A cross metathesis-based synthesis of analogues of the 2-O-alkyl glycerate part of the moenomycins

Article abstract of DOI:10.1016/S0040-4020(01)00988-7

Conditions are reported which allow to convert optically active methyl glycerate to the 2-O-allyl derivative without racemization. Cross metathesis reactions then lead to analogues of the 2-O-alkyl glycerate part of the moenomycin antibiotics.

Full text of DOI:10.1016/S0040-4020(01)00988-7

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 9737±9742
A cross metathesis-based synthesis of analogues of the 2-O-alkyl
glycerate part of the moenomycins
Uwe Eichelberger,a Madina Mansourova,a Lothar Hennig,a Matthias Findeisen,a Sabine Giesa,a
b
Dietrich Muller and Peter Welzel
a,p
È
a
È È
Fakultat fur Chemie and Mineralogie, Universitat Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Institut fur Analytische Chemie, Ruhr-Universitat Bochum, D-44780Bochum, Germany
È
b
È
È
Received 2 August 2001; revised 1 October 2001; accepted 10 October 2001
AbstractÐConditions are reported which allow to convert optically active methyl glycerate to the 2-O-allyl derivative without racemi-
zation. Cross metathesis reactions then lead to analogues of the 2-O-alkyl glycerate part of the moenomycin antibiotics. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
action has led to the conclusion that they are anchored to
the cytoplasmic membrane via their lipid chain and are then
highly selectively recognized at their sugar part by the bind-
ing site of the growing peptidoglycan strand which forms
the glycosyl donor in the transglycosylation reaction4.
The peptidoglycan layer is an important component of
bacterial cell walls. It consists of carbohydrate strands
with peptide crosslinks. The ®nal two steps in the assembly
of peptidoglycan from a disaccharide±oligopeptide inter-
mediate, a transglycosylation and a transpeptidation, occur
at the extracellular face of the cytoplasmic membrane. The
enzymes that catalyse these reactions are members of
the penicillin binding protein 5PBP) family.1 The only
compounds known with certainty2 to inhibit the transglyco-
sylase domain of bifunctional PBPs such as PBP 1a and 1b
5at nanomolar concentrations) are the moenomycins 5see
moenomycin A, 13) 5Scheme 1). Work on their mode of
Although membrane association is of prime importance for
the antibiotic activity it also causes the poor pharmaco-
kinetics of the moenomycins which has prevented their
use in human medicine so far.5
These facts demand to de®ne in detail the in¯uence of
different lipid chains on the antibiotic activity as well as
on the pharmacokinetics.
Scheme 1.
Keywords: antibiotics; alkylation; allyl ether; con®guration; metathesis.
Corresponding author. Tel.: 149-0-341-97-36551; fax: 149-0-341-97-36599; e-mail: welzel@organik.chemie.uni-leipzig.de
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00988-7

9738
U. Eichelberger et al. / Tetrahedron 57 62001) 9737±9742
Scheme 2.
Two approaches have been taken on to gain access to
moenomycin analogues with altered lipid chains, one modi-
fying moenomycin itself,6,7 the other one being based on
synthesis commencing from 2-O-alkyl glycerates.8 Neither
of these methods has been particularly successful so far.
2. Results and discussion
As already mentioned alkylation of suitably protected
glyceric acid esters suffers from poor yields caused by
elimination. On the other hand direct alkylation seems to
be the most direct way to 2-O-alkyl glycerates. If instead of
an alkyl halide an allyl halide would be used two advantages
are obvious, 5i) the greater reactivity of allyl halides in
comparison to alkyl halides, and 5ii) the opportunity of
using the allyl double bond to perform cross metathesis
reactions 5CMR)12 and, thus, introduce really an element
of library synthesis. These ideas could be reduced to
practice.
The synthesis of 2-O-alkyl glycerates is not straightforward
since these b-hydroxy carboxylic acids are very prone to
elimination. One route that avoids the elimination problem
commences from d-mannitol and involves 5i) protection of
the 1-, 3-, 4-, 6-OH groups, 5ii) alkylation of the OH-groups
at C-2 and C-5, 5iii) removal of the protecting groups,
5iv) glycol cleavage, and 5v) oxidation of the intermediate
2-O-alkylglyceraldehydes.9 This sequence is lengthy, and
it provides, when conducted as described, only one enantio-
meric series.10
Both methyl 5S)- and 5R)-glycerate 52a and ent-2a, obtained
from the corresponding acetonides) have been selectively
protected at the 3-position to give their 4,40-dimethoxytrityl
ethers 2b and ent-2b. The silver oxide-mediated allyl-
ation reaction with allyl bromide proceeded completely
eventually and provided the 2-O-allyl derivatives 3a and
ent-3a in more than 90% yield. The protecting group was
removed with 80% acetic acid at 208C to provide 3b and
ent-3b in about 90% yield. The two enantiomers were
converted into their respective Mosher esters on reaction
with 5S)-52)-3,3,3-tri¯uoro-2-methoxy-2-phenyl-propionyl
chloride. NMRrevealed that no racemization had occurred
in the course of the allylation reaction 5in the limits of the
NMRanalysis). In a model experiment 3a and 1-hexa-
decene were submitted to CMR13 under the in¯uence of
A second synthetic route is based on the hydroxymethyl-
ation of chiral enolates. The synthesis is ¯exible and permits
the preparation of structurally diverse 2-O-substituted
glycerates in both enantiomeric series. But the stereoselec-
tive hydroxymethylation is auxiliary-based and involves
with the attachment and removal of the of the auxiliary
two `unproductive' steps.11
Thus, there is much room for ®nding more ef®cient pro-
cedures for the synthesis of 2-O-alkylated glycerates
which, in addition, might be useful for the parallel synthesis
of analogue libraries.
Scheme 3.

U. Eichelberger et al. / Tetrahedron 57 62001) 9737±9742
9739
the Grubbs catalyst 5bis5tricyclohexylphosphine)benzilidine
ruthenium5IV) dichloride)12 5Scheme 2). The reaction
product 4c was obtained in 58% yield as a single 5E)-stereo-
isomer. Removal of the dimethoxytrityl group was achieved
under the conditions described above and furnished 4d in
93% yield. When the CMRwas performed with 3a and
styrene, 4a was obtained in 54% yield again as a single
5E)-isomer. The sample contained an impurity that could
not be removed. We were unable to determine the structure
of this impurity. Acetic acid removed the dimethyoxytrityl
protecting group to provide pure 4b after chromatographic
separation in 88% yield.
CH2Cl2 was added and the organic phase was sequentially
washed with water, saturated aq. NaHCO3 and saturated aq.
NaCl. After drying, solvent evaporation and FC 5toluene/
acetone 9:1) 2b was obtained as a colourless oil 53.20 g,
25
70%). [a]D ˆ13.97 5cˆ8.20, CHCl3). IR5KBr): 3469,
2951, 1742, 1606, 1507, 1248, 1178, 1033, 829,
1
756 cm21. H NMR5200 MHz, CDCl ): dˆ3.21 5d, 1H,
3
0
OH, JOH,2ˆ7.7 Hz), 3.37 5dd, 1H, 3-H, J3,3 ˆ9.4 Hz, J3,2ˆ
3.4 Hz), 3.48 5dd, 1H, 3-H0, J3 ,2ˆ2.9 Hz), 3.78 5s, 3H,
0
COOCH3), 3.79 5s, 6H, 2£Ar±O±CH3), 4.24±4.33 5m,
1H, 2-H), 6.79±7.45 5m, 13H, Ar±Hs). 13C NMR5APT,
50.3 MHz, CDCl3): dˆ52)52.88 5COOCH3), 52)55.64
52£Ar±O±CH3), 51)65.59 5C-3), 52)71.26 5C-2),
51)86.34 5CH2±O±Cquart), 52)113.65 54, C-3Ar±OMe
,
It turned out that removal of the 3-O-protecting group prior
to the CMRdid not impair the yields very much. Thus,
cross-coupling products 7a±d have been obtained from
ent-3b in respectable yields. In all these cases mixtures of
5E)- and 5Z)-disubstituted ole®ns have been isolated. From
these results we are led to the conclusion that the dimeth-
oxytrityloxy substituent in the 3-position in¯uences the
steric outcome of the CMRappreciably in this series
5Scheme 3).
C-5Ar±OMe), 52)127.36 5C-4Ph), 52)128.37 52, C-3Ph,
C-5Ph), 52)128.59 52, C-2Ph, C-6Ph), 52)130.53 54,
C-2Ar±OMe, C-6Ar±OMe), 51)136.24 5C-1Ar±OMe), 51)136.30
5C-10Ar±OMe),
51)145.14
5C-1Ph),
51)159.09
52,
C-4Ar±OMe), 51)174.14 5C-1). C25H26O6 5422.47, 422.17),
EI MS: m/z 5%)ˆ422 [M]1z 515), 303 5100). HRMS:
calc. 422.1729, found 422.1734. ent-2b was prepared
accordingly.
Finally, catalytic hydrogenation of 7a±d provided the
desired 2-O-alkyl glycerates 6a±d in practically quanti-
tative yields.
3.1.3. Methyl %S)-2-O-allyl-3-O-dimethoxytrityl)-glyce-
rate %3a). To a solution of methyl 2b 50.20 g, 0.47 mmol)
in dry diethyl ether 520 mL) allyl bromide 50.11 g,
0.95 mmol) was added dropwise. The mixture was stirred
under re¯ux for 10 min and over a period of 15 min silver
oxide 50.28 g, 1.23 mmol) was added in three portions.
Stirring was continued at re¯ux for 2 h and at 208C for
48 h 5exclusion of light). Solid material was removed by
®ltration and washed several times with diethyl ether. The
combined organic solutions were worked up as usual. FC
5toluene/acetone 50:1!2:1) furnished 3a 50.20 g, 91%) as a
In conclusion, we have developed a very ef®cient route to
the 2-O-alkyl glycerate motif of transglycosylase inhibitors
of the moenomycin type that involves an element of library
synthesis. Attaching these compounds to suitable sugar
components is actively pursued.
24
colourless oil. [a]D ˆ25.68 5cˆ1.14, CHCl3). IR5KBr):
3. Experimental
3.1. General
3478, 2950, 1747, 1607, 1507, 1249, 1177, 1033, 830,
1
756 cm21. H NMR5HH COSY, HOMO DECOUPLING,
200 MHz, CDCl3): dˆ3.41 5d, 2H, CH2-3, J3,2ˆ4.9 Hz),
3.76 5s, 3H, COOCH3), 3.79 5s, 3H, Ar±O±CH3), 3.80 5s,
0
For general methods and instrumentation, see Ref. 14.
3H, Ar±O±CH3), 4.05 5ddt, 1H, 1all-H, J1,1 ˆ12.8 Hz, J1,2ˆ
5.4 Hz, J1,3ˆ1.4 Hz), 4.13 5t, 1H, 2-H), 4.22 5ddt, 1H,
1all-H0), 5.23 5ddt, 1H, 3all-Hcis, J3all cis,3all transˆ1.8 Hz,
J3all cis,2allˆ10.3 Hz, J3all cis,1allˆ1.3 Hz), 5.33 5ddt, 1H,
3.1.1. Methyl %S)-glycerate %2a). A solution of methyl
5S)-2,3-O-isopropylideneglycerate 52.20 g, 13.70 mmol) in
70% acetic acid 513 mL) was stirred at 208C for 48 h. The
solution was evaporated to dryness under reduced pressure.
Toluene 55 mL) was added and the solvent was evaporated.
This procedure was repeated several times until acetic acid
3all-Htrans
,
J3all trans,2allˆ17.2 Hz,
J3all trans,1allˆ1.6 Hz),
5.82±6.07 5m, 1H, 2all-H), 6.78±7.53 5m, 13H, Ar±Hs).
13C NMR5HETCO,R APT, 50.3 MHz, CDCl
3): dˆ
51)52.38 5COOCH3), 51)55.64
52£Ar±O±CH3),
was removed completely. FC 5CH2Cl2/acetone 9:1) fur-
ˆ
51)64.71 5C-3), 51)72.14 5C-1all), 52)78.35 5C-2),
51)86.57 5CH2±O±Cquart), 52)113.62, 52)113.68 54,
Ar±Cs), 51)118.30 5C-3all), 52)127.28 5Ar±C), 52)128.32
52, Ar±Cs), 52)128.69 52, Ar±Cs), 52)130.61 54, Ar±Cs),
52)134.61 5C-2all), 51)136.44 52, Ar±Cs), 51)145.29
5Ar±C), 51)159.05 52, Ar±Cs), 51)172.04 5C-1).
C28H30O6 5462.54, 462.20), EI MS: m/z 5%)ˆ462 [M]1z
511), 303 5100). HRMS: calc. 462.2042, found 462.2034.
ent-3a was prepared accordingly.
25
nished 2a as a colourless oil 51.30 g, 79%). [a]D
210.71 5cˆ1.12, CHCl3). IR5KBr): 3385, 2959, 1740,
1258, 1106, 1030 cm21 1H NMR5200 MHz, CDCl 3):
.
dˆ2.83 5bs, 1H, CH2±OH), 3.61 5bs, 1H, CH±OH), 3.81
5s, 3H, OCH3), 3.83±3.99 5m, 2H, CH2-3), 4.28 5t, 1H, 2-H,
J2,3ˆ3.3 Hz). 13C NMR550.3 MHz, CDCl 3): dˆ53.25
5OCH3), 64.47 5C-3), 72.14 5C-2), 174.05 5C-1). C4H8O4
5120.10, 120.04), EI MS: m/z 5%)ˆ120 [M]1 5,1), 90
5100). HRMS: calc. 120.0423, found 120.0423. ent-2a was
prepared in the same way.
3.1.4. Methyl %S)-2-O-allyl-glycerate %3b). A solution of
3a 580 mg, 0.17 mmol) in 80% acetic acid 510 mL) was
stirred at 208C for 3 h. The reaction mixture was then
diluted with a pyridine/water mixture and evaporated. Dry
pyridine 55 mL) was added and the solvent was removed
under reduced pressure. FC 5CH2Cl2/acetone 50:1!1:1)
3.1.2. Methyl %S)-3-O-dimethoxytrityl-glycerate %2b). A
solution of 4,40-dimethoxytrityl chloride 54.66 g, 12.00
mmol) in dry THF 520 mL) was added dropwise to a solu-
tion of 2a 51.30 g, 11.00 mmol) in dry pyridine 520 mL) at
258C. The mixture was stirred at 258C for 16 h. Then

9740
U. Eichelberger et al. / Tetrahedron 57 62001) 9737±9742
provided 3b 524.3 mg, 89%) as
a
colourless oil.
5CH3-170), 51)22.84, 51)29.18, 51)29.36, 51)29.40,
51)29.51, 51)29.66, 51)29.76, 51)29.83, 51)32.07
5C-5hd±C16hd), 51)32.46 5C-4hd), 52)52.06 5COOCH3),
52)55.32 52, Ar±Cs), 51)64.34 5C-3), 51)71.67 5C-1hd),
52)77.50 5C-2), 51)86.17 5CH2±O±Cqu), 52)113.19,
52)113.28 54, Ar±Cs), 52)125.55 5C-2hd), 52)126.83,
52)127.88, 52)128.27, 52)129.25 55, Ar±Cs), 52)130.19
54, Ar±Cs), 51)136.02 52, Ar±Cs), 52)136.06 5C-3hd),
51)144.86 5Ar±C), 51)158.56, 51)158.74 52, Ar±Cs),
51)171.81 5C-1). C21H40O4 5658.92, 658.42), ESI MS:
C42H58NaO6 [M1Na]1: calc. 681.4133, found 681.4125.
25
[a]D ˆ26.59 5cˆ0.97, CHCl3). IR5KBr): 3458,
2959, 1743, 1259, 1114, 797 cm21 1H NMR5HOMO
.
DECOUPLING, 200 MHz, CDCl3): dˆ2.23 5t, 1H, OH),
3.78 5s, 3H, OCH3), 3.79±3.92 5m, 2H, CH2-3), 4.02 5ddt,
0
1H, 1all-H, J1,1 ˆ12.5 Hz, J1,2ˆ6.0 Hz, J1,3ˆ1.5 Hz), 4.06 5t,
1H, 2-H, J2,3ˆ4.8 Hz), 4.28 5ddt, 1H, 1all-H0), 5.24 5ddt, 1H,
3all-Hcis, J3all cis,3all-transˆ1.3 Hz, J3all cis,2allˆ10.6 Hz, J3all cis,1all
ˆ
1.3 Hz), 5.31 5ddt, 1H, 3all-Htrans, J3all trans,2allˆ17.2 Hz),
5.83±6.05 5m, 1H, 2all-H). 13C NMR5APT, 50.3 MHz,
CDCl3): dˆ52)54.14 5OCH3), 51)65.42 5C-3), 51)73.90
5C-1all), 52)80.46 5C-2), 51)120.39 5C-3all), 52)135.67
5C-2), 51)173.09 5C-1). C7H12O4 5160.16, 160.07), EI MS:
m/z 5%)ˆ160 [M]1z 5,1), 130 55), 41 5100). HRMS: calc.
160.0736, found 160.0744. ent-3b was prepared accordingly.
3.1.7. Methyl %S)-2-O-%%E)-2-heptadecen-1-yl)-glycerate
%4d). 4c 5180 mg, 0.27 mmol) was deprotected as described
for 3a. FC 5petroleum ether/ethyl acetate 5:1) provided 4d
25
589.7 mg, 0.25 mmol, 93%) as a colourless oil. [a]D
ˆ
3.1.5. Methyl %R)-2-O-allyl-1-O-%%S)-3,3,3-tri¯uoro-2-
methoxy-2-phenyl-propionyl)-glycerate %5). The mixture
of ent-3b 525 mg, 0.16 mmol), 5S)-52)-3,3,3-tri¯uoro-2-
methoxy-2-phenyl-propionyl chloride 550 mL, 0.4 mmol,
2.5 equiv.), triethylamine 5100 mL) and a catalytic amount
of N,N-dimethylaminopyridine in CH2Cl2 50.5 mL) was
stirred under argon for 14 h. TLC indicated the formation
of only one compound. The solvents were evaporated.
Removal of excess reagent by FC 5petroleum ether/ethyl
25.88 5cˆ2.54, CHCl3). IR5KBr): 3471, 2924, 1747,
1466, 1436, 1207, 1124, 1066, 974 cm21
.
1H NMR
5200 MHz, CDCl3): dˆ0.88 5t, 3H, CH3-17hd, Jˆ6.4 Hz),
1.20±1.48 5m, 24H, CH2-5hd±CH2-16hd), 1.95±2.12 5m, 2H,
CH2-4hd), 3.77 5s, 3H, OCH3), 3.75±3.90 5m, 1H, 3-H), 3.84
3
5t, 1H, 3-H, J2,3ˆ5.9 Hz), 3.97 5dd, 1H, 1hd-H, 2Jˆ11.7 Hz,
3
Jˆ6.6 Hz), 4.06 5dd, 1H, 3-H0, J3 ,2ˆ3.7 Hz), 4.21 5dd, 1H,
0
1hd-H, 3Jˆ5.9 Hz), 5.56, 5.74 52£dt, 2H, 2hd-H, 3hd-H,
3Jˆ15.4 Hz). 13C NMR5APT, 50.3 MHz, CDCl 3): dˆ
52)14.24 5CH3-170), 51)22.82, 51)29.10, 51)29.34,
51)29.48, 51)29.61, 51)29.73, 51)29.81, 51)32.05
5C-5hd±C-16hd), 51)32.39 5C-4hd), 52)52.21 5OCH3),
51)63.53 5C-3), 51)71.88 5C-1hd), 52)78.12 5C-2),
52)125.17 5C-2hd), 52)136.77 5C-3hd), 51)171.38 5C-1).
C21H40O4 5356.54, 356.29). ESI MS: C42H80NaO8 [2M1
Na]1: calc. 735.57454, found 735.57406.
acetate, 3:1) furnished
5
530 mg, 56%). 1H NMR
5200 MHz, CDCl3): dˆ7.56±7.38 5m, 5H, Ar±Hs), 5.81±
5.77 5m, 1H, CHvCH2), 5.32±5.17 5m, 2H, CHvCH2),
4.71±4.49 5m, 2H, CH2O), 4.25±4.16 5m, 2H, CH±
COOCH3, CH±OCHH0 ±CHvCH2), 4.04±3.94 5m, 1H,
OCHH0 ±CHvCH2), 3.74 5s, 3H, COOCH3), 3.56 5s, 3H,
CF3±C±OCH3). 13C NMR550.3 MHz, CDCl ): dˆ169.88
3
5COOCH3), 166.34 5OCOCqu), 133.63, 132.24 5CHvCH2),
129.75, 128.52, 127.64 5Ar±Cs), 118.34 5CHvCH2), 75.66
5CH±COOCH3), 71.97 5O±CH2±CHvCH2), 65.70 5CH2±
O), 55.67 5CF3±CO±CH3), 52.14 5COOCH3). 19F NMR
5188.3 MHz, CDCl3): dˆ4.49. 19F NMR5282.3 MHz,
C6D6): dˆ5.86. 3c was prepared accordingly. 5 and 3c
were indistinguishable by TLC, but in benzene solution
the 19F signals of the two diasteroisomers were well
separated.
3.1.8. Methyl %S)-3-O-dimethoxytrityl-2-O-%%E)-3-phenyl-
2-propen-1-yl)-glycerate %4a). 3a 575 mg, 0.16 mmol) and
styrene 533 mg, 0.32 mmol), bis5tricyclohexylphosphine)-
benzilidine ruthenium5IV) dichloride 57.24 mg, 8£
1024 mmol) was performed as described for 4c. FC
5toluene/acetone 50:1) furnished 4a 546.80 mg, 54%) as a
25
colourless oil. [a]D ˆ27.56 5cˆ3.82, CHCl3). IR5KBr):
3465, 2927, 1745, 1606, 1506, 1446, 1296, 1248, 1176,
1124, 1032, 829 cm21 1H NMR5300.1 MHz, CDCl 3):
.
3.1.6. Methyl %S)-3-O-dimethoxytrityl-2-O-%%E)-2-hepta-
decen-1-yl)-glycerate %4c). Through a solution of methyl
3a 575 mg, 0.17 mmol) in dry 1,2-dichloroethane 55 mL)
nitrogen was bubbled to remove oxygen. Bis5tricyclohexyl-
phosphine)benzilidine ruthenium5IV) dichloride 5STREM,
7.24 mg, 8£1024 mmol) was added. Under a stream of
nitrogen 1-hexadecene 579.70 mg, 0.34 mmol) was added
and the mixture was stirred under nitrogen for 72 h at
208C. After solvent evaporation and FC 5toluene/acetone
50:1) 4c 536.73 mg, 58%) was obtained as a colourless
dˆ3.42 5d, 2H, CH2-3, J3,2ˆ4.9 Hz), 3.73 5s, 3H,
COOCH3), 3.78 5s, 6H, 2£Ar±O±CH3), 4.16 5t, 1H, 2-H,
J2,3ˆ5.1 Hz), 4.21 5dd, 1H, 1prop-H, 2Jˆ11.9 Hz, 3Jˆ
3
6.5 Hz), 4.36 5dd, 1H, 1prop-H0, Jˆ5.9 Hz), 6.30 5dt, 1H,
2
prop-H, J2,3ˆ15.9 Hz, J2,1ˆ6.0 Hz), 6.63 5d, 1H, 3prop-H),
6.78±7.50 5m, 18H, Ar±Hs). 13C NMR5APT, 75.5 MHz,
CDCl3): dˆ52)52.11 5COOCH3), 52)55.33 52£Ar±O±
CH3), 51)64.44 5C-3), 51)71.49 5C-1prop), 52)77.97 5C-2),
51)86.28 5CH2±O±C), 52)113.25, 52)113.32 54, Ar±Cs),
52)125.48 5C-2prop), 52)126.72, 52)127.21, 52)127.93,
52)128.32, 52)128.70, 52)129.28 510£CPh), 52)130.22
54, Ar±Cs), 52)133.33 5C-3prop), 51)136.03 52, Ar±Cs),
51)139.63, 51)144.86 52, Ar±Cs), 51)158.63, 52, Ar±Cs),
25
oil. [a]D ˆ26.08 5cˆ1.26, CHCl3). IR5KBr): 2924,
2850, 1751, 1606, 1506, 1458, 1298, 1250, 1207, 1178,
1
829 cm21. H NMR5HOMO DECOUPLING, 200 MHz,
CDCl3): dˆ0.83 5t, 3H, CH3-17hd, J17,16ˆ6.4 Hz), 1.15±
1.40 5m, 24H, CH2-5hd±CH2-16hd), 1.95±2.12 5m, 2H,
CH2-4hd), 3.38 5d, 2H, CH2-3, J3,2ˆ5.1 Hz), 3.75 5s, 3H,
COOCH3), 3.79 5s, 6H, 2£Ar±O±CH3), 3.93 5dd, 1H,
51)171.64 5C-1). The second product gave H signals at
1
dˆ3.80 5s), 4.13 5dd), 4.44 5dd), and additional signals in
the aromatic region and 13C signals at dˆ52)52.29,
52)55.38, 51)64.44, 51)71.76, 52)78.59, 52)125.48,
52)126.74, 52)126.89, 52)127.98, 52)128.13, 52)128.74,
52)133.99, 51)136.70, 51)145.23, 51)158.79, 51)171.53.
C34H34O6 5538.64, 538.23), ESI MS: C34H34NaO6
[M1Na]1: calc. 561.22553, found 561.22330.
1hd-H, J1,1 ˆ12.1 Hz, J1,2ˆ6.2 Hz), 4.06 5t, 1H, 2-H), 4.06
0
5dd, 1H, 1hd-H), 5.49, 5.67 52£dt, 2H, 2hd-H, 3hd-H,
J2,3ˆ15.3 Hz), 6.78±7.50 5m, 13H, Ar±Hs). 13C NMR
5HETCOR, APT, 50.3 MHz, CDCl3): dˆ52)14.27

U. Eichelberger et al. / Tetrahedron 57 62001) 9737±9742
9741
3.1.9. Methyl %S)-2-O-%%E)-3-phenyl-2-propen-1-yl)-
glycerate %4b). Deprotection of 4a 5120 mg, 0.22 mmol)
was performed as described for 3a. FC 5petroleum ether/
ethyl acetate 5:1) gave 4b 546.2 mg, 88%) as a colourless
3.1.12. Methyl %R)-2-O-%2-dodecen-1-yl)-glycerate %7c).
ent-3b 578 mg, 0.49 mmol) and 1-undecene 50.19 mL,
0.98 mmol) were submitted to the cross metathesis as
described for 7a. Reaction time: 62 h. FC 5CH2Cl2/acetone
20:1) furnished 7c 565 mg, 47%, 5E)-/5Z)-isomers). Rf: 0.65
25
oil. [a]D ˆ210.42 5cˆ1.16, CHCl3). IR5KBr): 3442,
2949, 1743, 1446, 1272, 1207, 1128, 1065, 972,
.
5toluene/acetone 9:1). IR5®lm): 3394 5OH), 1739
744 cm21
1H, OH), 3.78 5s, 3H, OCH3), 3.84 5dd, 1H, 3-H, J3,3
1H NMR5300.1 MHz, CDCl 3): dˆ2.16 5bs,
11.7 Hz, J3,2ˆ5.9 Hz), 3.93 5dd, 1H, 3-H0, J3 ,2ˆ3.7 Hz),
5CvO) cm21. H NMR5200 MHz, CDCl ): dˆ5.76±5.45
1
3
0
ˆ
5m, 2H, OCH2±CHvCH), 4.30±3.76 5m, 5H, CH±
COOCH3, OCH2±CHvCH, CH2OH), 3.76 5s, 3H, OCH3),
2.22 5broad s, 1H, CH2±OH), 2.02 5m, 2H, OCH2±
CHvCH±CH2), 1.25 5m, 14H, 5CH2)7±CH3), 0.87 5t, 3H,
v-CH3). 13C NMR550.3 MHz, CDCl 3): dˆ171.40
5COOCH3), 136.75/135.40, 125.17/124.78 5O±CH2±
CHvCH), 78.43/78.15 5CH±COOCH3), 71.85 5O±CH2±
CHvCH2), 66.36/63.51 5CH2±OH), 52.20 5COOCH3),
32.39 5CHvCH±CH2±5CH2)6±), 32.01, 29.67, 29.43,
29.32, 29.08, 27.70 5CHvCH±CH2±5CH2)6±), 22.80
5CH2±CH3), 14.23 5v-CH3). C16H30O4 5286.41, 286.21),
FAB MS: m/zˆ309.2 [M1Na]1.
0
4.12 5dd, 1H, 2-H), 4.21 5ddd, 1H, 1prop-H, J1,1 ˆ12.3 Hz,
0
J1,2ˆ6.8 Hz, J1,3ˆ1.2 Hz), 4.43 5ddd, 1H, 1prop-H0), 6.30 5dt,
1H, 2prop-H, J2,3ˆ15.9 Hz), 6.63 5d, 1H, 3prop-H), 7.70±7.42
5m, 5H, Ph±Hs). 13C NMR5APT, 75.5 MHz, CDCl ): dˆ
3
52)52.44 5OCH3), 51)63.69 5C-3), 51)71.89 5C-1prop),
52)78.69 5C-2), 125.00 5C-2prop), 52)126.86, 52)128.26,
52)128.86, 51)136.56 56, Ph±Cs), 134.15 5C-3prop),
51)171.64 5C-1).
3.1.10. Methyl %R)-2-O-%2-decen-1-yl)-glycerate %7a). The
mixture of ent-3b 592 mg, 0.57 mmol) and bis5tricyclo-
hexylphosphine)benzilidine ruthenium5IV) dichloride
5catalytic amount) in dichloroethane 52 mL) were stirred
at 208C for 1 h under nitrogen, bubbled directly into the
reaction mixture. Then 1-nonene 50.19 mL, 1.14 mmol)
was added and the reaction mixture was stirred under the
same conditions for 62 h. Solid material was removed by
®ltration. The ®ltrate was evaporated. FC 5CH2Cl2/acetone
20:1) furnished 7a as a mixture of 5E)-/5Z)-isomers.
50.105 g, 70%). Rf: 0.65 5toluene/acetone 9:1). IR5®lm):
3.1.13. Methyl %R)-2-O-%2-tridecen-1-yl)-glycerate %7d).
ent-3b 5100 mg, 0.62 mmol) and 1-dodecene 5208 mg,
0.274 mL, 1.24 mmol) were submitted to the cross meta-
thesis as described for 7a. Reaction time: 62 h. FC
5CH2Cl2/acetone 20:1) 7d 576 mg, 41%, 5E)-/5Z)-isomers),
51% based on consumed ent-3b), 20 mg 520%) of ent-3b
were recovered. Rf: 0.65 5toluene/acetone 9:1). IR5®lm):
3444 5OH), 1747 5CvO) cm21 1H NMR5200 MHz,
.
CDCl3): dˆ5.80±5.45 5m, 2H, OCH2±CHvCH), 4.30±
3.80 5m, 5H, CH±COOCH3, OCH2±CHvCH, CH2OH),
3.77 5s, 3H, OCH3), 2.04 5m, 2H, OCH2±CHvCH±CH2),
1.26 5m, 16H, 5CH2)7±CH3), 0.87 5t, 3H, v-CH3). 13C NMR
550.3 MHz, CDCl3): dˆ171.15 5COOCH3), 136.71/135.42,
125.28/124.88 5O±CH2±CHvCH), 78.49/78.22 5CH±
COOCH3), 71.91 5O±CH2±CHvCH2), 66.46/63.571
5CH2±OH), 52.19 5COOCH3), 32.42 5CHvCH±CH2±
5CH2)5±CH2±CH3), 32.06, 29.76, 29.63, 29.48, 29.36,
29.14, 27.76 5CHvCH±CH2±5CH2)7±CH2±CH3), 22.83
5CH2±CH3), 14.23 5v-CH3). C17H32O4 5300.43, 300.23),
FAB MS: m/zˆ323.3 [M1Na]1.
3347 5OH), 1706 5CvO) cm21 1H NMR5200 MHz,
.
CDCl3): dˆ5.80±5.40 5m, 2H, OCH2±CHvCH), 4.16±
3.73 5m, 5H, CH±COOCH3, OCH2±CHvCH, CH2OH),
3.75 5s, 3H, OCH3), 2.30 5broad s, 1H, CH2±OH), 2.02
5m, 2H, OCH2±CHvCH±CH2), 1.25 5m, 10H, 5CH2)5±
CH3), 0.86 5t, 3H, v-CH3). 13C NMR550.3 MHz, CDCl ):
3
dˆ171.41 5COOCH3), 136.75/135.39, 125.17/124.78 5O±
CH2±CHvCH), 78.15 5CH±COOCH3), 71.84 5O±CH2±
CHvCH2), 64.02/63.49 5CH2±OH), 52.20 5COOCH3),
32.38 5CHvCH±CH2±5CH2)5±), 31.92, 29.27, 29.07,
27.70 5±CHvCH±CH2±5CH2)4±), 22.76 5CH2±CH3),
14.21 5v-CH3). C14H26O4 5258.35, 258.18), FAB MS:
m/zˆ281.2 [M1Na]1.
3.1.14. Methyl %R)-2-O-decyl-glycerate %6a). A mixture of
7a 570 mg, 0.26 mmol), methanol 54 mL), 5% Pd/C 5cata-
lytic amount) was stirred under hydrogen at 208C and
atmospheric pressure. After the reaction was complete
51 h, TLC: CH2Cl2/acetone 10:1), the mixture was ®ltered
5Celitew) and the solvent was evaporated. FC 5CH2Cl2/
acetone 10:1) furnished 6a 570 mg, 99%). Rf: 0.65 5C2H2/
3.1.11. Methyl %R)-2-O-%2-undecen-1-yl)-glycerate %7b).
ent-3b 5109 mg, 0.68 mmol) and 1-decene 50.26 mL,
1.36 mmol) were submitted to the cross metathesis as
described for 7a. Reaction time: 40 h. FC 5CH2Cl2/acetone
10:1) provided 7b 587 mg, 50%, mixture of 5E)-/5Z)-
isomers, 92% based on consumed ent-3b), 0.05 g 545%)
of ent-3b were recovered. Rf: 0.65 5toluene/acetone 9:1).
1
acetone 10:1). IR5®lm): 3392 5OH), 1739 5CO) cm 21. H
NMR5HH COSY, CDCl 3): dˆ3.99±3.64 5m, 4H,
CH±COOCH3, CH2OH, OCH2), 3.76 5s, 3H, OCH3),
3.46±3.38 5m, 1H, OCH2), 2.22 5broad s, 1H, CH2±OH),
1.60 5m, 2H, OCH2CH2±C8H17), 1.25 5m, 14H, 5CH2)7±
1
IR5®lm): 3475 5OH), 1745, 1706 5C vO) cm21. H NMR
5200 MHz, CDCl3): dˆ5.75±5.39 5m, 2H, OCH2±
CHvCH), 4.10 5d, 1H, CH±COOCH3), 4.10±3.99 5m,
2H, OCH2±CHvCH), 3.96±3.80 5m, 2H, CH2OH), 3.76
5s, 3H, OCH3), 2.04 5broad s, 1H, CH2±OH), 2.03 5m, 2H,
OCH2±CHvCH±CH2), 1.24 5m, 12H, 5CH2)6±CH3), 0.87 5t,
3H, v-CH3). 13C NMR550.3 MHz, CDCl 3): dˆ171.40
5COOCH3), 136.73/135.35, 125.18/124.98 5O±CH2±
CHvCH), 78.15 5CH±COOCH3), 71.85 5O±CH2±
CHvCH2), 63.51 5CH2±OH), 52.19 5COOCH3), 32.38
5CHvCH±CH2±5CH2)5±), 31.98, 29.54, 29.40, 29.36, 29.07
5CHvCH±CH2±5CH2)5±), 22.78 5CH2±CH3), 14.21 5v-CH3).
C15H28O4 5272.38, 272.20), FAB MS: m/zˆ295.2 [M1Na]1.
CH3), 0.86 5t, 3H, v-CH3). 13C NMR550.3 MHz, CDCl ):
3
dˆ171.39 5COOCH3), 79.74 5CH±COOCH3), 71.54
5O±CH2±C9H19), 63.53 5CH2±OH), 52.06 5COOCH3),
31.99, 29.78, 29.67, 29.52, 29.40, 26.08, 22.78 5OCH2±
5CH2)7±), 22.77 5CH2±CH3), 14.16 5v-CH3). C14H28O4
5260.37, 260.20), ESI MS: [M1H]1 calc. 261.20658,
found 261.20595, [M1Na]1 calc. 283.18853, found
283.18791, [2M1Na]1 calc. 543.38729, found 543.38672.
3.1.15. Methyl %R)-2-O-undecyl-glycerate %6b). 7b

9742
U. Eichelberger et al. / Tetrahedron 57 62001) 9737±9742
580 mg, 0.29 mmol) was hydrogenated as described above.
Reaction time: 40 min 5TLC: CH2Cl2/acetone, 10:1). FC
5CH2Cl2/acetone 10:1) provided 6b 575 mg, 92%).
Acknowledgements
We thank G. Reinhardt for running some of the FAB mass
spectra. The Leipzig group gratefully acknowledges
®nancial support by the Deutsche Forschungsgemeinschaft,
BC Biochemie GmbH 5Frankfurt), and the Fonds der
Chemischen Industrie.
25
[a]D ˆ132 5c 0.04, CHCl3). Rf: 0.60 5C2H2/acetone
1
10:1). IR5®lm): 3450 5OH), 1660 5C vO) cm21. H NMR
5200 MHz, CDCl3): dˆ4.02±3.70 5m, 3H, CH±COOCH3,
CH2OH), 3.79 5s, 3H, OCH3), 3.50±3.41 5m, 2H, OCH2),
2.22 5broad s, 1H, CH2±OH), 1.64 5m, 2H, OCH2CH2±
C9H19), 1.29 5m, 16H, 5CH2)8±CH3), 0.90 5t, 3H, v-CH3).
13C NMR550.3 MHz, CDCl 3): dˆ171.43 5COOCH3), 79.74
5CH±COOCH3), 71.54 5O±CH2±C10H21), 63.52 5CH2±
OH), 52.12 5COOCH3), 32.01, 29.76, 29.71, 29.67, 29.52,
29.43, 26.07 5OCH2±5CH2)8±CH2±CH3), 22.78 5CH2±
CH3), 14.19 5v-CH3). C15H30O4 5274.40, 274.21), ESI
MS: [M1Na]1 calc. 297.20418, found 297.20355,
[2M1Na]1 calc. 571.41859, found 571.41816.
References
1. Review: Bugg, T. H. D. Comprehensive Natural Products
Chemistry; Barton, D., Nakanishi, K., Eds.; Elsevier Science:
Amsterdam, 1999; Vol. 3, pp. 241±294.
2. Review: van Heijenoort, J. Glycobiology 2001, 13, 25R±36R.
È
3. Donnerstag, A.; Marzian, S.; MuÈller, D.; Welzel, P.; Bottger,
D.; Stark, A.; Fehlhaber, H. W.; Markus, A.; van Heijenoort,
È
Y.; van Heijenoort, J. Tetrahedron 1995, 51, 1931±1940 and
references therein.
3.1.16. Methyl %R)-2-O-dodecyl-glycerate %6c). 7c 550 mg,
0.17 mmol) was hydrogenated as described above. Reaction
time: 30 min 5TLC: CH2Cl2/acetone 10:1). FC 5CH2Cl2/
acetone 10:1) furnished 6c 547 mg, 93%). Rf: 0.57 5C2H2/
4. El-Abadla, N.; Lampilas, M.; Hennig, L.; Findeisen, M.;
Welzel, P.; MuÈller, D.; Markus, A.; van Heijenoort, J.
Tetrahedron 1999, 55, 699±722 and references therein.
5. See: 5a) Anikin, A.; Buchynskyy, A.; Kempin, U.; Stembera,
K.; Welzel, P.; Lantzsch, G. Angew. Chem. 1999, 111, 3931±
3935; Angew. Chem., Int. Ed. Engl. 1999, 38, 3703±3707.
6. Vogel, S.; Stembera, K.; Hennig, L.; Findeisen, M.; Giesa, S.;
Welzel, P.; Lampilas, M. Tetrahedron 2001, 57, 4139±4146.
7. Vogel, S.; Stembera, K.; Hennig, L.; Findeisen, M.; Giesa, S.;
Welzel, P.; Tillier, C.; Bonhomme, S.; Lampilas, M.
Tetrahedron 2001, 57, 4147±4160.
1
acetone 10:1). IR5®lm): 1652 5CO), 1589 cm 21. H NMR
5200 MHz, CDCl3): dˆ4.00±3.68 5m, 4H, CH±COOCH3,
CH2OH, OCH2), 3.76 5s, 3H, OCH3), 3.40 5m, 1H, OCH2),
2.19 5broad s, 1H, CH2±OH), 1.61 5m, 2H, OCH2CH2±
5CH2)9±), 1.25 5m, 18H, 5±CH2)9±), 0.87 5t, 3H, v-CH3).
13C NMR550.3 MHz, CDCl 3): dˆ171.40 5COOCH3), 79.76
5CH±COOCH3), 71.56 5O±CH2±C11H23), 63.55 5CH2±
OH), 52.08 5COOCH3), 32.04, 29.77, 29.68, 29.54, 29.10,
26.11 5OCH2±5CH2)9±), 22.80 5CH2±CH3), 14.18 5v-CH3).
C16H32O4 5288.42, 288.23), FAB MS: m/zˆ289.3 [M1H]1,
311.2 [M1Na]1.
8. See, for example 5a) Schubert, T.; Welzel, P. Angew. Chem.
1982, 94, 135±136; Angew. Chem., Int. Ed. Engl. 1982, 21,
137±138. 5b) Hecker, S. J.; Minich, M. L.; Lackey, K. J. Org.
Chem. 1990, 55, 4904±4911.
3.1.17. Methyl %R)-2-O-tridecyl-glycerate %6d). Methyl
5R)-2-O-5tridec-2-enyl)-glycerate 7d 560 mg, 0.20 mmol)
was hydrogenated as described above. Reaction time:
30 min 5TLC: CH2Cl2/acetone 10:1). FC 5CH2Cl2/acetone
9. Schubert, T.; Kunisch, F.; Welzel, P. Tetrahedron 1983, 39,
2211±2217.
10. Peters, U.; Bankova, W.; Welzel, P. Tetrahedron 1987, 43,
3803±3816.
25
10:1) furnished 6d 559 mg, 98%). [a]D ˆ172 5c 0.03,
11. Eichelberger, U.; Neundorf, I.; Hennig, L.; Findeisen, M.;
Giesa, S.; MuÈller, D.; Welzel, P. Tetrahedron, submitted for
publication.
CHCl3). Rf: 0.55 5CH2Cl2/acetone 10:1). IR5®lm): 3388
5OH), 1743 5CO) cm21 1H NMR5200 MHz, CDCl 3):
.
dˆ4.00±3.68 5m, 4H, CH±COOCH3, CH2OH, OCH2),
3.76 5s, 3H, OCH3), 3.40 5m, 1H, OCH2), 2.13 5broad s,
1H, OH), 1.59 5m, 2H, OCH2CH2±5CH2)10±), 1.24 5m,
20H, 5CH2)10), 0.86 5t, 3H, v-CH3). 13C NMR550.3 MHz,
CDCl3): dˆ171.45 5COOCH3), 79.74 5CH±COOCH3),
71.57 5O±CH2±C12H25), 63.55 5CH2±OH), 52.14
5COOCH3), 32.05, 29.91, 29.81, 29.78, 29.74, 29.70,
29.54, 29.47, 26.09 5O±CH2±5CH2)10±CH2±CH3), 22.81
5CH2±CH3), 14.22 55v-CH3). C17H34O4 5302.45, 302.25),
FAB MS: m/zˆ303.2 [M1H]1, 325.2 [M1Na]1.
12. For leading references, see: Sanford, M. S.; Love, J. A.;
Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543±6554.
Ç
13. For conditions, see: Gibson 5nee Thomas), S. E.; Gibson,
V. C.; Keen, S. P. Chem. Commun. 1997, 1107±1108.
È
È
14. Weigelt, D.; Krahmer, R.; Bruschke, K.; Hennig, L.;
Findeisen, M.; MuÈller, D.; Welzel, P. Tetrahedron 1999, 55,
687±698.