Total Synthesis of the Natural Herbicide MBH-001 and Analogues

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Accepted Article

Title: Total Synthesis of the Natural Herbicide MBH-001 and Analogues

Authors: Birgit Kuhn, David M. Barber, Hansjoerg Dietrich, Uwe Döller,

Michael G. Hoffmann, Dirk Schmutzler, Stefan Schnatterer,

Martin E. Maier, Tamer Kocakaya, and Marius Morkunas

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000294

Link to VoR: http://dx.doi.org/10.1002/ejoc.202000294

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10.1002/ejoc.202000294

European Journal of Organic Chemistry

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Total Synthesis of the Natural Herbicide MBH-001 and Analogues

Birgit Kuhn,*^[a]David M. Barber,^[a]Hansjörg Dietrich,^[a]Uwe Döller,^[a]Michael G. Hoffmann,^[a]Dirk

Schmutzler,^[a]Stefan Schnatterer,^[a]Martin E. Maier,*^[b]Tamer Kocakaya,^[b]Marius Morkunas^[b]

Dedication ((optional))

Abstract: The first total synthesis of the natural herbicide MBH-001

(1) is reported. Structurally it is a 2-methyloxazol-5(2H)-one with a (1-

hydroxyethyl) substituent at the 2-position. By relying on cyclic

nitrones, a flexible route to MBH-001 and relevant analogs was

developed. Key steps include the reaction of a 2-hydroxyimino ester

with an aldehyde to form a 5-oxo-2,5-dihydrooxazole 3-oxide. In an

aldol-type reaction, the anion of these cyclic nitrones reacted with an

aldehyde at the 2-position. A final reduction of the nitrone to the

corresponding imine using zinc led to the target compounds. The

cyclic nitrones are also accessible by reacting an -keto acid with an

oxime. These two versatile synthetic routes enabled us to prepare the

first MBH-001 analogues for structure activity relationship analysis of

the herbicidal efficacy. Thus, furthering our aim of developing new

herbicides to tackle the ever-growing problem of weed resistance.

cell division or pigment biosynthesis.²In order to confirm the

structure and to allow for the elucidation of the mode of action a

total synthesis of 1 was required. Ideally, the synthesis route

should be flexible enough to allow access to analogs for structure

activity studies. Quite recently, heterocyclic compounds called

conflamides, which also feature an N,O-acetal were isolated from

the mushroom Albatrellus confluens.³

Figure 1. Structure of the herbicide MBH-001 (1).

Introduction

A retrosynthesis (Scheme 1) for oxazolone 1 seems fairly simple.

Thus, reaction of -imino ester 2 with 3-hydroxybutanone (acetoin,

3) might lead to 1. In addition, oxazolones like 4a or 5 appear as

promising precursors. Thus, an aldol type reaction of 4a with

acetaldehyde might produce 1. Alternatively, alkylation of

oxazolone 5 under basic conditions might give rise to 1. The

problem is that such oxazolones can be present as tautomers

(Scheme 1), possibly resulting in the formation of regioisomers in

reactions.⁴Indeed, the regiochemistry of 5-oxazolones in the

reaction with electrophiles depends on the substituents on the

oxazolones, the type of electrophile and the reaction conditions.

For example, 2-aryl substituted azlactones 6a react with

nitrostyrenes 7 at the 2-position to form the oxazol-5(2H)-one 8.

In contrast, a sterically demanding tert-butyl substituent in 6b

directs the electrophile to the 4-position resulting in oxazol-5(4H)-

ones 9.⁵

Whilst the search for novel biologically active natural products is

time consuming, it can be worth the effort. This process may result

in lead structures and the discovery of new targets for

pharmaceutical or agrochemical research. Nevertheless, a lack of

chemical methods to synthesize the desired natural product can

pose a significant problem and prevent the new lead from being

further developed. This way scientists at Bayer Crop Science

came across the natural product MBH-001, 2-(1-hydroxy-ethyl)-4-

isobutyl-2-methyloxazol-5(2H)-one (1) in a Japanese patent

application¹(Figure 1). It was reported that this heterocycle is

produced by an insect symbiotic microorganism N1-Ishi-YC50807.

Compound 1 is an unique natural product with reported strong

herbicidal activity (200 g/ha) against monocots and dicots.

Regarding the mode of action of MBH-001 (1) nothing was

mentioned. Typical modes of action of herbicides are inhibition of

photosynthesis, fatty acid biosynthesis, amino acid biosynthesis,

[a]

Dr. Birgit Kuhn, Dr. David M. Barber, Dr. Hansjörg Dietrich, Dr. Uwe

Döller, Dr. Michael G. Hoffmann, Dr. Dirk Schmutzler, Dr. Stefan

Schnatterer

Bayer AG, Crop Science Division, Research & Development (R&D),

SMol, Industriepark Höchst, 65926 Frankfurt am Main, Germany

E-mail: Birgit.Kuhn@bayer.com

http://www.bayer.com

[b]

Prof. Dr. Martin E. Maier, Tamer Kocakaya, M.Sc., Dr. Marius

Morkunas

Eberhard Karls Universität Tübingen, Institut für Organische

Chemie, Auf der Morgenstelle 18, 72076 Tübingen, Germany

E-mail: martin.e.maier@uni-tuebingen.de

http://www.oc1.chemie.uni-tuebingen.de/

Supporting information for this article is given via a link at the end of

the document.((Please delete this text if not appropriate))

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Scheme 2. Synthesis of oxazol-5(2H)-ones 13a – 13c by aldol type reactions

of oxazol-5(4H)-one 4b with aromatic aldehydes 12a – 12c.

Unfortunately, the reaction of oxazolone 4b with acetaldehyde

under identical conditions took a different course (Scheme 3).

Thus, it seems hydroxyalkylation takes places at C4 to form

intermediate A. This intermediate could not be isolated since it

reacted with another acetaldehyde molecule to intermediate B

followed by opening of the oxazolone ring and formation of 1,3-

dioxanone 14, whose structure was confirmed by a single crystal

X-ray diffraction. We cannot rule out that other stereoisomers are

formed in this transformation. The aldol-like reaction between 4b

and acetaldehyde might be diastereoselective leading to

intermediate A. The formation of postulated intermediate B

certainly is an equilibrium reaction and only the indicated isomer

might then cyclize to the dioxanone 14.

Scheme 1. Retrosynthetic considerations for MBH-001 (1) and the issue of

regioselectivity in reactions of oxazolones with electrophiles.

Results and Discussion

Initial studies were performed on oxazolone 4b, obtained by the

Steglich method from acylated amino acid⁶10 using water soluble

carbodiimide⁷11 (Scheme 2). Reaction of aromatic aldehydes

12a-c with oxazolone 4b (isomer of 4a) in the presence of

triethylamine or diisopropylethylamine (Hünig's base) provided

the desired addition products with the carbinol connected to C-2

(Scheme 2). However, preliminary tests showed that these aryl

analogs 13a-13c of MBH-001 have no significant herbicidal

activity.

Scheme 3. Reaction of oxazol-5(4H)-one 4b with acetaldehyde leading to

dioxanone 14 containing two molecules of acetaldehyde. Some of the atoms of

the dioxanone derivative 14 are numbered.

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Eventually, by taking recourse to nitrones, two solutions to the

synthesis of MBH-001 and related structures could be found. In

this context, a paper by Bode et al. provided a good starting point.⁸

They reported the formation of 2,5-dihydrooxazole 3-oxides by

reaction of -keto acids with oximes. In their case, these

heterocycles were used to protect the -keto acid. The latter could

be regenerated by reduction of the cyclic nitrone with zinc

followed by treatment with acid. Accordingly, we hoped that with

this strategy MBH-001 (1) would be accessible. First, we prepared

oxime 15 by reacting acetoin (3) with hydroxylamine according to

a known procedure (Scheme 4).⁹While several methods for the

synthesis of -keto acids are known in the literature,¹⁰we opted

for the preparation of 20 from L-leucine (16) via the intermediate

methyl 2-hydroxy-4-methylpentanoate (18). Thus, diazotation of

amino acid¹¹16 led to -hydroxy acid 17. After its conversion to

methyl ester 18 using SOCl₂in methanol, the secondary alcohol

of 18 was oxidized using sodium hypobromite¹²to give methyl 4-

methyl-2-oxopentanoate ¹³(19). Basic hydrolysis of ester 19

furnished keto acid¹⁴20.

Reaction of keto acid 20 and oxime 15 (1.5 equiv.) turned out to

be quite sluggish. The reaction required 3 d in refluxing

dichloroethane to get full consumption of both reaction partners.

Despite this, only a moderate yield of 31% for the cyclic nitrones

21 could be obtained. The nitrones 21 were obtained as a

separable mixture of diastereomers in a 1:1 ratio. Next, the

isomers 21a and 21b were separately submitted to the reduction

of the nitrone functionality to the corresponding imine. Indeed,

treatment of the nitrones with activated zinc in the presence of

aqueous NH₄Cl solution gave the MBH-001 diastereomers 1a and

1b. Characteristic ¹H NMR data for isomer 1a, obtained from the

less polar nitrone 21a are a quartet for 1''-H (methine H) of the 1-

hydroxyethyl sidechain at 3.90 ppm. The 2-CH₃group appears at

1.58 ppm. The corresponding shift values for 1b are 3.83 and 1.56

ppm. In the ¹³C NMR spectrum, 1a and 1b also have similar

chemical shifts. For example C2 and C1' of 1a appear at 107.3

and 20.7 ppm whereas in 1b the corresponding values are 107.6

(C2) and 20.1 (C1') ppm.

Scheme 4. First generation synthesis of MBH-001 (1) via nitrones 21, obtained

from keto acid 20 and oxime 15.

The structure data of MBH-001 (1) could be confirmed as well as

the biological efficacy cited in the old patent application¹published

by Mitsubishi Petrochemicals. A detailed evaluation of the

biological data has been published.¹⁵

In order to analyze the SAR and different prodrug types, the

hydroxyl group of the oxazolone side chain has been derivatized

under standard conditions starting from the cyclic nitrones of type

21 or other MBH-001 analogs to form esters, carbonates and

urethanes (vide infra). The prepared nitrone esters could be

reduced to the oxazolones in medium to good yields. Some

examples can later be found in Schemes 12 and 14. These

derivatizations also helped us to assign the absolute

stereochemistry of the active isomer of MBH-001 (1), which has

not yet been published. Luckily, the 4-fluorobenzoyl derivative

22b of the more polar diastereomer formed crystals suitable for

X-ray analysis (Scheme 5). Moreover, the less polar MBH-001 (1)

isomer, after being converted to the carbamate 23a using 4-

bromophenyl isocyanate could also be crystallized.

All the X-ray structures shown from this paper were deposited in

the Cambridge Structural Database.^16,17These files contain the

supplementary crystallographic data for this paper. The data can

be obtained free of charge from The Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/structures.

Finally, the MBH-001 diastereomers were separated by chiral

HPLC [Chiralpak IC]. After conversion to the bromobenzoyl

derivatives, X-ray analyses secured the absolute configurations.

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Growth inhibition studies in duckweed (Lemna) showed that only

the more polar rel-(S,R)-diastereomer of MBH-001 (1) is

biologically active. Other in vivo studies confirmed that the active

enantiomer of 1 has the S,R-configuration.

Scheme 5. Determination of the relative and absolute configuration of MBH-001

and its congeners by X-ray. Growth inhibition assay shows that only one

diastereomer is active, the isomer corresponding to 24b.

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Scheme 6. Alternative route to nitrone 21 and MBH-001 (1) via aldol-type

reaction of nitrone 29 with acetaldehyde.

As we wanted to have access to some MBH-001 analogs for SAR

studies, a more flexible route was sought. We therefore

considered an alternative formation of cyclic nitrones. ¹⁸In a

model study the hydroxyimino ester ¹⁹25, derived from ethyl

pyruvate was reacted with cyclohexanone under various

conditions (Scheme 6). Best results were obtained by stirring 25

and cyclohexanone in toluene and adding 0.65 equiv. of aqueous

NaOH which gave rise to cyclic nitrone 26 in 50% yield. However,

other ketones like acetoin (3), TBS-protected acetoin,²⁰and 1-

(benzyloxy)-2-propanone ²¹did not give the desired products.

Based on the literature precedence we hoped that aldehydes

would react better with 2-hydroxyimino esters as compared to

ketones. First, methyl L-leucinate²²(27) was oxidized with H₂O₂

in the presence of sodium tungstate²³to oxime²⁴28. In the next

step, oxime 28 was reacted with acetaldehyde under basic

conditions by adding 0.1 M NaOH in portions to the mixture. Using

this method saponification of the ester could be largely

suppressed. Under these conditions, cyclic nitrone 29 was

obtained in 73% yield. The crucial question was now whether the

anion of azlactone derivative 29 would react with aldehydes at the

2 or 4 position. Gratifyingly, deprotonation of 29 with lithium

hexamethyldisilazide [LiN(SiMe₃)₂] at –78 °C followed by addition

of acetaldehyde exclusively gave the desired C2 addition product

21. In this case, also a 1:1 mixture of diastereomers was obtained.

The synthesis of MBH-001 (1) was completed by reduction of the

nitrone to the imine. Preliminary experiments showed that the

base can have an influence on the stereoselectivity of the aldol

We have also found an alternative route (Bode variant) being

more flexible to introduce different substituents starting from keto

acid 20 directly and condensing first with acetaldehyde oxime²⁶

(31) to get to type nitrone 29 in yields up to 67% after

chromatography (Scheme 7).

Scheme 7. Alternative route to nitrone 29 from keto acid 20 and acetaldehyde

oxime (31).

We felt that this strategy – formation of the cyclic nitrones,

followed by aldol type reaction with aldehydes – should allow for

the synthesis of several MBH-001 analogs. This was largely the

case - with certain limitations. For example, if sterically hindered

aldehydes are employed in the aldol-like reaction, the primary

addition product can undergo rearrangement to the six-

membered nitrone as was observed in the reaction of nitrone 29

with isobutyraldehyde (32) (Scheme 8). Thus, alkoxide C will form

tetrahedral intermediate D that collapses to the 6-oxo-3,6-

dihydro-2H-1,4-oxazine 4-oxide 33 and then converts to its ring

opened isomer. In this transformation, a formal umpolung of

acetaldehyde was realized. The ring opened form is clearly

evident from the carbonyl peak at  = 204.6 ppm in the ¹³C NMR

spectrum.

reaction. Thus, if nitrone 29 is deprotonated with the Schwesinger

25

base

30 (tert-butylimino-tri(pyrrolidino)phosphorane), the

reaction with acetaldehyde gave diastereomer 21a as the major

product (21a/21b = 3:1). Other bases than Schwesinger base and

LiHMDS can be used as well, for example tetramethylguanidine.

Scheme 8. Reaction of nitrone 29 with isobutyraldehyde (32).

According to this plan, various oximes (hydroxyimino esters) 34 –

37 were prepared (Scheme 9). Compounds 34 – 36 were

obtained by oxidation of the corresponding amino acid esters (cf.

Scheme 6). The yields are listed after the compound numbers.

Pyridyloximoester 37 was prepared by nitrosation of the

corresponding pyridylacetic acid ester.²⁷

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Scheme 9. Collection of hydroxyimino esters used for formation of cyclic

nitrones.

The hydroxyimino esters were then condensed with an aldehyde

to form the cyclic nitrones shown in Scheme 10. Phenyloxazolone

41 has been prepared from oxime ester 36, which was generated

from methyl phenylglycinate or by the condensation method

shown in Scheme 7 using 2-oxo-2-phenylacetic acid and oxime

31. Nitrone 43 was prepared from 4,4-dimethyl-2-oxopentanoic

acid²⁸and acetaldehyde oxime (31).

Scheme 11. Collection of aldol-type products obtained by deprotonation of the

cyclic nitrones and trapping the anions with carbonyl compounds. The possible

diastereomers are shown for nitrone aldol product 52.

With the nitrone aldol products in hand, a range of MBH-001

analogs could be obtained (Scheme 12). Again, reduction of the

nitrone functionality using activated zinc as the reducing agent

was the method of choice to obtain the oxazolones 55 – 63.

Unfortunately both diastereoisomers 54 decomposed during

reduction to the final compounds. Nitrone 48 was reduced to the

oxazolone 13b (63%) obtained by hydroxyalkylation of azlactone

4b with 4-chlorobenzaldehyde. The structure was in accordance

with the azlactone reaction product described earlier.

Scheme 10. Collection of 5-oxo-2,5-dihydrooxazole 3-oxides that were used in

this study.

Via deprotonation of the cyclic nitrones and reaction of the

corresponding anions with aldehydes the compounds 44 – 54

were obtained (Scheme 11). The aldehyde required for the

preparation of 46, but-3-enal was prepared according to a

literature procedure.²⁹Typically, the aldol-type reaction led to the

formation of two diastereomers. In Scheme 11, these are shown

for compounds 52a and 52b. Their structures were tentatively

assigned based on the analysis of 21a and 21b (vide supra). The

isomers a are less polar and move further on the TLC plate (silica

gel) than the corresponding b isomers. For 44 only isomer 44b

was isolated in pure form. Aldol products 45 and 48 were formed

as unseparable mixture of diastereomers. For the nitrones 46, 50,

51, 52, 53 and 54 the mixtures could be separated by

chromatography. In case of nitrone 49 essentially only one isomer

was formed.

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Scheme 12. Selection of prepared MBH-001 analogs that were obtained by

reduction of the nitrone functionality. The possible diastereomers are shown for

oxazolone 62.

Scheme 13. Selection of nitrone derivatives, obtained by converting the side

chain hydroxyl group to esters, urethanes and carbonates.

As mentioned before, in order to analyze the SAR and to explore

different prodrug types, the hydroxyl group of the oxazolone side

chain has been derivatized under standard conditions, starting

from the cyclic nitrones of type 21 or other MBH-001 analogs to

form esters (64, 65, 22b, 67, 69), carbonates (68) and urethanes

(66b) (Scheme 13).

Afterwards the nitrone esters were reduced with zinc to afford the

oxazolones 70–74, and 23 in medium to good yields. Some

examples can be found in Scheme 14.

Scheme 14. Selection of prepared MBH-001 analogs were the hydroxyl group

was derivatized, obtained by reduction of the nitrone functionality.

All prepared ester and carbonate prodrugs (Scheme 14) did not

show any significant improved biological activity compared to the

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ratio = 93:7)  = 0.90, 0.92 (2d, J = 6.7 Hz, 6H, 3'-H), 2.05–2.14 (m, 1H,

2'-H), 2.34–2.42 (m, 2H, 1'-H), 3.15 (bs, 1H, OH), 7.24–7.39 (m, 5H, Ph);

major isomer: 1.53 (s, 3H, 2-CH₃), 4.85 (s, 3H, 1''-H); minor isomer: 1.45

(s, 3H, 2-CH₃), 4.82 (s, 1H, 1''-H) ppm; ¹³C NMR (150 MHz, CDCl₃):

(isomeric ratio = 93:7)  = 21.5, 22.3, 22.4 (C-3', 2-CH₃), 26.3 (C-2'), 36.4

(C-1'), 77.1 (C-1''), 106.8 (C-2), 127.9, 128.1, 128.5, 137.3 (Ph), 164.1 (C-

4), 164.5 (C-5); minor isomer: 76.5 (C-1'), 106.4 (C-2), 137.3 (Ph), 164.1

(C-4), 165.5 (C-5) ppm.

corresponding MBH analogs in the greenhouse. The urethanes

were not biologically active at all.

Conclusions

The natural herbicide MBH-001 (1) features a 2-methyloxazol-

5(2H)-one core with a (1-hydroxyethyl) substituent at the 2-

position. While it was not possible to access this structure via

azlactone precursors, the N-oxide of azlactones (cyclic nitrones)

served this purpose well. The cyclic nitrones, 2-alkyl-5-oxo-2,5-

dihydrooxazole 3-oxides were obtained from 2-hydroxyimino

esters, obtained by oxidation of -amino acid esters, and an

aldehyde under basic conditions. It was found that the cyclic

nitrones can be deprotonated and the anion trapped with an

aldehyde to give the derivatives with the 1-hydroxyalkyl

substituent at the 2-position of the 2-alkyl-5-oxo-2,5-

dihydrooxazole 3-oxides. A final reduction of the nitrone with

activated zinc furnished MBH-001. Using this strategy, several

analogs were prepared. It seems that with the nitrone function,

the C=N double bond stays in place and the issue of regiocontrol

in the reaction with electrophiles, like with the azlactones, was not

observed. Further reactions of the cyclic nitrones (cycloaddition³⁰

or organocatalytic Michael reactions) are under investigation.

2-((4-Chlorophenyl)(hydroxy)methyl)-4-isobutyl-2-methyloxazol-5(2H)-

one (13b). Under nitrogen, azlactone 4b (0.250 g, 1.61 mmol) in CH₂Cl₂

(20 mL) was cooled down to –15 °C. Then, 4-chlorobenzaldehyde (12b)

(0.238 g, 1.69 mmol) was added followed by catalytic quantities of N-

ethyldiisopropylamine (21.0 mg, 0.16 mmol). The reaction mixture was

stored for 1 d at –18 °C before it was diluted with CH₂Cl₂and washed with

KH₂PO₄buffer and water. The organic layer was dried over Na₂SO₄,

filtered and concentrated in vacuo. The residue was purified by medium

pressure column chromatography on silica (Biotage SP1, gradient

heptane/EtOAc from 0–50% EtOAc) to give oxazol-5(2H)-one 13b (0.343

g, 65%, purity 90%) as a colorless oil; R_t= 1.48 (HPLC); ¹H NMR (600

MHz, CDCl₃): (isomeric ratio = 64:36)  = 0.92, 0.94 (2 d, J = 6.7 Hz, 6H,

3'-H), 1.51 (s, 3H, 2-CH₃), 2.09–2.16 (m, 1H, 2'-H), 2.40–2.46 (m, 2H, 1'-

H), 4.81 (s, 1H, 1''-H), 7.30–7.34 (m, 4H, Ar-H), minor: 1.46 (s, 3H, 2-CH₃),

4.81 (s, 1H, 1''-H) ppm; ¹³C NMR (150 MHz, CDCl₃): (isomeric ratio =

64:36)  (major) = 21.3, 22.3, 22.5, 26.4 (C-3', C-2', 2-CH₃), 36.6 (C-1'),

76.8 (C-1''), 106.4 (C-2), 128.4, 129.2, 134.6, 135.8, (Ar C), 164.4 (C-4),

165.3 (C-5), minor: 21.3, 22.3, 22.4, 26.3 (C-3', C-2', 2-CH₃), 36.6 (C-1'),

76.2 (C-1''), 106.2 (C-2), 128.5, 129.2, 134.7, 135.7, 164.2 (C-4), 165.3 (C-

5) ppm.

Experimental Section

Alternative synthesis of oxazolone 13b via nitrone 48. According to general

procedure 1, nitrone 48 (150 mg, 0.48 mmol) (low/high = 1:1) was

dissolved in THF (11 mL) and water (6 mL) and the resulting solution was

treated with activated zinc powder (189 mg, 2.88 mmol). After the addition

of NH₄Cl solution (154 mg, 2.88 mmol in 5.4 mL water), the grey

suspension was stirred vigorously for 60 min at r. t. Then the reaction

mixture was diluted with EtOAc, filtered through a pad of celite, which was

rinsed with EtOAc several times. The collected organic phases were

extracted with water, dried over Na₂SO_4,filtered, washed and concentrated

in vacuo to give oxazolone 13b (100 mg, 63%, 90% purity). The analytical

data were identical with the azlactone procedure; R_t= 1.52 (HPLC); HRMS

(ESI-TOF): calcd. for C₁₅H₁₈ClNO₃[M + H]⁺296.1053, found 296.1055.

General. HPLC-retention times refer to a Waters Acquity UPLC with

Sample Organizer, column: Zorbax Eclipse+ C18, 3 × 50mm; 0.1%

aqueous HCO₂H and acetonitrile (ACN, MeCN) as eluent (linear gradient

from 10% acetonitrile to 95% acetonitrile). Scheme 6 and Schemes 11–

14: To differentiate the diastereomers, the term "upper" and "lower" are

used. The term "upper diastereomer" refers to the less polar isomer,

whereas "lower diastereomer" refers to the more polar isomer on TLC.

(S)-4-Isobutyl-2-methyloxazol-5(4H)-one⁷(4b). Under

a

nitrogen

atmosphere N-acetyl-L-leucine (10) (1000 mg, 5.77 mmol) and EDCl

(1107 mg, 5.77 mmol) were dissolved at 0 °C in of diethyl ether (37 mL)

and directly hydrolyzed with ice cold water after 15 min. The reaction

mixture was washed once with 0 °C cold saturated NaHCO₃solution and

twice with ice water. The organic layer was dried over Na₂SO₄, filtered,

and concentrated in vacuo to give oxazolone 4b (250 mg, 27%) as a

2-((6-Chloropyridin-3-yl)(hydroxy)methyl)-4-isobutyl-2-methyloxazol-

5(2H)-one (13c). Under nitrogen, azlactone 4b (0.500 g, 3.22 mmol) in

CH₂Cl₂(20 mL) was cooled down to –15 °C. Then, 6-

chloronicotinaldehyde (12c) (0.479 g (3.38 mmol) was added followed by

N-ethyldiisopropylamine (0.416 g, 3.22 mmol). The reaction mixture was

stored for 2 d at –18 °C before it was diluted with CH₂Cl₂and washed with

KH₂PO₄buffer and water. The organic layer was dried over Na₂SO₄,

filtered and concentrated in vacuo. The residue was purified by medium

pressure column chromatography on silica (Biotage SP1, gradient

heptane/EtOAc from 30–100% EtOAc) to give oxazol-5(2H)-one 13c

(0.260 g, 26%, purity 95%) as a white solid; R_t= 1.28, 1.28 (HPLC); ¹H

NMR (600 MHz, CDCl₃): (isomeric ratio = 73:27)  = 0.92–0.97 (m, 6H, 3'-

H), 1.46, 1.49 (s, 3H, 2-CH₃), 2.12–2.22 (m, 1H, 2'-H), 2.41–2.50 (m, 2H,

1'-H), 4.83, 4.89 (s, 1H, 1''-H), 7.32–7.48 (m, 1H, pyridine), 7.72–7.79 (m,

1H, pyridine), 8.35–8.38 (m, 1H, pyridine) ppm; ¹³C NMR (150 MHz,

CDCl₃): (isomeric ratio = 73:27)  (major) = 21.2, 22.4, 22.5, 26.4 (C-3', C-

2', 2-CH₃), 36.6 (C-1'), 74.5 (C-1''), 106.0 (C-2), 124.1, 132.3, 138.5, 149.1,

151.6 (Ar C), 164.4 (C-9), 165.2 (C-5), minor: 20.9, 22.3, 22.4, 26.3 (C-3',

C-2', 2-CH₃), 36.6 (C-1'), 74.1 (C-1''), 106.0 (C-2), 124.2, 132.3, 138.5,

149.0, 151.7 (Ar C), 164.6 (C-4), 165.1 (C-5) ppm.

1

colorless oil; H NMR (600 MHz, CDCl₃):  = 0.95, 0.92 (2 d, J = 6.7 Hz,

6H, 3'-H), 1.50–1.55 (m, 1H, 1'-H_A), 1.66–1.72 (m, 1H, 1'-H_B), 1.95 (hept,

J = 6.8 Hz, 1H, 2'-H), 2.19 (s, 3H, 2-CH₃), 4.13–4.15 (m, 1H, 4-H). The

compound should be stored in a deep freezer and directly used for the next

steps.

2-(Hydroxy(phenyl)methyl)-4-isobutyl-2-methyloxazol-5(2H)-one

(13a).

Under nitrogen, azlactone 4b (2.00 g, 12.8 mmol) in CH₂Cl₂(8 mL) was

cooled down to –20 °C. Then trimethylamine (1.304 g, 1.80 mL, 12.8

mmol) was added followed by benzaldehyde (12a) (1.641 g, 1.58 mL, 15.4

mmol). The reaction mixture was stored for 11 d at –18 °C. Then the

reaction mixture was diluted with CH₂Cl₂and washed with KH₂PO₄buffer

and water. The organic layer was dried over Na₂SO₄, filtered and

concentrated in vacuo. The residue was purified by medium pressure

column chromatography on silica (Biotage SP1, gradient heptane/EtOAc

from 0–50% EtOAc) to give oxazol-5(2H)-one 13a (1.07 g, 32%) as a white

solid; mp = 71 °C; R_t= 1.20 (HPLC); ¹H NMR (600 MHz, CDCl₃): (isomeric

10.1002/ejoc.202000294

European Journal of Organic Chemistry

FULL PAPER

rel-N-[(2S,4R,5R)-5-Isobutyl-2,4-dimethyl-6-oxo-1,3-dioxan-5-

Methyl 4-methyl-2-oxopentanoate (19). NaOH (6.45 g, 0.16 mol) was

dissolved in water (80 mL) and then the solution was cooled to –5 °C.

Bromine (4.15 mL, 80.8 mmol) was added dropwise within 2 h so that the

temperature did not exceed 0 °C. Subsequently, a solution of hydroxy ester

18 (9.07 g, 62.1 mmol) in CH₂Cl₂(80 mL) was added to the generated

NaOBr solution dropwise while keeping the temperature below 0 °C.

Thereafter, concentrated HCl solution (1.56 mL, 18.7 mmol) was added

within a 15 min period at the same temperature. The ice-bath was removed

and the resulting two-phase orange solution was stirred overnight before

it was extracted with CH₂Cl₂(3 × 500 mL). The combined organic layers

were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue

was distilled at 30 °C under reduced pressure (1 mbar) to give -keto

ester¹³19 (6.0 g, 67%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃):  =

0.94 (d, J = 6.7 Hz, 6H, 5-H), 2.18 (qqt, J = 6.7, 6.7, 6.7 Hz, 1H, 4-H), 2.70

(d, J = 6.7 Hz, 2H, 3-H), 3.84 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 22.4 (C-5), 24.1 (C-4), 47.9 (OCH₃), 52.9 (C-3), 161.7 (C-1),

194.0 (C-2) ppm.

yl]acetamide (14). Under nitrogen, azlactone 4b (1.93 g, 12.4 mmol) in

CH₂Cl₂(8 mL) was cooled down to –20 °C. Then triethylamine (1.29 g,

1.78 mL, 12.4 mmol) was added, followed by acetaldehyde (0.822 g, 1.05

mL, 18.6 mmol). The reaction mixture was stored for 11 d at –18 °C before

it was diluted with CH₂Cl₂and washed with KH₂PO₄buffer and water. The

organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.

The residue was purified by medium pressure column chromatography on

silica (Biotage SP1, gradient heptane/EtOAc from 20% to 40% EtOAc) to

give dioxanone 14 (750 mg, 25%) as a white solid; mp = 130.7 °C; R_t=

1.04 (HPLC); ¹H NMR (600 MHz, CDCl₃):  = 0.94 (d, J = 6.6 Hz, 3H, 3'-

H), 1.03 (d, J = 6.6 Hz, 3H, 3-H), 1.24 (d, J = 6.6 Hz, 3H, 4-CH₃), 1.49–

1.53 (m, 1H, 1'-H_A), 1.72 (d, J = 5.7 Hz, 3H, 2-CH₃), 1.89–1.94 (m, 2H, 1'-

H_B, 2'-H), 2.01 (s, 3H, acetyl), 4.94 (q, J = 6.4 Hz, 1H, 4-H), 5.74 (bs, 1H,

NH), 5.75 (q, J = 5.6 Hz, 1H, 2-H) ppm; ¹³C NMR (150 MHz, CDCl₃):  =

14.2 (4-CH₃), 20.0 (2-CH₃), 23.2 (CH₃C=O) 23.3 (C-3'), 24.0 (C-2'), 24.6

(C-3'), 40.2 (C-1'), 60.3 (C-N (C-5)), 67.1 (C-4), 99.4 (C-2), 168.7, 170.09

(C-6, C=O acetamide) ppm; HRMS (ESI-TOF): calcd. for C₁₁H₁₉NO₄[M +

H]⁺230.1392, found 230.1393.

4-Methyl-2-oxopentanoic acid (20). To a solution of -keto ester 19 (2.0 g,

13.9 mmol) in MeOH (5 mL) was added a solution of NaOH (555 mg, 13.9

mmol) in water (10 mL) at 0 °C. Thereafter, the ice-bath was removed, and

the solution was stirred at 60 °C for 1.5 h. When TLC analysis showed full

conversion, the mixture was cooled down to 0 °C and acidified to pH = 1

using 15% HCl solution before it was extracted with EtOAc (3 × 100 mL).

The combined organic layers were dried over Na₂SO₄, filtered and

concentrated in vacuo to give -keto acid¹⁴20 (1.75 g, 97%) as a slightly

3-Hydroxybutan-2-one oxime (15). A suspension of 3-hydroxy-butan-2-

one (5.00 g, 56.7 mmol, 1 equiv), NH₂OH·HCl (9.57 g, 138 mmol, 2.4

equiv) and NaOAc (11.5 g, 140 mmol, 2.5 equiv) in EtOH (120 mL) and

H₂O (50 mL) was heated under reflux (90 °C) for 3 h. The mixture was

cooled to r.t. and stirred for 1.5 h at r.t. before saturated aqueous NaHCO₃

solution (75 mL) was added and the mixture was extracted with CH₂Cl₂/i-

PrOH 3:1 (4 × 200 mL). The combined organic layers were dried over

Na₂SO₄, filtered and concentrated in vacuo. The resulting yellow oil can be

distilled under reduced pressure (17 mbar, 160 °C) or purified by flash

chromatography (EtOAc/petroleum ether, 2:1) to furnish 3-hydroxy-butan-

2-one-oxime (15) (4.43 g, 43.0 mmol, 76%) as a colorless highly viscous

oil which formed a white solid upon cooling. ¹H NMR (DMSO-d₆, 400 MHz):

 = 1.13 (d, J = 6.5 Hz, 3H, 4-H), 1.69 (s, 3H, 1-H), 4.13 (q, J = 6.5 Hz, 1H,

1-H), 4.95 (bs, 1H, OH), 10.34 (bs, 1H, =NOH) ppm; ¹³C NMR (DMSO-d₆,

100 MHz):  = 8.7 (C-1), 20.8 (C-4), 67.7 (C-3), 158.4 (C-2) ppm.

1

yellowish oil of sufficient purity to be used in the next step. H NMR (400

MHz, CDCl₃):  = 0.97 (d, J = 6.7 Hz, 6H, 5-H), 2.21 (qqt, J = 6.7, 6.7, 6.7

Hz, 1H, 4-H), 2.82 (d, J = 6.8 Hz, 2H, 3-H), 8.32 (br s, 1H, OH) ppm; ¹³

C

NMR (100 MHz, CDCl₃):  = 22.4 (C-5), 24.4 (C-4), 45.9 (C-3), 160.2 (C-

1), 195.4 (C-2) ppm.

rel-(S)-2-((S)-1-Hydroxyethyl)-4-isobutyl-2-methyl-5-oxo-2,5-dihydro-

oxazole-3-oxide (21a) and rel-(S)-2-((R)-1-Hydroxyethyl)-4-isobutyl-2-

methyl-5-oxo-2,5-dihydrooxazole-3-oxide (21b). A mixture of 4-methyl-2-

oxopentanoic acid (20) (470 mg, 3.6 mmol) and 3-hydroxybutan-2-one

oxime (15) (560 mg, 5.4 mmol, 1.5 equiv) in dichloroethane (10 mL) was

refluxed for 3 d before it was cooled to r.t. and all volatiles were removed

under reduced pressure. After purification by flash chromatography

(petroleum ether/EtOAc, 3:1) the heterocycles 21a and 21b were obtained

in a ratio of 1:1 as a colorless oils, which solidified upon standing (240 mg,

31%).

(S)-2-Hydroxy-4-methylpentanoic acid (17). L-Leucine (16) (30.0 g, 0.23

mol) was dissolved in H₂SO₄(2M, 230 mL) and the solution cooled down

to 0 °C. Then a solution of NaNO₂(95.0 g, 1.38 mol, 6 equiv) in water (250

mL) was added slowly so that the reaction temperature does not exceed

5 °C (N₂outgassing). After complete addition, the reaction mixture was left

to stir for 3 h at 0 °C before it was allowed to reach r.t. slowly overnight.

The mixture was extracted with Et₂O (3 × 1 L) and the combined organic

layers were dried with MgSO₄, filtered, and concentrated in vacuo. The

residue was recrystallized from a mixture of petroleum ether/Et₂O to

produce hydroxy acid¹¹17 (20.6 g, 68%) as a yellow solid. ¹H NMR (400

MHz, CDCl₃):  = 0.96 (d, J = 6.7 Hz, 6H, 5-H), 1.56–1.68 (m, 2H, 3-H),

1.90 (qqdd, J = 6.9, 6.9, 6.7, 6.7 Hz, 1H, 4-H), 4.29 (dd, J = 8.3, 5.1 Hz,

1H, 2-H), 7.01 (br s, 1H, OH) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 21.4,

23.2, 24.4 (C-4, C-5), 43.2 (C-3), 68.9 (C-2), 180.6 (C-1) ppm.

Upper diastereomer 21a. R_f= 0.39 (petroleum ether/EtOAc, 2:1); ¹H NMR

(400 MHz, CDCl₃):  = 0.95 (2 d, J = 6.7 Hz, 6H, 3''-H), 1.29 (d, J = 6.4 Hz,

3H, 2'-H), 1.77 (s, 3H, 2-CH₃), 2.18 (qqdd, J = 7.1, 7.1, 6.7, 6.7 Hz, 1H, 2''-

H), 2.45 (dd, J = 13.9, 7.1 Hz, 2H, 1''-H), 3.18 (d, J = 3.9 Hz, 1H, OH), 3.94

(qd, J = 6.4, 3.9 Hz, 1H, 1'-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 16.5,

18.4, 22.4, 22.5, 26.3, 30.7 (2-CH₃, C-1'', C-2'', C-2', C-3''), 71.6 (C-1'),

104.5 (C-2), 131.3 (C-4), 164.3 (C-5) ppm; HRMS (ESI-TOF): calcd. for

C₁₀H₁₇NO₄[M + Na]⁺238.10498, found 238.10519.

Methyl (S)-2-hydroxy-4-methylpentanoate (18). To a solution of hydroxy

acid 17 (10.0 g, 75.7 mmol) in MeOH (70 mL) was added thionyl chloride

(8.4 mL, 0.12 mol) slowly at 0 °C. After complete addition, the ice-bath was

removed and the reaction mixture refluxed for 2 h. After the solution had

reached r.t., ice-water (500 mL) was added and the mixture extracted with

EtOAc (3 × 500 mL). The combined organic layers were dried with Na₂SO₄,

filtered and concentrated in vacuo to provide pure hydroxy ester^11b18

(9.08 g, 82%) as an oil. ¹H NMR (400 MHz, CDCl₃):  = 0.92, 0.94 (2 d, J

= 6.7 Hz, 6H, 5-H), 1.49–1.59 (m, 2H, 3-H), 1.87 (qqdd, J = 6.9, 6.9, 6.7,

6.7 Hz, 1H, 4-H), 2.74 (br s, 1H, OH), 3.77 (s, 3H, OCH₃), 4.20 (dd, 7.9,

5.4 Hz, 1H, 2-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 21.5, 23.2, 24.4

(C-4, C-5), 43.5 (C-3), 52.4 (OCH₃), 69.0 (C-2), 176.3 (C-1) ppm.

Lower diastereomer 21b. R_f= 0.31 (petroleum ether/EtOAc, 2:1); ¹H NMR

(400 MHz, CDCl₃):  = 0.95 (2 d, J = 6.7 Hz, 6H, 3''-H), 1.34 (d, J = 6.6 Hz,

3H, 2'-H), 1.71 (s, 3H, 2-CH₃), 2.12 (d, J = 8.2 Hz, 1H, OH), 2.18 (qqdd, J

= 6.9, 6.9, 6.8, 6.8 Hz, 1H, 2''-H), 2.45 (dd, J = 13.8, 7.4 Hz, 2H, 1''-H),

4.17 (qd, J = 8.1, 6.6 Hz, 1H, 1'-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  =

17.0, 20.6, 22.4, 22.5, 26.2, 30.7 (2-CH₃, C-1'', C-2'', C-2', C-3''), 68.6 (C-

1'), 105.6 (C-2), 131.8 (C-4), 165.0 (C-5) ppm; HRMS (ESI-TOF): calcd.

for C₁₀H₁₇NO₄[M + Na]⁺238.10498, found 238.10531.

rel-(S)-2-((R)-1-((4-Fluorobenzoyl)oxy)ethyl)-4-isobutyl-2-methyl-5-oxo-

2,5-dihydrooxazole 3-oxide (22b). To a solution of nitrone 21b (1.30 g,

6.04 mmol) in dry acetonitrile (6 mL) under nitrogen atmosphere were

10.1002/ejoc.202000294

European Journal of Organic Chemistry

FULL PAPER

consecutively added at 0 to –10 °C, N,N-diisopropylethylamine (1.51 g,

12.00 mmol), DMAP (0.221 g, 1.81 mmol) and then 4-fluorobenzoyl

chloride (1.053 g, 6.64 mol). The reaction was held for 2 h at 0 °C and

warmed up to room temperature. After 2 d, the reaction mixture was diluted

with EtOAC and extracted with water. The organic layer was dried over

Na₂SO₄, filtered, rinsed and concentrated in vacuo. The residue was

purified by flash chromatography on silica (Biotage Isolera, gradient

heptane/EtOAc) to give fluorobenzoate 22b (0.970 g, 48%) as a white solid

(mp = 80.5 °C); R_t= 1.61 min (HPLC); ¹H NMR (600 MHz, CDCl₃):  = 0.76,

0.80 (2d, J = 6.7 Hz, 6H, 3'-H), 1.53 (d, J = 6.6 Hz, 3H, 2''-H), 1.79 (s, 3H,

2-CH₃), 1.94–2.04 (m, 1H, 2'-H), 2.33, 2.36 (2 dd, J = 13.6, 7.0 Hz, 2H, 1'-

H), 5.57 (q, J = 6.6 Hz, 1H, 1''-H), 7.05–7.10 (m, 2H, Ar-H), 7.87–7.92 (m,

2H, Ar-H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 14.6 (C-2'), 21.0 (2-CH₃),

22.50, 22.53, 26.5 (C-3", C-2"), 30.7 (C-1"), 69.7 (C-1'), 104.8 (C-2), 115.7,

115.8, 125.30, 125.32, 125.30, 125.32 (Ar-F), 131.1 (C-4), 132.25, 132.27

(Ar-F), 163.4, 164.8, 165.3, 166.9 (C-5, Ester-CO, C-F) ppm; HRMS (ESI-

TOF): calcd. for C₁₇H₂₀FNO₅[M + H]⁺338.1404, found 338.1402.

stirred vigorously for 40 min. Thereafter, the reaction mixture was filtered

through a pad of celite, which was rinsed with Et₂O. The filtrate was treated

with water, and extracted thrice with Et₂O. The combined organic layers

were dried over MgSO₄, filtered and concentrated in vacuo. This way pure

oxazolone 1 was obtained.

1

Upper diastereomer 1a. R_f= 0.44 (petroleum ether/EtOAc, 2:1); H NMR

(400 MHz, CDCl₃):  = 0.98, 0.99 (2 d, J = 6.6 Hz, 6H, 3'-H), 1.29 (d, J =

6.5 Hz, 3H, 2''-H), 1.58 (s, 3H, 2-CH₃), 1.86 (br s, 1H, OH), 2.19 (qqdd, J

= 6.8, 6.8, 6.7, 6.7 Hz, 1H, 2'-H), 2.48 (dd, J = 14.8, 6.8 Hz, 2H, 1'-H), 3.90

(q, J = 6.5 Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 17.5, 20.7,

22.3, 22.4, 26.2, 36.6 (2-CH₃, C-1', C-2', C-2'', C-3'), 71.3 (C-1''), 107.3 (C-

2), 163.8, 165.4 (C-4, C-5) ppm; HRMS (ESI-TOF): calcd. for C₁₀H₁₇NO₃

[M + Na]⁺222.11006, found 222.11030.

1

Lower diastereomer 1b. R_f= 0.40 (petroleum ether/EtOAc, 2:1); H NMR

(400 MHz, CDCl₃):  = 0.98, 0.99 (2 d, J = 6.6 Hz, 6H, 3'-H), 1.32 (d, J =

6.5 Hz, 3H, 2''-H), 1.56 (s, 3H, 2-CH₃), 1.72 (br s, 1H, OH), 2.19 (qqdd, J

= 6.8, 6.8, 6.7, 6.7 Hz, 1H, 2'-H), 2.48 (dd, J = 15.0, 6.8 Hz, 2H, 1'-H), 3.83

(q, J = 6.5 Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 17.6, 20.1,

22.3, 22.4, 26.2, 36.5 (2-CH₃, C-1', C-2', C-2'', C-3'), 71.1 (C-1''), 107.6 (C-

2), 163.5, 165.5 (C-4, C-5) ppm; HRMS (ESI-TOF): calcd for C₁₀H₁₇NO₃

[M + Na]⁺222.11006, found 222.11031.

rel-(S)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl (4-

bromophenyl)carbamate (23a). Under nitrogen atmosphere MBH-001 high

1a (100 mg, 0.50 mmol) was dissolved in dry CH₂Cl₂(2.5 mL). Afterwards

4-bromophenylisocyanate (0.149 g, (0.75 mmol) in CH₂Cl₂(2.5 mL) and

N,N-diisopropylethylamine (71.4 mg, 0.55 mmol) were added. The

reaction mixture was stirred for 4 d at room temperature. After evaporation

of the solvent, the crude reaction mixture was directly purified by by flash

chromatography on silica (Biotage Isolera, gradient heptane/EtOAc) to

give of pure carbamate 23a (125 mg, 60%, purity 95%) as a white solid; R_t

= 1.66 min (HPLC); ¹H NMR (600 MHz, CDCl₃):  = 1.00 (t, J = 7.0 Hz, 6H,

3'-H), 1.31 (d, J = 6.6 Hz, 3H, 2''-H), 1.62 (s, 3H, 2-CH₃), 2.18–2.22 (m, 1H,

2'-H), 2.50 (bd, J = 5.1 Hz, 1'-H), 5.20 (q, J = 6.6 Hz, 1H, 1''-H), 6.56 (bs,

1H, NH), 7.23–7.30 (bm, 2H, Ar-H), 7.40–7.45 (m, 2H, Ar-H) ppm; ¹³C

NMR (150 MHz, CDCl₃):  = 15.0 (C-2'), 21.9, 22.35, 22.45 (C-3', 2-CH₃),

26.2 (C-2'), 36.6 (C-1'), 72.6 (C-1''), 105.6 (C-2), 120.4 (Ar C), 132.1 (Ar

C), 136. 5 (Ar C), 151.9 (O-(C=O)-N), 164.2 (C-4), 165.2 (C-5) ppm; HRMS

(ESI-TOF): calcd. for C₁₇H₂₁BrN₂O₄[M + H]⁺200.1287, found 200.1286.

rel-(S)-1-((S)-2-(1-Hydroxyethyl)-4-isobutyl-2-methyloxazol-5(2H)-one

(1a). According to general procedure 1, cyclic nitrone 21a (158 mg, 0.73

mmol) in THF (2 mL) was reduced with activated zinc powder (240 mg, 3.7

mmol, 5 equiv), in the presence of saturated aqueous NH₄Cl solution (2

mL). The resulting grey suspension was stirred vigorously for 40 min.

Thereafter, the mixture was filtered through a pad of celite, which was

rinsed with Et₂O (20 mL). The filtrate was treated with water (20 mL), and

extracted with Et₂O (3 × 20 mL). The combined organic layers were dried

over MgSO₄, filtered and concentrated in vacuo. This way pure oxazol-

5(2H)-one 1a (120 mg, 82%) was obtained as a colorless oil.

Preparation of pure enantiomers 1b (RS/SR)

(R)-1''-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

4-

bromobenzoate (24b). Under a nitrogen atmosphere of (2S,1''R)-1b (50.0

mg, 0.251 mmol) was dissolved in dry CH₂Cl₂(5 mL) and cooled to 0 °C.

Then triethylamine (38.1 mg, 0.376 mmol) and DMAP (6.1 mg, 0.05 mmol)

were added. Next, 4-bromobenzoyl chloride (60.6 mg, 0.276 mmol) in

CH₂Cl₂(2 mL) was added at that temperature and the mixture warmed up

to r.t. After 12 h stirring at r.t., additional trimethylamine (38.1 mg, 0.376

mmol), DMAP (6.1 mg, 0.05 mmol) and 4-bromobenzoyl chloride (60.6 mg,

0.276 mmol) in CH₂Cl₂(2 mL) were added. After 12 h the reaction mixture

was concentrated in vacuo and purified directly by flash chromatography

on silica (Biotage Isolera, gradient heptane/EtOAc from 0% – 30% EtOAc)

to give pure benzoate (2S,1''R)-24b (50.0 mg, 52%) as colorless solid; R_t

= 1.75 (HPLC); ¹H NMR (600 MHz, CDCl₃):  = 1.01, 1.02 (2d, J = 6.6 Hz,

6H, 3'-H), 1.36 (d, J = 6.4 Hz, 2''-H), 1.64 (s, 3H, 2-CH₃), 2.21 (sept, J =

6.7 Hz, 1H, 2'-H), 2.52 (d, J = 7.0 Hz, 2H, 1'-H), 5.44 (q, J = 6.6 Hz, 1H,

1''-H), 7.57 (d, J = 8.6 Hz, 2H, Ar-H), 7.80 (d, J = 8.6 Hz, 2H, Ar-H) ppm;

¹³C NMR (150 MHz, CDCl₃):  = 14.9 (C-2''), 22.0, 22.4, 22.5, 26.1 (C-2'),

36.6 (C-1'), 72.1 (C-1''), 105.6 (C-2), 128.5, 128.6, 131.1, 131.8 (Ar C),

164.2, 165.5, 165.2 (C-4, C-5, ester C=O) ppm; HRMS (ESI-TOF): calcd.

for C₁₇H₂₀BrNO₄[M + H]⁺382.0654, found 382.0655.

a) Racemic 1b (300 mg, 1.39 mmol) was separated into its enantiomers

by chiral chromatography on Chiralpak IC (heptane/propanol, 90:10) to

give (2R,1''S)-1b (132 mg,44%) and (2S,1''R)-1b (174 mg, 57%).

b) Alternatively, nitrone 21b (300 mg, 1.39 mmol) was separated into its

enantiomers by chiral chromatography on CHIRALCEL OX (Sepiatec, 80

mL, 10% B ACN + 0.1% HCOOH) to give pure nitrone (2R,1''S)-21b [100

mg, 33%, R_t= 1.0 min (HPLC); R_t= 1.57 min (chiral HPLC on Chiralpak

OX, MeCN)] and pure nitrone (2S,1''R)-21b [105 mg, 35%, R_t= 0.99 min

(HPLC), R_t= 1.88 min (chiral HPLC on Chiralpak OX, MeCN].

c1) According to general procedure 1, nitrone (2R,1''S)-21b (100 mg, 0.46

mmol) was dissolved in THF (6 mL) and the resulting solution was treated

with activated zinc powder (182 mg, 2.78 mmol). After the addition of

NH₄Cl solution (149 mg, 2.78 mmol, in 3 mL water), the grey suspension

was stirred vigorously for 60 min at r.t. Then the reaction mixture was

diluted with EtOAc, filtered through a pad of celite, which was rinsed with

EtOAc several times. The collected organic phases were washed with

water, dried over Na₂SO₄, filtered, the filter cake rinsed with EtOAc and

the filtrate concentrated in vacuo to give (2R,1''S)-1b (85.0 mg, 89%, 97%

purity) as a colorless oil; R_t= 1.06 min (HPLC); R_t= 6.53 (Chiralpak IC;

heptane/iPrOH, 90:10); HRMS (ESI-TOF): calcd. for C₁₀H₁₇NO₃[M + H]⁺

200.1287, found 200.1287; []₂₀^D= –23.62 (c = 2.405 in CHCl₃).

Benzoate ent-24b was prepared in a similar way.

Reduction of the cyclic nitrones with zinc. General procedure 1.

To a solution of nitrone 21 in THF (≈ 2.5 mL per 1 mmol) activated zinc

powder³¹(5 equiv) was added, followed by addition of saturated aqueous

NH₄Cl solution (1:1 solvent ratio). The resulting grey suspension was

c2) According to general procedure 1, nitrone (2S,1''R)-21b (105 mg, 0.48

mmol) was dissolved in THF (6 mL) and the resulting solution was treated

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with activated zinc powder (191 mg, 2.92 mmol). After the addition of

NH₄Cl solution (157 mg, 2.92 mmol, in 3 mL water), the grey suspension

was stirred vigorously for 60 min at r.t. Then the reaction mixture was

diluted with EtOAc, filtered through a pad of celite, which was rinsed with

EtOAc several times. The collected organic phases were washed with

water, dried over Na₂SO₄, filtered, the filter cake rinsed with EtOAc, and

the filtrate concentrated in vacuo to give (2S,1''R)-1b (80.0 mg, 78%, 95%

purity) as a colorless oil; R_t= 1.06 (HPLC); R_t= 8.56 (Chiralpak IC;

heptane/iPrOH, 90:10); HRMS (ESI-TOF): calcd. for C₁₀H₁₇NO₃[M + H]⁺

200.1287, found 200.1289; []₂₀^D= +22.76 (c = 2.46 in CHCl₃).

Methyl 2-(hydroxyimino)-4-methylpentanoate (28). According to general

procedure 2, methyl leucinate (27) (10.0 g, 0.07 mol, 1 equiv) was oxidized

to pure oxime²⁴28 (10.3 g, 94%), white powder. R_f= 0.23 (petroleum

ether/EtOAc, 4:1); ¹H NMR (400 MHz, CDCl₃):  = 0.92 (d, J = 6.7 Hz, 6H,

5-H), 2.04 (qqt, J = 6.9, 6.9, 6.8 Hz, 1H, 4-H), 2.53 (d, J = 7.5 Hz, 2H, 3-

H), 3.83 (s, 3H, OCH₃), 8.70 (br s, 1H, OH) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 22.6 (C-5), 26.5 (C-4), 33.3 (C-3), 52.6 (OCH₃), 152.5 (C-2),

164.2 (C-1) ppm; HRMS (ESI-TOF): calcd. for C₇H₁₃NO₃[M

Na]⁺182.07876, found 182.07897.

+

Synthesis of cyclic nitrones, General procedure 3.

3-Methyl-2-oxo-1-oxa-4-azaspiro[4.5]dec-3-ene 4-oxide (26). To

a

suspension of methyl 2-(hydroxyimino)propanoate¹⁹(25) (400 mg, 3.05

mmol) and cyclohexanone (1.37 mL, 1.3 g, 123.3 mmol, 4.3 equiv) in water

(10 mL) was added NaOH solution (0.1M, 10 mL, 1 mmol, 0.33 equiv) at

0 °C in portions (2 mL every 30 min). After being stirred for 12 h at 0 °C

and 24 h at room temperature, the mixture was extracted with Et₂O (3 ×

20 mL). The combined organic layers were dried over MgSO₄, filtered and

concentrated in vacuo. Purification of the residue by flash chromatography

(petroleum ether/EtOAc, 4:1) gave cyclic nitrone 26 (317 mg, 57%) as a

white solid, m.p. = 115 °C. R_f= 0.39 (petroleum ether/EtOAc, 4:1); ¹H NMR

(400 MHz, CDCl₃):  = 1.26–1.37 (m, 1H), 1.63–1.82 (m, 5H), 1.85–1.94

(m, 2H), 2.11 (s, 3H, CH₃), 2.18–2.26 (m, 2H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 7.6 (CH₃), 22.1, 23.7, 34.1 (CH₂), 105.9 (C-5, spiro C), 127.3

(C-3), 164.7 (C-2) ppm; HRMS (EI): calcd. for C₉H₁₃NO₃[M – e^–]⁺

183.08899, found 183.09045.

A solution of the oxime 28 (1 equiv) in toluene or as suspension in distilled

water (≈ 2.5 mL per 1 mmol, 0.4M) was cooled down to 5 °C before the

addition of the aldehyde (4 equiv) under N₂atmosphere. The resulting

mixture was treated with a freshly prepared NaOH solution (0.1M, 0.05

equiv). The same amount of the NaOH solution (0.1M, 0.05 equiv) was

added every 90 min after the reaction was started at 5 °C (5 portions

altogether) and the resulting suspension was stirred at the same

temperature overnight. Thereafter, the reaction mixture was transferred to

a separation funnel and extracted thrice with Et₂O. The combined organic

layers were washed with saturated NaCl solution, dried over MgSO₄,

filtered, and concentrated in vacuo. The crude oxazolone 3-oxides were

purified by flash chromatography using a petroleum ether/EtOAc system

to give the oxazolone 29 as colorless oil.

4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazole 3-oxide (29). According to

general procedure 3, oxime 28 (1.0 g, 6.3 mmol) was dissolved in toluene

(15 mL) and cooled down to 5 °C. Then acetaldehyde (1.4 mL, 25.1 mmol)

was added at once following by the addition of aqueous NaOH solution

(0.1M, 3 mL). The remaining four portions of NaOH solution (0.1M) were

added every 90 min at the same temperature. After being stirred overnight,

the reaction mixture was extracted with Et₂O (3 × 100 mL). The combined

organic layers were washed with saturated NaCl solution (100 mL), dried

over MgSO₄, filtered, and concentrated in vacuo. The crude product was

purified by flash chromatography (petroleum ether/EtOAc, 4:1) to give

oxazolone 29 as colorless oil (790 mg, 73%). R_f= 0.33 (petroleum

ether/EtOAc, 4:1); ¹H NMR (400 MHz, CDCl₃):  = 0.94, 0.95 (2 d, J = 6.7

Hz, 6H, 3'-H), 1.77 (d, J = 6.0 Hz, 3H, 2-CH₃), 2.18 (qqdd, J = 6.9, 6.9, 6.9,

6.9 Hz, 1H, 2'-H), 2.45 (dd, J = 13.9, 7.0 Hz, 2H, 1'-H), 5.60 (q, J = 6.0 Hz,

1H, 2-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 19.2, 22.4, 22.5, 26.2, 30.6

(2-CH₃, C-1', C-2', C-3'), 95.1 (C-2), 131.1 (C-4), 164.9 (C-5) ppm; HRMS

(ESI-TOF): calcd. for C₈H₁₃NO₃[M + Na]⁺194.07876, found 194.07895.

Methyl 2-amino-4-methylpentanoate (27). Thionyl chloride (30.5 mL, 0.42

mol, 1.1 equiv) was added dropwise within 20 min to methanol (400 mL)

at 0 °C, followed by addition of L-leucine (50.0 g, 0.38 mol, 1 equiv) in

portions. The resulting solution was left to stir at r.t. overnight. After that,

all volatiles were removed by evaporation and the white solid

(hydrochloride salt) was suspended in chloroform (270 mL). To this

suspension a solution of triethylamine (54.0 mL, 0.39 mol) in chloroform

(270 mL) was added dropwise at r.t. After 4 h of stirring at r.t., the mixture

was refluxed for 1 h. Then it was cooled again to r.t. and concentrated in

vacuo to a white solid, which was diluted with Et₂O (0.5 – 1 L) and filtered.

The white solid (Et₃N·HCl) was washed with of Et₂O (500 mL). The

combined filtrates were concentrated and the resulting oil was distilled

under vacuum (oil pump, bath temperature < 50 °C). The colorless free

amino acid ester²²27 (49.8 g, 90%) was kept in a fridge (–18 °C). ¹H NMR

(400 MHz, CDCl₃):  = 0.88, 0.90 (2 d, J = 6.7 Hz, 6H, 5-H), 1.34–1.43 (m,

1H, 3-H), 1.45–1.51 (m, 2H, NH₂), 1.49–1.57 (m, 1H, 3-H), 1.74 (qqdd, J =

6.7, 6.7, 6.7, 6.7 Hz, 1H, 4-H), 3.41–3.47 (m, 1H, 2-H), 3.68 (s, 3H, OCH₃)

ppm; ¹³C NMR (100 MHz, CDCl₃):  = 21.7, 22.9, 24.7 (C-4, C-5), 44.0 (C-

3), 51.8 (C-2), 52.7 (OCH₃), 177.0 (C-1) ppm.

Condensation of -ketoacid 20 with aldoximes to oxazolone-N-oxides.

General procedure 4.

Oxidation of amino acid methyl esters to the 2-hydroxyimino esters.

General procedure 2.

4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazole 3-oxide (29). A solution of

acetaldehyde oxime²⁶(31) (2.72 g, 46.1 mmol) in CH₂Cl₂(6 mL) was

added to a solution of 4-methyl-2-oxopentanoic acid (20) (4.00 g, 30.7

mmol) in CH₂Cl₂(5 mL) at r.t. After stirring overnight, the solvent was

evaporated and the residue directly purified by chromatography on a diol

column Chromabond 40, with a flow rate of 25 mL/min, heptane/EtOAc

with a gradient from 3-30% EtOAc to give oxazolone 29 (3.30 g, 63%) as

a colorless oil. HPLC retention time = 1.04 min. The spectral data were in

full agreement with the above data.

To a solution of the amino acid methyl ester (1 equiv) in ethanol (1.6 mL

per mmol of ester) was added sodium tungstate dihydrate (0.1 equiv). After

stirring of the solution for 30 min at 0 °C, hydrogen peroxide solution (31%

in H₂O, 1 mL per mmol, 13 equiv) was added dropwise over a period of 20

min. Thereafter, water (1.6 mL per mmol) was added and the mixture

stirred overnight with concomitant warming to r.t. The mixture was poured

into a separation funnel containing saturated NH₄Cl solution (15 mL per

mmol) and EtOAc (6 ml per mmol). After separation of the layers, the

aqueous layer was extracted thrice with EtOAc. The combined organic

layers were washed with sodium thiosulfate solution (1M, 15 mL per mmol)

and saturated NaCl solution (15 mL per mmol). They were dried over

Na₂SO₄or MgSO₄, filtered and concentrated in vacuo to give the pure 2-

(hydroxyimino)ester.

Reaction of cyclic nitrones with aldehydes using LiN(SiMe₃)₂as base,

General procedure 5.

A solution of cyclic nitrone (1 equiv) in THF (≈ 3.5 mL per 1 mmol) was

cooled down to –78 °C and treated with a LiHMDS solution in THF (1M,

1.05 equiv) in a dropwise fashion under N₂atmosphere. The resulting

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yellow suspension was left to stir for 1 h at –78 °C. The corresponding

aldehyde (1.5 equiv) was added and stirring was continued for 0.5 h at –

78 °C. Thereafter, the reaction mixture was quenched with saturated

NH₄Cl solution, brought to ambient temperature and extracted thrice with

Et₂O. The combined organic layers were dried over MgSO₄, filtered, and

concentrated in vacuo. After purification by flash chromatography

(petroleum ether/EtOAc or petroleum ether/Et₂O) the 2-(1-hydroxyalkyl)

substituted cyclic nitrone was isolated.

CDCl₃):  = 14.1 (CH₃CH₂), 19.4 (CH₃CH₂₎, 26.6 (CH₃CH₂CH₂), 52.6

(OCH₃), 152.9 (C=NOH), 164.0 (CO₂CH₃) ppm.

Methyl 2-(hydroxyimino)-3-methylbutanoate (35). According to general

procedure 2, methyl valinate (5.0 g, 38.1 mmol, 1 equiv) in ethanol (60 mL)

was oxidized with hydrogen peroxide solution (31% in H₂O, 38 mL, 13

equiv) in the presence of sodium tungstate dihydrate (1.26 g, 3.81 mmol,

0.1 equiv) to oxime 35 (4.98 g, 90%) which was obtained as a white solid.

In this case, both oxime isomers are visible in the ¹H NMR spectrum. R_f=

0.45 (petroleum ether/Et₂O, 1:1); ¹H NMR (400 MHz, CDCl₃):  = 1.16 (d,

J = 6.8 Hz, 0.6H (minor isomer), (CH₃)₂CH), 1.23 (d, J = 7.1 Hz, 6H,

(CH₃)₂CH), 2.79 (sept, J = 6.8 Hz, 0.08H (minor isomer), (CH₃)₂CH), 3.48

(sept, J = 7.1 Hz, 1H, (CH₃)₂CH), 3.82 (s, 3H, OCH₃), 3.87 (s, 0.28H (minor

isomer), OCH₃), 9.11 (s, br, 1H, C=NOH) ppm.

2-(1-Hydroxyethyl)-4-isobutyl-2-methyl-5-oxo-2,5-dihydrooxazole-3-oxide

(21). a) Using LiHMDS as base: According to general procedure 5, a

solution of nitrone 29 (1.46 g, 8.5 mmol) in THF (30 mL) was cooled to –

78 °C. To the resulting suspension a solution of LiHMDS in THF (1M, 8.95

mL, 8.95 mmol) was added dropwise. After 1 h of stirring, acetaldehyde

(0.72 mL, 12.81 mmol) was added and stirring was continued for 0.5 h at

–78 °C. Then saturated NH₄Cl solution (50 mL) was added and the

resulting two-layer mixture was allowed to reach r.t. The layers were

separated and the aqueous layer was extracted with Et₂O (3 × 200 mL).

The combined organic layers were dried over MgSO₄, filtered, and

concentrated in vacuo. After purification by flash chromatography

(petroleum ether/EtOAc, 3:1) both diastereoisomers 21a and 21b were

isolated in 1:1 ratio as colorless oils, which solidified while kept in a freezer

(1.47 g, 80%). The spectral data were in full agreement with the previously

described ones.

Methyl 2-(hydroxyimino)-2-phenylacetate (36). According to general

procedure 2, to

a solution of (S)-methyl 2-amino-2-phenylacetate

hydrochloride (1.20 g, 5.95 mmol) in H₂O (16.8 mL) was added at 0 °C a

sodium hydroxide solution in H₂O (2M, 2.975 mL, 239 mg, 5.95 mmol) and

then after 5 min tungstate dihydrate (198 mg, 0.59 mmol) in one portion.

After stirring the mixture for 30 min at 0 °C, aqueous hydrogen peroxide

(35%, 1.735 g, 17.8 mmol) was added, the mixture was warmed-up to

room temperature and then stirred 2 h at this temperature. The reaction

mixture was diluted with CH₂Cl₂and extracted thrice with CH₂Cl₂(20 mL).

The combined organic phases were stirred with sodium thiosulfate solution

(1M, 30 mL) for 30 min, causing disappearance of the yellow color. The

phases were separated and the organic layer was dried over MgSO₄,

filtered, and concentrated under reduced pressure. The organic residue

was purified by flash chromatography on silica (25 g, Biotage Isolera,

gradient heptane/EtOAc from 0 – 100% EtOAc, 75mL/min) to give pure

oxime ester 36 (560.0 mg, 53%) as a slightly yellow oil. R_t= 0.75 (HPLC);

¹H NMR (400 MHz, CDCl₃):  = 3.89 (s, 3H, OCH₃), 7.42–7.50 (m, 5H, Ph)

ppm.

b) Using Schwesinger base 30: To a –78 °C cooled solution of nitrone 29

(357 mg, 2.08 mmol) in THF (10 mL) Schwesinger base (30) (0.475 mL,

2.3 mmol) was added. Thereafter, acetaldehyde (0.175 mL, 3.13 mmol)

was added and the resulting reaction mixture was left to stir at this

temperature overnight. Next day, saturated NH₄Cl solution (50 mL) was

added. The layers were separated and the aqueous layer was extracted

with Et₂O (3 × 50 mL). The combined organic layers were dried over

MgSO₄, filtered and concentrated in vacuo. Purification of the residue by

flash chromatography (petroleum ether/EtOAc, 2:1) gave 21a (248 mg,

55%) and 21b (80 mg, 18%).

Methyl (2-(hydroxyimino)-2-(pyridin-2-yl)acetate^27b(37). To a solution of

methyl pyridin-2-ylacetate (4.54 g, 30.0 mmol) in acetic acid (33 mL) at

0 °C was added a solution of sodium nitrite (2.07 g, 30.0 mmol) in water

(27 mL). The resulting mixture was warmed to r.t. and stirred for 1 h upon

which time water (90 mL) was added and stirring continued for an

additional 1 h. The reaction mixture was concentrated under reduced

pressure to remove most of the AcOH, then basified to pH 8-9 with

saturated aqueous Na₂CO₃and extracted with EtOAc (2 × 100 mL). The

combined organic extracts were washed with saturated NaCl solution (100

mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure.

Purification by flash chromatography on silica gel (Biotage Isolera,

gradient heptane/EtOAc from gradient 0 – 75% EtOAc, 50mL/min)

afforded oxime ester 37 (5.001 g, 92%) in different fractions: fraction 1

single stereoisomer as a colorless oil (1.533 g, 28% yield), fraction 2 as a

mixture of stereoisomers as a pale yellow gum (1.241 g, 23% yield);

fraction 3 single (other) stereoisomer as a white solid (2.227 g, 41% yield);

R_t= 0.54/0.65 (HPLC); ¹H NMR (600 MHz, CDCl₃): major isomer:  = 3.99

(s, OCH₃), 7.30 (ddd, J = 7.5, 5.0, 1.3 Hz, 1H, pyridine), 7.72 (td, J = 7.8,

1.8 Hz, 1H, pyridine), 7.79 (bs, 1H, OH), 7.84 (dt, J = 8.0, 1.1 Hz, 1H,

pyridine), 8.60–8.62 (m, 1H, pyridine) ppm; minor isomer:  = 3.95 (s,

OCH₃), 7.50 (ddd, J = 7.5, 5.0, 1.3 Hz, 1H, pyridine), 7.96 (td, J = 7.8, 1.8

Hz, 1H, pyridine), 7.79 (bs, 1H, OH), 8.15 (dt, J = 8.4, 1.1 Hz, 1H, pyridine),

8.53–8.55 (m, 1H, pyridine) ppm.

2-Methyl-4-oxopentan-3-yl-2-(hydroxyimino)-4-methylpentanoate

(33).

Nitrone 29 (1.65 g, 9.63 mmol) was dissolved in THF (45 mL) and cooled

to –78 °C. Then, LiHMDS in THF (1M, 11.6 mL, 11.6 mmol, 1.2 equiv) was

added dropwise under N₂atmosphere. The resulting yellow suspension

was left to stir for 1 h at –78 °C, before isobutyraldehyde (1.32 mL, 1.042

g, 14.45 mmol, 1.5 eq) was added. After being stirred for 1 h at –78 °C,

the reaction mixture was quenched with sat. NH₄CI solution (220 mL) and

extracted with diethyl ether (3 x 300 mL). The combined organic layers

were dried over MgSO₄, filtered, and concentrated in vacuo. After

purification by flash chromatography (petroleum ether/Et₂O, 4:1) ester 33

was isolated as a colorless oil (1.041 g, 44%). R_f= 0.33 (petroleum

1

ether/EtOAc, 3:1); H NMR (400 MHz, CDCl₃):  = 0.93 (2 d, J = 6.6 Hz,

6H, 5-H), 0.96 (d, J = 6.9 Hz, 3H, 5'-H), 1.03 (d, J = 6.9 Hz, 3H, 5'-H), 2.03–

2.10 (m, 1H, 4-H), 2.16 (s, 3H, 1'-H), 2.27–2.35 (m, 1H, 4'-H), 2.54 (d, J =

7.5 Hz, 2H, 3-H), 5.0 (d, J = 4.2 Hz, 1H, 3'-H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 16.6 (C-5'), 19.1 (C-5'), 22.7, 22.7 (C-5), 26.5 (C-4), 26.9 (C-

1'), 29.6 (C-4'), 33.4 (C-3), 83.9 (C-3'), 151.8 (C-2), 163.4 (C-1), 204.6 (C-

1') ppm.

Methyl 2-(hydroxyimino)pentanoate (34). According to general procedure

2, methyl norvalinate (0.50 g, 3.81 mmol, 1 equiv) in ethanol (6 mL) was

oxidized with hydrogen peroxide solution (31% in H₂O, 3.8 mL, 13 equiv)

in the presence of sodium tungstate dihydrate (0.126 g, 0.381 mmol, 0.1

equiv) to oxime 34 (0.464 g, 84%) which was obtained as a white solid. R_f

= 0.47 (petroleum ether/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃):  = 0.96

(t, 3H, CH₃CH₂), 1.57 (m, 2H, CH₃CH₂CH₂), 2.60 (m, 2H, CH₂C=NOH),

3.85 (s, 3H, OCH₃), 8.20–10.80 (b, 1H, C=N-OH) ppm; ¹³C NMR (100 MHz,

4-Isobutyl-2-isopropyl-5-oxo-2,5-dihydrooxazole 3-oxide (38). According

to general procedure 3, oxime 28 (600 mg, 3.77 mmol) was dissolved in

toluene (10 mL) and cooled down to 5 °C. Then, isobutyraldehyde (32) (1.4

mL, 15.34 mmol) was added at once following by the addition of aqueous

NaOH solution (0.1M, 1.8 mL). The remaining four portions of NaOH

solution (0.1M) were added every 90 min at the same temperature. After

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being stirred overnight, the reaction mixture was extracted with Et₂O (3 ×

50 mL). The combined organic layers were washed with saturated NaCl

solution (1 × 50 mL), dried over MgSO₄, filtered, and concentrated in vacuo.

The crude product was purified by flash chromatography (petroleum

ether/EtOAc, 6:1) to give oxazolone 38 as colorless oil (510 mg, 68%). R_f

= 0.5 (petroleum ether/EtOAc, 4:1); ¹H NMR (400 MHz, CDCl₃):  = 0.78

(d, J = 6.8 Hz, 3H, 2''-H or 3'-H), 0.93 (2 d, J = 6.7 Hz, 6H, 2''-H or 3'-H),

1.14 (d, J = 7.1 Hz, 3H, 2''-H or 3'-H), 2.15 (qqdd, J = 6.8, 6.8, 6.8, 6.8 Hz,

1H, 2'-H), 2.38 (ddd, J = 13.8, 7.3, 1.0 Hz, 1H, 1'-H), 2.48 (dd, J = 13.8,

7.1 Hz, 1H, 1'-H), 2.57 (qqd, J = 7.0, 7.0, 2.4 Hz, 1H, 1''-H), 5.42 (d, J =

2.2 Hz, 1H, 2-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 12.4, 17.2, 22.5,

22.6, 26.0, 30.0, 30.6 (C-1'', C-1', C-2'', C-2', C-3'), 100.7 (C-2), 132.1 (C-

4), 165.4 (C-5) ppm.

b) From keto acid: According to general procedure 4, phenylglyoxylic acid

(441 mg, 2.94 mmol) was dissolved in dry CH₂Cl₂(5 mL) before

acetaldehyde oxime²⁶31 (260.3 mg, 4.41 mmol) in CH₂Cl₂(5 mL) was

added and the mixture stirred for 3 d at r.t. After evaporation of the solvent,

the crude product was directly purified by flash chromatography on

Chromabond Diol (15 g, Biotage Isolera, gradient heptane/EtOAc

20mL/min, 0 – 30% EtOAc) to give pure nitrone 41 (140.0 mg, 24%) as an

oil; R_t= 1.16 (HPLC); ¹H NMR (600 MHz, CDCl₃):  = 1.87 (d, J = 6.0 Hz,

3H, 2-CH₃), 5.69 (q, J = 6.0 Hz, 1H, 2-H), 7.50-7.55 (m, 3H, Ph), 8.64-8.65

(m, 2H, Ph) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 19.2 (2-CH₃), 94.3 (C-

2), 124.3 (Ph), 126.9 (Ph), 128.6 (Ph), 132.0 (C-4), 163.7 (C-5) ppm;

HRMS (ESI-TOF): calcd. for C₁₀H₉NO₃[M + H]⁺192.0661, found 192.0663.

2-Methyl-5-oxo-4-(pyridin-2-yl)-2,5-dihydrooxazole 3-oxide (42). The

crude product from the reaction was directly used for the preparation of 54.

2-Methyl-5-oxo-4-propyl-2,5-dihydrooxazole 3-oxide (39). According to

general procedure 3, oxime 34 (10.0 g, 68.9 mmol) was suspended in

distilled water (160 mL) and cooled down to 5 °C. Then acetaldehyde (15.4

mL, 0.27 mol) was added at once following by the addition of aqueous

NaOH solution (0.1M, 32.9 mL).The remaining four portions of NaOH

solution (0.1M) were added every 90 min at the same temperature. After

being stirred overnight, the reaction mixture was extracted with Et₂O (3 ×

500 mL). The combined organic layers washed with saturated NaCl

solution (1 × 500 mL), dried over MgSO₄, filtered, and concentrated in

vacuo. The crude product was purified by flash chromatography

(petroleum ether/EtOAc, 4:1) to give oxazolone 39 as colorless oil (7.35 g,

68%). R_f= 0.52 (petroleum ether/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃):

 = 0.96 (t, J = 7.5 Hz, 3H, 3'-H), 1.67 (qdd, J = 15.1, 7.4, 7.4 Hz, 2H, 2'-

H), 1.76 (d, J = 6.1 Hz, 3H, 2-CH₃), 2.54 (dd, J = 15.2, 7.5 Hz, 2H, 1'-H),

5.58 (q, J = 6.1 Hz, 1H, 2-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 13.8,

18.3, 19.1, 23.8 (2-CH₃, C-1', C-2', C-3'), 95.1 (C-2), 131.4 (C-4), 164.7 (C-

5) ppm.

2-Methyl-4-neopentyl-5-oxo-2,5-dihydrooxazole 3-oxide (43). Under a

nitrogen atmosphere 4,4-dimethyl-2-oxopentanoic acid²⁸(3.00 g, 20.8

mmol) was dissolved in dry CH₂Cl₂(10 mL) and stirred at room

temperature. Then acetaldehyde oxime (31) (1.844 g, 31.2 mmol),

dissolved in dry CH₂Cl₂(10 mL) was added dropwise. The reaction was

stirred overnight and after concentration in vacuo, purified by flash

chromatography on a diol phase (Chromabond 40, Biotage Isolera,

gradient heptane/EtOAc, 25mL/min, from 3 – 30% EtOAc) to give nitrone

43 (2.80 g, 65%, 90% pure) as an oil; R_t= 1.32 (HPLC); ¹H NMR (600 MHz,

CDCl₃):  = 1.01 (s, 9H, 3'-H), 1.78 (d, J = 6.0 Hz, 2-CH₃), 2.47, 2.54 (2 d,

J = 13.2 Hz, 2H, 1'-H), 5.61 (q, J = 6.0 Hz, 2-H) ppm; ¹³C NMR (150 MHz,

CDCl₃):  = 19.4 (2-CH₃), 30.0 (C-3'), 35.4 (C-1'), 48.0 (C-2'), 95.2 (C-2),

159.4 (C-4), 165.4 (C-5) ppm; HRMS (ESI-TOF): calcd. for C₉H₁₅NO₃[M

+ H]⁺186.1130, found 186.1131.

rel-(S)-2-((R)-1-Hydroxypropyl)-4-isobutyl-2-methyl-5-oxo-2,5-dihydro-

oxazole 3-oxide (44b). According to general procedure 5, nitrone 29 (0.59

g, 3.45 mmol) was dissolved in THF (12 mL) and cooled to –78 °C. To the

resulting suspension a solution of LiHMDS in THF (1M, 3.6 mL, 3.6 mmol)

was added dropwise. After 1 h of stirring, propionaldehyde (0.37 mL, 5.16

mmol) was added and stirring was continued for 0.5 h at –78 °C before

saturated NH₄Cl solution (20 mL) was added. The layers were separated

and the aqueous layer was extracted with Et₂O (3 × 20 mL). The combined

organic layers were dried over MgSO₄, filtered, and concentrated in vacuo.

After careful purification by flash chromatography (petroleum ether/EtOAc,

4:1) only the lower diastereoisomer 44b was isolated in a pure form as

colorless oil (0.24 g, 30%). R_f= 0.38 (lower diastereomer) (petroleum

ether/EtOAc, 2:1); ¹H NMR (400 MHz, CDCl₃):  = 0.95, 0.96 (2 d, J = 6.7

Hz, 3H each, 3'-H), 1.06 (t, J = 7.4 Hz, 3H, 3''-H), 1.49 (qd, J = 10.5, 7.4

Hz, 1H, 2''-H), 1.71 (s, 3H, 2-CH₃), 1.72 (qdd, J = 10.2, 7.4, 2.6 Hz, 1H, 2''-

H), 2.04 (br s, 1H, OH), 2.18 (qqdd, J = 6.8, 6.8, 6.7, 6.7 Hz, 1H, 2'-H),

2.41, 2.48 (2 dd, J = 13.9, 7.4 Hz, 2H, 1'-H), 3.89 (dd, J = 10.5, 2.6 Hz, 1H,

1''-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 10.2 (C-3''), 20.7, 22.4, 22.5,

23.6, 26.2, 30.8 (2-CH₃, C-1', C-2', C-2'', C-3'), 73.6 (C-1''), 105.6 (C-2),

131.7 (C-4), 165.0 (C-5) ppm.

4-Isopropyl-2-methyl-5-oxo-2,5-dihydrooxazole 3-oxide (40). According to

general procedure 3, oxime 35 (4.74 g, 32.65 mmol) was suspended in

distilled water (80 mL) and cooled down to 5 °C. Then acetaldehyde (7.4

mL, 0.13 mol) was added at once following by the addition of aqueous

NaOH solution (0.1M, 16.3 mL).The remaining four portions of NaOH

solution (0.1M) were added every 90 min at the same temperature. After

being stirred overnight, the reaction mixture was extracted with Et₂O (3 ×

250 mL). The combined organig layers were washed with saturated NaCl

solution (1 × 250 mL), dried over MgSO₄, filtered, and concentrated in

vacuo. The crude product was purified by flash chromatography

(petroleum ether/EtOAc, 4:1) to give oxazolone 40 as colorless oil (3.62 g,

71%). R_f= 0.38 (petroleum ether/Et₂O, 1:1); ¹H NMR (400 MHz, CDCl₃): 

= 1.28 (d, J = 7.1 Hz, 6H, 2'-H), 1.73 (d, J = 6.1 Hz, 3H, 2-CH₃), 3.17 (qq,

J = 7.1, 7.1 Hz, 1H, 1'-H), 5.52 (q, J = 6.1 Hz, 1H, 2-H) ppm; ¹³C NMR (100

MHz, CDCl₃):  = 17.3, 19.0 (2-CH₃, C-2'), 23.6 (C-1'), 94.5 (C-2), 134.7

(C-4), 163.7 (C-5) ppm.

2-Methyl-5-oxo-4-phenyl-2,5-dihydrooxazole 3-oxide (41). a) From oxime

36: According to general prodedure 3, a solution of oxime 36 (450 mg, 2.51

mmol) in toluene (6.1 mL) was cooled down to 5 °C before the addition of

acetaldehyde (443 mg, 10.0 mmol) under nitrogen atmosphere. The

resulting mixture was treated with a freshly prepared NaOH solution (0.1M,

1.2 mL, 0.12 mmol). The same amount of the NaOH solution (0.1M) was

added every 90 min after the reaction was started at 5 °C (5 portions

altogether) and the resulting suspension was stirred at the same

temperature overnight. Thereafter, the reaction mixture was transferred to

a separation funnel and extracted thrice with Et₂O. The combined organic

layers were washed with saturated NaCl solution, dried over Na₂SO₄,

filtered, and concentrated in vacuo. The yellow crude product (500 mg,

>100%) was purified by flash chromatography on silica (Biotage Isolera,

gradient heptane/EtOAc from 0 – 20% EtOAc; 25mL/min) to give pure

nitrone 41 (180.0 mg, 38%) as an oil.

2-(Cyclopropyl(hydroxy)methyl)-4-isobutyl-2-methyl-5-oxo-2,5-

dihydrooxazole 3-oxide (45a/b). A solution of cyclic nitrone 29 (400 mg,

2.33 mmol) in THF (5.6 mL) was cooled down to –78 °C and treated with

a LiHMDS solution (1M, 2.45 mL, 2.45 mmol, 411 mg) in THF in a dropwise

fashion under nitrogen atmosphere. The resulting yellow suspension was

left to stir for 1 h at –78 °C before cyclopropylcarbaldehyde (180 mg, 2.57

mmol) was added and stirring continued for 1 h at –78 °C. Thereafter,

additional cyclopropylcarbaldehyde was added (180 mg, 2.57 mmol) and

the reaction mixture was stirred for 1 h. The reaction mixture was

quenched with saturated NH₄Cl solution (17 mL), brought to ambient

temperature and extracted thrice with EtOAc. The combined organic layers

were dried over Na₂SO₄, filtered, and concentrated in vacuo. After

10.1002/ejoc.202000294

European Journal of Organic Chemistry

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purification by flash chromatography on a diol phase (Chromabond,

Biotage Isolera, gradient heptane/EtOAc, 20ml/min, 3 – 30%EtOAc) pure

nitrone 45 (560 mg, 94%) was isolated as an oil (mixture of

diastereoisomers 56:44 = low/high); R_t= 1.17 (low), 1.20 (high) (HPLC);

¹H NMR (400 MHz, CDCl₃, mixture of isomers):  = 0.39–0.80 (m, 4H,

cyclopropyl), 0.94–0.96 (m, 6H, 3'-H), 1.05–1.18 (m, 1H, cyclopropyl), 1.80,

1.84 (s, 3H, 2-CH₃), 2.19 (sept, J = 6.8 Hz, 1H, 2'-H), 2.39–2.52 (m, 2H,

1'-H), 3.24 (d, J = 8.3 Hz, "1H", 1''-H), 3.29 (d, J = 9.2 Hz, "1H", 1''-H) ppm.

(500.0 mg, 2.92 mmol) in dry THF (10 mL) was added LiHMDS solution

(1M in THF, 2.78 mL, 464.3 mg, 2.78 mmol) at –78 °C under nitrogen

atmosphere. After stirring of the mixture for 1 h at –78 °C, acetone (204

mg, 260 L, 3.50 mmol) was added and the mixture was left overnight at

–78 °C. The reaction was quenched at this temperature with saturated

NH₄Cl solution (20 mL), and after warm-up to r.t., additional NH₄Cl solution

(19 mL) was added. The aqueous phase was extracted three times with

EtOAc. The combined organic phases were dried over Na₂SO₄, filtered,

the filter cake washed with EtOAc, and evaporated in vacuo to give nitrone

47 (330 mg, 37%, purity 75%) as an oil, which was purified by flash

chromatography on a Chromabond diol phase (Biotage Isolera, gradient

heptane/EtOAc from 3% – 30% EtOAc) to give 47 (38%, 90% pure) as a

colorless oil; R_t= 1.14 (HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.96, 0.98

(2 d, J = 6.8 Hz, 6H, 3'-H), 1.16 (s, 3H, 2''-H), 1.35 (s, 3H, 2''-H), 1.59 (bs,

1H, OH), 1.84 (s, 3H, 2-CH₃), 2.13–2.25 (m, 1H, 2'-H), 2.41–2.51 (m, 2H,

1'-H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 19.6 (2-CH₃), 22.5, 22.8 (C-

2''), 23.5, 23.9 (C-3'), 26.1 (C-2'), 30.8 (C-1'), 73.6 (C-1''), 106.1 (C-2),

132.2 (C-4), 164.4 (C-5) ppm; HRMS (ESI-TOF): calcd. for C₁₁H₁₉NO₄[M

+ H]⁺230.1392, found 230.1393.

Preparation of homoallylaldehyde (but-3-enal)

a) Preparation of octa-1,7-diene-4,5-diol.²⁹To a solution of allyl bromide

(1.25 g, 10.3 mmol), potassium iodide (2.86 g, 17.2 mmol) and

tin(II)dichloride dihydrate (2.33 g, 10.3 mmol) in water (12.5 mL), a solution

of glyoxal in water (40%, 500 mg, 3.44 mmol) was added, followed by

stirring of the mixture for 2 h at 40 °C and 15 h at r.t. The reaction mixture

was quenched with aqueous HCl (1M, 5 mL) and extracted with EtOAc.

The organic phase was then washed with aqueous sodium bisulfite

(NaHSO₃) solution to achieve decoloration. The water phase again was

extracted three times with EtOAc. The combined organic layers were dried

over Na₂SO₄, filtered and concentrated in vacuo to give the title diol (375

mg, 76%). The analytical data were in accordance with literature data.

rel-(S)-2-((S)-(4-Chlorophenyl)(hydroxy)methyl)-4-isobutyl-2-methyl-5-

oxo-2,5-dihydrooxazole

3-oxide

(48a)

and

rel-(S)-2-((R)-(4-

chlorophenyl)(hydroxy)methyl)-4-isobutyl-2-methyl-5-oxo-2,5-

dihydrooxazole 3-oxide (48b). According to general procedure 5, a

solution of cyclic nitrone 29 (400 mg, 2.33 mmol) in THF (3 mL) was cooled

down to –78 °C and treated with a LiHMDS solution (1M in THF, 411.0 mg,

2.45 mL, 2.45 mmol) in a dropwise fashion under N₂atmosphere. The

resulting yellow suspension was left to stir for 1 h at –78 °C. Then 4-

chlorobenzaldehyde (361 mg, 2.57 mmol) was added and stirring was

continued for 2 h at –78 °C. Thereafter, the reaction mixture was quenched

with saturated NH₄Cl solution, brought to ambient temperature and

extracted thrice with EtOAc. The combined organic layers were dried over

Na₂SO₄, filtered, and concentrated in vacuo. After purification by flash

chromatography on a Chromabond diol phase (Biotage Isolera, gradient

heptane/EtOAc, 20mL/min, 3-30% EtOAc) of pure nitrone 48 (560 mg,

73%) as a mixture of 25% low and 75% high) was obtained; R_t= 1.48 high,

1.43 low (HPLC).

b) Preparation of homoallylaldehyde (but-3-enal). A solution of octa-1,7-

diene-4,5-diol (316 mg, 2.2 mmol) in CH₂Cl₂/H₂O (1:1, 5.0 mL) was treated

with NaIO₄(468 mg, 2.2 mmol) at 0 °C. After stirring of the mixture for 2.5

h at 0 °C, the organic phase was separated, dried over Na₂SO₄, filtered,

and the filter cake washed with CH₂Cl₂. This solution was directly used

without further purification for the next step.

rel-(S)-2-((S)-1-Hydroxybut-3-en-1-yl)-4-isobutyl-2-methyl-5-oxo-2,5-

dihydrooxazole 3-oxide (46a) and rel-(S)-2-((R)-1-hydroxybut-3-en-1-yl)-

4-isobutyl-2-methyl-5-oxo-2,5-dihydrooxazole 3-oxide (46b). According to

general procedure 5, a solution of cyclic nitrone 29 (500 mg, 2.92 mmol)

in THF (3 mL) was cooled down to –78 °C and treated with a LiHMDS

solution (1M in THF, 3.06 mL, 513 mg, 3.06 mmol) in a dropwise fashion

under N₂atmosphere. The resulting yellow suspension was left to stir for

1 h at –78 °C. Then homoallylaldehyde (but-3-enal, 308 mg, 4.40 mmol) in

CH₂Cl₂(about 10 mL) was added and stirring was continued for 4 h at –

78 °C. Thereafter, the reaction mixture was quenched with saturated

NH₄Cl solution, brought to ambient temperature and extracted thrice with

Et₂O. The combined organic layers were dried over MgSO₄, filtered and

concentrated in vacuo to give 660 mg (94%) of a mixture of nitrones 46.

The crude product was purified by flash chromatography on preparative

HPLC (Luna C18; neutral, MeCN/H₂O) to give pure 46a (100.0 mg, 14%)

and pure 46b (100.0 mg, 14%) as colorless oils.

Upper diastereomer 48a: ¹H NMR (600 MHz, CDCl₃):  = 0.86, 0.92 (2d, J

= 6.7 Hz, 6H, 3'-H), 1.62 (s, 3H, 2-CH₃), 2.34–2.47 (m, 2H, 1'-H), 2.94 (bd,

1H, J = 6.5 Hz, OH), 5.01 (bd, J = 6.5 Hz, 1H, 2''-H), 7.26–7.39 (m, 4H, Ar-

H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 21.32, 22.31 (C-3'), 22.40 (2-

CH₃), 26.36 (C-2'), 31.0 (C-1'), 74.4 (C-1''), 106.41 (C-2), 128.50, 129.24

(Ar CH), 134.59, 135.75 (Ar C), 164.41, 165.31 (C-4, C-5) ppm; HRMS

(ESI-TOF): calcd. for C₁₅H₁₈ClNO₄[M + H]⁺312.1003, found 312.1003.

Lower diastereomer 48b, minor isomer: ¹H NMR (600 MHz, CDCl₃):  =

0.71, 0.83 (2d, 6H, J = 6.7 Hz, 3'-H), 1.58 (s, 3H, 2-CH₃) 1.91–1.96 (m, 1H,

2'-H), 2.22–2.32 (m, 2H, 1'-H), 3.45 (bd, J = 3.2 Hz, 1H, OH), 4.96 (bd, J =

3.2 Hz, 1H, 1''-H), 7.30–7.38 (m, 4H, Ar-H) ppm; ¹³C NMR (150 MHz,

CDCl₃):  = 21.34, 22.33, 22.46 (2-CH₃), 26.31 (C-2'), 36.58 (C-1'), 76.17

(C-1''), 106.18 (C-2), 128.42, 129.23, 134.65, 135.72, 164.21, 165.27 ppm.

Upper diastereomer 46a: R_t= 1.19 (HPLC); R_f= 0.52 (Petrolether/EtOAc,

2:1); ¹H NMR (400 MHz, CDCl₃):  = 0.97 (2 d, J = 6.7 Hz, 6H, 3'-H), 1.80

(s, 3H, 2-CH₃), 2.13–2.24 (m, 1H, 2'-H), 2.27–2.50 (m, 4H, 2''-H, 1'-H), 3.08

(bs, 1H, OH), 3.84 (dd, J = 8.8, 4.1 Hz, 1H, 1''-H), 5.14–5.21 (m, 2H, 4''-

H), 5.83 (ddt, J =17.1, 10.2, 6.9, 6.9 Hz, 1H, 3''-H) ppm.

2-(1-Hydroxyethyl)-4-isobutyl-2-isopropyl-5-oxo-2,5-dihydrooxazole

3-

Lower diastereomer 46b: R_t= 1.14 (HPLC); R_f= 0.42 (Petrolether/EtOAc,

2:1); ¹H NMR (600 MHz, CDCl₃):  = 0.97 (2 d, J = 6.7 Hz, 3'-H), 1.73 (s,

3H, 2-CH₃), 2.14–2.54 (m, 5H, 2''-H, 1'-H, 2'-H), 4.04–4.09 (m, 1H, 1''-H),

5.20–5.24 (m, 2H, 4''-H), 5.77–5.88 (m, 1H, 3'-H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 20.5, 22.4, 22.5 (2-CH₃, C-3'), 26.2 (C-2'), 30.0 (C-1'), 35.3 (C-

2''), 70.7 (C-1''), 105.2 (C-2), 120.0 (C-4''), 131.6 (C-4), 132.5 (C-3''), 165.0

(C-5) ppm.

oxide (49). To a cooled (–78 °C) solution of nitrone 38 (415 mg, 2.08 mmol)

in THF (7 mL), Schwesinger base 30 (0.7 mL, 2.29 mmol) was added.

Thereafter, acetaldehyde (0.18 mL, 3.2 mmol) was added and the resulting

reaction mixture was left to stir at this temperature overnight. Then

saturated NH₄Cl solution (50 mL) was added, and when the resulting two-

layer mixture had reached r.t., the layers were separated, and the aqueous

layer was extracted with Et₂O (3 × 50 mL). The combined organic layers

were dried over MgSO₄, filtered, and concentrated in vacuo. Purification

by flash chromatography (petroleum ether/EtOAc, 4:1) gave aldol product

49 (314 mg, 62%) as a single diastereomer. R_f= 0.11 (petroleum

2-(2-Hydroxypropan-2-yl)-4-isobutyl-2-methyl-5-oxo-2,5-dihydrooxazole

3-oxide (47). According to general procedure 5, to a solution of nitrone 29

10.1002/ejoc.202000294

European Journal of Organic Chemistry

FULL PAPER

1

ether/EtOAc, 6:1); ¹H NMR (400 MHz, CDCl₃):  = 0.88 (d, J = 6.8 Hz, 3H,

2'-H or 2'''-H or 3''-H), 0.96, 0.97 (2 d, J = 6.6 Hz, 3H each, 2'-H or 2'''-H or

3''-H), 1.08 (d, J = 7.0 Hz, 3H, 2'-H or 2'''-H or 3''-H), 1.42 (d, J = 6.7 Hz,

3H, 2'-H or 2'''-H or 3''-H), 2.04 (br s, 1H, OH), 2.18 (qq, J = 6.9, 6.9 Hz,

1H, 1'-H), 2.44 (d, J = 7.3 Hz, 2H, 1''-H), 2.63 (qqdd, J = 6.9, 6.9, 6.9, 6.9

Hz, 1H, 2''-H), 4.29 (q, J = 6.7 Hz, 1H, 1'''-H) ppm.

Lower diastereomer 51b: R_f= 0.33 (petroleum ether/Et₂O, 1:1); H NMR

(400 MHz, CDCl₃):  = 1.28, 1.30 (2 d, J = 7.1 Hz, 6H, 2'-H), 1.31 (d, J =

6.6 Hz, 3H, 2''-H), 1.70 (s, 3H, 2-CH₃), 2.07 (br s, 1H, OH), 3.18 (qq, 7.1

Hz, 1H, 1'-H), 4.13 (q, J = 6.6 Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 16.8, 17.3, 17.5, 20.4, 23.7 (2-CH₃, C-1', 2 × C-2', C-2''), 68.8

(C-1''), 104.6 (C-2), 135.6 (C-4), 163.7 (C-5) ppm.

rel-(S)-2-((S)-1-Hydroxyethyl)-2-methyl-5-oxo-4-propyl-2,5-dihydro-

oxazole 3-oxide (50a) and rel-(S)-2-((R)-1-hydroxyethyl)-2-methyl-5-oxo-

4-propyl-2,5-dihydrooxazole 3-oxide (50b). According to general

procedure 5, the nitrone 39 (2.0 g, 12.7 mmol) was dissolved in THF (40

mL) and cooled to –78 °C. To the resulting suspension a solution of

LiHMDS in THF (1M, 13.4 mL, 13.4 mmol) was added dropwise. After 1 h

of stirring, acetaldehyde (1.1 mL, 19.6 mmol) was added and stirring was

continued for 0.5 h at –78 °C. Then saturated NH₄Cl solution (70 mL) was

added, and when the resulting two-layer mixture had reached r.t., the

layers were separated, and the aqueous layer was extracted with Et₂O (3

× 200 mL). The combined organic layers were dried over MgSO₄, filtered,

and concentrated in vacuo. After purification by flash chromatography

(petroleum ether/Et₂O, 2:1) both diastereoisomers 50 were isolated in

1.2:1 ratio (the upper and the lower one respectively) as white crystals

(1.25 g, 49%).

rel-(S)-2-((S)-1-Hydroxypropyl)-2-methyl-4-neopentyl-5-oxo-2,5-

dihydrooxazole 3-oxide (52a) and rel-(S)-2-((R)-1-hydroxypropyl)-2-

methyl-4-neopentyl-5-oxo-2,5-dihydrooxazole 3-oxide (52b). According to

general procedure 5, a solution of cyclic nitrone 43 (1.00 g, 5.39 mmol) in

THF (12 mL) was cooled down to –78 °C and treated with a LiHMDS

solution (1M in THF, 5.67 mL, 5.66 mmol, 949.0 mg) in a dropwise fashion

under nitrogen atmosphere. The resulting yellow suspension was left to

stir for 1 h at –78 °C. Then, propionaldehyde (345 mg, 5.93 mmol) was

added and stirring was continued for 1 h at –78 °C. Thereafter, the reaction

mixture was quenched with saturated NH₄Cl solution (44 mL), brought to

ambient temperature and extracted thrice with EtOAc. The combined

organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo

to give nitrone 52 (770 mg, 59%). The crude product was purified by flash

chromatography on Chromabond Diol (40 g, Biotage Isolera, gradient

heptane/EtOAc, 25mL/min from 0 – 30% EtOAc) to obtain the two

diastereoisomers, 52a (210.0 mg, 16%) as an oil and 52b (210.0 mg, 16%)

as a white solid.

Upper diastereomer 50a: R_f= 0.31 (petroleum ether/EtOAc, 2:1); ¹H NMR

(400 MHz, CDCl₃):  = 0.96 (t, J = 7.4 Hz, 3H, 3'-H), 1.27 (d, J = 6.4 Hz,

3H, 2''-H), 1.67 (qdd, J = 15.0, 7.4, 7.4 Hz, 2H, 2'-H), 1.77 (s, 3H, 2-CH₃),

2.54 (dd, J = 15.2, 7.4 Hz, 2H, 1'-H), 3.02 (br s, 1H, OH), 3.94 (q, J = 6.4

Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 13.8, 18.3, 23.8 (2-

CH₃, C-2'', C-3'), 16.5, 18.3 (C-1', C-2'), 71.5 (C-1''), 104.5 (C-2), 131.7 (C-

4), 164.1 (C-5) ppm.

Upper diastereomer 52a: R_t= 1.24 (HPLC); ¹H NMR (400 MHz, CDCl₃): 

= 1.02 (s, 9H, 3'-H), 1.05 (t, J = 7.5 Hz, 3H, 3''-H), 1.60–1.68 (m, 2H, 2''-

H), 1.78 (s, 3H, 2-CH₃), 2.49 (br s, 2H, 1'-H), 3.21 (bd, J = 2.8 Hz, 1H, OH),

3.63 (dt, J = 10.4, 2.8 Hz, 1''-H) ppm.

Lower diastereomer 52b: R_t= 1.18 (HPLC); ¹H NMR (400 MHz, CDCl₃): 

= 1.02 (s, 9H, 3'-H), 1.08 (t, J = 7.5 Hz, 3H, 3''-H), 1.46–1.52, 1.69–1.78 (2

m, 2H, 2''-H), 1.73 (s, 3H, 2-CH₃), 1.88 (bd, 1H, OH), 2.45, 2.53 (2 d, J =

13.2 Hz, 1'-H), 3.91 (m, 1H, 1''-H) ppm.

Lower diastereomer 50b: R_f= 0.22 (petroleum ether/EtOAc, 2:1); ¹H NMR

(400 MHz, CDCl₃):  = 0.96 (t, J = 7.5 Hz, 3H, 3'-H), 1.33 (d, J = 6.6 Hz,

3H, 2''-H), 1.68 (qdd, J = 14.9, 7.5, 7.5 Hz, 2H, 2'-H), 1.71 (s, 3H, 2-CH₃),

2.16 (br s, 1H, OH), 2.51 (dd, J = 14.2, 7.5 Hz, 1H, 1'-H), 2.58 (dd, J = 14.2,

7.6 Hz, 1H, 1'-H), 4.15 (qd, J = 6.7, 6.6 Hz, 1H, 1''-H) ppm; ¹³C NMR (100

MHz, CDCl₃):  = 13.7, 18.3, 23.8 (2-CH₃, C-2'', C-3'), 16.9, 20.5 (C-1', C-

2'), 68.6 (C-1''), 105.5 (C-2), 132.2 (C-4), 164.7 (C-5) ppm.

rel-(S)-2-((S)-1-Hydroxyethyl)-2-methyl-5-oxo-4-phenyl-2,5-

dihydrooxazole 3-oxide (53a) and rel-(S)-2-((R)-1-hydroxyethyl)-2-methyl-

5-oxo-4-phenyl-2,5-dihydrooxazole 3-oxide (53b). In analogy to general

procedure 5, cyclic nitrone 41 (200 mg, 1.11 mmol) was dissolved in

acetonitrile (1.1 mL) and cooled down to 0 °C. Then acetaldehyde (295 mg,

6.69 mmol) and K₂CO₃(154 mg, 1.11 mmol) were added and the reaction

mixture was left at ambient temperature for 44 h. The reaction mixture was

diluted with H₂O (5 mL) and extracted thrice with DCM (7 mL). The

combined organic phases were dried over Na₂SO₄, filtered and

concentrated under reduced pressure to give 380 mg of a yellow oil, which

was purified by flash chromatography on silica (Biotage Isolera, gradient

rel-(S)-2-((S)-1-Hydroxyethyl)-4-isopropyl-2-methyl-5-oxo-2,5-dihydro-

oxazole 3-oxide (51a) and rel-(S)-2-((R)-1-hydroxyethyl)-4-isopropyl-2-

methyl-5-oxo-2,5-dihydrooxazole 3-oxide (51b). According to general

procedure 5, the nitrone 40 (0.5 g, 3.2 mmol) was dissolved in THF (10

mL) and cooled to –78 °C. To the resulting suspension a solution of

LiHMDS in THF (1M, 3.4 mL, 3.4 mmol) was added dropwise. After 1 h of

stirring, acetaldehyde (0.27 mL, 4.81 mmol) was added and stirring was

continued for 0.5 h at –78 °C. Then saturated NH₄Cl solution (20 mL) was

added, and when the resulting two-layer mixture had reached r.t., the

layers were separated, and the aqueous layer was extracted with Et₂O (3

× 20 mL). The combined organic layers were dried over MgSO₄, filtered,

and concentrated in vacuo. After purification by flash chromatography

(petroleum ether/EtOAc, 5:2) both diastereoisomers 51 were isolated in

2:1 ratio (the upper and the lower one respectively) as white crystals (0.48

g, 75%).

heptane/EtOAc from 0%

– 20% EtOAc, 25 mL/min). The two

diastereomers 53a (28.0 mg, 11%) and 53b (110.0 mg, 42%) could be

isolated as colorless oils.

Upper diastereomer 53a: R_t= 1.07 (HPLC); ¹H NMR (400 MHz, CDCl₃): 

= 1.34 (d, J = 6.4 Hz, 3H, 2'-H), 1.88 (s, 3H, 2-CH₃), 3.12 (d, J = 4.3 Hz,

1H, OH), 4.07 (dd, J = 6.4, 4.2 Hz, 1H, 1'-H), 7.48–7.57, 8.62–8.67 (2 m,

5 H, Ph) ppm.

1

Lower diastereomer 53b: R_t= 1.03 (HPLC); ¹H NMR (400 MHz, CDCl₃): 

= 1.40 (d, J = 6.5 Hz, 3H, 2'-H), 1.82 (s, 3H, 2-CH₃), 2.10 (d, J = 8.0 Hz,

1H, OH), 4.23–4.30 (m, 1H, 1'-H), 7.45–7.55, 8.54–8.76 (2 m, 5H, Ph) ppm.

Upper diastereomer 51a: R_f= 0.42 (petroleum ether/Et₂O, 1:1); H NMR

(400 MHz, CDCl₃):  = 1.26 (d, J = 6.4 Hz, 3H, 2''-H), 1.29, 1.30 (2 d, J =

7.1 Hz, 6H, 2'-H), 1.76 (s, 3H, 2-CH₃), 3.07 (br s, 1H, OH), 3.17 (qq, 7.1

Hz, 1H, 1'-H), 3.93 (q, J = 6.4 Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 16.4, 17.2, 17.3, 18.3, 23.7 (2-CH₃, C-1', C-2', C-2''), 71.5 (C-

1''), 103.7 (C-2), 135.0 (C-4), 163.2 (C-5) ppm.

rel-(S)-2-((S)-1-Hydroxyethyl)-2-methyl-5-oxo-4-(pyridin-2-yl)-2,5-

dihydrooxazole 3-oxide (54a) and rel-(S)-2-((R)-1-hydroxyethyl)-2-methyl-

5-oxo-4-(pyridin-2-yl)-2,5-dihydrooxazole 3-oxide (54b). In analogy to

general procedure 5, cyclic nitrone 42 (540.5 mg, 3.0 mmol) was dissolved

10.1002/ejoc.202000294

European Journal of Organic Chemistry

FULL PAPER

in acetonitrile (30 mL) and cooled down to 0 °C. Then acetaldehyde (793.0

mg, 18.0 mmol) and K₂CO₃(414.6 mg, 3.00 mmol) were added and the

reaction mixture was left at ambient temperature for 4 h. The reaction

mixture was diluted with EtOAc (100 mL), filtered and concentrated under

reduced pressure. Purification by flash chromatography on silica gel

(Biotage Isolera, gradient heptane/EtOAc from 0% – 75% EtOAc) afforded

the two diastereomers of the desired product, nitrone 54a as a pale yellow

solid [167 mg, 24% yield, dr = 95:5 (high/low)] and nitrone 54b (146 mg,

21%) as a white solid [dr = 93:7 (low/high)].

12.9, 13.0, 21.3, 21.6, 22.4, 22.4, 22.48, 22.50, 26.3 (2-CH₃, 3'-H, 2'-H,

cyclopropyl CH), 36.6, 36.7 (C-1'), 78.3, 78.8 (C-1''), 107.4, 107.5 (C-2),

163.4, 164.0 (C-4), 165.5, 165.9 (C-5) ppm; HRMS (ESI-TOF): calcd. for

C₁₂H₁₉NO₃[M + H]⁺226.1443, found 226.1445.

rel-(S)-2-((S)-1-Hydroxybut-3-en-1-yl)-4-isobutyl-2-methyloxazol-5(2H)-

one (57a). According to general procedure 1, nitrone 46a (75.0 mg, 0.31

mmol) was dissolved in THF (3 mL) and the resulting solution was treated

with activated zinc powder (102 mg, 1.55 mmol). After the addition of

NH₄Cl (83 mg, 1.55 mmol) in H₂O (1.5 mL), the grey suspension was

stirred vigorously for 1 h at r.t. Then the reaction mixture was filtered

through a pad of celite, which was rinsed three times with Et₂O. The

combined filtrates were washed with water, the layers were separated, and

the combined organic layers were dried over Na₂SO₄, filtered, and

concentrated in vacuo to give to give oxazolone 57a (70 mg, 95%) as

colorless oil; R_t= 1.31 (HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.99 (2 d,

J = 6.7 Hz, 6H, 3'-H), 1.60 (s, 3H, 2-CH₃), 1.90 (bd, J = 4.9 Hz, OH), 2.23–

2.30 (m, 2H, 2''-H), 2.42–2.57 (m, 3H, 1'-H, 2'-H), 3.71–3.77 (m, 1H, 1''-H),

5.13–5.20 (m, 2H, 4''-H), 5.79–5.89 (m, 1H, 3''-H) ppm.

Upper diastereomer 54a: ¹H NMR (400 MHz, CDCl₃):  = 1.37 (d, J = 6.5

Hz, 3H, 2'-H), 1.89 (s, 3H, 2-CH₃), 3.04 (bs, 1H, OH), 4.12 (q, J = 6.5 Hz,

1H, 1'-H), 7.41 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H, pyridyl), 7.86 (ddd, J = 7.8,

7.8, 1.9 Hz, 1H, pyridyl), 8.45 (ddd, J = 7.9, 0.9, 0.9 Hz, 1H, pyridyl), 8.86

(ddd, J = 4.8, 1.8, 0.8 Hz, 1H, pyridyl) ppm; ¹³C NMR (150 MHz, CDCl₃): 

= 16.5, 18.7 (2-CH₃, C-2'), 71.5 (C-1'), 104.6 (C-2), 120.3, 127.9, 136.9

(pyridyl), 143.8 (C-4), 150.2 (pyridyl), 152.1 (C-4), 161.9 (C-5) ppm.

Lower diastereomer 54b: ¹H NMR (400 MHz, CDCl₃):  = 1.42 (d, J = 6.6

Hz, 3H, 2'-H), 1.79 (s, 3H, 2-CH₃), 2.50–3.50 (bs, 1H, OH), 4.34 (q, 1H, J

= 6.7 Hz, 1'-H), 7.35 (dd, J = 7.6, 4.8 Hz, 1H, pyridyl), 7.77–7.80 (m, 1H,

pyridyl), 8.33–8.35 (m, 1H, pyridyl), 8.77–8.79 (m, 1H, pyridyl) ppm; ¹³C

NMR (150 MHz, CDCl₃):  = low: 17.0, 20.3 (2-CH₃, C-2'), 68.9 (C-1'),

106.0 (C-2), 123.9, 125.2, 136.8 (pyridyl) 143.8 (C-4), 145.0 (pyridyl),

162.7 (C-5), ppm; HRMS (ESI-TOF): calcd. for C₁₁H₁₂N₂O₄[M + H]⁺

237.0875, found 237.0876.

rel-(S)-2-((R)-1-Hydroxybut-3-en-1-yl)-4-isobutyl-2-methyloxazol-5(2H)-

one (57b). According to general procedure 1, nitrone 46b (90 mg, 0.37

mmol) was dissolved in THF (3.5 mL) and the resulting solution was

treated with activated zinc powder (122 mg, 1.86 mmol). After the addition

of NH₄Cl (100 mg, 1.86 mmol) in H₂O (1.75 mL), the grey suspension was

stirred vigorously for 1 h at r.t. Then the reaction mixture was filtered

through a pad of celite, which was rinsed three times with Et₂O. The

combined filtrates were washed with water, the layers were separated, and

the combined organic layers were dried over Na₂SO₄, filtered, and

concentrated in vacuo to give to give oxazolone 57b (60.0 mg, 68%) as

colorless oil; R_t= 1.26 (HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.99 (2 d,

J = 6.7 Hz, 6H, 3'-H), 1.59 (s, 3H, 2-CH₃), 1.81 (bd, J = 4.9 Hz, 1H, OH),

2.24–2.28 (m, 2H, 2''-H), 2.48 (dd, J = 7.3, 3.0 Hz, 1H), 2.51–2.57 (m, 3H,

1'-H, 2'-H), 3.72 (dd, J = 10.0, 3.0 Hz, 1H, 1''-H), 5.13–5.21 (m, 2H, 4''-H),

5.79–5.89 (m, 1H, 3''-H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 20.5, 22.4

(2-CH₃, C-3'), 26.2 (C-2'), 36.1, 36.6 (C-2'', C-1'), 73.6 (C-1''), 106.9 (C-2),

118.8 (C-4''), 133.7 (C-3''), 163.6 (C-4), 165.5 (C-5) ppm; HRMS (ESI-

TOF): calcd. for C₁₂H₁₉NO₃[M + H]⁺226.1443, found 226.1443.

rel-(S)-2-((R)-1-Hydroxypropyl)-4-isobutyl-2-methyloxazol-5(2H)-one

(55b). According to general procedure 1, nitrone 44 (220 mg, 0.96 mmol)

was dissolved in THF (2.5 mL) and the resulting solution was treated with

activated zinc powder (315 mg, 4.82 mmol). After the addition of saturated

NH₄Cl solution (2.5 mL), the grey suspension was stirred vigorously for 40

min at r.t. Then the reaction mixture was filtered through a pad of celite,

which was rinsed with Et₂O (10 mL). The filtrate was treated with water (15

mL), the layers were separated and the aqueous layer was extracted with

Et₂O (3 × 15 mL). The combined organic layers were dried over MgSO₄,

filtered and concentrated in vacuo to provide oxazol-5(2H)-one 55b (150

mg, 73%) as colorless oil. Lower diastereomer 55b: R_f= 0.42 (petroleum

1

ether/EtOAc, 2:1); H NMR (400 MHz, CDCl₃):  = 0.98 (2 d, J = 6.7 Hz,

6H, 3'-H), 1.03 (t, J = 7.4 Hz, 3H, 3''-H), 1.46 (qd, J = 10.3, 7.2 Hz, 1H, 2''-

H), 1.55 (s, 3H, 2-CH₃), 1.78 (qdd, J = 10.0, 7.6, 2.5 Hz, 1H, 2''-H), 2.07

(br s, 1H, OH), 2.18 (qqdd, J = 6.8, 6.8, 6.8, 6.8 Hz, 1H, 2'-H), 2.47 (dd, J

= 14.8, 6.9 Hz, 2H, 1'-H), 3.51 (dd, J = 10.3, 2.5 Hz, 1H, 1''-H) ppm; ¹³C

NMR (100 MHz, CDCl₃):  = 10.6 (C-3''), 20.3, 22.4, 24.4, 26.2, 36.6 (2-

CH₃, C-1', C-2', C-2'', C-3'), 107.7 (C-2), 163.4, 165.5 (C-4, C-5) ppm; The

signal for C-1'' is obscured.

2-(2-Hydroxypropan-2-yl)-4-isobutyl-2-methyloxazol-5(2H)-one

(58).

According to general procedure 1, a solution of nitrone 47 (100 mg, 0.43

mmol) in THF (12 mL) was treated with activated zinc powder (171 mg,

2.61 mmol). After the addition of NH₄Cl solution (140 mg, 2.61 mmol, in 6

mL water), the grey suspension was stirred vigorously for 60 min at r.t.

Then the reaction mixture was diluted with EtOAc, filtered through a pad

of celite, which was rinsed with EtOAc several times. The collected organic

phases were extracted with water, dried over Na₂SO₄, filtered, the filter

cake washed with EtOAc, and concentrated in vacuo to give oxazolone 58

(60.0 mg, 61%, 95% purity) as a colorless oil; R_t= 1.17 (HPLC); ¹H NMR

(600 MHz, CDCl₃):  = 1.00 ("t", J = 6.7 Hz, 6H, 3'-H), 1.29 (s, 3H, 2''-H),

1.33 (s, 3H, 2''-H), 1.61 (s, 3H, 2-CH₃), 2.06 (bs, 1H, OH), 2.16–2.22 (m,

1H, 2'-H), 2.49 (d, J = 7.2 Hz, 2H, 1'-H) ppm; ¹³C NMR (150 MHz, CDCl₃):

 = 20.8 (2-CH₃), 22.4, 22.5, (C-2''), 24.7, 25.0, (C-3'), 26.3 (C-2'), 36.6 (C-

1'), 73.8 (C-1''), 109.3 (C-2), 163.4 (C-4), 165.7 (C-5) ppm; HRMS (ESI-

TOF): calcd. for C₁₁H₁₉NO₃[M + H]⁺214.1443, found 214.1443.

2-(Cyclopropyl(hydroxy)methyl)-4-isobutyl-2-methyloxazol-5(2H)-one (56).

According to general procedure 1, nitrone 45 (560 mg, 2.32 mmol) was

dissolved in THF (17.8 mL) and the resulting solution was treated with

activated zinc powder (910.6 mg, 13.9 mmol). After the addition of NH₄Cl

(745 mg, 13.9 mmol) in H₂O (8.9 mL), the grey suspension was stirred

vigorously for 1 h at r.t. Then the reaction mixture was filtered through a

pad of celite, which was rinsed three times with EtOAc. The combined

organic filtrates were washed with water, the layers were separated, and

the combined organic layers were dried over Na₂SO₄, filtered, and

concentrated in vacuo to give oxazolone 56 (240 mg, 44%) as colorless oil

(isomeric mixture = 58:42) after purification on a diol phase (Chromabond,

Biotage Isolera, gradient heptane/EtOAc, 20mL/min, 3 – 30%EtOAc); R_t=

1.24, 1.25 (HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.36–0.47 (m, 2H,

cyclopropyl), 0.55–0.75 (m, 2H, cyclopropyl), 0.98–1.01 (m, 6H, 3'-H),

1.02–1.12 (m, 1H, cyclopropyl), 1.66, 1.67 (2 s, 3H, 2-CH₃), 2.16–2.25 (m,

1H, 2'-H), 2.46–2.52 (m, 2H, 1'-H), 3.08–3.13 (m, 1H, 1''-H) ppm; ¹³C NMR

(150 MHz, CDCl₃):  = (ca 58:42 ratio) 2.1, 2.4, 4.3, 4.5 (cyclopropyl CH₂),

rel-(S)-2-((R)-1-Hydroxyethyl)-4-isobutyl-2-isopropyloxazol-5(2H)-one

(59b). According to general procedure 1, nitrone 49b (165 mg, 0.68 mmol)

was dissolved in THF (1.5 mL) and the resulting solution was treated with

activated zinc powder (222 mg, 3.4 mmol). After the addition of saturated

NH₄Cl solution (1.5 mL), the grey suspension was stirred vigorously for 40

min at r.t. Then the reaction mixture was filtered through a pad of celite,

which was rinsed with Et₂O (10 mL). The filtrate was treated with water (10

mL), the layers were separated and the aqueous layer was extracted with

10.1002/ejoc.202000294

European Journal of Organic Chemistry

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Et₂O (3 × 10 mL). The combined organic layers were dried over MgSO₄,

filtered, and concentrated in vacuo to give oxazol-5(2H)-one 59 (118 mg,

77%) as colorless oil. R_f= 0.15 (petroleum ether/EtOAc, 6:1); ¹H NMR (400

MHz, CDCl₃):  = 0.84 (d, J = 6.8 Hz, 3H, 2'-H or 2'''-H or 3''-H), 0.95 (d, J

= 6.9 Hz, 3H, 2'-H or 2'''-H or 3''-H), 1.00 (d, J = 6.7 Hz, 6H, 2'-H or 2'''-H

or 3''-H), 1.23 (d, J = 6.5 Hz, 3H, 2'-H or 2'''-H or 3''-H), 1.78 (br s, 1H, OH),

2.19 (qq, J = 6.8, 6.8 Hz, 1H, 1'-H), 2.50 (dd, J = 14.9, 6.9 Hz, 2H, 1''-H),

2.52 (qqdd, J = 6.9, 6.9, 6.9, 6.9 Hz, 1H, 2''-H), 4.29 (q, J = 6.5 Hz, 1H, 1'''-

H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 16.1, 17.4, 22.4, 22.5, 26.4, 31.1,

36.6 (C-1', C-1'', C-2', C-2'', C-2''', C-3''), 67.8 (C-1'''), 110.8 (C-2), 164.4,

165.8 (C-4, C-5) ppm.

3H, 2''-H), 1.55 (s, 3H, 2-CH₃), 2.25 (br s, 1H, OH), 2.97 (qq, J = 6.9, 6.9

Hz, 1H, 1'-H), 3.82 (q, J = 6.5 Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 17.4, 19.1, 19.2, 20.2, 28.1 (2-CH₃, C-1', C-2', C-2''), 71.0 (C-

1''), 107.2 (C-2), 164.7, 168.3 (C-4, C-5) ppm.

rel-(S)-2-((S)-1-Hydroxypropyl)-2-methyl-4-neopentyloxazol-5(2H)-one

(62a). According to general procedure 1, nitrone 52a (210 mg, 0.86 mmol)

was dissolved in THF (2.5 mL) and the resulting solution was treated with

activated zinc powder (339 mg, 5.17 mmol). After the addition of NH₄Cl

(277 mg, 5.17 mmol) in H₂O (1.30 mL), the grey suspension was stirred

vigorously for 1 h at r.t. Then the reaction mixture was filtered through a

pad of celite, which was rinsed three times with EtOAc. The combined

organic filtrates were washed with water. The combined organic layers

were dried over Na₂SO₄, filtered, and concentrated in vacuo to give pure

oxazolone 62a (155 mg, 79%) as white solid; R_t= 1.34 (HPLC); ¹H NMR

(600 MHz, CDCl₃):  = 1.04 (s, 9H, 3'-H), 1.05 (t, J = 7.4 Hz, 3H, 3''-H),

1.47–1.52, 1.70–1.76 (2 m, 2H, 2''-H), 1.60 (s, 3H, 2-CH₃), 1.90 (bs, 1H,

OH), 2.47, 2.56 (2 d, J = 13.2 Hz, 2H, 1'-H), 3.61 (dd, J = 10.3, 2.1 Hz, 1''-

H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 10.6 (C-3''), 21.0 (2-CH₃), 24.7

(C-1'), 29.4 (C-3'), 32.2 (C-2'), 40.1 (C-2''), 76.8 (C-1''), 107.1 (C-2), 163.1

(C-4), 166.0 (C-5) ppm; HRMS (ESI-TOF): calcd. for C₁₂H₂₁NO₃[M + H]⁺

228.1600, found 228.1600.

rel-(S)-2-((S)-1-Hydroxyethyl)-2-methyl-4-propyloxazol-5(2H)-one (60a)

and

rel-(S)-2-((R)-1-hydroxyethyl)-2-methyl-4-propyloxazol-5(2H)-one

(60b). According to general procedure 1, nitrone 50 (0.5 g, 2.5 mmol) was

dissolved in THF (6 mL) and the resulting solution was treated with

activated zinc powder (0.81 g, 12.4 mmol). After the addition of saturated

NH₄Cl solution (6 mL), the grey suspension was stirred vigorously for 40

min at r.t. Then the reaction mixture was filtered through a pad of celite,

which was rinsed with Et₂O (20 mL). The filtrate was treated with water (30

mL), the layers were separated and the aqueous layer was extracted with

Et₂O (3 × 30 mL). The combined organic layers were dried over MgSO₄,

filtered, and concentrated in vacuo to give oxazol-5(2H)-one 60 (0.30 g,

65%) as colorless oil.

rel-(S)-2-((R)-1-Hydroxypropyl)-2-methyl-4-neopentyloxazol-5(2H)-one

(62b). According to general procedure 1, nitrone 52b (210 mg, 0.86 mmol)

was dissolved in THF (2.5 mL) and the resulting solution was treated with

activated zinc powder (339.0 mg, 5.17 mmol). After the addition of NH₄Cl

(277 mg, 5.17 mmol) in H₂O (1.30 mL), the grey suspension was stirred

vigorously for 1 h at r.t. Then the reaction mixture was filtered through a

pad of celite, which was rinsed three times with EtOAc. The combined

organic filtrates were washed with water, the layers were separated the

combined organic layers were dried over Na₂SO₄, filtered, and

concentrated in vacuo to give oxazolone 62b (130.0 mg, 64%, 95% pure)

as an oil; R_t= 1.32 (HPLC). ¹H NMR (600 MHz, CDCl₃):  = 1.04 (s, 9H,

3'-H), 1.05 (t, J = 7.4 Hz, 3H, 3''-H), 1.44–1.52, 1.76–1.85 (2 m, 2H, 2''-H),

1.56 (s, 3H, 2-CH₃), 1.76 (bs, 1H, OH), 2.48, 2.54 (2 d, J = 13.4 Hz, 1'-H),

3.53 (bd, J = 10.1 Hz, 1''-H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 10.6 (C-

3''), 20.3 (2-CH₃), 24.5 (C-1'), 29.4 (C-3'), 32.1 (C-2'), 40.01 (C-2''), 76.7

(C-1''), 107.5 (C-2), 162.7 (C-4), 166.0 (C-5) ppm; HRMS (ESI-TOF): calcd.

for C₁₂H₂₁NO₃[M + H]⁺228.1600, found 228.1600.

1

Upper diastereomer 60a: R_f= 0.32 (petroleum ether/Et₂O, 2:1); H NMR

(400 MHz, CDCl₃):  = 0.99 (t, J = 7.4 Hz, 3H, 3'-H), 1.26 (d, J = 6.5 Hz,

3H, 2''-H), 1.57 (s, 3H, 2-CH₃), 1.74 (qdd, J = 14.9, 7.4, 7.4 Hz. 2H, 2'-H),

2.17 (br s, 1H, OH), 2.57 (dd, J = 14.9, 7.4 Hz, 2H, 1'-H), 3.88 (q, J = 6.4

Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 13.6, 17.4, 19.1, 20.6,

29.8 (2-CH₃, C-1', C-2', C-2'', C-3'), 71.2 (C-1''), 107.4 (C-2), 164.3, 165.3

(C-4, C-5) ppm.

1

Lower diastereomer 60b: R_f= 0.25 (petroleum ether/Et₂O, 2:1); H NMR

(400 MHz, CDCl₃):  = 0.99 (t, J = 7.4 Hz, 3H, 3'-H), 1.30 (d, J = 6.5 Hz,

3H, 2''-H), 1.54 (s, 3H, 2-CH₃), 1.74 (qdd, J = 14.9, 7.4, 7.4 Hz. 2H, 2'-H),

2.40 (br s, 1H, OH), 2.56 (dd, J = 15.0, 7.4 Hz, 2H, 1'-H), 3.82 (q, J = 6.4

Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz, CDCl₃):  = 13.6, 17.5, 19.1, 20.1,

29.8 (2-CH₃, C-1', C-2', C-2'', C-3'), 71.0 (C-1''), 107.6 (C-2), 164.1, 165.3

(C-4, C-5) ppm.

rel-(S)-2-((S)-1-Hydroxyethyl)-2-methyl-4-phenyloxazol-5(2H)-one (63a).

According to general procedure 1, nitrone 53a (80 mg, 0.34 mmol) was

dissolved in THF (2.0 mL) and the resulting solution was treated with

activated zinc powder (111.0 mg, 1.70 mmol). After the addition of NH₄Cl

(245 mg, 4.58 mmol)) in H₂O (2.0 mL), the grey suspension was stirred

vigorously for 10 min at r.t. Then the reaction mixture was filtered and

washed three times with CH₂Cl₂. The combined organic filtrates were

washed with water, the layers were separated, and the organic layer was

dried over Na₂SO₄, filtered and concentrated in vacuo to give after

purification by flash chromatography on silica (Biotage Isolera, gradient

heptane/EtOAc/2%NEt₃from 0% – 100% EtOAc) oxazolone 63a (10 mg,

13%) as a slightly yellow oil; R_t= 1.11 (HPLC); ¹H NMR (400 MHz, CDCl₃):

 = 1.35 (d, J = 6.4 Hz, 3H, 2'-H), 1.70 (s, 3H, 2-CH₃), 1.88 (bs, 1H, OH),

3.97 (q, J = 6.4 Hz, 1H, 1'-H,), 7.50–7.60, 8.37–8.41 (2 m, 5H, Ph) ppm;

¹³C NMR (150 MHz, CDCl₃, contains some DMSO):  = 17.6 (C-2'), 20.7

(2-CH₃), 71.7 (C-1'), 107.5 (C-2), 128.6 (Ph), 128.7 (Ph), 128.8 (Ph), 132.6

(Ph), 157.1 (C-4), 164.2 (C-5) ppm; HRMS (ESI-TOF): calcd. for

C₁₂H₁₃NO₃[M + H]⁺220.0974, found 220.0976.

rel-(S)-2-((S)-1-Hydroxyethyl)-4-isopropyl-2-methyloxazol-5(2H)-one

(61a) and rel-(S)-2-((R)-1-Hydroxyethyl)-4-isopropyl-2-methyloxazol-

5(2H)-one (61b). According to general procedure 1, nitrone 51 (0.30 g, 1.5

mmol) was dissolved in THF (4 mL) and the resulting solution was treated

with activated zinc powder (0.49 g, 7.5 mmol). After the addition of

saturated NH₄Cl solution (4 mL), the grey suspension was stirred

vigorously for 40 min at r.t. Then the reaction mixture was filtered through

a pad of celite, which was rinsed with Et₂O (15 mL). The filtrate was treated

with water (20 mL), the layers were separated and the aqueous layer was

extracted with Et₂O (3 × 20 mL). The combined organic layers were dried

over MgSO₄, filtered and concentrated in vacuo to provide oxazol-5(2H)-

one 61 (209 mg, 76%) as colorless oil.

1

Upper diastereomer 61a: R_f= 0.35 (petroleum ether/Et₂O, 2:1); H NMR

(400 MHz, CDCl₃):  = 1.23 (d, J = 6.5 Hz, 3H, 2''-H), 1.27 (d, J = 6.9 Hz,

6H, 2'-H), 1.56 (s, 3H, 2-CH₃), 2.14 (br s, 1H, OH), 2.96 (qq, J = 6.9, 6.9

Hz, 1H, 1'-H), 3.86 (q, J = 6.5 Hz, 1H, 1''-H) ppm; ¹³C NMR (100 MHz,

CDCl₃):  = 17.3, 19.1, 19.2, 20.6, 28.1 (2-CH₃, C-1', C-2', C-2''), 71.3 (C-

1''), 106.9 (C-2), 164.7, 168.3 (C-4, C-5) ppm.

rel-(S)-2-((R)-1-Hydroxyethyl)-2-methyl-4-phenyloxazol-5(2H)-one (63b).

According to general procedure 1, nitrone 53b (300 mg, 1.27 mmol) was

dissolved in THF (5.5 mL) and the resulting solution was treated with

activated zinc powder (417 mg, 6.37 mmol). After the addition of NH₄Cl

1

Lower diastereomer 61b: R_f= 0.31 (petroleum ether/Et₂O, 2:1); H NMR

(400 MHz, CDCl₃):  = 1.27 (d, J = 6.9 Hz, 6H, 2'-H), 1.29 (d, J = 6.5 Hz,

10.1002/ejoc.202000294

European Journal of Organic Chemistry

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(428.5 mg, 8.01 mmol) in H₂O (5.5 mL), the grey suspension was stirred

vigorously for 10 min at r.t. Then the reaction mixture was filtered and

washed three times with CH₂Cl₂. The combined organic filtrates were

washed with water, the layers were separated, and the organic layer was

dried over Na₂SO₄, filtered and concentrated in vacuo to give, after

purification by flash chromatography on silica (Biotage Isolera, gradient

heptane/EtOAc/2%NEt₃from 0% - 100% EtOAc), oxazolone 63b (49 mg

1H, 1'-H), 2.50 (dd, J = 14.1, 7.2 Hz, 1H, 1'-H), 5.35 (q, J = 6.6 Hz, 1H, 1''-

H) ppm.

1

Lower diastereomer 65b: H NMR (400 MHz, CDCl₃):  = 0.78–0.96 (m,

4H, cyclopropyl), 0.97 (d, J = 6.7 Hz, 6H, 3'-H), 1.42 (d, J = 6.8 Hz, 3H, 1''-

H), 1.43–1.49 (m, 1H, cyclopropyl), 1.73 (s, 3H, 2-CH₃), 2.17 (m, 1H, 2'-H),

2.42 (dd, J = 13.4, 7.6 Hz, 1H, 1'-H_A), 2.51 (dd, J = 13.5, 6.8 Hz, 1H, 1'-

HB), 5.31 (q, J = 6.5Hz, 1H, 1''-H) ppm.

1

(17%) in a ratio low/high = 88:12; R_t= 1.11 (HPLC); H NMR (400 MHz,

CDCl₃):  = 1.38 (d, J = 6.4 Hz, 3H, 2'-H), 1.67 (s, 3H, 2-CH₃), 19.7 (bs,

1H, OH), 3.95 (q, J = 6.4 Hz, 1H, 1'-H), 7.45–7.60 (m, 5H, Ph) ppm; ¹³C

NMR (150 MHz, CDCl₃):  = 17.6 (C-2'), 20.2 (2-CH₃), 71.4 (C-1'), 106.7

(C-2), 128.5 (Ph), 128.8 (Ph), 132.6 (Ph), 156.9 (C-4), 164.3 (C-5) ppm;

HRMS (ESI-TOF): calcd. for C₁₂H₁₃NO₃[M + H]⁺220.0974, found

220.0972.

rel-(S)-2-((R)-1-(((4-Bromophenyl)carbamoyl)oxy)ethyl)-4-isobutyl-2-

methyl-5-oxo-2,5-dihydrooxazole 3-oxide (66b). Under

a

nitrogen

atmosphere nitrone 21b (75.9 mg, 0.35 mmol) in CH₂Cl₂(5 mL) and 4-

bromophenylisocyanate (36.3 mg, 0.28 mmol) were treated with N,N-

diisopropylethylamine (36.3 mg, 0.28 mmol) and the mixture was stirred at

room temperature for 1 d. After evaporation of the solvents in vacuo, the

crude mixture was directly purified by flash chromatography on a diol

phase (Biotage Isolera, gradient heptane/EtOAc from 3% – 30% EtOAc)

and then on silica (gradient heptane/EtOAc from 3% – 30% EtOAc) and

on Luna C18 (Gilson GX; acetonitrile/water) to give nitrone 66b (35.0 mg,

32%, purity 95%) as a white solid; R_t= 1.56 min (HPLC); ¹H NMR (400

MHz, CDCl₃):  = 0.91, 0.93 (2 d, J = 6.4 Hz, 6H, 3'-H), 1.49 (d, J = 6.7 Hz,

3H, 2''-H), 1.76 (s, 3H, 2-CH₃), 2.10–2.17 (bm, 1H, 2'-H), 2.37–2.45 (bm,

2H, 1'-H), 5.37 (q, J = 6.8 Hz, 1H, 1''-H); 6.55 (bs, 1H, NH), 7.21 (bd, J =

8.1 Hz, 2H, Ar-H), 7.38–7.41 (m, 2H, Ar-H) ppm.

rel-(S)-2-((S)-1-Acetoxyethyl)-4-isobutyl-2-methyl-5-oxo-2,5-

dihydrooxazole 3-oxide (64a) and rel-(S)-2-((R)-1-Acetoxyethyl)-4-

isobutyl-2-methyl-5-oxo-2,5-dihydrooxazole 3-oxide (64b). Under an

argon atmosphere hydroxynitrone 21 (400.0 mg, 1.85 mmol) was diluted

with dry CH₂Cl₂(18.6 mL), then triethylamine (282.1 mg, 2.78 mmol),

DMAP (45.4 mg, 0.37 mmol) and at last acetyl chloride (160.5 mg, 2.04

mmol) were added in small portions followed by stirring of the mixture for

2 h at r.t. Thereafter, the reaction mixture was poured on saturated

aqueous NaHCO₃solution (15 mL). After separation of the organic layer,

the aqueous layer was extracted thrice with CH₂Cl₂(30 mL). The combined

organic layers were washed with saturated aqueous NaHCO₃solution (15

mL). The organic layer was dried over Na₂SO₄, filtered and evaporated in

vacuo. The crude product was purified by flash chromatography on silica

(Biotage Isolera, gradient heptane/EtOAc from 5% – 100% EtOAc, 50 g

SiO₂, 100 mL/min) to give acetate derivatives 64a (210 mg, 54%) and 64b

(188 mg, 39%) as slightly yellow oils.

rel-(S)-4-Isobutyl-2-methyl-2-((S)-1-((3-methylbutanoyl)oxy)ethyl)-5-oxo-

2,5-dihydrooxazole 3-oxide (67a) and rel-(S)-4-Isobutyl-2-methyl-2-((R)-1-

((3-methylbutanoyl)oxy)ethyl)-5-oxo-2,5-dihydrooxazole 3-oxide (67b).

Under an argon atmosphere hydroxynitrone 21 (250.0 mg, 1.16 mmol) was

diluted with dry CH₂Cl₂(11.6 mL), then triethylamine (176.3 mg, 1.74

mmol), DMAP (28.4 mg, 0.23 mmol) and at last 3-methylbutanoyl chloride

(154.1 mg, 1.27 mmol) were added and the mixture was stirred for 1 h at

r.t. Thereafter, the reaction mixture was poured on saturated aqueous

NaHCO₃solution (15 mL). After separation of the organic layer, the

aqueous layer was extracted thrice with CH₂Cl₂(30 mL). The combined

organic layers were washed with saturated aqueous NaHCO₃solution (15

mL). The organic layer was dried over Na₂SO₄, filtered and evaporated in

vacuo. The crude product was purified by flash chromatography on silica

(Biotage Isolera, gradient heptane/EtOAc from 5% – 40% EtOAc, 40 g

SiO₂, 50 mL/min) to give nitrone ester 67a (95.0 mg, 27%) and nitrone

ester 67b (159.0 mg, 46%) as colorless oils.

Upper diastereomer 64a: ¹H NMR (400 MHz, CDCl₃):  = 0.97, 0.98 (2 d,

J = 6.7 Hz, 3H each, 3'-H), 1.30 (d, J = 6.7 Hz, 3H, 2''-H), 1.77 (s, 3H, 2-

CH₃), 2.07 (s, 3H, Ac), 2.15–2.23 (m, 1H, 2'-H), 2.43 (dd, J = 13.8, 7.3 Hz,

1H, 1'-H_A), 2.51 (dd, J = 13.8, 7.0 Hz, 1H, 1'-H_B), 5.32 (q, J = 6.7 Hz, 1H,

1''-H) ppm.

Lower diastereomer 64b: ¹H NMR (400 MHz, CDCl₃):  = 0.97 (2 d, J = 6.7

Hz, 6H, 3'-H), 1.43 (d, J = 6.5 Hz, 3H, 2''-H), 1.73 (s, 3H, 2-CH₃), 1.96 (s,

3H, Ac), 2.12–2.19 (m, 1H, 2'-H), 2.37–2.53 (m, 2H, 1'-H), 5.28 (q, J = 6.50

Hz, 1H, 1''-H) ppm. )

1

Upper diastereomer 67a: H NMR (400 MHz, CDCl₃):  = 0.93–0.99 (m,

rel-(S)-2-((S)-1-((Cyclopropanecarbonyl)oxy)ethyl)-4-isobutyl-2-methyl-5-

12H, 3'-H, 3'''-H), 1.30 (d, J = 6.7 Hz, 3H, 2''-H), 1.77 (s, 3H, 2-CH₃), 2.03–

2.10 (m, 1H, 2'''-H), 2.15–2.22 (m, 3H, 1'''-H, 2'-H), 2.43 (dd, J = 14.1, 7.5

Hz, 1H, 1'-H_A), 2.50 (dd, J = 14.1, 6.8 Hz, 1H, 1'-H_B), 5.33 (q, J = 6.7 Hz,

1H, 1''-H) ppm.

oxo-2,5-dihydrooxazole

3-oxide

(65a)

and

rel-(S)-2-((R)-1-

((Cyclopropanecarbonyl)oxy)ethyl)-4-isobutyl-2-methyl-5-oxo-2,5-

dihydrooxazole 3-oxide (65b). Under an argon atmosphere hydroxynitrone

21 (50.0 mg, 0.23 mmol) was diluted with dry CH₂Cl₂(2.3 mL), then

triethylamine (35.3 mg, 0.34 mmol), DMAP (5.7 mg,0.04 mmol) and at last

cyclopropanecarbonyl chloride (26.7 mg, 0.25 mmol) were added and the

mixture stirred for 6 h at r.t. The reaction mixture was poured on saturated

aqueous NaHCO₃solution (5 mL). After separation of the layers, the

aqueous layer was extracted thrice with CH₂Cl₂(10 mL). The combined

organic layers were washed with saturated aqueous NaHCO₃solution (5

mL). The organic layer was dried over Na₂SO₄, filtered and evaporated in

vacuo. The crude product was purified by flash chromatography on silica

(Biotage Isolera, gradient heptane/EtOAc from 0% – 20% EtOAc, 15 g

SiO₂, 25 ml/min) to give nitrone ester 65a (14.0 mg, 21%) and nitrone ester

65b (45.0 mg, 69%), both as slightly yellow oils.

Lower diastereomer 67b: ¹H NMR (400 MHz, CDCl₃):  = 0.88, 0.89, 0.95,

0.96 (4 d, 12H, 3'-H, 4'''-H), 1.40 (d, J = 6.5 Hz, 3H, 2''-H), 1.73 (s, 3H, 2-

CH₃), 1.94–2.02 (m, 1H, 3'''-H), 2.05–2.07 (m, 2H, 2'''-H), 2.12–2.19 (m,

1H, 2'-H), 2.38-2.47 (m, 2H, 1'-H), 5.29 (q, J = 6.5 Hz, 1H, 1''-H) ppm.

rel-(S)-4-Isobutyl-2-((S)-1-((methoxycarbonyl)oxy)ethyl)-2-methyl-5-oxo-

2,5-dihydrooxazole 3-oxide (68a) and rel-(S)-4-Isobutyl-2-((R)-1-

((methoxycarbonyl)oxy)ethyl)-2-methyl-5-oxo-2,5-dihydrooxazole 3-oxide

(68b). Under an argon atmosphere, hydroxynitrone 21 (1.00 g, 4.64 mmol)

was diluted with dry CH₂Cl₂(46.5 mL), then triethylamine (705 mg, 6.96

mmol) and DMAP (114 mg, 0.92 mmol), and at last methylchloroformate

(483 mg, 5.11 mmol) were added. The mixture was stirred overnight, then

additional trimethylamine (1.410 g, 13.92 mmol), DMAP (228 mg, 1.84

mmol) and methylchloroformate (966 mg, 10.22 mmol) were added in two

portions during about 36 h. The reaction mixture was poured on saturated

1

Upper diastereomer 65a: H NMR (400 MHz, CDCl₃):  = 0.89–0.94 (m,

2H, cyclopropyl), 0.99 (t, J = 6.3 Hz, 6H, 3'-H), 1.01–1.05 (m, 2H,

cyclopropyl), 1.28 (d, J = 6.6 Hz, 3H, 2''-H), 1.55–1.59 (m, 1H, cyclopropyl),

1.77 (s, 3H, 2-CH₃), 2.15–2.22 (m, 1H, 2'-H), 2.44 (dd, J = 14.1, 7.5 Hz,

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European Journal of Organic Chemistry

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aqueous NaHCO₃solution (50 mL). After separation of the organic layer,

the aqueous layer was extracted twice with CH₂Cl₂(50 mL). The combined

organic layers were washed with saturated aqueous NaHCO₃solution (25

mL). The organic layer was dried over MgSO₄, filtered and evaporated in

vacuo. The crude product was purified by flash chromatography on silica

(Biotage Isolera, gradient heptane/EtOAc from 0% – 100% EtOAc, 40 g

SiO₂, 100 mL/min) to give carbonate 68a (344 mg, 27%) as an oil (dr =

85:15 (high:low) and 68b (410 mg, 32%) as an oil.

of saturated aqueous NH₄Cl solution (4.5 mL), the grey suspension was

stirred vigorously for 30 min at r.t. Then the reaction mixture was filtered

through a pad of celite, which was rinsed with CH₂Cl₂(15 mL). The

combined organic filtrates were washed with water (10 mL). After

separation of the layers, the water layer was re-extracted twice with CH₂Cl₂

(15 mL). The combined organic layers were dried over Na₂SO₄, filtered,

and concentrated in vacuo to give oxazolone acetate 70b (135.0 mg, 77%,

purity 65%), which was purified by flash chromatography on spherical silica

(Biotage Isolera, 2% NEt₃/heptane, then gradient heptane/EtOAc from 0%

– 100% EtOAc, 36 mL/min) to give 70b (97 mg, 55%) as an oil; R_t= 1.39

(HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.98 (d, J = 6.5 Hz, 3H, 3'-H), 0.99

(d, J = 6.7 Hz, 6H, 3'-H), 1.35 (d, J = 6.5 Hz, 3H, 2''-H), 1.57 (s, 3H, 2-CH₃),

1.990 (s, 3H, Ac), 2.13–2.20 (m, 1H, 2'-H), 2.46–2.48 (m, 2H, 1'-H), 5.10

(q, J = 6.5 Hz 1H, 1''-H) ppm.

Upper diastereomer 68a: ¹H NMR (600 MHz, CDCl₃):  = 0.97 ("t", J = 6.3

Hz, 6H, 3'-H), 1.38 (d, J = 6.6 Hz, 3H, 2''-H), 1.80 (s, 3H, 2-CH₃), 2.15–

2.22 (m, 1H, 2'-H), 2.42 (dd, J = 13.8, 7.4 Hz, 1H, 1'-H_A), 2.51 (dd, J = 13.8,

7.2 Hz, 1H, 1'-H_B), 3.80 (s, 3H, OCH₃), 5.15 (q, J = 6.6 Hz, 1H, 1''-H) ppm;

¹³C NMR (150 MHz, CDCl₃):  = 13.3 (C-2''), 20.7, 22.4, 22.6, 26.3 (2-CH₃,

C-2', C-3'), 30.8 (C-1'), 55.3 (OCH₃), 74.4 (C-1''), 103.4 (C-2), 131.8 (C-4),

154.6 (OC=O), 164.5 (C-5) ppm.

rel-(S)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

cyclopropanecarboxylate (71a). According to general procedure 1, a

solution of nitrone 65a (62.0 mg, 0.21 mmol) in THF (1.5 mL) was treated

with activated zinc powder (72.0 mg, 1.09 mmol). After the addition of

saturated aqueous NH₄Cl solution (1.5 mL) the grey suspension was

stirred vigorously for 30 min at r.t. Then the reaction mixture was filtered

and the filter washed with CH₂Cl₂(10 mL). The combined organic filtrates

were washed with water (10 mL). After separation of the layers, the water

layer was re-extracted twice with CH₂Cl₂(5 mL). The combined organic

layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give,

after purification by flash chromatography on silica (15 g) (Biotage Isolera,

2% NEt₃/heptane, then gradient heptane/EtOAc from 5% – 40% EtOAc,

25 mL/min) pure oxazolone ester 71a (23.0 mg, (39%) as a colorless oil;

R_t= 1.43 (HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.81–1.01 (m, 4H,

cyclopropyl), 1.02 (2 d, J = 6.7 Hz, 6H, 3'-H), 1.30 (d, J = 6.4 Hz, 3H, 2''-

H), 1.47–1.53 (m, 1H, cyclopropyl), 1.60 (s, 3H, 2-CH₃), 2.17–2.23 (m, 1H,

2'-H), 2.47 (dd, J = 14.6, 6.4 Hz, 1H, 1'-H_A), 2.40 (dd, J = 14.6, 7.5 Hz, 1H,

1'-H_B), 5.21 (q, J = 6.5 Hz, 1H, 1''-H) ppm.

Lower diastereomer 68b: ¹H NMR (400 MHz, CDCl₃):  = 0.94, 0.96 (2 d,

J = 6.7 Hz, 6H, 3'-H), 1.49 (d, J = 6.5 Hz, 3H, 2''-H), 1.73 (s, 3H, 2-CH₃),

2.11–2.21 (m, 1H, 2'-H), 2.39 (dd, J = 13.8, 7.5 Hz, 1H, 1'-H_A), 2.51 (dd, J

= 13.8, 7.15 Hz, 1H, 1'-H_B), 3.73 (s, 3H, OCH₃), 5.16 (q, 1H, J = 6.5 Hz,

1''-H) ppm.

para-Bromobenzoate 69b. Under a nitrogen atmosphere, nitrone 44b (200

mg, 0.87 mmol) was dissolved in CH₂Cl₂(5 mL) and cooled to 0 °C. Then

trimethylamine (183 L, 133 mg, 1.30 mmol) and 4-dimethylaminopyridine

(DMAP) (21.3 mg, 0.17 mmol) and at last 4-bromobenzoyl chloride (211

mg, 0.96 mmol) were added followed by stirring of the mixture overnight at

ambient temperature. After treatment with additional trimethylamine (133

mg, 1.30 mmol) and 4-bromobenzoyl chloride (211 mg, 0.96 mmol), the

reaction was concentrated after 3 d and the residue purified without further

work-up by flash chromatography on silica (Biotage Isolera, gradient

heptane/EtOAc from 0–30% EtOAc) to give pure benzoate 69b (175 mg,

46%) as an oil. R_t= 1.80 (HPLC); ¹H NMR (400 MHz, CDCl₃):  = 0.74 (d,

J = 6.7 Hz, 6H, 3'-H), 1.00 (t, J = 7.5 Hz, 3H, 3''-H), 1.80 (s, 3H, 2-CH₃),

1.87–1.99 (m, 3H, 2'-H, 2''-H), 2.28 (dd, J = 7.2, 2.5 Hz, 1'-H), 5.63 (dd, J

= 9.3, 3.7 Hz, 1''-H), 7.20-7.62 (m, 2H, Ar-H), 7.78-7.84 (m, 2H, Ar-H) ppm.

rel-(R)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

cyclopropanecarboxylate (71b). According to general procedure 1, a

solution of nitrone 65b (400 mg, 1.41 mmol) in THF (10 mL) was treated

with activated zinc powder (462 mg, 7.05 mmol). After the addition of

saturated aqueous NH₄Cl solution (10 mL) the grey suspension was stirred

vigorously for 2 h at r.t. Then the reaction mixture was filtered and the filter

washed with CH₂Cl₂(20 mL). The combined organic filtrates were washed

with water (10 mL). After separation of the layers the water layer was re-

extracted twice with CH₂Cl₂(10 mL). The combined organic layers were

dried over Na₂SO₄, filtered, and concentrated in vacuo to give, after

purification by flash chromatography on silica (15 g) (Biotage Isolera,

gradient heptane/EtOAc from 0% – 100% EtOAc, 75 mL/min) pure

oxazolone ester 71b (370.0 mg, 98%) as a colorless oil; R_t= 1.50 (HPLC);

¹H NMR (600 MHz, CDCl₃):  = 0.83-0.97 (m, 4H, cyclopropyl), 1.00 (2d, J

= 6.8 Hz, 6H, 3'-H), 1.36 (d, J = 6.5 Hz, 3H, 1''-H), 1.48–1.52 (m, 1H,

cyclopropyl), 1.57 (s, 3H, 2-CH₃), 2.14–2.21 (m, 1H, 2-H), 2.48 (d, J = 6.8

Hz, 2H, 1'-H), 5.15 (q, J = 6.5 Hz, 1H, 1''-H) ppm; ¹³C NMR (150 MHz,

CDCl₃):  = 8.75, 8.82, (cyclopropyl CH₂), 12.8, 15.3, 21.3, 22.4, 22.5, 26.1

(C-2'', 2-CH₃, C-3', cyclopropyl CH, C-2'), 36.5 (C-1'), 70.8 (C-1''), 105.8

(C-2), 163.8 (C-4), 165.4 (C-5), 173.3 (cyclopropyl-C=O) ppm.

rel-(S)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

acetate (70a). According to general procedure 1, nitrone 64a (217.0 mg,

0.84 mmol) was dissolved in THF (5.5 mL) and the resulting solution was

treated with activated zinc powder (276.0 mg, 4.21 mmol). After the

addition of saturated aqueous NH₄Cl solution (5.5 mL), the grey

suspension was stirred vigorously for 30 min at r.t. Then the reaction

mixture was filtered through a pad of celite, which was rinsed with CH₂Cl₂

(15 mL). The combined organic filtrates were washed with water (10 mL).

After separation of the layers, the water layer was re-extracted twice with

CH₂Cl₂(10 mL). The combined organic layers were dried over Na₂SO₄,

filtered, and concentrated in vacuo to give oxazolone acetate 70a (193.0

mg, 95%, purity 84%), which was purified by flash chromatography on

spherical silica (Biotage Isolera, 2% NEt₃/heptane, then gradient

heptane/EtOAc from 0% – 100% EtOAc, 36 mL/min) to give oxazolone 70a

(79.0 mg, 39%) as an oil; R_t= 1.40 (HPLC); ¹H NMR (600 MHz, CDCl₃): 

= 1.00 (2 d, J = 6.7 Hz, 6H, 1.07 Hz, 3'-H), 1.30 (d, J = 6.5 Hz, 3H, 2''-H),

1.58 (s, 3H, 2-CH₃), 1.99 (s, 3H, Ac), 2.16–2.23 (m, 1H, 2'-H), 2.45, 2.53

(2 dd, J = 14.7, 7.2 Hz, 2H, 1'-H), 5.2 (q, J = 6.5 Hz, 1H, 1''-H) ppm; ¹³C

NMR (150 MHz, CDCl₃):  = 15.2 (C-2''), 20.9, 21.3, 22.4, 26.3 (2-CH₃, C-

3', Ac), 36.6 (C-1'), 71.3 (C-1''), 105.4 (C-2), 164.3 (C-4), 165.1 (C-5),

169.56 (acetate C=O) ppm.

rel-(S)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

3-

methylbutanoate (72a). According to general procedure 1, nitrone 67a

(74.0 mg, 0.24 mmol) was dissolved in THF (2.0 mL) and the resulting

solution was treated with activated zinc powder (81.0 mg, 1.23 mmol).

After the addition of saturated aqueous NH₄Cl solution (2.0 mL), the grey

suspension was stirred vigorously for 30 min at r.t. Then the reaction

mixture was filtered and the filter washed with CH₂Cl₂(10 mL). The

combined organic filtrates were washed with water (10 mL). After

separation of the layers, the water layer was re-extracted twice with CH₂Cl₂

rel-(R)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

acetate (70b). According to general procedure 1, nitrone 64b (188.0 mg,

0.73 mmol) was dissolved in THF (4.5 mL) and the resulting solution was

treated with activated zinc powder (239 mg, 3.65 mmol). After the addition

10.1002/ejoc.202000294

European Journal of Organic Chemistry

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(5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and

concentrated in vacuo to give, after purification by flash chromatography

on silica (Biotage Isolera, 2% NEt₃/heptane, then gradient heptane/EtOAc

from 5% – 40% EtOAc, 25 mL/min) pure oxazolone ester 72a (21.0 mg,

30%) as a slightly yellow oil; R_t= 1.68 (HPLC);¹H NMR (400 MHz, CDCl₃):

 = 0.92, 1.01 (2d, J = 6.7 Hz, 12H, 3'-H, 4'''-H), 1.31 (d, J = 6.5 Hz, 3H,

2''-H), 1.59 (s, 3H, 2-CH₃), 1.98–2.07 (m, 1H, 2'''-H), 2.10 (s, br, 1H, 3'''-H),

2.12 (d, J = 1.6 Hz, 1H, 2'-H), 2.16–2.23 (m, 1H, 2'''-H), 2.46 (dd, J = 14.8,

7.0 Hz, 1H, 1'-H_A), 2.54 (dd, J = 14.8, 7.3 Hz, 1H, 1'-H_B), 5.20 (q, J = 6.5

Hz, 1H, 1''-H) ppm.

(410 mg, 1.50 mmol) was dissolved in THF (10.0 mL) and the resulting

solution was treated with activated zinc powder (491 mg, 7.50 mmol). After

the addition of saturated aqueous NH₄Cl solution (10.0 mL), the grey

suspension was stirred vigorously for 2 h at r.t. Then the reaction mixture

was filtered through a pad of celite, which was rinsed with CH₂Cl₂(20 mL).

The combined organic filtrates were washed with water (10 mL). After

separation of the layers, the water layer was re-extracted twice with CH₂Cl₂

(15 mL). The combined organic layers were dried over Na₂SO4, filtered,

and concentrated in vacuo to give pure pure oxazolone carbonate 73b

(364 mg, 94%) as an oil; R_t= 1.38 (HPLC); ¹H NMR (600 MHz, CDCl₃): 

= 0.97 (2d, J = 6.7 Hz, 6H, 3'-H), 1.434 (d, J = 6.6 Hz, 3H, 2''-H), 1.57 (s,

3H, 2-CH₃), 2.13–2.00 (m, 1H, 2"-H), 2.43–2.50 (m, 2H, 1"-H), 3.73 (s, 3H,

OCH₃), 4.93 (q, J = 6.6 Hz, 1H, 1''-H) ppm; ¹³C NMR (150 MHz, CDCl₃): 

= 15.3 (C-2''), 21.1, 22.2, 22.4 (2-CH₃, C-3'), 26.1 (C-2'), 36.5 (C-1'), 75.1

(C-1''), 105.4 (C-2), 154.8 (O-CO), 164.12 (C-4), 165.2 (C-5) ppm.

rel-(R)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

3-

methylbutanoate (72b). According to general procedure 1, nitrone 67b

(155.0 mg, 0.51 mmol) was dissolved in THF (3.5 mL) and the resulting

solution was treated with activated zinc powder (169.0 mg, 2.58 mmol).

After the addition of saturated aqueous NH₄Cl solution (3.5 mL), the grey

suspension was stirred vigorously for 2 h at r.t. Then the reaction mixture

was filtered and the filter washed with CH₂Cl₂(20 mL). The combined

organic filtrates were washed with water (10 mL). After separation of the

layers, the water layer was re-extracted twice with CH₂Cl₂(15 mL). The

combined organic layers were dried over Na₂SO₄, filtered, and

concentrated in vacuo to give after purification by flash chromatography

on silica (Biotage Isolera, 2% NEt₃/heptane, then gradient heptane/EtOAc

from 5% – 40% EtOAc, 15 g SiO₂, 25 mL/min) oxazolone ester 72b (64.0

mg, 44%) (low/high = 83:17); R_t= 1.67 (HPLC); ¹H NMR (600 MHz,

CDCl₃):  = 0.92 (d, J = 6.6 Hz, 6H, 4'''-H), 0.99 (2d, J = 6.8 Hz, 6H, 3'-H),

1.36 (d, J = 6.4 Hz, 3H, 2''-H), 1.57 (s, 3H, 2-CH₃), 2.00–2.05 (m, 1H, 2'''-

H), 2.09–2.12 (m, 2H, 2'''-H), 2.14–2.19 (m, 1H, 2'-H), 2.45 (dd, J = 15.0,

7.3 Hz, 1H, 1'-H_A), 2.49 (dd, J = 15.1, 6.8 Hz, 1H, 1'-H_B), 5.11 (q, J = 6.4

Hz, 1H, 1''-H) ppm; ¹³C NMR (150 MHz, CDCl₃):  = 15.3 (C-2''), 21.3,

22.25, 22.32, 22.5, 25.7, 26.1, 30.3 (C-2', C-2''', C-3', C-3''', 2-CH₃), 36.5

(C-1'), 43.3 (C-1'''), 74.6 (C-1''), 105.8 (C-2), 163.9 (C-4), 165.3 (C-5),

171.5 (ester) ppm.

rel-(R)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)propyl 4-

bromobenzoate (74b). According to general procedure 1, nitrone 69b (110

mg, 0.26 mmol) was dissolved in THF (2.5 mL) and the resulting solution

was treated with activated zinc powder (105 mg, 1.60 mmol). After the

addition of NH₄Cl solution (86 mg, 1.60 mmol, in 1.3 mL water), the grey

suspension was stirred vigorously for 60 min at r.t. Then the reaction

mixture was diluted with EtOAc, filtered through a pad of celite, which was

rinsed with EtOAc several times. The collected organic phases were

extracted with water, dried over Na₂SO₄, filtered, and concentrated in

vacuo to give pure oxazolone 74b (95 mg, 90%); R_t= 2.02 (HPLC); ¹H

NMR (600 MHz, CDCl₃):  = 0.83 (2 d, J = 6.6 Hz, 6H, 3'-H), 0.96 (t, J =

7.5 Hz (x2), 3H, 3''-H), 1.64 (s, 3H, 2-CH₃), 1.80–1.88 (m, 1H, 2'-H), 1.95–

2.03 (m, 2H, 2''-H), 2.26 (dd, J = 15.3, 7.3 Hz, 1H, 1'-H_A), 2.36 (dd, J =

15.3, 6.7 Hz, 1H, 1'-H_B), 5.34 (dd, J = 10.3, 3.0 Hz, 1H, 1''-H), 7.57 (d, J =

8.6 Hz, 2H, Ar-H), 7.80 (d, J = 8.6 Hz, 2H, Ar-H) ppm; ¹³C NMR (150 MHz,

CDCl₃):  = 10.0 (C-3''), 21.5, 22.2, 22.4 (2-CH₃, C-3'), 23.0 (C-2''), 25.9

(C-2'), 36.4 (C-1'), 75.8 (C-1''), 105.9 (C-2), 128.2, 128.6, 131.1, 132.9 (Ar

C) 163.9, 164.6, 165.4 (C-4, C-5, ArCO) ppm; HRMS (ESI-TOF): calcd. for

C₁₈H₂₂BrNO₄[M + H]⁺396.0810, found 396.0809.

rel-(S)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

methyl carbonate (73a). According to general procedure 1, nitrone 68a

(77.0 mg, 0.28 mmol) was dissolved in THF (1.5 mL) and the resulting

solution was treated with activated zinc powder (92.0 mg, 1.40 mmol).

After the addition of saturated aqueous NH₄Cl solution (1.5 mL), the grey

suspension was stirred vigorously for 30 min at r.t. Then the reaction

mixture was filtered and the filter residue rinsed with CH₂Cl₂(10 mL). The

combined organic filtrates were washed with water and the water layer was

re-extracted twice with CH₂Cl₂(10 mL). The combined organic layers were

dried over Na₂SO₄, filtered, and concentrated in vacuo to give pure

oxazolone carbonate 73a (54 mg, 75%) as an oil; R_t= 1.39 (HPLC); ¹H

NMR (400 MHz, CDCl₃):  = 1.10 (d, 6H, J = 6.7 Hz, 3'-H), 1.39 (d, J = 6.5

Hz, 3H, 2''-H), 1.59 (s, 3H, 2-CH₃), 2.14–2.24 (m, 1H, 2'-H), 2.47 (dd, J =

14.6, 6.8 Hz, 1H, 1'-H_A), 2.47 (dd, J = 14.6, 7.2 Hz, 1H, 1'-H_B), 3.76 (s, 3H,

OCH₃), 5.02 (q, J = 6.5 Hz, 1H, 1''-H) ppm.

Acknowledgements ((optional))

We thank Claudia Braun, Florian Herrmann (CTA, University of

Tübingen), Ann-Katrin Kopp, Stefanie Schmengler, Oliver Smieja

(CTA, Bayer AG), Dr. Anna Kromm and Dr. Hans-Christoph Weiß

(both Currenta GmbH; X-ray analysis) for contributions to this

project.

Keywords: herbicides • azlactones • nitrone • nitrone aldol •

keyword 5

rel-(R)-1-((S)-4-Isobutyl-2-methyl-5-oxo-2,5-dihydrooxazol-2-yl)ethyl

methyl carbonate (73b). According to general procedure 1, nitrone 68b

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European Journal of Organic Chemistry

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10.1002/ejoc.202000294

European Journal of Organic Chemistry

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Cyclic nitrones are the key: A

Dr. Birgit Kuhn, Dr. David M. Barber, Dr.

Hansjörg Dietrich, Dr. Uwe Döller, Dr.

Michael G. Hoffmann, Dr. Dirk

Schmutzler, Dr. Stefan Schnatterer,

Prof. Dr. Martin E. Maier, Tamer

flexible route to the natural herbicide

MBH-001 was developed. As opposed

to azlactones, the use of the

corresponding nitrones secured the

regiochemistry (2 vs. 4-position) in the

aldol type reaction of the anions with

aldehydes. The work also led to the

determination of the relative and

absolute stereochemistry of MBH-001.

Kocakaya, M.Sc., Dr. Marius Morkunas

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Total Synthesis of the Natural

Herbicide MBH-001 and Analogues

key topic: Synthesis of a novel herbicide

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Total Synthesis of the Natural Herbicide MBH-001 and Analogues

DOI: 10.1002/ejoc.202000294

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