthesis, since a variety

of β-lactams are readily available in both enantiomeric forms in

an excellent optical purity.⁷

compounds 18a and 18b in the mixtures obtained from

substrates 1 and 15, and analogously compounds 2a and 2b in

the mixtures resulting from reactions of β-lactams 16−17

(Figure 1). However, these seem to be the products of the

Figure 1. ¹H NMR study of Pd(PPh₃)₄/InI/N-MI-mediated

crotylation of benzaldehyde with β-lactam 1- and 15−17-derived ε-

amido-allylindiums.

reactions of the geometrical isomers of the starting β-lactams 1

and 15−17 present in their samples in small but not equal

amounts (dr (Z/E) = 95:5, 91:9, 98:2, and 96:4 for 1, 15, 16,

and 17, respectively), which is detailed in the further

paragraphs. The obtained results indicate a high stereo-

selectivity of the formation of the conﬁgurationally stable ε-

amido-organoindium intermediates reacting with benzalde-

hyde in the subsequent crotylation step.¹⁵Furthermore,

obtaining the almost identical sets of products 2a−2b or

18a−18b from the diﬀerently conﬁgured pairs of substrates 1,

15, or 16−17, respectively, clearly shows that the presented

allylations occur under thermodynamic control, where the

equilibration of the initially formed organoindiums is

signiﬁcantly faster than their subsequent addition to the

electrophile. Thus, the scope of the isomeric enediols

potentially available from β-lactams 1 and 15−17 is reduced,

although the two isomers of the starting β-lactam can be

applied to obtain the desired product, depending on its relative

availability in the individual cases.

Next, a series of experiments using cis- and trans-substituted

4-propenylazetidin-2-ones 1 and 15−17 diﬀering in the relative

double CC bond conﬁguration were conducted in order to

determine the eﬀect of β-lactam chirality on the reaction

outcome, which led to very interesting observations (Scheme

3). Surprisingly, the application of trans-azetidin-2-one 15

bearing (Z)-propenyl provided nearly the same mixture of

products 2a and 2b as previously used cis-4-(E)-propenyl-β-

lactam 1, while the use of trans-(E)- and cis-(Z)-substituted

isomers 16−17 aﬀorded compounds 18−18b of completely

diﬀerent conﬁgurations and ratios. However, almost equal sets

of products were obtained in both cases. Slight diﬀerences

1

visible in the H NMR spectra of the crude reaction mixtures

arise from the presence of small but not equal quantities of

D

DOI: 10.1021/acs.joc.8b02333

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Scheme 4. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 1- and 15-Derived ε-Amido-

allylindiums: Possible Reaction Pathway

Scheme 5. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 16- and 17-Derived ε-Amido-

allylindiums: Possible Reaction Pathway

The plausible reaction pathway of the above trans-

formations, based on the observed regio- and stereoselectivity,

is depicted in Schemes 4 and 5. In all cases, the initial step

consists of a stereoselective C4−N β-lactam bond cleavage by

Pd(PPh₃)₄attack occurring from the opposite side of the C−N

bond of azetidin-2-one ring with inversion of conﬁguration,

followed by reductive transmetalation of the transient π-

allylpalladium(II) species with the active InI·N-MI complex,

retaining the stereochemistry. Subsequent fast equilibration via

a sequence of rapid 1,3-rearrangements delivers diﬀerent pairs

E

DOI: 10.1021/acs.joc.8b02333

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Scheme 6. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 19-, (+)-19-, 20-, and (−)-20-Derived

ε-Amido-allylindiums

a

b

c

d

1

Isolated yields. Assayed by H NMR integration. Detrermined by chiral HPLC analysis. Assayed by ¹⁹F NMR integration.

of isomeric chiral ε-amido-allylindiums, depending on whether

β-lactam 1, 15, or 16−17 was applied.¹⁵In all generated

allylindiums, the metal atom is situated in the γ position as a

consequence of the coordination of indium to the N-Ts-

carboxamide group. Thus, the reactions take place on the other

carbon of the allyl system, bearing a methyl substituent, which

explains the observed rare high α-regioselectivity of the

process.¹⁻³Due to a signiﬁcant disparity in energy between

trans-(E)- and cis-(Z)-organoindiums generated from β-lactam

1 or 15, the equilibrium is shifted far toward the

thermodynamically favored trans-(E)-isomer in this case

(Scheme 4). Conversely, similarly stable trans-(Z) and cis-

(E)-isomers formed from β-lactam 16 or 17 are present at

comparable concentrations, which results in a reduced

stereoselectivity (Scheme 5). Assuming the addition step

occurs via bicyclic, rigid transition states, ts-1-ts-4 or ts-5-ts-8,

depending on the substrate used, diﬀerent ratios of enediols

may be produced. In the ﬁrst case, thermodynamically favored

trans-(E)-ε-amido-allylindium reacts with benzaldehyde via

transition states ts-1 and ts-2, aﬀording the corresponding

enediols 2a and 2b (Scheme 4). However, due to the strong

preference of ts-1, in which the group next to the indium

adopts the axial position, compound 2a is formed in great

predominance. It should be pointed out that the preference of

the transition structure ts-1, leading to the (Z)-substituted

product over ts-2, is not general and strongly depends on the

applied reaction conditions, which have been discussed in our

previous study.^3aIn contrast, due to a severe 1,3-diaxial strain

existing in transition state ts-3, minor cis-(Z)-ε-amido-

allylindium reacts with the aldehyde only via transition state

ts-4, giving (E)-substituted enediol 2b′ exclusively. As a

consequence, compound 2a arises in a high yield with a nearly

perfect stereoselectivity (98:2 dr), while the (E)-enediols result

in minor amounts as the inseparable mixture of isomers 2b and

2b′ additionally contaminated by comparable quantities of

isomers 18a and 18b resulting from the moderately (E)-

stereoselective reactions of 16 or 17, present in the samples of

substrates 1 and 15 in small amounts, as depicted in Scheme 5

(dr (E/Z) = 95:5 and dr (Z/E) = 91:9 for 1 and 15,

respectively).

In the case of reactions of β-lactam 16 or 17, involving a pair

of ε-amido-allylindiums, cis-(E) and trans-(Z), the addition

occurs analogously, except that these intermediates would exist

in comparable concentrations, probably due to their similar

energies (Scheme 5). The cis-(E)-ε-amido-allylindium reacts

with benzaldehyde via transition states ts-5 and ts-6, aﬀording

the corresponding enediols 18a and 18b′ in 33% and 12%

yields, respectively (45% overall). In contrast, due to a severe

1,3-diaxial strain existing in transition state ts-7, ε-amido-

allylindium trans-(Z) reacts exclusively via transition state ts-8,

giving (E)-substituted enediol 18b in 47% yield. Conversely to

the former example, where the obtained (E)-endiols 2b and

2b′ were contaminated by small amounts of isomers 18b and

18b′, in this case, (Z)-enediol 18a is contaminated with small

amounts of compound 2a, resulting from the highly (Z)-

stereoselective allylation involving small amounts of compound

1 or 15 present in the samples of β-lactams 16 and 17, as

depicted in Scheme 4 (dr (Z/E) = 92:8 and dr (Z/E) = 96:4

for 16 and 17, respectively). However, in both cases,

incomplete stereoselectivity of the presented processes cannot

be fully discounted either.

Additional experiments involving racemic and enantioen-

riched β-lactams 19−20, (−)-19, and (+)-20 with an

unsubstituted C3 position of the azetidinone ring conﬁrmed

the conﬁgurational stability of the generated in situ ε-amido-

allylindiums and the occurrence of the reaction under

thermodynamic control (Scheme 6). As expected, the

treatment of racemic substrates 19 and 20 diﬀering in the

geometry of the CC double bond in the propenyl

substituent with benzaldehyde under optimized reaction

F

DOI: 10.1021/acs.joc.8b02333

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Scheme 7. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 1- and 24−31-Derived ε-Amido-

allylindiums: The Eﬀect of Allyl Moiety Substitution

a

b

c

1

Isolated yield. Assayed by H NMR integration. Reactions were carried out with 2 equiv of benzaldehyde, 2 equiv of InI, and 5 mol %

d

Pd(PPh₃)₄in a 3:1 THF/HMPA mixture at 25 °C. cis-Substituted β-lactam 30 was applied. A mixture of (3E)-enediols 38b was also formed (28%

yield, 54:46 dr). trans-Substituted β-lactam 31 was applied. A mixture of (3E)-enediols 38b was also formed (30% yield, 51:49 dr). cis-Substituted

β-lactam 30 was applied. A mixture of (3E)-enediols 38b was also formed (13% yield, 52:48 dr); 63% of β-lactam 30 was recovered.

e

f

conditions resulted in the formation of the same (Z)-

substituted homoallylic alcohol 21 in similar yields and the

same high diastereoselectivity (57 and 60% yields, respectively,

>98:2 dr). The experiments with the use of analogous

enantioenriched substrates bearing a stereogenic center of

the same absolute conﬁguration, in turn, delivered the

enantiomers (−)-21 and (+)-21 with the er fully correspond-

ing to the dr of the starting β-lactams (+)-19 and (−)-20,

which was proved by a ¹⁹F NMR study of Mosher’s esters 28

and 29.¹⁰Notably, the absence of substituent at C3 of the β-

lactam ring in compounds 19−20, (−)-19, and (+)-20 did not

aﬀected the selectivity of the process since, in all cases, (Z)-

substituted adducts were obtained in great predominance with

a high diastereomeric excess. However, the chemical yield of

the reaction suﬀered due to the signiﬁcantly faster (with regard

to allylation involving C3-substituted substrates) competitive

β-elimination.

Next, a number of β-lactams diﬀering in double CC bond

substitution (positions α and β) or with an additional methyl

substituent at C4 of the azetidin-2-one ring (position γ) were

subjected to the reaction with benzaldehyde in order to

investigate the eﬀect of the allyl moiety substitution on the

reaction outcome (Scheme 7). Application of β-lactam 24,

bearing an (E)-oriented i-Pr substituent at the α position of the

vinyl fragment, delivered the expected product with a

somewhat lower yield, but with the same high diastereose-

lectivity, showing that the substrates with larger aliphatic

substituents can be applied likewise (74% yield, 98:2 dr,

Scheme 7, structure 32). Also β-lactams bearing aromatic

substituents or additional functional groups at the α position,

such as phenyl in compound 25 or ethyl ester in azetidin-2-one

26, were tolerated and the desired (Z)-substituted enediols

33−34 were obtained in high yields and excellent 2,5-syn-2,6-

anti-selectivities, indicating a broad applicability of the

asymmetric allylation under examination (Scheme 7, structures

33 and 34). To our delight, the use of azetidin-2-one 27

bearing a methyl group in the β position resulted in the

formation of the triply substituted enediol 35 in a high 85%

yield with an excellent 95:5 diastereoselectivity. However, the

use of analogous substrate 28 with an acetoxy group in the β

position as well as β-lactam 29 bearing two methyl substituents

in the α and β positions failed, since no conversion was

observed in both cases within 24 h. Most likely, the inertness of

these substrates under our reaction conditions results from

insuﬃcient electrophilicity of the CC double bond, caused

by the presence of the strongly electron-donating acetoxy

group in 28 and two moderately electron-donating methyl

substituents in 29, which result in an insuﬃcient reactivity with

the nucleophilic Pd(PPh₃)₄catalyst. Although an increased

steric hindrance in 28 and 29 in comparison with 27 and 1,

respectively, as the reason for the reduced reactivity cannot be

fully excluded, in the light of the formerly presented results, it

seems to play a minor role. The application of cis-substituted β-

lactam 30, bearing a methyl substituent at quaternary C4 of the

azetidin-2-one ring, led to the formation of triply substituted

enediol 38a in a moderate 46% yield, but with the same

excellent 1,5-asymmetric induction (>98:2). In this case, the

(Z/E)-selectivity of the reaction appeared reduced since 28%

of (E)-enediol 44b was also formed as a mixture of two

diastereomers in a 54:46 ratio. Interestingly, the use of the

trans-substituted isomer of β-lactam 30, i.e., azetidin-2-one 31,

in sharp contrast to the analogous reactions of pairs of cis- and

trans-substituted 4-(E)-propenyl-β-lactams 1, 15, and 16−17

described in former paragraphs (Schemes 3, 4, and 5), led to

the formation of exactly the same set of products in almost

equal amounts and stereoselectivities. While in apparent

opposition, the obtained results stay in line with previous

observations. The diﬀerence results from the lack of the trans-

or cis-oriented methyl group at the α position of the vinyl

substituent, which causes the stereochemical information

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Scheme 8. Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of Benzaldehyde with β-Lactam 30- and 31-Derived ε-Amido-

allylindiums: Possible Reaction Pathway

a

Reaction was carried out with benzaldehyde (2 equiv), InI (2 equiv), and Pd(PPh₃)₄(5 mol %) in a 3:1 THF/HMPA mixture at 25 °C.

Scheme 9. Pd(PPh₃)₄/InI/N-MI-Mediated Allylation of Benzaldehyde with β-Lactam 39−43-Derived ε-Amido-allylindiums:

The Eﬀect of C3 β-Lactam Substitution

a

Condition A: PhCHO (2 equiv), InI (3 equiv), N-MI (2 equiv), Pd(PPh₃)₄(5 mol %), THF/EtOH (9:1), 25 °C. Condition B: PhCHO (2

b

c

d

1

equiv), InI (2 equiv), Pd(PPh₃)₄(5 mol%), THF/HMPA (3:1), 25 °C. Isolated yield. Assayed by H NMR integration. trans-Substituted β-

lactam 42 was applied.

coming from the β-lactam relative conﬁguration to be lost

during the fast equilibration preceding the addition step

(Scheme 8). Further studies conﬁrmed that this is always the

case when the azetidin-2-ones without a substituent at the vinyl

α position are applied. Additionally, comparative experiments

applying previously developed conditions (2 equiv of

benzaldehyde, 2 equiv of InI, and 5 mol % of Pd(PPh₃)₄in

a 3:1 THF/HMPA mixture at 25 °C)^3awere conducted using

β-lactams 27 and 30. Similarly to the reaction of β-lactam 1,

application of azetidin-2-one 27 under these conditions failed

as only ∼5% of conversion was observed within 24 h at 25 °C.

The use of β-lactam 30, in turn, resulted in less than 30% of its

conversion within 1 h, whereas no further progress was

observed in the next 23 h. The obtained results emphasize the

advantage of the newly developed protocol over the previously

reported method for β-lactams with a substituted allyl moiety.

In order to investigate the eﬀect of C3 substitution of the β-

lactam ring on the reaction outcome, 4-vinyl-azetidin-2-ones

39−43 were synthesized¹⁰and subjected to the reaction with

benzaldehyde under newly developed and previously reporte-

d^3areaction conditions (Scheme 9, Conditions A and B,

respectively). As in the case of azetidin-2-one 39 bearing an

OTIPS substituent, also cis- and trans-substituted β-lactams 41

and 42 with an i-Pr group, as well as the β-lactam 40 with a

methyl substituent at C3 of β-lactam ring delivered the desired

(Z)-enediols in good yields and with high 2,6-anti-stereo-

H

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Article

selectivities, especially when Condition B was applied showing

that the substrates with smaller substituents at this position are

just as viable (Scheme 10, structures 44a−46a and 44b−46b).

Next, a series of experiments with the use of 4-vinyl-β-

lactams with Ts, Ms, Boc, and PMP groups attached to the

nitrogen atom were conducted under Conditions A and B in

order to verify the possibility of the use of other more common

protective groups and their inﬂuence on the reaction outcome

(Scheme 11). However, only N-Ts- or N-Ms-substituted

azetidin-2-ones 39 and 50 proved to be suitable substrates for

the method under development. Using these substrates,

corresponding (Z)-enediols 44a and 53a were obtained in

high yields and, especially under Condition B, an excellent 2,6-

anti-stereoselectivity. As in our previous study,^3aBoc- and

PMP-protected β-lactams 51 and 52 appeared inert also under

the newly developed conditions, conﬁrming that a strongly

electron-withdrawing group attached to the nitrogen atom of

the azetidin-2-one ring is necessary.

Scheme 10. Synhesis of (3Z)-2,5-syn-2,6-anti-Aminoalcohol

49 via Pd(PPh₃)₄/InI/N-MI-Mediated Crotylation of

Benzaldehyde with β-Lactam 48-Derived ε-Amido-

allylindiums

a

b

1

Isolated yield. Assayed by H NMR integration.

Finally, in order to verify if the stereochemical course of the

addition of the β-lactam-derived chiral ε-amido-allyindiums to

aldehydes is determined by the chirality in the reagent or in the

aldehyde, the enantiomeric azetidin-2-ones (+)-1 and (−)-1

were subjected to the reaction with (R)-(+)-glyceraldehyde

acetonide under our standard reaction conditions (Scheme

12). Interestingly, no matching and mismatching was observed,

since in both cases the reaction proceeded with the same rate

and the products (−)-56 and (+)-57 were obtained in nearly

equal yields with the same excellent 2,5-syn-2,6-anti-stereo-

selectivity. The obtained results clearly show that the presented

crotylations are strongly reagent-controlled and chirality in the

aldehyde does not aﬀect the course of the process.

Interestingly, the application of the more classical azetidin-2-

one 43 with a phthalimide-protected amino group at the C3

position of the β-lactam ring delivered the expected (Z)-2,6-

anti-aminoalcohol in a similarly high yield and with an

excellent stereoselectivity (75% yield, 88:12 dr (Condition

A), 74% yield, 98:2 dr (Condition B), Scheme 9, structures

47a−47b). Applying Condition A to azetidin-2-one 48 bearing

an (E)-propenyl substituent at C4 of the β-lactam ring, in turn,

delivered the related 2,5-syn-2,6-anti-(Z)-aminoalcohol 49 with

a somewhat lower yield, but with the same excellent remote

1,4,5-stereocontol, showing that the methodology under

development can also serve in the asymmetric synthesis of

this class of highly desirable organic compounds (63% yield,

>98:2 dr, Scheme 10).¹⁶It is noteworthy that although the

desired (Z)-adducts were obtained in great predominance in

comparable yields using both protocols, under Condition B,

noticeably higher 2,6-anti-stereoselectivities were obtained in

all conducted experiments, showing this procedure to be

superior for β-lactams with an unsubstituted 4-vinyl group.

Since the application of Condition A enables the reactions of

azetidin-2-ones with a diﬀerently substituted allyl moiety, both

protocols appear to be complementary.

A number of methods were used to determine the

conﬁguration of obtained enediols, aminoalcohols, and

homoallylic alcohols. The (Z/E)-conﬁguration of compounds

bearing double substituted CC bonds was easily assigned by

an analysis of coupling constants of the oleﬁn protons in the

¹H NMR spectra (J ∼ 10 Hz for (Z)- and J ∼ 15 Hz for (E)-

isomers). In the case of enediols 35 and 38a−38b with the

triply substituted CC bond, the (Z/E)-conﬁgurations were

assigned by NOE measurements.¹⁰Also, the dr of all (3Z)- and

1

(3E)-products was established using H NMR spectroscopy.

The relative conﬁgurations of enediols 2a, 2b, 2b′, 18a, 18b,

and 18b′ were assigned by NOE measurements in

Scheme 11. Pd(PPh₃)₄/InI/N-MI-Mediated Allylation of Benzaldehyde with β-Lactam 39- and 50−52-Derived ε-Amido-

allylindiums: The Eﬀect of a Protective Group at the Nitrogen Atom of the Azetidin-2-one Ring

a

Condition A: PhCHO (2 equiv), InI (3 equiv), N-MI (2 equiv), Pd(PPh₃)₄(5 mol %), THF/EtOH (9:1), 25 °C. Condition B: PhCHO (2

b

c

1

equiv), Pd(PPh₃)₄(5 mol %), THF/HMPA (3:1), 25 °C. Isolated yield. Assayed by H NMR integration.

I

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Scheme 12. Pd(PPh₃)₄/InI/N-MI-Mediated Allylation of (R)-(+)-Glyceraldehyde Acetonide with Enantioenriched β-Lactam

(+)-1- and (−)-1-Derived ε-Amido-allylindiums: The Eﬀect of Chirality in the Organoindium Reagent and Aldehyde

a

b

c

1

Determined by chiral HPLC analysis. Isolated yield. Assayed by H NMR integration.

Scheme 13. Synthesis of 3,6,7-Trisubstituted Caprolactones 61−63: Determination of the Relative Conﬁguration of (3Z)- and

(3E)-2,6-Enediols 2a−2b and 18a−18b

a

b

c

1

Isolated yield. Assayed by H NMR integration. Obtained in 58% yield from β-lactam 1 and benzaldehyde during optimization using InI (3

equiv) and Pd(PPh₃)₄(10 mol %) in anhydrous THF at 25 °C.

J

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Scheme 14. Synthesis of (4Z)-3,6-syn-3,7-anti-Caprolactones (−)-65 and (+)-67 from (3Z)-2,5-syn-2,6-anti-Enediols (−)-56

and (+)-57

a

b

1

Isolated yield. Assayed by H NMR integration.

caprolactones 61−63 derived from them, using well-

established methods (Scheme 13).¹⁰In the cases of enediol

2a and caprolactone 62a, the assignments were further

conﬁrmed by X-ray analysis.¹⁰Also relative conﬁguration of

enediol 13 was established using X-ray diﬀractometry.¹⁰

Relative conﬁgurations of (Z)-enediols (−)-56 and (+)-57 in

turn were determined by X-ray analysis of caprolactones

(−)-65 and (+)-67 derived from them in two steps using

standard procedures (Scheme 14).¹⁰The conﬁgurations of

other enediols, amino alcohols, and homoallylic alcohols were

assigned by analogy. It is noteworthy that although

caprolactones 61−63, (−)-65, and (+)-67 depicted in

Schemes 13 and 14 were synthesized to determine the relative

conﬁguration of obtained adducts, they also constitute a simple

example of the application of β-lactam-derived enediols in

asymmetric synthesis of this type of highly desirable chiral

heterocycles.¹⁷

purity.⁷The utility of the obtained enediols was exempliﬁed in

the preparation of highly substituted chiral caprolactones with

three stereogenic centers in the ring. Further elaboration of the

chemistry presented and its application in asymmetric

synthesis of other types of heterocycles and selected natural

products is currently in progress.

EXPERIMENTAL SECTION

■

General Experimental Methods. InI was purchased from

Sigma-Aldrich and powdered in a mortar prior to use. Other reagents

were purchased from ABCR, Acros, Alfa Aesar, or Sigma-Aldrich and

used as received. Dry solvents were obtained by distillation over Na/

benzophenone (THF) or CaH₂(CH₂Cl₂). Air- and moisture-sensitive

reactions were conducted in oven-dried glassware under an

atmosphere of argon. Column chromatography was carried out

using Kiesel gel (230−400 mesh). Analytical TLC was performed on

silica gel 60 F254 aluminum plates (Merck, Darmstadt). Indication

was achieved with UV light (λ = 254 nm) and common dip stains

(potassium permanganate or cerium ammonium molybdate). NMR

spectra were recorded on Varian Mercury 400 MHz, Bruker DRX 500

Avance, or Varian VNMRS 600 MHz spectrometer in a CDCl₃,

MeOH-d₄, or acetone-d₆solution. Chemical shifts are quoted on the δ

scale, ppm, and are calibrated using the following residual solvents

CONCLUSIONS

■

We demonstrated that the application of an N-methylimidazole

(N-MI) ligand in the Pd(0)/InI-promoted allylations of

aldehydes with β-lactam-derived organoindiums enables the

use of azetidin-2-ones with a diversely substituted allyl moiety,

inert under our previously developed conditions,^3afor the ﬁrst

time. At this stage, we assume that the in situ formation of the

reactive InI·N-MI complex in the course of the process is

responsible for the observed beneﬁcial eﬀect of the N-

methylimidazole on the rate, yield, and stereoselectivity of

the process. As a result, eﬃcient entry to a broad range of

previously unavailable conﬁgurationally stable chiral ε-amido-

allylindiums bearing an α-, β-, or γ-substituted allyl fragment

was developed. We showed that the additions of these

particular cyclic intermediates to the aldehydes are strongly

reagent-controlled and proceed under thermodynamic control

with atypical allylindium reagent α-regioselectivity¹⁻³and a

very eﬃcient remote 1,5- or 1,4,5-asymmetric induction. The

resulting semiprotected (3Z)-substituted enediols, amino-

alcohols, or homoallylic alcohols are obtained in a modest or

high yield with an excellent 2,5-syn-2,6-anti- or 2,5-anti-2,6-

anti-selectivity depending on the β-lactam relative conﬁg-

uration used. Importantly, when enantioenriched substrates

were applied, no racemization was observed, demonstrating

that the developed methodology can be successively applied in

asymmetric synthesis, since a variety of β-lactams are readily

available in both enantiomeric forms in an excellent optical

1

signals: H NMR CDCl₃7.26 ppm, MeOH-d₄3.31 ppm, acetone-d₆

2.05 ppm; ¹³C{¹H} NMR CDCl₃77.16 ppm, MeOH-d₄49.00 ppm,

acetone-d₆29.84 ppm. Multiplicities for ¹H NMR signals are

described using the following abbreviations: s = singlet, d = doublet,

t = triplet, q = quartet, quint = quintet, sep = septet, m = multiplet, br

= broad signal. Coupling constants, J, are given in hertz (Hz). Infrared

spectra (IR) were measured on a FT-IR-1600-PerkinElmer

spectrophotometer and are reported in cm⁻¹. The samples were

prepared as thin ﬁlms. High-resolution mass spectra (HRMS) were

obtained on an ESI-TOF Mariner spectrometer (Perspective

Biosystem) and are given in m/z. Melting points (mp) were

determined with a melting point meter MPM-H2 apparatus and are

uncorrected. Optical rotations [α] were measured on a Jasco P-2000

Polarimeter in a quartz glass cuvette at λ = 589 nm (Na D line).

Concentrations [c] are given in g/100 mL. Analytical high-

performance liquid chromatography (HPLC) was performed using

a Knauer HPLC system (WellChrom K-1001 pump, WellChrom K-

2501 UV detector, WellChrom K-2301 RI detector) outﬁtted with a

Daicel Chiralpak ASH (250 mm × 4.6 mm, 5 μm) column. Operating

procedures and retention times were reported with the corresponding

chromatograms. (1E,2E)-N-(4-Methoxyphenyl)-3-phenylprop-2-en-1-

imine (v),¹⁸(1E,2Z)-N¹,N²-bis(4-methoxyphenyl)propane-1,2-dii-

mine (xviii),¹⁹β-lactams (3R*,4R*)-3-isopropyl-1-(4-methoxyphen-

yl)-4-((E)-styryl)azetidin-2-one (xxi),²⁰(2R*,3R*)-1-(4-methoxy-

phenyl)-3-methyl-4-oxoazetidine-2-carbaldehyde (xxvi),²¹

(2R*,3R*)-3-(1,3-dioxoisoindolin-2-yl)-1-(4-methoxyphenyl)-4-oxoa-

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zetidine-2-carbaldehyde (xxviii),²²2-((3R*,4S*)-1-(4-methoxyphen-

yl)-2-oxo-4-((E)-prop-1-en-1-yl)azetidin-3-yl)isoindoline-1,3-dione

(xxxii),²³(3R*,4S*)-1-tosyl-3-((triisopropylsilyl)oxy)-4-vinylazetidin-

2-one (39),^3a(3R*,4S*)-3-isopropyl-1-tosyl-4-vinylazetidin-2-one

(41),^3a(3R*,4S*)-1-(methylsulfonyl)-3-((triisopropylsilyl)oxy)-4-vi-

nylazetidin-2-one (50),^3btert-butyl (3R*,4S*)-2-oxo-3-

((triisopropylsilyl)oxy)-4-vinylazetidine-1-carboxylate (51),²⁴and

(3R*,4S*)-1-(4-methoxyphenyl)-3-((triisopropylsilyl)oxy)-4-vinyla-

zetidin-2-one (52)²⁴were prepared following the previously reported

procedures, and their analytical data were consistent with those

published in the literature.

(101 MHz, CDCl₃) δ 169.5, 161.7, 156.6, 131.2, 128.9, 127.4, 118.4,

114.5, 75.8, 64.3, 55.6, 20.5, 13.7, 12.7; IR (ﬁlm) v 2935, 2837, 1754,

1667, 1585, 1514, 1442, 1373, 1248, 1226, 1113, 1032, 830 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₁₆H₁₉NNaO₄[M + Na⁺]

312.1212, found 312.1199.

Preparation of β-Lactams (−)-i and (+)-i.²⁵To a vigorously

stirred suspension of racemic β-lactam i (11.012 g, 40 mmol) in 0.2 M

sodium phosphate buﬀer (pH 7.5, 450 mL)²⁶and acetonitrile (50

mL) was added Amano Lipase PS (10 g, immobilized on diatomite)

in one portion at 50 °C. After 36 h at the same temperature (ca. 55%

conversion according to ¹H NMR of the crude reaction mixture), the

mixture was cooled to 25 °C, ﬁltered through a pad of Celite, and

extracted with CH₂Cl₂(3 × 100 mL). The combined extracts were

dried over MgSO₄and concentrated under reduced pressure, and the

resulting enantioenriched β-lactams (−)-i (4.567 g, >98% ee) and

(−)-vii (3.438 g, 92% ee) were separated by column chromatography

on silica gel using an ethyl acetate/hexane mixture as an eluent. 3-

OH-β-Lactam (−)-vii was then dissolved in an anhydrous 50% vinyl

acetate/hexane mixture (80 mL), and to this solution were added PS

Amano Lipase (3 g, immobilized on diatomite) and 4 Å molecular

sieves (2 g) sequentially both in one portion at 25 °C under an

atmosphere of argon. The resulting mixture was heated to 50 °C for

Preparation of β-Lactams i−iv. To a vigorously stirred solution

of crotonaldehyde were added (E)-4-methylpent-2-enal, methacrolein,

or tiglic aldehyde (66 mmol) and p-anisidine (7.389 g, 60 mmol) in

anhydrous CH₂Cl₂(75 mL), and Na₂SO₄(42.612 g, 300 mmol) at 25

°C in one portion under an atmosphere of argon. After 3 h at the

same temperature, Na₂SO₄was ﬁltered oﬀ and the solvent was

removed under reduced pressure. Resulting crude imines were then

dissolved in anhydrous CH₂Cl₂(150 mL) and cooled to −78 °C

under an atmosphere of argon. NEt₃(12.544 mL, 90 mmol) was

added in one portion followed by the addition of acetoxyacetyl

chloride (7.74 mL,72 mmol) dropwise over 15 min. The mixture was

stirred for an additional hour at −78 °C and then allowed to warm to

25 °C slowly overnight. At the end of this time, the reaction was

quenched with 5% aqueous HCl solution (100 mL), poured into

water, and extracted with CH₂Cl₂(2 × 100 mL). Combined extracts

were washed successively with 5% aqueous HCl solution (100 mL),

saturated solution of NaHCO₃(100 mL), and water (100 mL), dried

over MgSO₄, and concentrated. Puriﬁcation of the crude product by

column chromatography on silica gel using an ethyl acetate/hexane

mixture as an eluent aﬀorded β-lactams i−iv as colorless crystals.

(3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)-

azetidin-3-yl Acetate (i): 5.844 g (25% yield); colorless crystals; mp

1

30 min (ca. 90% conversion according to H NMR of the crude

reaction mixture). After the mixture was cooled to 25 °C, the mixture

was ﬁltered through a pad of Celite, washed with EtOAc (25 mL),

and concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane mixture as an eluent aﬀorded enantioenriched β-

lactam (+)-i (3.788 g, >99% ee) as colorless crystals.

(3R,4S)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)-

azetidin-3-yl Acetate ((−)-i): 4.567 g (42% yield); colorless crystals;

mp 110.5−111.2 °C; R_f(30% AcOEt/hexane) 0.60; [α]²_D⁴−6.3 (c

0.83, CHCl₃); >98% ee; NMR and IR spectra were consistent with

those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for

C₁₅H₁₇NNaO₄[M + Na⁺] 298.1055, found 298.1049.

(3S,4R)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)-

azetidin-3-yl Acetate ((+)-i): 3.788 g (34% yield); colorless crystals;

mp 111.1−111.5 °C; R_f(30% AcOEt/hexane) 0.60; [α]²_D⁴+6.0 (c

0.82, CHCl₃); >99% ee; NMR and IR spectra were consistent with

those recorded for the racemate; HRMS (ESI-TOF) m/z calcd for

C₁₅H₁₇NNaO₄[M + Na⁺] 298.1055, found 298.1046.

Preparation of β-Lactam vi. To a vigorously stirred solution of

(1E,2E)-N-(4-Methoxyphenyl)-3-phenylprop-2-en-1-imine (v),

(2.373 g, 10 mmol) and NEt₃(2.091 mL, 15 mmol) in anhydrous

CH₂Cl₂(25 mL), acetoxyacetyl chloride (1.290 mL, 12 mmol) was

added dropwise over 15 min at −78 °C under an atmosphere of

argon. The mixture was stirred for an additional hour at the same

temperature and then was allowed to warm to 25 °C slowly overnight.

At the end of this time, the reaction was quenched with 5% aqueous

HCl solution (25 mL), poured into water and extracted with CH₂Cl₂

(2 × 25 mL). Combined extracts were washed successively with 5%

aqueous HCl solution (25 mL), saturated solution of NaHCO₃(25

mL) and water (25 mL), dried over MgSO₄and concentrated.

Puriﬁcation of the crude product by column chromatography on silica

gel using an acetone/hexane mixture as an eluent aﬀorded β-lactam vi

as colorless crystals.

(3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-styryl)azetidin-3-yl

acetate (vi): 3.273 g (97% yield); colorless crystals; R_f(30% acetone/

hexane) 0.45. Analytical data were consistent with previously reported

values.²⁷

Preparation of β-Lactams vii, (+)-vii, and (−)-vii. To a

vigorously stirred solution of β-lactam i, (−)-i, or (+)-i (5.506 g, 20

mmol) in MeOH (250 mL) was added a solution of K₂CO₃(5.528 g,

40 mmol) in water (125 mL) in one portion at 25 °C, and the mixture

was stirred for 5 min at the same temperature. The reaction was then

quenched with an aqueous saturated NH₄Cl solution (100 mL),

poured into water, and extracted with EtOAc (3 × 100 mL). The

combined extracts were successively washed with water (200 mL), a

saturated solution of NaHCO₃(100 mL) and brine (100 mL), dried

over anhydrous MgSO₄, and concentrated under reduced pressure.

1

94.3−95.8 °C; R_f(30% AcOEt/hexane) 0.60; H NMR (400 MHz,

CDCl₃) δ 7.42−7.31 (m, 2H), 6.90−6.81 (m, 2H), 5.96 (dqd, J =

15.5, 6.5, 0.8, 1H), 5.80 (d, J = 4.9, 1H), 5.44 (ddq, J = 15.5, 8.1, 1.7,

1H), 4.72 (dd, J = 8.1, 4.9, 1H), 3.78 (s, 3H), 2.13 (s, 3H), 1.76 (dd, J

= 6.5, 1.7, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.6, 161.4,

156.7, 134. 7, 131.0, 123.6, 118.9, 114.5, 76.2, 60.1, 55.6, 20.5, 18.2;

IR (ﬁlm) v 2938, 2838, 1753, 1670, 1513, 1442, 1391, 1246, 1224,

1112, 1033, 830 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₁₅H₁₇NNaO₄[M + Na⁺] 298.1055, found 298.1046.

(2S*,3R*)-1-(4-Methoxyphenyl)-2-((E)-3-methylbut-1-en-1-yl)-4-

oxoazetidin-3-yl Acetate (ii): 12.013 g (66% yield); colorless crystals;

1

mp 87.1−88.2 °C; R_f(25% AcOEt/hexane) 0.50; H NMR (400

MHz, CDCl₃) δ 7.41−7.32 (m, 2H), 6.90−6.81 (m, 2H), 5.92 (ddd, J

= 15.7, 6.7, 0.8, 1H), 5.78 (d, J = 4.9, 1H), 5.36 (ddd, J = 15.7, 8.0,

1.4, 1H), 4.71 (ddd, J = 8.0, 4.9, 0.8, 1H), 3.78 (s, 3H), 2.45−2.27

(m, 1H), 2.11 (s, 3H), 0.99 (d, J = 6.8, 3H), 0.98 (d, J = 6.8, 3H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.5, 161.4, 156.6, 146.7,

131.0, 119.4, 118.9, 114.4, 76.2, 60.1, 55.6, 31.2, 22.2, 22.1, 20.5; IR

(ﬁlm) v 3943, 2960, 2839, 1757, 1666, 1514, 1464, 1390, 1373, 1246,

1225, 1104, 1035, 831 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₁₇H₂₁NNaO₄[M + Na⁺] 326.1368, found 326.1359.

(3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-(prop-1-en-2-yl)-

azetidin-3-yl Acetate (iii): 13.049 g (79% yield); colorless crystals;

1

mp 128.9−130.2 °C; R_f(30% AcOEt/hexane) 0.45; H NMR (400

MHz, CDCl₃) δ 7.39−7.29 (m, 2H), 6.91−6.80 (m, 2H), 5.93 (d, J =

5.2, 1H), 5.20−5.18 (m, 1H), 5.14−5.11 (m, 1H), 4.72 (d, J = 5.2,

1H), 3.77 (s, 3H), 2.11 (s, 3H), 1.74 (s, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 169.5, 161.5, 156.8, 138.2, 131.0, 118.4, 117.7, 114.6,

75.5, 62.6, 55.6, 20.6, 19.1; IR (ﬁlm) v 2980, 2943, 2844, 1749, 1514,

1465, 1370, 1248, 1221, 1111, 1015, 831 cm⁻¹; HRMS (ESI-TOF)

m/z calcd for C₁₅H₁₇NNaO₄[M + Na⁺] 298.1055, found 298.1045.

(2S*,3R*)-2-((E)-But-2-en-2-yl)-1-(4-methoxyphenyl)-4-oxoazeti-

din-3-yl Acetate (iv): 11.110 g (64% yield); colorless crystals; mp

120.1−120.4 °C; R_f(30% AcOEt/hexane) 0.60; ¹H NMR (400 MHz,

CDCl₃) δ 7.37−7.28 (m, 2H), 6.88−6.79 (m, 2H), 5.89 (d, J = 5.1,

1H), 5.73−5.62 (m, 1H), 4.67 (d, J = 5.1, 1H), 3.77 (s, 3H), 2.08 (s,

3H), 1.68 (dd, J = 6.8, 1.2, 3H), 1.63−1.57 (m, 3H); ¹³C{¹H} NMR

L

DOI: 10.1021/acs.joc.8b02333

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The Journal of Organic Chemistry

Article

Crystallization of the crude product from ethyl acetate/hexane

mixture aﬀorded β-lactams vii, (+)-vii, and (−)-vii as colorless

crystals.

at the same temperature. Then the cooling bath was removed, and the

stirring was continued for an additional 30 min at 25 °C. At the end of

this time, the reaction was poured into water and extracted with

CH₂Cl₂(2 × 50 mL). The combined extracts were washed

successively with a 5% aqueous solution of HCl (50 mL), saturated

solution of NaHCO₃(50 mL) and water (50 mL), dried over

anhydrous MgSO₄, and concentrated under reduced pressure.

Puriﬁcation of the crude product by column chromatography on

silica gel using an ethyl acetate/hexane mixture as an eluent aﬀorded

β-lactam ix as colorless crystals.

(3R*,4S*)-3-Hydroxy-1-(4-methoxyphenyl)-4-((E)-prop-1-en-1-

yl)azetidin-2-one (vii): 4.265 g (91% yield); colorless crystals; mp

139.2−139.7 °C; R_f(30% AcOEt/hexane) 0.20; ¹H NMR (400 MHz,

CDCl₃) δ 7.42−7.31 (m, 2H), 6.89−6.79 (m, 2H), 6.04−5.90 (m,

1H), 5.60 (ddq, J = 15.5, 7.6, 1.7, 1H), 5.01 (dd, J = 7.8, 5.2, 1H),

4.64 (dd, J = 7.6, 5.2, 1H), 3.78 (s, 3H), 3.02 (d, J = 7.8, 1H), 1.82

(dd, J = 6.6, 1.7, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.4,

156.5, 133.9, 131.1, 124.8, 119.0, 114.4, 76.8, 61.3, 55.6, 18.3; IR

(ﬁlm) v 3346, 2924, 2836, 1878, 1721, 1672, 1518, 1445, 1396, 1255,

1128, 1034, 965, 827 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₁₃H₁₅NNaO₃[M + Na⁺] 256.0950, found 256.0941.

(3R,4S)-3-Hydroxy-1-(4-methoxyphenyl)-4-((E)-prop-1-en-1-yl)-

azetidin-2-one ((+)-vii): 3.640 g (78% yield); colorless crystals; mp

134.5−135.1 °C; R_f(30% AcOEt/hexane) 0.20; [α]²_D⁵+152.9 (c 0.94,

CHCl₃); >99% ee; NMR and IR spectra were consistent with those

recorded for the racemate; HRMS (ESI-TOF) m/z calcd for

C₁₃H₁₅NNaO₃[M + Na⁺] 256.0950, found 256.0944.

β-Lactam ix (2.74 g, 8.8 mmol) and anhydrous sodium acetate

(3.609 g, 44 mmol) were dissolved in anhydrous DMSO (110 mL),

and the mixture was stirred at 130 °C for 24 h under an atmosphere

of argon. After being cooled to 25 °C, the mixture was poured into

water and extracted with ethyl acetate (3 × 75 mL). The combined

extracts were washed with a 5% aqueous solution of HCl (200 mL),

water (4 × 200 mL), and brine (100 mL), dried over anhydrous

MgSO₄, and concentrated under reduced pressure. The residue was

dissolved in MeOH (100 mL), and the solution of K₂CO₃(2.433 g,

17.6 mmol) in water (50 mL) was added in one portion at 25 °C.

After 5 min of stirring at the same temperature, the reaction was

quenched with an aqueous saturated NH₄Cl solution (100 mL),

poured into water, and extracted with EtOAc (3 × 50 mL). The

combined extracts were successively washed with water (100 mL), a

saturated solution of NaHCO₃(50 mL), and brine (50 mL), dried

over anhydrous MgSO₄, and concentrated under reduced pressure.

Filtration of the residue through a pad of silica gel with ethyl acetate/

hexane aﬀorded the crude alcohol, which was then dissolved in

anhydrous DMF (10 mL), and imidazole (1.498 g, 22 mmol) and

TIPSCl (1.977 mL, 9.24 mmol) were sequentially added in one

portion at 0 °C under an atmosphere of argon. The mixture was

stirred for 15 min at the same temperature. Then the cooling bath was

removed, and the stirring was continued at 25 °C overnight. Then the

reaction mixture was poured into water and extracted with ethyl

acetate (3 × 50 mL). Combined extracts were washed with a 5%

aqueous solution of HCl (150 mL), saturated solution of NaHCO₃

(50 mL), and brine (50 mL), dried over anhydrous MgSO₄, and

concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane mixture as an eluent aﬀorded β-lactam x as colorless

crystals.

(3S,4R)-3-Hydroxy-1-(4-methoxyphenyl)-4-((E)-prop-1-en-1-yl)-

azetidin-2-one ((−)-vii): 3.956 g (85% yield); colorless crystals; mp

134.2−134.8 °C; R_f(30% AcOEt/hexane) 0.20; [α]²_D⁵−153.5 (c 1.13,

CHCl₃); >99% ee; NMR and IR spectra were consistent with those

recorded for the racemate; HRMS (ESI-TOF) m/z calcd for

C₁₃H₁₅NNaO₃[M + Na⁺] 256.0950, found 256.0941.

Preparation of β-Lactams viii, (+)-viii, and (−)-viii. To a

stirred solution of β-lactam vii, (+)-vii, or (−)-vii (2.333 g, 10 mmol)

and imidazole (1.702 g, 25 mmol) in anhydrous DMF (10 mL) was

added TIPSCl (2.247 mL, 10.5 mmol) in one portion at 0 °C under

an atmosphere of argon, and the mixture was stirred for 15 min at the

same temperature. Then the cooling bath was removed, and the

stirring was continued at 25 °C overnight. At the end of this time, the

reaction mixture was poured into water and extracted with EtOAc (3

× 50 mL). Combined extracts were washed with a 5% aqueous

solution of HCl (150 mL), saturated solution of NaHCO₃(50 mL)

and brine (50 mL), dried over anhydrous MgSO₄, and concentrated

under reduced pressure. Puriﬁcation of the crude product by column

chromatography on silica gel using an ethyl acetate/hexane mixture as

an eluent aﬀorded β-lactams viii, (+)-viii, and (−)-viii as colorless

crystals.

(3R*,4S*)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (viii): 3.701 g (95% yield);

colorless crystals; mp 76.6−77.8 °C; R_f(30% AcOEt/hexane) 0.90;

¹H NMR (400 MHz, CDCl₃) δ 7.42−7.34 (m, 2H), 6.88−6.79 (m,

2H), 5.92 (dqd, J = 15.4, 6.4, 0.6, 1H), 5.61 (ddq, J = 15.4, 8.7, 1.7,

1H), 5.05 (d, J = 5.0, 1H), 4.53 (dd, J = 8.7, 5.0, 1H), 3.77 (s, 3H),

1.77 (dd, J = 6.4, 1.7, 3H), 1.24−0.98 (m, 21H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 165.6, 156.2, 132.7, 131.8, 126.8, 118.7, 114.4, 77.8,

62.1, 55.6, 18.1, 17.84, 17.79, 12.1; IR (ﬁlm) v 2943, 2866, 1751,

1671, 1513, 1464, 1387, 1246, 1181, 1128, 1036, 966, 829 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₃Si [M + Na⁺]

412.2284, found 412.2269.

(3R,4S)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one ((+)-viii): 3.818 g (98% yield);

colorless crystals; mp 75.4−76.3 °C; R_f(30% AcOEt/hexane) 0.90;

[α]²_D⁵+73.5 (c 2.36, CHCl₃); NMR and IR spectra were consistent

with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd

for C₂₂H₃₅NNaO₃Si [M + Na⁺] 412.2284, found 412.2273.

(3S,4R)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one ((−)-viii): 3.779 g (97% yield);

colorless crystals; mp 76.1−76.9 °C; R_f(30% AcOEt/hexane) 0.90;

[α]²_D⁵−77.1 (c 1.58, CHCl₃); NMR and IR spectra were consistent

with those recorded for the racemate; HRMS (ESI-TOF) m/z calcd

for C₂₂H₃₅NNaO₃Si [M + Na⁺] 412.2284, found 412.2267.

(3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-((E)-prop-1-en-1-yl)-

azetidin-3-yl Methanesulfonate (ix): 2.740 g (88% yield); colorless

crystals; mp 110.3−111.7 °C; R_f(30% AcOEt/hexane) 0.30; ¹H

NMR (400 MHz, CDCl₃) δ 7.40−7.31 (m, 2H), 6.91−6.82 (m, 2H),

6.05 (ddd, J = 15.4, 6.6, 0.7, 1H), 5.64 (d, J = 5.2, 1H), 5.54 (ddd, J =

15.4, 8.5, 1.7, 1H), 4.77 (dd, J = 8.5, 5.2, 1H), 3.78 (s, 3H), 3.24 (s,

3H), 1.81 (dd, J = 6.6, 1.7, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

159.8, 157.0, 135.7, 130.5, 123.5, 119.0, 114.6, 79.8, 60.3, 55.6, 39.4,

18.2; IR (ﬁlm) v 3018, 2937, 2838, 1756, 1671, 1585, 1514, 1442,

1365, 1248, 1179, 1081, 890, 831 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₁₄H₁₇NNaO₅S [M + Na⁺] 334.0725, found 334.0713.

(3S*,4S*)-1-(4-Methoxyphenyl)-4-((E)-prop-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (x): 1.851 g (54% yield);

colorless crystals; mp 86.1−86.6 °C; R_f(30% AcOEt/hexane) 0.90;

¹H NMR (400 MHz, CDCl₃) δ 7.41−7.30 (m, 2H), 6.89−6.79 (m,

2H), 5.95 (dq, J = 15.4, 6.5, 1H), 5.52 (ddq, J = 15.4, 8.6, 1.7, 1H),

4.66 (d, J = 1.6, 1H), 4.23 (dd, J = 8.6, 1.6, 1H), 3.77 (s, 3H), 1.76

(dd, J = 6.5, 1.7, 3H), 1.21−1.05 (m, 21H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 165.2, 156.2, 131.7, 131.6, 127.7, 118.9, 114.4, 82.6,

65.5, 55.6, 18.0, 17.8, 12.1; IR (ﬁlm) v 2943, 2867, 1756, 1670, 1513,

1464, 1386, 1247, 1151, 1035, 830, 687 cm⁻¹; HRMS (ESI-TOF) m/

z calcd for C₂₂H₃₅NNaO₃Si [M + Na⁺] 412.2284, found 412.2274.

Preparation of β-Lactams xi and (+)-xi. To a solution of β-

lactam vii or (+)-vii (2.333 g, 10 mmol) and CBr₄(8.291 g, 25

mmol) in anhydrous THF (150 mL) was added a solution of PPh₃

(6.557 g, 25 mmol) in anhydrous THF (150 mL) dropwise at 25 °C

under an atmosphere of argon. The mixture was stirred for 15 min at

the same temperature and then reﬂuxed for an additional 30 min.

After being cooled to 25 °C, the mixture was diluted with MTBE (300

Preparation of β-Lactams ix and x. To a solution of β-lactam

vii (2.333 g, 10 mmol), DMAP (122 mg, 1 mmol), and NEt₃(5.575

mL, 40 mmol) in anhydrous CH₂Cl₂(100 mL) was added

methanesulfonyl chloride (1.548 mL, 20 mmol) dropwise at 0 °C

under an atmosphere of argon, and the mixture was stirred for 15 min

M

DOI: 10.1021/acs.joc.8b02333

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The Journal of Organic Chemistry

Article

mL) and ﬁltered through a pad of Celite. Removal of solvents under

reduced pressure and ﬁltration of the residue through a pad of silica

gel using CH₂Cl₂aﬀorded the crude bromide, which was then

dissolved in THF (100 mL) with the addition of acetic acid (10 mL).

To this mixture was added Zn dust (6.516 mg, 100 mmol)

portionwise at 25 °C under an atmosphere of argon. After an

additional 15 min at the same temperature, reaction mixture was

poured carefully into a vigorously stirred saturated solution of

NaHCO₃(100 mL) and extracted with AcOEt (3 × 75 mL).

Combined extracts were washed with water (100 mL) and brine (100

mL) and dried over anhydrous MgSO₄. Solvents were then removed

under reduced pressure, and the crude product was puriﬁed by

column chromatography on silica gel using an acetone/hexane

mixture as an eluent to aﬀord β-lactam xi or (+)-xi.

(3R*,4S*)-4-((E)-But-2-en-2-yl)-1-(4-methoxyphenyl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (xiv): 1.978 g (98% yield);

colorless crystals; mp 93.5−94.7 °C; R_f(15% AcOEt/hexane) 0.70;

¹H NMR (400 MHz, CDCl₃) δ 7.39−7.31 (m, 2H), 6.88−6.77 (m,

2H), 5.72−5.61 (m, 1H), 5.06 (d, J = 5.1, 1H), 4.52 (d, J = 5.1, 1H),

3.76 (s, 3H), 1.70 (dd, J = 6.7, 1.2, 3H), 1.64 (t, J = 1.2, 3H), 1.18−

1.04 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.0, 156.2,

132.1, 131.9, 125.8, 118.2, 114.4, 77.8, 66.4, 55.5, 17.8, 17.7, 13.6,

12.9, 12.0; IR (ﬁlm) v 2943, 2867, 1751, 1514, 1465, 1384, 1248,

1182, 1128, 829, 686 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₃H₃₇NNaO₃Si [M + Na⁺] 426.2440, found 426.2426.

( 3 R *, 4 S * ) - 1 - ( 4 - M e t h o x y p h e n y l ) - 4 - ( ( E ) - s t y r y l ) - 3 -

((triisopropylsilyl)oxy)azetidin-2-one (xv): 2.213 g (98% yield); R_f

(15% AcOEt/hexane) 0.60. Analytical data were consistent with

previously reported values.²⁹

(R*,E)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one

(xi): 1.086 g (50% yield); colorless oil; R_f(15% acetone/hexane) 0.45.

Analytical data were consistent with previously reported values.²⁸

(R,E)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one

((+)-xi): 1.108 g (51% yield); colorless oil; R_f(15% acetone/hexane)

0.45; [α]²_D⁵+61.1 (c 1.35, CHCl₃); NMR and IR spectra were

consistent with those recorded for the racemate; HRMS (ESI-TOF)

m/z calcd for C₁₃H₁₅NNaO₂[M + Na⁺] 240.1000, found 240.0994.

Preparation of β-Lactams xii−xv. To a solution of β-lactam ii−

iv or vi (5 mmol) in MeOH (70 mL) was added a solution of K₂CO₃

(1.382 g, 10 mmol) in water (35 mL) in one portion at 25 °C, and the

mixture was stirred for 5 min at the same temperature. The reaction

was then quenched with an aqueous saturated NH₄Cl solution (50

mL), poured into water, and extracted with EtOAc (3 × 50 mL). The

combined extracts were washed successively with water (100 mL), a

saturated solution of NaHCO₃(50 mL), and brine (50 mL), dried

over anhydrous MgSO₄, and concentrated under reduced pressure.

The obtained crude alcohols were dissolved in anhydrous DMF (5

mL), and imidazole (851 mg, 12.5 mmol) and TIPSCl (1.121 mL,

5.25 mmol) were sequentially added both in one portion at 0 °C

under an atmosphere of argon. The mixture was stirred for 15 min at

the same temperature. Then the cooling bath was removed, and the

stirring was continued at 25 °C overnight. At the end of this time, the

reaction mixture was poured into water and extracted with ethyl

acetate (3 × 50 mL). Combined extracts were washed with a 5%

aqueous solution of HCl (100 mL), saturated solution of NaHCO₃

(50 mL), and brine (50 mL), dried over anhydrous MgSO₄, and

concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane mixture as an eluent aﬀorded β-lactams xii−xv as

colorless crystals.

(3R*,4S*)-1-(4-Methoxyphenyl)-4-((E)-3-methylbut-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (xii): 2.067 g (99% yield);

colorless crystals; mp 97.9−98.4 °C; R_f(15% AcOEt/hexane) 0.70;

¹H NMR (400 MHz, CDCl₃) δ 7.43−7.34 (m, 2H), 6.89−6.77 (m,

2H), 5.91 (dd, J = 15.6, 6.4, 1H), 5.55 (ddd, J = 15.6, 8.8, 1.4, 1H),

5.05 (d, J = 5.0, 1H), 4.52 (dd, J = 8.8, 5.0, 1H), 3.77 (s, 3H), 2.37

(dheptd, J = 13.5, 6.7, 1.4, 1H), 1.19−1.06 (m, 21H), 1.02 (dd, J =

6.7, 0.9, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.6, 156.2,

145.2, 131.9, 122.4, 118.6, 114.3, 77.7, 62.4, 55.6, 31.2, 22.1, 21.9,

17.89, 17.86, 12.0; IR (ﬁlm) v 3073, 2957, 2867, 1877, 1749, 1663,

1515, 1463, 1386, 1248, 1129, 1033, 839, 688 cm⁻¹; HRMS (ESI-

TOF) m/z calcd for C₂₄H₃₉NNaO₃Si [M + Na⁺] 440.2597, found

440.2592.

Preparation of Chloride xvi. To a vigorously stirred solution of

methyl {[tri(propan-2-yl)silyl]oxy}acetate (12.321 g, 50 mmol) in

THF (30 mL) cooled to −10 °C, KOH (2.973 g, 52.5 mmol)

dissolved in 30% MeOH/water mixture (18 mL) was added carefully

so that the reaction temperature did not exceed −5 °C. Then the

reaction was warmed to 5 °C and stirring was continued for additional

30 min. At the end of this time the mixture was diluted with water

(200 mL), washed with Et₂O (100 mL) and phases were separated.

Aqueous layer was cooled to 0 °C, acidiﬁed by addition of 10%

aqueous solution o HCl (20 mL) and extracted with Et₂O (3 × 100

mL). Combined extracts were washed with water (200 mL) and brine

(100 mL), dried over anhydrous MgSO₄and concentrated under

reduced pressure. The resulting crude acid was dissolved in anhydrous

toluene (60 mL) and oxalyl chloride (6.542 mL, 75 mmol) was added

dropwise at 25 °C under an atmosphere of argon. Then the reaction

was heated to reﬂux until evolution of gaseous side products stopped

(about 30−40 min) and the solvents and oxalyl chloride excess were

distilled oﬀ to give chloride xvi as colorless oil.

2-((Triisopropylsilyl)oxy)acetyl chloride (xvi): 10.661 g (85%

yield); colorless oil; analytical data were consistent with previously

reported values;³⁰¹H NMR (400 MHz, CDCl₃) δ 4.62 (s, 2H), 1.18−

1.03 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.9, 70.3.

Preparation of β-Lactam xvii. To a vigorously stirred solution of

(E)-4-oxo-2-butenoic acid ethyl ester (2.819 g, 22 mmol) and p-

anisidine (2.463 g, 20 mmol) in anhydrous CH₂Cl₂(25 mL) was

added Na₂SO₄(14.204 g, 100 mmol) in one portion at 25 °C under

an atmosphere of argon. After the mixture was stirred for 3 h at the

same temperature, Na₂SO₄was ﬁltered oﬀ and the solvent was

removed under reduced pressure. The resulting crude imine was

dissolved in anhydrous toluene (300 mL), and NEt₃(4.181 mL, 30

mmol) was added followed by chloride xvi (6.02 g, 24 mmol) both in

one portion at 25 °C under an atmosphere of argon. Then the

reaction was heated to 80 °C for 2.5 h. After being cooled to 25 °C,

the mixture was poured into the water and the layers were separated.

The water layer was extracted with a portion of toluene (50 mL), and

the combined extracts were washed with a 5% aqueous HCl solution

(300 mL), saturated solution of NaHCO₃(300 mL), and brine (300

mL), dried over MgSO₄, and concentrated. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane mixture as an eluent aﬀorded β-lactam xvii as colorless

crystals.

Ethyl (E)-3-((2S*,3R*)-1-(4-methoxyphenyl)-4-oxo-3-

((triisopropylsilyl)oxy)azetidin-2-yl)acrylate (xvii): 5.909 g (66%

yield); colorless crystals; mp 49.7−50.9 °C; R_f(15% AcOEt/hexane)

0.65; ¹H NMR (400 MHz, CDCl₃) δ 7.36−7.27 (m, 2H), 7.00 (dd, J

= 15.8, 7.6, 1H), 6.89−6.79 (m, 2H), 6.13 (dd, J = 15.8, 0.9, 1H),

5.19 (d, J = 5.1, 1H), 4.71 (ddd, J = 7.6, 5.1, 0.9, 1H), 4.19 (qq, J =

10.9, 7.1, 1H), 3.78 (s, 3H), 1.27 (t, J = 7.1, 3H), 1.21−1.02 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl3) δ 165.2, 164.8, 142.7,

126.5, 118.5, 114.6, 78.6, 60.8, 60.1, 55.6, 17.9, 17.8, 14.3, 12.0; IR

(ﬁlm) v 2944, 2867, 1757, 1722, 1659, 1584, 1514, 1465, 1388, 1249,

1179, 1122, 1037, 882, 830, 688 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₄H₃₇NNaO₅Si [M + Na]⁺470.2339, found 470.2325.

(3R*,4S*)-1-(4-Methoxyphenyl)-4-(prop-1-en-2-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (xiii): 1.868 g (96% yield);

colorless crystals; mp 81.7−82.9 °C; R_f(30% AcOEt/hexane) 0.80;

¹H NMR (400 MHz, CDCl₃) δ 7.41−7.31 (m, 2H), 6.88−6.79 (m,

2H), 5.17 (p, J = 1.6, 1H), 5.13 (dt, J = 1.6, 0.8, 1H), 5.11 (d, J = 5.2,

1H), 4.58 (d, J = 5.2, 1H), 3.77 (s, 3H), 1.80−1.77 (m, 3H), 1.21−

1.07 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.7, 156.3,

141.1, 131.9, 118.2, 116.6, 114.5, 77.7, 64.7, 55.6, 19.1, 17.9, 17.8,

12.1; IR (ﬁlm) v 3078, 2944, 2867, 1753, 1583, 1513, 1464, 1388,

1248, 1183, 1127, 1036, 881, 830, 685 cm⁻¹; HRMS (ESI-TOF) m/z

calcd for C₂₂H₃₅NNaO₃Si [M + Na⁺] 412.2284, found 412.2279.

Preparation of β-Lactams xix and xxa−xxb. To a solution of

(1E,2Z)-N¹,N²-bis(4-methoxyphenyl)propane-1,2-diimine (xviii)

N

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(5.647 g, 20 mmol) in anhydrous toluene (300 mL) were added NEt₃

(4.181 mL, 30 mmol) and chloride xvi (6.02 g, 24 mmol) sequentially

both in one portion at 25 °C under an atmosphere of argon, and the

reaction was heated at 80 °C for 3 h. After the mixture cooled to 25

°C, a 5% aqueous solution of HCl was added in one portion (300

mL) and stirring was continued for an additional 1 h. At the end of

this time, the phases were separated and the aqueous one was

extracted with toluene (2 × 100 mL). Combined extracts were

washed with a 5% aqueous HCl solution (2 × 100 mL), saturated

solution of NaHCO₃(100 mL), and brine (100 mL), dried over

MgSO₄, and concentrated. Puriﬁcation of the crude product by

column chromatography on silica gel using CH₂Cl₂as an eluent

aﬀorded β-lactam xix as colorless crystals.

To a vigorously stirred solution of β-lactam xix (3.916 g, 10 mmol)

in anhydrous toluene (400 mL) was added 0.6 M Tebbe reagent

solution in toluene (16.667 mL, 10 mmol) dropwise at 0 °C under an

atmosphere of argon, and stirring was continued for 15 min at the

same temperature. At the end of this time, the reaction was quenched

with a 5% aqueous HCl solution (200 mL), poured into water, and

extracted with toluene (2 × 100 mL). Combined extracts were

washed successively with a 5% aqueous HCl solution (100 mL),

saturated solution of NaHCO₃(100 mL), and brine (100 mL), dried

over MgSO₄, and concentrated. Puriﬁcation of the crude product by

column chromatography on silica gel using an ethyl acetate/hexane

mixture as an eluent aﬀorded β-lactams xxa and xxb as colorless

crystals.

formylazetidinon-2-ones, which were used in the next step without

further puriﬁcation.

To a vigorously stirred suspension of methyltriphenylphosphonium

bromide (4.644 g, 13 mmol) or ethyltriphenylphosphonium bromide

(4.826 g, 13 mmol) in anhydrous THF (200 mL) was added a 2.5 M

solution of n-butyllithium in hexanes (5.2 mL, 13 mmol) dropwise at

−78 °C under an atmosphere of argon, and the mixture was stirred for

10 min at the same temperature. Then the cooling bath was removed,

and the stirring was continued for 30 min at 25 °C. After the mixture

was cooled to −78 °C, the generated in situ ylide was transferred via

cannula to the vigorously stirred solution of the previously prepared

crude 4-formylazetidinon-2-ones in anhydrous THF (150 mL),

cooled to −78 °C under an atmosphere of argon. The mixture was

stirred for an additional hour at the same temperature and then

allowed to warm to 25 °C slowly overnight. The reaction was

quenched with a saturated aqueous NH₄Cl solution (100 mL),

poured into water, and extracted with EtOAc (3 × 100 mL).

Combined extracts were successively washed with water (100 mL), a

saturated solution of NaHCO₃(50 mL), and brine (50 mL), dried

over anhydrous MgSO₄, and concentrated under reduced pressure.

Puriﬁcation of the crude product by column chromatography on silica

gel using an ethyl acetate/hexane or acetone/hexane mixture as an

eluent aﬀorded β-lactams xxii−xxiv, (−)-xxiv, and xxv as colorless

crystals.

(3R*,4S*)-1-(4-Methoxyphenyl)-4-((Z)-prop-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (xxii): 2.805 mg (72% yield);

Z/E = 86:14, colorless crystals; mp 120.1−121.3 °C; R_f(15% AcOEt/

hexane) 0.75; ¹H NMR (400 MHz, CDCl₃) δ (major) 7.37−7.28 (m,

2H), 6.88−6.79 (m, 2H), 5.91 (dqd, J = 11.3, 7.1, 1.0, 1H), 5.57

(ddq, J = 11.3, 10.0, 1.8, 1H), 5.08 (d, J = 4.9, 1H), 4.90 (ddd, J =

10.0, 4.9, 1.0, 1H), 3.77 (s, 3H), 1.86 (dd, J = 7.1, 1.8, 3H), 1.22−

1.01 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ (major): 165.6,

156.3, 131.6, 131.1, 125.8, 118.5, 114.4, 77.6, 56.2, 55.6, 17.84, 17.80,

13.6, 12.1; IR (ﬁlm) v 2943, 2866, 1745, 1658, 1514, 1460, 1383,

1249, 1127, 1032, 903, 837, 694 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₂H₃₅NNaO₃Si [M + Na]⁺412.2284, found 412.2273.

(3S*,4S*)-1-(4-Methoxyphenyl)-4-((Z)-prop-1-en-1-yl)-3-

((triisopropylsilyl)oxy)azetidin-2-one (xxiii): 2.883 g (74% yield), Z/

E = 82:18; after crystallization from MeOH 1.831 g (47% yield), Z/E

= 95:5, colorless crystals; mp 97.1−97.5 °C; R_f(15% AcOEt/hexane)

0.75; ¹H NMR (400 MHz, CDCl₃) δ 7.36−7.28 (m, 2H), 6.88−6.80

(m, 2H), 5.85 (dqd, J = 10.9, 7.0, 1.0, 1H), 5.49−5.37 (m, 1H), 4.69

(d, J = 1.7, 1H), 4.61 (ddd, J = 10.2, 1.7, 1.0, 1H), 3.77 (s, 3H), 1.89

(dd, J = 7.0, 1.8, 3H), 1.22−1.06 (m, 21H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 165.2, 156.3, 131.5, 130.7, 127.2, 118.6, 114.4, 82.5,

60.2, 55.6, 17.8, 13.8, 12.1; IR (ﬁlm) v 2943, 2867, 1757, 1657, 1586,

1513, 1465, 1386, 1248, 1152, 1037, 941, 830, 716 cm⁻¹; HRMS

(ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₃Si [M + Na]⁺412.2284,

found 412.2276.

(2R*,3R*)-1-(4-Methoxyphenyl)-2-methyl-4-oxo-3-

((triisopropylsilyl)oxy)azetidine-2-carbaldehyde (xix): 4.229 g (54%

yield), white solid; mp 97.8−99.1 °C; R_f(1% MeOH/CH₂Cl₂) 0.65;

¹H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H), 7.26−7.18 (m, 2H),

6.88−6.82 (m, 2H), 4.82 (s, 1H), 3.77 (s, 3H), 1.62 (s, 3H), 1.20−

1.02 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 201.7, 164.5,

157.1, 129.6, 119.2, 114.8, 114.8, 86.0, 70.3, 55.6, 17.7, 17.7, 14.9,

11.9; IR (ﬁlm) v 2945, 2868, 2718, 1763, 1612, 1584, 1513, 1464,

1380, 1250, 1150, 1036, 832, 688 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₁H₃₃NNaO₄Si [M + Na⁺] 414.2077, found 414.2065.

(3R*,4S*)-1-(4-Methoxyphenyl)-4-methyl-3-((triisopropylsilyl)-

oxy)-4-vinylazetidin-2-one (xxa): 740 mg (19% yield); colorless

crystals; mp 69.3−70.2 °C; R_f(15% AcOEt/hexane) 0.70; relative

1

conﬁguration was assigned by NOE measurements; H NMR (400

MHz, CDCl₃) δ 7.46−7.37 (m, 2H), 6.88−6.78 (m, 2H), 6.15 (dd, J

= 17.6, 10.9, 1H), 5.45 (dd, J = 10.9, 0.9, 1H), 5.40 (dd, J = 17.6, 0.9,

1H), 4.68 (s, 1H), 1.67 (s, 3H), 1.24−0.99 (m, 21H); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 165.1, 156.3, 138.0, 130.7, 119.5, 118.5, 114.4,

84.9, 66.9, 55.6, 19.6, 17.9, 17.8, 12.1; IR (ﬁlm) v 3087, 2944, 2867,

1751, 1583, 1513, 1464, 1378, 1247, 1155, 1038, 829, 685 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₃Si [M + Na]⁺

412.2284, found 412.2268.

(3R*,4R*)-1-(4-Methoxyphenyl)-4-methyl-3-((triisopropylsilyl)-

oxy)-4-vinylazetidin-2-one (xxb): 234 mg (6% yield); colorless

crystals; mp 52.8−53.9 °C; R_f(15% AcOEt/hexane) 0.75; relative

(R*,Z)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one

(xxiv): 891 mg (41% yield), Z/E = 78:22, colorless crystals; mp 63.5−

64.6 °C; R_f(25% AcOEt/hexane) 0.50; ¹H NMR (400 MHz, CDCl₃)

δ (major) 7.31−7.25 (m, 2H), 6.86−6.80 (m, 2H), 5.78 (dqd, J =

11.0, 7.0, 1.0, 1H), 5.52−5.43 (m, 1H), 4.75 (dddd, J = 9.3, 5.5, 2.6,

1.0, 1H), 3.75 (s), 3.31 (dd, J = 15.0, 5.5, 1H), 2.76 (dd, J = 15.0, 2.6,

1H), 1.84 (dd, J = 7.0, 1.8, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

163.9, 156.0, 131.9, 129.8, 128.9, 117.9, 114.4, 55.5, 47.7, 43.7, 13.5;

IR (ﬁlm) v 2997, 2951, 2836, 1745, 1658, 1583, 1512, 1442, 1379,

1245, 1140, 1036, 830, 517 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₁₃H₁₅NNaO₂[M + Na]⁺240.1000, found 240.0994.

1

conﬁguration was assigned by NOE measurements; H NMR (400

MHz, CDCl₃) δ 7.49−7.40 (m, 2H), 6.87−6.78 (m, 2H), 6.07 (dd, J

= 17.5, 10.8, 1H), 5.33 (d, J = 17.5, 2H), 5.32 (d, J = 10.8, 1H), 4.65

(s, 1H), 3.77 (s, 3H), 1.63 (s, 3H), 1.22−1.03 (m, 21H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 165.4, 156.1, 139.9, 130.9, 119.2, 117.0,

114.3, 83.9, 66.6, 55.6, 18.0,17.9, 17.8, 16.5, 12.1; IR (ﬁlm) v 2944,

2867, 1753, 1513, 1464, 1377, 1247, 1156, 1039, 829, 686 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₃Si [M + Na]⁺

412.2284, found 412.2271.

Preparation of β-Lactams xxii−xxiv, (−)-xxiv, and xxv. A

mixture of β-lactam viii, x, xi, (+)-xi or xxi (10 mmol) and saturated

ethanolic solution of ozonizable dye Sudan red 7B (0.2 mL) in

anhydrous CH₂Cl₂(50 mL) was cooled to −78 °C, and ozone was

bubbled through it until the deep red color of the reaction mixture

turned to pale yellow. Then dimethyl sulﬁde (2.5 mL) was added in

one portion; the cooling bath was removed, and the stirring was

continued for 3 h at 25 °C. At the end of this time, the solvents were

removed under reduced pressure and the residue was ﬁltered through

a pad silica gel using a MeOH/CH₂Cl₂mixture to aﬀord crude 4-

(R,Z)-1-(4-Methoxyphenyl)-4-(prop-1-en-1-yl)azetidin-2-one

((−)-xxiv): 1.029 g (47% yield), Z/E = 76:24, colorless oil; R_f(25%

AcOEt/hexane) 0.50; [α]_D²⁵−20.9 (c 0.70, CHCl₃); NMR and IR

spectra were consistent with those recorded for the racemate; HRMS

(ESI-TOF) m/z calcd for C₁₃H₁₅NNaO₂[M + Na]⁺240.1000, found

240.0996.

(3R*,4R*)-3-Isopropyl-1-(4-methoxyphenyl)-4-vinylazetidin-2-

one (xxv): 1.662 g (81% yield); colorless wax; R_f(20% acetone/

1

hexane) 0.75; H NMR (400 MHz, CDCl₃) δ 7.40−7.30 (m, 2H),

6.88−6.79 (m, 2H), 5.93 (ddd, J = 17.1, 10.3, 8.0, 1H), 5.44 (dt, J =

O

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

17.1, 0.9, 1H), 5.30 (dt, J = 10.3, 0.9, 1H), 4.16 (dd, J = 8.0, 2.4, 1H),

3.76 (s, 3H), 2.79 (dd, J = 8.3, 2.4, 1H), 2.19−2.02 (m, 1H), 1.12 (d,

J = 6.7, 3H), 1.03 (d, J = 6.7, 3H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 166.4, 156.0, 136.8, 131.9, 118.7, 118.2, 114.4, 64.0, 58.4,

55.6, 28.5, 20.3, 20.2; IR (ﬁlm) v 3081, 2958, 2873, 1742, 1641, 1584,

1513, 1465, 1386, 1246, 1147, 1032, 928, 830, 522 cm⁻¹; HRMS

(ESI-TOF) m/z calcd for C₁₅H₁₉NNaO₂[M + Na]⁺268.1313, found

268.1302.

167.2, 160.5, 156.6, 134.6, 132.0, 131.7, 131.3, 123.8, 123.2, 118.6,

114.5, 60.8, 57.6, 55.6; IR (ﬁlm) v 2957, 2837, 1756, 1721, 1612,

1586, 1513, 1466, 1388, 1247, 1131, 1032, 945, 830, 714 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₀H₁₆N₂NaO₄[M + Na]⁺

371.1008, found 371.1003.

Preparation of β-Lactams xxx and xxxi. A mixture of xiv

(4.036 g, 10 mmol) and saturated ethanolic solution of ozonizable dye

Sudan red 7B (0.2 mL) in anhydrous CH₂Cl₂(40 mL) was cooled to

−78 °C, and ozone was bubbled through it until the deep red color of

the reaction mixture turned to pale yellow. Then a dimethyl sulﬁde (4

mL) was added in one portion; the cooling bath was removed, and

stirring was continued for an additional 3 h at 25 °C. At the end of

this time, the reaction mixture was concentrated under reduced

pressure and the resulting crude product was puriﬁed by column

chromatography on silica gel using an ethyl acetate/hexane mixture as

an eluent to aﬀord β-lactam xxx as colorless crystals.

To a vigorously stirred solution of β-lactam xxx (3.916 g, 10 mmol)

in anhydrous THF (40 mL), a mixture of NaHMDS (3.668 g, 20

mmol) and TMEDA (2.998 mL, 20 mmol) in anhydrous THF (80

mL) was added dropwise at 0 °C under an argon atmosphere and the

cooling bath was removed. The stirring was continued at 25 °C for an

additional 30 min, and the mixture was transferred via cannula to a

vigorously stirred solution of acetyl chloride (1.422 mL, 20 mmol) in

anhydrous THF (80 mL) at 25 °C under an argon atmosphere. After

the next 30 min at the same temperature, the reaction was quenched

with an aqueous saturated NH₄Cl solution (200 mL), poured into

water, and extracted with EtOAc (3 × 100 mL). The combined

extracts were washed successively with water (200 mL), a saturated

solution of NaHCO₃(100 mL), and brine (100 mL), dried over

anhydrous MgSO₄, and concentrated under reduced pressure.

Filtration of the residue through a pad of silica gel with CH₂Cl₂

aﬀorded the crude intermediate vinyl acetate accompanied by

unreacted β-lactam xxx, which were without further puriﬁcation

dissolved in the mixture of acetonitrile (400 mL) and water (80 mL)

and cooled to −10 °C. Then a solution of CAN (19.188 g, 35 mmol)

in water (320 mL) was added dropwise within 15 min, and the

reaction was stirred at the same temperature for 3.5 h. At the end of

this time, the reaction was quenched with a saturated aqueous

Na₂S₂O₃solution (100 mL), poured into water, and extracted with

ethyl acetate (3 × 150 mL). Combined extracts were washed with

water (500 mL), a saturated aqueous solution of NaHCO₃(300 mL),

and brine (300 mL), dried over MgSO₄, and concentrated under

reduced pressure. Puriﬁcation of the crude product by column

chromatography on silica gel using a MTBE/hexane mixture as an

eluent aﬀorded β-lactam xxxi as colorless crystals

Preparation of β-Lactam xxvii. To a vigorously stirred

suspension of methyltriphenylphosphonium bromide (4.644 g, 13

mmol) in anhydrous THF (200 mL) was added a 2.5 M solution of n-

butyllithium in hexanes (5.2 mL, 13 mmol) dropwise over 15 min at

−78 °C under an atmosphere of argon, and the mixture was stirred for

10 min at the same temperature. Then the cooling bath was removed,

and the stirring was continued for 30 min at 25 °C. After the mixture

cooled to −78 °C, the generated in situ ylide was transferred via

cannula to the vigorously stirred solution of 4-formylazetidinon-2-one

xxvi (10 mmol) in anhydrous THF (150 mL), cooled to −78 °C

under an atmosphere of argon. The mixture was stirred for an

additional hour at the same temperature and then allowed to warm to

25 °C slowly overnight. The reaction was quenched with an aqueous

saturated NH₄Cl solution (100 mL), poured into water, and extracted

with EtOAc (3 × 100 mL). The combined extracts were washed

successively with water (100 mL), a saturated solution of NaHCO₃

(50 mL), and brine (50 mL), dried over anhydrous MgSO₄, and

concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane mixture as an eluent aﬀorded β-lactam xxvii as

colorless crystals.

(3R*,4S*)-1-(4-Methoxyphenyl)-3-methyl-4-vinylazetidin-2-one

(xxvii): 1.890 g (87% yield); colorless crystals; mp 78.1−78.5 °C; R_f

1

(30% AcOEt/hexane) 0.65; H NMR (400 MHz, CDCl₃) δ 7.37−

7.28 (m, 2H), 6.86−6.77 (m, 2H), 5.84 (ddd, J = 17.6, 10.2, 7.6, 1H),

5.46−5.36 (m, 2H), 4.52 (ddt, J = 7.6, 5.8, 0.9, 1H), 3.75 (s, 3H),

3.47 (qd, J = 7.6, 5.8, 1H), 1.19 (d, J = 7.6, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 167.8, 156.0, 133.6, 131.9, 120.7, 118.2, 114.3, 57.4,

55.5, 48.3, 9.7; IR (ﬁlm) v 3081, 2971, 2933, 2836, 1863, 1741, 1642,

1584, 1513, 1443, 1388, 1246, 1159, 1032, 931, 831, 526 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₁₃H₁₅NNaO₂[M + Na]⁺

240.1000, found 240.0992.

Preparation of β-Lactam xxix. To a vigorously stirred

suspension of methyltriphenylphosphonium bromide (3.929 g, 11

mmol) in anhydrous THF (200 mL) was added a 2.5 M solution of n-

butyllithium in hexanes (4.4 mL, 11 mmol) dropwise at −78 °C

under an atmosphere of argon, and the mixture was stirred for 10 min

at the same temperature. Then the cooling bath was removed, and the

stirring was continued for 30 min at 25 °C. After the mixture cooled

to −78 °C, the generated in situ ylide was transferred via cannula to a

vigorously stirred solution of 4-formylazetidinon-2-one xxviii (3.503

g, 10 mmol) in anhydrous THF (700 mL),³¹cooled to −78 °C under

an atmosphere of argon. The reaction mixture was stirred for 30 min

at the same temperature; then the cooling bath was removed, and

stirring was continued until the reaction mixture reached 25 °C. Then

an aqueous saturated NH₄Cl solution (150 mL) was added, and THF

was carefully distilled oﬀ under reduced pressure without separating

phases. The concentrated reaction mixture was diluted with water

(300 mL) and extracted with CH₂Cl₂(3 × 150 mL). The combined

extracts were successively washed with water (250 mL) and a

saturated solution of NaHCO₃(150 mL), dried over anhydrous

MgSO₄, and concentrated under reduced pressure. Puriﬁcation of the

crude product by column chromatography on silica gel using an

acetone/hexane mixture as an eluent aﬀorded β-lactam xxix as

colorless crystals.

(3R*,4R*)-4-Acetyl-1-(4-methoxyphenyl)-3-((triisopropylsilyl)-

oxy)azetidin-2-one (xxx): 2.858 g (73% yield); colorless crystals; mp

105.1−106.2 °C; R_f(15% AcOEt/hexane) 0.55; ¹H NMR (400 MHz,

CDCl₃) δ 7.26−7.21 (m, 2H), 6.88−6.83 (m, 2H), 5.25 (d, J = 5.5,

1H), 4.51 (d, J = 5.5, 1H), 3.77 (s, 3H), 2.20 (s, 3H), 1.23−1.04 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 205.8, 164.7, 156.9,

130.8, 118.0, 114.8, 78.0, 66.0, 55.6, 27.8, 17.8, 17.7, 12.0; IR (ﬁlm) v

3004, 2944, 2867, 1877, 1756, 1721, 1517, 1463, 1298, 1251, 1185,

1123, 1031, 962, 830, 683 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₁H₃₃NNaO₄Si [M + Na⁺] 414.2077, found 414.2069.

1-((2R*,3R*)-4-Oxo-3-((triisopropylsilyl)oxy)azetidin-2-yl)vinyl

Acetate (xxxi): 754 mg (23% yield); colorless crystals; mp 77.8−78.7

1

°C; R_f(30% MTBE/hexane) 0.7; H NMR (400 MHz, CDCl₃) δ

6.24 (br s, 1H), 5.10 (s, 2H), 5.03 (dd, J = 4.8, 2.2, 1H), 4.25 (d, J =

4.8, 1H), 2.13 (s, 3H), 1.18−1.01 (m, 21H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 169.7, 169.3, 151.3, 105.5, 79.6, 57.3, 21.1, 17.8, 17.7,

12.0; IR (ﬁlm) v 2941, 2865, 1760, 1674, 1462, 1370, 1228, 1178,

1040, 881, 686 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₁₆H₂₉NNaO₄Si [M + Na⁺] 350.1764, found 350.1751.

2-((3R*,4S*)-1-(4-Methoxyphenyl)-2-oxo-4-vinylazetidin-3-yl)-

isoindoline-1,3-dione (xxix): 2.264 g (65% yield); colorless crystals;

Synthesis of N-Ts-Azetidin-2-ones 1, (+)-1, (−)-1, 15−17, 19,

(+)-19, 20, (−)-20, 24−31, 40, 42−43, and 48: General

Procedures. Method A. To a solution of N-PMP-azetidin-2-one (5

mmol) in acetonitrile (200 mL) and water (40 mL) cooled to −10 °C

was added a solution of CAN (9.594 g, 17.5 mmol) in water (160

mL) dropwise within 15 min, and the reaction was stirred at the same

1

mp 161.4−161.8 °C; R_f(30% acetone/hexane) 0.5; H NMR (400

MHz, CDCl₃) δ 7.92−7.79 (m, 2H), 7.79−7.69 (m, 2H), 7.47−7.38

(m, 2H), 6.92−6.83 (m, 2H), 5.92 (dt, J = 17.6, 10.4, 8.1, 1H), 5.59

(d, J = 5.5, 1H), 5.50 (d, J = 17.6, 1H), 5.34 (d, J = 10.4, 1H), 4.84 (t,

J = 8.1, 5.5, 1H), 3.78 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

P

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

temperature for 3.5 h. At the end of this time, the reaction was

quenched with a saturated aqueous Na₂S₂O₃solution (50 mL),

poured into water (500 mL), and extracted with ethyl acetate (3 ×

100 mL). The combined extracts were washed with water (300 mL), a

saturated aqueous solution of NaHCO₃(300 mL), and brine (300

mL), dried over MgSO₄, and concentrated under reduced pressure.

Filtration of the residue through a pad of silica gel with CH₂Cl₂(to

remove quinone formed as the byproduct) and then an ethyl acetate/

hexane mixture aﬀorded the crude NH-β-lactam, which was then

dissolved in toluene (25 mL) and added in one portion to a

vigorously stirred mixture of TsCl (4.766 g, 25 mmol), TBAB (161

mg, 0.5 mmol), and solid NaOH (15 g) in toluene (275 mL) at 25

°C. After 15 min at the same temperature, an excess of NaOH was

ﬁltered oﬀ and washed with a portion of toluene (50 mL). Combined

ﬁltrates were then washed with water (300 mL), a saturated aqueous

solution of NH₄Cl (100 mL), and a saturated aqueous solution of

NaHCO₃(100 mL), dried over MgSO₄, and concentrated.

Puriﬁcation of the crude product by column chromatography on

silica gel using an ethyl acetate/hexane, acetone/hexane, or Et₂O/

hexane mixture as an eluent aﬀorded the desired N-Ts-azetidin-2-one

as colorless crystals.

NaHCO₃(50 mL), dried over anhydrous MgSO₄, and concentrated

under reduced pressure. Puriﬁcation of the crude product by column

chromatography on silica gel using an ethyl acetate/hexane mixture as

an eluent aﬀorded the desired N-Ts-azetidin-2-one as colorless

crystals.

(3R*,4S*)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one (1): Method A; 1.576 g (72% yield); E/Z = 95:5,

colorless crystals; mp 122.7−124.5 °C; R_f(15% AcOEt/hexane) 0.5;

¹H NMR (400 MHz, CDCl₃) δ 7.87−7.78 (m, 2H), 7.36−7.30 (m,

2H), 5.90 (dq, J = 15.4, 6.6, 1H), 5.29 (ddq, J = 15.4, 9.2, 1.7, 1H),

5.00 (d, J = 5.7, 1H), 4.63 (dd, J = 9.2, 5.7, 1H), 2.44 (s, 3H), 1.70

(dd, J = 6.6, 1.7, 3H), 1.14−0.93 (m, 21H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 165.0, 145.2, 136.6, 134.7, 129.9, 127.8, 124.0, 77.7,

64.5, 21.8, 18.0, 17.6, 17.6, 11.8; IR (ﬁlm) v 2945, 2868, 1800, 1464,

1366, 1171, 1091, 728 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₂H₃₅NNaO₄SSi [M + Na⁺] 460.1954, found 460.1941.

(3S,4R)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one ((−)-1): Method A; 1.707 g (78% yield); E/Z = 98:2;

ee > 99%; colorless crystals; mp 98.2−98.8 °C; R_f(15% AcOEt/

hexane) 0.5; [α]²_D³−43.9 (c 0.89, CHCl₃); NMR and IR spectra were

consistent with those recorded for the racemate; HRMS (ESI-TOF)

m/z calcd for C₂₂H₃₅NNaO₄SSi [M + Na⁺] 460.1954, found

460.1945.

Method B. To a solution of N-PMP-azetidin-2-one (5 mmol) in

acetonitrile (200 mL) and water (40 mL) cooled to −10 °C was

added a solution of CAN (9.594 g, 17.5 mmol) in water (160 mL)

dropwise within 15 min, and the reaction was stirred at the same

temperature for 3.5 h. At the end of this time, the reaction was

quenched with a saturated aqueous Na₂S₂O₃solution (50 mL),

poured into water (500 mL), and extracted with ethyl acetate (3 ×

100 mL). The combined extracts were washed with water (300 mL), a

saturated aqueous solution of NaHCO₃, and brine (300 mL), dried

over MgSO₄, and concentrated under reduced pressure. Filtration of

the residue through a pad silica gel with CH₂Cl₂(to remove quinone

formed as the byproduct) and then an ethyl acetate/hexane mixture

aﬀorded the crude NH-β-lactam, which was then dissolved in

anhydrous THF (200 mL). To this mixture was added 2 M NaHMDS

solution in THF (2.5 mL, 5 mmol) dropwise at −78 °C under an

argon atmosphere. The stirring was continued for 30 min at the same

temperature, and the mixture was transferred via cannula to the

vigorously stirred solution of tosyl chloride in anhydrous THF (100

mL) at −78 °C under an argon atmosphere. After the next 30 min at

the same temperature, the cooling bath was removed, and once

warmed to 25 °C, the reaction was quenched with an aqueous

saturated NH₄Cl solution (100 mL), poured into water, and extracted

with EtOAc (3 × 75 mL). The combined extracts were washed

successively with water (100 mL), a saturated solution of NaHCO₃

(50 mL), and brine (50 mL), dried over anhydrous MgSO₄, and

concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane, acetone/hexane, or Et₂O/hexane mixture as an eluent

aﬀorded the corresponding N-Ts-azetidin-2-one as colorless crystals.

Method C. To a solution of N-PMP-azetidin-2-one (5 mmol) in

acetonitrile (200 mL) and water (40 mL) cooled to −10 °C was

added a solution of CAN (9.594 g, 17.5 mmol) in water (160 mL)

dropwise within 15 min, and the reaction was stirred at the same

temperature for 3.5 h. At the end of this time, the reaction was

quenched with a saturated aqueous Na₂S₂O₃solution (50 mL),

poured into water (500 mL), and extracted with ethyl acetate (3 ×

100 mL). The combined extracts were washed with water (300 mL), a

saturated aqueous solution of NaHCO₃, and brine (300 mL), dried

over MgSO₄, and concentrated under reduced pressure. Filtration of

the residue through a pad of silica gel with CH₂Cl₂(to remove

quinone formed as the byproduct) and then an ethyl acetate/hexane

mixture aﬀorded the crude NH-β-lactam, which was then dissolved in

anhydrous CH₂Cl₂(35 mL). To this mixture were sequentially added

NEt₃(2.788 mL, 20 mmol), DMAP (61 mg, 0.5 mmol), and Ts₂O

(6.528 g, 20 mmol) all in one portion at 0 °C under an argon

atmosphere, and the cooling bath was removed. After 24 h at 25 °C,

the reaction mixture was poured into water and extracted with

CH₂Cl₂(3 × 25 mL). The combined extracts were washed

successively with water (100 mL) and a saturated solution of

(3R,4S)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one ((+)-1): Method A; 1.751 g (80% yield); E/Z = 95:5;

ee > 99%; colorless crystals; mp 98.7−99.9 °C; R_f(15% AcOEt/

hexane) 0.5; [α]²_D³+41.5 (c 0.63, CHCl₃); NMR and IR spectra were

consistent with those recorded for the racemate; HRMS (ESI-TOF)

m/z calcd for C₂₂H₃₅NNaO₄SSi [M + Na⁺] 460.1954, found

460.1946.

(3R*,4R*)-4-((Z)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one (15): Method A; 1.510 g (69% yield); Z/E = 91:9,

colorless crystals; mp 79.6−80.7 °C; R_f(20% Et₂O/hexane) 0.55; ¹H

NMR (400 MHz, CDCl₃) δ 7.87−7.79 (m, 2H), 7.37−7.30 (m, 2H),

5.87 (dqd, J = 10.8, 7.0, 0.9, 1H), 5.40−5.28 (m, 1H), 4.61 (ddd, J =

9.8, 2.6, 0.9, 1H), 4.57 (d, J = 2.6, 1H), 2.44 (s, 3H), 1.80 (dd, J = 7.0,

1.8, 3H), 1.12−0.96 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

165.0, 145.3, 136.2, 132.5, 130.0, 127.7, 125.2, 82.2, 62.3, 21.8, 17.6,

17.6, 13.6, 11.9; IR (ﬁlm) v 2945, 2868, 1803, 1464, 1368, 1171,

1090, 720 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₄SSi

[M + Na⁺] 460.1954, found 460.1941.

(3R*,4S*)-4-((Z)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one (16): Method A; 1.795 g (82% yield); Z/E = 76:24;

897 mg (41% yield), Z/E = 98:2 after an additional column eluting

with a MTBE/hexane mixture; colorless crystals; mp 82.8−83.5 °C;

(20% Et₂O/hexane) 0.55; ¹H NMR (400 MHz, CDCl₃) δ 7.88−7.79

(m, 2H), 7.35−7.28 (m, 2H), 5.88 (dq, J = 10.9, 7.0, 1H), 5.38−5.25

(m, 1H), 5.11−5.00 (m, 2H), 2.43 (s, 3H), 1.81 (dd, J = 7.0, 1.8,

3H), 1.13−0.96 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

165.0, 145.2, 136.6, 133.3, 129.9, 127.7, 122.7, 77.6, 58.4, 21.8, 17.7,

17.6, 13.4, 11.9; IR (ﬁlm) v 2945, 2893, 2868, 1801, 1464, 1365,

1170, 1091, 896, 608 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₂H₃₅NNaO₄SSi [M + Na⁺] 460.1954, found 460.1942.

(3R*,4R*)-4-((E)-Prop-1-en-1-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one (17): Method A; 1.444 g (66% yield); E/Z = 96:4,

colorless crystals; mp 107.8−108.3 °C; R_f(20% Et₂O/hexane) 0.55;

¹H NMR (400 MHz, CDCl₃) δ 7.82 (m, 2H), 7.33 (m, 2H), 5.94

(dq, J = 15.2, 6.5, 1H), 5.38 (ddq, J = 15.2, 8.9, 1.7, 1H), 4.56 (d, J =

2.6, 1H), 4.20 (dd, J = 8.9, 2.6, 1H), 2.44 (s, 3H), 1.75 (dd, J = 6.5,

1.7, 3H), 1.09−0.97 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

165.0, 145.3, 136.2, 133.6, 130.0, 127.7, 126.0, 82.1, 67.8, 21.8, 17.9,

17.6, 11.9; IR (ﬁlm) v 2945, 2893, 2868, 1803, 1464, 1171, 1092, 882,

719 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₄SSi [M +

Na⁺] 460.1954, found 460.1946.

(R*,E)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one (19): Method C;

637 mg (48% yield);³²E/Z = 95:5; colorless oil; R_f(30% AcOEt/

1

hexane) 0.60; H NMR (400 MHz, CDCl₃) δ 7.91−7.76 (m, 2H),

7.41−7.29 (m, 2H), 5.91 (dq, J = 15.2, 6.6, 1H), 5.34 (ddt, J = 15.2,

8.8, 1.7, 1H), 4.50 (ddd, J = 8.8, 6.1, 3.3, 1H), 3.20 (dd, J = 16.0, 6.1,

1H), 2.72 (dd, J = 16.0, 3.3, 1H), 2.44 (s, 3H), 1.71 (dd, J = 6.6, 1.7,

Q

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 163.6, 145.2, 136.5, 133.0,

130.0, 127.7, 127.4, 56.3, 43.8, 21.8, 17.8; IR (ﬁlm) v 2998, 2951,

2920, 1793, 1598, 1450, 1362, 1169, 1091, 962, 678 cm⁻¹; HRMS

(ESI-TOF) m/z calcd for C₁₃H₁₅NNaO₃S [M + Na⁺] 288.0670,

found 288.0661.

(R,E)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one ((+)-19): Method

C; 742 mg (56% yield);³²E/Z = 93:7; ee > 99%; colorless crystals;

mp 100.2−101.9 °C; R_f(30% AcOEt/hexane) 0.60; [α]²_D⁵+20.1 (c

1.48, CHCl₃); NMR and IR spectra were consistent with those

recorded for the racemate; HRMS (ESI-TOF) m/z calcd for

C₁₃H₁₅NNaO₃S [M + Na⁺] 288.0670, found 288.0663.

6.1, 1H), 2.44 (s, 3H), 1.57 (s, 3H), 1.12−0.95 (m, 21H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 165.1, 145.4, 139.1, 135.9, 130.1, 127.7,

118.3, 78.0, 67.3, 21.8, 18.7, 17.7, 17.6, 11.9; IR (ﬁlm) v 3082, 2945,

2893, 2868, 2730, 1931, 1801, 1598, 1464, 1366, 1243, 1171, 1139,

882, 725 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₄SSi

[M + Na⁺] 460.1954, found 460.1956.

1-((2R*,3R*)-4-Oxo-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-2-

yl)vinyl Acetate (28): Modiﬁed Method C, isolated NH-azetidin-2-

one xxxi (2.5 mmol) subjected to the tosylation step directly; 795 mg

(66% yield); colorless crystals; mp 125.6−126.9 °C; R_f(30% Et₂O/

1

hexane) 0.45; H NMR (400 MHz, CDCl₃) δ 7.93−7.86 (m, 2H),

7.37−7.30 (m, 2H), 5.45 (d, J = 2.4, 1H), 5.10 (d, J = 5.8, 1H), 5.08

(d, J = 2.4, 1H), 4.65 (d, J = 5.8, 1H), 2.44 (s, 3H), 1.71 (s, 3H),

1.13−0.97 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.2,

164.9, 146.2, 145.4, 136.0, 129.9, 127.9, 106.9, 77.5, 63.5, 21.8, 21.1,

17.7, 17.6, 11.9; IR (ﬁlm) v 2945, 2894, 2868, 1809, 1769, 1597,

1464, 1367, 1200, 1170, 1137, 884, 688 cm⁻¹; HRMS (ESI-TOF) m/

z calcd for C₂₃H₃₅NNaO₆SSi [M + Na⁺] 504.1852, found 504.1835.

(3R*,4S*)-4-((E)-But-2-en-2-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one (29): Method A; 1.739 g (77% yield); E/Z = 98:2;

colorless crystals; mp 145.7−146.5 °C; R_f(15% acetone/hexane)

0.55; ¹H NMR (400 MHz, CDCl₃) δ 7.88−7.81 (m, 2H), 7.37−7.29

(m, 2H), 5.61 (q, J = 6.7, 1H), 5.01 (d, J = 6.0, 1H), 4.63 (d, J = 6.0,

1H), 2.44 (s, 3H), 1.61 (d, J = 6.7, 3H), 1.34 (s, 3H), 1.13−0.95 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.4, 145.2, 136.0,

130.0, 129.9, 128.3, 127.7, 78.0, 69.2, 21.8, 17.62, 17.55, 13.6, 12.6,

11.8; IR (ﬁlm) v 2945, 2893, 2868, 1798, 1597, 1464, 1365, 1200,

1171, 1137, 883, 731 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₃H₃₇NNaO₄SSi [M + Na⁺] 474.2110, found 474.2103.

(3R*,4S*)-4-Methyl-1-tosyl-3-((triisopropylsilyl)oxy)-4-vinylazeti-

din-2-one (30): Method B; 647 mg (74% yield, starting from 2 mmol

of xxa); colorless crystals; mp 84.7−85.5 °C; R_f(25% Et₂O/hexane)

0.55; ¹H NMR (400 MHz, CDCl₃) δ 7.91−7.84 (m, 2H), 7.36−7.29

(m, 2H), 5.79 (dd, J = 17.4, 10.8, 1H), 5.44 (d, J = 17.4, 1H), 5.38 (d,

J = 10.8, 1H), 4.62 (s, 1H), 2.44 (s, 3H), 1.77 (s, 3H), 1.10−0.97 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.1, 145.2, 136.9,

135.0, 129.9, 127.8, 119.5, 84.5, 71.6, 21.8, 21.4, 17.7, 17.6, 11.9; IR

(ﬁlm) v 2945, 2894, 2868, 1795, 1598, 1463, 1365, 1200, 1173, 1090,

882, 712 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₅NNaO₄SSi

[M + Na⁺] 460.1954, found 460.1936.

(R*,Z)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one (20): Method C;

387 mg (29% yield);³³Z/E = 60:40; 93 mg (7% yield ), Z/E = 83:17,

after crystallization from DCM/hexane mixture; colorless crystals; mp

1

86.2−87.6 °C; R_f(30% AcOEt/hexane) 0.60; H NMR (400 MHz,

CDCl₃) δ (major) 7.89−7.78 (m, 2H), 7.39−7.30 (m, 2H), 5.80

(dqd, J = 10.8, 7.0, 1.0, 1H), 5.35−5.27 (m, 1H), 4.90 (dddd, J = 9.5,

6.2, 3.3, 1.0, 1H), 3.26 (dd, J = 15.9, 6.2, 1H), 2.72 (dd, J = 16.0, 3.3,

1H₍₁₉₎), 2.70 (dd, J = 15.9, 3.3, 1H), 2.44 (s, 3H), 1.80 (dd, J = 7.0,

1.8, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 163.6, 145.2, 136.4,

132.0, 130.0, 127.5, 126.6, 50.6, 43.9, 21.7, 13.4; IR (ﬁlm) v 3021,

2953, 2923, 2864, 1793, 1597, 1449, 1362, 1169, 1091, 962, 816, 678

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₁₃H₁₅NNaO₃S [M + Na⁺]

288.0670, found 288.0659.

(R,Z)-4-(Prop-1-en-1-yl)-1-tosylazetidin-2-one ((−)-20): Method

C; 398 mg (30% yield);³³Z/E = 60:40; ee > 99%; colorless crystals;

mp 78.7−79.4 °C; R_f(30% AcOEt/hexane) 0.60; [α]²_D⁴−10.2 (c 1.00,

CHCl₃); NMR and IR spectra were consistent with those recorded

for the racemate; HRMS (ESI-TOF) m/z calcd for C₁₃H₁₅NNaO₃S

[M + Na⁺] 288.0670, found 288.0659.

(3R*,4S*)-4-((E)-3-Methylbut-1-en-1-yl)-1-tosyl-3-

((triisopropylsilyl)oxy)azetidin-2-one (24): Method A; 1.797 g (76%

yield); E/Z > 98:2, colorless crystals; mp 156.1−156.7 °C; R_f(15%

AcOEt/hexane) 0.55; ¹H NMR (400 MHz, CDCl₃) δ 7.87−7.79 (m,

2H), 7.37−7.28 (m, 2H), 5.88 (dd, J = 15.5, 6.2, 1H), 5.19 (ddd, J =

15.5, 9.3, 1.5, 1H), 5.03 (d, J = 5.7, 1H), 4.65 (dd, J = 9.3, 5.7, 1H),

2.44 (s, 3H), 2.35−2.21 (m, 1H), 1.14−0.97 (m, 21H), 0.94 (t, J =

6.5, 6H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.0, 146.7, 145.2,

136.7, 129.9, 127.8, 119.7, 77.7, 64.8, 31.1, 21.8, 21.8, 21.6, 17.71,

17.67, 11.9; IR (ﬁlm) v 3506, 2946, 2893, 2868, 1930, 1793, 1464,

1357, 1264, 1169, 1136, 733 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₄H₃₉NNaO₄SSi [M + Na⁺] 488.2267, found 488.2254.

(3R*,4S*)-4-((E)-Styryl)-1-tosyl-3-((triisopropylsilyl)oxy)azetidin-

2-one (25): Method A; 700 mg (28% yield); E/Z = 98:2; colorless

crystals; mp 119.2−119.7 °C; R_f(15% AcOEt/hexane) 0.65; ¹H

NMR (400 MHz, CDCl₃) δ 7.83−7.78 (m, 2H), 7.35−7.19 (m, 7H),

6.73 (d, J = 15.9, 1H), 5.92 (dd, J = 15.9, 9.2, 1H), 5.13 (d, J = 5.7,

1H), 4.86 (dd, J = 9.2, 5.7, 1H), 2.38 (s, 3H), 1.14−0.93 (m, 21H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 164.8, 145.3, 137.8, 136.5,

135.9, 130.0, 128.70, 128.6, 127.8, 126.8, 121.5, 78.1, 64.6, 21.8, 17.7,

17.6, 11.8; IR (ﬁlm) v 3029, 2945, 2893, 2867, 1798, 1464, 1367,

1243, 1170, 1120, 883, 671 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₇H₃₇NNaO₄SSi [M + Na⁺] 522.2110, found 522.2093.

Ethyl (E)-3-((2S*,3R*)-4-Oxo-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-yl)acrylate (26): Method C; 1.239 g (50% yield); E/Z >

98:2; colorless crystals; mp 84.8−86.6 °C; R_f(25% AcOEt/hexane)

0.75; ¹H NMR (400 MHz, CDCl₃) δ 7.88−7.80 (m, 2H), 7.39−7.30

(m, 2H), 6.70 (dd, J = 15.7, 8.5, 1H), 6.10 (dd, J = 15.7, 0.8, 1H),

5.11 (d, J = 5.7, 1H), 4.76 (ddd, J = 8.5, 5.7, 0.8, 1H), 4.27−4.10 (m,

2H), 2.44 (s, 3H), 1.26 (t, J = 7.1, 3H), 1.14−0.95 (m, 21H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 164.8, 164.0, 145.7, 139.5,

135.8, 130.2, 127.8, 127.7, 78.7, 62.1, 60.8, 21.8, 17.9, 17.6, 14.3, 11.8;

IR (ﬁlm) v 2945, 2894, 2868, 1804, 1723, 1597, 1464, 1369, 1264,

1171, 1090, 882, 669 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₄H₃₇NNaO₆SSi [M + Na⁺] 518.2009, found 518.1999.

(3R*,4R*)-4-Methyl-1-tosyl-3-((triisopropylsilyl)oxy)-4-vinylazeti-

din-2-one (31): Method B; 157 mg (55% yield, starting from 0.65

mmol of xxb); colorless crystals; mp 69.8−70.5 °C; R_f(25% Et₂O/

1

hexane) 0.60; H NMR (400 MHz, CDCl₃) δ 7.93−7.86 (m, 2H),

7.37−7.30 (m, 2H), 5.98 (dd, J = 17.3, 10.8, 1H), 5.38 (d, J = 17.3,

1H), 5.32 (d, J = 10.8, 1H), 4.62 (s, 1H), 2.44 (s, 3H), 1.58 (s, 3H),

1.13−0.97 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.2,

145.2, 138.3, 137.1, 130.0, 127.7, 117.6, 83.2, 71.6, 21.8, 17.71, 17.67,

17.4, 11.9; IR (ﬁlm) v 2945, 2893, 2868, 1792, 1598, 1463, 1365,

1200, 1171, 1090, 882, 673 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₂H₃₅NNaO₄SSi [M + Na⁺] 460.1954, found 460.1934.

(3R*,4S*)-3-Methyl-1-tosyl-4-vinylazetidin-2-one (40): Method

C; 438 mg (33% yield); colorless crystals; mp 55.2−56.1 °C; R_f

1

(30% AcOEt/hexane) 0.65; H NMR (400 MHz, CDCl₃) δ 7.91−

7.81 (m, 2H), 7.39−7.30 (m, 2H), 5.68 (ddd, J = 17.0, 10.3, 8.2, 1H),

5.45 (dd, J = 17.0, 0.9, 1H), 5.40 (dt, J = 10.3, 0.9, 1H), 4.58 (ddt, J =

8.2, 6.6, 0.8, 1H), 3.43 (qd, J = 7.7, 6.6, 1H), 2.45 (s, 3H), 1.12 (d, J =

7.7, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.4, 145.3, 136.3,

131.4, 130.1, 127.6, 122.1, 60.4, 49.1, 21.8, 9.4; IR (ﬁlm) v 2978,

2936, 2877, 1792, 1598, 1454, 1362, 1248, 1170, 1090, 717, 602

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₁₃H₁₅NNaO₃S [M + Na⁺]

288.0670, found 288.0661.

(3R*,4R*)-3-Isopropyl-1-tosyl-4-vinylazetidin-2-one (42): Meth-

od B; 719 mg (49% yield); colorless crystals; mp 59.9−61.8 °C; R_f

1

(15% AcOEt/hexane) 0.45; H NMR (400 MHz, CDCl₃) δ 7.89−

7.81 (m, 2H), 7.37−7.29 (m, 2H), 5.81 (ddd, J = 17.0, 10.2, 8.0, 1H),

5.43 (dt, J = 17.0, 0.9, 1H), 5.29 (dd, J = 10.2, 0.9, 1H), 4.20 (dd, J =

8.0, 3.3, 1H), 2.75 (dd, J = 8.1, 3.3, 1H), 2.43 (s, 3H), 2.04−1.87 (m,

1H), 0.95 (d, J = 6.7, 3H), 0.85 (d, J = 6.7, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 166.1, 145.2, 136.3, 134.7, 130.0, 127.6, 120.1, 63.4,

(3R*,4S*)-4-(Prop-1-en-2-yl)-1-tosyl-3-((triisopropylsilyl)oxy)-

azetidin-2-one (27): Method C; 1.532 g (70% yield); colorless

crystals; mp 120.1−121.0 °C; R_f(15% AcOEt/hexane) 0.60; ¹H

NMR (400 MHz, CDCl₃) δ 7.91−7.84 (m, 2H), 7.38−7.31 (m, 2H),

5.13−5.07 (m, 1H), 5.07 (br s, 1H), 5.05 (d, J = 6.1, 1H), 4.68 (d, J =

R

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

60.7, 28.0, 21.8, 19.8, 19.7; IR (ﬁlm) v 3564, 2963, 2875, 1790, 1597,

1466, 1365, 1170, 1089, 668, 547 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₁₅H₁₉NNaO₃S [M + Na⁺] 316.0983, found 316.0977.

8.00−7.88 (m, 2H), 7.41−7.25 (m, 7H), 5.56 (td, J = 10.8, 1.2, 1H),

5.39 (dd, J = 10.8, 8.8, 1H), 5.05 (dd, J = 8.8, 1.2, 1H), 4.29 (d, J =

9.2, 1H), 3.63 (br s, 1H), 2.81−2.67 (m, 1H), 2.43 (s, 3H), 1.15−

1.00 (m, 21H), 0.72 (d, J = 6.6, 3H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 170.5, 145.2, 142.6, 138.3, 135.7, 129.7, 128.6, 128.5, 128.1,

127.8, 127.1, 78.9, 70.7, 41.6, 21.8, 18.0, 17.9, 17.2, 12.2; IR (ﬁlm) v

3475, 3349, 3066, 2944, 2867, 1740, 1598, 1459, 1176, 1124, 1088,

882, 724, 662 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₉H₄₃NNaO₅SSi [M + Na⁺] 568.2529, found 568.2523.

(2R,5S,6S,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide ((−)-2a): Method A, starting

from 1, 53.9 mg (79% yield); dr = 98:2; ee > 99%; colorless wax; R_f

(25% acetone/hexane) 0.65; [α]²_D⁵−153.5 (c 1.51, CHCl₃); NMR

and IR spectra were consistent with those recorded for the racemate;

HRMS (ESI-TOF) m/z calcd for C₂₉H₄₃NNaO₅SSi [M + Na⁺]

568.2529, found 568.2523.

2-((3R*,4S*)-2-Oxo-1-tosyl-4-vinylazetidin-3-yl)isoindoline-1,3-

dione (43): Method B; 1.130 g (57% yield); cis/trans = 89:11;

colorless crystals; mp 159.5−161.8 °C; ¹H NMR (400 MHz, CDCl₃)

δ (major) 8.00−7.91 (m, 2H), 7.87−7.79 (m, 2H), 7.78−7.70 (m,

2H), 7.46−7.38 (m, 2H), 5.63 (ddd, J = 17.3, 10.3, 8.5, 1H), 5.55 (d,

J = 6.4, 1H), 5.43 (d, J = 17.3), 5.26 (d, J = 10.3, 1H), 4.93 (dd, J =

8.5, 6.4, 1H), 2.48 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

(major): 166.7, 160.6, 145.7, 136.0, 134.9, 131.5, 130.2, 129.8, 127.8,

124.4, 124.1, 63.2, 57.5, 21.9; IR (ﬁlm) v 3288, 3064, 2922, 1806,

1781, 1726, 1597, 1467, 1389, 1251, 1170, 1090, 712, 586 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₀H₁₆N₂NaO₅S [M + Na⁺]

419.0678, found 419.0665.

2-((3R*,4S*)-2-Oxo-4-((E)-prop-1-en-1-yl)-1-tosylazetidin-3-yl)-

isoindoline-1,3-dione (48): Method B; 1.026 g (50% yield); E/Z =

93:7; colorless crystals; mp 205.2−205.5 °C; R_f(40% acetone/

(2R*,5R*,6R*,E)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (2b). A sample was obtained

from β-lactam 1 and benzaldehyde during the optimization of reaction

conditions according to the modiﬁed Method B where anhydrous

THF was used instead of a 25% HMPA/THF mixture and Pd(PPh₃)₄

loading was increased to 10 mol %: 36.8 mg (54% yield); dr =

1

hexane) 0.75; H NMR (400 MHz, CDCl₃) δ 7.96−7.88 (m, 2H),

7.88−7.78 (m, 2H), 7.80−7.70 (m, 2H), 7.43−7.36 (m, 2H), 5.91

(dq, J = 15.4, 6.6, 1H), 5.52 (d, J = 6.3, 1H), 5.26−5.14 (m, 1H), 4.91

(dd, J = 9.2, 6.3, 1H), 2.48 (s, 3H), 1.55 (dd, J = 6.6, 1.7, 3H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.8, 160.8, 145.5, 137.1,

1

81:10:5:4; colorless wax; R_f(25% acetone/hexane) 0.60; H NMR

136.2, 134.8, 131.5, 130.0, 127.8, 124.1, 122.3, 63.4, 57.4, 21.9, 18.0;

IR (ﬁlm) v 2945, 1803, 1781, 1721, 1596, 1389, 1363, 1249, 1170,

1090, 881, 720, 672 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₁H₁₈N₂NaO₅S [M + Na⁺] 433.0834, found 433.0828.

(400 MHz, CDCl₃) δ (major) 9.96 (s, 1H), 8.00−7.88 (m, 2H),

7.41−7.25 (m, 7H), 5.56 (td, J = 10.8, 1.2, 1H), 5.39 (dd, J = 10.8,

8.8, 1H), 5.05 (dd, J = 8.8, 1.2, 1H), 4.29 (d, J = 9.2, 1H), 3.63 (br s,

1H), 2.81−2.67 (m, 1H), 2.43 (s, 3H), 1.15−1.00 (m, 21H), 0.72 (d,

J = 6.6, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.5, 145.2,

142.6, 138.3, 135.7, 129.7, 128.6, 128.5, 128.1, 127.8, 127.1, 78.9,

70.7, 41.6, 21.8, 18.0, 17.9, 17.2, 12.2; IR (ﬁlm) v 3490, 3356, 3063,

2944, 2867, 1734, 1598, 1457, 1408, 1352, 1176, 1122, 1088, 881,

662 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₉H₄₃NNaO₅SSi [M +

Na⁺] 568.2529, found 568.2519.

(2R*,5S*,6S*,Z)-6-Hydroxy-6-(4-methoxyphenyl)-5-methyl-N-

tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (3): Method A; 61.9

mg (86% yield); dr = 98:2; colorless crystals; mp 135.1−136.2 °C; R_f

(30% acetone/hexane) 0.65; ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s,

1H), 7.95−7.88 (m, 2H), 7.33−7.27 (m, 2H), 7.27−7.23 (m, 2H),

6.91−6.87 (m, 2H), 5.55 (td, J = 10.8, 1.2, 1H), 5.37 (t, J = 10.8, 8.9,

1H), 5.04 (dd, J = 8.9, 1.2, 1H), 4.25 (dd, J = 9.3, 3.9, 1H), 3.81 (s,

3H), 3.45 (d, J = 3.9, 1H), 2.78−2.66 (m, 1H), 2.42 (s, 3H), 1.13−

0.98 (m, 21H), 0.70 (d, J = 6.5, 3H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 170.4, 159.5, 145.1, 138.3, 135.8, 134.6, 129.7, 128.5, 128.2,

127.8, 114.0, 78.5, 70.7, 55.4, 41.6, 21.8, 17.98, 17.95, 17.2, 12.2; IR

(ﬁlm) v 3475, 3349, 3071, 2943, 2867, 1739, 1611, 1513, 1464, 1350,

1249, 1176, 1124, 1088, 882, 661 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₃₀H₄₅NNaO₆SSi [M + Na⁺] 598.2635, found 598.2626.

(2R*,5S*,6S*,Z)-6-(4-Cyanophenyl)-6-hydroxy-5-methyl-N-tosyl-

2-((triisopropylsilyl)oxy)hex-3-enamide (4): Method A; 61.4 mg

(86% yield); dr = 97:3; colorless crystals; mp 177.4−178.6 °C; R_f

(30% acetone/hexane) 0.65; ¹H NMR (400 MHz, CDCl₃) δ 9.50 (s,

1H), 7.97−7.90 (m, 2H), 7.66−7.59 (m, 2H), 7.47−7.40 (m, 2H),

7.36−7.29 (m, 2H), 5.53 (dd, J = 10.9, 1.2, 1H), 5.40 (dd, J = 10.9,

8.3, 1H), 5.00 (dd, J = 8.3, 1.2, 1H), 4.32 (dd, J = 9.0, 5.0, 1H), 4.05

(d, J = 5.0, 1H), 2.74−2.59 (m, 1H), 2.44 (s, 3H), 1.13−1.01 (m,

21H), 0.71 (d, J = 6.6, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

171.1, 148.3, 145.6, 137.7, 135.3, 132.3, 129.8, 128.6, 128.4, 128.0,

111.7, 78.0, 71.1, 41.9, 21.9, 17.96, 17.92, 17.0, 12.1; IR (ﬁlm) v 3457,

3344, 3071, 2943, 2867, 2228, 1738, 1598, 1463, 1412, 1349, 1175,

1123, 1088, 1017, 881, 661 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₃₀H₄₂N₂NaO₅SSi [M + Na⁺] 593.2481, found 593.2477.

Pd/InI- and Pd/InI/N-MI-Promoted Additions of N-Ts-β-

Lactams to Aldehydes and Syntheses of Enediols 2a−2b,

(−)-2a, 3−14, (−)-11, 18a−18b, 32−35, 38a−38b, 44a−47a,

44b−47b, 49, 53a−53b, (−)-56, (+)-57, Aminoalcohols 47, 49,

and Homoallylic Alcohols 21 (−)-21, (+)-21, 45a−45b, 46a−

46b: General Procedures. Method A. To a vigorously stirred

solution of N-Ts- or N-Ms-β-lactam (0.125 mmol) and aldehyde

(0.25 mmol) in an anhydrous 10% EtOH/THF mixture (2 mL) were

sequentially added N-methylimidazole (20 μL, 0.25 mmol) and the

mixture of InI (90.7 mg, 0.375 mmol) and Pd(PPh₃)₄(7.2 mg, 6.25

μmol) in one portion at 25 °C under an argon atmosphere. The

stirring was continued at the same temperature until full conversion of

the starting β-lactam was observed (TLC monitoring, 1−12 h). The

reaction was then quenched with 1 M aqueous HCl solution (2 mL),

poured into water, and extracted with EtOAc (3 × 10 mL). The

combined extracts were washed successively with water (30 mL), a

saturated solution of NaHCO₃(30 mL), and brine (30 mL), dried

over anhydrous MgSO₄, and concentrated under reduced pressure.

Puriﬁcation of the crude product by column chromatography on silica

gel using an ethyl acetate/hexane with addition of 0.5% v/v HCO₂H³⁴

or acetone/hexane mixture as an eluent aﬀorded the desired

compound as colorless crystals or a colorless wax.

Method B. To a vigorously stirred solution of N-Ts- or N-Ms-β-

lactam (0.125 mmol) and aldehyde (0.25 mmol) in an anhydrous

25% HMPA/THF mixture (2 mL) was added InI (60.5 mg, 0.25

mmol) in one portion followed by Pd(PPh₃)₄(7.2 mg, 6.25 μmol) at

25 °C under an argon atmosphere. The stirring was continued at the

same temperature until full conversion of the starting β-lactam was

observed or no further progress in conversion was found (TLC

monitoring, 30 min to 24 h). The reaction was then quenched with a

1 M aqueous HCl solution (2 mL), poured into water, and extracted

with CH₂Cl₂(3 × 10 mL). Combined extracts were then washed with

water (3 × 30 mL) and a saturated solution of NaHCO₃(30 mL),

dried over MgSO₄, and concentrated. Puriﬁcation of the crude

product by column chromatography on silica gel using an ethyl

acetate/hexane with addition of 0.5% v/v HCO₂H,³⁴Et₂O/hexane

with addition of 0.5% v/v HCO₂H³⁴or acetone/hexane mixture as an

eluent aﬀorded the desired products as colorless crystals or a colorless

wax.

(2R*,5S*,6S*,Z)-6-Hydroxy-5-methyl-6-(naphthalen-2-yl)-N-

tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide (5): Method A; 64.8

mg (87% yield); dr = 95:5; colorless crystals; mp 142.9−143.8 °C; R_f

1

(30% acetone/hexane) 0.65; H NMR (400 MHz, CDCl₃) δ 7.98−

7.91 (m, 2H), 7.89−7.80 (m, 3H), 7.77−7.72 (m, 1H), 7.54−7.45

(m, 3H), 7.34−7.27 (m, 2H), 5.61 (dd, J = 10.9, 1.2, 1H), 5.41 (t, J =

10.9, 8.8, 1H), 5.10 (dd, J = 8.8, 1.2, 1H), 4.46 (dd, J = 9.3, 3.1, 1H),

3.80−3.74 (m, 1H), 2.91−2.76 (m, 1H), 2.43 (s, 3H), 1.17−1.00 (m,

21H), 0.73 (d, J = 6.5, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

(2R*,5S*,6S*,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (2a): Method A, starting from

1, 56.6 mg (83% yield), dr = 97:3; starting from 15, 55.3 mg (81%

yield), dr = 97:3; colorless crystals; mp 129.1−130.0 °C; R_f(25%

1

acetone/hexane) 0.65; H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H),

S

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

170.6, 145.2, 139.9, 138.4, 135.6, 133.4, 133.3, 129.7, 128.54, 128.45,

128.1, 120.0, 127.9, 126.5, 126.3, 126.1, 124.7, 79.1, 70.8, 41.6, 21.8,

18.01, 17.97, 17.3, 12.2; IR (ﬁlm) v 3467, 3347, 3060, 2943, 2867,

1739, 1598, 1464, 1409, 1349, 1174, 1124, 1088, 880, 662 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₃₃H₄₅NNaO₅SSi [M + Na⁺]

618.2685, found 618.2681.

(ﬁlm) v 3512, 3349, 3068, 2943, 2867, 1737, 1598, 1463, 1411, 1350,

1176, 1124, 1089, 881, 661, 549 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₆H₄₅NNaO₆SSi [M + Na⁺] 550.2635, found 550.2629.

(2R*,5S*,6R*,Z)-6-Hydroxy-5,7-dimethyl-N-tosyl-2-

((triisopropylsilyl)oxy)oct-3-enamide (11): Method A; 48.0 mg (75%

1

yield); dr = 98:2; colorless wax; R_f(30% acetone/hexane) 0.55; H

NMR (400 MHz, CDCl₃) δ 9.81 (s, 1H), 7.94−7.87 (m, 2H), 7.33−

7.26 (m, 2H), 5.49 (dd, J = 10.9, 1.2, 1H), 5.29 (dd, J = 10.9, 9.0,

1H), 4.93 (dd, J = 9.0, 1.2, 1H), 3.20 (dd, J = 9.2, 2.3, 1H), 2.63−2.48

(m, 1H), 2.42 (s, 3H), 1.90−1.79 (m, 1H), 1.11−1.00 (m, 24H), 0.91

(d, J = 6.5, 3H), 0.87 (d, J = 6.8, 3H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 170.4, 145.1, 139.1, 135.8, 129.7, 128.5, 126.8, 79.0, 70.7,

37.2, 29.4, 21.8, 20.6, 17.99, 17.96, 16.8, 13.9, 12.2; IR (ﬁlm) v 3513,

3350, 3071, 2943, 2868, 1741, 1654, 1598, 1465, 1412, 1351, 1177,

1124, 1089, 882, 720, 662 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₆H₄₅NNaO₅SSi [M + Na⁺] 534.2685, found 534.2664.

( 2 R , 5 S , 6 R , Z ) - 6 - H y d r o x y - 5, 7 - d i m e t h y l- N - t o s y l - 2 -

((triisopropylsilyl)oxy)oct-3-enamide ((−)-11): Method A; 45.4 mg

(71% yield); dr = 98:2; ee > 99%; colorless wax; R_f(30% acetone/

hexane) 0.55; [α]²_D⁵−77.7 (c 1.78, CHCl₃); NMR and IR spectra

were consistent with those recorded for the racemate; HRMS (ESI-

TOF) m/z calcd for C₂₆H₄₅NNaO₅SSi [M + Na⁺] 534.2685, found

534.2670.

(2R*,5S*,6S*,Z)-6-(Furan-2-yl)-6-hydroxy-5-methyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (6): Method A; 51.8 mg (77%

1

yield); dr = 98:2; colorless wax; R_f(30% acetone/hexane) 0.55; H

NMR (400 MHz, CDCl₃) δ 9.67 (s, 1H), 7.96−7.87 (m, 2H), 7.42−

7.37 (m, 1H), 7.33−7.26 (m, 2H), 6.40−6.30 (m, 1H), 6.31−6.24

(m, 1H), 5.53 (dd, J = 10.9, 1.2, 1H), 5.39 (dd, J = 10.9, 8.7, 1H),

5.03 (dd, J = 8.7, 1.2, 1H), 4.33 (d, J = 9.5, 1H), 3.04−2.92 (m, 1H),

2.42 (s, 3H), 1.16−0.99 (m, 21H), 0.78 (d, J = 6.6, 3H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 170.6, 145.2, 139.9, 138.4, 135.6, 133.4,

133.3, 129.7, 128.54, 128.45, 128.1, 128.0, 127.9, 126.5, 126.3, 126.1,

124.7, 79.1, 70.8, 41.6, 21.8, 18.01, 17.97, 17.3, 12.2; IR (ﬁlm) v 3472,

3349, 3097, 2941, 2868, 1739, 1598, 1463, 1410, 1350, 1174, 1123,

1089, 1012, 879, 663 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₇H₄₁NNaO₆SSi [M + Na⁺] 558.2322, found 558.2300.

(2R*,5S*,6S*,Z)-6-Hydroxy-5-methyl-6-(thiophen-2-yl)-N-tosyl-

2-((triisopropylsilyl)oxy)hex-3-enamide (7): Method A; 53.1 mg

(77% yield); dr = 97:3; white solid; mp 83.9−84.7 °C; R_f(30%

1

acetone/hexane) 0.55; H NMR (400 MHz, CDCl₃) δ 9.78 (s, 1H),

(2R*,5S*,6R*,Z)-6-Cyclopentyl-6-hydroxy-5-methyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (12): Method A; 54.5 mg

(81% yield); dr = 98:2; white solid; mp 106.0−106.6 °C; R_f(30%

8.07−7.74 (m, 2H), 7.42−7.24 (m, 4H), 6.97 (m, 2H), 5.54 (td, J =

10.9, 1.1, 1H), 5.40 (dd, J = 10.9, 8.8, 1H), 5.02 (dd, J = 8.8, 1.1, 1H),

4.60 (d, J = 9.1, 1H), 3.72 (s, 1H), 2.85−2.70 (m, 1H), 2.43 (s, 3H),

1.16−0.97 (m, 21H), 0.82 (d, J = 6.5, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 170.4, 146.3, 145.2, 137.8, 135.6, 129.7, 128.6, 128.2,

126.6, 125.4, 125.2, 74.3, 70.7, 42.3, 21.8, 17.99, 17.95, 17.4, 12.2; IR

(ﬁlm) v 3467, 3349, 3102, 2942, 2868, 1739, 1598, 1464, 1410, 1350,

1174, 1124, 1088, 879, 664 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₇H₄₁NNaO₅S₂Si [M + Na⁺] 574.2093, found 574.2092.

1

acetone/hexane) 0.60; H NMR (400 MHz, CDCl₃) δ 9.71 (s, 1H),

7.95−7.88 (m, 2H), 7.34−7.26 (m, 2H), 5.51 (dd, J = 10.9, 1.2, 1H),

5.28 (t, J = 10.9, 8.9, 1H), 4.92 (dd, J = 8.9, 1.2, 1H), 3.37 (m, 1H),

2.64 (s, 1H), 2.57−2.46 (m, 1H), 2.42 (s, 3H), 2.08 (td, J = 8.4, 3.6,

1H), 1.73−1.43 (m, 8H), 1.14−0.99 (m, 21H), 0.95 (d, J = 6.6, 3H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.4, 145.1, 139.0, 135.8,

129.7, 128.5, 126.7, 76.9, 70.8, 42.3, 38.7, 29.6, 25.96, 25.95, 24.8,

21.8, 18.00, 17.97, 17.2, 12.2; IR (ﬁlm) v 3515, 3351, 3069, 2945,

2867, 1739, 1598, 1463, 1411, 1351, 1176, 1123, 1088, 881, 661

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₈H₄₇NNaO₅SSi [M + Na⁺]

560.2842, found 560.2838.

( 2 R * , 5 S * , 6 R * , Z ) - 6 - H y d r o x y - 5 - m e t h y l - N - t o s y l - 2 -

((triisopropylsilyl)oxy)oct-3-enamide (8): Method A; 44.8 mg (72%

1

yield); dr = 98:2; colorless wax; R_f(30% acetone/hexane) 0.60; H

NMR (400 MHz, CDCl₃) δ 9.67 (s, 1H), 7.95−7.88 (m, 2H), 7.33−

7.26 (m, 2H), 5.49 (dd, J = 10.9, 1.2, 1H), 5.30 (t, J = 10.9, 8.9, 1H),

4.92 (d, J = 8.9, 1H), 3.32−3.24 (m, 1H), 2.54−2.39 (m, 4H), 1.74−

1.61 (m, 1H), 1.44−1.31 (m, 1H), 1.15−0.95 (m, 24H), 0.93 (d, J =

6.6, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.4, 146.3, 145.2,

137.8, 135.6, 129.7, 128.6, 128.2, 126.6, 125.4, 125.2, 74.3, 70.7, 42.3,

21.8, 17.99, 17.95, 17.4, 12.2; IR (ﬁlm) v 3507, 3350, 3070, 2943,

2868, 1739, 1598, 1464, 1411, 1350, 1176, 1124, 1089, 881, 724, 661

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₅H₄₃NNaO₅SSi [M + Na⁺]

520.2529, found 520.2526.

(2R*,5S*,6S*,Z)-6-Hydroxy-5,7,7-trimethyl-N-tosyl-2-

((triisopropylsilyl)oxy)oct-3-enamide (13): Method A; 28.3 mg (43%

yield); dr = 96:4; colorless crystals; mp 108.4−109.2 °C; R_f(30%

1

acetone/hexane) 0.70; H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H),

7.96−7.88 (m, 2H), 7.33−7.26 (m, 2H), 5.67 (dd, J = 10.9, 1.3, 1H),

5.14 (ddd, J = 10.9, 8.4, 0.8, 1H), 4.89 (dd, J = 8.4, 1.3, 1H), 3.07 (d, J

= 5.9, 1H), 2.85−2.71 (m, 1H), 1.12−0.99 (m, 24H), 0.90 (s, 9H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.0, 145.1, 138.8, 135.7,

129.6, 128.5, 124.8, 83.0, 71.2, 36.3, 35.2, 26.8, 21.8, 20.5, 17.99,

17.97, 12.2; IR (ﬁlm) v 3528, 3357, 2946, 2868, 1732, 1598, 1464,

1408, 1351, 1177, 1156, 1088, 873, 662 cm⁻¹; HRMS (ESI-TOF) m/

z calcd for C₂₇H₄₇NNaO₅SSi [M + Na⁺] 548.2842, found 548.2837.

(2R*,5S*,6S*,Z)-6-Hydroxy-5,8-dimethyl-N-tosyl-2-

((triisopropylsilyl)oxy)nona-3,7-dienamide (14): Method A; 48.5 mg

(74% yield); dr = 95:5; colorless crystals; mp 92.3−93.4 °C; R_f(30%

acetone/hexane) 0.70; ¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H),

7.93−7.86 (m, 2H), 7.28 (m, 2H), 5.48 (td, J = 10.9, 1.0, 1H), 5.33

(dd, J = 10.9, 9.1, 1H), 5.18 (dp, J = 9.2, 1.4, 1H), 4.94 (dd, J = 9.1,

1.0, 1H), 4.09 (t, J = 9.2, 1H), 2.78 (s, 1H), 2.52−2.43 (m, 1H), 2.41

(s, 3H), 1.76 (d, J = 1.4, 3H), 1.69 (d, J = 1.4, 3H), 1.10−0.99 (m,

21H), 0.86 (d, J = 6.6, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

170.1, 144.9, 138.0, 137.4, 135.9, 129.6, 128.5, 127.6, 126.0, 72.5,

70.4, 40.2, 26.0, 21.8, 18.6, 17.97, 17.95, 16.8, 12.2; IR (ﬁlm) v 3480,

3354, 3070, 2927, 2867, 1740, 1598, 1465, 1407, 1348, 1176, 1124,

1089, 882, 730 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₇H₄₅NNaO₅SSi [M + Na⁺] 546.2685, found 546.2686.

(2R*,5S*,6R*,Z)-6-Hydroxy-5-methyl-8-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)oct-3-enamide (9): Method A; 58.1 mg (81%

1

yield); dr > 95:5; colorless wax; R_f(30% acetone/hexane) 0.65; H

NMR (400 MHz, CDCl₃) δ 9.48 (s, 1H), 7.97−7.90 (m, 2H), 7.37−

7.13 (m, 7H), 5.47 (d, J = 10.9, 1H), 5.31 (t, J = 10.9, 8.8, 1H), 4.93

(d, J = 8.8, 1H), 3.37−3.28 (m, 1H), 2.93−2.84 (m, 1H), 2.74−2.65

(m, 1H), 2.51−2.39 (m, 4H), 1.96−1.85 (m, 1H), 1.71−1.58 (m,

1H), 1.09−0.99 (m, 21H), 0.91 (d, J = 6.6, 3H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 170.7, 145.3, 142.5, 138.8, 135.5, 129.7, 128.7,

128.53, 128.50, 127.0, 125.9, 74.2, 71.0, 40.2, 36.5, 31.9, 21.8, 17.98,

17.95, 17.0, 12.1; IR (ﬁlm) v 3507, 3351, 3063, 2942, 2867, 1739,

1655, 1599, 1462, 1410, 1351, 1176, 1123, 1088, 881, 661 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₃₁H₄₇NNaO₅SSi [M + Na⁺]

596.2842, found 596.2834.

(2R*,5S*,6R*,Z)-6,9-Dihydroxy-5-methyl-N-tosyl-2-

((triisopropylsilyl)oxy)non-3-enamide (10): Method A; 44.9 mg

(68% yield); dr = 98:2; colorless wax; R_f(30% acetone/hexane) 0.60;

¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 7.95−7.86 (m, 2H),

7.34−7.26 (m, 2H), 5.48 (dd, J = 10.9, 1.1, 1H), 5.30 (t, J = 10.9, 9.0,

1H), 4.92 (dd, J = 9.0, 1.1, 1H), 3.80−3.63 (m, 2H), 3.37 (td, J = 8.8,

2.3, 1H), 2.42 (s, 4H), 1.91−1.66 (m, 3H), 1.41 (ddt, J = 13.2, 8.8,

6.5, 1H), 1.13−0.98 (m, 21H), 0.95 (d, J = 6.5, 3H); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 170.5, 145.1, 138.4, 135.8, 129.7, 128.4, 127.0,

75.2, 70.7, 63.2, 39.9, 32.3, 29.14, 21.8, 17.98, 17.95, 17.1, 12.2; IR

(2R*,5R*,6R*,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (18a): Method A, starting

from 16, 22.5 mg (33% yield), dr = 87:13; starting from 17, 21.2

mg (31% yield), dr = 94:6; colorless wax; R_f(50% Et₂O/hexane +

1

0.5% HCO₂H) 0.60; H NMR (400 MHz, CDCl₃) δ 7.96−7.88 (m,

2H), 7.37−7.25 (m, 7H), 5.62 (dd, J = 10.9, 1.5, 1H), 5.34 (dd, J =

10.9, 7.3, 1H), 4.88 (dd, J = 7.3, 1.5, 1H), 4.37 (d, J = 7.7, 1H), 3.05−

T

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2.90 (m, 1H), 2.42 (s, 3H), 1.08−0.96 (m, 21H), 0.82 (d, J = 6.8,

3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.5, 145.1, 142.6, 137.9,

135.8, 129.6, 128.5, 128.5, 128.0, 127.9, 126.8, 78.9, 72.8, 41.4, 21.8,

18.03, 18.01, 17.4, 12.1; IR (ﬁlm) v 3548, 3351, 3063, 2943, 2867,

1731, 1598, 1461, 1407, 1351, 1160, 1087, 871, 665, 549 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₉H₄₃NNaO₅SSi [M + Na⁺]

568.2529, found 568.2529.

(2R*,5S*,6R*,E)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (18b) and (2R*,5S*,6S*,E)-6-

Hydroxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-

enamide (18b′): Method A, starting from 16, 40.3 mg (59% yield),

18b/18b′ = 79:21; starting from 17, 38.2 mg (56% yield), 18b/18b′

= 78:22; colorless wax; R_f(50% Et₂O/hexane + 0.5% HCO₂H) 0.50;

¹H NMR (400 MHz, CDCl₃) δ 8.85 (br s, 1H + 1H′), 7.96−7.89 (m,

7.03 (m, 2H), 6.91−6.84 (m, 2H), 6.17 (td, J = 10.8, 1.4, 1H), 5.43

(dd, J = 10.8, 8.4, 1H), 5.09 (dd, J = 8.4, 1.4, 1H), 4.76 (d, J = 9.1,

1H), 3.91 (t, J = 10.0, 1H), 3.58 (s, 1H), 2.45 (s, 3H), 0.97−0.85 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.5, 145.3, 142.2,

139.5, 135.58, 135.57, 129.7, 128.6, 128.5, 128.4, 128.3, 128.0, 127.5,

126.9, 126.8, 78.7, 70.9, 54.1, 21.8, 17.9, 17.8, 12.0; IR (ﬁlm) v 3466,

3347, 3063, 3031, 2944, 2867, 1739, 1598, 1457, 1411, 1351, 1176,

1088, 871, 669, 549 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₃₄H₄₅NNaO₅SSi [M + Na⁺] 630.2685, found 630.2681.

Ethyl (2S*,5R*,Z)-2-((S)-Hydroxy(phenyl)methyl)-6-((4-

methylphenyl)sulfonamido)-6-oxo-5-((triisopropylsilyl)oxy)hex-3-

enoate (34): Method A; 48.3 mg (64% yield); dr = 98:2; white solid;

mp 130.1−131.4 °C; R_f(30% AcOEt/hexane + 0.5% HCO₂H) 0.55;

¹H NMR (400 MHz, CDCl₃) δ 9.53 (s, 1H), 7.98−7.91 (m, 2H),

2H + 2H′), 7.37−7.20 (m, 5H + 5H′), 5.89 (ddd, J = 15.6, 7.7, 1.5,

1H′), 5.78 (ddd, J = 15.6, 7.2, 1.5, 1H), 5.49 (ddd, J = 15.6, 5.5, 1.1,

1H′), 5.39 (ddd, J = 15.6, 5.5, 1.3, 1H), 4.58 (dd, J = 5.5, 1.5, 1H′),

4.53−4.49 (m, 2H), 4.40 (d, J = 6.9, 1H′), 2.63−2.47 (m, 1H + 1H′),

2.43 (s, 3H + 3H′), 1.08−0.92 (m, 24H + 21H′), 0.86 (d, J = 6.9,

3H′); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.7, 145.3, 142.6,

142.4, 136.5, 136.3, 135.6, 129.6, 129.6, 128.49, 128.45, 128.4, 127.8,

127.80, 127.76, 127.0, 126.7, 126.5, 78.1, 75.2, 44.1, 43.4, 29.8, 21.8,

18.0, 17.94, 17.91, 16.4, 14.4, 12.1, 12.0; IR (ﬁlm) v 3541, 3357, 3063,

2944, 2868, 1732, 1598, 1455, 1408, 1352, 1160, 1089, 881, 663, 548

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₉H₄₃NNaO₅SSi [M + Na⁺]

568.2529, found 568.2535.

(5S*,6S*,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enam-

ide (21): Method A, starting from 25, 26.6 mg (57% yield), dr > 95:5;

starting from 26, 28 mg (60% yield), dr > 95:5; white solid; mp

121.2−122.1 °C; R_f(30% acetone/hexane) 0.50; ¹H NMR (400

MHz, CDCl₃) δ 10.86 (s, 1H), 7.93−7.86 (m, 2H), 7.42−7.27 (m,

7H), 5.61 (t, J = 10.6, 1H), 5.50 (td, J = 10.9, 5.0, 1H), 4.36 (d, J =

9.5, 1H), 3.38 (dd, J = 14.8, 11.0, 1H), 3.12 (s, 1H), 2.83−2.67 (m,

2H), 2.43 (s, 3H), 0.70 (d, J = 6.7, 3H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 169.1, 144.7, 142.0, 139.0, 136.3, 129.5, 128.8, 128.6, 128.4,

127.1, 121.3, 79.3, 39.7, 37.3, 21.8, 17.2; IR (ﬁlm) v 3488, 3064, 2875,

1712, 1453, 1347, 1172, 1149, 1088, 860, 764, 703, 663, 549 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₁₅H₁₇O₃SiNa [M + Na⁺]

396.1245, found 396.1237.

7.39−7.26 (m, 7H), 5.93 (td, J = 10.9, 1.3, 1H), 5.54 (dd, J = 10.9,

8.5, 1H), 5.03 (dd, J = 8.5, 1.3, 1H), 4.81 (d, J = 9.1, 1H), 3.88−3.75

(m, 2H), 3.69 (dd, J = 10.9, 9.1, 1H), 2.44 (s, 3H), 1.15−0.98 (m,

21H), 0.91 (t, J = 7.1, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

170.5, 170.4, 145.5, 141.3, 135.3, 131.0, 130.9, 129.9, 128.6, 128.5,

128.3, 126.8, 75.4, 70.9, 60.9, 55.2, 21.8, 18.0, 17.9, 13.9, 12.1; IR

(ﬁlm) v 3457, 3349, 3094, 3033, 2944, 2868, 1735, 1598, 1462, 1413,

1353, 1175, 1125, 1088, 879, 700, 663, 549 cm⁻¹; HRMS (ESI-TOF)

m/z calcd for C₃₁H₄₅NNaO₇SSi [M + Na⁺] 626.2584, found

626.2571.

(2R*,6S*,Z)-6-Hydroxy-4-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (35): Method A; 58.0 mg

(85% yield); dr = 95:5; white solid; mp 76.1−76.9 °C; R_f(20%

1

acetone/hexane) 0.45; H NMR (400 MHz, CDCl₃) δ 9.67 (s, 1H),

7.98−7.92 (m, 2H), 7.42−7.27 (m, 7H), 5.25 (d, J = 9.1, 1H), 4.93

(d, J = 9.1, 1H), 4.89−4.80 (m, 1H), 3.98 (s, 1H), 2.65 (dd, J = 13.6,

10.2, 1H), 2.45 (s, 3H), 2.24 (dd, J = 13.6, 2.7, 1H), 1.85 (s, 3H),

1.07−0.97 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.4,

145.3, 144.9, 139.1, 135.5, 129.7, 128.6, 128.5, 127.5, 125.6, 125.5,

71.3, 71.1, 44.3, 23.7, 21.8, 17.9, 17.8, 12.1; IR (ﬁlm) v 3470, 3345,

3066, 2943, 2867, 1739, 1663, 1598, 1462, 1412, 1352, 1175, 1123,

1089, 883, 662, 548 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₉H₄₃NNaO₅SSi [M + Na⁺] 568.2529, found 568.2519.

(2R*,6S*,Z)-6-Hydroxy-3-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (38a): Method A, starting

from 30, 31.4 mg (46% yield), dr = 98:2; starting from 31, 32.8

mg (48% yield), dr = 98:2; white solid; mp 129.4−130.8 °C; R_f(30%

(5S,6S,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enamide

((−)-21): Method A; 28.0 mg (60% yield); dr > 95:5; 86% ee (¹⁹F

NMR analysis of Mosher’s ester 28); white solid; mp 127.2−128.9

°C; R_f(30% acetone/hexane) 0.50; [α]²_D³−263.6 (c 1.66, CHCl₃);

NMR and IR spectra were consistent with those recorded for the

racemate; HRMS (ESI-TOF) m/z calcd for C₁₅H₁₇O₃SiNa [M +

Na⁺] 396.1245, found 396.1235.

1

acetone/hexane) 0.45; H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H),

7.96−7.90 (m, 2H), 7.41−7.26 (m, 7H), 5.55 (dd, J = 10.6, 5.7, 1H),

5.09 (s, 1H), 4.73 (dd, J = 9.8, 2.9, 1H), 3.52 (s, 1H), 2.59−2.47 (m,

1H), 2.44 (s, 3H), 2.41−2.33 (m, 1H), 1.58 (s, 3H), 1.13−0.93 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.7, 145.2, 144.3,

135.7, 135.6, 129.7, 128.7, 128.5, 127.74, 127.71, 125.7, 73.6, 71.7,

39.3, 21.8, 18.0, 17.9, 17.8, 12.2; IR (ﬁlm) v 3477, 3350, 3065, 2944,

2867, 1739, 1598, 1464, 1408, 1350, 1176, 1122, 1088, 882, 661, 554

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₉H₄₃NNaO₅SSi [M + Na⁺]

568.2529, found 568.2527.

(5R,6R,Z)-6-Hydroxy-5-methyl-6-phenyl-N-tosylhex-3-enamide

((+)-21): Method A; 8.5 mg (61% yield); dr > 95:5; 20% ee (¹⁹F

NMR analysis of Mosher’s ester 29); colorless wax; R_f(30% acetone/

hexane) 0.50; [α]²_D⁴+40.3 (c 1.86, CHCl₃); NMR and IR spectra were

consistent with those recorded for the racemate; HRMS (ESI-TOF)

m/z calcd for C₁₅H₁₇O₃SiNa [M + Na⁺] 396.1245, found 396.1242.

(2R*,5S*,Z)-5-((S)-Hydroxy(phenyl)methyl)-6-methyl-N-tosyl-2-

((triisopropylsilyl)oxy)hept-3-enamide (32): Method A; 53.1 mg

(74% yield); dr = 98:2; white solid; mp 126.4−127.7 °C; R_f(20%

(2R*,6R*,E)-6-Hydroxy-3-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (38b) and (2R*,6S*,E)-6-

Hydroxy-3-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-

enamide (38b′): Method A, starting from 30, 19.1 mg (28% yield), dr

= 54:46; starting from 31, 20.5 mg (30% yield), dr = 51:49; colorless

1

acetone/hexane) 0.45; H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1H),

1

7.98−7.91 (m, 2H), 7.41−7.28 (m, 7H), 5.74 (td, J = 11.3, 1.4, 1H),

5.55 (dd, J = 11.3, 8.0, 1H), 5.08 (dd, J = 8.0, 1.4, 1H), 4.46 (d, J =

10.0, 1H), 3.59 (s, 1H), 2.79−2.71 (m, 1H), 2.42 (s, 3H), 1.44−1.34

(m, 1H), 1.18−1.01 (m, 21H), 0.83 (d, J = 6.9, 3H), 0.75 (d, J = 6.9,

3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.1, 145.2, 143.4, 135.6,

133.2, 130.9, 129.7, 128.7, 128.5, 128.0, 127.1, 76.3, 71.4, 51.9, 28.2,

22.3, 21.8, 18.14, 18.11, 15.9, 12.4; IR (ﬁlm) v 3469, 3351, 3066,

2956, 2868, 1738, 1598, 1463, 1412, 1350, 1175, 1127, 1088, 880,

663, 548 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₃₁H₄₇NNaO₅SSi

[M + Na⁺] 596.2842, found 596.2833.

wax; R_f(30% acetone/hexane) 0.40; H NMR (400 MHz, CDCl₃) δ

= 9.04 (br s, 1H), 9.01 (br s, 1H′), 8.00−7.87 (m, 2H + 2H′), 7.45−

7.20 (br m, 7H + 7H′), 5.66−5.54 (m, 1H + 1 H′), 4.74−4.64 (m,

1H + 1 H′), 4.41 (s, 1H), 4.39 (s, 1H′), 2.60−2.36 (m, 2H + 2H′),

2.43 (s, 3H + 3H′), 2.06 (br s, 1H + 1H′), 1.48 (s, 3H + 3H′), 1.09−

0.91 (m, 21H + 21H′); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.86,

169.85, 145.2, 143.9, 143.8, 135.67, 134.9, 134.6, 129.6, 128.6, 128.5,

127.8, 126.3, 126.1, 125.9, 79.54, 79.50, 73.84, 73.80, 37.7, 37.5, 21.8,

17.91, 17.87, 12.1, 12.02; IR (ﬁlm) v 3352, 3063, 2944, 2867, 2730,

1920, 1729, 1598, 1459, 1406, 1351, 1176, 1088, 881, 663, 550 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₉H₄₃NNaO₅SSi [M + Na⁺]

568.2529, found 568.2515.

(2R*,5R*,6S*,Z)-6-Hydroxy-5,6-diphenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (33): Method A; 54.7 mg

(72% yield); dr = 98:2; white solid; mp 134.9−136.0 °C; R_f(30%

(2R*,6S*,Z)-6-Hydroxy-6-phenyl-N-tosyl-2-((triisopropylsilyl)-

oxy)hex-3-enamide (44a): Method A, 51.9 mg (78% yield), dr =

87:13; Method B, 58.5 mg (88% yield), dr = 95:5; colorless wax; R_f

1

acetone/hexane) 0.65; H NMR (400 MHz, CDCl₃) δ 9.66 (s, 1H),

8.02−7.95 (m, 2H), 7.40−7.32 (m, 2H), 7.18−7.09 (m, 6H), 7.08−

U

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(20% acetone/hexane) 0.45. Analytical data were consistent with

previously reported values.⁷

(2R,6R,E)-6-Hydroxy-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)-

hex-3-enamide (44b): Method A, 8.6 mg (13% yield), dr = 51:49;

Method B, 10.0 mg (15% yield), dr = 92:8; colorless wax; R_f(20%

acetone/hexane) 0.40. Analytical data were consistent with previously

reported values.⁷

128.2, 127.0, 125.3, 124.4, 74.3, 56.7, 43.2, 21.6; IR (ﬁlm) v 3512,

3245, 2922, 1777, 1718, 1597, 1434, 1387, 1351, 1176, 1147, 1088,

852, 721, 549 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₇H₂₄N₂NaO₆S [M + Na⁺] 527.1253, found 527.1243.

(2R*,5S*,6S*,Z)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-5-meth-

yl-6-phenyl-N-tosylhex-3-enamide (49): 40.8 mg (63% yield); dr =

91:1; colorless solid; mp 154.2−154.7 °C; R_f(40% acetone/hexane)

1

(2R*,6S*,Z)-6-Hydroxy-2-methyl-6-phenyl-N-tosylhex-3-enam-

ide (45a): Method A, 37.4 mg (80% yield), dr = 91:9; Method B, 34.6

mg (74% yield), dr = 95:5; white solid; mp 125.8−126.7 °C; R_f(30%

acetone/hexane) 0.50; ¹H NMR (400 MHz, CDCl₃) δ 10.97 (s, 1H),

7.93−7.86 (m, 2H), 7.42−7.27 (m, 7H), 5.74 (dd, J = 10.9, 5.3, 1H),

5.34 (d, J = 10.9, 1H), 4.82 (d, J = 10.8, 1H), 3.45 (dq, J = 10.9, 6.6,

1H), 3.30 (s, 1H), 2.68 (dt, J = 14.1, 11.1, 1H), 2.43 (s, 3H), 2.24

(ddt, J = 15.8, 5.4, 1.8, 1H), 1.09 (d, J = 6.6, 3H); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 171.6, 144.5, 143.8, 136.4, 131.5, 129.5, 129.4,

128.8, 128.3, 128.2, 125.6, 74.12, 39.4, 37.7, 21.8, 14.8; IR (ﬁlm) v

3487, 3087, 2978, 2877, 1722, 1598, 1453, 1400, 1344, 1175, 1086,

0.45; H NMR (400 MHz, acetone-d₆) δ 11.47 (s, 1H), 7.94−7.86

(m, 2H), 7.55−7.48 (m, 2H), 7.47−7.30 (m, 5H), 6.23 (td, J = 10.6,

0.8, 1H), 5.99−5.87 (m, 2H), 4.54 (d, J = 9.6, 1H), 3.09 (td, J = 10.1,

6.6, 1H), 2.44 (s, 3H), 0.73 (d, J = 6.6, 3H); ¹³C{¹H} NMR (101

MHz, acetone-d₆) δ 167.8, 166.3, 145.5, 143.9, 142.3, 137.6, 135.4,

132.7, 130.2, 129.2, 129.1, 128.8, 128.2, 124.1, 121.9, 79.5, 52.5, 40.8,

21.5, 17.1; IR (ﬁlm) v 3501, 2985, 2848, 2791, 1773, 1712, 1597,

1465, 1389, 1348, 1162, 1018, 849, 756, 551 cm⁻¹; HRMS (ESI-

TOF) m/z calcd for C₂₈H₂₆N₂NaO₆S [M + Na⁺] 541.1409, found

541.1396.

(2R*,6S*,Z)-6-Hydroxy-N-(methylsulfonyl)-6-phenyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (53a): Method A, 41.0 mg

(72% yield), dr = 90:10; Method B, 9.3 mg (69% yield), dr = 94:6;

849, 663, 569 cm⁻¹

; HRMS (ESI-TOF) m/z calcd for

C₂₀H₂₃NNaO₄S [M + Na⁺] 396.1245, found 396.1241.

(2R*,6R*,E)-6-Hydroxy-2-methyl-6-phenyl-N-tosylhex-3-enam-

ide (45b) and (2R*,6S*,E)-6-Hydroxy-2-methyl-6-phenyl-N-tosyl-

hex-3-enamide (45b′): Method A, 1.9 mg (4% yield), 45b/45b′ =

53:47; Method B, 7.0 mg (15% yield), 45b/45b′ = 74:26; colorless

1

white solid; mp 88.5−89.6 °C; R_f(30% acetone/hexane) 0.45; H

NMR (400 MHz, CDCl₃) δ 9.61 (s, 1H), 7.41−7.23 (m, 5H), 5.84

(td, J = 10.7, 6.2, 1H), 5.54 (t, J = 10.7, 8.8, 1H), 5.10 (dd, J = 8.8,

1.2, 1H), 4.78 (dd, J = 9.6, 3.6, 1H), 3.48−3.31 (m, 1H), 3.26 (s,

3H), 2.65 (dt, J = 14.3, 9.6, 1H), 2.56−2.46 (m, 1H), 1.17−0.95 (m,

21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.8, 144.2, 131.9,

129.7, 128.7, 127.8, 125.7, 73.3, 70.5, 41.5, 39.3, 18.0, 17.9, 12.1; IR

(ﬁlm) v 3480, 3355, 3064, 3030, 2944, 2867, 1733, 1657, 1463, 1397,

1346, 1181, 1120, 1068, 973, 881, 700, 518 cm⁻¹; HRMS (ESI-TOF)

m/z calcd for C₂₂H₃₇NNaO₅SSi [M + Na⁺] 478.2059, found

478.2052.

1

wax; R_f(30% acetone/hexane) 0.45; H NMR (400 MHz, CDCl₃) δ

9.56 (s, 1H + 1H′), 7.99−7.89 (m, 2H + 2H′), 7.43−7.23 (m, 7H +

7H′), 5.80−5.67 (m, 1H), 5.70−5.58 (m, 1H′), 5.58−5.49 (m, 1H′),

5.47 (ddt, J = 15.3, 9.2, 1.1, 1H), 4.87 (dd, J = 7.0, 4.8, 1H′), 4.80

(dd, J = 9.2, 4.1, 1H), 3.11−2.92 (m, 1H + 1H′), 2.60−2.32 (m, 4H +

4H′), 1.20 (d, J = 7.1, 3H′), 1.18 (d, J = 7.0, 3H); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 172.2, 172.1, 145.0, 144.9, 143.9, 143.7, 136.0,

135.9, 132.6, 132.3, 132.1, 131.0, 129.64, 129.62, 128.8, 128.7, 128.6,

128.1, 127.9, 125.8, 125.7, 73.6, 73.4, 45.2, 44.8, 42.3, 41.7, 21.8, 15.9,

15.7; IR (ﬁlm) v 3506, 3249, 3063, 2979, 2931, 1717, 1597, 1453,

1342, 1173, 1087, 843, 661, 548 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₀H₂₃NNaO₄S [M + Na⁺] 396.1245, found 396.1230.

(2R*,6R*,E)-6-Hydroxy-N-(methylsulfonyl)-6-phenyl-2-

((triisopropylsilyl)oxy)hex-3-enamide (53b): Method A, 8.5 mg

(15% yield), dr = 61:39; Method B, 10.8 mg (19% yield), dr =

1

87:13; colorless wax; R_f(30% acetone/hexane) 0.40; H NMR (400

(2R*,6S*,Z)-6-Hydroxy-2-isopropyl-6-phenyl-N-tosylhex-3-en-

amide (46a): Method A, starting from 41, 42.2 mg (84% yield), dr =

96:4; Method B, starting from 41, 38.1 mg (76% yield), dr = 98:2,

starting from 42, 5.6 mg (71% yield), dr = 99:1; colorless wax; R_f

(30% acetone/hexane) 0.45. Analytical data were consistent with

previously reported values.^3a

(2R*,6R*,E)-6-Hydroxy-2-isopropyl-6-phenyl-N-tosylhex-3-en-

amide (46b): Method A, starting from 41, 3.5 mg (7% yield), dr =

86:14; Method B, starting from 41, 11.0 mg (22% yield), dr = 98:2,

starting from 42, 11.0 mg (22% yield), dr = 89:11; colorless wax; R_f

(30% acetone/hexane) 0.40. Analytical data were consistent with

previously reported values.^3a

(2R*,6S*,Z)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-6-phenyl-N-

tosylhex-3-enamide (47a): Method A, 47.3 mg (75% yield), dr =

88:12; Method B, 46.7 mg (74% yield), dr = 98:2; colorless crystals;

mp 201.3−202.1 °C; R_f(45% AcOEt/hexane + 0.5% HCO₂H) 0.60;

¹H NMR (400 MHz, CDCl₃) δ 11.04 (s, 1H), 7.96−7.86 (m, 2H),

7.85−7.74 (m, 2H), 7.73−7.64 (m, 2H), 7.48−7.25 (m, 7H), 6.37

(td, J = 10.7, 1.3, 1H), 6.05 (td, J = 11.2, 5.0, 1H), 5.79 (d, J = 10.7,

1H), 4.92 (dd, J = 11.0, 2.2, 1H), 3.32 (s, 1H), 2.88 (dd, J = 14.1,

11.2, 1H), 2.43 (s, 3H), 2.39−2.31 (m, 1H); ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 167.3, 165.1, 145.0, 143.2, 135.8, 134.4, 134.3, 131.9,

129.7, 128.9, 128.5, 128.4, 125.8, 123.7, 74.0, 51.2, 37.5, 21.8; IR

(ﬁlm) v 3476, 3067, 2882, 1775, 1714, 1597, 1468, 1386, 1347, 1176,

1152, 1086, 853, 718, 546 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₇H₂₄N₂NaO₆S [M + Na⁺] 527.1253, found 527.1251.

MHz, CDCl₃) δ 8.80 (s, 1H), 7.40−7.26 (m, 5H), 5.89 (dtd, J = 15.7,

7.2, 1.4, 1H), 5.59 (ddt, J = 15.4, 5.8, 1.4, 1H), 4.79−4.66 (m, 2H),

3.25 (s, 3H), 2.59−2.52 (m, 2H), 1.14−0.99 (m, 21H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 171.16, 143.6, 131.1, 129.5, 128.7, 127.9,

126.0, 75.1, 73.6, 41.9, 41.5, 17.99, 17.96, 12.1; IR (ﬁlm) v 3358,

3030, 2944, 2868, 1724, 1461, 1397, 1348, 1181, 1149, 1056, 972,

881, 688, 519 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₂H₃₇NNaO₅SSi [M + Na⁺] 478.2059, found 478.2046.

(2R,5S,6S,Z)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-hydroxy-5-

methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide ((−)-56):

48.4 mg (68% yield); dr > 98:2; colorless wax; R_f(20% acetone/

hexane) 0.50; [α]²_D⁵−60.9 (c 2.25, CHCl₃); H NMR (400 MHz,

1

CDCl₃) δ 9.78 (s, 1H), 7.95−7.88 (m, 2H), 7.35−7.27 (m, 2H), 5.51

(t, J = 10.8, 1H), 5.31 (t, J = 9.9, 1H), 4.88 (d, J = 8.9, 1H), 4.16 (q, J

= 6.2, 1H), 3.97 (t, J = 7.3, 1H), 3.89 (t, J = 7.6, 1H), 3.56 (t, J = 6.3,

1H), 2.92 (s, 1H), 2.62−2.47 (m, 1H), 2.42 (s, 3H), 1.43 (s, 3H),

1.36 (s, 3H), 1.13−0.97 (m, 21H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 170.1, 145.1, 137.1, 135.8, 129.6, 128.4, 127.4, 109.3, 77.7,

74.9, 70.5, 65.4, 37.4, 26.7, 25.5, 21.8, 17.95, 17.94, 17.0, 12.2; IR

(ﬁlm) v 3511, 3355, 3110, 2943, 2868, 1737, 1598, 1462, 1406, 1351,

1176, 1121, 1087, 871, 661, 548 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₈H₄₇NNaO₇SSi [M + Na⁺] 592.2740, found 592.2739.

(2S,5R,6R,Z)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-hydroxy-5-

methyl-N-tosyl-2-((triisopropylsilyl)oxy)hex-3-enamide ((+)-57):

47.0 mg (66% yield); dr > 98:2; colorless wax; R_f(20% acetone/

hexane) 0.45; [α]²_D⁵+61.3 (c 2.48, CHCl₃); H NMR (400 MHz,

1

(2R*,6R*,E)-2-(1,3-Dioxoisoindolin-2-yl)-6-hydroxy-6-phenyl-N-

tosylhex-3-enamide (47b): Method A, 8.2 mg (13% yield), dr =

55:45; Method B, 8.2 mg (13% yield), dr = 90:10; colorless wax; R_f

CDCl₃) δ 9.38 (s, 1H), 7.94−7.87 (m, 2H), 7.35−7.25 (m, 2H), 5.58

(td, J = 10.9, 1.4, 1H), 5.28 (dd, J = 10.9, 8.3, 1H), 4.89 (dd, J = 8.3,

1.4, 1H), 4.11−3.99 (m, 2H), 3.96−3.85 (m, 1H), 3.29−3.22 (m,

1H), 3.19−3.13 (m, 1H), 2.80−2.68 (m, 1H), 2.42 (s, 3H), 1.43 (s,

3H), 1.36 (s, 3H), 1.11−0.96 (m, 21H); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 170.0, 145.2, 137.3, 135.6, 129.6, 128.6, 127.2, 109.4, 76.3,

75.1, 71.1, 66.5, 36.3, 26.6, 25.5, 21.8, 18.0, 17.9, 17.1, 12.1; IR (ﬁlm)

v 3495, 3352, 3071, 2943, 2868, 1736, 1652, 1598, 1462, 1410, 1352,

1

(45% AcOEt/hexane + 0.5% HCO₂H) 0.50; H NMR (400 MHz,

MeOH-d₄) δ 7.88−7.80 (m, 6H), 7.41−7.33 (m, 2H), 7.27−7.19 (m,

2H), 7.19−7.09 (m, 2H), 7.08−6.98 (m, 1H), 5.90−5.72 (m, 2H),

5.23 (d, J = 7.3, 1H), 4.65 (dd, J = 7.5, 6.0, 1H), 2.60−2.47 (m, 1H),

2.47−2.35 (m, 4H); ¹³C{¹H} NMR (101 MHz, MeOH-d₄) δ 168.6,

168.3, 146.2, 145.4, 137.6, 136.5, 135.6, 133.2, 130.5, 129.3, 129.1,

V

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1177, 1122, 1088, 879, 661, 548 cm⁻¹; HRMS (ESI-TOF) m/z calcd

for C₂₈H₄₇NNaO₇SSi [M + Na⁺] 592.2740, found 592.2728.

Synthesis of Mosher’s Esters 22 and 23. To a solution of (Z)-

5,6-anti-enediol 21, (−)-21, or (+)-21 (7.5 mg, 0.02 mmol), DMAP

(0.6 mg; 0.005 mmol), and Et₃N (5.6 μL, 0.04 mmol) in anhydrous

CH₂Cl₂(0.65 mL) was added a 1 M solution of (+)-MTPACl in

CH₂Cl₂(22 μL, 0.022 mmol) dropwise at 25 °C. After 1 h at the

same temperature, the reaction was quenched with a saturated

aqueous solution of NH₄Cl (0.5 mL), poured into water (10 mL),

and extracted with CH₂Cl₂(3 × 5 mL). Combined extracts were then

washed with brine (15 mL), dried over MgSO₄, and concentrated.

Filtration of the crude product through a pad of silica gel with an

acetone/hexane mixture aﬀorded Mosher’s esters 22 and 23 as

inseparable mixtures of diastereomers.

(1S,2S,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1-

phenylhex-3-en-1-yl (S)-3,3,3-Triﬂuoro-2-methoxy-2-phenylpropa-

noate (22) and (1R,2R,Z)-2-Methyl-6-((4-methylphenyl)-

sulfonamido)-6-oxo-1-phenylhex-3-en-1-yl (S)-3,3,3-Triﬂuoro-2-

methoxy-2-phenylpropanoate (23): obtained according to a general

procedure using 21; inseparable mixture; 7.2 mg (61% yield); 22/23

= 50:50; colorless oil; R_f(30% acetone/hexane) 0.45; ¹⁹F NMR (376

MHz, CDCl₃) δ −71.14 (23), −71.20 (22); HRMS (ESI-TOF) m/z

calcd for C₃₀H₃₀F₃NNaO₆SSi [M + Na⁺] 612.1644, found 612.1630.

(1S,2S,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1-

phenylhex-3-en-1-yl (S)-3,3,3-Triﬂuoro-2-methoxy-2-phenylpropa-

noate (22): obtained according to a general procedure using (−)-21;

8.0 mg (68% yield); 22/23 = 97:3 (86% de); colorless oil; R_f(30%

acetone/hexane) 0.45; ¹⁹F NMR (376 MHz, CDCl₃) δ −71.14 (23),

−71.20 (major signal 22); HRMS (ESI-TOF) m/z calcd for

C₃₀H₃₀F₃NNaO₆SSi [M + Na⁺] 612.1644, found 612.1636.

(1R,2R,Z)-2-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxo-1-

phenylhex-3-en-1-yl (S)-3,3,3-Triﬂuoro-2-methoxy-2-phenylpropa-

noate (23): obtained according to a general procedure using

(+)-21;7.0 mg (59% yield); 23/22 = 60:40 (20% de); colorless oil;

R_f(30% acetone/hexane) 0.45; ¹⁹F NMR (376 MHz, CDCl₃) δ

−71.14 (major signal 23), −71.21 (22); HRMS (ESI-TOF) m/z

calcd for C₃₀H₃₀F₃NNaO₆SSi [M + Na⁺] 612.1644, found 612.1631.

Reduction of (3Z)- and (3E)-Enediols 2a−2b and 18a−18b.

To a solution of 2,6-enediol 2a, 2b, 18a, or 18b (109.6 mg, 0.2 mmol)

in toluene (5 mL) was added PtO₂(6.8 mg, 0.03 mmol) in one

portion at 25 °C, and the resulting suspension was saturated with H₂.

After 24 h at the same temperature, the reaction mixture was diluted

with toluene (5 mL) and ﬁltered through a pad of Celite. Removal of

solvent under reduced pressure and puriﬁcation of the crude product

by column chromatography on silica gel using an acetone/hexane

mixture as an eluent aﬀorded saturated 2,6-diols 58−60 as colorless

oils.

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₉H₄₅NNaO₅SSi [M + Na⁺]

570.2685, found 570.2687.

(2R*,5S*,6R*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hexanamide (60) and (2R*,5S*,6S*)-6-Hy-

droxy-5-methyl-6-phenyl-N-tosyl-2-((triisopropylsilyl)oxy)-

hexanamide (60′): inseparable mixture; 96.6 mg (86% yield); 60b/

60b′ = 78:22; colorless oil; R_f(25% acetone/hexane) 0.60; ¹H NMR

(400 MHz, CDCl₃) δ 8.92 (br s, 1H + 1H′), 7.97−7.91 (m, 2H +

2H′), 7.37−7.18 (m, 7H + 7′), 4.44 (d, J = 5.0, 1H), 4.31 (d, J = 7.2,

1H′), 4.22 (t, J = 5.2, 1H′), 4.16 (t, J = 5.1, 1H), 2.42 (s, 3H), 2.42 (s,

3H′), 1.82−1.56 (m, 4H + 4H′), 1.24−1.16 (m, 1H + 1H′), 1.08−

0.94 (m, 21H + 21H′), 0.79 (d, J = 6.7, 3H), 0.64 (d, J = 6.8, 3H′);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.6, 145.3, 145.2, 143.5,

143.3, 135.7, 135.7, 129.6, 128.6, 128.41, 128.37, 127.7, 127.44, 126.8,

126.3, 78.8, 77.7, 74.1, 74.0, 40.2, 40.0, 33.3, 32.9, 27.2, 26.4, 21.8,

18.00, 17.97, 15.8, 14.0, 12.2, 12.2; IR (ﬁlm) v 3548, 3357, 3062,

2944, 2868, 1728, 1598, 1460, 1406, 1352, 1176, 1088, 880, 662, 549

cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₉H₄₅NNaO₅SSi [M + Na⁺]

570.2685, found 570.2694.

Synthesis of 3,6,7-Trisubstituted Caprolactones 61−63. To

a vigorously stirred solution of 2,6-diol 58−60 (110 mg, 0.2 mmol)

and TBAB (32 mg, 0.1 mmol) in MeI (2.5 mL) was added K₂CO₃(1

g) in one portion at 25 °C. After 12 h at the same temperature, excess

of K₂CO₃was ﬁltered oﬀ and washed with CH₂Cl₂(25 mL), and

combined ﬁltrates were concentrated under reduced pressure.

Filtration of the residue through a pad of silica gel with an

acetone/hexane mixture aﬀorded crude products, which were

subsequently, without further puriﬁcation, dissolved in the anhydrous

THF (50 mL). To this mixture was added 2 M NaHMDS solution in

THF (100 μL, 0.2 mmol) dropwise at −50 °C under an argon

atmosphere, and the stirring was continued for 10 min at the same

temperature. Then the reaction was quenched with a saturated

solution of NH₄Cl (50 mL), poured into water, and extracted with

EtOAc (3 × 25 mL). The combined extracts were washed

successively with water (50 mL), a saturated solution of NaHCO₃

(50 mL), and brine (50 mL), dried over anhydrous MgSO₄, and

concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an MTBE/

hexane mixture as an eluent aﬀorded lactones 61−63 as colorless

crystals or a colorless wax.

(3R*,6S*,7S*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)-

oxepan-2-one (61): 52.0 mg (69% yield); dr > 98:2; colorless oil; R_f

1

(15% MTBE/hexane) 0.45; H NMR (400 MHz, CDCl₃) δ 7.37−

7.26 (m, 5H), 5.94 (d, J = 8.1, 1H), 4.77 (dd, J = 6.4, 1.7, 1H), 2.14−

1.86 (m, 4H), 1.82−1.74 (m, 1H), 1.24−1.05 (m, 21H), 0.57 (d, J =

6.3, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.8, 139.9, 128.6,

128.3, 127.4, 85.8, 74.4, 39.1, 31.2, 30.3, 20.3, 18.1, 18.0, 12.1; IR

(ﬁlm) v 3032, 2937, 2867, 1735, 1460, 1268, 1211, 1120, 1016, 880,

695 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₆NaO₃Si [M +

Na⁺] 399.2331, found 399.2329.

(2R*,5S*,6S*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hexanamide (58): 82.0 mg (73% yield); dr =

1

97:3; colorless oil; R_f(25% acetone/hexane) 0.60; H NMR (400

MHz, CDCl₃) δ 8.95 (s, 1H), 7.99−7.92 (m, 2H), 7.35−7.19 (m,

7H), 4.30 (d, J = 7.2, 1H), 4.21 (t, J = 5.1, 1H), 2.41 (s, 3H), 1.83−

1.66 (m, 4H), 1.52−1.40 (m, 1H), 1.10−0.96 (m, 21H), 0.63 (d, J =

6.8, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.6, 145.2, 143.3,

135.7, 129.6, 128.5, 128.4, 127.7, 126.7, 78.8, 74.1, 39.9, 32.9, 26.4,

21.8, 17.99, 17.97, 15.8, 12.2; IR (ﬁlm) v 3539, 3357, 3062, 2926,

2867, 1728, 1598, 1459, 1406, 1351, 1175, 1088, 880, 662, 549 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₉H₄₅NNaO₅SSi [M + Na⁺]

570.2685, found 570.2688.

(3R*,6R*,7R*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)-

oxepan-2-one (62a): 52.7 mg (70% yield); dr > 98:2, colorless

1

crystals; mp 92.9−93.8 °C; R_f(15% MTBE/hexane) 0.60; H NMR

(400 MHz, CDCl₃) δ 7.40−7.29 (m, 5H), 4.83−4.73 (m, 2H), 2.22−

1.97 (m, 4H), 1.70−1.59 (m, 1H), 1.22−1.04 (m, 21H), 0.66 (d, J =

6.7, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 173.5, 139.3, 128.6,

128.6, 127.3, 86.3, 70.5, 38.4, 34.1, 33.2, 18.8, 18.1, 12.4; IR (ﬁlm) v

3065, 3035, 2942, 2866, 2724, 1880, 1748, 1459, 1384, 1196, 1144,

882, 699 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₆NaO₃Si [M

+ Na⁺] 399.2331, found 399.2319.

(2R*,5R*,6R*)-6-Hydroxy-5-methyl-6-phenyl-N-tosyl-2-

((triisopropylsilyl)oxy)hexanamide (59): starting from 2b, 93.3 mg

(83% yield), dr = 81:10:5:4; starting from 18a, 79.8 mg (71% yield),

(3R*,6R*,7S*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)-

1

oxepan-2-one (62b): 6.0 mg (8% yield); dr > 98:2; colorless oil; R_f

dr = 95:5; colorless oil; R_f(25% acetone/hexane) 0.60; H NMR

1

(15% MTBE/hexane) 0.70; H NMR (400 MHz, CDCl₃) δ 7.41−

(400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.96−7.92 (m, 2H), 7.36−7.21

(m, 7H), 4.31 (d, J = 6.8, 1H), 4.22 (dd, J = 5.7, 3.6, 1H), 2.43 (s,

3H), 1.91−1.51 (m, 5H), 1.11−0.93 (m, 21H), 0.62 (d, J = 6.8, 3H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.6, 145.2, 143.5, 135.7,

129.6, 128.54, 128.50, 128.4, 127.6, 126.6, 78.8, 74.1, 40.2, 33.1, 25.6,

21.8, 17.99, 17.95, 15.9, 12.1; IR (ﬁlm) v 3464, 3358, 3062, 2926,

2867, 1729, 1664, 1598, 1461, 1406, 1351, 1176, 1088, 881, 662, 549

7.32 (m, 4H), 7.30−7.24 (m, 1H), 6.46 (s, 1H), 4.80−4.74 (m, 1H),

2.57−2.44 (m, 1H), 2.28−2.15 (m, 1H), 2.01−1.89 (m, 2H), 1.63

(dq, J = 13.9, 3.8, 1H), 1.22−1.04 (m, 21H), 0.87 (d, J = 7.2, 3H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.8, 140.7, 128.3, 127.4,

125.8, 81.5, 74.7, 38.9, 28.7, 25.6, 18.1, 18.0, 12.1, 9.3; IR (ﬁlm) v

3457, 3062, 3030, 2939, 2866, 1737, 1460, 1364, 1283, 1181, 1123,

W

DOI: 10.1021/acs.joc.8b02333

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

999, 877, 694 cm⁻¹; HRMS (ESI-TOF) m/z calcd for C₂₂H₃₆NaO₃Si

[M + Na⁺] 399.2331, found 399.2313.

(5% MeOH/CH₂Cl₂) 0.45; [α]²_D⁵−33.4 (c 0.86, CHCl₃); H NMR

(400 MHz, CDCl₃) δ 5.93−5.76 (m, 2H), 5.70 (dd, J = 10.9, 3.1,

1H), 4.80 (d, J = 7.4, 1H), 3.96−3.81 (m, 2H), 3.76 (dd, J = 11.2, 3.6,

1H), 2.70−2.44 (m, 2H), 2.27 (s, 1H), 1.21−0.94 (m, 24H);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.6, 141.8, 123.3, 81.5, 71.5,

1

(3R*,6S*,7R*)-6-Methyl-7-phenyl-3-((triisopropylsilyl)oxy)-

oxepan-2-one (63): 50.5 mg (67% yield); colorless oil; R_f(15%

MTBE/hexane) 0.65; ¹H NMR (400 MHz, CDCl₃) δ 7.45−7.32 (m,

4H), 7.33−7.24 (m, 1H), 5.44 (s, 1H), 4.66 (dd, J = 10.3, 3.2, 1H),

2.26−2.04 (m, 3H), 2.00−1.83 (m, 2H), 1.21−1.03 (m, 21H), 0.81

(d, J = 7.1, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 173.6, 139.8,

128.4, 127.7, 125.7, 81.7, 70.9, 37.9, 33.1, 29.9, 18.1, 12.4, 10.1; IR

(ﬁlm) v 3032, 2942, 2866, 1755, 1463, 1385, 1143, 883, 684 cm⁻¹;

HRMS (ESI-TOF) m/z calcd for C₂₂H₃₆NaO₃Si [M + Na⁺]

399.2331, found 399.2321.

70.9, 61.9, 36.7, 17.94, 17.91, 17.2, 12.0; IR (ﬁlm) v 3410, 3023, 2943,

2868, 1739, 1651, 1464, 1292, 1095, 1012, 882, 685 cm⁻¹; HRMS

(ESI-TOF) m/z calcd for C₁₈H₃₄NaO₅Si [M + Na⁺] 381.2073, found

381.2065.

(3S,6R,7R)-7-((R)-1,2-Dihydroxyethyl)-6-methyl-3-

((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((+)-67): 69.9

mg (78% yield); dr = 95:5; colorless crystals; mp 135.1−136.2 °C; R_f

(5% MeOH/CH₂Cl₂) 0.45; [α]²_D⁵+39.0 (c 1.26, CHCl₃); H NMR

1

Synthesis of Caprolactones (−)-64 and (+)-66. To a

vigorously stirred solution of 2,6-syn-enediol (−)-56 or (+)-57 (204

mg, 0.35 mmol) and TBAB (56 mg, 0.175 mmol) in MeI (5 mL) was

added K₂CO₃(2 g) in one portion at 25 °C. After 12 h at the same

temperature, an excess of K₂CO₃was ﬁltered oﬀ and washed with

CH₂Cl₂(25 mL), and combined ﬁltrates were concentrated under

reduced pressure. Filtration of the residue through a pad of silica gel

with an acetone/hexane mixture aﬀorded crude products, which

without further puriﬁcation were dissolved in the anhydrous THF (50

mL). To this mixture was added a 2 M NaHMDS solution in THF

(175 μL, 0.35 mmol) dropwise at −50 °C under an argon

atmosphere, and the stirring was continued for 10 min at the same

temperature. Then the reaction was quenched with a cold saturated

solution of NH₄Cl (50 mL), poured into water, and extracted with

EtOAc (3 × 30 mL). The combined extracts were washed

successively with water (100 mL), a saturated solution of NaHCO₃

(50 mL), and brine (50 mL), dried over anhydrous MgSO₄, and

concentrated under reduced pressure. Puriﬁcation of the crude

product by column chromatography on silica gel using an MTBE/

hexane mixture as an eluent aﬀorded lactones (−)-64 and (+)-66 as

colorless oils.

(400 MHz, CDCl₃) δ 5.92−5.79 (m, 2H), 5.45 (d, J = 10.5, 1H), 4.78

(dd, J = 6.8, 1.4, 1H), 3.94−3.85 (m, 2H), 3.68 (q, J = 7.7, 1H),

2.98−2.88 (m, 1H), 2.72 (s, 2H), 1.17−0.99 (m, 24H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 170.7, 142.5, 122.6, 80.3, 71.0, 70.9, 64.9,

35.9, 17.9, 17.9, 17.3, 12.0; IR (ﬁlm) v 3498, 3243, 3028, 2948, 2868,

1714, 1463, 1293, 1084, 1015, 881, 693 cm⁻¹; HRMS (ESI-TOF) m/

z calcd for C₁₈H₃₄NaO₅Si [M + Na⁺] 381.2073, found 381.2064.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.8b02333.

■

S

¹H and ¹³C NMR spectra for all new and selected known

compounds, ¹⁹F NMR spectra for Mosher’s esters,

HPLC chromatograms, and X-ray crystallographic data

(PDF)

X-ray crystal data for 2a (CIF)

X-ray crystal data for 13 (CIF)

X-ray crystal data for 62a (CIF)

X-ray crystal data for (−)-65 (CIF)

X-ray crystal data for (+)-67 (CIF)

(3R,6S,7S)-7-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-methyl-3-

((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((−)-64): 90.7

mg (65% yield); dr > 98:2; colorless oil; R_f(20% MTBE/hexane)

0.55; [α]²_D⁵−2.8 (c 0.51, CHCl₃); H NMR (400 MHz, CDCl₃) δ

1

5.89−5.75 (m, 2H), 5.48 (dd, J = 10.4, 6.2, 1H), 4.78 (d, J = 7.1, 1H),

4.23−4.09 (m, 2H), 4.02−3.91 (m, 1H), 2.58−2.47 (m, 1H), 1.36 (d,

J = 9.2, 6H), 1.19 (d, J = 7.3, 3H), 1.17−1.01 (m, 21H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 170.1, 142.4, 122.9, 110.1, 79.7, 76.8,

71.1, 67.0, 39.4, 26.5, 26.0, 17.94, 17.90, 17.3, 12.0; IR (ﬁlm) v 2943,

2868, 1746, 1650, 1462, 1255, 1064, 883, 688 cm⁻¹; HRMS (ESI-

TOF) m/z calcd for C₂₁H₃₈NaO₅Si [M + Na⁺] 421.2386, found

421.2368.

AUTHOR INFORMATION

Corresponding Author

*E-mail: bartosz.zambron@icho.edu.pl.

ORCID

■

́

Bartosz K. Zambron: 0000-0002-7170-4174

Notes

The authors declare no competing ﬁnancial interest.

(3S,6R,7R)-7-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-methyl-3-

((triisopropylsilyl)oxy)-6,7-dihydrooxepin-2(3H)-one ((+)-66): 87.9

mg (63% yield); dr > 98:2; ee > 99%; colorless oil; R_f(20% MTBE/

ACKNOWLEDGMENTS

We gratefully thank the National Science Centre for ﬁnancial

support (SONATA UMO-2015/19/D/ST5/00713).

■

hexane) 0.65; [α]²_D⁵+54.2 (c 0.46, CHCl₃); H NMR (400 MHz,

1

CDCl₃) δ 5.87−5.80 (m, 2H), 5.41 (dd, J = 10.3, 2.0, 1H), 4.83−4.75

(m, 1H), 4.32 (td, J = 7.2, 2.0, 1H), 4.05−3.96 (m, 2H), 2.86 (dq, J =

10.3, 7.2, 1H), 1.47 (s, 3H), 1.37 (s, 3H), 1.15 (d, J = 7.2, 3H), 1.12−

0.99 (m, 21H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.3, 142.4,

123.0, 109.8, 76.8, 74.4, 71.1, 65.3, 36.9, 26.2, 26.0, 17.9, 17.9, 17.4,

12.0; IR (ﬁlm) v 2943, 2868, 1744, 1650, 1463, 1370, 1264, 1085,

1063, 993, 885, 687 cm⁻¹; HRMS (ESI-TOF) m/z calcd for

C₂₁H₃₈NaO₅Si [M + Na⁺] 421.2386, found 421.2375.

Preparation of Caprolactones (−)-65 and (+)-67. The lactone

(−)-64 or (+)-66 (100 mg, 0.25 mmol) dissolved in a 60% aqueous

solution of AcOH (5 mL) was stirred for 24 h at 25 °C. Then the

reaction mixture was diluted with toluene (25 mL), and the solvents

were removed under reduced pressure. The residue was dissolved in

toluene (25 mL) and again concentrated under reduced pressure to

remove the remaining acetic acid and water. Puriﬁcation of the crude

product by column chromatography on silica gel using an MeOH/

CH₂Cl₂mixture as an eluent aﬀorded lactones (−)-65 or (+)-67 as

colorless crystals.

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(31) The increased amount of solvent had to be used due to poor

solubility of starting 4-formyloxy-azetidin-2-one xxviii in anhydrous

THF.

(32) The reduced yield is caused by the volatility of intermediate

(E)-4-(prop-1-en-1-yl)azetidin-2-one.

(33) The reduced yield is caused by the volatility of intermediate

(Z)-4-(prop-1-en-1-yl)azetidin-2-one.

(34) In these cases, collected fractions were diluted with toluene

(50% v/v) before removal of eluent under reduced pressure to avoid

HCO₂H concentration.

Z

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Article Doi

Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic Stereoselective Reactions of β-Lactams with Aldehydes: The Effect of the N-Methylimidazole Ligand

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