Regioselective 2-imino-1,3-thiazolidine vs. 2-imino-1,3-oxazolidine formation from the vicinal sec-amino alcohol of desosamine

Article abstract of DOI:10.1002/ejoc.201300266

In order to optimize Mukaiyama reagent-induced cyclization of vicinal sec-amino alcohols of desosamine origin towards exclusive formation of N′-substituted-2-imino-1,3-thiazolidines via a thiocarbamoyl intermediate, the influence of reaction conditions was studied. A novel, mild, one-pot, two-step method was developed, and the formation of N′-substituted-2- imino-1,3-oxazolidines as side products was minimized. The inversion of configuration at C-2′ was unambiguously established using NMR-based conformational analysis. A reaction mechanism was proposed. A test series of novel desosamine-modified 14- and 15-membered macrolides, bearing N′-alkyl-2-imino-1,3-thiazolidines fused to the desosamine sugar were prepared. A regioselective and mild one-pot method based on the Mukaiyama reagent-induced cyclization of vicinal sec-amino alcohols of desosamine origin to N′-alkyl-2-imino-1,3-thiazolidines was developed. The inversion of configuration at the carbon bearing the hydroxy group was unambiguously established using NMR-based conformational analysis. The reaction mechanism was proposed. Copyright

Full text of DOI:10.1002/ejoc.201300266

FULL PAPER
DOI: 10.1002/ejoc.201300266
Regioselective 2-Imino-1,3-thiazolidine vs. 2-Imino-1,3-oxazolidine Formation
from the Vicinal sec-Amino Alcohol of Desosamine
[a][‡]
[a][‡]
Ines Vujasinovic,
´
ˇ [a][‡]
Ana Cikos,
and Goran Kragol*[a][‡]
ˇ
ˇ ´ ˇ
Zorica Marusic Istuk,
Keywords: Medicinal chemistry / Macrocycles / Heterocycles / Amino alcohols / Cyclization
In order to optimize Mukaiyama reagent-induced cyclization
of vicinal sec-amino alcohols of desosamine origin towards
exclusive formation of NЈ-substituted-2-imino-1,3-thiazolid-
ines via a thiocarbamoyl intermediate, the influence of reac-
tion conditions was studied. A novel, mild, one-pot, two-step
method was developed, and the formation of NЈ-substituted-
2-imino-1,3-oxazolidines as side products was minimized.
The inversion of configuration at C-2Ј was unambiguously
established using NMR-based conformational analysis. A re-
action mechanism was proposed. A test series of novel desos-
amine-modified 14- and 15-membered macrolides, bearing
NЈ-alkyl-2-imino-1,3-thiazolidines fused to the desosamine
sugar were prepared.
different approaches to their synthesis via cyclization of N-
(hydroxyalkyl)thioureas have been studied.[5] However, such
approaches usually use harsh conditions and provide a mix-
ture of cyclized products. Here we present a mild one-pot
alternative suitable for sensitive macrolide chemistry based
on the Mukaiyama reagent-induced cyclization of thiocarb-
amoyl intermediates to NЈ-substituted-2-imino-1,3-thiazol-
idines.
Introduction
In the course of our studies of diverse antibacterial mac-
rolide transformations through the modifications of the de-
sosamine sugar,[1,2] macrolide derivatives that showed po-
tent anti-inflammatory properties but were devoid of anti-
bacterial activity were discovered.[3] These anti-inflamma-
tory macrolides were prepared by an efficient tandem reac-
tion for the fusion of NЈ-substituted-2-imino-1,3-oxazolid-
ine moieties to the desosamine sugar. The tandem reaction
involved cyclization of the secondary amine at position 3Ј-
C and the vicinal hydroxy group at position 2Ј-C of desos-
amine to form exclusively a 2-imino-1,3-oxazolidine moiety
via an intermediate 3Ј-N-thiocarbamoyl. Interestingly, this
exclusivity was lost when a polymer-supported Mukaiyama
reagent (N-methyl-2-chloropyridinium iodide)[4] was used
as a thiophilic reagent, providing a 2-imino-1,3-thiazolidine
side product in which the configuration at 2Ј-C was sup-
posed to be inverted (Scheme 1).[1] Such desosamine modifi-
cation should also diminish antibacterial activity of the par-
ent macrolides, and consequently make them suitable for
the treatment of various diseases not connected to bacterial
action.[6] Therefore, we were keen to find conditions for the
exclusive fusion of NЈ-substituted-2-imino-1,3-thiazolidines
with desosamines of 14- and 15-membered antibacterial
macrolides. The 2-imino-1,3-thiazolidine moiety can be
found as a part of many biologically active compounds, and
Results and Discussion
The conversion of 3Ј-N-demethylated 9-deoxo-9a-
methyl-9a-aza-9a-homoerythromycin A[1,2] (1) to 2Ј-deoxy-
2Ј-(S)-S,3Ј-N-(NЈ-benzylcarbonimidoyl)-3Ј-N-demethyl-9-
deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (4) was
used as a model reaction (Scheme 1). In order to optimize
reaction conditions for the synthesis of mainly NЈ-substi-
tuted-2-imino-1,3-thiazolidine compounds and to avoid for-
mation of NЈ-substituted-1,3-oxazolidines, the influence of
solvent, base, temperature, and reagent ratios on the course
of the Mukaiyama reagent-induced cyclization of NЈ-
thiocarbamoyl 2 was studied. Since the Mukaiyama reagent
also reacts with secondary amines, although more slowly
than with alcohols,[1] the synthesis had to be conducted in
two steps (Scheme 1): (1) the formation of 3Ј-(NЈ-benzyl)-
thiocarbamoyl intermediate 2 via reaction of 1 with benzyl
isothiocyanate;[1] and (2) subsequent cyclization using the
polymer supported Mukaiyama reagent. The ratio of ox-
azolidine 3/thiazolidine 4 compounds was determined using
LC-MS.
[a] GlaxoSmithKline Research Centre Zagreb,
Prilaz b. Filipovic´a 29, Zagreb, Croatia
[‡] Current address: Fidelta,
Prilaz b. Filipovic´a 29, Zagreb, Croatia
Fax: +385-18886443
First, the effect of the solvent on the course of the cycli-
zation of thiocarbamoyl intermediate 2 was assessed
(Table 1, Entries 1–8). Triethylamine was used as a base in
order to avoid cladinose cleavage.[1] It was found that the
E-mail: goran.kragol@glpg.com
Homepage: www.fidelta.eu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300266.
4666
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Heterocycles Derived from Desosamine
Scheme 1. Model reaction used for optimization of the regioselective synthesis of NЈ-substituted 2-imino-1,3-thiazolidines from the vicinal
sec-amino alcohol of desosamine.
Table 1. Effects of solvent, base, and polymer support on the cyclization course (Scheme 1.) In all experiments, 1.2 equiv. of benzyl
isothiocyanate was used.
Entry
Reagent
/equiv.
Base
/equiv.
Solvent
Time
[h]
Temp.
[°C]
Ratio
[%]
Conversion
[%]
Ref.[1]
1
2
3
4
5
6
7
8
EDC/2
–
acetonitrile
dimethylformamide
tetrahydrofuran
ethyl acetate
acetone
water
toluene
chloroform
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
pyridine
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
24
20
20
20
20
20
20
20
20
20
20
20
20
20
1
60
60
60
60
60
60
60
60
60
82
60
60
60
60
60
0
3/4 = 100:0
degradation
3/4 = 100:0
3/4 = 80:20
3/4 = 80:20
3/4 = 80:20
3/4 = 90:10
3/4 = 90:10
3/4 = 50:50
3/4 = 55:45
degradation
3/4 = 100:0
3/4 = 20:80
–
3/6 = 20:80
3/6 = 15:85
3/6 = 15:85
3/6 = 10:90
3/6 = 5:95
3/4 = 5:95
100
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
PS-Mukaiyama/3
Mukaiyama/1.3
Mukaiyama/1.3
Mukaiyama/1.3
Mukaiyama/1.3
Mukaiyama/1.3
Mukaiyama/1.3
TEA/6
TEA/6
TEA/6
TEA/6
TEA/6
TEA/6
TEA/6
TEA/6
TEA/6
NaH/6
DMAP/6
DBU/6
–
DBU/6
DBU/6
DBU/1.3
DBU/1.3
DBU/1.3
DBU/1.3
70
80
70
25
90
70
80
80
9
10
11
12
13
14
15
16
17
18
19
70
50
0
90
90
90
90
80
100
1
1
1
1
0
–22
–41
1 h (–22 °C) + o.n. (60 °C)
solvent type had a striking effect on the reaction course. form all other optimization reactions in a one-pot manner:
The reaction in tetrahydrofuran afforded oxazolidine 3 as the thiocarbamoyl intermediate 2 was prepared in aceto-
the sole product (Entry 2), while in dimethylformamide nitrile at 60 °C, and to this solution, which was heated or
only degradation occurred (Entry 1). When some other sol- cooled to the desired temperature, polymer supported Mu-
vents were used, various amounts of thiazolidine 4 were kaiyama reagent and a base were added, and the reaction
noticed. The best ratio of thiazolidine 4 (50%) was obtained continued.
in acetonitrile (Entry 8). The reaction also proceeded in
Increasing the temperature of the cyclization reaction
water, albeit with low conversion (Entry 5).
from 60 °C to reflux temperature of acetonitrile (82 °C) did
Since acetonitrile was used for the synthesis of the thio- not substantially change the ratio of 4 (Entry 9), but rather
carbamoyl intermediate 2, there was an opportunity to per- a small drop from 50% to 45% was noticed.
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FULL PAPER
On the other hand, the use of different bases showed
striking influence on the reaction course (Entries 10–13,
Table 1).
The reaction conducted with 4-(dimethylamino)pyridine
(DMAP) afforded exclusively oxazolidine 3 (Entry 11).
There was no cyclization reaction noticed in pyridine (Entry
13) and only degradation occurred if sodium hydride was
used (Entry 10). However, 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) substantially shifted the ratio of cyclized prod-
ucts to the side of the thiazolidine 4 (3/4 = 20:80%) with
moderate conversion (Entry 12).
In an attempt to increase the conversion, we tested non-
supported Mukaiyama reagent instead of polymer sup-
ported analogue,[7] with DBU as the base (Entry 14). Inter-
estingly, the conversion of the thiocarbamoyl intermediate
2 was finished after only 1 h, providing a minor amount of
oxazolidine 3 along with a major unknown product.
Attempts to isolate this product were unsuccessful due to
its partial conversion to thiazolidine 4 on standing as well
as during column chromatography. However, LC-MS and
NMR analysis performed on the mixture of this unknown
intermediate with thiazolidine 4 indicated covalent binding
of Mukaiyama reagent to the hydroxy group at position 2Ј-
C of the thiocarbamoyl intermediate 2 (Figure 1, com-
pound 6).
This result confirmed the mechanistic routes to both 2-
imino-1,3-oxazolidine 3 and 2-imino-1,3-thiazolidine 4
(Figure 1), clearly indicating that the course of the reaction
depends on the equilibrium between deprotonated 2Ј-OH
and thiocarbamoyl moieties. In order to form the 2-imino-
1,3-oxazolidine product 3, the Mukaiyama reagent reacts
with the thiolate tautomer of the deprotonated thiocarb-
amoyl moiety to form intermediate 5, which closes the five-
membered oxazolidine ring. On the other hand, reaction of
the Mukaiyama reagent with the deprotonated 2Ј-OH leads
to formation of 6. Subsequently, five-membered thiazolid-
ine ring formation occurs via nucleophilic attack of the
thiocarbamoyl sulfur on 2Ј-C in order to provide the 2-
imino-1,3-thiazolidine ring 4. Since only one stereoisomer
of thiazolidine ring (with inverted configuration at 2Ј-C)
was formed, the mechanism of the five-membered thiazolid-
ine ring formation must occur in a concerted manner. The
fact that intermediate 5 could not be detected in the reac-
tion mixture indicates that the steady-state concentration of
6 may be a consequence of a relatively slow ring-closure Figure 1. Proposed reaction mechanisms for oxazolidine 3 vs. thi-
azolidine 4 formation.
step to the thiazolidine ring in comparison to immediate
cyclization of intermediate 5 to the oxazolidine ring.
The decrease of the reaction temperature to 0 °C pushed thiazolidine 4, without increasing the ratio of oxazolidine
the equilibrium further towards deprotonation of 2Ј-OH, side product 3.
slowed down the formation of oxazolidine 3, and afforded
Having in hand an optimized one-pot, two-step pro-
a better ratio of the Mukaiyama adduct 6 (Entry 15). A cedure for the preparation of NЈ-benzyl-2-imino-1,3-thiaz-
smaller excess of the DBU base gave the same ratio of prod- olidine 4 on a small scale, the procedure described in Entry
ucts 3 and 6 (Entry 16). By decreasing the reaction tempera- 19 (Table 1) was applied to three 3Ј-N-demethylated anti-
ture further to –22 °C and –41 °C (Entries 17 and 18, bacterial macrolide scaffolds [9-deoxo-9a-methyl-9a-aza-9a-
respectively), the ratio of intermediate 6 increased in a lin- homo-erythromycin A (1), 6-O-methyl-erythromycin A (7),
ear fashion, and in the best case, 95% of thiazolidine 6 6-O-methyl-9a-aza-9a-homo-erythromycin A (8)][1,2] on a
could be found in the mixture. Subsequent overnight heat- larger scale. This procedure demonstrated similar results on
ing at 60 °C (Entry 19, Table 1) converted intermediate 6 to all three scaffolds providing moderate yields of the thiazol-
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Heterocycles Derived from Desosamine
idine products 4, 9, and 10 after purification by column conformational change of the desosamine sugar. Therefore,
chromatography (Scheme 2).
with the aim of unambiguously establishing the stereochem-
istry and 3D structure of desosamine in both the thiazolid-
ine and oxazolidine analogues, NMR analysis of coupling
constants (Table 2) and nOe contacts was performed on 3
vs. 4 (Figure 2).
Table 2. Desosamine proton–proton coupling constants (in Hz) for
compounds 3 and 4.
3Jn,m
3
4
1Ј,2Ј
2Ј,3Ј
3Ј,4Јa
3Ј,4Јb
4Јa,5Ј
4Јb,5Ј
5Ј,5ЈCH3
7.9
10.6
3.5
2.8
5.9
5.9
11.2
1.6
11.2
6.1
11.7
[a]
11.0
6.1
[a] Coupling constants not measurable due to the signal overlap.
Scheme 2. Synthesis of novel 2Ј,3Ј-bridged macrolides having vari-
ous substituents attached to the NЈ-position, yields were calculated
after chromatographic purification.
In comparison to their oxazolidine analogues,[1] the H
NMR spectra of the thiazolidines 4, 9, and 10 showed a
downfield shift of the 2Ј-H and 3Ј-H resonance lines.
Equally, a large upfield shift of the 2Ј-C signal was apparent
1
Figure 2. Comparison of the most important nOe contacts ob-
served for oxazolidine 3 (a) and thiazolidine 4 (b).
The system of strong nOe’s between the protons 1Ј-H,
in the 13C NMR spectra of all thiazolidines, consistent with 3Ј-H and 5Ј-H (visible in both compounds) showed that
the insertion of a sulfur in the 2Ј,3Ј bridge. Although ob- the desosamine sugar adopted the usual Everett–Tyler chair
served vicinal coupling constants between 2Ј-H and 1Ј-H conformation.[8] The nOe contacts of 4Ј-Ha with 3Ј-H, 5Ј-
of ca. 2.5 Hz in thiazolidines (compared to ca. 8.0 Hz in H and 5Ј-CH3 pointed towards the equatorial position of
oxazolidines) strongly indicate the inversion of configura- 4Ј-Ha in both compounds, establishing 4Ј-Hb as axial. The
tion at 2Ј-C in thiazolidine, it might also be the result of the same was discovered by analysing the coupling constants
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FULL PAPER
between 4Ј-Ha, 4Ј-Hb and 5Ј-H, because they have similar
A test library of novel desosamine modified macrolides
11–17, which have various substituents attached to the NЈ-
3
values in both compounds (3J4Јa,5Ј ≈ 1.5 Hz; J4Јb,5Ј
≈
11 Hz). As a result, the presence of an nOe contact between position of the fused 2-imino-1,3-thiazolidine moiety, was
4Ј-Hb and 2Ј-H in 3 reveals the stereochemistry at position designed, and alkyl derivatives were successfully prepared
2Ј to be R. Similarly, the absence of the aforementioned (Scheme 2). However, when the same reaction conditions
interaction and the presence of two new nOe contacts (1Ј- were applied to the compounds in which an aromatic ring
H/2Ј-H and 2Ј-H/3Ј-H) establishes the inversion of stereo- was bound directly to the thiourea amine, only oxazolidine
chemistry at position 2Ј in 4 (Figure 2). Coupling constants analogues 18[3] and 19[1] were obtained (Scheme 3). Accord-
3
3J1Ј,2Ј = 7.9 Hz and J2Ј,3Ј = 10.6 Hz in 3 vs. 3J1Ј,2Ј = 2.7 Hz ing to the proposed reaction mechanisms (Figure 1), this is
3
and J2Ј,3Ј = 5.9 Hz in 4 lead to the same conclusion. In expected because such aromatic rings stabilize deprotonated
previously described oxazolidines[1] the imine bond stereo- thiocarbamoyl moiety by conjugation, pushing the equilib-
chemistry was determined to be Z. Analysis of nOe data for rium towards thiolate tautomer.
compound 3 confirmed that stereochemistry through the
absence of nOe contacts between the benzyl CH2 protons
Conclusions
and 3Ј-NCH3. Compound 4 showed an identical set of nOe
contacts for 3Ј-NCH3. as in 3, suggesting the same stereo-
chemistry (Z) in thiazolidines.
In conclusion, a mild and regioselective one-pot method
based on the Mukaiyama reagent-induced cyclization of
vicinal sec-amino alcohols of desosamine origin to NЈ-
alkyl-2-imino-1,3-thiazolidines via intermediate thiocarb-
amoyl moieties was developed. The mechanism of the
formation of 2-imino-1,3-thiazolidine vs. 2-imino-1,3-ox-
azolidine rings was proposed. The applicability of this reac-
tion to various vicinal sec-amino alcohols was investigated.
The new N-alkyl-1,3-thiazolidin-2-ones fused to the desosa-
mine sugars of 14- and 15-membered macrolide derivatives
are potential agents for various biological targets.
Upon observing the overall conformations of molecules
3 and 4, it appears that the changes to the desosamine sugar
do not affect its usual orientation with respect to the cladi-
nose ring, nor the usual position of either ring relative to
the macrocycle.[9] Observed nOe contacts between sugar
moieties (like 1Ј-H/5ЈЈ-H and 1Ј-H/3ЈЈ-OCH3) suggest an
up-up orientation of the alpha faces of the two sugars.
Furthermore, nOe signals between 1Ј-H/5-H and 1Ј-H/4-
CH3 confirm the perpendicular orientation of the desosam-
ine, while 1Ј-H/5ЈЈ-H and 5-H/5ЈЈ-H indicate an approxi-
mately parallel orientation of the cladinose sugar with re-
spect to the macrocycle.
Experimental Section
General: All solvents and reagents were used as supplied, unless
noted otherwise. Mass spectra were recorded with a Varian MAT
311 instrument (FAB), and Platform LCZ or LCQ Deca instru-
ments (ESI). HRMS (ESI) were recorded with a Micromass Qtof2
1
instrument. The structure confirmations, complete H and 13C as-
signments, as well as the conformational analysis were made on the
basis of one- and two-dimensional NMR spectra (1H, APT, COSY,
NOESY, ROESY, edited HSQC and HMBC). All spectra were re-
corded with Bruker Avance III 600 and Bruker Avance DRX500
spectrometers equipped with 5 mm inverse-detection probes with a
z-gradient accessory. The spectra were acquired using standard
Bruker pulse sequences, on compounds dissolved in CDCl3 or
[D6]DMSO, run at 25 °C with TMS as the internal standard.
NOESY spectra were obtained with a mixing time of 400 ms.
General One-Pot Procedure: To a solution of 3Ј-N-demethyl deriva-
tives 1–3 in acetonitrile (c = 0.065 g/mL), the corresponding iso-
thiocyanate (1.5 equiv.) and triethylamine (2 equiv.) were added.
The reaction was stirred at 60 °C until the thiourea intermediate
was formed (according to LC-MS around 30 min), and then cooled
to –22 °C (dry ice/CCl4). Mukaiyama reagent (1.3 equiv.) and DBU
(1.3 equiv.) were then added. The reaction mixture was stirred at
–22 °C for 45 min and then overnight at 60 °C. The solvent was
evaporated, and the residue was purified using column chromatog-
raphy [eluent 1.5% MeOH/CH2Cl2 – MeOH/CH2Cl2/NH4OH
(4.5:90:0.25)] to afford chromatographically homogeneous frac-
tions of final compounds.
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-(NЈ-benzylcarbonimidoyl)-3Ј-N-demethyl-
9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (4):[1] According
to the general procedure, reaction of 1 (0.5 g, 0.68 mmol) afforded
4 (0.23 g, 38%) as a white foam.
Scheme 3. Formation of 2-imino-1,3-oxazolidines when aryl-NCS
reagents were used, yields were calculated after chromatographic
purification.
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Heterocycles Derived from Desosamine
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-(NЈ-benzylcarbonimidoyl)-3Ј-N-demethyl- rolide: δ = 179.5 (1-C), 177.4 (9-C), 158.3 (C=N), 98.0 (1Ј-C), 95.6
6-O-methyl-erythromycin A (9): According to the general pro-
(1ЈЈ-C), 80.6 (5-C), 79.0 (6-C), 78.4 (13-C), 77.7 (4ЈЈ-C), 76.3 (3-C),
74.1 (12-C), 73.0 (3ЈЈ-C), 72.8 (11-C), 67.3 (5Ј-C), 65.8 (5ЈЈ-C), 60.5
cedure, reaction of 7 (0.5 g, 0.68 mmol) afforded 9 (0.18 g, 38%) as
1
a white foam. H NMR (500 MHz, CDCl3) benzyl: δ = 7.44 (d, J (3Ј-C), 51.5 (6-OCH3), 49.5 (3ЈЈ-OCH3), 46.3 (2Ј-C), 45.3 (10-C),
= 7.0 Hz, 2 H, 2ϫCH), 7.35 (t, J = 7.6 Hz, 2 H, 2ϫCH), 7.32 (t,
44.5 (2-C), 40.9 (4-C), 39.8 (7-C), 35.6 (8-C), 34.7 (2ЈЈ-C), 31.8 (3Ј-
J = 7.3 Hz, 1 H, CH), 4.67 (d, J = 15.3 Hz, 1 H, CH2), 4.49 (d, J NCH3), 31.1 (4Ј-C), 21.4 (3ЈЈ-CH3), 21.1 (5Ј-CH3), 20.6 (14-C), 20.4
= 15.3 Hz, 1 H, CH2) ppm; macrolide: δ = 5.08 (dd, J = 11.3,
2.1 Hz, 1 H, 13-H), 5.03 (d, J = 2.7 Hz, 1 H, 1Ј-H), 4.90 (d, J =
3.7 Hz, 1 H, 1ЈЈ-H), 4.38 (dd, J = 6.6, 2.6 Hz, 1 H, 2Ј-H), 4.19 (dt,
J = 1.3, 6.0 Hz, 1 H, 3Ј-H), 3.90 (dq, J = 8.5, 6.4 Hz, 1 H, 5ЈЈ-H),
3.73 (d, J = 7.3 Hz, 1 H, 11-H), 3.71 (br.s, 1 H, 3-H), 3.70 (d, J =
9.8 Hz, 1 H, 5Ј-H), 3.43–3.51 (m, J = 11.3, 5.5, 5.5, 5.5, 1.2 Hz, 1
H, 5-H), 3.40 (s, 3 H, 3Ј-NCH3), 3.31 (s, 3 H, 3ЈЈ-OCH3), 3.19 (s,
1 H, OH), 3.08 (t, J = 8.9 Hz, 1 H, 4ЈЈ-H), 3.04 (s, 3 H, 6-OCH3),
3.00 (q, J = 7.3 Hz, 1 H, 10-H), 2.85 (dq, J = 9.5, 7.3 Hz, 1 H, 2-
H), 2.52–2.64 (m, J = 11.6, 7.0, 7.0, 7.0, 1.2 Hz, 1 H, 8-H), 2.31
(dd, J = 15.0, 0.9 Hz, 1 H, 2ЈЈ-Ha), 1.97 (d, J = 8.9 Hz, 1 H, 4Ј-
Ha), 1.93 (dd, J = 12.5, 6.1 Hz, 1 H, 14-Ha), 1.91 (quint, J = 7.3 Hz,
1 H, 4-H), 1.76 (dd, J = 13.6, 12.2 Hz, 1 H, 7-Ha), 1.62 (dd, J =
15.0, 14.9 Hz, 1 H 2ЈЈ-Hb), 1.48 (ddq, J = 14.0, 11.0, 7.3 Hz, 1 H
14-Hb), 1.42 (d, J = 14.1 Hz, 1 H, 7-Hb), 1.38 (s, 3 H, 6-CH3), 1.37
(dd, J = 12.0, 11.3 Hz, 1 H, 4Ј-Hb), 1.30 (d, J = 6.4 Hz, 3 H, 5ЈЈ-
CH3), 1.28 (d, J = 7.6 Hz, 3 H, 5Ј-CH3), 1.27 (s, 3 H, 3ЈЈ-CH3),
1.21 (d, J = 7.3 Hz, 3 H, 2-CH3), 1.18 (d, J = 7.0 Hz, 3 H, 8-CH3),
1.15 (d, J = 7.6 Hz, 3 H, 10-CH3), 1.15 (s, 3 H, 12-CH3), 0.93 (d,
J = 7.3 Hz, 3 H, 4-CH3), 0.85 (t, J = 7.3 Hz, 3 H, 15-H) ppm. 13C
NMR (125 MHz, CDCl3) benzyl: δ = 136.6 (C), 128.6 (2ϫCH),
128.1 (2ϫCH), 127.8 (CH), 52.9 (CH2) ppm; macrolide: δ = 220.5
(9-C), 175.4 (1-C), 166.5 (C=N), 96.6 (1Ј-C), 96.3 (1ЈЈ-C), 83.2 (5-
C), 78.6 (3-C), 77.8 (6-C), 77.4 (4ЈЈ-C), 77.1 (13-C), 74.1 (12-C),
73.0 (3ЈЈ-C), 69.0 (11-C), 67.1 (5Ј-C), 66.2 (5ЈЈ-C), 63.6 (3Ј-C), 50.7
(6-OCH3), 49.7 (3ЈЈ-OCH3), 48.4 (2Ј-C), 45.0 (8-C), 44.8 (2-C), 39.0
(7-C), 38.3 (4-C), 37.2 (10-C), 35.5 (3Ј-NCH3), 34.9 (2ЈЈ-C), 31.6
(4Ј-C), 21.3 (3ЈЈ-CH3), 20.9 (5Ј-CH3), 20.9 (14-C), 19.5 (6-CH3),
18.5 (5ЈЈ-CH3), 18.0 (8-CH3), 16.0 (12-CH3), 15.8 (2-CH3), 12.2
(10-CH3), 10.5 (15-C), 9.1 (4-CH3) ppm. HRMS (ES): calcd. for
C45H73N2O12S [M + H+] 865.4884; found 865.4889.
(6-CH3), 19.4 (8-CH3), 18.4 (5ЈЈ-CH3), 16.0 (12-CH3), 15.2 (2-
CH3), 13.9 (10-CH3), 11.0 (15-C), 8.8 (4-CH3) ppm. HRMS (ES):
calcd. for C45H74N3O12S [M + H+] 880.4993; found 880.4991.
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-(NЈ-isopropylcarbonimidoyl)-3Ј-N-demeth-
yl-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (11): Accord-
ing to the general procedure, reaction of 1 (0.5 g, 0.68 mmol) af-
forded 11 (0.18 g, 33 %) as a white foam. 1H NMR (500 MHz,
CDCl3) isopropyl: δ = 3.20 (dt, J = 12.4, 6.3 Hz, 1 H, CH), 1.14
(d, J = 6.2 Hz, 3 H, CH3), 1.13 (d, J = 6.2 Hz, 3 H, CH3) ppm;
macrolide: δ = 5.11 (d, J = 4.6 Hz, 1 H, 1ЈЈ-H), 4.96 (d, J = 2.7 Hz,
1 H, 1Ј-H), 4.69 (dd, J = 10.1, 2.1 Hz, 1 H, 13-H), 4.25 (dd, J =
4.9, 1.5 Hz, 1 H, 3-H), 4.02 (dq, J = 9.5, 6.1 Hz, 1 H, 5ЈЈ-H), 4.01
(dd, J = 5.8, 2.7 Hz, 1 H, 2Ј-H), 3.68 (d, J = 7.3 Hz, 1 H, 5-H),
3.64–3.66 (m, 1 H, 11-H), 3.62 (dt, J = 10.9, 5.7 Hz, 1 H, 3Ј-H),
3.37–3.46 (m, 1 H, 5Ј-H), 3.33 (s, 3 H, 3ЈЈ-OCH3), 3.07 (t, J =
9.6 Hz, 1 H, 4ЈЈ-H), 2.91 (s, 1 H, OH), 2.84 (s, 3 H, 3Ј-NCH3), 2.78
(dq, J = 7.3, 6.0 Hz, 1 H, 2-H), 2.70 (q, J = 6.7 Hz, 1 H, 10-H),
2.55 (d, J = 10.4 Hz, 1 H, 9-Ha), 2.35 (d, J = 14.6 Hz, 1 H, 2ЈЈ-
Ha), 2.33 (s, 3 H, 9a-NCH3), 2.07 (dd, J = 16.0, 10.8 Hz, 1 H, 9-
Hb), 1.99–2.03 (m, 1 H, 8-H), 1.96 (quint, J = 7.3 Hz, 1 H, 4-H),
1.85–1.94 (m, 1 H, 14-Ha), 1.72 (ddd, J = 13.1, 5.5, 1.2 Hz, 1 H,
4Ј-Ha), 1.70 (d, J = 14.6 Hz, 1 H, 7-Ha), 1.62 (d, J = 15.3, 4.9 Hz,
1 H, 2ЈЈ-Hb), 1.44–1.53 (m, 1 H, 14-Hb), 1.41 (q, J = 13.1 Hz, 1 H,
4Ј-Hb), 1.35 (s, 3 H, 6-CH3), 1.33 (d, J = 6.4 Hz, 1 H, 5ЈЈ-CH3),
1.26 (d, J = 7.2 Hz, 3 H, 5Ј-CH3), 1.26 (s, 3 H, 3ЈЈ-CH3), 1.20–1.25
(m, 1 H, 7-Hb), 1.20 (d, J = 7.6 Hz, 3 H, 2-CH3), 1.09 (d, J =
7.0 Hz, 3 H, 10-CH3), 1.07 (s, 3 H, 12-CH3), 0.95 (d, J = 6.7 Hz,
3 H, 8-CH3), 0.91 (d, J = 7.2 Hz, 3 H, 4-CH3), 0.88 (t, J = 7.3 Hz,
3 H, 15-H) ppm. 13C NMR (125 MHz, CDCl3) isopropyl: δ = 56.5
(CH), 24.8 (CH3), 24.3 (CH3) ppm; macrolide: δ = 178.5 (1-C),
154.9 (C=N), 98.4 (1Ј-C), 94.9 (1ЈЈ-C), 85.3 (5-C), 78.1 (3-C), 77.9
(4ЈЈ-C), 77.5 (13-C), 74.1 (12-C), 73.9 (11-C), 73.3 (3ЈЈ-C), 73.1 (6-
C), 67.4 (5Ј-C), 70.9 (9-C), 65.7 (5ЈЈ-C), 62.3 (10-C), 60.4 (3Ј-C),
49.4 (3ЈЈ-OCH3), 46.2 (2Ј-C), 45.1 (2-C), 41.9 (7-C), 41.3 (4-C), 36.9
(9a-NCH3), 34.7 (2ЈЈ-C), 31.9 (3Ј-NCH3), 30.8 (4Ј-C), 27.3 (6-CH3),
26.6 (8-C), 21.9 (8-CH3), 21.5 (3ЈЈ-CH3), 21.1 (14-C), 20.9 (5Ј-
CH3), 18.1 (5ЈЈ-CH3), 16.1 (12-CH3), 14.9 (2-CH3), 11.1 (15-C), 8.7
(4-CH3), 7.2 (10-CH3) ppm. HRMS (ES): calcd. for C41H75N3O11S
[M + H+] 817.5117; found 817.5138.
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-(NЈ-benzylcarbonimidoyl)-3Ј-N-demethyl-
6-O-methyl-9a-aza-9a-homoerythromycin A (10): According to the
general procedure, reaction of 8 (0.5 g, 0.67 mmol) afforded 10
(0.15 g, 25%) as a white foam. 1H NMR (500 MHz, CDCl3) benzyl:
δ = 7.35 (d, J = 7.6 Hz, 2 H, 2ϫCH), 7.28 (t, J = 7.6 Hz, 2 H,
2ϫCH), 7.21 (d, J = 7.3 Hz, 1 H, CH), 4.35–4.45 (m, 2 H, CH2)
ppm; macrolide: δ = 6.09 (d, J = 7.9 Hz, 1 H, 9a-NH), 4.96 (d, J
= 2.7 Hz, 1 H, 1Ј-H), 4.86 (d, J = 4.9 Hz, 1 H, 1ЈЈ-H), 4.67 (d, J =
10.1 Hz, 1 H, 13-H), 4.17–4.21 (m, 2 H, 3-H, 10-H), 4.05 (dd, J = 2Ј-Deoxy-2Ј-(S)-S,3Ј-N-(NЈ-isopropylcarbonimidoyl)-3Ј-N-demeth-
6.0, 2.6 Hz, 1 H, 2Ј-H), 4.02 (dq, J = 9.2, 6.1 Hz, 1 H, 5ЈЈ-H), 3.79 yl-6-O-methyl-erythromycin A (12): According to the general pro-
(d, J = 6.7 Hz, 1 H, 5-H), 3.69 (dt, J = 10.9, 5.7 Hz, 1 H, 3Ј-H), cedure, reaction of 0.41 g of 7 (0.55 mmol) afforded 12 (0.067 g,
1
3.37–3.45 (m, 1 H, 5Ј-H), 3.33 (s, 6 H, 6-OCH3, 3ЈЈ-OCH3), 3.30
15%) as a white foam. H NMR (500 MHz, CDCl3) isopropyl: δ =
(br.s, 1 H, OH), 3.21 (d, J = 4.3 Hz, 1 H, 11-H), 3.07 (t, J = 9.3 Hz, 3.18 (dt, J = 12.7, 6.3 Hz, 1 H, CH), 1.17 (d, J = 6.2 Hz, 3 H,
1 H, 4ЈЈ-H), 2.91 (s, 3 H, 3Ј-NCH3), 2.83 (quint, J = 6.7 Hz, 1 H,
2-H), 2.41 (br.s, 1 H, OH), 2.34 (d, J = 15.0 Hz, 1 H, 2ЈЈ-Ha), 2.22
(quint, J = 7.2 Hz, 1 H, 8-H), 2.15 (d, J = 9.8 Hz, 1 H, OH), 1.99
(dd, J = 14.8, 8.1 Hz, 1 H, 7-Ha), 1.81–1.93 (m, 2 H, 4-H, 14-Ha),
1.78 (dd, J = 12.2, 5.5 Hz, 1 H, 4Ј-Ha), 1.60 (dd, J = 15.1, 5.0 Hz,
CH3), 1.16 (d, J = 6.3 Hz, 3 H, CH3) ppm; macrolide: δ = 5.08 (dd,
J = 11.0, 2.1 Hz, 1 H, 13-H), 4.97 (d, J = 2.4 Hz, 1 H, 1Ј-H), 4.93
(d, J = 4.6 Hz, 1 H, 1ЈЈ-H), 4.04 (dd, J = 5.6, 2.6 Hz, 1 H, 2Ј-H),
4.00 (s, 1 H, OH), 3.95 (dq, J = 9.0, 6.2 Hz, 1 H, 5ЈЈ-H), 3.75 (s, 1
H, 11-H), 3.75 (d, J = 8.9 Hz, 1 H, 3-H), 3.71 (d, J = 7.0 Hz, 1 H,
1 H, 2ЈЈ-Hb), 1.51–1.59 (m, 1 H, 14-Hb), 1.44 (q, J = 11.6 Hz, 1 5-H), 3.64 (dt, J = 11.0, 5.5 Hz, 1 H, 3Ј-H), 3.35–3.43 (m, 1 H, 5Ј-
H,4Ј-Hb), 1.38 (s, 3 H, 6-CH3), 1.34 (d, J = 6.4 Hz, 3 H, 5ЈЈ-CH3),
1.29–1.32 (m, 1 H, 7-Hb), 1.27 (d, J = 7.2 Hz, 3 H, 5Ј-CH3), 1.26
(s, 3 H, 3ЈЈ-CH3), 1.24 (d, J = 7.6 Hz, 3 H, 2-CH3), 1.18 (s, 3 H,
12-CH3), 1.17 (d, J = 7.2 Hz, 3 H, 10-CH3), 1.13 (d, J = 7.0 Hz, 3
H, 8-CH3), 0.90 (d, J = 6.2 Hz, 3 H, 15-H), 0.89 (t, J = 7.0 Hz, 3
H), 3.32 (s, 3 H, 3ЈЈ-OCH3), 3.19 (s, 1 H, OH), 3.07 (d, J = 9.5 Hz,
3 H, 4ЈЈ-H), 3.05 (s, 3 H, 6-OCH3), 3.01 (q, J = 7.3 Hz, 1 H, 10-
H), 2.82–2.88 (m, 1 H, 2-H), 2.85 (s, 3 H, 3Ј-NCH3), 2.54–2.64 (m,
1 H, 8-H), 2.37 (d, J = 15.3 Hz, 1 H, 2ЈЈ-Ha), 2.11 (d, J = 9.8 Hz,
1 H, OH), 1.90–1.97 (m, 1 H, 14-Ha), 1.91 (quint, J = 7.0 Hz, 1 H,
H, 4-CH3) ppm. 13C NMR (125 MHz, CDCl3) benzyl: 141.2 (C), 4-H), 1.80 (dd, J = 14.6, 12.0 Hz, 1 H, 7-Ha), 1.73 (dd, J = 13.1,
128.0 (2ϫCH), 127.4 (2ϫCH), 126.2 (CH), 58.5 (CH2) ppm; mac- 5.5 Hz, 1 H, 4Ј-Ha), 1.68 (br.s, 1 H, OH), 1.62 (dd, J = 15.3, 5.2 Hz,
Eur. J. Org. Chem. 2013, 4666–4673
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4671

ˇ
Z. M. Isˇtuk, I. Vujasinovic´, A. Cikosˇ, G. Kragol
FULL PAPER
1 H, 2ЈЈ-Hb), 1.60 (dd, J = 14.0, 1.5 Hz, 1 H, 7-Hb), 1.45–1.51 (m,
(m, 1 H, 5Ј-H), 3.32 (s, 3 H, 6-OCH3), 3.32 (s, 3 H, 3ЈЈ-OCH3),
1 H, 14-Hb), 1.45 (s, 3 H, 6-CH3), 1.35–1.42 (m, 1 H, 4Ј-Hb), 1.33 3.16–3.28 (m, 1 H, 11-H), 3.07 (t, J = 9.6 Hz, 1 H, 4ЈЈ-H), 2.83
(d, J = 6.1 Hz, 3 H, 5ЈЈ-CH3), 1.27 (s, 3 H, 3ЈЈ-CH3), 1.26 (d, J =
6.2 Hz, 3 H, 5Ј-CH3), 1.21 (d, J = 7.3 Hz, 3 H, 2-CH3), 1.14 (br.s,
(dq, J = 7.9, 6.8 Hz, 1 H, 2-H), 2.82 (s, 3 H, 3Ј-NCH3), 2.36 (s, 1
H, OH), 2.33 (d, J = 15.3 Hz, 1 H, 2ЈЈ-Ha), 2.22 (quint, J = 7.1 Hz,
3 H, 8-CH3), 1.13 (d, J = 7.0 Hz, 3 H, 10-CH3), 1.12 (s, 3 H, 12- 1 H, 8-H), 2.10 (d, J = 10.1 Hz, 1 H, OH), 1.99 (dd, J = 15.0,
CH3), 0.97 (d, J = 7.3 Hz, 3 H, 4-CH3), 0.86 (t, J = 7.3 Hz, 3 H, 8.2 Hz, 1 H, 7-Ha), 1.80–1.93 (m, 2 H, 4-H, 14-Ha), 1.74 (dd, J =
15-H) ppm. 13C NMR (125 MHz, CDCl3) isopropyl: δ = 56.7 (CH), 12.5, 5.2 Hz, 1 H, 4Ј-Ha), 1.59 (dd, J = 15.3, 4.9 Hz, 1 H, 2ЈЈ-Hb),
24.8 (CH3), 24.3 (CH3) ppm; macrolide: δ = 220.9 (9-C), 175.5 (1- 1.52–1.62 (m, 1 H, 14-Hb), 1.35–1.43 (m, 1 H, 4Ј-Hb), 1.39 (s, 3 H,
C), 166.5 (C=N), 98.4 (1Ј-C), 96.3 (1ЈЈ-C), 82.8 (5-C), 78.6 (3-C), 6-CH3), 1.34 (d, J = 6.1 Hz, 3 H, 5ЈЈ-CH3), 1.28 (d, J = 15.0 Hz, 1
78.1 (6-C), 77.7 (4ЈЈ-C), 77.1 (13-C), 74.1 (12-C), 72.9 (3ЈЈ-C), 69.0 H, 7-Hb), 1.27 (s, 3 H, 5Ј-CH3), 1.27 (d, J = 6.2 Hz, 3 H, 3ЈЈ-CH3),
(11-C), 67.5 (5Ј-C), 65.9 (5ЈЈ-C), 60.2 (3Ј-C), 50.6 (6-OCH3), 49.5 1.25 (d, J = 7.6 Hz, 3 H, 2-CH3), 1.18 (s, 3 H, 12-CH3), 1.16 (d, J
(3ЈЈ-OCH3), 46.1 (2Ј-C), 45.2 (8-C), 44.9 (2-C), 38.9 (7-C), 38.7 (4-
C), 37.2 (10-C), 34.8 (2ЈЈ-C), 32.0 (3Ј-NCH3), 30.8 (4Ј-C), 21.4 (3ЈЈ-
= 6.2 Hz, 3 H, 10-CH3), 1.13 (d, J = 7.0 Hz, 3 H, 8-CH3), 0.91 (t,
J = 7.2 Hz, 3 H, 15-H), 0.89 (d, J = 7.6 Hz, 3 H, 4-CH3) ppm.
CH3), 21.0 (5Ј-CH3), 20.9 (14-C), 19.6 (6-CH3), 18.5 (5ЈЈ-CH3), 13C NMR (125 MHz, CDCl3) methoxypropyl: δ = 70.9 (CH2), 58.4
18.0 (8-CH3), 16.0 (12-CH3), 15.9 (2-CH3), 12.2 (10-CH3), 10.5 (15- (OCH3), 51.8 (CH2), 31.4 (CH2) ppm; macrolide: δ = 179.6 (1-C),
C), 8.9 (4-CH3) ppm. HRMS (ES): calcd. for C41H73N2O12S [M +
177.5 (9-C), 156.5 (C=N), 98.1 (1Ј-C), 95.5 (1ЈЈ-C), 80.6 (5-C), 79.1
(6-C), 78.5 (13-C), 77.7 (4ЈЈ-C), 76.3 (3-C), 74.1 (12-C), 73.0 (3ЈЈ-
C), 72.7 (11-C), 67.3 (5Ј-C), 65.8 (5ЈЈ-C), 60.4 (3Ј-C), 51.5 (6-
OCH3), 49.5 (3ЈЈ-OCH3), 46.1 (2Ј-C), 45.3 (10-C), 44.6 (2-C), 40.9
(4-C), 39.9 (7-C), 35.7 (8-C), 34.7 (2ЈЈ-C), 31.8 (3Ј-NCH3), 31.0 (4Ј-
C), 21.4 (3ЈЈ-CH3), 21.1 (5Ј-CH3), 20.6 (14-C), 20.5 (6-CH3), 19.5
(8-CH3), 18.4 (5ЈЈ-CH3), 16.0 (12-CH3), 15.2 (2-CH3), 13.8 (10-
CH3), 11.1 (15-C), 8.9 (4-CH3) ppm. HRMS (ES): calcd. for
C42H76N3O13S [M + H+] 862.5099; found 862.5109.
H+] 817.4884; found 817.4896.
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-(NЈ-isopropylcarbonimidoyl)-3Ј-N-demeth-
yl-6-O-methyl-9a-aza-9a-homoerythromycin A (13): According to
the general procedure, reaction of 8 (0.7 g, 0.93 mmol) afforded 13
(0.36 g, 46%) as a white foam. 1H NMR (500 MHz, CDCl3) iso-
propyl: 3.16–3.22 (m, 1 H, CH), 1.24 (d, J = 6.2 Hz, 3 H, CH3),
1.23 (d, J = 6.2 Hz, 3 H, CH3) ppm; macrolide: δ = 6.10 (d, J =
8.2 Hz, 1 H, 9a-NH), 4.94 (d, J = 2.4 Hz, 1 H, 1Ј-H), 4.86 (d, J =
4.6 Hz, 1 H, 1ЈЈ-H), 4.66 (d, J = 10.4 Hz, 1 H, 13-H), 4.13–4.22 2Ј-Deoxy-2Ј-(S)-S,3Ј-N-{NЈ-[3-(methylthio)propyl]carbonimidoyl}-
(m, 1 H, 10-H), 4.18 (d, J = 6.4 Hz, 1 H, 3-H), 4.01 (dq, J = 8.8, 3Ј-N-demethyl-6-O-methyl-9a-aza-9a-homoerythromycin A (15): Ac-
6.1 Hz, 1 H, 5ЈЈ-H), 3.98 (dd, J = 5.6, 2.0 Hz, 1 H, 2Ј-H), 3.78 (d, cording to the general procedure, reaction of 8 (0.4 g, 0.53 mmol)
J = 6.7 Hz, 1 H, 5-H), 3.60 (dt, J = 11.0, 5.5 Hz, 1 H, 3Ј-H), 3.39 afforded 15 (0.18 g, 39%) as a white foam. 1H NMR (500 MHz,
(dq, J = 11.3, 5.8 Hz, 1 H, 5Ј-H), 3.33 (s, 3 H, 6-OCH3), 3.32 (s, 3
H, 3ЈЈ-OCH3), 3.16–3-22 (m, 1 H, 11-H), 3.07 (t, J = 9.6 Hz, 1 H,
CDCl3) methylthiopropyl: δ = 3.25 (td, J = 12.9, 6.3 Hz, 2 H, CH2),
2.58 (d, J = 7.9 Hz, 2 H, CH2), 2.13 (s, 3 H, SCH3), 1.83–1.93 (m,
4ЈЈ-H), 2.79–2.87 (m, 1 H, 2-H), 2.82 (s, 3 H, 3Ј-NCH3), 2.39 (s, 1 2 H, CH2) ppm; macrolide: δ = 6.08 (d, J = 8.2 Hz, 1 H, 9a-NH),
H, OH), 2.34 (d, J = 15.3 Hz, 1 H, 2ЈЈ-Ha), 2.22 (quint, J = 7.1 Hz,
1 H, 8-H), 2.12 (d, J = 9.8 Hz, 1 H, OH), 1.97 (dd, J = 15.0, 7.9 Hz,
1 H, 7-Ha), 1.84–1.92 (m, 2 H, 4-H, 14-Ha), 1.82 (br.s, 1 H, OH),
1.72 (dd, J = 12.5, 5.2 Hz, 3 H, 4Ј-Ha), 1.60 (dd, J = 15.1, 5.0 Hz,
4.95 (d, J = 2.7 Hz, 1 H, 1Ј-H), 4.86 (d, J = 4.6 Hz, 1 H, 1ЈЈ-H),
4.67 (d, J = 9.8 Hz, 1 H, 13-H), 4.12–4.23 (m, 2 H, 10-H, 3-H),
4.02 (dd, J = 5.6, 2.6 Hz, 1 H, 5ЈЈ-H), 4.00 (dq, J = 9.6, 6.2 Hz, 1
H, 2Ј-H), 3.78 (d, J = 6.7 Hz, 1 H, 5-H), 3.65 (dt, J = 10.9, 5.7 Hz,
1 H, 2ЈЈ-Hb), 1.56 (m, 1 H, 14-Hb), 1.40 (q, J = 11.6 Hz, 3 H, 4Ј- 1 H, 3Ј-H), 3.35–3.43 (m, 1 H, 5Ј-H), 3.31 (s, 3 H, 6-OCH3), 3.31
Hb), 1.39 (s, 3 H, 6-CH3), 1.35 (d, J = 7.6 Hz, 3 H, 5ЈЈ-CH3), 1.34 (s, 3 H, 3ЈЈ-OCH3), 3.21 (d, J = 4.0 Hz, 1 H, 11-H), 3.07 (t, J =
(d, J = 6.1 Hz, 3 H, 5Ј-CH3),1.31 (d, J = 15.0 Hz, 1 H, 7-Hb), 1.27 9.5 Hz, 1 H, 4ЈЈ-H), 2.84 (dq, J = 9.0, 7.0 Hz, 1 H, 2-H), 2.84 (s, 3
(s, 3 H, 3ЈЈ-CH3), 1.24 (d, J = 7.6 Hz, 3 H, 2-CH3), 1.18 (s, 3 H,
12-CH3), 1.16 (d, J = 7.2 Hz, 3 H, 10-CH3), 1.13 (d, J = 7.2 Hz, 3
H, 8-CH3), 0.90 (t, J = 6.7 Hz, 3 H, 15-H), 0.89 (d, J = 6.8 Hz, 3
H, 3Ј-NCH3), 2.36 (s, 1 H, OH), 2.33 (d, J = 15.0 Hz, 1 H, 2ЈЈ-
Ha), 2.23 (quint, J = 7.0 Hz, 1 H, 8-H), 1.99 (dd, J = 15.0, 7.9 Hz,
1 H, 7-Ha), 1.83–1.93 (m, 2 H, 4-H, 14-Ha), 1.74 (dd, J = 12.1,
H, 4-CH3) ppm. 13C NMR (125 MHz, CDCl3) isopropyl: δ = 56.5 5.6 Hz, 1 H, 4Ј-Ha), 1.58 (dd, J = 15.1, 5.0 Hz, 1 H, 2ЈЈ-Hb), 1.52–
(CH), 24.7 (CH3), 24.2 (CH3) ppm; macrolide: δ = 179.5 (1-C), 1.61 (m, 1 H, 14-Hb), 1.35–1.43 (m, 1 H, 4Ј-Hb), 1.39 (s, 3 H, 6-
177.4 (9-C), 154.9 (C=N), 98.2 (1Ј-C), 95.5 (1ЈЈ-C), 80.6 (5-C), 79.1
CH3), 1.33 (d, J = 6.4 Hz, 3 H, 5ЈЈ-CH3), 1.30 (d, J = 15.0 Hz, 1
(6-C), 78.4 (13-C), 77.7 (4ЈЈ-C), 76.4 (3-C), 74.1 (12-C), 73.0 (3ЈЈ- H, 7-Hb), 1.27 (d, J = 5.8 Hz, 3 H, 5Ј-CH3), 1.27 (s, 3 H, 3ЈЈ-CH3),
C), 72.8 (11-C), 67.4 (5Ј-C), 65.8 (5ЈЈ-C), 60.2 (3Ј-C), 51.5 (6- 1.25 (d, J = 7.6 Hz, 3 H, 2-CH3), 1.19 (s, 3 H, 12-CH3), 1.16 (d, J
OCH3), 49.5 (3ЈЈ-OCH3), 46.0 (2Ј-C), 45.3 (10-C), 44.6 (2-C), 40.9
(4-C), 39.8 (7-C), 35.6 (8-C), 34.7 (2ЈЈ-C), 31.9 (3Ј-NCH3), 30.8 (4Ј-
= 7.0 Hz, 3 H, 10-CH3), 1.13 (d, J = 7.0 Hz, 3 H, 8-CH3), 0.92 (t,
J = 7.6 Hz, 3 H, 15-H), 0.88 (d, J = 7.6 Hz, 3 H, 4-CH3) ppm. 13C
C), 21.8 (5Ј-CH3), 21.4 (3ЈЈ-CH3), 20.6 (14-C), 20.4 (6-CH3), 19.4 NMR (125 MHz, CDCl3) methylthiopropyl: δ = 54.1 (CH2), 32.0
(8-CH3), 18.4 (5ЈЈ-CH3), 16.0 (12-CH3), 15.3 (2-CH3), 13.8 (10-
CH3), 11.1 (15-C), 8.9 (4-CH3) ppm. HRMS (ES): calcd. for
C40H69N3O12S [M + H+] 815.4596; found 815.4604.
(CH2), 31.1 (CH2), 15.5 (OCH3) ppm; macrolide: δ = 179.6 (1-C),
177.4 (9-C), 156.5 (C=N), 98.1 (1Ј-C), 95.5 (1ЈЈ-C), 80.6 (5-C), 79.1
(6-C), 78.5 (13-C), 77.7 (4ЈЈ-C), 76.3 (3-C), 74.1 (12-C), 73.0 (3ЈЈ-
C), 72.7 (11-C), 67.3 (5Ј-C), 65.8 (5ЈЈ-C), 60.4 (3Ј-C), 51.5 (6-
OCH3), 49.5 (3ЈЈ-OCH3), 46.1 (2Ј-C), 45.3 (10-C), 44.6 (2-C), 40.9
(4-C), 39.9 (7-C), 35.6 (8-C), 34.7 (2ЈЈ-C), 31.7 (3Ј-NCH3), 31.0 (4Ј-
C), 21.4 (3ЈЈ-CH3), 21.1 (5Ј-CH3), 20.6 (14-C), 20.4 (6-CH3), 19.4
(8-CH3), 18.4 (5ЈЈ-CH3), 16.0 (12-CH3), 15.2 (2-CH3), 13.9 (10-
CH3), 11.1 (15-C), 8.9 (4-CH3) ppm. HRMS (ES): calcd. for
C42H76N3O12S2 [M + H+] 878.4870; found 878.4879.
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-{NЈ-[3-(methyloxy)propyl]carbonimidoyl}-
3Ј-N-demethyl-6-O-methyl-9a-aza-9a-homoerythromycin A (14): Ac-
cording to the general procedure, reaction of 8 (0.4 g, 0.53 mmol)
afforded 14 (0.26 g, 56%) as a white foam. 1H NMR (500 MHz,
CDCl3) methoxypropyl: δ = 3.46 (d, J = 6.7 Hz, 3 H, CH2), 3.36 (s,
3 H, CH3), 3.16–3.28 (m, 2 H, CH2), 1.80–1.93 (m, 2H, CH2) ppm;
macrolide: 6.07 (d, J = 7.9 Hz, 1 H, 9a-NH), 4.94 (d, J = 2.7 Hz,
1 H, 1Ј-H), 4.86 (d, J = 4.6 Hz, 1 H, 1ЈЈ-H), 4.67 (d, J = 10.7 Hz,
2Ј-Deoxy-2Ј-(S)-S,3Ј-N-[NЈ-(2-furanylmethyl)carbonimidoyl]-3Ј-N-
1 H, 13-H), 4.13–4.21 (m, 2 H, 10-H, 3-H), 4.02 (dq, J = 9.2, demethyl-6-O-methyl-9a-aza-9a-homoerythromycin A (16): Accord-
6.1 Hz, 1 H, 5ЈЈ-H), 3.99 (d, J = 7.6 Hz, 1 H, 2Ј-H), 3.78 (d, J =
6.7 Hz, 1 H, 5-H), 3.64 (dt, J = 7.6, 5.5 Hz, 1 H, 3Ј-H), 3.35–3.43
ing to the general procedure, reaction of 8 (0.4 g, 0.53 mmol) af-
forded 16 (0.16 g, 33 %) as a white foam. 1H NMR (500 MHz,
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4666–4673

Heterocycles Derived from Desosamine
CDCl3) 2-furanylmethyl: δ = 7.36 (s, 1 H, CH), 6.31 (t, J = 1.8 Hz,
1 H, CH), 6.20 (d, J = 2.7 Hz, 1 H, CH), 4.38 and 4.33 (d, J =
(3-C), 74.1 (12-C), 73.0 (11-C), 72.8 (3ЈЈ-C), 67.4 (5Ј-C), 65.8 (5ЈЈ-
C), 60.5 (3Ј-C), 51.5 (6-OCH3), 49.5 (3ЈЈ-OCH3), 46.1 (2Ј-C), 45.3
15.3 Hz, 1 H, CH2) ppm; macrolide: δ = 6.08 (d, J = 8.2 Hz, 1 H, (10-C), 44.6 (2-C), 40.9 (4-C), 39.9 (7-C), 35.7 (8-C), 34.7 (2ЈЈ-C),
9a-NH), 4.96 (d, J = 2.7 Hz, 1 H, 1Ј-H), 4.87 (d, J = 4.6 Hz, 1 H, 31.7 (3Ј-NCH3), 31.1 (4Ј-C), 21.4 (3ЈЈ-CH3), 21.0 (5Ј-CH3), 20.6
1ЈЈ-H), 4.67 (d, J = 10.4 Hz, 1 H, 13-H), 4.13–4.22 (m, 2 H, 10-H, (14-C), 20.5 (6-CH3), 19.5 (8-CH3), 18.4 (5ЈЈ-CH3), 16.0 (12-CH3),
3-H), 4.06 (dd, J = 5.8, 2.1 Hz, 1 H, 2Ј-H), 4.02 (dq, J = 9.2, 6.4 Hz, 15.2 (2-CH3), 13.8 (10-CH3), 11.1 (15-C), 8.9 (4-CH3) ppm. HRMS
1 H, 5ЈЈ-H), 3.79 (d, J = 6.7 Hz, 1 H, 5-H), 3.68 (dt, J = 10.9, (ES): calcd. for C43H76N3O13S [M + H+] 874.5099; found 874.5094.
5.7 Hz, 1 H, 3Ј-H), 3.36–3.44 (m, 1 H, 5Ј-H), 3.33 (s, 3 H, 6-OCH3),
2Ј-O,3Ј-N-{NЈ-[1-(4-Methoxyphenyl)]carbonimidoyl}-3Ј-N-demeth-
3.33 (s, 3 H, 3ЈЈ-OCH3), 3.21 (d, J = 4.3 Hz, 1 H, 11-H), 3.07 (d,
yl-6-O-methyl-9a-aza-9a-homoerythromycin A (18):[3] According to
J = 8.5 Hz, 1 H, 4ЈЈ-H), 2.89 (s, 3 H, 3Ј-NCH3), 2.83 (quint, J =
the general procedure, reaction of 8 (0.4 g, 0.53 mmol) afforded 18
(0.18 g, 38%) as a white foam.
7.6 Hz, 1 H, 2-H), 2.37 (br.s, 1 H, OH), 2.33 (d, J = 15.3 Hz, 1 H,
2ЈЈ-Ha), 2.22 (quint, J = 7.1 Hz, 1 H, 8-H), 2.00 (dd, J = 14.8,
2Ј-O,3Ј-N-[NЈ-1-(2,6-Difluorophenyl)carbonimidoyl]-3Ј-N-demeth-
8.1 Hz, 1 H, 7-Ha), 1.85–1.95 (m, 2 H, 4-H, 14-Ha), 1.77 (dd, J =
yl-6-O-methyl-9a-aza-9a-homoerythromycin A (19):[1] According to
12.4, 5.3 Hz, 1 H, 4Ј-Ha), 1.59 (dd, J = 15.0, 4.9 Hz, 1 H, 2ЈЈ-Hb),
the general procedure, reaction of 8 (0.4 g, 0.53 mmol) afforded 19
(0.16 g, 34%) as a white foam.
1.50–1.60 (m, 1 H, 14-Hb), 1.45 (q, J = 12.8 Hz, 1 H, 4Ј-Hb), 1.38
(s, 3 H, 6-CH3), 1.35 (d, J = 6.1 Hz, 3 H, 5ЈЈ-CH3), 1.29 (br.s, 1 H,
Supporting Information (see footnote on the first page of this arti-
7-Hb), 1.26 (d, J = 7.2 Hz, 3 H, 5Ј-CH3), 1.26 (s, 3 H, 3ЈЈ-CH3),
1.25 (d, J = 7.9 Hz, 3 H, 2-CH3), 1.18 (s, 3 H, 12-CH3), 1.18 (d, J
= 7.2 Hz, 3 H, 10-CH3), 1.13 (d, J = 7.0 Hz, 3 H, 8-CH3), 0.91 (t,
J = 7.0 Hz, 3 H, 15-H), 0.89 (d, J = 7.0 Hz, 3 H, 4-CH3) ppm.
13C NMR (125 MHz, CDCl3) 2-furanylmethyl: δ = 154.4 (C), 141.4
(CH), 110.0 (CH), 106.0 (CH), 51.7 (CH2); macrolide: δ = 179.5 (1-
C), 177.4 (9-C), 159.3 (C=N), 98.0 (1Ј-C), 95.5 (1ЈЈ-C), 80.6 (5-C),
79.1 (6-C), 78.5 (13-C), 77.7 (4ЈЈ-C), 76.4 (3-C), 74.1 (12-C), 73.0
(3ЈЈ-C), 72.7 (11-C), 67.4 (5Ј-C), 65.8 (5ЈЈ-C), 60.7 (3Ј-C), 51.5 (6-
OCH3), 49.5 (3ЈЈ-OCH3), 46.4 (2Ј-C), 45.3 (10-C), 44.6 (2-C), 40.9
(4-C), 39.9 (7-C), 35.7 (8-C), 34.7 (2ЈЈ-C), 31.8 (3Ј-NCH3), 31.2 (4Ј-
C), 21.4 (3ЈЈ-CH3), 21.1 (5Ј-CH3), 20.6 (14-C), 20.5 (6-CH3), 19.5
(8-CH3), 18.4 (5ЈЈ-CH3), 16.0 (12-CH3), 15.2 (2-CH3), 13.8 (10-
CH3), 11.1 (15-C), 8.9 (4-CH3) ppm. HRMS (ES): calcd. for
C43H72N3O13S [M + H+] 870.4786; found 870.4788.
1
cle): Copies of the H NMR and 13C NMR spectra of final prod-
ucts, as well as NOESY spectra for compounds 3 and 4 are pro-
vided.
Acknowledgments
The authors would like to thank Bill Leavens for providing HRMS
ˇ
data, Zeljko Osman for the purity and Mark Vine for valuable com-
ments and productive discussions.
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D. Jelic´, I. Glojnaric´, D. Verbanac, O. Culic´, J. Padovan, S.
(500 MHz, CDCl3) tetrahydro-2-furanylmethyl: δ = 4.10 (quint, J =
6.3 Hz, 1 H, CH), 3.95–4.04 (m, 1 H, CH2), 3.73–3.81 (m, 1 H,
CH2), 3.25 (d, J = 6.1 Hz, 1 H, CH2), 3.19 (br.s, 1 H, CH2), 1.93–
2.02 (m, 2 H, CH2), 1.69–1.82 (m, 1 H, CH2), 1.83–1.93 (m, 1 H,
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(s, 1 H, 1Ј-H), 4.86 (d, J = 4.6 Hz, 1 H, 1ЈЈ-H), 4.67 (d, J = 10.4 Hz,
1 H, 13-H), 4.13–4.23 (m, 2 H, 10-H, 3-H), 3.95–4.04 (m, 2 H, 5ЈЈ-
H, 2Ј-H), 3.73–3.81 (m, 1 H, 5-H), 3.64 (dt, J = 11.0, 5.5 Hz, 1 H,
3Ј-H), 3.35–3.43 (m, 1 H, 5Ј-H), 3.33 (s, 6 H, 6-OCH3, 3ЈЈ-OCH3),
3.18 (dd, J = 14.0, 5.8 Hz, 1 H, 11-H), 3.07 (d, J = 8.9 Hz, 1 H,
4ЈЈ-H), 2.83 (q, J = 6.7 Hz, 1 H, 2-H), 2.83 (s, 3 H, 3Ј-NCH3), 2.37
(br.s, 1 H, OH), 2.33 (d, J = 15.3 Hz, 1 H, 2ЈЈ-Ha), 2.22 (quint, J
= 6.9 Hz, 1 H, 8-H), 2.10 (br.s, 1 H, OH), 1.93–2.02 (m, 3 H, 7-
Ha, CH2), 1.83–1.93 (m, 4 H, 4-H, 14-Ha, CH2), 1.69–1.82 (m, 3
H, 4Ј-Ha, CH2), 1.58 (dd, J = 15.3, 4.9 Hz, 1 H, 2ЈЈ-Hb), 1.52–1.61
(m, 1 H, 14-Hb), 1.38–1.46 (m, 1 H, 4Ј-Hb), 1.39 (s, 3 H, 6-CH3),
1.34 (d, J = 6.1 Hz, 3 H, 5ЈЈ-CH3), 1.30 (s, 1 H, 7-Hb), 1.27 (s, 3
H, 3ЈЈ-CH3), 1.26 (br.s, 3 H, 5Ј-CH3), 1.25 (d, J = 7.6 Hz, 3 H, 2-
CH3), 1.18 (s, 3 H, 12-CH3), 1.18 (br.s, 3 H, 10-CH3), 1.13 (d, J =
7.0 Hz, 3 H, 8-CH3), 0.91 (t, J = 7.3 Hz, 3 H, 15-H), 0.89 (br.s, 3
H, 4-CH3) ppm. 13C NMR (125 MHz, CDCl3): tetrahydro-2-furan-
ylmethyl: δ = 79.5 (CH), 68.2 (CH2), 29.3 (CH2), 25.6 (CH2) ppm;
macrolide: δ = 179.5 (1-C), 177.4 (9-C), 159.3 (C=N), 98.1 (1Ј-C),
95.5 (1ЈЈ-C), 80.6 (5-C), 79.1 (6-C), 78.5 (13-C), 77.8 (4ЈЈ-C), 76.4
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Received: February 20, 2013
Published Online: June 7, 2013
Eur. J. Org. Chem. 2013, 4666–4673
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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