Synthesis of 8-fluorinated erythromycin cyclic 2',3'-carbamates

Article abstract of DOI:10.1080/00397910802618455

Methodology is described for the preparation of a 2',3'-carbamate-11,12- carbonate analog of flurithromycin and its 3-O-descladinosylflurithromycin analog from (9E)-erythromycin A 9-oxime. Phosgene was used for the carbonylation reactions. SelectfluorTM was an effective fluorinating agent of the intermediate 8,9-anhydro-N-demethylerythromycin A 2',3'-carbamate-11,12- carbonate-6,9-hemiketal under mild aqueous conditions.

Full text of DOI:10.1080/00397910802618455

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Synthesis of 8-Fluorinated
Erythromycin Cyclic 2′,3′-
Carbamates
a
a
Audun Heggelund & Kjell Undheim
a
Department of Chemistry, University of Oslo, Oslo,
Norway
Published online: 27 Apr 2009.
To cite this article: Audun Heggelund & Kjell Undheim (2009): Synthesis of 8-
Fluorinated Erythromycin Cyclic 2′,3′-Carbamates, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:11,
1903-1913
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1
Synthetic Communications , 39: 1903–1913, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802618455
Synthesis of 8-Fluorinated Erythromycin
0
0
Cyclic 2 ,3 -Carbamates
Audun Heggelund and Kjell Undheim
Department of Chemistry, University of Oslo, Oslo, Norway
0
0
Abstract: Methodology is described for the preparation of a 2 ,3 -carbamate-
1,12-carbonate analog of flurithromycin and its 3-O-descladinosylflurithromycin
analog from (9E)-erythromycin A 9-oxime. Phosgene was used for the carbonyla-
1
TM
tion reactions. Selectfluor
ate 8,9-anhydro-N-demethylerythromycin A 2 ,3 -carbamate-11,12-carbonate-6,9-
was an effective fluorinating agent of the intermedi-
0
0
hemiketal under mild aqueous conditions.
Keywords: Antibacterial activity, carbonylation, fluorination, phosgene reactions
Semisynthetic modifications of the important macrolide erythromycin A
have provided new groups of antibacterial drugs with improved physico-
[1]
chemical properties for in vivo availability. Encouraged by findings
reported from an x-ray analysis of macrolides, which had been cocrystal-
[2]
lized with bacterial ribosomes, we have initiated a project to modify
0
0
0
the 3 -dimethylamino group in the desosamine sugar into cyclic 2 ,3 -
3,4]
[
carbamates.
In this report, we describe work on analogs of flurithro-
mycin. The small fluorine atom forms particularly stable bonds with car-
bon, and the C-F bond is only rarely ionized. The non-activated fluorine
substituent is not readily substituted. Because of its chemical stability and
small size, fluorine is often regarded as a hydrogen bioisoster and has
become an important tool in modern drug discovery to fine-tune biologi-
cal effects and in studies of the binding affinity in protein–ligand com-
[
5]
plexes. The antibiotic flurithromycin, (8S)-8-fluoroerythromycin A, is
Received July 1, 2008.
Address correspondence to Kjell Undheim, Department of Chemistry, Univer-
sity of Oslo, N-0315 Oslo, Norway. E-mail: kjell.undheim@kjemi.uio.no
1
903

1904
A. Heggelund and K. Undheim
a second-generation macrolide that has been reported to be more stable
than erythromycin toward degradation of the macrolide structure in
[6,7]
acidic media.
Furthermore, there is a significant increase in serum
levels of the fluoro derivative, which presumably promotes the efficacy
[
8]
of the drug.
The targeted fluoro derivatives in this work are shown in Fig. 1. The
substrate for fluorination was to be the cyclic 6,9-enol ether 2 (Scheme 1).
To effect fluorination in the 8-position, the 9-oxo group should be free to
enolize or be in the form of a vinyl ether. A cyclic vinyl ether moiety is a
[
9]
part of substrate 2. Treatment of the dry enol ether 1 with phosgene
and pyridine as base led to carbonylation with introduction of the
0 0
1
1,12-carbonate and the 2 ,3 -carbamate functionalities. The use of liquid
diphosgene (trichloromethyl chloroformate) or solid triphosgene [bis(tri-
chloromethyl) carbonate] as a safer substitute for phosgene has not been
[
10]
00
explored. In the phosgene reaction, the 4 -OH group in the cladinose
sugar was transformed into a carbonyl chloride, which was not isolated
but hydrolyzed and decarboxylated in situ. This reaction sequence
furnished the target compound 2 in a low yield, ca. 20% from erythromy-
cin A. The low yield may be caused by reactions of the nucleophilic enol
ether with the electrophilic phosgene. Therefore, in an alternative
procedure, the substrate was (9E)-N-demethylerythromycin A 9-oxime
0
0
2
,3 -carbamate-11,12-carbonate (3), which was available from a previous
[
4]
reaction sequence from erythromycin A. Deoximation with sodium
hydrogen sulfite has proven useful for deoximation of various erythromy-
cin A oximes, when the C-6 hydroxyl group is protected as an alkyl
[
11,12]
[13]
ether.
The aqueous workup with hydrochloric acid,
however,
furnished a mixture of products in the present case because of the typical
[
decomposition reactions of erythromycins in acidic media. When pyri-
14]
[15]
[16]
dinium chlorochromate (PCC) or Dess–Martin periodinane (DMP)
Figure 1. Targets A: R¼cladinosyl, R¼H.

Fluorination of Erythromycin Derivatives
1905
Scheme 1. Reagents and conditions for carbonylations: (i) (a) COCl
2
, pyridine,
2 2 2 2 2
CH Cl , rt, 6 h; (b) H O, 4.5 h; and (ii) PCC, CH Cl , rt, 1 h.
were used as reagents, one major product was formed after deoximation
and enol ether formation.
Vigorous conditions for fluorination have been described for the
[7]
preparation of flurithromycin. The toxic and explosive gaseous reagents
trifluoromethyl hypofluorite (CF OF) or perchloryl fluoride (FClO ) were
used. 1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo-[2.2.2]octane bis(tetra-
3
3
TM
fluoroborate), Selectfluor , is a recent and relatively reactive, nonexplosive,
[
17,18]
and less toxic fluorinating agent,
electrophilic fluorination of various functional groups.
and is recommended for site-selective
When the enol
[19]
ether 2 was treated with Selectfluor at room temperature in wet acetonitrile,
full conversion to the 8-fluoride was achieved after 40 min, and the product
was isolated in 80% yield (Scheme 2). In principle, the product is a mixture of
TM
Scheme 2. Reagents and conditions for fluorination: (i) Selectfluor , MeCN—
H O (9:1), rt, 40 min; and (ii) AcOH-H O (1:1), reflux, 30 min.
2
2

1906
A. Heggelund and K. Undheim
at least two tautomeric forms, the hemiketal 4a and the hydroxy-ketone 4b.
For comparison, erythromycin A in a deuterated chloroform solution
exists in equilibria with the hydroxy-ketone, the 6,9-hemiketal, and the
[
20]
9
,12-hemiketal tautomers, with the former as the dominating isomer. In
more polar solvents such as deuterated methanol, dimethyl formamide
DMF), or dimethyl sulfoxide (DMSO), the equilibria are shifted toward
(
the hemiketals. Flurithromycin has also been reported as a mixture of
hydroxy-ketone and hemiketal tautomers with the 6,9-hemiketal tautomer
[6]
as the dominant form in deuterated chloroform solution.
Equilibration studies of the hemiketal 4a and the hydroxy-ketone tau-
tomer 4b mixture in aqueous acetic acid with increasing acid concentrations
showed no apparent changes until the acid strength caused cleavage of the
cladinose sugar. Preparatively, the descladinosyl compound 5 was isolated
in 88% yield using a weak acid procedure for hydrolysis (Scheme 2). The
preference for the hemiketal tautomeric form remained the same in the
new product. Heating the product 5 and oxalic acid in acetic acid–water
(1:1) left the hemiketal intact. Hence, it is concluded that the hemiketal form
of the flurithromycin analog 4 was the preferred tautomer.
No attempts were made to determine the stereochemistry at C-9 in
the hemiketals. In other erythromycins, nuclear Overhauser effects
(NOE) in NMR have been reported to yield valuable information on
the hemiketal stereochemistry.
[21]
The antibacterial activities of compounds 2, 3, and 4 were measured as
the minimum inhibitory concentration (MIC) of bacterial growth against
[
22]
Staph. aureus ATCC 25923 and E. coli ATCC 25922. All compounds
tested were inactive within the limits of the analysis. The findings further
emphasize recent reports that the antibacterial activities of certain erythro-
mycins are lowered when the parent compounds are converted into cyclic
0
0
[3,4]
2
the basic tertiary amino center in the desosamine sugar moiety.
,3 -carbamates.
Reduced activity may in part be attributed to loss of
CONCLUSION
0
0
Methodology is described for a synthesis of the 2 ,3 -carbamate-11,12-
carbonate derivatives of flurithromycin and its 3-O-descladinosylfluri-
thromycin analogue from (9E)-erythromycin A 9-oxime.
EXPERIMENTAL
1
H NMR spectra were recorded in CDCl at 500 MHz with Bruker DRX
3
1
00. The C NMR spectra were recorded at 125 MHz. Chemical shifts
3
5
are reported in parts per million (ppm) using CHCl (7.24 ppm) and
3

Fluorination of Erythromycin Derivatives
1907
CDCl (77 ppm) as references. Mass spectra were recorded at 70 eV. The
3
spectra are presented as m=z (% relative intensity). Electrospray spectra
(
ES) were obtained with a Micromass QTOF 2 W spectrometer with
electrospray ionization quadrupole time of flight. Infrared (IR) spectra
were recorded on a Nicolet Magna Fourier transform—infrared (FT-
IR) 550 spectrometer using ATR (attenuated total reflectance). Melting
points are uncorrected.
All reactions were performed under an inert atmosphere. Dichloro-
methane and triethylamine were distilled from calcium hydride. Merck
silica gel 60 (230–400 mesh) was used for flash chromatography.
[9]
8
,9-Anhydroerythromycin A 6,9-Hemiketal (1)
A solution of erythromycin A (300 mg, 0.41 mmol) in acetic acid (3 mL)
was stirred at room temperature for 45 min. The mixture was evaporated
at reduced pressure, and residual water and acetic acid were removed by
chasing with toluene. The product was used in the next step without
further purification. In the literature, no analytical data for this com-
pound were presented because it was used directly for a subsequent
operation. Our analytical data are therefore included. HRMS, ESI
þ
pos.: Found: 716.4567; calc. for M þ H ¼ C H NO : 716.4579. IR
3
7
66
12
ꢀ
1
ATR, cm ): 3451m (br, O-H), 2970s (C-H), 2936s (C-H), 2879m (C-
(
H), 2832m (C-H), 2787w (C-H), 1728s (C¼O), 1577w, 1456m, 1381m,
1
9
1
7
3
1
332w, 1278m, 1188m, 1165m, 1108m, 1055s, 1014s, 1001s, 959w,
1
3
37w, 900w, 868w, 733 m; C NMR (75 MHz, CDCl ): d 178.3 (C-1),
3
51.7 (C-9), 102.9 (C-8), 101.5, 94.8, 85.5, 80.5, 78.22, 78.18, 76.7, 75.4,
3.0, 70.8, 70.5, 68.5, 65.6, 49.5 (OMe), 44.8, 43.2, 42.6, 40.1 (NMe2),
4.7, 30.4, 29.3, 26.2, 21.6, 21.3, 21.0, 18.3, 16.2, 14.9, 13.6, 11.9,
0.9, 8.8; MS, ESI pos. m=z (% rel. int.): 533.8 (4), 537.8 (8), 558.3 (11,
þ
þ
[
[
M–cladinose þ H ]), 569.7 (7), 716.3 (100, [M þ H ]), 738.3 (6,
þ
M þ Na ]).
0 0
,9-Anhydro-N-demethylerythromycin A 2 ,3 -Carbamate-11,12-
Carbonate-6,9-hemiketal (2)
8
Method 1
Pyridine (0.39 mL, 4.8 mmol) and phosgene (20% in toluene, 1.2 mL,
2.3 mmol) were added to a solution in dichloromethane (6 mL) of the
crude 8,9-anhydroerythromycin A 6,9-hemiketal (1) (0.41 mmol) from
above. The reaction mixture was stirred at room temperature for 6 h

1908
A. Heggelund and K. Undheim
before water (2 mL) was added. After stirring for another 4.5 h (dark
brown solution), aqueous sodium hydroxide was added. The product
was extracted into dichloromethane; the combined organic layers were
washed with water and brine, dried (MgSO ), and filtered. The filtrate
4
evaporated to dryness. The residual brown oil (387 mg) was subjected to
flash chromatography on silica gel (25 g) using CH Cl –2-PrOH–NEt
3
2
2
9
8:1:1; yield 61 mg (20% over two steps from erythromycin A) of a pale
brown solid. Recrystallization from toluene–hexane removed the disco-
loration. The product was an off-white solid. The spectroscopic data were
the same as reported for the product prepared by the alternative Method 2.
Method 2
Pyridinium chlorochromate (PCC, 605 mg, 2.81 mmol) was suspended in
dichloromethane (24 mL), and a solution of (9E)-N-demethylerythromy-
0
0
[4]
cin A 9-oxime 2 ,3 -carbamate-11,12-carbonate (3) (1.19 g, 1.51 mmol)
in dichloromethane (12 mL) was added. The reaction mixture was stirred
thoroughly at room temperature for 1 h. The resulting brown mixture
was filtered, and aqueous sodium hydroxide was added. The product
was extracted into dichloromethane; the combined organic layers were
washed with water and brine and dried (MgSO ). The filtrate was evapo-
4
rated, and the residual pale brown solid (953 mg) was subjected to flash
chromatography on silica gel (50 g) using CH Cl –2-PrOH–NEt 98:1:1.
2
2
3
Data
ꢁ
Yield 710 mg (63%) of a white solid with mp 166–169 C (toluene–
hexane). Found: C, 60.28; H, 7.36. Calc. for C H NO : C, 60.54; H,
3
8
59
14
7
.89%.
HRMS,
ESI
pos.:
Found
776.3797;
ꢀ1
calc.
for
þ
M þ Na ¼ C H NNaO :776.3827. IR (ATR, cm ): 3524m (br, O-
3
8
59
14
H), 2973s (C-H), 2936s (C-H), 2883m (C-H), 2829m (C-H), 2745w,
1
1
1
7
806s (C¼O), 1771s (C¼O), 1741s (C¼O), 1702w, 1636w, 1538w,
455m, 1425m, 1381m, 1343m, 1326m, 1293m, 1235m, 1173s, 1130s,
115s, 1079s, 1051s, 1009s, 958m, 944m, 905m, 875w, 860w, 803w,
1
73m, 735w, 702w, 673w; H NMR (500 MHz, CDCl ): d 4.87–4.82
3
0
00
(
3H, m, H-13, H-1 , H-1 ), 4.17 (1H, d, J ¼ 11.1 Hz, H-11), 3.97 (1H,
0
0
dq, J ¼ 6.3, 9.4 Hz, H-5 ), 3.87 (1H, dd, J ¼ 1.9, 3.9 Hz, H-3), 3.82 (1H,
0
d, J ¼ 7.6 Hz, H-5), 3.70–3.66 (1H, m, H-5 ), 3.62 (1H, dd, J ¼ 8.0,
0
00
1
3
2
1.4 Hz, H-2 ), 3.29 (3H, s, 3 -OMe), 3.15 (1H, dt, J ¼ 3.4, 11.8 Hz, H-
0
00
), 3.05 (1H, t, J ¼ 9.3 Hz, H-4 ), 2.83 (1H, dq, J ¼ 6.8, 11.0 Hz, H-10),
.79 (3H, s, NMe), 2.67 (1H, dq, J ¼ 4.3, 7.4 Hz, H-2), 2.58 (1H, d,

Fluorination of Erythromycin Derivatives
1909
0
0
J ¼ 15.7 Hz, H-7a), 2.39 (1H, d, J ¼ 15.4 Hz, H-2 a), 2.06 (1H, d,
0
0
0
J ¼ 10.2 Hz, 4 -OH), 1.99 1.95 (1H, m, H-4 a), 1.89–1.85 (2H, m, H-4,
H-7b), 1.81 (1H, ddq, J¼3.1, 7.5, 14.5 Hz, H-14a), 1.60–1.41 (3H, m,
0
00
H-14b, H-4 b, H-2 b), 1.59 (3H, s, Me at C-8), 1.37 (3H, s, Me at
0
C-12), 1.30 (3H, s, Me at C-6), 1.28 (3H, d, J ¼ 6.2 Hz, Me at C-5 =C-
0
0
0
0
0
00
5
3
), 1.27 (3H, d, J ¼ 6.2 Hz, Me at C-5 =C-5 ), 1.24 (3H, s, Me at C-
), 1.17 (3H, d, J ¼ 6.7 Hz, Me at C-10), 1.11 (3H, d, J ¼ 7.4 Hz, Me
at C-2), 0.97 (3H, d, J ¼ 7.5 Hz, Me at C-4), 0.87 (3H, t, J ¼ 7.4 Hz, H-
1
3
1
5a-c); C NMR (125 MHz, CDCl ): d 176.6 (C-1), 159.7 (O-(C¼O)-
3
0
N), 153.2 (O-(C¼O)-O), 147.6 (C-9), 104.9 (C-8), 99.5 (C-1 ), 95.5 (C-
0
0
0
1
(
), 86.9 (C-6), 85.1 (C-12), 82.4 (C-11), 80.8 (C-5), 79.5 (C-2 ), 77.9
00 00 0 00
C-4 ), 77.0 (C-3), 75.7 (C-13), 73.2 (C-3 ), 70.4 (C-5 ), 65.7 (C-5 ),
0 00
1.3 (C-3 ), 49.7 (3 -OMe), 43.6 (C-2), 42.7 (C-4), 41.8 (C-7), 36.2 (C-
6
4
2
0
00
), 34.6 (C-2 ), 31.8 (C-10), 30.0 (NMe), 25.4 (Me at C-6), 22.1 (C-14),
0
0
0
00
1.5 (Me at C-3 ), 20.8 (Me at C-5 ), 18.1 (Me at C-5 ), 15.7 (Me at
C-10), 13.5 (Me at C-12), 13.2 (Me at C-2), 12.1 (Me at C-8), 10.5 (C-
5), 8.2 (Me at C-4); MS, ESI pos. m=z (% rel. int.): 776.1 (18,
1
þ
þ
[
M þ Na ]), 596.1 (5, [M–cladinose þ H ]), 569.7 (47), 555.7 (14), 537.7
(
100), 535.7 (13), 533.8 (7), 207.3 (4), 175.3 (5).
0
0
(
1
9E)-N-Demethylerythromycin A 9-Oxime 2 ,3 -carbamate-
1,12-carbonate (3)
[
4]
Compound 3 was prepared as we previously described.
0
0
N-Demethylflurithromycin 2 ,3 -Carbamate-11,12-carbonate-
6
,9-hemiketal (4)
TM
Selectfluor
dro-N-demethylerythromycin
(72 mg, 0.20 mmol) was added to a solution of 8,9-anhy-
0 0
A
2 ,3 -carbamate-11,12-carbonate-6,9-
hemiketal (2) (125 mg, 0.17 mmol) in acetonitrile–water 9:1 (4 mL). The
reaction mixture was stirred at room temperature for 40 min before eva-
poration of the volatiles at reduced pressure. The residue was subjected to
flash chromatography on silica gel (12 g) using EtOAc–NEt 98:2.
3
ꢁ
Yield 105 mg (80%) of a white solid with mp 168–170 C (EtOH–
þ
H O). HRMS, ESI pos.: Found 812.3873. Calc. for M þ Na ¼
2
ꢀ
1
C H FNNaO :812.3839. IR (ATR, cm ): 3503m (br, O-H), 2974s
3
8
60
15
(
(
1
7
C-H), 2937s (C-H), 2884m (C-H), 2830w (C-H), 1801s (C¼O), 1770s
C¼O), 1738s (C¼O), 1457m, 1426m, 1381m, 1325m, 1293w, 1236m,
165s, 1100m, 1078m, 1042m, 1013s, 944w, 930w, 906w, 880w, 862w,
1
74m, 734 m; H NMR (500 MHz, CDCl ): d 5.00 (1H, s, H-11), 4.97
3

1910
A. Heggelund and K. Undheim
0
0
(
1H, dd, J ¼ 2.4, 10.3 Hz, H-13), 4.93 (1H, d, J ¼ 4.6 Hz, H-1 ), 4.66 (1H,
0
d, J ¼ 7.8 Hz, H-1 ), 4.00 (1H, dd, J ¼ 2.3, 5.9 Hz, H-3), 3.90 (1H, dq,
0
0
0
J ¼ 6.4, 9.2 Hz, H-5 ), 3.72–3.65 (1H, m, H-5 ), 3.64 (1H, dd, J ¼ 7.7,
0
0
1
3
1.2 Hz, H-2 ), 3.44 (1H, d, J ¼ 8.6 Hz, H-5), 3.29–3.25 (1H, m, H-3 ),
0
0
00
.24 (3H, s, 3 -OMe), 3.00 (2H, d, J ¼ 11.2 Hz, H-7a, H-4 ), 2.92 (1H,
s, 9-OH), 2.79 (3H, s, NMe), 2.75 (1H, pent., J ¼ 6.8 Hz, H-2), 2.34
0
0
(
1H, d, J ¼ 15.2 Hz, H-2 a), 2.21 (1H, dd, J ¼13.2 Hz, J ¼22.4 Hz,
H-H
H-F
0
H-7b), 2.03–1.97 (1H, m, H-4 a), 1.97–1.91 (1H, m, H-4), 1.95 (1H, q,
J ¼ 6.9 Hz, H-10), 1.79 (1H, ddq, J ¼ 2.6, 7.4, 14.2 Hz, H-14a), 1.64
0 00
3H, s, Me at C-6), 1.61–1.49 (3H, m, H-14b, H-4 b, H-2 b), 1.45 (3H,
(
d, JH-F ¼ 23.0 Hz, Me at C-8), 1.40 (3H, s, Me at C-12), 1.29 (3H, d,
0
00
J ¼ 6.1 Hz, Me at C-5 ), 1.22–1.20 (3H, m, Me at C-5 ), 1.20 (3H, s,
0
0
Me at C-3 ), 1.15 (3H, d, J ¼ 7.3 Hz, Me at C-2), 1.06 (3H, d, J ¼ 6.8 Hz,
Me at C-10), 1.02 (3H, d, J ¼ 7.2 Hz, Me at C-4), 0.88 (3H, t, J¼7.3 Hz,
1
3
Hz, H-15a-c); C NMR (125 MHz, CDCl ): d 177.2 (C-1), 159.6 [O-
3
2
(
C¼O)-N], 153.5 [O-(C¼O)-O], 104.2 (d, J ¼18.6 Hz, C-9), 100.5 (d,
C-F
00
1
0
J
¼190.4 Hz, C-8), 100.4 (C-1 ), 97.3 (C-1 ), 84.5 (C-12), 84.4 (C-5),
C-F
3
0
8
3.8 (d, J ¼9.3 Hz, C-6), 80.9 (C-11), 79.3 (C-2 ), 78.6 (C-3), 77.9
C-F
00 00 00 0 00
(
6
4
C-13=C-4 ), 77.8 (C-13=C-4 ), 72.7 (C-3 ), 71.0 (C-5 ), 65.5 (C-5 ),
0
00
2
1.0 (C-3 ), 49.4 (3 -OMe), 47.5 (d, J ¼22.1 Hz, C-7), 45.2 (C-2),
C-F
0
00
1.6 (C-4), 38.2 (C-10), 36.2 (C-4 ), 34.9 (C-2 ), 32.1 (Me at C-6), 30.0
2
(
NMe), 21.8 (d, J ¼ 26.3 Hz, Me at C-8), 21.7 (C-14), 21.5 (Me at
C-F
0
0
0
0
C-3 ), 20.6 (Me at C-5 ), 17.6 (Me at C-5 ), 15.1 (Me at C-2), 14.4 (Me
at C-12), 11.4 (Me at C-4), 10.1 (C-15), 8.2 (Me at C-10); MS, ESI pos.
þ
m=z (% rel. int.): 1104.4 (4), 911.4 (4), 812.3 (100, [M þ Na ]), 807.4
þ
(
6), 632.3 (4, [M–cladinose þ H ]), 614.3 (9), 569.9 (15), 537.8 (19),
3
89.9 (8), 353.0 (7), 315.0 (12), 293.1 (7).
0
0
N-Demethyl-3-O-descladinosylflurithromycin 2 ,3 -carbamate-11,12-
carbonate-6,9-hemiketal (5)
0
0
A solution of N-demethylflurithromycin 2 ,3 -carbamate-11,12-carbo-
nate-6,9-hemiketal (4) (190 mg, 0.24 mmol) in acetic acid–water (1:1,
5
mL) was heated under reflux for 30 min. The volatiles were then dis-
tilled off at reduced pressure, and the residual product was subjected to
flash chromatography on silica gel using CH Cl –2-PrOH–NEt 98:1:1.
2
2
3
ꢁ
Yield 133 mg (88%) of a white solid with mp > 315 C (acetic acid=
þ
water). HRMS, ESI pos.: Found 654.2887. Calc. for M þ Na ¼ C H
3
0
46
ꢀ
1
FNNaO 654.2896; IR (ATR, cm ): 3511m (br, O-H), 2976s (C-H),
1
2
2
1
1
937s (C-H), 2882m (C-H), 1797s (C¼O), 1766s (C¼O), 1457m,
1
043m, 1018s, 990s, 917w, 853w, 774m, 735 m; H NMR (500 MHz,
426m, 1383s, 1361m, 1327m, 1293m, 1236s, 1158s, 1101s, 1080m,

Fluorination of Erythromycin Derivatives
1911
CDCl ): d 4.93 (1H, dd, J ¼ 3.4, 9.6 Hz, H-13), 4.82 (1H, s, H-11), 4.77
3
0
(
1H, d, J ¼ 7.8 Hz, H-1 ), 4.19 (1H, dd, J ¼ 2.0, 8.3 Hz, H-3), 3.74 (1H,
0
0
ddq, J ¼ 1.7, 6.1, 10.0 Hz, H-5 ), 3.60 (1H, dd, J ¼ 7.8, 11.3 Hz, H-2 ),
0
3
.53 (1H, d, J ¼ 2.4 Hz, H-5), 3.28 (1H, dt, J ¼ 3.5, 11.8 Hz, H-3 ), 3.08
4
(
(
(
2
1
1
1
1H, d, J ¼ 5.3 Hz, 9-OH), 2.94 (1H, dq, J ¼ 2.6, 7.1 Hz, H-2), 2.79
H-F
3
3H, s, NMe), 2.71 (1H, dd, J ¼ 7.8 Hz, J
H-F
¼ 13.4 Hz, H-7a), 2.64
H-F
H-H
3
1H, s, br, 3-OH), 2.22 (1H, dd, JH-H ¼ 13.4 Hz, J ¼ 24.0 Hz, H-7b),
0
.06–1.98 (3H, m, H-4, H-10, H-4 a), 1.78 (1H, ddq, J ¼ 3.5, 7.4,
4.1 Hz, H-14a), 1.64 ꢀ 1.59 (1H, m, H-14b), 1.60 (3H, s, Me at C-6),
3
0
.56 (3H, d, J ¼ 23.1 Hz, Me at C-8), 1.51 ꢀ 1.43 (1H, m, H-4 b),
H-F
0
.47 (3H, s, Me at C-12), 1.32 (3H, d, J ¼ 6.2 Hz, Me at C-5 ), 1.16
(
3H, d, J ¼ 7.1 Hz, Me at C-2), 1.13 ꢀ 1.10 (6H, m, Me at C-4 and
3
1
3
C-10), 0.92 (3H, t, J ¼ 7.5 Hz, H-15a-c); C NMR d 125 MHz, CDCl ):
(
178.9 (C-1), 159.4 [O-(C¼O)-N], 153.5 [O-(C¼O)-O], 105.5 (d,
C-F C-F
2
1
0
J
¼ 18.4 Hz, C-9), 101.3 (d, J ¼ 189.1 Hz, C-8), 98.2 (C-1 ), 86.4
3
0
(
C-5), 84.9 (C-12), 84.3 (d, J ¼ 7.6 Hz, C-6), 81.2 (C-11), 78.9 (C-2 ),
C-F
0
0
2
7
C-7), 42.3 (C-2), 38.6 (C-10), 38.0 (C-4), 36.3 (C-4 ), 30.0 (NMe), 29.3
8.4 (C-13), 71.9 (C-3), 71.3 (C-5 ), 61.1 (C-3 ), 48.4 (d, J ¼ 22.5 Hz,
C-F
0
2
(
at C-5 ), 15.3 (Me at C-4), 14.8 (Me at C-12), 10.7 (Me at C-2), 10.2
Me at C-6), 22.4 (d, J ¼ 26.7 Hz, Me at C-8), 22.3 (C-14), 20.7 (Me
C-F
0
(
C-15), 8.8 (Me at C-10); MS, ESI pos. m=z (% rel. int.): 654.3 (6,
þ
[
M þ Na ]), 619.9 (8), 601.9 (8), 591.9 (13), 578.9 (41), 569.9 (74), 555.9
(
38), 537.8 (100), 523.8 (5), 386.9 (7).
ACKNOWLEDGMENTS
We thank the Norwegian Research Council and Alpharma AS for
financial support and a research fellowship (A. H.).
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1913
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