Synthesis of cyclic amino acid derivatives via ring closing metathesis on a poly(ethylene glycol) supported substrate

Full text of DOI:10.1021/jo000898a

J . Org. Chem. 2000, 65, 6787-6790
6787
Sch em e 1
Syn th esis of Cyclic Am in o Acid Der iva tives
via Rin g Closin g Meta th esis on a
P oly(eth ylen e glycol) Su p p or ted Su bstr a te
Ste´phane Varray, Christine Gauzy, Fre´de´ric Lamaty,*
Rene´ Lazaro, and J ean Martinez
Laboratoire des Aminoacides, Peptides et Prote´ines (LAPP),
CNRS-Universite´s Montpellier 1 et 2,
Place Euge`ne Bataillon, 34095 Montpellier Cedex 5, France
frederic@crit.univ-montp2.fr
Received J une 12, 2000
Liquid-phase organic synthesis where soluble polymers
such as poly(ethylene glycol) (PEG) are used as polymeric
support is a practical alternative to solid-phase organic
synthesis (SPOS).1 Recently we have developed several
PEG-supported syntheses of amino acid derivatives2 and
we have studied the effect that can be induced by the
polymer. Because of its polyoxygenated structure, the
polymer exerts an influence on the reactivity of the
supported reacting center as well as on the reagents or
catalysts used during the course of the synthesis. We
have shown that a synthesis of arylglycine using orga-
nozinc reagents could not be adapted on PEG because of
the detrimental effect of the polymer.2e On the contrary,
in the case of a Heck reaction used in the synthesis of
glutamic acid analogues, PEG has an accelerating effect
on the course of the reaction.2c
tion has been adapted to SPOS,4 but to our knowledge,
no reaction of RCM on soluble PEG has been published.
In the following report, we present the results obtained
in investigating the compatibility of RCM reaction condi-
tions with the presence of PEG, and we describe the
synthesis of various amino acid derivatives using this
method.
Since our interest lies in the synthesis of amino acids
and peptidomimetics, we chose to adapt first the synthe-
sis of a cyclic amino acid,5 and we compared the results
obtained with the molecule supported on PEG with the
same reaction carried out in solution. Linear substrates
4 and 5a were synthesized as described in Scheme 1.
Since it was preferable to obtain at each step of the
synthesis on the soluble support complete conversion of
the starting material to the expected product, we decided
to use a tosyl group as a nitrogen-protecting group which
also makes the amine proton more acidic for the alkyl-
ation reaction. Tosylation of commercially available (L)-
allylglycine was adapted from a known procedure.6
Esterification of 1 with MeOH in the presence of TMSCl
yielded 2, which was smoothly N-alkylated with allyl
bromide in the presence of potassium carbonate to give
4. Bifunctional poly(ethylene glycol) with an average
mass of 3400 was used as the soluble support because it
presents the right compromise between loading and good
precipitation properties.2b Since the Ts group made
allylglycine sensitive to racemization, we preferred to
avoid classical coupling conditions and we chose a Mit-
sunobu reaction for anchoring the Ts allylglycine 1 on
both of the hydroxyl groups of the PEG to give 3.7
Alkylation with allyl bromide in the presence of potas-
sium carbonate yielded the PEG-supported N-allyl
allylglycine 5a .
Ring closing metathesis (RCM) has emerged as a
powerful tool in organic synthesis for generating cyclic
structures via C-C bond formation.3 Recently this reac-
(1) Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489.
(2) (a) Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J . Tetra-
hedron Lett. 1998, 39, 821. (b) Sauvagnat, B.; Lamaty, F.; Lazaro, R.;
Martinez, J . J . Comb. Chem. 2000, 2, 134. (c) Sauvagnat, B.; Lamaty,
F.; Lazaro, R.; Martinez, J . C. R. Acad. Paris Se´r. IIc 1998, 1, 777. (d)
Nouvet, A.; Binard, M.; Lamaty, F.; Martinez, J .; Lazaro, R. Tetrahe-
dron 1999, 55, 4685. (e) Bouifraden, S.; Drouot, C.; El Hadrami, M.;
Guenoun, F.; Lecointe, L.; Mai, N.; Paris, M.; Pothion, C.; Sadoune,
M.; Sauvagnat, B.; Amblard, M.; Aubagnac, J . L.; Calmes, M.;
Chevallet, P.; Daunis, J .; Enjalbal, C.; Fehrentz, J . A.; Lamaty, F.;
Lavergne, J . P.; Lazaro, R.; Rolland, V.; Roumestant, M. L.; Viallefont,
P.; Vidal Y.; Martinez, J . Amino Acids 1999, 16, 345.
(3) For reviews see: (a) Schuster, M.; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2037. (b) Ivin, K. J . J . Mol. Catal. A: Chemical
1998, 1. (c) Randall, M. L.; Snapper, M. L. J . Mol. Catal. A: Chemical
1998, 29. (d) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998,
371. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (f)
Fu¨rstner, A. Topics in Organomet. Chem. 1998, 1, 1.
(4) (a) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem.
Soc. 1996, 118, 9606. (b) Schuster, M.; Pernerstorfer, J .; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1979. (c) Nicolaou, K. C.;
Wissinger, N.; Pastor, J .; Ninkovic, S.; Sarabia, F.; He, Y.; Vourioumis,
D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387,
268. (d) van Maarseven, J . H.; Denhartog, J . A. J .; Engelen, V.; Finner,
E.; Visser, G.; Kruse, C. G. Tetrahedron Lett. 1996, 37, 8249. (e)
Pernerstorfer, J .; Schuster, M.; Blechert, S. Chem. Commun. 1997,
1949. (f) Peters, J . U.; Blechert, S. Synlett 1997, 348. (g) Piscopio, A.
D.; Miller, J . F. Koch, K. Tetrahedron Lett. 1997, 38, 7143. (h) Veerman,
J . J . N.; van Maarseveen, J . H.; Visser, G. M.; Kruse, C. G.; Schoe-
maker, H. E.; Hiemstra, H.; Rutjes, F. P. J . T. Eur. J . Org. Chem. 1998,
2583. (i) Heerding, D. A.; Takata, D. T.; Kwon, C.; Huffman, W. F.;
Samanen, J . Tetrahedron Lett. 1998, 39, 6815. (j) Piscopio, A. D.; Miller,
J . F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667. (k) Schurer, S. C.;
Blechert, S. Synlett 1999, 1879. (l) J arvo, E. R.; Copeland, G. T.;
Papaioannou, N.; Bonitatebus, P. J .; Miller, S. J . J . Am. Chem. Soc.
1999, 121, 11638. (m) Reichwein, J . F.; Wels, B.; Krujitzer, J . A. W.;
Versluis, C.; Liskamp, R. M. J . Angew. Chem., Int. Ed. Engl. 1999,
38, 3684. (n) Knerr, L.; Schmidt, R. R. Synlett 1999, 1802. (o) Piscopio,
A. D.; Miller, J . F.; Koch, K. Tetrahedron 1999, 55, 8189.
Linear substrates 4 and 5a were submitted to classical
RCM reaction conditions using Grubbs’ catalyst in vari-
ous amounts (Scheme 2) and the results are presented
in Table 1.
(5) For the synthesis by RCM of dehydropipecolic acid derivatives
but with different N-protecting groups than Ts see: (a) reference 4a.
(b) Rutjes, F. P. J . T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38,
677. (c) 4f.
(6) Nouvet, A.; Binard, M.; Lamaty, F.; Lazaro, R. Lett. Pept. Sci.
1999, 6, 239.
(7) Nouvet, A.; Lamaty, F.; Lazaro, R. Tetrahedron Lett. 1998, 39,
3469.
10.1021/jo000898a CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

6788 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Sch em e 2
Ta ble 1. Rea ction Con d ition s for Rin g Closin g
Meta th esis of 4 a n d 5a
F igu r e 1. Two possible unproductive chelates that may be
present in our case.
linear
cat.
temp reaction
ethers have been synthesized by RCM.11 Even the pres-
ence of glycol ethers did not change significantly the
catalyst turnover number in the metathesis of styrene.11a
It is known that the presence of functional groups such
as esters and ethers could be necessary for a RCM to
proceed. Nevertheless, in certain cases, the coordination
of these groups on the metal carbene may generate
unproductive chelate complexes.12 In the case of 4, the
reaction time was short, indicating that the presence of
tosyl amino and methyl ester functions did not interfere
negatively with the reaction. During the RCM of 5a , it
seemed that the metal carbene was sequestered by the
PEG oxygens. To confirm the fact that the mere presence
of the oxygens of the PEG could inhibit this reaction, a
RCM of 4 was performed in the presence of 0.5 equiv of
PEG-OMe (3400) (MeO-(CH2CH2O)m-Me) obtained by
methylation of the corresponding PEG-OH (3400). Sur-
prisingly, the reaction proceeded to completion within 15
min. So it seemed that the main factor for the slowing
down of the reaction was not the presence of the oxygens
in the reaction mixture (even if they interfere) but the
fact that the linear substrate was anchored on the
polymer. This limitation was also described in SPOS in
the case of a PEG/polystyrene support where the cycliza-
tion of a tetrapeptide required a higher amount of
catalyst to reach only 60% conversion.4a Figure 1 depicts
two possible unproductive chelates that may be present
in our case. Once the metal carbene has reacted with
either one of the olefins of the linear substrate, it
produces a metallacycle or a new metal carbene that
instead of reacting with the second olefin, could be
chelated by the polymer, which is in the right position
to generate a strong complex.
entry substrate mol % solvent (°C) time (h) conversion
1
2
3
4
5
6
7
8
9
4
10
10
10
30
30
40
10
40
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
20
20
40
40
20
0.17
2
>24
2
>24
8
100
38
50
82
90
100
45
100
20
100
100
100
5a
5a
5a
5a
5a
5a
5a
5a
5a
4
toluene 110
toluene 110
8
8
H2O
H2O
a
20
20
b
>24
10
11
12
50
10
50
24
0.17
0.17
5a
a
b
a
The reaction was carried out in the absence of solvent under
b
microwave. Not measured.
Three reaction solvents for the reaction were chosen,
CH2Cl2, toluene, and water, since PEG-bound molecules
are soluble in all these solvents. The reaction was also
carried out in the absence of solvent. Conversion of the
starting material into the expected product was deter-
1
mined by H NMR.
The reaction of 4 was complete within 10 min using
10 mol % of catalyst (entry 1). In sharp contrast, the
reaction of 5a under the same conditions reached only
38% conversion to 7a (entry 2), clearly indicating a
retarding effect due to the presence of the polymer.
Increasing the reaction time to over 24 h slightly in-
creased the conversion (entry 3). The use of a higher
amount of catalyst and higher temperature (entry 4) did
not give better conversion than 82%. It seems that after
several hours of reaction the catalytic activity of the
ruthenium catalyst decreased. Finally the best conditions
we found were to use 40 mol % of catalyst at room
temperature, then the reaction was complete within 8
h. In the case of toluene, 40 mol % of catalyst was needed
also (entries 7 and 8). Using water as solvent8 did not
give better results (entry 9).
The cyclization was also carried out under microwave
activation9 (entries 11 and 12). Ruthenium catalyst (50
mol %) was needed for cyclizing 5a in the absence of
solvent, but in this case, the reaction time was dramati-
cally reduced [from 8 h (entry 6) to 10 min (entry 12)].
Cyclization took place also in the absence of PEG, since
4 in the presence of 10 mol % of the ruthenium catalyst
and in the absence of solvent yielded 91% of isolated 5
(entry 11). To our knowledge these are the first examples
of microwave-assisted RCM using Grubbs’ catalyst.10
The presence of the oxygen atoms of the PEG did not
seem at first to be a problem, since polyethers and crown
One can find in the literature examples of additives
which could be employed to alleviate this problem. A
13
Lewis acid such as Ti(OPr-i)4 has been used to avoid
unproductive complexes, while olefins such as 1-octene4d
or styrene4f have been employed to promote the reactiva-
tion of the catalyst. When Ti(OPr-i)4 (3 equiv) was used
in our case, the conversion was higher (70% with 20 mol
% catalyst) than in the absence of the Lewis acid, but
full conversion was not reached. When the reaction was
carried out with 2 equiv of 1-octene, it was possible to
cut by half the amount of catalyst used (20 mol %), but
so far we were not able to drop further this amount, even
when employing a larger quantity of 1-octene. Styrene
did not give better results. In this case, the presence of
(11) (a) Ko¨nig, B.; Horn, C. Synlett 1996, 1013. (b) Marsella, M. J .;
Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997,
36, 1101. (c) Rodr´ıguez, R. M.; Morales, E. A.; Delgado, C. G.; Espı´nola,
C. G.; Alvarez, E.; Pe´rez, R.; Mart´ın, J . D. Org. Lett. 1999, 1, 725.
(12) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792.
(8) Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J . Org. Chem. 1998,
63, 9904.
(9) Blettner, C.; Ko¨nig, W. A.; Stenzel, W.; Schotten, T. J . Org. Chem.
1999, 64, 3885.
(10) For a metathesis polymerization under microwave activation,
see: Dhanalakshmi, K.; Sundararajan, G. Polym. Bull. 1997, 39, 333.
(13) (a) Fu¨rstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119,
9130. (b) Cossy, J .; Bauer, D.; Bellosta, V. Tetrahedron Lett. 1999, 40,
4187. (c) Ramachandran, P. A.; Reddy, M. V. R.; Brown, H. C.
Tetrahedron Lett. 2000, 41, 583.

Notes
Ta ble 2. Exa m p les of RCM for th e Syn th esis of Cyclic
J . Org. Chem., Vol. 65, No. 20, 2000 6789
Microwave-assisted reactions were performed in a domestic
microwave at a power of 850 W.
Am in o Acid Der iva tives
The HPLC analyses were carried out at a wavelength of 214
nm, using a reversed phase Nucleosil C18 column (5 µm, 250 ×
10 mm) with a flow rate of 1 mL/min (eluents: solvent A, 0.1%
TFA in H2O; solvent B, 0.1% TFA in CH3CN). The chiral HPLC
analyses were carried out at a wavelength of 230 nm, using a
Chiralcel OD column, (5 µm, 250 × 4.6 mm) with a flow rate of
1 mL/min (eluent: hexane/2-propanol/TFA (92/8/0.4)).
cat.
yield of
Optical rotations were recorded on a polarimeter at 589 nm
and reported as RD (concentration in grams/100 mL of solvent).
(L)-N-Tosyla llylglycin e (1). To a suspension of allylglycine
(0.570 g, 5.00 mmol) in 10 mL of CH2Cl2 at room temperature
was added trimethylsilyl chloride (0.540 g 5.00 mmol). The
mixture was heated under reflux for 2 h, and Et3N (1.01 g, 10.0
mmol) was added, followed by addition of p-toluenesulfonyl
chloride (0.950 g, 5.00 mmol) in 5 mL of CH2Cl2. The resulting
mixture was vigorously stirred for 1 h at room temperature, then
MeOH (0.640 g, 20.0 mmol) was added. Evaporation was
followed by addition of water and K2CO3 in order to obtain pH
) 8. The aqueous layer was washed with Et2O and then acidified
to pH ) 1 with 1 N HCl and extracted three times with EtOAc.
The combined organic phases were dried over MgSO4 and
concentrated to afford 1.06 g (79%) of the title compound: IR
entry
R1
5
mol %
n
R2
7 (%)
1
2
3
4
5
6
allyl
a
b
c
d
e
f
20a
40
40
1
1
1
2
3
1
H
H
92
86
95
90
82
80
PhCHdCHCH2
H2CdCH(CH3)
H2CdCH(CH2)2
H2CdCH(CH2)3
H2CtC-CH2
CH3
40
H
H
40
40a
CHdCH2
a
2 equiv of 1-octene was used.
an allyl-substituted olefin could displace the complex to
a more reactive form. But this process seemed somewhat
limited, since 20 mol % of catalyst was still needed.
Table 2 presents different examples of ruthenium-
catalyzed cyclizations which led to the synthesis of amino
acid derivatives. PEG supported (L)-allylglycine 3 was
readily alkylated with different bromides to yield linear
substrates 5a -f, which were cyclized to 7a -f. First it
has to be noted that 5b (entry 2) yields the same final
product as 5a . We chose a cinnamyl substituent on the
nitrogen with the idea of being able to decrease the
amount of ruthenium catalyst by stabilizing the metal
carbene generated during the reaction.8 Nevertheless, 40
mol % was needed for the cyclization to reach completion.
A methyl substitutent on the olefin did not hamper the
cyclization (entry 3). By varying the chain length on R1,
7- and 8-membered rings 7d and 7e could be obtained in
good yields. We checked also the formation of the novel
8-membered ring starting from the methyl ester analogue
of 5e. The cyclization in the absence of PEG proceeded
smoothly in 15 min in the presence of 10 mol % of
ruthenium catalyst. Finally, enyne metathesis14 could
also be performed on the PEG-supported substrate 5f;
however, a higher amount of catalyst was needed in this
case.
To release the Ts amino acid from the polymer, a
racemization free acidic hydrolysis was performed (in
refluxing 6 N HCl for 4 h), and the free acids were
obtained in good yields.
In conclusion, we have presented here the first ex-
amples of RCM on a soluble PEG-supported substrate.
Although a relatively high amount of catalyst was
needed, this method allows for the efficient synthesis of
optically active cyclic amino acid derivatives with various
ring sizes. Further investigation to improve the catalytic
efficiency of this reaction is under study in our laboratory.
(KBr) 2945 (s), 1441 (m), 1347 (s), 1286 (s), 1244 (s) cm-1 1H
;
NMR (CD3OD, Me4Si) δ 2.30-2.55 (m, 5 H), 3.90 (dd, J 1 ) 6.0
Hz, J 2 ) 7.0 Hz, 1 H), 5.00-5.15 (m, 2 H), 5.60-5.85 (m, 1 H),
7.35 (d, J ) 8.5 Hz, 2 H), 7.75 (d, J ) 8.5 Hz, 2 H); 13C NMR
(CD3OD, Me4Si) δ 20.46, 37.41, 56.03, 117.84, 127.22, 129.54,
132.95, 138.30, 143.65, 173.06; MS (electrospray) m/z 270 (M +
H)+, 539 (2M + H)+.
Meth yl (L)-N-Tosyla llylglycin a te (2). To a solution of 1
(1.00 g, 3.7 mmol) in 25 mL of MeOH was added trimethylsilyl
chloride (1.00 mL, 7.9 mmol). The mixture was refluxed for 7 h
and was concentrated after cooling to yield 1.00 g (95%) of the
title compound: IR (CCl4) 3274 (w), 2951 (m), 2352 (w), 1743
1
(s), 1349 (s) cm-1; H NMR (CD3OD, Me4Si) δ 2.30-2.50 (m, 5
H) 3.45 (s, 3 H), 3.95 (t, J ) 7.0 Hz, 1 H), 5.00-5.15 (m, 2 H),
5.60-5.80 (m, 1 H), 7.40 (d, J ) 8.5 Hz, 2 H), 7.75 (d, J ) 8.5
Hz, 2 H); 13C NMR (CD3OD, Me4Si) δ 20.41, 37.24, 51.41, 56.15,
117.94, 127.22, 129.53, 132.77, 138.19, 143.73, 171.85; MS
(electrospray) m/z 284 (M + H)+, 567 (2M + H)+, 589 (2M +
Na)+.
P oly(eth ylen e glycol) 3400 Di((L)-N-tosyla llylglycin a te)
(3). To a solution of PEGOH (1.95 g, 0.574 mmol) in 15 mL of
THF was added a solution of triphenylphosphine (0.63 g, 2.4
mmol) in 5 mL of THF. The mixture was stirred at room
temperature for 1 h. A solution of DEAD (0.468 g,2.40 mmol)
and 1 (0.650 g, 2.40 mmol) in 2 × 5 mL of THF was added to
the mixture. The reaction was refluxed for 10 h. After cooling
and evaporation of the solvent, the residue was dissolved in CH2-
Cl2 and precipitated in Et2O, and the product was filtered and
dried in vacuo to yield 2.04 g (91%) of the title compound: IR
(KBr) 2876 (s), 1743 (m), 1466 (m), 1095 (m) cm-1 1H NMR
;
(CDCl3, Me4Si) δ 2.40 (s, 6 H), 2.50 (t, J ) 6.5 Hz, 4 H), 3.50-
3.70 (large s, ∼310 H), 4.00-4.10 (m, 6 H), 5.00-5.15 (m, 4 H),
5.40 (d, J ) 9.0 Hz, 2 H), 5.55-5.75 (m, 2 H), 7.30 (d, J ) 8.5
Hz, 4 H), 7.75 (d, J ) 8.5 Hz, 4 H); 13C NMR (CDCl3, Me4Si) δ
21.91, 37.89, 55.62, 62.00, 64.84, 68.95, 70.67, 70.91, 72.89,
120.04, 127.73, 130.13, 131.81, 137.33, 143.88, 171.14.
Meth yl (L)-N-Allyl-N′-tosyla llylglycin a te (4). To a solution
of 2 (0.150 g, 0.500 mmol) in 10 mL of DMF were added K2CO3
(0.370 g, 2.70 mmol) and allyl bromide (0.085 g, 0.795 mmol).
The mixture was stirred at room temperature for 10 h, then 10
mL of EtOAc and 10 mL of H2O were added. The aqueous layer
was washed twice with EtOAc. The combined organic phases
were washed three times with H2O, dried over MgSO4, and
concentrated to afford 0.150 g (88%) of the title compound: IR
Exp er im en ta l Section
Gen er a l. All reagents including poly(ethylene glycol) 3400
were obtained from Aldrich Chemical Co. and used without
purification. 1H- and 13C NMR analyses were performed, re-
spectively, with 200 and 400 MHz NMR spectrometers. Infrared
spectra were recorded by diffuse reflectance as a microcup of
KBr or by transmittance in KBr salt plates. Mass spectra
(electrospray ionization mode, ESIMS) were recorded on a
quadrupole mass spectrometer fitted with an electrospray
interface.
1
(CCl4) 2950 (w), 2356 (w), 1743 (s), 1350 (s), 1165 (s) cm-1; H
NMR (CD3OD, Me4Si) δ 2.45 (s, 3 H), 2.40-2.80 (m, 2 H), 3.50
(s, 3 H), 3.90 (dd, J 1 ) 1.5 Hz, J 2 ) 6.5 Hz, 2 H), 4.60 (dd, J 1
)
6.5 Hz, J 2 ) 9.0 Hz, 1 H), 5.05-5.25 (m, 4 H), 5.60-5.90 (m, 2
H), 7.30 (d, J ) 8.5 Hz, 2 H), 7.75 (d, J ) 8.5 Hz, 2 H); 13C NMR
(CDCl3, Me4Si) δ 21.93, 34.86, 48.61, 52.34, 59.71, 118.03, 118.85,
127.95, 129.79, 133.65, 135.38, 137.53, 143.80, 171.36; ΜS
(electrospray) m/z 324 (M + H)+, 346 (M + Na)+, 647 (2M +
(14) For a synthesis in solution of a vinyl dehydro pipecolic acid via
enyne metathesis see: Mori, M.; Sakakibara, N.; Kinoshita, A. J . Org.
Chem. 1998, 63, 6082.
H)+, 669 (2M + Na)+
.

6790 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
P oly(et h ylen e glycol)-3400 Di((L)-N-a llyl-N′-t osyla llyl-
glycin a te) (5a ). Allyl bromide (0.073 g, 0.603 mmol) was added
to 3 (0.784 g, 0.200 mmol) and potassium carbonate (0.273 g,
2.00 mmol) in 30 mL of DMF. The mixture was stirred vigorously
for 8 h. The reaction was concentrated and dissolved in CH2Cl2,
the base was filtered, and the filtrate precipitated in Et2O. The
product was filtered and dried in vacuo to yield 0.660 g (83%) of
the title compound: IR (KBr) 2874 (s), 1739 (m), 1474 (m), 1345
Cl2, and the mixture was stirred at room temperature for 8 h
and then precipitated in Et2O twice. The product was filtered
and dried in vacuo to yield 0.120 g (86%) of the title compound.
Meth od c. The ruthenium catalyst (0.002 g, 0.003 mmol) was
added to a solution of 5a (0.050 g, 0.013 mmol) and 1-octene
(0.003 g, 0.026 mmol) in 5 mL of CH2Cl2, and the mixture was
stirred at room temperature for 8 h and then precipitated in
Et2O twice. The product was filtered and dried in vacuo to yield
0.047 g (92%) of the title compound.
(m), 1094 (m) cm-1 1H NMR (CDCl3, Me4Si) δ 2.40 (s, 6 H),
;
2.45-2.80 (m, 4 H), 3.50-3.70 (large s, ∼310 H), 3.85-3.90 (m,
6 H), 4.65 (dd, J 1 ) 6.5 Hz, J 2 ) 9.0 Hz, 2 H), 5.05-5.20 (m, 8
H), 5.65-5.90 (m, 4 H), 7.25 (d, J ) 8.5 Hz, 4 H), 7.1 (d, J ) 8.5
Hz, 4 H); 13C NMR (CDCl3, Me4Si) δ 21.93, 34.95, 48.64, 59.82,
61.87, 64.46, 68.93, 70.51, 72.91, 117.99, 119.82, 124.74, 127.97,
129.81, 130.56, 133.67, 135.56, 170.82.
Meth yl (L)-N-Tosyl-4,5-d id eh yd r op ip ecola te (6). Meth od
a . The ruthenium catalyst RuCl2(dCHPh)(PCy3)2 (0.003 g, 0.004
mmol) was added to a solution of 4 (0.014 g, 0.043 mmol) in 15
mL of CH2Cl2, and the mixture was stirred at room temperature
for 10 min and purified on silica gel (30% EtOAc/hexane). The
organic layer was dried and concentrated to afford 0.012 g (95%)
of the title compound.
Meth od b. The ruthenium catalyst (0.003 g, 0.004 mmol) was
added to a suspension of 4 (0.014 g, 0.043 mmol) in 15 mL of
H2O, and the mixture was vigorously stirred at room tempera-
ture for 24 h. The aqueous layer was washed twice with CH2-
Cl2, and the organic layers were combined, dried over MgSO4,
concentrated, and purified on silica gel (30% EtOAc/hexane) to
afford 0.010 g (80%) of the title compound.
Meth od c. The ruthenium catalyst (0.003 g, 0.004 mmol) was
added to 4 (0.014 g, 0.043 mmol), the mixture was activated
under microwave (850 W) during 10 min. The residue was
purified on silica gel (30% EtOAc/hexane) to afford 0.012 g (91%)
of the title compound.
Meth od d . The ruthenium catalyst (0.005 g, 0.0065 mmol)
was added to 5a (0.050 g, 0.013 mmol), and the mixture was
activated under microwave (850 W) for 10 min and then
precipitated in Et2O twice. The product was filtered and dried
in vacuo to yield 0.047 g (92%) of the title compound.
Meth od e. The ruthenium catalyst (0.005 g, 0.007 mmol) was
added to a solution of 5a (0.050 g, 0.013 mmol) in 5 mL of water,
and the mixture was vigorously stirred at room temperature for
24 h and then concentrated. The residue was dissolved in CH2-
Cl2 and then precipitated twice in Et2O. The product was filtered
and dried in vacuo to yield 0.040 g (81%) of the title compound:
1
IR (KBr) 2359 (s), 1484 (w), 1349 (m), 1113 (m) cm-1; H NMR
(CDCl3, Me4Si) δ 2.45 (s, 6 H), 2.55 (sl, 4 H), 3.50-3.70 (large s,
∼ 310 H), 4.90 (t, J ) 4.0 Hz, 2 H), 5.70 (s, 4 H), 7.30 (d, J ) 8.5
Hz, 4 H), 7.70 (d, J ) 8.5 Hz, 4 H); 13C NMR (CDCl3, Me4Si) δ
21.93, 28.21, 42.52, 52.89, 64.43, 68.96, 70.92, 122.50, 123.86,
127.65, 129.85, 136.66, 143.64, 170.67.
(L)-N-Tosyl-4,5-d id eh yd r op ip ecolic Acid . A solution of 7a
(0.050 g, 0.013 mmol) in 2 mL of 6 N HCl was stirred at reflux
for 4 h. The residue was concentrated and dissolved in CH2Cl2
and then precipitated in Et2O. The poly(ethylene glycol) 3400
was filtered, the filtrate was washed with an aqueous solution
of NaHCO3, the aqueous layer was acidified to pH ) 1 and
washed with CH2Cl2. The organic layer was dried over MgSO4
and concentrated to yield 0.005 g (68%)of the title compound:
Meth od d . The ruthenium catalyst (0.003 g, 0.004 mmol) was
added to a solution of 4 (0.014 g, 0.043 mmol) and PEGOMe
(0.074 g, 0.022 mmol) in 15 mL of CH2Cl2, the mixture was
stirred at room temperature for 15 min, purified on silica gel
(30% EtOAc/hexane) and concentrated to afford 0.012 g (91%)
of the title compound: IR (neat) 2949 (m), 1735 (s), 1341 (m),
IR (neat) 2913 (m), 1724 (m), 1348 (m), 1323 (m), 1159 (s) cm-1
;
1H NMR (CDCl3, Me4Si) δ 2.45 (s, 3 H), 2.60 (s, 2 H), 4.00 (dd,
J 1 ) 18.0 Hz, J 2 ) 30.0 Hz, 2 H), 4.90 (dd, J 1 ) 5.0 Hz, J 2 ) 8.5
Hz, 1 H,), 5.70 (sl, 1H), 7.30 (d, J ) 8.0 Hz, 2 H), 7.70 (d, J )
8,5 Hz, 2 H); 13C NMR (CDCl3, Me4Si) δ 21.97, 27.84, 30.13,
42.44, 122.70, 123.87, 127.67, 129.97, 136.64, 144.06, 207.49; MS
(electrospray) m/z 282 (M + H)+, 304 (M + Na)+, 585 (2M +
1288 (m) cm-1 1H NMR (CDCl3, Me4Si) δ 2.45 (s, 3 H), 2.55
;
(large s, 2 H), 3.50 (s, 3 H), 3.75-4.15 (m, 2 H), 4.90 (t, J ) 4.0
Hz, 1 H), 5.60-5.70 (large s, 2 H), 7.30 (d, J ) 8.5 Hz, 2 H),
7.70 (d, J ) 8.5 Hz, 2 H);13C NMR (CDCl3, Me4Si) δ 21.97, 28.18,
42.57, 52.55, 52.99, 122.69, 123.81, 127.68, 129.88, 136.61,
143.78, 171.35; MS (electrospray) m/z 296 (M + H)+, 318 (M +
Na)+; HPLC tR ) 20.74 min; Chiral HPLC tR ) 16.9 min; [R]20
D
) -6.6 (0.45, MeOH); HRMS calcd for C13H16NO4S (MH+)
282.0800, found 282.0796.
Ack n ow led gm en t. We thank the MENRT and
CNRS for financial support. F.L. thanks the University
of Montpellier 2 for a Young Investigator Award.
Na)+, 334 (M + K)+
.
P oly(eth ylen e glycol)-3400 Di((L)-N-tosyl-4,5-d id eh yd r o-
p ip ecola te) (7a ). Meth od a . The ruthenium catalyst (0.004 g,
0.005 mmol) was added to a solution of 5a (0.050 g, 0.013 mmol)
in 5 mL of CH2Cl2, and the mixture was stirred at room
temperature for 8 h and then precipitated in Et2O twice. The
product was filtered and dried in vacuo to yield 0.047 g (92%) of
the title compound.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of 5b-f, 7c-f, and hydrolysis products from 7c-
f, and corresponding spectral data; 13C NMR spectra of
compounds 3, 5b-f, 7a -f. This material is available free of
charge via the Internet at http://pubs.acs.org.
Meth od b. The ruthenium catalyst (0.012 g, 0.014 mmol) was
added to a solution of 5b (0.150 g, 0.036 mmol) in 15 mL of CH2-
J O000898A