Amphipathic 1,3-oxazolidines from: N-Alkyl glucamines and benzaldehydes: Stereochemical and mechanistic studies

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Amphipathic 1,3-oxazolidines from N-alkyl

glucamines and benzaldehydes: stereochemical

and mechanistic studies†

Cite this: New J. Chem., 2021,

45, 4365

Esther Matamoros, * Pedro Cintas

and Juan C. Palacios

*

Construction of enantiopure carbohydrate conjugates incorporating heterocyclic fragments is often

hampered by the necessity of protection/deprotection protocols and multistep routes. Here we show

the preparation and structural features of a broad series of chiral 1,3-oxazolines and 1,3-oxazines

embedded in a hydrophilic chain based on glycamines, which bypass the disadvantages associated with

labile anomeric positions. These substances, however, interconvert in solution and show dynamic

equilibria that can be altered by crystallization. A variety of substitution patterns at the heterocyclic

moiety disclose the structural and stereochemical relationships. Equilibria monitored by NMR experiments

and aided by DFT calculations provide data on kinetic and thermodynamic stability. The reaction proceeds

via the intermediacy of iminium ions as a unifying element controlling the steric outcome.

Received 10th November 2020,

Accepted 11th January 2021

DOI: 10.1039/d0nj05503d

rsc.li/njc

species that further evolves to 1,3-oxazolidine derivatives (4), as

described for the condensation of N-methyl-^D-glucamine

Introduction

In line with one of the basic pillars of Green Chemistry, the use (1, RQMe) with diﬀerent mono and polysubstituted benzalde-

of renewable materials is preferred over those from fossil hydes, 1-naphthaldehydes, and cinnamaldehydes.⁶Moreover,

resources.¹Carbohydrates clearly satisfy the criteria and are the asymmetric reaction starting from an enantiomerically pure

therefore privileged synthons, which can be obtained from sugar and creating a new stereogenic center proceeds with high

abundant and cheap biomass.²The use of unprotected sugars, or complete stereoselection.

however, even if desirable, faces chemical limitations such as

In order to investigate the scope of other N-alkyl glycamines

the promiscuous reactivity of hydroxy groups, anomerizations, en route to chiral 1,3-oxazolidines, the present study is aimed at

epimerizations, and rearrangements, thereby leading to lengthy this goal and determining in detail the structural factors

synthetic protocols.³The alternative use of alditols and 1-(alkyl)- governing the mechanism and stereochemical outcome. In

amino-1-deoxy-^D-alditols, i.e. amino- and N-alkylaminopolyols, addition, oxazolines and saturated oxazolidines are attractive

also available from biomass after little manipulation and microbial heterocyclic units present in natural products and synthetic

sources, makes them much more appealing. The diﬀerential derivatives showing biological activity.^7–9Some oxazoline derivatives

reactivity of the amino group at the non-labile C1 position relative have also been tested as corrosion inhibitors in industrial

to side-chain hydroxyls allows transformations without protecting settings,¹⁰and as mentioned above, both chiral oxazolines and

groups and makes it suitable for heterocyclization. In previous oxazolidines have proven to be versatile auxiliaries as chiral ligands

studies we have shown that imines (2) derived from sugar amino- in asymmetric induction.^4,11,12

polyols, such as ^D-glucamine (1, RQH), can be converted into

inherently chiral N-acyloxazolidines (3) under acylating conditions,

a process that occurs through the intermediacy of a transient

Results and discussion

Reactivity and stereochemistry

iminium ion (Scheme 1).^4,5This procedure has become the usual

and convenient synthesis for such saturated heterocycles.⁴The

corresponding N-alkylated aminopolyols aﬀord likewise an iminium The condensation of N-ethyl-^D-glucamine (6) with substituted

benzaldehydes (7–19) was performed by heating equimolar

´

Departamento de Quımica Organica e Inorganica, Facultad de Ciencias, and IACYS-

amounts of such reagents in benzene at reflux with azeotropic

removal of water formed in the reaction (Dean–Stark). The

insoluble adducts were subsequently filtered and crystallized

from ethanol. Certainly, the use of benzene is not a green

choice, although it enabled high-yielding reactions and could

´

Unidad de Quımica Verde y Desarrollo Sostenible, Universidad de Extremadura,

E-06006 Badajoz, Spain. E-mail: esthermc@unex.es, palacios@unex.es

† Electronic supplementary information (ESI) available: General methods, spec-

troscopic data, and Cartesian coordinates for all optimized species. See DOI:

10.1039/d0nj05503d

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Scheme 1 Synthetic strategy leading to ring closure from D-glucamine imines (see ref. 5 for previous work).

be recycled. Yet, an eco-friendly aqueous alcoholic procedure oxazolidine, in which the new chiral center possesses an

could be employed as well (see the Experimental section, absolute R-configuration (24a–31a). This stereochemistry

method B), but the yields were generally lower. Oxazolidines remained unaffected after recrystallization, with the exception

having R or trans (20a) and/or S or cis (20b) configurations can of oxazolidine 24a, for which the formation of a small amount

be formed (Scheme 2, for clarity atom numbering is indicated). of the S-configured oxazolidine could be observed (ratio

The yields of both raw and recrystallized products are shown in 24a : 24b = 20 : 3). When the reaction was carried out with

Table 1. Although crude products were in most cases pure benzaldehyde 19, the process also took place with high selec-

enough, recrystallization led to lower isolated yields in a few tivity; however, this was the only case in which the crude

cases. It is worth mentioning that derivatives 27a and 31a could product consisted exclusively of the S-configured oxazolidine

not be purified by this method.

(32b). The behavior exhibited by 18 is striking and contrasts

Experimental results show that the stereochemical outcome with those from 9 and 10, for which a steric effect has no

depends on the substitution pattern. The reaction of 6 with apparent influence on the stereochemical result.

aldehydes 8 and 9 aﬀorded a mixture of R and S oxazolidines in

Similarly, the condensation of N-octyl-^D-glucamine (33) with

a 1 : 1 ratio (crude material), which was slightly altered by various substituted benzaldehydes was conducted as well, with

recrystallization: 5 : 3 for adduct 21a : 21b and 4 : 5 for adduct the aim of elucidating the eﬀect of a longer chain at the

22a : 22b. When the condensation was performed with nitrogen atom on both yields and product stereochemistry.

2-methylbenzaldehyde (10), the crude product obtained was a Moreover, glucamine 33 enables the synthesis of amphiphilic

mixture of oxazolidines 23a and 23b, in which the R-isomer molecules with a larger lipophilic moiety. Crude yields are

predominates according to the integration of proton signals in generally high and decrease slightly after recrystallization.

1

the H NMR spectrum (R : S 5 : 2). However, after recrystalliza- Some resisted this solvent-mediated purification and decomposed

tion, pure S-oxazolidine (23b) could be obtained.

substantially upon heating (Table 1). When the reaction was

In stark contrast, when the reaction was carried out with carried out with 4-nitrobenzaldehyde (7), the only product

aldehydes 11–18, it proceeded with high stereoselectivity and obtained, irrespective of recrystallization, was cis-oxazolidine

the only crude product obtained was the corresponding 34b having absolute S-stereochemistry. The reaction with

Scheme 2 Condensation of N-alkyl-D-glucamine with benzaldehydes aﬀording oxazolidine adducts.

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Table 1 Yields (%) and R : S ratios of 21–32 and 34–41

Compounds^a

X

Yield^a

R : S^b

Yield^c

R : S^d

21a + 21b

22a + 22b

23a + 23b

24a

25a

26a

27a

28a

29a

30a

31a

32b

34b

35a + 35b

36a + 36b

37a + 37b

38a + 38b

39a

40a

41a

4-NO₂

2-Cl

2-Me

3-F

3-MeO

4-Me

H

98

95

90

91

90

93

83

74

73

94

85

92

98

66

71

65

35

73

90

91

1 : 1

5 : 2

1 : 0

0 : 1

10 : 9

10 : 7

7 : 1

4 : 1

1 : 0

82

65

63

31

74

71

—

30

49

74

—

35

78

54

26

—

15

—

56

—

5 : 3

4 : 5

0 : 1

20 : 3

1 : 0

—

1 : 0

—

0 : 1

1 : 16

0 : 1

—

1 : 0

—

4-Et

4-ⁱPr

3-Me

4-MeO

2,4-Me₂

4-NO₂

3-NO₂

3-F

4-ⁱPr

H

3-MeO

3-Me

4-Me

1 : 0

—

a

b

c

d

Crude product. R : S ratio of crude products. Recrystallized. R : S ratio of recrystallized materials.

aldehydes 7 and 11, also bearing electron-withdrawing groups, obtained from aldehyde 14, the R-isomer (38a) predominated

gave rise to a mixture of the corresponding R- and S-configured largely and recrystallization allowed it to be obtained in pure

oxazolidines in similar proportions (35a/35b and 36a/36b, respec- form. Finally, when aldehydes 12, 13 and 17 were used, the only

tively). Despite the slight excess of the R-stereoisomer, recrystalli- product generated was the corresponding trans-oxazolidine (39a,

zation of the crude mixture aﬀorded pure S-oxazolidine 36b and 40a and 41a, respectively), for which the chiral center has an

essentially pure S-35b (ratio 35a :35b = 1 : 16). Aldehyde 16 also absolute R-configuration.

produced a mixture (37a/37b), with the R-isomer dominating (ratio

We have also explored the condensation of N-methyl-^D-

37a :37b = 7 : 1). In contrast, in the crude mixture (38a/38b) galactamine 42 with 4-nitrobenzaldehyde, benzaldehyde and

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Scheme 3 Reaction of N-methyl-D-galactamine with benzaldehydes leading to 1,3-oxazolidines and 1,3-oxazines.

4-methoxybenzaldehyde, thus covering the influence of electro- heterocycles. The stretching vibrations originated from the

nic eﬀects of the substituents, from

strong electron- C–O bonds are observed between 1100 and 1000 cm^ꢀ1. In the

a

withdrawing group to an electron donating-group. That spectra of 21, 34b, and 45, intense asymmetric and symmetrical

together with the stereochemical switching of the polyol chain stretching vibrations of the nitro group at 1523 and 1342 cm^ꢀ1

(epimer at C-4 relative to ^D-glucamine) would allow us to respectively stand out, while in 25a, 31a, 39a, and 45 the

interrogate such influences on reactivity and creation of new asymmetric stretching of the ether group at B1257 cm^ꢀ1is

chiral centers. The products formed in these syntheses are both likewise noticeable.

1,3-oxazolidines and 1,3-oxazines derivatives (Scheme 3).

The most significant data are provided by NMR spectra. Tables

The synthetic protocol was carried out as above for N-ethyl S1 and S2 (ESI†) show the chemical shifts of proton and carbon

and N-octyl-^D-glucamine. Remarkably, the solutions gel upon nuclei of the heterocyclic moiety along with their coupling

cooling. Therefore, they were brought to dryness giving rise to constants (see Schemes 2 and 3 for numbering). Two signals

either an oil or foam that was washed with abundant diethyl characterizing the presence of an oxazolidine ring should be

ether to remove aldehyde residues. Whenever possible, the mentioned: a peak at 4.5–5.5 ppm (¹H NMR) and the other at

crude product was recrystallized from acetone. Both yields 91–97 ppm (¹³C NMR) (Fig. S1 and S2, ESI†). These signals agree

and structural composition are collected in Table 2. In general with the typical values reported for the H-2 and C-2 resonances

crude yields range from moderate to good. In the case of in oxazolidine rings.^13–15The OH groups lie in the range of 4.2–

aldehydes 8 and 14, a mixture of three products is formed: 4.6 ppm and are easily identified because they disappear after

oxazolidines with R- and S-configurations, and R-oxazine, with exchanging with D₂O. The remaining protons of the polyhydroxyl

the latter predominating. In the first case, recrystallization chain resonate upfield (3.2–3.8 ppm). The carbon atoms in this side

aﬀorded pure oxazine 43c. On the other hand, when using chain are located in the narrow range of 72–63 ppm, in agreement

aldehyde 18, only the corresponding oxazolidine (45a) could be with conformationally flexible polyhydroxyalkyl fragments.^5,16

obtained, although recrystallization from acetone gave a mix-

Unambiguous signal assignments were obtained through

ture of three products (45a–45c), again with a predominance of two-dimensional ¹H-¹H (COSY) and ¹H–¹³C (HMQC) correla-

oxazine 45c.

tions (Fig. S3 and S4, ESI†). The protons of the methylene

heterocycle (C-4) are diastereotopic showing an appreciable

chemical shift difference (Dd_H-4B 1.15 ppm). Also, the methylene

protons of the N-Et group are diastereotopic, although with a lesser

difference in chemical shifts (Dd_NCH2B 0.25 ppm), which does not

occur with their counterparts of the ethyl group attached to the

benzene ring.

The corresponding spectra of 23b (S-stereoisomer) are

shown in Fig. S5–S8 (ESI†). Data are similar to those recorded

for 28a, thus showing that the stereochemical change at C-4 has

little effect on the chemical shifts. However, it is noteworthy

that the chemical shift of H-2 in 23b (S-configured) is greater

than that shown by 23a (R) (Dd_H-2= d_H-2(S)ꢀ d_H-2(R)Z 0.1 ppm)

and the same applies to the C-2 signal (Dd_C-2= d_C-2(S)ꢀ d_C-2(R)Z

0.5 ppm) (see Table S1, ESI†). The diastereotopic protons at C-4

show a smaller chemical shift difference (Dd_H-4B 0.40 ppm)

than that shown by the homologous protons of 28a.

Structural analyses

All structures of these heterocyclic derivatives are supported by

analytical and spectroscopic methods. FT-IR spectra show the

absorptions caused by the stretching vibrations of the hydroxy

groups in the range of 3500–3100 cm^ꢀ1. The aromatic ring

generates an absorption at approximately 1610–1600 cm^ꢀ1

;

whereas above and up to 2800 cm^ꢀ1, no absorption could be

observed, consistent with the saturated character of such

Table 2 Yields (%) and composition of products 43–45

X

Compounds

Yield^a

a : b : c^b

Yield^c

a : b : c^d

4-NO₂

H

4-OMe

43a + 43b + 43c

44a + 44b + 44c

45a + 45b + 45c

52

63

71

2 : 1 : 6

3 : 1 : 4

1 : 0 : 0

32

—

21

0 : 0 : 1

—

5 : 2 : 6

a

b

c

d

Duplication of signals is observed in the spectra of com-

pounds derived from aldehydes 7–10, consistent with a mixture

Crude product. Ratio of crude products. Recrystallized. Ratio of

recrystallized products.

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of R- and S-isomers. A representative example of such pairs is

provided by isomers 21a/21b (Fig. S9–S11, ESI†) and 35a/35b

(Fig. S16 and S17, ESI†), which show two signal sets for the H-2

and C-2 signals, characteristic of the oxazolidine ring.

Isolation of pure oxazine 43c and oxazolidine 45a makes it

possible to assign single proton and carbon signals with confi-

dence (Fig. S23–S26, ESI†). Tables S3 and S4 show the characteristic

proton and carbon shifts for compounds 43–45 (Fig. S19–S22,

ESI†).

Furthermore, it is possible to diﬀerentiate between oxazolidine

and oxazine structures derived from N-methyl-^D-galactamine even

though H-2 and C-2 lie in the same range, because of a significant

diﬀerence in shifts of the H-5 and C-5 signals as well as the C1⁰or

C-6 carbons of oxazolidines and oxazines, respectively. In the

five-membered rings, the H-5 signal appears between 4.5 and 4.3

ppm, while it resonates upfield in oxazines at B3.7 ppm (Dd 4

0.5 ppm). There is also a significant diﬀerence for the C-5 signal,

which resonates in oxazolidines at B77 ppm and at B63 ppm in

oxazines (Dd 4 13 ppm). The C-1⁰atom in oxazolidines is a part

of the polyhydroxylalkyl chain, whereas it is located within the

heterocycle (C-6) in oxazines, which translates into a significant

chemical shift diﬀerence: the C-1⁰peak of oxazolidines typically

resonates within 70–72 ppm, whereas the analogous signal in

oxazines is shifted downfield at 78–79 ppm (Dd 4 6.5 ppm).

Fig. 1 Diagnostic chemical shift diﬀerences for (2R) and (2S)-configured

oxazolidines.

inferred from tabulated data. Thus, the H-2 signal is shifted

upfield in the R-isomer (Dd Z 0.1 ppm), while H-5 moves

slightly downfield (Dd 4 0.01 ppm). Moreover, the C-4 peak

resonates downfield in the R isomer (Dd Z 1.2 ppm). Com-

pounds 35a–41a exhibit a large chemical shift difference

between the H-4a and H-4b signals (Dd_H-4B1), which points

to the R-configuration. In stark contrast, the S-isomers show

smaller differences and Dd_H-4varies from 0.11 to 0.52 ppm

(34b–38b).

Notably, optical rotations can advantageously be used to

corroborate the absolute stereochemistry at C-2. This could be

achieved thanks to the isolation of several oxazolidines in pure

form, derived from N-ethyl and N-octyl-^D-glucamine, whose

configurations (2R,5S) and (2S,5S) were unequivocally assigned

through the proton shifts at C-4 of the heterocycle (Table 3).

A simple rule could be extracted from the optical rotations to

assign the configuration at the C-2 position. Oxazolidines with

Dd_H-44 1 ppm show a positive value of optical rotation,

whereas compounds showing Dd_H-4o 0.5 have negative values.

This can be attributed to the fact that optical rotations are

dominated by the specific contribution of the chirality at C-2,

while other chiral atoms cancel each other, probably due to the

conformational flexibility of the polyol chain.

Absolute configuration of the new chiral center

There is some background dealing with the steric course of the

cyclization of imines and iminium ions to predict the configu-

ration adopted by the new chiral center generated in oxazoli-

dines after ring closure.^4,17In previous work we showed that

the absolute stereochemistry of the new chiral center formed in

oxazolidines from N-methyl-^D-glucamine could be established

by correlation of spectroscopic data.⁶The starting point for that

assignment was the unequivocal determination of the absolute

stereochemistry of oxazolidine 46b by single crystal X-ray

diﬀraction (S-configuration at C-2). It was observed that the two

protons of the oxazolidine ring, H-4a and H-4b, of 46b exhibit

By applying the van’t Hoﬀ superposition principle^18,19and

carrying out an analysis analogous to that used in the Hudson

isorotation rules,²⁰the contribution of the chiral center at C-2

0

diﬀerent chemical shifts with Dd_H-4= d_H4ꢀ d_H4o 0.5 ppm; while

for the R-isomer (46a) that diﬀerence is even greater, Dd_H-4

4

0.5 ppm and, in most cases close to 1 ppm (Fig. 1). These data

also agree with those found in N-acyloxazolidines derived from

D-glucamine,⁵thereby confirming the stereochemistry assigned

previously in tentative form.

Table 3 C-2 Stereochemistry of N-ethyl and N-octyloxazolidines^a

b

e

Compound

H-4a

H-4b

Dd_H-4

Configuration^d

[a]_D

Based on these results, we could establish the absolute

stereochemistry of the new chiral center of oxazolidines 21–23

and determine the shift differences between the protons at C-4

(Dd_H-4) (Fig. S11, ESI†). Table S1 (ESI†) shows such data and

reveals that oxazolidines 24a–31a have an R stereochemistry,

while 32b presents S-configuration. Also, in the case of oxazolidine

23 derived from 2-methylbenzaldehyde (9), recrystallization of the

crude product allowed the obtainment of the pure S-isomer (23b).

As indicated previously, the chemical shift of C-2 for the

S-stereoisomer is greater than that shown by the R-antipode

(Dd_C-2Z 0.5 ppm), which can be used to assign the absolute

configuration at C-2 in other oxazolidines. In addition, other

correlations associated with the stereochemistry at C-2 can be

25a

26a

27a^c

28a

29a

30a

31a

32b

34b

35b

39a

40a

41a

3.40

3.39

3.40

3.39

3.41

3.10

2.89

2.95

3.38

3.39

2.24

2.23

2.25

2.24

2.25

2.23

2.64

2.78

2.77

2.24

2.23

2.21

1.16

1.17

1.15

1.16

1.14

1.18

0.46

0.11

0.18

1.14

1.16

1.18

R

S

R

+21.5

+17.0

+15.9

+16.7

+17.0

+26.5

+36.7

ꢀ55.2

ꢀ19.6

ꢀ24.9

+23.2

+29.0

+32.7

a

b

c

d

At 500 MHz in DMSO-d₆. Dd_H-4= d_H-4aꢀ d_H-4b

.

At 400 MHz. At C-2.

e

In 1ꢁmL g^ꢀ1dm^ꢀ1

.

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to the whole rotation can be estimated approximately. The does not help in determining whether R- or S-configurations

latter will be the sum of the optical rotations supplied by the occur owing to similar values of this parameter for the three

C-2 atom (R for 2R-oxazolidines) and the other chiral centers isomers obtained.

(C); therefore, we can write:

Isomerization of 1,3-oxazolidines

[a]^R_D= R + C

(1)

As indicated before and shown in Tables 1 and 2, the recrys-

tallization of crude mixtures alters the product composition.

Thus, starting from the 23a/23b mixture (R : S ratio, 5 : 2),

isolated in 90% yield, recrystallization aﬀords only 23b in

60% yield. Clearly, compound 23a is partly transformed into

23b. Further studies were then undertaken to elucidate the

equilibria in solution involving the interconversion of such

isomers. When a DMSO-d₆solution of the oxazolidines

obtained is monitored over time by ¹H NMR, they transform

into a mixture of R- and S-configured oxazolidines 47a and 47b,

respectively, with the occasional appearance of the oxazine

derivative (47c) until equilibrium is reached (Scheme 4). This

transformation between oxazolidine and/or oxazine rings must

take place through an acyclic species, the iminium ion 48. The

participation of either the first or second hydroxyl group of the

polyol chain will lead to five- or six-membered rings, respectively.

Transformations of 23b, 24a, 26a, and 27a and the mixture of

21a–21b obtained by recrystallization were monitored by record-

For the 2S-oxazolidine the following equation applies

because R = –S:

[a]^S_D= S + C = –R + C

(2)

By subtracting eqn (2) from (1), the contribution of C-2 is

obtained:

[a]^R_Dꢀ [a]^S_D= 2R - R = ([a]_D^Rꢀ [a]^S_D)/2

On the other hand, the sum of both equations gives rise to

the contribution (C) of the remaining chiral atoms:

[a]^R_D+ [a]^S_D= 2C - C = ([a]_D^R+ [a]^S_D)/2

We do not have a couple of epimeric oxazolidines at C-2, but

the strategy can be applied to other oxazolidine pairs that lead

us to approximate values of R and C. Thus, taking the values of

39a and 35b, both compounds with strong electron-withdrawing

groups in the meta-position, we can calculate the value of R:

1

ing the H NMR spectra of their solutions for two weeks until

equilibrium was reached. Fig. 2 and 3 display two selected

examples and Table 4 shows the temporal variation of the

percentages found for every species involved. The isomeric

composition of crude product 23 (Fig. 2, ratio 23a : 23b B 7 : 1)

varies scarcely over time and the final composition (ratio

23a : 23b B 7 : 3) is essentially the same as that obtained from

pure 23b (Fig. 3) and similar to that shown by the equilibrium

solutions of 21 and 27. Compounds 24 and 26 show a similar

evolution of their isomers and almost identical final compositions.

R = ([a]^R_Dꢀ [a]^S_D)/2 = [23.2 ꢀ (ꢀ24.9)]/2 = 241

Even on choosing the pair with the lowest absolute values of

optical rotations, 27a and 34b, a minimum value for R of 181 is

obtained (note that the substituents at the aromatic ring are not

identical).

The [a]_Dvalues of 39a and 35b lead to a value of C close to 01.

C = ([a]^R_D+ [a]^S_D)/2 = [23.2 + (ꢀ24.9)]/2 = ꢀ21

Likewise, for the couple with the highest absolute values of

rotations, 31a and 35b, the value of C does not exceed 61. It should

be pointed out that the abnormal value shown by 2,4-dimethyl

derivative 32b was not taken into account, as its (2R)-epimer most

likely has a highly positive value of [a]_D.

From these calculations it follows that since the absolute

value of R or S is greater than that of C, the absolute configu-

ration at C-2 will be the one that determines the sign of the

specific rotation. Accordingly, for oxazolidines derived from

aminopolyols, a positive value of optical rotation indicates an

absolute R-configuration at the C-2 atom while a negative value

is consistent with an absolute S-configuration. Similar rules have

been proposed in the literature for other acyclic compounds,

such as sugar nitriles, aminonitriles, amides, hydrazides, and

(alditol-1-yl)-heterocycles.^21–23Also the spectroscopic data and

optical rotations of oxazolidines derived from N-methyl-D-

glucamine⁶agree with this rule and confirm the assigned con-

figurations (Table S5, ESI†).

In the case of N-methyl-^D-galactosamine derivatives, the

absolute configuration of the new oxazolidines and oxazines

could not be determined. Unfortunately the magnitude of Dd_H-4

Scheme 4 Equilibration of oxazolidines and oxazine through an acyclic

iminium intermediate.

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Fig. 2 Temporal variation of the heterocyclic composition of the crude mixture of 23 (23a + 23b).

According to tabulated data (Tables 1 and 2), the composition of a solutions of 43, 44 and 45 were monitored within two weeks to

recrystallized sample of 21 reflects thermodynamic control, since ascertain their evolution and verifying the formation of oxazine

the composition in solution does not change over time. The crude as the most stable species (Table 5). Oxazine 43c is partially

product obtained in the preparation of 24 shows a similar transformed into oxazolidines R and S (43a and 43b). The same

behavior. However, formation of compounds 26a and 27a would occurs on starting from oxazolidine 45a, where a balance is

have occurred under kinetic control as they transform into a established with 45b and 45c. Little variation, however, could be

mixture gradually. In short, a comparative assessment of com- observed for the reaction mixture of compound 44.

positions in solution agrees with product formation under

Configurational stability of N-alkyl-1,3-oxazolidines and

tetrahydro-1,3-oxazines

complete or partial kinetic control.

Oxazolidine 34b, having an absolute S-configuration, is

partially converted into R-configured oxazolidine 34a accom- In order to gain insight into the stability of the diﬀerent hetero-

panied by a third signal appearing at B5 ppm, corresponding cyclic isomers, a series of DFT calculations²⁵were carried out at

to an oxazine structure (34c). However, oxazolidine 36b, also the M06-2X/6-311G(d,p) level^26,27with the role of the solvent

with the absolute S-configuration, changes much more slowly; simulated through the SMD method,²⁸using the Gaussian09

after one week a small peak corresponding to the H-2 signal of package.²⁹As representative examples, Table 6 shows the calcu-

the R-oxazine 36a is detected. Oxazolidines 38a and 39a, both lated relative energies for the R-configured oxazolidines 21a, 27a

being R-configured, balance rapidly in solution with their S-counter- and 31a, S-oxazolidines 21b, 27b and 31b, R-oxazines 21c, 27c

parts 38b and 39b, respectively, while the corresponding oxazines and 31c, and S-oxazines 21d, 27d and 31d. Moreover, some key

38c and 39c emerge after two weeks (Fig. S27, ESI†).

conformational issues were taken into account: the conforma-

It is interesting to highlight that only one of the two possible tion of the heterocyclic ring (starting conformations: ²E and E₂in

2

diastereomeric oxazines is detected in equilibrium mixtures oxazolidines and C₅in oxazines), the dispositions of the ethyl

(Fig. 4). We have assigned an R-configuration to the C-2 of that group and the aromatic substituent with respect to the ring of

oxazine, because it would aﬀord the most stable isomer by oxazolidine and oxazine (i.e. pseudo-axial or pseudo-equatorial

5

minimizing the steric hindrance in the C₂conformation, the arrangements) as well as the influence exerted by the first

aromatic ring being arranged equatorially.²⁴The S-isomer hydroxyl of the side chain, which can be oriented towards the

would instead show gauche (1,3-diaxial) interactions between nitrogen or oxygen atoms of the heterocycle, thus forming an

the aromatic ring and the axial hydrogens at C-4 and C-6; which intramolecular hydrogen bridge.

are absent in the R-configured oxazine.

Thus, Fig. 5 for the R-isomer of oxazolidine in conformation

In solution both R- and S-oxazolidines and the oxazines ²E shows the axial–equatorial aromatic ethyl (eq–ax) and axial–

derived from N-methyl-^D-galactosamine undergo interconversion axial aromatic ethyl (ax–ax) arrangements. In the first case, we

establishing an equilibrium. If one compares the composition of considered the possible formation of an intramolecular

the crude materials with that of the recrystallized products, six-membered hydrogen bridge involving the first hydroxyl of

variations are immediately obvious. Thus, 45a was isolated in the polyol chain with nitrogen, or a five-membered system with

pure form as the crude product, whereas a mixture of 45a, 45b heterocyclic oxygen; the latter being realizable with oxygen

and 45c was obtained upon recrystallization. This result can only only. An equatorial–equatorial arrangement (eq–eq) in E₂con-

be explained by assuming that 45a is partly transformed into 45b formation has also been calculated. For the S-isomer, always

and 45c during the purification step. For this reason, DMSO-d₆in the ²E conformation, both eq–eq and ax–eq dispositions

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Fig. 3 Isomerization of 23b (S-configured oxazolidine) as monitored in solution for two weeks.

Table 4 Product distribution of oxazolidine (a, b) and oxazine (c) isomers

as monitored by NMR in solution for compounds 21, 23, 24, 26, 27, 34, 36,

38 and 39^a

Configuration

Initial (%)

1 week (%)

2 weeks (%)

21^b

23^c

23b

24^d

26a

27a

34

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

60.3

39.7

0.0

87.7

12.3

0.0

100.0

0.0

90.1

9.9

0.0

100.0

0.0

100.0

0.0

100.0

0.0

100.0

0.0

100.0

0.0

59.9

40.1

0.0

61.7

31.5

6.8

63.0

29.5

7.5

88.1

11.9

0.0

92.6

7.4

0.0

68.5

25.3

6.2

28.3

62.9

8.8

3.8

96.2

0.0

90.0

9.1

0.9

85.5

8.6

5.9

60.3

39.7

0.0

64.5

29.0

6.5

62.5

30.6

6.8

87.7

12.3

0.0

87.1

12.5

0.4

60.3

32.3

6.7

37.2

59.1

6.3

4.0

96.0

—

80.5

15.3

4.2

79.4

13.5

7.1

Fig. 4 Preferred conformers of oxazine rings with R- and S-

configurations at C-2.

Table 5 Temporal evolution of oxazolidine (a, b) and oxazine (c) rings for

compounds 43–45^a

Initial (%)

1 week (%)

2 weeks (%)

43

44

45

A

B

C

A

B

C

A

B

C

0.0

10.3

3.5

14.5

4.9

100

40.8

9.4

49.8

100

0.0

86.2

35.7

13.3

51.0

35.2

14.5

50.3

80.6

34.9

13.1

52.0

35.0

14.5

50.5

36

0.0

a

At 500 MHz in DMSO-d₆.

38

(SMD method) was computed for benzene, the solvent in which

the syntheses were carried out, and DMSO, where NMR spectra

and oxazolidine–oxazine isomerizations have been recorded.

Along with the five-membered ring-forming hydrogen bridge

between the first hydroxyl of the polyol chain and heterocyclic

oxygen, H-bonding can also be established between the hydroxyl

and the oxazine heteroatom at C-5.

39

100.0

0.0

a

b

c

At 500 MHz in DMSO-d₆. Recrystallized product (21a + 21b). Crude

d

product (23a + 23b). Recrystallized product (24a + 24b).

have been calculated with the corresponding intramolecular

H-bonding.

As shown in Table 6 the energy diﬀerences along the

structural landscape are small, namely DE o 3 kcal mol^ꢀ1

In addition, the eq–eq and ax–eq dispositions of R-oxazines and DG o 3 kcal mol^ꢀ1, with the exception of structures 31a

together with eq–ax and ax–ax of S-oxazines, both in the ⁵C₂and 31b for which the energy diﬀerence in DMSO lie above

conformation (Fig. 6) were modelled as well. Bulk solvation

4 kcal mol^ꢀ1. Also, Table S6 (ESI†) shows the geometric data for

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Table 6 Relative electronic and Gibbs energies for isomers and confor-

mers of 21, 27 and 31^a

Gas phase

Benzene

DMSO

Ethyl^bAryl^cH-Bond^dDE DG

DE DG

21a eq

ax

eq

ax

eq

ax

eq

ax

O

N

O

N

O

N

O

N

O

N

O

N

O

3.88

2.36

1.99

3.63

1.48

0.00

5.29

1.81

3.20

3.43

0.94

4.35

2.41

2.69

4.00

4.46 4.22

2.79 2.28

1.58 2.46

2.66 3.91

1.02 1.81

0.00 0.00

5.32 5.91

1.69 1.59

3.59 3.36

4.26 3.54

2.16 1.28

3.53 4.73

1.68 2.50

1.72 3.11

1.80 4.23

4.02 4.12 3.83

2.85 2.16 2.42

2.78 2.89 2.62

2.70 4.21 3.26

2.11 2.18 2.00

0.00 0.00 0.00

5.83 5.54 5.88

1.49 1.26 1.61

3.46 2.88 2.91

3.62 3.45 3.89

1.87 1.54 2.91

3.61 4.63 3.98

1.81 2.58 1.08

2.55 3.40 2.27

2.30 4.32 3.19

0.09 2.25 0.79

0.00 0.00 0.00

5.24 5.65 5.19

eq

ax

eq

21b eq

eq

ax

21c eq

ax

21d eq

ax

27a eq

eq

ax

eq

27b eq

eq

ax

27c eq

ax

27d eq

ax

31a eq

eq

ax

eq

31b eq

eq

ax

31c eq

ax

31d eq

ax

1.68 ꢀ0.03 2.07

0.00

5.36

1.65

3.23

3.67

1.35

4.38

2.39

2.68

3.75

1.44

0.00

5.24

1.40

3.18

3.65

1.26

0.00 0.00

4.18 5.99

0.37 1.59 ꢀ0.02 1.43 0.60

Fig. 6 Configurational and conformational arrangements of the oxazine

ring with their vicinal groups.

2.97 3.42

3.25 3.88

1.11 1.72

4.64 4.70

2.96 2.37

2.89 3.07

1.86 3.98

0.07 1.75

0.00 0.00

5.41 5.79

1.30 1.26

4.01 3.37

3.99 3.78

2.60 1.52

3.54 3.10 3.34

2.80 3.95 3.96

1.24 2.00 1.53

5.05 6.21 5.34

2.53 4.07 3.57

3.82 5.06 4.79

2.43 5.70 3.63

1.41 3.61 1.69

0.00 0.00 0.00

6.29 7.07 6.69

1.49 2.85 1.55

4.33 4.67 4.54

4.62 5.51 5.69

3.27 3.54 4.31

heterocyclic oxygen or nitrogen atoms, respectively. The results

obtained for the three substituents are quite similar and Fig. 7

illustrates the most stable structure for compound 27 in DMSO

solution.

Irrespective of the gas phase or solvent-based calculations,

the S-configured oxazolidine is the most stable isomer. The

latter corresponds to a conformation in which the N-ethyl and

aromatic groups are both arranged pseudo-equatorially,

thereby enabling the formation of H-bonding between the first

OH group and the nitrogen atom of the heterocycle, such as

structure 27b (eq–eq conformer, Fig. 7). Next, R-configured

oxazolidine and oxazine structures follow in relative stability.

In the former, the most stable conformer is the one having an

arrangement of equatorial N-ethyl and axial phenyl groups, and

a

b

In kcal mol^ꢀ1

.

Disposition of the ethyl with respect to the ring.

c

Arrangement of the aromatic ring relative to the oxazolidine or

d

oxazine ring. Heteroatom involved in H-bonding with the first OH

of the side chain leading to a pseudo-cycle.

the five- and six-membered intramolecular H-bridges arising leading to H-bond formation analogous to that found in S-oxazo-

from the interaction of the first hydroxyl of the side chain with lidine: 27a (eq–ax). Six-membered pseudo-rings generated by

Fig. 5 Diﬀerent configurational and conformational arrangements of the oxazolidine ring with neighbouring groups.

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Fig. 7 Optimized structures of isomeric 27a–c in DMSO (SMD method).

Fig. 8 Oxazolidines and oxazine structures derived from N-octyl-D-

glucamine evaluated by theoretical methods.

H-bonding in 27a (eq–ax) and 27b (eq–eq) should also contribute

significantly to their relative stabilities. The most stable confor-

mation adopted by R-oxazine is ⁵C₂with the ethyl and phenyl

groups in equatorial arrangement: 27c (eq–eq). An intramolecular

hydrogen bond is generated as well, five-membered cycle never-

theless, involving the interaction of the first OH group with

endocyclic oxygen (Fig. 7). Finally, all the S-oxazine conformers

are the most unstable structures. Summing up, the thermo-

dynamic stability of the heterocyclic systems follows the order:

data are summarized in Table 7 for the R- and S-configured

oxazolidines and oxazines of compounds 38. In all cases the

energy diﬀerences were found to be small, DE o 3 kcal mol^ꢀ1

and DG o 3 kcal mol^ꢀ1, with the exception of structures 38a and

39d having a higher gap in stability in the gas phase, which

decreases to less than 3 kcal mol^ꢀ1when solvation (benzene and

DMSO) is taken into account.

The results obtained for the three aromatic substituents are

very similar for 34 and 39 (see Table S8, ESI†). Both in the gas

phase and in the presence of a solvent (DMSO and benzene),

the calculations show an enhanced stability of the S-configured

oxazolidine, the same as the N-ethyl derivative. The remaining

structures, however, exhibit an order depending on the environ-

ment. While in gas phase or benzene, the order is S-oxazolidine 4

R-oxazine 4 S-oxazine 4 R-oxazolidine; in DMSO the R-oxazoli-

dine is the second in stability. There are some discrepancies with

the experimental data showing the isolation of the S-isomer of 34b

and of 28a, 39b with R-configurations (theory predicts the most

stable S-isomer for 38 and 39). Certainly, the energy diﬀerence

S-oxazolidine 4 R-oxazolidine 4 R-oxazine 4 S-oxazine

If we look at the experimental data for comparative purposes,

the R-isomer is obtained for 27a and 31a, whereas a 4-nitro

substituent aﬀords an isomeric mixture (21a, 21b) with almost

identical proportion in the crude product, which enriches in the

R-isomer after recrystallization. These experimental data disagree

however with theoretical calculations, a fact indicating that ring

formation occurs under kinetic control. On the other hand, the

above equilibrium studies point to a reversed order of thermo-

dynamic stability as follows:

R-oxazolidine 4 S-oxazolidine 4 R-oxazine

between the R and S isomers in 38 and 39 is DG o 1 kcal mol^ꢀ1

,

although it is higher in the case of 34 (DG = 2.45 kcal mol^ꢀ1).

At this stage, the discrepancy could be attributed to inaccu- These results point again to heterocycle formation under kinetic

rate modeling of solvent eﬀects, as inclusion of discrete solvent control, which deviates from the thermodynamic stability.

molecules may simulate better substrate–solvent interactions

than a bulk cage of a given dielectric constant.

Also, Table 7 shows the relative energies calculated for the

structures of R- and S-configured oxazolidines and oxazines of

The NBO analysis³⁰of the gas-phase structures calculated compound 44, derived from N-methyl-^D-galactosamine, taking

for 27a, 27b, 27c and 27d indicates that there is an interaction into account the equatorial or axial arrangement of the methyl

between the non-binding orbital of nitrogen and the OH of the bonded to endocyclic nitrogen (Fig. 9).

polyol chain when they orient each other, while weak inter-

action occurs with the non-bonding electron pairs on the most stable structures calculated in DMSO for compound 44

oxazolidine oxygen (Table S7, ESI†). are shown in Fig. 10 (for 43 and 45, see Table S9, ESI†). The

Energy data are similar for the three compounds and the

In line with the preceding analysis, the stability calculation energy diﬀerences between oxazine and the S- and R-isomers of

has been extended to the heterocyclic systems derived from oxazolidine lie in a narrow range too, thus consistent with a

N-octyl^-D-glucamine (Fig. 8). Relative electronic and Gibbs energy thermodynamic balance and agreeing with the fact that some

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Table 7 Relative electronic and Gibbs energies for isomers and confor-

mers of compounds 38 and 44^a

Gas phase Benzene

DMSO

Alkyl^bAryl^cH-bond^dDE

DG

DE DG DE

DG

0.99

38a Eq

38b Eq

38c Eq

38d Ax

44a Eq

Eq

ax

eq

ax

eq

ax

eq

ax

2.70 3.57 2.80 2.70

0.00 0.00 0.00 0.00

1.72 0.93 1.54 0.81

1.06 1.98 1.33 1.66

3.84 3.31 4.40 3.84

2.30 1.95 2.21 2.17

2.61 1.06 2.84 1.65

2.47 1.23 3.10 1.63

1.59 0.81 2.08 1.48

0.00 0.00 0.00 0.00

4.01 3.31 4.63 3.76

2.93

0.00

1.52

1.63

4.53

2.07

3.09

3.63

2.34

0.00

4.85

0.00

0.60

2.09

3.78

2.00

1.83

2.94

1.48

0.00

4.15

O

N

O

N

O

Eq

Ax

44b Eq

Eq

Ax

44c Eq

Ax

44d Eq

Ax

2.28 1.51 1.54 0.78 ꢀ0.40 ꢀ0.63

Fig. 10 Optimized structures of isomeric 44a–c in DMSO (SMD method).

4.27 4.10 3.94 4.23

5.96 4.81 5.29 5.64

4.34 4.34 4.21 3.72

3.08

4.11

3.61

3.06

3.78

3.16

alternative 6-endo-trig that leads to the tetrahydro-1,3-oxazine

ring (52).³¹Cyclization of iminium ions constitutes a valuable

strategy for the synthesis of chiral heterocycles, in particular of

alkaloid skeletons.⁴

a

b

In kcal mol^ꢀ1

.

Arrangement of the octyl group with respect to the

c

ring. Arrangement of the aromatic ring with respect to either oxazo-

lidine or oxazine rings.

The stereochemical outcome can be interpreted by assuming

that cyclization of the iminium ion takes place preferably through

the most stable conformation. The first and second chiral centers

of N-alkyl-^D-glucamine have S- and R-configurations, respectively,

and their hydroxyl substituents lie in the Re,Re side of the iminium

ion.³²When cyclization involves such a face, the new chiral center

should be R and, accordingly the relative stereochemistry between

the polyhydroxyalkyl chain at C-5 and the aromatic moiety at C-2

should be trans (Scheme 6).

can be detected spectroscopically in the reaction mixtures. Both

in the gas phase and benzene, the S-oxazolidine is always the

most stable structure; although the R-configured oxazine

becomes the most stable one in DMSO solution, in full agree-

ment with the experiment.

Formation of oxazolidine and tetrahydro-1,3-oxazine rings:

mechanism and stereochemistry

The above-discussed issues on the structure and equilibria of

oxazolidines and tetrahydro-1,3-oxazines derived from N-ethyl

and N-octyl-^D-glucamine, and N-methyl-D-galactamine provide

suﬃcient insight into a mechanistic rationale as well. Plausible

routes accounting for heterocycle formation are depicted in

Scheme 5. Oxazolidine rings (51) are generated by a 5-endo-trig

cyclization of the iminium ion 50, entropically favored over the

The most stable conformation of an N-alkyl-^D-glucamine is

not an extended zig-zag chain (P), which would cause a severe

1,3-diaxial interaction between the OH groups at C-2 and C-4,

but the ₃G⁺conformation generated by 1201-rotation around

the bond between C-3 and C-4 (Scheme 7).³³From this initial

conformation combined with slight rotation around the C-N

bond, the geometric arrangement 54 can easily be adopted,

suitable to reach the transition state leading to trans-oxazolidine

(2R-configured) (55, attack a).

A counterclockwise rotation of 1201 around the bond joining

C-1 and C-2 generates the G^ꢀ₃G⁺conformation (57), in which

1

the flat iminium group is located near the middle of the OH

groups at C-2 and C-3 carbons. The former is placed in the Si,Si

face while the second lies in the Re,Re face. Cyclization of such

hydroxyls would lead respectively to cis-(2S)-oxazolidine (58,

attack b) and cis-(2R)-tetrahydro-1,3-oxazine (59, attack c), the

former being entropically favored.

The ₁G^ꢀ₃G⁺conformation (57) should be less stable than 54,

because the iminium group bisects the angle between the OH

substituent at C-2 and the sugar chain, thus causing two strong

gauche interactions and, in addition it would present a 1,3-

diaxial interaction between the hydroxyl at C-3 and the iminium

group. Conversely, only a gauche interaction with the hydroxyl

group appears in 54. Consequently, the transition states result-

ing in 58 and 59, which are reached through conformation 57,

will also be less stable than that leading to 55 from conforma-

tion 54. This explains the relative proportions usually found in

Fig. 9 Oxazolidines and oxazine structures derived from N-methyl-D-

galactosamine evaluated by theoretical methods.

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Scheme 5 Cyclization of iminium intermediates leading to either five- or six-membered heterocycles (Ch = D-erythro or D-threo-CHOHCHOHCH₂OH

chain, R = Me, Et, octyl).

Scheme 6 Stereochemical results from iminium ion cyclization involving prochiral faces to aﬀord oxazolidine and oxazine isomers (Ch = D-erythro or

D-threo-CHOHCHOHCH₂OH chain, R = Me, Et, octyl).

Scheme 7 Conformational equilibria of the iminium intermediate in N-alkyl-D-glucamines (Ch = D-glycero-CHOHCH₂OH chain, R = Et, octyl).

the reaction mixtures, which are not always coincidental with cyclization at C-3 has not been observed experimentally

those based on thermodynamic stability.

(Scheme 8).

The mechanism yielding the oxazolidines and tetrahydro-

The ₁G^ꢀ₃G^ꢀconformation, generated by a clockwise rotation

of 1201 around the C-1-C-2 bond, and having lower energy than 1,3-oxazines derived from N-methyl-^D-galactamine (Scheme 9)

₁G^ꢀ3G⁺(57) indeed, puts apart the iminium group from the should be the same as that shown for N-ethyl and N-octyl-

hydroxyl and makes ring closure impossible. As an alternative D-glucamines. Also, the first and second chiral centers of

to cyclization on the Si,Si face of the (E)-iminium cation, N-methyl-^D-galactamine have S- and R-configurations, respec-

cyclization of the OH group at C-2 involving the Re,Si face of tively; and the most stable conformation (P) of N-methyl-^D-

the (Z)-iminium cation (60) would give rise to a cis-oxazolidine galactamine exhibits an extended zig-zag chain (62), since the

(58). However, the cis-oxazine resulting from the OH group configurational inversion at C-4 with respect to ^D-glucamine

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Scheme 8 Stereochemical outcome from iminium ion cyclization involving the prochiral Re,Si face to aﬀord oxazolidine 58 (Ch = D-glycero-

CHOHCH₂OH chain, R = Et, octyl).

Scheme 9 Ring closures from iminium ion cyclization for N-methyl-D-galactamine derivatives (Ch = D-glycero-CHOHCH₂OH chain).

eliminates the 1,3-diaxial interaction between the C2-OH and interconversion of trans (55) and cis (58) oxazolidines and

C4-OH groups.

tetrahydro-1,3-oxazine (59). It is obvious that these transforma-

trans-Oxazolidine 64 is obtained from 63 by cyclization tions should be occurring through the intermediacy of acyclic

involving the ReRe face (attack a), while starting from the G^ꢀcations 69–71, whose formation could also be assisted by

1

(65) conformation, formation of the cis-(2S)-oxazolidine isomer solvent molecules (Scheme 11). This behavior suggests that

occurs by cyclization through the Re face (66, attack b) and cis oxazolidine isomerization occurs easily, despite the fact that

(2R)-tetrahydro-1,3-oxazine on the Si face (67, attack c).

according to Baldwin’s rules,³¹the 5-endo-trig cyclization

A key point deserving some thoughts is the seemingly surprising affording such rings should be disfavored with respect to the

fact that N-methyl,⁶N-ethyl and N-octyl-D-glucamine are reluctant 6-endo-trig cyclization, which would lead to the corresponding

to form oxazine derivatives, while in the case of N-methyl-^D- oxazines. Other studies,³⁴however, have shown that 5-endo-trig

galactamine such six-membered heterocycles are formed cyclization on imine and iminium ion bonds to form oxazoli-

together with oxazolidines to a similar extent. Cyclization to dines or oxazines proceeds rapidly.³⁵Moreover, an asymmetric

oxazine 68 of N-alkyl-^D-glucamines through the G^ꢀ₃G⁺confor-

1

mation (57) should be quite diﬃcult, since this conformation

shows gauche interactions among carbon atoms at 2-3-4-5 posi-

tions, which are absent in the G^ꢀ(65) conformation adopted by

1

Nmethyl-^D-galactamine derivatives. The arrangement of the acyclic

chain with respect to the oxazine ring is clearly witnessed by the high

coupling constant J_H3,H4(B9 Hz) of oxazines 67 (Scheme 10).

Although the OH group at C-4, and hence the configuration

of the latter, is not directly involved in ring-forming pathways,

that group alters the relative stability of the diﬀerent species

and converts actually the 2R-configured tetrahydro-1,3-oxazine

(67) into the most stable structure, in agreement with both

experiment and theoretical calculations.

Finally and in mechanistic context, we have shown through

recrystallizations and equilibration experiments the facile

Scheme 10 Steric interactions during the cyclization of iminium ion to

oxazine rings (Ch = ^D-glycero-CHOHCH₂OH chain, R = Et, octyl).

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Scheme 11 Stereochemical interconversion of oxazolidine and oxazine rings through the intermediacy of open-chain iminium cations (Ch = D-erythro

or D-threo-CHOHCHOHCH₂OH chain, R = Me, Et, octyl).

one-pot synthesis of 1,3-oxazolidines and 1,3-oxazines involving was carried out in a rotary evaporator at temperatures below

hemiaminal intermediates has also been reported.³⁶

50 1C and pressures estimated between 15 and 30 mmHg.

Melting points were determined using an Electrothermal IA

9000 apparatus and are uncorrected. Quantitative elemental

analyses were performed on a Leco^sCHNS-932 analyzer.

Optical rotations were measured on a PerkinElmer 241 polari-

meter, with sodium light (D line, l = 589 nm) and mercury light

(l = 578, 546, 463, 365 nm). Thin layer chromatography was

used with qualitative analytical character, using chromato-

grams (7 ꢂ 3 cm) made of Polygram Silica G/UV254 supplied

by Aldrich^s. The common eluent was ethyl acetate:petroleum

ether (2 : 1, v/v). UV light of wavelengths 254 and 360 nm, and

iodine vapors were used as developers. FT-IR spectra were

recorded on a Thermo IR-300 spectrophotometer in the range

of 4000–600 cm^ꢀ1. The spectra of solid products were obtained

using dry potassium bromide pellets (Merck^sfor spectro-

scopy). NMR spectra were recorded on Bruker Avance 400 and

500 spectrometers (400 MHz and 500 MHz for ¹H, and 100 MHz

and 125 MHz for ¹³C nuclei, respectively).

Chemical shifts (d, ppm) refer to tetramethylsilane (Me₄Si,

TMS) as the internal reference (d = 0.0 ppm). Coupling constants

( J) are given in Hz and correspond to the apparent values,

measured directly on the recorded spectrum. Structural elucida-

tion was facilitated through DEPT (distortionless enhancement by

polarization transfer), 2D correlation spectroscopy (COSY), and

heteronuclear multiple-quantum correlation (HMQC) experi-

ments, as well as isotope exchange with deuterium oxide. High-

resolution mass spectroscopy (HRMS) was carried out using the

chemical ionization (CI) or fast atom bombardment (FAB) tech-

niques at the Center for Technological Research and Innovation

(CITIUS) at the University of Seville, while electrospray ionization

(ESI) measurements were performed using the Servicio de Apoyo a

Conclusions

Reactions of O-unprotected N-alkyl-D-glucamines with substituted

benzaldehydes aﬀord adducts of cis- and trans-1,3-oxazolidines,

whereby a new chiral center is also created. The analogous

condensation with N-methyl-^D-galactamine (epimer at C-4 of the

D-gluco side chain) gives rise to a mixture of 1,3-oxazolidines and

1,3-oxazines. The absolute configuration of the new stereogenic

center could be established by correlating spectroscopic and

polarimetric data, thereby identifying a useful rule to assign the

chirality for this family of compounds. The yields and product

distribution vary with recrystallization, thus reflecting isomeriza-

tion equilibria in solution, which were assessed by NMR experi-

ments. Compositions are largely consistent with ring-forming

processes under kinetic control. Thermodynamic stability was

computed at the M06-2X/6-311G(d,p) level taking into account

the configuration of the new chiral center, the relative dispositions

between the sugar chain and the heterocycle, as well as the

conformational bias of both fragments. Solvation has little eﬀect

on stabilization with energy diﬀerences smaller than 3 kcal mol^ꢀ1

,

although DMSO produces changes in isomer stability with respect

to gas-phase calculations. S-Configured oxazolidines are the most

stable species, whose origin can be inferred from stabilizing non-

bonding interactions and minimization of steric eﬀects. Ring

closures can be rationalized in terms of 5-endo-trig and 6-endo-trig

cyclizations resulting in oxazolidines and oxazines, respectively,

and involving intramolecular attacks to transient iminium ions as

common intermediates.

´

la Investigacion (SAIUEx) at the University of Extremadura.

Experimental section

Methods

Computational analyses

All solvents and reagents were obtained from commercial All calculations were carried out using the Gaussian09

suppliers and used as received. The evaporation of solvents package.²⁹Geometries were optimized using the global-hybrid

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Paper

meta-GGA functional M06-2X²⁶in combination with the Pople (m, 1H, C4⁰-OH), 4.20 (c, J_4a,5E J_5,1= 7.0 Hz, 1H, H-5), 3.70

0

6-311G(d,p) basis set.²⁷Geometries were optimized with inclu- (t, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1⁰), 3.61 (m, 1H, H-4⁰), 3.50

0

sion of solvation eﬀects using the SMD method.²⁸All saddle (m, 1H, H-3⁰), 3.40 (m, 1H, H-4⁰⁰), 3.20 (t, J_{2 ,3}E J_{2 ,OH}= 8.5 Hz,

points linking specific reactants and products through the 1H, H-2⁰), 2.88 (dd, J_4a,5= 7.0 Hz, J_4a,4b= 11.0 Hz, 1H, H-4a), 2.81

0

reaction path were confirmed using intrinsic reaction coordi- (dd, J_4b,5= 7.0 Hz, J_4a,4b= 10.5 Hz, 1H, H-4b), 2.58 (m, 1H, CH₂),

nate (IRC) analysis. Frequency calculations were carried out at 2.44 (m, 1H, CH₂⁰⁰), 1.03 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (125

298.15 K at the above-mentioned level of theory. Saddle points MHz, DMSO-d₆) d 148.4, 147.4, 128.6, 123.1 (arom), 95.2 (C-2),

and energy minima were characterized by one or none imaginary 79.5 (C-5), 71.3, 71.1, 70.9 (C-1⁰, C-2⁰, C-3⁰), 63.4 (C-4⁰), 52.5

frequencies, respectively.

(C-4), 46.6 (CH₂), 13.9 (CH₃).

(2R,5S)-2-(2-Chlorophenyl)-3-ethyl-5-(^D-arabino-1,2,3,4-tetra-

hydroxybutyl)oxazolidine (22a) and (2S,5S)-2-(2-chlorophenyl)-

3-ethyl-5-(^D-arabino-1,2,3,4-tetrahydroxybutyl)oxazolidine (22b).

Synthesis of N-alkyl-polyhydroxyalkyl-1,3-oxazolidines and

N-alkyl-polyhydroxyalkyl-1,3-oxazines

General procedure A. To a suspension of N-ethyl or N-octyl-^D- Method A. Following the general procedure and from 2-

glucamine or N-methyl-^D-galactamine (10.0 mmol) in benzene chlorobenzaldehyde the title compounds were obtained (95%)

(15 mL), the corresponding aromatic aldehyde (15.0 mmol) was in 1 : 1 ratio of 22a : 22b. After recrystallization from absolute

added. The reaction was refluxed for 4–5 h, removing the ethanol (69%) the ratio changes to 4 : 5; m.p. 123–125 1C; IR (KBr)

resulting water with a Dean–Stark trap. The mixture was nꢀ_max/cm^ꢀ13500–3200 (OH), 1595, 1575, 1466, 1439 (arom), 1098,

allowed to cool to room temperature and the solid formed 1086, 1051, 1027 (C–O).

1

was filtered and washed with cold benzene and ethyl ether. In

Spectroscopic data of 22a. H NMR (500 MHz, DMSO-d₆) d

the case of N-methyl-^D-galactamine, the reaction medium was 7.67 (dd, J = 2.0 Hz, J = 7.5 Hz,1H, arom), 7.41 (m, 3H, arom),

brought to dryness under vacuum, yielding either a clear 5.18 (s, 1H, H-2), 4.55 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.48

0

viscous oil, which was treated with ethyl ether precipitating a (d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.32 (m, 2H, C2⁰-OH, C4⁰-OH),

0

white solid that was filtered and washed with ethyl ether.

4.28 (dt, J_4a,5E J_5,1= 7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), 3.69

Procedure B. To a solution of N-ethyl-D-glucamine (2.61 g, (t, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.50 (m,

0

12.5 mmol) in water (16 mL), the corresponding aromatic 1H, H-3⁰), 3.42 (m, 2H, H-4⁰⁰,₀H-4a), 3.24 (t, J_{2 ,3}E J_{2 ,OH}= 8.0 Hz,

aldehyde (12.5 mmol), dissolved in a given volume of hot 1H, H-2⁰), 2.41 (m, 1H, ₀C₀H₂), 2.31 (t, J_4a,4bE J_4a,5= 9.0 Hz 1H,

methanol (15–25 mL) to facilitate homogenization, was added. H-4b), 2.29 (m, 1H, CH₂), 0.96 (t, J = 9.0 Hz, 3H, CH₃); ¹³C NMR

The resulting adduct either precipitates spontaneously or after (125 MHz, DMSO-d₆) d 137.0, 133.3, 130.1, 129.3, 129.1, 127.1

0

solvent evaporation.

(arom), 91.8 (C-2), 79.2 (C-5), 71.7, 71.3, 71.0 (C-1⁰, C-2⁰, C-3⁰),

(2R,5S)-3-Ethyl-2-(4-nitrophenyl)-5-(^D-arabino-1,2,3,4-tetrahydroxy- 63.3 (C-4⁰), 53.6 (C-4), 45.0 (CH₂), 13.6 (CH₃).

1

butyl)oxazolidine (21a) and (2S,5S)-3-ethyl-2-(4-nitrophenyl)-5-(^D-

Spectroscopic data of 22b. H NMR (500 MHz, DMSO-d₆) d

arabino-1,2,3,4-tetrahydroxybutyl)oxazolidine (21b). Method A. 7.71 (dd, J = 2 Hz, J = 7.0 Hz, 1H, arom), 7.36 (m, 3H, arom), 5.28

Following the general procedure and from 4-nitrobenzaldehyde (s, 1H, H-2), 4.47 (d, J_{1 ,OH}= 5.5 Hz, 1H, C1⁰-OH), 4.45 (d, J_{3 ,OH}

=

0

a mixture of the title compounds (98%) was obtained in a 1 : 1 5.5 Hz, 1H, C3⁰-OH), 4.40 (d, J_{2 ,OH}= 7.5 Hz, 1H, C2⁰-OH), 4.30

ratio of 21a : 21b. After recrystallizing from absolute ethanol (m, 1H, C4⁰-OH), 4.19 (dt, J_4a,5E J_5,1= 6.0 Hz, J_4b,5= 7.5 Hz, 1H,

0

(82%) the ratio changes to 5 : 3, which showed m.p. 145-147 1C. H-5), 3.75 (t, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1 ), 3.59 (m, 1H, H-4 ),

IR (KBr) nꢀ_max/cm^ꢀ13500–3200 (OH), 1610 (arom), 1528 (NO₂), 3.50 (m, 1H, H-3⁰), 3.43 (m, 1H, H-4⁰⁰), 3.28 (t, J_{2 ,3}E J_{2 ,OH}

1456 (arom), 1345 (NO₂), 1082, 1054, 1030 (C–O).

7.0 Hz, 1H, H-2⁰), 3.09 (dd, J_4a,5= 5.5 Hz, J_4a,4b= 9.5 Hz, 1H,

Method B. A mixture of the title compounds (52%) was H-4a), 2.73 (dd, J_4b,5= 7.5 Hz, J_4a,4b= 9.5 Hz, 1H, H-4b), 2.50 (m,

=

0

obtained in a 1 : 1 ratio.

1H, CH₂), 2.42 (m, 1H, CH₂⁰⁰), 0.98 (t, J = 7.5 Hz, 3H, CH₃); ¹³C

0

1

Spectroscopic data of 21a. H NMR (500 MHz, DMSO-d₆) d NMR (125 MHz, DMSO-d₆) d 136.9, 133.2, 129.9, 129.3, 129.0,

8.22 (m, 2H, arom), 7.72 (d, J = 8.5 Hz, 2H, arom), 4.90 (s, 1H, 127.1 (arom), 93.0 (C-2), 78.0 (C-5), 71.1, 70.9, 70.9 (C-1⁰, C-2⁰,

H-2), 4.58 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.48 (d, J_{3 ,OH}

5.5 Hz, 1H, C3⁰-OH), 4.32 (m, 2H, C2⁰-OH, C4⁰-OH), 4.28 (m, 1H,

=

C-3⁰), 63.4 (C-4⁰), 52.0 (C-4), 46.0 (CH₂), 13.8 (CH₃).

0

(2R,5S)-3-Ethyl-2-(2-methylphenyl)-5-(^D-arabino-1,2,3,4-tetra-

H-5), 3.70 (dt, J_{1 ,2}= 1.5 Hz, J_{1 ,OH}E J_5,1= 7.0 Hz, 1H, H-1⁰), hydroxybutil)oxazolidine (23a) and (2S,5S)-3-ethyl-2-(2-methyl-

3.58 (m, 1H, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.41 (m, 2H, H-4⁰⁰, H-4a), phenyl)-5-(^D-arabino-1,2,3,4-tetrahydroxybutil)oxazolidine (23b).

0

3.24 (t, J_{2 ,3}E J_{2 ,OH}= 7.0 Hz, 1H, H-2⁰), 2.44 (m, 1H, CH2⁰), 2.34 Method A. Following the general procedure and from 2-

(t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, H-4b), 2.15 (ddd, J = 7.0 Hz, J = methylbenzaldehyde the title compounds were obtained (90%)

11.5 Hz, 1H, CH₂⁰⁰), 0.97 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (125 in a 5 : 2 ratio of 23a : 23b. After recrystallization from absolute

MHz, DMSO-d₆) d 147.8, 147.6, 129.1, 123.2 (arom), 94.7 (C-2), ethanol, 23b (63%) was obtained; m.p. 102–104 1C; IR (KBr)

79.5 (C-5), 71.1, 71.1, 71.0 (C-1⁰, C-2⁰, C-3⁰), 63.3 (C-4⁰), 53.6 nꢀ_max/cm^ꢀ13500–3100 (OH), 1485, 1463 (arom), 1088, 1068, 1049,

0

25

(C-4), 45.3 (CH₂), 13.6 (CH₃).

1027 (C–O); [a]²_D⁵ꢀ63.01; [a]

ꢀ66.11; [a]

ꢀ74.61; [a]

578

546

436

1

Spectroscopic data of 21b. H NMR (500 MHz, DMSO-d₆) d ꢀ129.31 (c 0.5, pyridine).

8.22 (m, 2H, arom), 7.76 (d, J = 9.0 Hz, 2H, arom), 5.17 (s, 1H,

Spectroscopic data of 23a. ¹H NMR (500 MHz, DMSO-d₆)

d 7.44 (dd, J = 1.5 Hz, J = 7.5 Hz, 1H, arom), 7.17 (m, 3H, arom),

6.0 Hz, 1H, C3⁰-OH), 4.36 (d, J_{2 ,OH}= 7.5 Hz, 1H, C2⁰-OH), 4.29 4.90 (s, 1H, H-2), 4.50 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.47

H-2), 4.52 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.43 (d, J_{3 ,OH}

=

0

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(d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 6.0 Hz, 3.67 (dt, J_{1 ,2}= 1.5 Hz, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1⁰), 3.59

0

00

0

1H, C4⁰-OH), 4.28 (d, J_{2 ,OH}= 7.0 Hz, 1H, C2⁰-OH), 4.22 (dt, (m, 1H, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.48 (m, 1H, H-4⁰⁰), 3.24 (m, 1H,

0

J_4a,5E J_5,1= 7.0 Hz, J_4b,5= 9.5 Hz, 1H, H-5), 3.68 (dt, J_{1 ,2}

=

H-2⁰), 2.97 (dd, J_4a,5= 6.0 Hz, J_4a,4b= 10.0 Hz, 1H, H-4a), 2.71 (dd,

0

1.5 Hz, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.49 J_4b,5= 7.5 Hz, J_4a,4b= 10.0 Hz, 1H, H-4b), 2.53 (m, 1H, CH₂), 2.36

0

00

(m, 1H, H-3⁰), 3.42 (m, 2H, H-4⁰⁰, H-4a), 3.22 (dt, J_{1 ,2}= 1.5 Hz, (ddd, J = 7.0 Hz, J = 19.0 Hz, 1H, CH₂), 1.01 (t, J = 7.0 Hz, 3H,

0

J_{2 ,3}E J_{2 ,OH}= 9.0 Hz, 1H, H-2⁰), 2.39 (s, 3H, CH₃-arom), 2.37 CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 140.9, 123.1, 114.7, 113.4

(m, 1H, CH₂’), 2.27 (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, H-4b), 2.15 (arom), 95.1 (C-2), 77.2 (C-5), 70.7, 70.3 (C-1⁰, C-2⁰, C-3⁰), 62.9

(ddd, J = 7.0 Hz, J = 12.0 Hz, J = 14.0 Hz, 1H, CH₂⁰⁰), 0.97 (t, J = (C-4⁰), 51.9 (C-4), 45.6 (CH₂), 13.3 (CH₃).

0

7.0 Hz, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 136.9, 136.7,

(2R,5S)-3-Ethyl-2-(3-methoxyphenyl)-5-(^D-arabino-1,2,3,4-tetra-

130.1, 128.1, 128.0, 125.2 (arom), 94.1 (C-2), 78.2 (C-5), 71.0, hydroxybutyl)oxazolidine (25a). Method A. Following the general

70.9 (C-1⁰, C-2⁰, C-3⁰), 63.2 (C-4⁰), 53.6 (C-4), 44.9 (CH₂), 18.5 procedure and from 3-methoxybenzaldehyde the title compound

(CH₃-arom), 13.5 (CH₃).

(90%) was obtained; recrystallized from absolute ethanol (74%)

1

25

Spectroscopic data of 23b. H NMR (500 MHz, DMSO-d₆) d shows m.p. 122–124 1C; [a]²_D⁵+21.51; [a]

+22.81; [a]

+26.51;

578

546

7.51 (dd, J = 1.5 Hz, J = 7.0 Hz, 1H, arom), 7.19 (m, 3H, arom), [a]²₄₃⁵₆+43.71 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–3100 (OH),

5.06 (s, 1H, H-2), 4.43 (m, 2H, C2⁰-OH, C3⁰-OH) 4.41 (d, J_{1 ,OH}

=

1602, 1462 (arom), 1099, 1030 (C–O).

0

6.0 Hz, 1H, C1⁰-OH-1⁰), 4.31 (bs, 1H, C4⁰-OH), 4.17 (dt, J_4a,5

E

Method B. The title compound was obtained in 75% yield

according to this procedure.

0

J_5,1= 5.5 Hz, J_4b,5= 7.5 Hz, 1H, H-5), 3.71 (t, J_{1 ,OH}E J_5,1

=

6.0 Hz, 1H, H-1⁰), 3.59 (d, J_{4 ,4}= 11.0 Hz, 1H, H-4 ), 3.49 (bs, 1H,

¹H NMR (500 MHz, DMSO-d₆) d 7.27 (t, J = 8.0 Hz, 1H, arom),

0

00

H-3⁰), 3.39 (m, 1H, H-4⁰⁰), 3.26 (t, J_{2 ,3}E J_{2 ,OH}= 6.5 Hz, 1H, 7.01 (d, J = 7.5 Hz, 1H, arom), 6.99 (s, 1H, arom), 6.90 (dd, J =

0

H-2⁰), 3.08 (dd, J_4a,5= 5.5 Hz, J_4a,4b= 10.0 Hz, 1H, H-4a), 2.68 1.5 Hz, J = 8.0 Hz, 1H, arom), 4.66 (s, 1H, H-2), 4.54 (d, J_{1 ,OH}

=

0

(dd, J_4b,5= 8.0 Hz, J_4a,4b= 10.0 Hz, 1H, H-4b), 2.46 (m, 1H, CH₂), 6.5 Hz, 1H, C1⁰-OH), 4.48 (d, J_{3 ,OH}= 5.5 Hz, 1H, C3⁰-OH), 4.33

0

2.38 (s, 3H, CH₃-arom), 2.30 (ddd, J = 5.0 Hz, J = 14.0 Hz, J = 18.5 Hz, (t, J_{4 ,OH}E J_{4 ,OH}= 5.5 Hz, 1H, C4⁰-OH), 4.43 (d, J_{2 ,OH}= 7.5 Hz,

0

00

0

1H, CH₂), 0.99 (t, J = 7.5 Hz, 3H, CH₃); ¹³C NMR (125 MHz, 1H, C2⁰-OH), 4.24 (ddd, J_4a,5E J_5,1= 6.5 Hz, J_4b,5= 8.5 Hz, 1H,

0

DMSO-d₆) d 137.2, 137.1, 130.3, 128.2, 127.4, 125.6 (arom), 94.6 H-5), 3.75 (s, 3H, OCH₃), 3.67 (t, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1 ),

(C-2), 77.6 (C-5), 71.2, 71.1, 71.0 (C-1⁰, C-2⁰, C-3⁰), 63.7 (C-4⁰), 3.59 (m, 1H, H-4⁰), 3.50 (m, 1H, H-3⁰), 3.40 (m, 2H, H-4a, H-4⁰⁰),

52.3 (C-4), 45.1 (CH₂), 19.2 (CH₃-arom), 14.4 (CH₃).

3.23 (t, J_{2 ,3}E J_{2 ,OH}= 7.5 Hz, 1H, H-2⁰), 2.41 (ddd, J = 7.5 Hz, J =

0

(2R,5S)-3-Ethyl-2-(3-fluorophenyl)-5-(^D-arabino-1,2,3,4-tetrahydroxy- 15.0 Hz, J = 19.5 Hz, 1H, CH₂), 2.24 (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H,

butyl)oxazolidine (24a) and (2S,5S)-3-ethyl-2-(3-fluorophenyl)-5- H-4b), 2.17 (ddd, J = 7 Hz, J = 14.0 Hz, J = 19.0 Hz, 1H, CH₂⁰⁰),

(^D-arabino-1,2,3,4-tetrahydroxybutyl)oxazolidine (24b). Method A. 0.96 (t, J = 7.5 Hz, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d

Following the general procedure and from 2-fluorobenzaldehyde 159.0, 141.7, 129.0, 120.2, 114,1, 113.1 (arom), 96.0 (C-2), 78.9

pure 24a is obtained (91%); m.p. 119–121 1C; IR (KBr) nꢀ_max/cm^ꢀ1(C-5), 71.1, 71.0 (C-1⁰, C-2⁰, C-3⁰), 63.3 (C-4⁰), 54.9 (OCH₃), 53.7

3600–3200 (OH), 1617, 1595, 1487, 1454 (arom), 1094, 1065, 1031 (C-4), 45.1 (CH₂) 13.6 (CH₃). Anal. calcd for C₁₆H₂₅NO₆ꢁ1/2H₂O:

25

546

25

436

(C–O); [a]²_D⁵+20.91; [a] +22.21; [a] +25.01; [a] +42.21 (c 0.5, C, 57.13, H, 7.79, N, 4.16. Found: C, 57.57, H, 7.52, N, 4.06.

578

pyridine); ¹H NMR (500 MHz, DMSO-d₆) d 7.40 (m, 1H, arom), 7.29

(2R,5S)-3-Ethyl-2-(4-methylphenyl)-5-(^D-arabino-1,2,3,4-tetra-

(d, J = 6.5 Hz, 1H, arom), 7.23 (d, J = 10.0 Hz, 1H, arom), 7.17 (dt, J = hydroxybutyl)oxazolidine (26a). Method A. Following the general

0

2.0 Hz, J = 8.0 Hz,1H, arom), 4.74 (s, 1H, H-2), 4.55 (d, J_{1 ,OH}= 6.5 Hz, procedure and from 4-methylbenzaldehyde the title compound

1H, C1⁰-OH), 4.48 (d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.32 (m, 2H, C2⁰- was obtained (93%); recrystallized from absolute ethanol (71%)

0

25

OH, C4⁰-OH), 4.22 (dt, J_4a,5E J_5,1= 7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), shows m.p. 138–140 1C; [a]²_D⁵+17.01; [a]₅₇₈+18.71; [a]₅₄₆+20.91;

0

3.67 (dt, J_{1 ,2}= 1.5 Hz, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1⁰), 3.59 (m, 1H, [a]₄²₃⁵₆+21.91 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–3200 (OH),

0

1

H-4⁰), 3.49 (m, 1H, H-3⁰), 3.40 (m, 2H, H-4⁰⁰, H-4a), 3.22 (dt, J_{1 ,2}

=

1514, 1455 (arom), 1098, 1069, 1032 (C–O); H NMR (500 MHz,

0

1.5 Hz, J_{2 ,3}E J_{2 ,OH}= 8.5 Hz, 1H, H-2⁰), 2.42 (ddd, J = 7.5 Hz, J = DMSO-d₆) d 7.31 (d, J = 8.0 Hz, 2H, arom), 7.16 (d, J = 8.0 Hz, 2H,

0

12.0 Hz, J = 14.5 Hz, 1H, CH₂), 2.27 (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, arom), 4,63 (s, 1H, H-2), 4.53 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.48

0

H-4b), 2.15 (td, J = 7.0 Hz, J = 14.0 Hz, 1H, CH₂), 0.97 (t, J = 7.5 Hz, (d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.33 (t, J_{4 ,OH}E J_{4 ,OH}= 5.5 Hz, 1H,

00

0

00

3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 161.5 (d, J = 242 Hz, 1C, C4⁰-OH), 4.29 (d, J_{2 ,OH}= 7.5 Hz, 1H, C2⁰-OH), 4.24 (dt, J_4a,5E J_5,1

=

0

C3-arom), 120.8 (d, J = 25.5 Hz, 1C, C3-arom), 129.5 (d, J = 32.5 Hz, 7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), 3.67 (t, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H,

1C, C3-arom), 123.5 (arom), 114.9 (d, J = 20.88 Hz, 1C, C3-arom), H-1⁰), 3.59 (m, 1H, H-4⁰), 3.50 (m, 1H, H-3⁰), 3.40 (m, 2H, H-4a,

113.7 (d, J = 21.5 Hz, 1C, C3-arom), 94.7 (C-2), 78.6 (C-5), 70.6, 70.5, H-4⁰⁰), 3.23 (t, J_{2 ,3}E J_{2 ,OH}= 7.5 Hz, 1H, H-2’), 2.37 (ddd, J =

70.5 (C-1⁰, C-2⁰, C-3⁰), 62.8 (C-4⁰), 53.1 (C-4), 44.7 (CH₂), 13.5 (CH₃). 7.0 Hz, J = 14.5 Hz, J = 19.0 Hz, 1H, CH₂’), 2.30 (s, 3H, CH₃), 2.23

After recrystallization from absolute ethanol, a mixture of 24a :24b (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, H-4b), 2.14 (ddd, J = 7.5 Hz, J =

0

is obtained (31%) in a 20 : 3 ratio.

14.5 Hz, J = 19.0 Hz, 1H, CH₂), 0.95 (t, J = 7.0 Hz, 3H, CH₃); ¹³C

00

1

Spectroscopic data of 24b. H NMR (500 MHz, DMSO-d₆) d NMR (125 MHz, DMSO-d₆) d 137.8, 137.0, 128.5, 127.9 (arom), 96.1

7.41 (m, 1H, arom), 7.31 (d, J = 7.5 Hz, 1H, arom), 7.29 (m, 1H, (C-2), 78.8 (C-5), 71.1, 71.0 (C-1⁰, C-2⁰, C-3⁰), 63.3 (C-4⁰), 53.7 (C-4),

arom), 7.14 (dt, J = 2.5 Hz, J = 8.0 Hz,1H, arom), 4.98 (s, 1H, 44.9 (CH₂), 20.8 (CH₃-arom), 13.5 (CH₃). Anal. calcd for C₁₆H₂₅NO₅ꢁ

H-2), 4.50 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.45 (d, J_{3 ,OH}= 6.0 Hz, H₂O: C, 58.34, H, 8.26, N, 4.25. Found: C, 58.70, H, 8.07, N, 4.49.

0

1H, C3⁰-OH), 4.40 (d, J_{2 ,OH}= 7.0 Hz, 1H, C2⁰-OH), 4.32 (m, 1H,

(2R,5S)-3-Ethyl-2-phenyl-5-(^D-arabino-1,2,3,4-tetrahydroxybutyl)-

0

C4⁰-OH), 4.18 (dt, J_4a,5E J_5,1= 6.0 Hz, J_4b,5= 7.0 Hz, 1H, H-5), oxazolidine (27a). Method A. Following the general procedure and

0

4380 | New J. Chem., 2021, 45, 4365ꢀ4386

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NJC

Paper

i

00

from benzaldehyde the title compound was obtained (83%); m.p. 1H, CH₂), 1.2 (s, 3H, CH₃- Pr), 1.19 (s, 3H, CH₃- Pr), 0.96 (t, J =

22

98–100 1C; [a]²_D²+15.91; [a]

+16.91; [a]

+18.71; [a]

+30.41 7.0 Hz, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 148.7, 137.4,

578

546

436

(c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13400–3100 (OH), 1477, 1456 127.9, 125.8 (arom), 96.4 (C-2), 78.7 (C-5), 71.1, 71.1 (C-1⁰, C-2⁰,

(arom), 1099, 1066, 1032 (C–O); H NMR (400 MHz, DMSO-d₆) C-3⁰), 63.3 (C-4⁰), 53.7 (C-4), 45.0 (CH₂), 33.1 (CH-ⁱPr), 23.8

1

d 7.43 (dd, J = 2.0 Hz, J = 7.6 Hz, 2H, arom), 7.35 (m, 3H, arom), (CH₃-ⁱPr), 13.6 (CH₃). Anal. calcd. for C₁₈H₂₉NO₅ꢁ1/2H₂O: C,

4,68 (s, 1H, H-2), 4.54 (d, J_{1 ,OH}= 6.4 Hz, 1H, C1⁰-OH), 4.49 62.05, H, 8.68, N, 4.02. Found: C, 62.28, H, 8.45, N, 4.13.

0

(d, J_{3 ,OH}= 4.8 Hz, 1H, C3⁰-OH), 4.30 (m, 2H, C4⁰-OH, C2⁰-OH),

(2R,5S)-3-Ethyl-2-(3-methylphenyl)-5-(^D-arabino-1,2,3,4-tetra-

hydroxybutyl)oxazolidine (30a). Method A. Following the general

0

4.25 (dt, J_4a,5E J_5,1= 6.0 Hz, J_4b,5= 8.8 Hz, 1H, H-5), 3.68 (t, J_{1 ,OH}

E

J_5,1= 6.0 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.50 (m, 1H, H-3⁰), procedure and from 3-methylbenzaldehyde the title compound

0

3.40 (m, 2H, H-4a, H-4⁰⁰), 3.23 (t, J_{2 ,3}E J_{2 ,OH}= 7.2 Hz, 1H, H-2’), was obtained (94%); recrystallized from absolute ethanol (74%)

0

2.40 (ddd, J = 7.2 Hz, J = 11.6 Hz, J = 14.8 Hz, 1H, CH₂’), 2.25 (t, J_4a,4bshows m.p. 130-132 1C; [a]²_D⁵+26.51; [a]

+27.81; [a]

+31.31;

25

578

25

546

E J_4a,5= 8.8 Hz, 1H, H-4b), 2.17 (ddd, J = 6.8 Hz, J = 12.0 Hz, J = [a]²₄₃⁵₆+31.31 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–1200 (OH),

14.0 Hz, 1H, CH₂⁰⁰), 0.96 (t, J = 7.2 Hz, 3H, CH₃); ¹³C NMR 1476, 1454 (arom), 1078, 1067, 1031 (C–O); H NMR (500 MHz,

1

(100 MHz, DMSO-d₆) d 140.0, 128.6, 127.9 (arom), 96.2 (C-2), DMSO-d₆) d 7.22 (m, 3H, arom), 7.14 (d, J = 7.0 Hz, 1H, arom),

78.9 (C-5), 71.1, 71.0 (C-1⁰, C-2⁰, C-3⁰), 63.3 (C-4⁰), 53.7 (C-4), 4.63 (s, 1H, H-2), 4.51 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.47

0

45.0 (CH₂), 13.6 (CH₃). Anal. calcd for C₁₅H₂₃NO₅ꢁ1/2H₂O: C, (d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 6.0 Hz,

0

00

0

58.81, H, 7.90, N, 4.57. Found: C, 58.61, H, 7.60, N, 4.59.

1H, C4⁰-OH), 4.28 (d, J_{2 ,OH}= 7.0 Hz, 1H, C2⁰-OH), 4.25 (dt, J_4a,5

E

0

(2R,5S)-3-Ethyl-2-(4-ethylphenyl)-5-(^D-arabino-1,2,3,4-tetrahydroxy- J_5,1= 7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), 3.67 (dt, J_{1 ,2}= 1.5 Hz,

butyl)oxazolidine (28a). Method A. Following the general proce- J_1’,OHE J_5,1= 7.0 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.99 (m, 1H,

dure and from 4-ethylbenzaldehyde the title compound was H-3⁰), 3.39 (m, 2H, H-4a, H-4⁰⁰), 3.24 (dt, J_{1 ,2}= 1.5 Hz, J_{2 ,3}

0

E

0

obtained (74%); recrystallized from absolute ethanol (30%) shows J_{2 ,OH}= 8.5 Hz, 1H, H-2’), 2.37 (ddd, J = 7.5 Hz, J = 11.5 Hz, J =

25

m.p. 113–115 1C; [a]²_D⁵+16.71; [a]

+17.21; [a]

+19.41; [a]

436

14.5 Hz, 1H, CH₂’), 2.31 (s, 3H, CH₃-arom), 2.25 (t, J_4a,4bE J_4a,5=

578

546

+32.81 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–3100 (OH), 9.0 Hz, 1H, H-4b), 2.16 (ddd, J = 7.0 Hz, J = 14.0 Hz, J = 19.0 Hz,

1514, 1476, 1455 (arom), 1094, 1031 (C–O); H NMR (500 MHz, 1H, CH₂), 0.96 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (125 MHz,

1

00

DMSO-d₆) d 7.33 (d, J = 8.0 Hz, 2H, arom), 7.19 (d, J = 8.0 Hz, 2H, DMSO-d₆) d 140.5, 137.6, 129.7, 129.0, 128.3, 125.7 (arom), 96.8

arom), 4.64 (s, 1H, H-2), 4.51 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.47 (C-2), 79.4 (C-5), 71.7, 71.6, 71.6 (C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 54.2

0

(d, J_{3 ,OH}= 5.5 Hz, 1H, C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 5.0 Hz, 1H, (C-4), 45.5 (CH₂), 21.5 (CH₃-arom), 14.1 (CH₃).

0

00

C4⁰-OH), 4.24 (d, J_{2 ,OH}= 6.5 Hz, 1H, C2⁰-OH), 4.23 (dt, J_4a,5E J_5,1

=

(2R,5S)-3-Ethyl-2-(4-methoxyphenyl)-5-(^D-arabino-1,2,3,4-tetra-

0

7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), 3.67 (t, J_{1 ,OH}E J_5,1= 6.0 Hz, 1H, hydroxybutyl)oxazolidine (31a). Method A. Following the general

H-1⁰), 3.59 (m, 1H, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.39 (m, 2H, H-4a, procedure and from 4-methoxybenzaldehyde the title compound

25

H-4⁰⁰), 3.23 (t, J_{2 ,3}E J_{2 ,OH}= 7.5 Hz, 1H, H-2’), 2.39 (ddd, J = 7.5 Hz, was obtained (86%) showing m.p. 135–137 1C; [a]²_D⁵+30.21; [a]₅₇₈

0

25

0

J = 12.0 Hz, J = 15 Hz, 1H, CH₂), 2.24 (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, +32.21; [a]₅₄₆+36.71; [a]₄₃₆+62.81 (c 0.5, pyridine); IR (KBr)

H-4b), 2.15 (ddd, J = 7.0 Hz, J = 14.0 Hz, J = 18.5 Hz, 1H, CH₂), 1.18 nꢀ_max/cm^ꢀ13500–3200 (OH), 1611, 1458 (arom), 1091, 1069,

00

(t, J = 7.5 Hz, 3H, CH₃), 0.95 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR 1031 (C–O); ¹H NMR (500 MHz, DMSO-d₆) d 7.35 (dd, J =

(125 MHz, DMSO-d₆) d 144.7, 137.8, 128.5, 127.8 (arom), 96.6 (C-2), 1.5 Hz, J = 8.5 Hz, 2H, arom), 6.90 (d, J = 9.0 Hz, 2H, arom),

79.3 (C-5), 71.7, 71.6 (C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 54.2 (C-4), 45.5 4.61 (s, 1H, H-2), 4.53 (bs, 2H, OH), 4.33 (sa, 2H, OH), 4.25 (dt,

0

(CH₂), 28.4 (CH₂-arom), 16.1 (CH₃-arom), 14.1 (CH₃). Anal. calcd J_4a,5E J_5,1= 7.0 Hz, J_4b,5= 8.5 Hz, 1H, H-5), 3.75 (s, 3H, OCH₃),

for C₁₇H₂₇NO₅ꢁH₂O: C, 59.46, H, 8.36, N, 4.08. Found: C, 59.45, H, 3.68 (d, J_{1 ,OH}E J_5,1= 7.0 Hz, 1H, H-1⁰), 3.60 (dd, J_OH,4= 3.0 Hz,

0

00

8.25, N, 4.26.

J_{4 ,4}= 11.0 Hz 1H, H-4⁰), 3.51 (m, 1H, H-3⁰), 3.41 (m, 2H, H-4a,

(2R,5S)-3-Ethyl-2-(4-isopropylphenyl)-5-(^D-arabino-1,2,3,4-tetra- H-4⁰⁰), 3.25 (d, J_{2 ,3}E J_{2 ,OH}= 8.0 Hz, 1H, H-2’), 2.37 (ddd, J =

hydroxybutyl)oxazolidine (29a). Method A. Following the general 7.5 Hz, J = 14.5 Hz, J = 19.0 Hz, 1H, CH₂’), 2.23 (t, J_4a,4bE J_4a,5

procedure and from 4-isopropylbenzaldehyde the title compound 9.0 Hz, 1H, H-4b), 2.17 (ddd, J = 7.0 Hz, J = 14.0 Hz, J = 18.5 Hz,

0

=

was obtained (73%); recrystallized from absolute ethanol (49%) 1H, CH₂), 0.95 (t, J = 7.5 Hz, 3H, CH₃); ¹³C NMR (125 MHz,

00

25

shows m.p. 120-122 1C; [a]²_D⁵+17.01; [a]

+17.81; [a]

+20.01; DMSO-d₆) d 160.1, 132.4, 129.8, 128.8, 113.9, 113.9 (arom), 96.5

578

546

[a]₄²₃⁵₆+33.21 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–3100 (OH), (C-2), 79.1 (C-5), 71.7, 71.6 (C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 55.5

1457, 1457 (arom), 1094, 1081, 1031 (C–O); H NMR (500 MHz, (OCH₃), 54.2 (C-4), 45.4 (CH₂) 14.1 (CH₃).

1

DMSO-d₆) d 7.34 (d, J = 8.0 Hz, 2H, arom), 7.22 (d, J = 8.0 Hz, 2H,

(2S,5S)-2-(2,4-Dimethylphenyl)-3-ethyl-5-(^D-arabino-1,2,3,4-tetra-

arom), 4.64 (s, 1H, H-2), 4.50 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.47 hydroxybutyl)oxazolidine (32b). Method A. Following the general

0

(d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 5.5 Hz, procedure and from 2,4-dimethylbenzaldehyde, the title com-

0

00

1H, C4⁰-OH), 4.28 (d, J_{2 ,OH}= 7.5 Hz, 1H, C2⁰-OH), 4.23 (dt, J_4a,5

E

pound was obtained (92%); recrystallized from absolute ethanol

0

J_5,1= 7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), 3.67 (dt, J_{1 ,2}= 1.5 Hz, J_{1 ,OH}(35%) shows m.p. 102–104 1C; [a]²_D⁵ꢀ55.21; [a]₅₇₈ꢀ56.71; [a]₅₄₆

25

0

E J_5,1= 7.0 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.51 (m, 1H, H-3⁰), ꢀ64.81; [a]₄₃₆ꢀ112.21 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–

25

0

3.39 (m, 2H, H-4a, H-4⁰⁰), 3.23 (dt, J_{1 ,2}= 1.5 Hz, J_{2 ,3}E J_{2 ,OH}

=

3000 (OH), 1618, 1462 (arom), 1085, 1068, 1048, 1027 (C–O);

0

8.5 Hz, 1H, H-2’), 2.88 (q, J = 7.0 Hz, 1H, H-ⁱPr), 2.40 (ddd, J = ¹H NMR (500 MHz, DMSO-d₆) d 7.39 (d, J = 7.5 Hz, 1H, arom),

7.5 Hz, J = 12.0 Hz, J = 15.0 Hz, 1H, CH₂’), 2.24 (t, J_4a,4bE J_4a,56.98 (d, J = 7.5 Hz, 1H, arom), 6.96 (s, 1H, arom), 4.99 (s, 1H, H-2),

9.0 Hz, 1H, H-4b), 2.15 (ddd, J = 7.0 Hz, J = 14.0 Hz, J = 18.5 Hz, 4.48 (sa, 2H, C1⁰-OH, C3⁰-OH), 4.39 (bs, 1H, C2⁰-OH), 4.32 (bs, 1H,

=

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C4⁰-OH), 4.16 (dt, J_4a,5E J_5,1= 5.5 Hz, J_4b,5= 8.0 Hz, 1H, H-5), 3.71 7.94 (d, J = 7.6 Hz, 1H, arom), 7.67 (t, J = 8.0 Hz, 1H, arom), 5.12

0

(d, J_{1 ,OH}E J_5,1= 7.5 Hz, 1H, H-1⁰), 3.59 (dd, J_4’,OH= 3.0 Hz, J_{4 ,4}

=

(s, 1H, H-2), 4.53 (d, J_{1 ,OH}= 6.0 Hz, 1H, C1⁰-OH), 4.44 (d, J_{3 ,OH}

=

0

00

0

11.0 Hz, 1H, H-4⁰), 3.50 (m, 1H, H-3⁰), 3.39 (dd, J_4’,OH= 6.0 Hz, 6.0 Hz, 1H, C3⁰-OH), 4.38 (d, J_{2 ,OH}= 7.6 Hz, 1H, C2⁰-OH), 4.30 (t,

J_{4 ,4}= 11.0 Hz, 1H, H-4⁰⁰), 3.27 (d, J_{2 ,3}E J_{2 ,OH}= 8.0 Hz, 1H, H-2’), J_{4 ,OH}E J_{4 ,OH}= 5.6 Hz, 1H, C4⁰-OH), 4.20 (c, J_4a,5E J_5,1= 7.2 Hz,

3.10 (dd, J_4a,5= 5.0 Hz, J_4a,4b= 9.5 Hz, 1H, H-4a), 2.64 (dd, J_4b,5

7.5 Hz, J_4a,4b= 9.5 Hz, 1H, H-4b), 2.43 (ddd, J = 7.5 Hz, J = 14.5 Hz, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.40 (m, 1H, H-4⁰⁰), 3.21 (t, J_{2 ,3}

J = 19.0 Hz, 1H, CH₂), 2.34 (s, 3H, CH₃-arom), 2.27 (m, 1H, CH₂), J_{2 ,OH}= 7.6 Hz, 1H, H-2’), 2.95 (dd, J_4a,5= 6.4 Hz, J_4a,4b= 10.0 Hz,

2.25 (s, 3H, CH₃-arom), 0.98 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR 1H, H-4a), 2.77 (dd, J_4b,5= 7.2 Hz, J_4a,4b= 10.4 Hz, 1H, H-4b), 2.45

(125 MHz, DMSO-d₆) d 137.0, 136.7, 133.7, 130.6, 127.2, 125.9 (m, 2H, CH₂, CH₂), 1.39 (m, 2H, CH₂), 1.17 (m, 10H, CH₂), 0.82

(arom), 94.2 (C-2), 77.2 (C-5), 70.8, 70,7 (C-1⁰, C-2⁰, C-3⁰), 63.3 (C-4⁰) (t, J = 6.8 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) d 148.2,

0

00

0

00

0

=

1H, H-5), 3.65 (t, J_{1 ,OH}E J_5,1= 7.2 Hz, 1H, H-1⁰), 3.57 (m, 1H,

0

E

0

00

0

00

52.0 (C-4), 45.6 (CH₂), 20.4, 18.4 (CH₃-arom), 13.7 (CH₃).

143.7, 134.9, 130.1, 123.8, 122.5 (arom), 95.9 (C-2), 78.6 (C-5),

(2S,5S)-2-(4-Nitrophenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetrahydroxy- 71.9, 71.6, 71.4 (C-1⁰, C-2⁰, C-3⁰), 64.0 (C-4⁰), 53.4 (C-4), 52.5, 31.7,

butyl)oxazolidine (34b). Method A. Following the general proce- 29.1, 28.8, 27.0, 22.5 (CH₂), 14.4 (CH₃).

dure and from 4-nitrobenzaldehyde the title compound was

(2R,5S)-2-(3-Fluorophenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetrahydroxy-

obtained (98%); recrystallized from ethanol (78%) shows m.p. butyl)oxazolidine (36a) and (2S,5S)-2-(3-fluorophenyl)-3-octyl-5-

16

120–122 1C; [a]¹_D⁶ꢀ19.61; [a]

ꢀ20.21; [a]

ꢀ22.41; [a]

(^D-arabino-1,2,3,4-tetrahydroxybutyl)oxazolidine (36b). Method A.

578

546

436

ꢀ44.91 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–3200 (OH), Following the general procedure and from 3-fluorobenzaldehyde a

1609 (arom), 1523 (NO₂), 1467 (arom), 1343 (NO₂), 1107, 1081, 10 : 7 ratio mixture of 36a:36b is obtained (71%). After recrystalliza-

1

1067, 1036 (C–O); H NMR (500 MHz, DMSO-d₆) d 8.22 (d, J = tion from absolute ethanol, pure 36b is obtained (26%); m.p. 119–

9.0 Hz, 2H, arom), 7.75 (d, J = 9.0 Hz, 2H, arom), 5.13 (s, 1H, H-2), 121 1C; IR (KBr) nꢀ_max/cm^ꢀ13500–3200 (OH), 1593, 1487, 1455

4.52 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.43 (d, J_{3 ,OH}= 6.0 Hz, 1H, (arom), 1084, 1064, 1029 (C–O); ¹H NMR (400 MHz, DMSO-d₆)

0

C3⁰-OH), 4.36 (d, J_{2 ,OH}= 7.5 Hz, 1H, C2⁰-OH), 4.31 (t, J_{4 ,OH}

E

d 7.39 (m, 1H, arom), 7.28 (m, 2H, arom), 7.15 (d, J = 6.0 Hz, 1H,

0

J_{4 ,OH}= 5.5 Hz, 1H, C4⁰-OH), 4.19 (c, J_4a,5E J_5,1= 6.5 Hz, 1H, H-5), arom), 4.93 (s, 1H, H-2), 4.50 (d, J_{1 ,OH}= 4.8 Hz, 1H, C1⁰-OH), 4.45 (d,

00

0

3.63 (dt, J_{1 ,2}= 1.0 Hz, J_{1 ,OH}E J_5,1= 7.5 Hz, 1H, H-1 ), 3.57 (m, 1H, J_{3 ,OH}= 4.8 Hz, 1H, C3⁰-OH), 4.38 (d, J_{2 ,OH}= 5.6 Hz, 1H, C2⁰-OH),

0

H-4⁰), 3.48 (m, 1H, H-3⁰), 3.38 (m, 1H, H-4⁰⁰), 3.19 (t, J_{2 ,3}E J_{2 ,OH}

=

4.31 (t, J_{4 ,OH}E J_{4 ,OH}= 4.4 Hz, 1H, C4⁰-OH), 4.17 (dd, J_4a,5E J_5,1

=

0

00

0

8.5 Hz, 1H, H-2’), 2.89 (dd, J_4a,5= 6.5 Hz, J_4a,4b= 10.5 Hz, 1H, H-4a), 5.6 Hz, J_4b,5= 10.8 Hz, 1H, H-5), 3.66 (t, J_{1 ,OH}E J_5,1= 5.2 Hz, 1H,

2.78 (dd, J_4b,5= 7.0 Hz, J_4a,4b= 10.5 Hz 1H, H-4b), 2.46 (m, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.48 (m, 1H, H-3⁰), 3.39 (m, 1H, H-4⁰⁰),

0

00

CH₂), 2.41 (m, 1H, CH₂), 1.40 (m, 2H, CH₂), 1.18 (m, 10H, CH₂), 3.23 (t, J_{2 ,3}E J_{2 ,OH}= 6.0 Hz, 1H, H-2⁰), 2.98 (dd, J_4a,5= 4.8 Hz,

0

0.83 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) d 149.0, J_4a,4b= 8.0 Hz, 1H, H-4a), 2.68 (dd, J_4b,5= 6.4 Hz, J_4a,4b= 7.6 Hz,

0

00

148.0, 129.3, 123.6 (arom), 96.1 (C-2), 78.6 (C-5), 71.9, 71.6, 71.4 1H, H-4b), 2.52 (m, 1H, CH₂), 2.31 (m, 1H, CH₂), 1.38 (m, 2H,

(C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 53.4 (C-4), 52.8, 31.7, 29.2, 29.1, 28.9, CH₂), 1.20 (m, 10H, CH₂), 0.83 (t, J = 5.2 Hz, 3H, CH₃); ¹³C NMR

27.0, 22.5 (CH₂), 14.4 (CH₃).

(100 MHz, DMSO-d₆) d 162.6 (d, J = 242 Hz, 1C, C3-arom), 144.0

(2R,5S)-2-(3-Nitrophenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetrahydroxy- (d, J = 7 Hz, 1C, C1-arom), 130.4 (d, J = 8 Hz, 1C, C5-arom), 124.3

butyl)oxazolidine (35a) and (2S,5S)-2-(3-nitrophenyl)-3-octyl-5-(^D- (arom), 115.7 (d, J = 21 Hz, 1C, C2-arom), 114.5 (d, J = 22 Hz, 1C,

arabino-1,2,3,4-tetrahydroxybutyl)oxazolidine (35b). Method A. C4-arom), 96.4 (C-2), 78.2 (C-5), 71.7, 71.6, 71.4 (C-1⁰, C-2⁰, C-3⁰),

Following the general procedure and from 3-nitrobenzaldehyde a 64.0 (C-4⁰), 53.3 (C-4), 52.2, 32.7, 29.1, 28.7, 26.9, 22.5 (CH₂), 14.4

10 : 9 ratio of 35a :35b was obtained (66%). After recrystallization (CH₃).

1

from absolute ethanol the ratio changes to 1 : 16 (54%); m.p. 108–

Spectroscopic data of 36a. H NMR (500 MHz, DMSO-d₆) d

109 1C; IR (KBr) nꢀ_max/cm^ꢀ13500–3100 (OH), 1531 (NO₂), 1467 7.41 (m, 1H, arom), 7.29 (m, 1H, arom), 7.22 (d, J = 10.0 Hz, 1H,

0

(arom), 1351 (NO₂), 1084, 1029 (C–O).

arom), 7.18 (m, 1H, arom), 4.73 (s, 1H, H-2), 4.54 (d, J_{1 ,OH}

=

1

Spectroscopic data of 35a. H NMR (400 MHz, DMSO-d₆) d 7.5 Hz, 1H, C1⁰-OH), 4.49 (d, J_{3 ,OH}= 6.0 Hz, 1H, C3⁰-OH), 4.31

0

8.28 (s, 1H, arom), 8.22 (d, J = 10.4 Hz, 1H, arom), 7.89 (d, J = (m, 2H, C2⁰-OH, C4⁰-OH), 4.25 (dt, J_4a,5E J_5,1= 7.0 Hz, J_4b,5

=

0

7.6 Hz, 1H, arom), 7.68 (t, J = 8.0 Hz, 1H, arom), 4.90 (s, 1H, H-2), 9.0 Hz, 1H, H-5), 3.67 (t, J_{1 ,OH}E J_5,1= 7.0 Hz, 1H, H-1⁰), 3.59

0

4.57 (d, J_{1 ,OH}= 6.8 Hz, 1H, C1⁰-OH), 4.49 (d, J_{3 ,OH}= 5.6 Hz, 1H, (m, 1H, H-4⁰), 3.48 (m, 1H, H-3⁰), 3.39 (m, 2H, H-4⁰⁰,H-4a), 3.22

0

C3⁰-OH), 4.34 (m, 3H, C2⁰-OH, C4⁰-OH, H-5), 3.69 (t, J_{1 ,OH}E J_5,1

=

(t, J_{2 ,3}E J_{2 ,OH}= 8.0 Hz, 1H, H-2’), 2.31 (m, 1H, CH₂’), 2.26

0

6.8 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.48 (m, 1H, H-3⁰), 3.41 (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, H-4b), 2.20 (m, 1H, CH₂⁰⁰), 1.37

(m, 2H, H-4⁰⁰,₀H-4a), 3.23 (t, J_{2 ,3}E J_{2 ,OH}= 7.2 Hz, 1H, H-2⁰), 2.39 (m, 2H, CH₂), 1.19 (m, 10H, CH₂), 0.83 (t, J = 7.0 Hz, 3H, CH₃);

0

(m, 1H, CH₂), 2.32 (t, J_4a,4bE J_4a,5= 8.4 Hz, 1H, H-4b), 2.27 ¹³C NMR (125 MHz, DMSO-d₆) d 162.2 (d, J = 242 Hz, 1C,

00

(m, 1H, CH₂), 1.37 (m, 2H, CH₂), 1.17 (m, 10H, CH₂), 0.80 (t, J = C3-arom), 143.5 (d, J = 7 Hz, 1C, C1-arom), 130.1 (d, J = 8 Hz, 1C,

7.2 Hz, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆) d 143.4, 135.3, C5-arom), 124.2 (arom), 115.5 (d, J = 21 Hz, 1C, C2-arom), 114.4

130.2, 124.0, 122.9 (arom), 95.3 (C-2), 80.1 (C-5), 71.7, 71.6, 71.5 (d, J = 22 Hz, 1C, C4-arom), 95.5 (C-2), 79.3 (C-5), 71.2, 71.1, 71.0

(C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 54.5 (C-4), 51.3, 31.7, 29.1, 29.0, 28.4 (C-1⁰, C-2⁰, C-3⁰), 63.5 (C-4⁰), 54.2 (C-4), 50.9, 31.3, 28.7, 28.0,

(CH₂), 13.4 (CH₃).

26.6, 22.1 (CH₂), 14.0 (CH₃).

16

546

Spectroscopic data of 35b. [a]¹_D⁶ꢀ24.91; [a]

ꢀ25.61; [a]

(2R,5S)-2-(4-Isopropylphenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetra-

578

16

ꢀ29.21; [a] ꢀ44.31 (c 0.5, pyridine); ¹H NMR (400 MHz, DMSO- hydroxybutyl)oxazolidine (37a) and (2S,5S)-2-(4-isopropylphenyl)-

436

d₆) d 8.31 (s, 1H, arom), 8.19 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H, arom), 3-octyl-5-(^D-arabino-1,2,3,4-tetrahydroxybutyl)oxazolidine (37b).

4382 | New J. Chem., 2021, 45, 4365ꢀ4386

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Method A. Following the general procedure and starting from 4- (d, J_{3 ,OH}= 7.5 Hz, 1H, C3⁰-OH), 4.41 (d, J_{2 ,OH}= 6.5 Hz, 1H, C2⁰-

isopropylbenzaldehyde a 1: 7 ratio of 37a:37b was obtained OH), 4.28 (m, 1H, C4-OH), 4.18 (dt, J_4a,5E J_1’,5= 5.0 Hz, J_4b,5

0

=

(65%); m.p. 125–127 1C; IR (KBr) nꢀ_max/cm^ꢀ13600–3200 (OH), 7.5 Hz, 1H, H-5), 3.72 (dt, J_{1 ,2}= 0.5 Hz, J_{1 ,OH}E J_5,1= 7.0 Hz,

0

1466 (arom), 1086, 1064, 1025 (C–O).

1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.50 (m, 1H, H-3⁰), 3.40 (m, 1H,

1

Spectroscopic data of 37a. H NMR (400 MHz, DMSO-d₆) d H-4⁰⁰), 3.30 (d, J_{2 ,3}E J_{2 ,OH}= 7.5 Hz, 1H, H-2⁰), 3.09 (dd, J_4a,5

=

0

7.34 (d, J = 8.0 Hz, 2H, arom), 7.21 (d, J = 8.0 Hz, 2H, arom), 4.63 5.0 Hz, J_4a,4b= 10.0 Hz, 1H, H-4a), 2.63 (dd, J_4b,5= 7.5 Hz, J_4a,4b

=

0

(s, 1H, H-2), 4.49 (d, J_{1 ,OH}= 6.4 Hz, 1H, C1⁰-OH), 4.47 (d, J_{3 ,OH}

=

9.5 Hz, 1H, H-4b), 2.37 (m, 1H, CH₂), 2.25 (m, 1H, CH₂⁰⁰), 1.34

0

5.6 Hz, 1H, C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 5.6 Hz, 1H, (m, 2H, CH₂), 1.16 (m, 10H, CH₂), 0.83 (t, J = 7.0 Hz, 3H, CH₃);

0

00

C4⁰-OH), 4.28 (d, J_{2 ,OH}= 7.2 Hz, 1H, C2⁰-OH), 4.22 (dt, J_4a,5

E

¹³C NMR (125 MHz, DMSO-d₆) d 140.4, 129.0, 128.3 (arom), 97.5

0

J_5,1= 6.8 Hz, J_4b,5= 8.4 Hz, 1H, H-5), 3.66 (t, J = 6.4 Hz, 1H, (C-2), 78.1 (C-5), 71.6, 71.4 (C-1⁰, C-2⁰, C-3⁰), 64.1 (C-4⁰), 53.4

0

H-1⁰), 3.58 (m, 1H, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.40 (m, 2H, (C-4) 51.9, 31.7, 29.1, 29.1, 28.4, 27.1, 22.5 (CH₂), 14.4 (CH₃).

H-4⁰⁰,H-4a), 3.22 (t, J_{1 ,OH}E J_5,1= 7.6 Hz, 1H, H-2⁰), 2.88 (q,

(2R,5S)-2-(3-Methoxyphenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetra-

0

i

0

J = 7.2 Hz, 1H, H- Pr), 2.31 (td, J = 7.6 Hz, J = 11.2 Hz, 1H, CH₂), hydroxybutyl)oxazolidine (39a). Method A. Following the general

2.23 (t, J_4a,4bE J_4a,5= 9.2 Hz, 1H, H-4b), 2.12 (m, 1H, CH₂⁰⁰), procedure and from 3-methoxybenzaldehyde the title compound

14

578

1.35 (m, 2H, CH₂), 1.20 (s, 3H, CH₃-ⁱPr), 1.19 (s, 3H, CH₃-ⁱPr), was obtained (73%); m.p. 88–90 1C; [a]¹_D⁴+23.21; [a]

+24.11;

14

546

14

436

1.17 (m, 10H, CH₂), 0.83 (t, J = 6.8 Hz, 3H, CH₃); ¹³C NMR [a]

+27.31; [a]

+43.71 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ1

1

(100 MHz, DMSO-d₆) d 148.7, 137.4, 128.0, 125.8 (arom), 96.2 3500–3200 (OH), 1601, 1466 (arom), 1085, 1032 (C–O); H NMR

(C-2), 78.8 (C-5), 71.1, 71.0 (C-1⁰, C-2⁰, C-3⁰), 63.3 (C-4⁰), 54.1 (500 MHz, DMSO-d₆) d 7.26 (t, J = 8.0 Hz, 1H, arom), 7.00 (d, J =

(C-4), 50.7 (CH₂), 33.2 (CH-ⁱPr), 31.2, 28.5, 27.9, 26.5 (CH₂), 23.8 8.0 Hz, 1H, arom), 6.99 (s, 1H, arom), 6.89 (m, 1H, arom), 4.65

(CH₃-ⁱPr), 22.0 (CH₂), 13.9 (CH₃).

(s, 1H, H-2), 4.51 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.47 (d, J_{3 ,OH}

=

0

1

Spectroscopic data of 37b. H NMR (400 MHz, DMSO-d₆) d 5.5 Hz, 1H, C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 5.5 Hz, 1H, C4⁰-OH),

0

00

7.37 (d, J = 8.4 Hz, 2H, arom), 7.21 (d, J = 8.4 Hz, 2H, arom), 4.76 4.28 (d, J_{2 ,OH}= 7.5 Hz, 1H, C2⁰-OH), 4.23 (dt, J_4a,5E J_5,1= 7.0 Hz,

0

(s, 1H, H-2), 4.48 (m, 2H, C1⁰-OH, C3⁰-OH), 4.40(d, J_{2 ,OH}

=

J_4b,5= 9.0 Hz, 1H, H-5⁰), 3.75 (s, 3H, OCH3), 3.67 (t, J_{1 ,OH}E J_5,1

=

0

6.0 Hz, 1H, C2⁰-OH), 4.30 (m, 1H, C4⁰-OH), 4.17 (dt, J_4a,5E J_5,1

6.5 Hz, 1H, H-1⁰), 3.58 (m, 1H, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.38 (m,

0

5.2 Hz, J_4b,5= 7.6 Hz, 1H, H-5), 3.71 (t, J_{1 ,OH}E J_5,1= 6.8 Hz, 1H, 2H, H-4a, H-4⁰⁰), 3.22 (t, J_{2 ,3}E J_{2 ,OH}= 8.0 Hz, 1H, H-2⁰), 2.33 (dt,

H-1⁰), 3.58 (m, 1H, H-4⁰), 3.49 (m, 1H, H-3⁰), 3.40 (m, 1H, H-4⁰⁰), J = 8.0 Hz, J = 12.0 Hz, 1H, CH₂’), 2.24 (t, J_4a,4bE J_4a,5= 9.0 Hz,

0

3.32 (m, 1H, H-2⁰), 3.12 (dd, J_4a,5= 4.8 Hz, J_4a,4b= 9.6 Hz, 1H, 1H, H-4b), 2.15 (m, 1H, CH₂⁰⁰), 1.35 (q, J = 7 Hz, 2H, CH₂), 1.36

i

H-4a), 2.88 (m, 1H, H- Pr), 2.60 (m, 1H, H-4b), 2.31 (m, 1H, CH₂), (m, 10H, CH₂), 0.83 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (125 MHz,

0

i

00

2.23 (m, 1H, CH₂), 1.35 (m, 2H, CH₂), 1.20 (s, 3H, CH₃- Pr), 1.19 DMSO-d₆) d 159.6, 142.3, 129.5, 120.9, 114.7, 113.6 (arom), 96.7

(s, 3H, CH₃-ⁱPr), 1.17 (m, 10H, CH₂), 0.83 (t, J = 6.8 Hz, 3H, CH₃); (C-2), 79.5 (C-5), 71.7, 71.6 (C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 55.4

¹³C NMR (100 MHz, DMSO-d₆) d 137.1, 127.4, 125.5 (arom), 96.5 (OCH₃), 54.6 (C-4), 51.3, 31.7, 29.1, 29.1, 28.4, 27.1, 22.5 (CH₂),

(C-2), 77.1 (C-5), 71.1, 70.3 (C-1⁰, C-2⁰, C-3⁰), 63.2 (C-4⁰), 54.5 (C-4), 14.4 (CH₃).

50.7 (CH₂), 33.2 (CH-ⁱPr) 28.1, 27.4, 26.7 (CH₂), 13.9 (CH₃).

(2R,5S)-2-(3-Methylphenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetra-

(2R,5S)-2-Phenyl-3-octyl-5-(^D-arabino-1,2,3,4-tetrahydroxybutyl)- hydroxybutyl)oxazolidine (40a). Method A. Following the general

oxazolidine (38a) and (2S,5S)-2-phenyl-3-octyl-5-(^D-arabino-1,2,3,4- procedure and from 3-methylbenzaldehyde the title compound

tetrahydroxybutyl)oxazolidine (38b). Method A. Following the was obtained (90%); recrystallized from ethanol (56%) shows

16

general procedure and from benzaldehyde a 4 : 1 ratio of m.p. 105–107 1C; [a]¹_D⁶+29.01; [a]

+31.01; [a]

+35.91; [a]

578

546 436

38a : 38b was obtained (23%); m.p. 96–98 1C; IR (KBr) nꢀ_max/cm^ꢀ1+59.11 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ13500–3200 (OH), 1455

1

3500–3200 (OH), 1456 (arom), 1095, 1064, 1029 (C–O).

(arom), 1097, 1032 (C–O); H NMR (400 MHz, DMSO-d₆) d 7.22

1

Spectroscopic data of 38a. H NMR (500 MHz, DMSO-d₆) d (m, 3H, H2-arom), 7.14 (d, J = 6.8 Hz, 1H, arom), 4.62 (s, 1H, H-2),

7.43 (dd, J = 2.5 Hz, J = 8.0 Hz, 2H, arom), 7.34 (m, 3H, arom), 4.52 (d, J_{1 ,OH}= 6.4 Hz, 1H, C1⁰-OH), 4.48 (d, J_{3 ,OH}= 6.0 Hz, 1H,

0

4.67 (s, 1H, H-2), 4.51 (d, J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.46 C3⁰-OH), 4.32 (t, J_{4 ,OH}E J_{4 ,OH}= 5.6 Hz, 1H, C4⁰-OH), 4.31 (d,

0

00

(d, J_{3 ,OH}= 5.5 Hz, 1H, C3⁰-OH), 4.31 (t, J_{4 ,OH}E J_{4 ,OH}= 6.0 Hz, J_{2 ,OH}= 7.6 Hz, 1H, C2⁰-OH), 4.19 (dt, J_4a,5E J_5,1= 6.8 Hz, J_4b,5

=

0

00

0

1H, C4⁰-OH), 4.28 (m, 1H, C2⁰-OH), 4.25 (dt, J_4a,5E J_{1 ,5}

=

9.2 Hz, 1H, H-5), 3.66 (t, J_{1 ,OH}E J_5,1= 6.4 Hz, 1H, H-1 ), 3.59 (m,

0

5.5 Hz, J_4b,5= 7.5 Hz, 1H, H-5), 3.68 (dt, J_{1 ,2}= 1.5 Hz, J_{1 ,OH}

E

1H, H-4⁰), 3.48 (m, 1H, H-3⁰), 3.39 (m, 2H, H-4⁰⁰,H-4a), 3.22 (t,

J_5,1= 7.5 Hz, 1H, H-1⁰), 3.59 (m, 1H, H-4⁰), 3.50 (m, 1H, H-3⁰), J_{2 ,3}E J_{2 ,OH}= 8.0 Hz, 1H, H-2’), 2.32 (m, 1H, CH₂), 2.30 (s, 3H,

0

3.40 (m, 2H, H-4⁰⁰, H-4a), 3.23 (dt, J_{1 ,2}= 1.5 Hz, J_{2 ,3}E J_{2 ,OH}

=

CH₃-arom), 2.23 (t, J_4a,4bE J_4a,5= 8.8 Hz, 1H, H-4b), 2.12 (m,

1H, CH₂), 1.34 (m 2H, CH₂), 1.17 (m, 10H, CH₂), 0.83 (t, J = 6.8 Hz,

0

8.5 Hz, 1H, H-2⁰), 2.30 (m, 1H, CH₂), 2.25 (t, J_4a,4bE J_4a,5

0

00

9.0 Hz, 1H, H-4b), 2.15 (m, 1H, CH₂⁰⁰), 1.34 (m, 2H, CH₂), 1.16 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 140.5, 137.5, 129.7,

(m, 10H, CH₂), 0.83 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (125 MHz, 129.1, 128.3, 125.7 (arom), 96.9 (C-2), 79.5 (C-5), 71.7, 71.5 (C-1⁰,

DMSO-d₆) d 140.6, 129.1, 129.0, 128.3 (arom), 96.9 (C-2), 79.5 C-2⁰, C-3⁰), 63.9 (C-4⁰), 54.6 (C-4), 51.2, 31.7, 29.1, 28.4, 27.1, 22.5

(C-5), 71.7, 71.6 (C-1⁰, C-2⁰, C-3⁰), 63.9 (C-4⁰), 54.6 (C-4), 51.3, (CH₂), 21.5 (CH₃-arom), 14.4 (CH₃).

31.7, 29.1, 29.1, 28.4, 27.1, 22.5 (CH₂), 14.4 (CH₃).

(2R,5S)-2-(4-Methylphenyl)-3-octyl-5-(^D-arabino-1,2,3,4-tetra-

1

Spectroscopic data of 38b. H NMR (500 MHz, DMSO-d₆) d hydroxybutyl)oxazolidine (41a). Method A. Following the general

7.47 (dd, J = 2.0 Hz, J = 8.0 Hz, 2H, arom), 7.36 (m, 3H, arom), procedure and from 4-methylbenzaldehyde the title compound

14

4.83 (s, 1H, H-2), 4.43 (d, J_{1 ,OH}= 6.0 Hz, 1H, C1⁰-OH), 4.42 was obtained (65%); m.p. 110–112 1C; [a]_D¹⁴+ 32.71; [a]₅₇₈+33.81;

0

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14

546

14

436

[a]

+39.11; [a]

+63.71 (c 0.5, pyridine); IR (KBr) nꢀ_max/cm^ꢀ1in a 3 : 1 : 4 ratio (63%). M.p. 93–95 1C; IR (KBr) nꢀ_max/cm^ꢀ13600–

3500–3200 (OH), 1515, 1457 (arom), 1096, 1084, 1058, 1031 3200 (OH), 1470, 1455 (arom), 1094, 1062, 1043, 1020 (C–O).

1

(C–O); H NMR (500 MHz, DMSO-d₆) d 7.30 (d, J = 8.0 Hz, 2H, HRMS-ESI (C₁₄H₂₁NO₅[M

arom), 7.15 (d, J = 7.5 Hz, 2H, arom), 4.60 (s, 1H, H-2), 4.53 (d, 284.1532.

+

H]⁺): calcd 284.1453; found

1

J_{1 ,OH}= 6.5 Hz, 1H, C1⁰-OH), 4.47 (d, J_{3 ,OH}= 5.5 Hz, 1H, C3⁰-OH),

Spectroscopic data of 44a. H NMR (500 MHz, DMSO-d₆) d

0

4.33 (t, J_{4 ,OH}E J_{4 ,OH}= 5.5 Hz, 1H, C4⁰-OH), 4.28 (d, J_{2 ,OH}= 7.0 Hz, 7.41 (m, 2H, arom), 7.35 (m, 3H, arom), 4.64 (d, J = 5.0 Hz, 1H,

0

00

0

1H, C2⁰-OH), 4.23 (dt, J_4a,5E J_5,1= 7.0 Hz, J_4b,5= 9.0 Hz, 1H, H-5), OH), 4.58 (s, 1H, H-2), 4.46 (ddd, J = 2.5 Hz, J = 6.5 Hz, J = 9.0 Hz,

0

3.66 (dt, J_{1 ,2}= 1.0 Hz, J_{1 ,OH}E J_5,1= 6.5 Hz, 1H, H-1 ), 3.58 (m, 1H, 1H, H-5), 4.45–4.20 (m, 3H, OH), 3.70–3.30 (m, 5H, H-1⁰, H2⁰,

0

H-4⁰), 3.48 (m, 1H, H-3⁰), 3.39 (m, 2H, H-4⁰⁰,H-4a), 3.22 (dt, J_{1 ,2}

=

H3⁰, H4⁰, H-4⁰⁰), 3.25 (m, 1H, H-4a), 2.66 (m, 1H, H-4b), 2.09

0

1.0 Hz, J_{2 ,3}E J_{2 ,OH}= 8.0 Hz, 1H, H-2⁰), 2.30 (s, 3H, CH₃-arom), (s, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 140.1, 129.1,

0

2.27 (m, 1H, CH₂), 2.21 (t, J_4a,4bE J_4a,5= 9.0 Hz, 1H, H-4b), 2.10 128.7, 128.4, 128.3 (arom), 98.2 (C-2), 76.8 (C-5), 70.6, 70.5, 70.3

(m, 1H, CH₂), 1.34 (m 2H, CH₂), 1.17 (m, 10H, CH₂), 0.83 (t, J = (C-1⁰, C-2⁰, C-3⁰), 63.4 (C-4⁰), 56.8 (C-4), 37.7 (CH₃).

00

7 Hz, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 138.3, 137.6,

Spectroscopic data of 44b. H NMR (500 MHz, DMSO-d₆) d

1

129.0, 128.8, 128.5 (arom), 96.8 (C-2), 79.4 (C-5), 71.7, 71.5 (C-1⁰, 7.51 (m, 2H, arom), 7.35 (m, 3H, arom), 4.61 (s, 1H, H-2), 4.33

C-2⁰, C-3⁰), 63.9 (C-4⁰), 54.6 (C-4), 51.1, 31.7, 29.1, 28.4, 27.1, 22.5 (m, 1H, H-5), 4.45–4.20 (m, 4H, OH), 3.70–3.30 (m, 5H, H-1⁰,

(CH₂), 21.3 (CH₃-arom), 14.4 (CH₃).

H2⁰, H3⁰, H4⁰, H-4⁰⁰), 3.26 (m, 1H, H-4a), 2.70 (m, 1H, H-4b),

(2R,5S) and (2S,5S)-3-Methyl-2-(4-nitrophenyl)-5-(^D-lyxo- 2.14 (s, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d 139.6, 129.5,

1,2,3,4-tetrahydroxybutyl)oxazolidines (43a and 43b) and 129.2, 127.9 (arom), 98.0 (C-2), 76.6 (C-5), 72.1, 70.5, 70.5 (C-1⁰,

(2R,5S,6R)-5-hydroxy-3-methyl-2-(4-nitrophenyl)-6-(^D-threo-1,2,3- C-2⁰, C-3⁰), 63.6 (C-4⁰), 56.6 (C-4), 38.3 (CH₃).

1

trihydroxy-propyl)tetrahydro-1,3-oxazine (43c). Method A. Following

Spectroscopic data of 44c. H NMR (500 MHz, DMSO-d₆) d

the general procedure and from 4-nitrobenzaldehyde a mixture 7.46 (m, 2H, arom), 7.35 (m, 3H, arom), 4.49 (s, 1H, H-2), 4.45–

0

of 43a : 43b : 43c was obtained in a 2: 1 : 6 ratio (52%). Recrystal- 4.20 (m, 4H, OH), 3.76 (m, 1H, H-5), 3.68 (d, J_{2 ,3}E J_{2 ,OH}

=

lization from acetone gave pure 43c (37%); m.p. 106–107 1C; IR 8.5 Hz, 1H, H-1⁰), 3.55 (dd, J = 1.0 Hz, J = 13.5 Hz, 1H, H-6), 3.46

(KBr) nꢀ_max/cm^ꢀ13600–3100 (OH), 1611 (arom), 1513 (NO₂), 1458, (m, 1H, H-2⁰), 3.40–3.36 (m, 2H, H-3⁰, H-3⁰⁰), 3.08 (dd, J_4a,5= 2.5 Hz,

1425 (arom), 1348 (NO₂), 1095, 1072, 1049, 1024 (C–O). ¹H NMR J_4a,4b= 12.5 Hz, 1H, H-4a), 2.63 (dd, J_4a,5= 2.0 Hz, J_4a,4b= 12.5

(400 MHz, DMSO-d₆) d 8.23 (d, 2H, arom), 7.76 (d, 2H, arom), Hz, 1H, H-4b), 1.88 (s, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆)

4.73 (s, 1H, H-2), 4.38 (d, J = 4.0 Hz, 2H, C5-OH, C3⁰-OH), 4.19 d 140.3, 128.5, 128.4, 128.4, 128.2 (arom), 96.2 (C-2), 78.9 (C-6),

(m, 2H, C1⁰-OH, C2⁰-OH), 3.78 (d, J = 7.8 Hz, 1H, H-5), 3.72 (t, 69.7, 67.6 (C-1⁰, C-2⁰), 63.3 (C-3⁰), 63.2 (C-5), 61.0 (C-4), 40.0

J_{2 ,3}E J_{2 ,OH}= 8.8 Hz, 1H, H-1⁰), 3.60 (d, J = 9.2 Hz, 1H, H-6), 3.52 (CH₃).

(c, J = 6.4 Hz 1H, H-2⁰), 3.39 (m, 2H, H-3⁰, H-3⁰⁰), 3.11 (d, J_4a,4b

(2R,5S)

0

=

and

(2S,5S)-3-Methyl-2-(4-methoxyphenyl)-5-

12.4 Hz, 1H, H-4a), 2.63 (d, J_4a,4b= 12.4 Hz, 1H, H-4b), 1.92 (s, 3H, (^D-lyxo-1,2,3,4-tetrahydroxybutyl)oxazolidines (45a and 45b)

CH₃); ¹³C NMR (100 MHz, DMSO-d₆) d 147.9, 147.4, 129.5, 123.7 and (2R,5S,6R)-5-hydroxy-3-methyl-2-(4-methoxyphenyl)-6-(^D-threo-

(arom), 94.4 (C-2), 78.9 (C-6), 69.6 (C-2’), 67.5 (C-1⁰), 63.2 (C-3⁰), 1,2,3-trihydroxypropyl)tetrahydro-1,3-oxazine (45c). Method A.

63.1 (C-5), 60.7 (C-4), 39.5 (CH₃). HRMS-ESI (C₁₄H₂₀N₂O₇[M + Following the general procedure and from 4-methoxybenzaldehyde,

H]⁺): calcd 329.1304; found 329.1356.

pure compound 45a was obtained (70.4%) and had m.p. 108–110 1C;

1

24

Spectroscopic data of 43a. H NMR (500 MHz, DMSO-d₆) d [a]_D²⁴ꢀ3.51; [a] ꢀ4.01; [a] ꢀ5.91; [a] ꢀ15.11 (c 0.5, pyridine); IR

578

546

436

8.23 (d, 2H, arom), 7.76 (d, 2H, arom), 4.75 (s, 1H, H-2), 4.70 (d, (KBr) nꢀ_max/cm^ꢀ13600–3200 (OH), 1615, 1516, 1472 (arom), 1066,

J = 7.5 Hz, 1H, OH), 4.51 (m, 1H, H-5), 4.22–4.16 (m, 3H, OH), 1032 (C–O). ¹H NMR (400 MHz, DMSO-d₆) d 7.33 (d, 2H, arom), 6.90

3.80–3.38 (m, 5H, H-1⁰, H-2’, H-3⁰, H-4⁰, H-4⁰⁰), 3.29 (m, 1H, (d, 2H, arom), 4.60 (d, J = 8.0 Hz, 1H, OH), 4.52 (s, 1H, H-2), 4.43 (m,

H-4a), 2.74 (m, 1H, H-4b), 2.14 (s, 3H, CH₃); ¹³C NMR (125 MHz, 2H, H-5, OH), 4.18 (m, 2H, OH), 3.75 (s, 4H, H-1⁰, OCH₃), 3.50–3.30

DMSO-d₆) d 148.2, 147.7, 129.7, 123.7 (arom), 96.7 (C-2), 77.5 (m, 4H, H-2⁰, H-3⁰, H-4⁰, H-4⁰⁰), 3.24 (dd, J_4a,5= 8.0 Hz, J_4a,4b= 11.0 Hz

(C-5), 70.4, 70.4, 70.3 (C-1⁰, C-2⁰, C-3⁰), 63.4 (C-4⁰), 56.7 (C-4), 1H, H-4a), 2.66 (t, J_4a,5= J_4a,4b= 11.5 Hz, 1H, H-4b), 2.07 (s, 3H, CH₃);

37.8 (CH₃).

¹³C NMR (100 MHz, DMSO-d₆) d 160.00, 131.94, 129.75, 113.78

1

Spectroscopic data of 43b. H NMR (500 MHz, DMSO-d₆) d (arom), 97.97 (C-2), 76.50 (C-5), 70.64, 70.40, 70.27 (C-1⁰, C-2⁰, C-3⁰),

8.20 (d, 2H, arom), 7.81 (d, 2H, arom), 4.90 (s, 1H, H-2), 4.35 (m, 63.42 (C-4⁰), 56.71 (C-4), 55.52 (OCH₃), 37.62 (CH₃). HRMS-ESI

1H, H-5), 4.44–4.42 (m, 2H, OH), 4.18 (m, 2H, OH), 3.80–3.30 (C₁₅H₂₃NO₆[M + H]⁺): calcd 314.1559; found 314.1597.

(m, 5H, H-1⁰, H2⁰, H3⁰, H4⁰, H-4⁰⁰), 3.18 (dd, J_4a,5= 5.5 Hz, J_4a,4b

=

Recrystallization of 45a from acetone gave a mixture of

10.0 Hz 1H, H-4a), 2.74 (m, 1H, H-4b), 2.24 (s, 3H, CH₃); ¹³C 45a : 45b : 45c in a 5 : 2:6 ratio (22%);

1

NMR (125 MHz, DMSO-d₆) d 148.2, 147.7, 129.7, 123.7 (arom),

96.7 (C-2), 77.3 (C-5), 71.6, 70.7 (C-1⁰, C-2⁰, C-3⁰), 63.4 (C-4⁰), 56.1 7.41 (d, 2H, arom), 6.90 (m, 2H, arom), 4.53 (s, 1H, H-2), 4.31

Spectroscopic data of 45b. H NMR (500 MHz, DMSO-d₆) d

(C-4), 38.3 (CH₃).

(m, 1H, H-5), 4.15 (m, 4H, OH), 3.75 (s, 3H, OCH₃), 3.75–3.30

(2R,5S) and (2S,5S)-2-Phenyl-3-methyl-5-(^D-lyxo-1,2,3,4-tetra- (m, 5H, H-1⁰, H2⁰, H3⁰, H4⁰, H-4⁰⁰), 3.27 (m, 1H, H-4a), 2.69

hydroxybutyl)oxazolidines (44a and 44b) and (2R,5S,6R)-2- (m, 1H, H-4b), 2.10 (s, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆)

phenyl-5-hydroxy-3-methyl-6-(^D-threo-1,2,3-trihydroxypropyl)tetrahydro- d 159.6, 130.7, 129.0, 113.3 (C-arom), 97.2 (C-2), 75.7 (C-5), 71.7,

1,3-oxazine (44c). Method A. Following the general procedure 71.3, 69.9 (C-1⁰, C-2⁰, C-3⁰), 63.0 (C-4⁰), 54.9 (OCH₃), 54.3 (C-4),

and from benzaldehyde a mixture of 44a : 44b : 44c was obtained 37.4 (CH₃).

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Spectroscopic data of 45c. ¹H NMR (500 MHz, DMSO-d₆)

d 7.37 (d, 2H, arom), 6.90 (m, 2H, arom), 4.39 (s, 1H, H-2), 4.10–

9 J. F. Branco-Junior, D. R. C. Teixeira, M. C. Pereira, I. R. Pitta

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0

4.25 (m, 4H, OH), 3.75 (s, 4H, H-5, OCH₃), 3.67 (d, J_{1 ,2}

E

J_{1 ,OH}= 5.0 Hz, 1H, H-1⁰), 3.53 (dd, J = 1.0 Hz, J = 9.5 Hz, 1H,

H-6), 3.50–3.30 (m, 3H, H-2⁰, H-3⁰, H-3⁰⁰), 3.07 (dd, J_4a,5= 3.0 Hz,

J_4a,4b= 12.5 Hz, 1H, H-4a), 2.57 (dd, J_4a,5= 1.5 Hz, J_4a,4b= 12.0 Hz,

1H, H-4b), 1.86 (s, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆) d

159.1, 131.9, 128.8, 113.2 (arom), 95.5 (C-2), 78.2 (C-6), 69.1, 67.1

(C-1⁰, C-2⁰), 63.7 (C-3⁰), 62.6 (C-5), 60.5 (C-4), 54.9 (OCH₃), 37.0

(CH₃).

0

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Conflicts of interest

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13 K. Neuvonen, F. Fu¨lop, H. Neuvonen, A. Koch, E. Kleinpeter

The authors declare no conflict of interest.

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(b) F. Fu¨lop, K. Pihlaja, K. Neuvonen, G. Bernath, G. Argay

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We thank the Junta de Extremadura (Consejerıa de Economıa,

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Regional (Grants IB16167 and GR18015) for financial support.

We also gratefully acknowledge the computer resources at

Lusitania and the technical assistance provided by the super-

computing center CenitS and Computaex Foundation.

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Article Doi

Amphipathic 1,3-oxazolidines from: N-Alkyl glucamines and benzaldehydes: Stereochemical and mechanistic studies

DOI: 10.1039/d0nj05503d

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