Diastereoselective syntheses of deoxydysibetaine, dysibetaine, and its 4-epimer

Article abstract of DOI:10.1021/jo040216+

(±)-Deoxydysibetaine 2 and 4-epi-dysibetaine 3 were prepared in a few steps from methyl pyroglutamate through a regioselective Mannich reaction at C-2. Natural (2S,4S)-dysibetaine 1, a sponge metabolite isolated from Dysidea herbacea, and (2S)-2 were synt

Full text of DOI:10.1021/jo040216+

Dia ster eoselective Syn th eses of Deoxyd ysibeta in e, Dysibeta in e,
a n d Its 4-Ep im er
Nicole Langlois* and Bao K. Le Nguyen
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
nicole.langlois@icsn.cnrs-gif.fr
Received J une 14, 2004
(()-Deoxydysibetaine 2 and 4-epi-dysibetaine 3 were prepared in a few steps from methyl
pyroglutamate through a regioselective Mannich reaction at C-2. Natural (2S,4S)-dysibetaine 1, a
sponge metabolite isolated from Dysidea herbacea, and (2S)-2 were synthesized from enantiopure
(S)-pyroglutaminol with very high stereoselectivity. The key steps were an original formation of
stereogenic quaternary center C-2 and the diastereoselective hydroxylation at C-4.
SCHEME 1
In tr od u ction
Synthetic studies of natural products of marine origin
are still the focus of great interest due to their scarcity
and their potential biological activities.1 As part of our
contribution in this field,2 we envisioned the synthesis
of dysibetaine 1, a sponge metabolite isolated in 1999
from Dysidea herbacea collected in Yap (Micronesia). As
dysibetaine is able to induce convulsive behavior in mice,
this compound was suspected of acting to glutamate
receptors in the central nervous system.3
from methyl pyroglutamate 4, a direct addition at C-2 of
dimethyliminium iodide (Eschenmoser’s salt) seemed the
simplest route to add a N,N-dimethylaminomethyl group
at C-2. The regioselective deprotonation of pyroglutamates
at C-2 or C-4 depends on the absence, or not, of an
electrowithdrawing N-protecting group. Thus, N-alkoxy-
carbonyl groups direct the addition of electrophiles at C-4,
and such a regioselectivity in the addition of Eschen-
moser’s salt has already been verified in our laboratory.5
Accordingly, methyl pyroglutamate was directly depro-
tonated at C-2 with LiHMDS (2.1 equiv) without being
N-protected and was alkylated with Eschenmoser’s salt
at - 60 °C providing 5 in 82% yield (Scheme 1).6 The
isolation of 5 however was rather difficult and needed a
rapid extraction, due to the unstability of the methyl
ester function. Indeed, this ester is particularly sensitive
to water and rapidly hydrolyzed at room temperature
with the assistance of the neighboring amino group, to
give 6 as outlined in the Scheme 1. This hydrolysis was
responsible of decreased yields when prolonged isolation
stages occurred, but the compound 5 could be recovered
by treatment of 6 with diazomethane.
Resu lts a n d Discu ssion
Before the achievement of this work, only one total
synthesis of dysibetaine has been described by Snider et
al., assigning its absolute configuration.4a A second syn-
thesis, involving a nitrenium ion cyclization, has been
reported very recently.4b This lactam can be considered
as a cyclized R,γ-disubstituted glutamic acid, and the R-
substitution by a trimethylammoniummethyl group con-
stitutes an original structural feature. The introduction
of a dimethylaminomethyl substituent as precursor of
this functional group, starting either from methyl pyro-
glutamate 4 or enantiopure (S)-pyroglutaminol, repre-
sented our first target to give access to deoxydysibetaine
2.
Such a participation of the nitrogen lone pair in a
hydrolysis process has been already observed with the
acetate of vindoline.7 Moreover, the corresponding salts
of 5 (hydrochloride or trifluoroacetate) proved to be
stable.
Ra cem ic Meth yl 2-N,N-Dim eth yla m in om eth ylp y-
r oglu ta m a te fr om Meth yl P yr oglu ta m a te 4. Starting
(1) (a) Faulkner, D. J . Nat. Prod. Rep. 2002, 19, 1-48. (b) See also:
Special Issue in Honor of D. J ohn Faulkner and Paul J . Scheuer. J .
Nat. Prod. 2004, 67, (8).
(2) (a) Langlois, N. Tetrahedron Lett. 2001, 42, 5709. (b) Langlois,
N. 10th International Symposium on Marine Natural Products, Nago,
Okinawa, J une 24-29, 2001. (c) Langlois, N. Org. Lett. 2002, 4, 185.
(3) Sakai, R.; Oiwa, C.; Takaishi, K.; Kamiya, H.; Tagawa, M.
Tetrahedron Lett. 1999, 40, 6941.
(4) (a) Snider, B. B.; Gu, Y. Org. Lett. 2001, 3, 1761. (b) Wardrop,
D. J .; Burge, M. S. J . Chem. Soc., Chem. Commun. 2004, 1230.
(5) Panday, S. K.; Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett.
1994, 35, 6673.
(6) Le Nguyen, B. K.; Langlois, N. Tetrahedron Lett. 2003, 44, 5961.
(7) Diatta, L.; Langlois, Y.; Langlois, N.; Potier, P. Bull. Soc. Chim.
1975, 671.
10.1021/jo040216+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/29/2004
7558
J . Org. Chem. 2004, 69, 7558-7564

Diastereoselective Synthesis of Deoxydysibetaine
SCHEME 2
SCHEME 3
E n a n t iop u r e (S)-Met h yl 2-N,N-Dim et h yla m in o-
m eth ylp yr oglu ta m a te (S)-5 fr om (S)-P yr oglu ta m i-
n ol. With racemic intermediate 5 in hand, the route to
its enantiopure counterpart (S)-5 was investigated from
(S)-methyl 2-hydroxymethylpyroglutamate 11.6,8 This
ester was derived from (S)-2-hydroxymethylglutamic acid
hydrochloride (10, HCl),9,10 efficiently and stereoselec-
tively prepared from the bicyclic silyloxypyrrole 7,11,12
according to Scheme 2. The stable 5-hydroxy derivative
8 was easily obtained in 77% yield by successive treat-
ment of silyloxypyrrole 7 with Lewis acid such as SnCl4
and then with aqueous sodium bicarbonate solution.
Starting from 7, this nucleophilic addition of hydroxide
anion at C-5 is equivalent to a double protonation at C-7
and C-6 followed by trapping the resulting iminium ion
with the nucleophile. The entire process probably took
place upon quenching of the reaction mixture with
aqueous alkaline solution, leading to a slow hydrolysis
of the complex between silyloxypyrrole 7 and SnCl4.10 The
diastereoselectivity of this nucleophilic addition was
complete, with an attack of the iminium ion on the face
hindered by the phenyl group at C-2, and this was
confirmed by X-ray crystal analysis of 8.13 Other nucleo-
philes could replace the hydroxyl group of 8 under similar
conditions. A cyano group was introduced at C-5 by
means of trimethylsilylcyanide in the presence of SnCl4,
affording 9. Only one diastereomer was detected and was
isolated in 65% yield.12 Acidic hydrolysis of 9 gave rise
to (S)-2-hydroxymethyl glutamic acid 10, HCl (98%),
which was methylated with trimethylsilyldiazomethane
or with an excess of diazomethane in ether and cyclized
in the same step into (S)-methyl 2-hydroxymethylpyro-
glutamate 11 (67%), along with some N-methyl derivative
12 (∼10%). The presence of methanol as cosolvent to
increase the solubility of the diacid could explain this
N-methylation.14
roglutamate (S)-5 following Scheme 3. Primary amine 15
was obtained in 78% overall yield through mesylate 13
and azidomethyl derivative 14. N-Dimethylation with
aqueous formaldehyde under hydrogen furnished (S)-5
(64%).
Deoxyd ysibeta in e 2. Both racemic 5 and (S)-5 led to
the corresponding trimethylammonium iodides 16 in good
yields (86%), by classical reaction with iodomethane, as
shown in the Scheme 3 for the (S)-enantiomer, and 16
afforded deoxydysibetaine 2 by treatment with resin
Dowex 550A (HO- form, 85-100%), according to the
protocol described by Snider et al.4a Trimethylammonium
iodide (S)-16 was also obtained more efficiently (94%) by
direct trimethylation of the primary amine 14 with
iodomethane in excess in the presence of diisopropyl-
ethylamine. This more direct route avoided the isolation
of the labile compound (S)-5.
Na tu r a l Dysibeta in e 1. The synthesis of dysibetaine
1 involved a hydroxylation step at C-4. Several electro-
philic reagents were tested to introduce this hydroxyl
group in the R-position of lactam-carbonyl through
enolates. For this purpose, (S)-methyl 2-hydroxymethyl
pyroglutamate 11 was monoprotected as O-TBDMS (17,
100%) and then N-protected as tert-butyl carbamate (18,
91%). The reaction of potassium enolate of 18 with oxygen
gas15 failed to provide any hydroxylated compound in the
presence of trimethyl phosphite. Dibenzyl peroxydicar-
bonate16,17 has been previously described to oxidize N-
Boc-O-TBDMS pyroglutaminol, affording the correspond-
ing benzyloxycarbonyloxy derivative in 50% yield and
high diastereoselecivity.18 As potassium enolates were
reported to give better results than lithium analogues,17
the derivative 18 was deprotonated with KHMDS at -78
°C and treated with (BnOCOO)2. Surprisingly, two dia-
stereomers 19 and 20 were isolated in only 34% yield and
low stereoselectivity (dr 2.4:1, Scheme 4).
(S)-Methyl 2-hydroxymethylpyroglutamate 11 was con-
verted into (S)-methyl 2-N,N-dimethylaminomethylpy-
(8) Andrews, M. D.; Brewster, A. G.; Moloney, M. G.; Owen, K. L.
J . Chem. Soc., Perkin Trans. 1 1996, 227.
(9) Zhang, J .; Flippen-Anderson, J . L.; Kozikowski, A. P. J . Org.
Chem. 2001, 66, 7555.
(10) (a) Choudhury, P. K.; Le Nguyen, B. K.; Langlois, N. Tetrahe-
dron Lett. 2002, 43, 463. (b) Battistini, L.; Curti, C.; Zanardi, F.; Rassu,
G.; Auzzas, L.; Casiraghi, G. J . Org. Chem. 2004, 69, 2611 and
references cited therein.
(11) Uno, H.; Baldwin, J . E.; Churcher, I.; Russel, A. T. Synlett 1997,
390.
(12) Langlois, N.; Choudhury, P. K. Tetrahedron Lett. 1999, 40, 2525.
(13) (a) Le Nguyen, B. K.; Chiaroni, A.; Tran Huu Dau, M.-E.;
Langlois, N. Xth French-American Conference, Saint-Malo, J une 2-6,
2002. (b) Chiaroni, A. Cambridge Crystallographic Data Centre
(CCDC) deposit 237766.
(15) (a) Wasserman, H. H.; Lipshutz, B. H. Tetrahedron Lett. 1975,
1731. (b) Hartwig, W.; Born, L. J . Org. Chem. 1987, 52, 4352.
(16) Strain, F.; Bissinger, W. E.; Dial, W. R.; Rudoff, H.; DeWitt, B.
J .; Stevens, H. C.; Langston, J . H. J . Am. Chem. Soc. 1950, 72, 1254.
(17) Gore, M. P.; Vederas, J . C. J . Org. Chem. 1986, 51, 3700.
(18) Oliveira, D. de J .; Coelho, F. Tetrahedron Lett. 2001, 42, 6793.
(14) Ralls, J . W. J . Org. Chem. 1961, 26, 66.
J . Org. Chem, Vol. 69, No. 22, 2004 7559

Langlois and Le Nguyen
TABLE 1. Hyd r oxyla tion s a t C-7 of Bicyclic La cta m s
Der ived fr om (S)-P yr oglu ta m in ol
SCHEME 4
yield
(%)
entry lactam
base
reagent
7S/7R
ref
1
2
3
4
4
6
7
8
23a
23b
23b
23c
23d
9
KHMDS Davis reagent 68
NaHMDS Davis reagent 83
1:1
2:3
9:1
31
this work
32
LDA
LDA
LDA
MoOPD
MoOPD
MoOPH
78
53 3:2 or 2:3
77
50
33
34
100:0
∼1:1
3:1
KHMDS (BnOCOO)2
this work
this work
this work
9
9
KHMDS Davis reagent 52
KHMDS MoOPH 81
SCHEME 5
80:1
chosen for the hydroxylation step (Scheme 5). The
behavior of 9 was expected to be closely related to that
of models devoid of a cyano substituent at the C-5 center.
We postulated that the cyano group may be a minor
factor in the diastereofacial selectivity, due to a small
effect of this angular substituent on the position of the
pyramidal-nitrogen lone pair and on the approach of the
electrophile. The analogues 23 have been already hy-
droxylated by others and by us with 2-phenylsulfonyl-3-
phenyloxaziridine (Davis reagent) and MoOPH29 or
MoOPD,30 and the results are summarized in Table 1 for
comparison purposes with our own study (entries 2, 6,
7, 8).
The configuration 4S was assigned to 20 after removal
of the benzyl carbonate functionality (H2-10% Pd/C)19
affording 21. These disappointing results led us to use
the more common reagents oxaziridines.20 Benzyl N-Boc-
pyroglutamate has been hydroxylated in 61% yield in this
way with complete stereoselectivity,21 but this yield could
not be reproduced in our laboratory,22 as well as by other
groups.23,24 Nevertheless, the oxidation of 18-potassium
enolate with 2-phenylsulfonyl-3-phenyloxaziridine gave
diastereomers 21 and 22 in better yields (47 to 51%) and
better, although still modest, diastereoselectivity (dr 3.2:
1, Scheme 4). The spectral data, particularly NMR data
of 21 and 22, are very similar and NOESY experiments
are not very informative. However, the configuration at
C-4 of the major diastereomer 21 was shown to be the
same as dysibetaine (4S) by a chemical correlation
described below (Scheme 6).
Taking accounts of these preliminary results, we
turned toward an earlier precursor of dysibetaine involv-
ing a bicyclic lactam structure to improve both the ef-
ficiency and the diastereoselectivity. Such rigid bicyclic
substrates, particularly lactams derived from pyroglutami-
nol,25 are known to afford a high degree of diastereose-
lectivity in several types of reaction.26-28 Moreover, the
intrinsic protection of both nitrogen and primary alcohol
in this compound avoided useless steps. The nitrile 9 was
Using dibenzyl peroxydicarbonate as electrophile, the
diastereomers endo-24 and exo-25 were isolated in 50%
yield without stereoselectivity (entry 6), whereas 2-phe-
nylsulfonyl-3-phenyloxaziridine afforded 7-hydroxy de-
rivatives endo-26 and exo-27 in 3:1 dr and 52% yield
(entry 7), and this relatively low yield compared with that
of the hydroxylation of analogue 23b (entry 2) remains
unclear. The best result was obtained with MoOPH
giving rise to endo-26 in 80% yield (entry 8). NOESY
experiments are not significant owing to a too small effect
between Hâ-6 and H-7 in 27 and also to the absence of
hydrogen at C-5. The configurations at C-7 of 26 (7S) and
(19) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.; Fujii, S.; Ikeda,
K.; Katsumura, S. J . Org. Chem. 2002, 67, 4839.
(20) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
(21) Ohta; T.; Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988, 29, 329.
(22) (a) Delcroix, J .-M. DEA of Organic Chemistry 1995, Paris XI
University, Orsay, France, 1995.
(23) Avent, G.; Bowler, A. N.; Doyle, P. M.; Marchand, C. M.; Young,
D. W. Tetrahedron Lett. 1992 33, 1509.
(24) Merino, P.; Mates, J . A.; Revuelta, J .; Tejero, T.; Chiacchio, U.;
Romeo, G.; Iannazzo, D.; Romeo, R. Tetrahedron: Asymmetry 2002,
13, 173.
1
27 (7R) were established by H NMR and comparison of
the observed coupling constants J 6,7 with the calculated
values and those of described analogues31,32 and were
confirmed by subsequent synthesis. The high diastereo-
selectivity observed with MoOPH favoring the required
endo-attack could be due to predominant anti-stereoelec-
tronic directing effect of the nitrogen lone pair.35,36
Chemical correlations between 25, 27, and 28 and
between 22 and 28, respectively, ascertained the con-
(25) Thottathil, J . K.; Moniot, J . L.; Mueller, R. H.; Wong, M. K. Y.;
Kissick, T. P. J . Org. Chem. 1986, 51, 3140.
(26) Hanessian, S.; Ratovelomanana, V. Synlett 1990, 501.
(27) (a) Langlois, N.; Van Bac, N.; Dahuron, N.; Delcroix, J .-M.;
Deyine, A.; Griffart-Brunet, D.; Chiaroni, A.; Riche, C. Tetrahedron
1995, 51, 3571. (b) Langlois, N.; Calvez, O.; Radom, M.-O. Tetrahedron
Lett. 1997, 38, 8037.
(28) (a) Herdeis, C.; Aschenbrenner, A.; Kirfel, A.; Schwabenla¨nder
F. Tetrahedron: Asymm. 1997, 8, 2421. (b) Zhang, R.; Mamai, A.;
Madalengoitia, J . S. J . Org. Chem. 1999, 64, 547.
(29) Vedejs, E.; Engler, D. A.; Telschow, J . E. J . Org. Chem. 1978,
34, 188.
(30) Anderson, J . C.; Smith, S. C. Synlett. 1990, 107.
(31) Nagasaka, T.; Imai, T. Chem. Pharm. Bull. 1995, 43, 1081.
(32) Hara, O.; Takizawa, J .-i.; Yamatake, T.; Makino, K.; Hamada,
Y. Tetrahedron Lett. 1999, 40, 7787.
7560 J . Org. Chem., Vol. 69, No. 22, 2004

Diastereoselective Synthesis of Deoxydysibetaine
SCHEME 6
SCHEME 7
figurations at the carbon bearing the hydroxyl group
(Scheme 6).
enolate was oxidized with MoOPH37 to give the 4-hydroxy
derivative 39 (66%) together with the diastereomer 40
(8%) and some R-dicarbonylated compound 41 (ca. 3%,
Scheme 7).
Thus, the benzyl carbonate 25 was partially depro-
tected under hydrogen and 10% Pd/C as catalyst, provid-
ing 27 (7R). Compound 27 was also correlated with the
compound 22 obtained from the monocyclic lactam 18.
So, acidic hydrolysis of 27, followed by methylation with
diazomethane, afforded (2S,4R)-methyl 4-hydroxy-2-hy-
droxymethyl pyroglutamate 28 (46% for two steps) also
obtained from the compound 22 under the same condi-
tions.
The major 7S hydroxy compound 26 was converted to
natural dysibetaine 1, after hydrolysis with 6 N HCl and
treatment with excess diazomethane leading to 29 [57%
for the two steps, together with some N-methylated
derivative 30 (6%)]. (2S,4S)-Methyl 4-hydroxy-2-hy-
droxymethylpyroglutamate 29 was treated as described
for its deoxy analogue deoxydysibetaine 2 (Scheme 3).
The monomesylation of the primary alcohol 29 was
stopped before completion (starting material recovered
41%) to avoid the reaction of the secondary alcohol at C-4,
and the yield of this step (38%) was not optimized. The
four last steps were achieved in 56% overall yield.
4-epi-Dysibeta in e 3. To prepare structural analogues
of dysibetaine, we anticipated that the presence of a N,N-
dimethylaminomethyl group at C-2 in monocyclic lactam
could direct the hydroxylation at C-4 in a 2,4-trans
relative configuration. Accordingly, the compound 38 was
prepared by classical N-Boc protection of (()-5 and then
deprotonated at C-4 with KHMDS, and the potassium
The major diastereomer 39 was rapidly converted into
its more stable salt trifluoroacetate, whereas prolonged
treatment with trifluoroacetic in dichloromethane af-
forded quantitatively N-deprotected compound 42. In the
1H NMR spectrum of 42, characteristic chemical shifts
and coupling constants are closely related to the data
described for the ethyl ester4a and agree with a trans
relationship between the N,N-methylaminomethyl group
at C-2 and the hydroxyl group at C-4. This statement
was confirmed by the conversion of 39 into (()-4-epi-
dysibetaine 3 through the trimethylammonium iodide 43,
as described for its deoxy analogue 2 and shown in the
scheme 7. Obviously, this route constitutes also a formal
synthesis of (2S,4R)-4-epi-dysibetaine. On the other hand,
the conversion of the minor compound 40 into (()-36
under the same conditions confirmed its 4S configuration.
Con clu sion
In conclusion, we took advantage of the access to
quaternary stereogenic centers through stereospecific
addition of nucleophiles at C-5, starting from silyloxy-
pyrrole 7, to achieve an efficient and highly diastereo-
selective synthesis of marine sponge metabolite dysibe-
taine, as well as deoxy and 4-epi analogues. Other
applications of this methodology are currently under
investigation.
(33) Bailey, J . H.; Byfield, A. T. J .; Davis, P. J .; Foster, A. C.; Leech,
M.; Moloney, M. G.; Mu¨ller, M.; Prout, C. K. J . Chem. Soc., Perkin
Trans. 1 2000, 1977.
(34) Makino, K.; Shintani, K.; Yamatake, T.; Hara, O.; Hatano, K.;
Hamada, Y. Tetrahedron 2002, 58, 9737.
(35) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J . F.; Williard,
P. G. J . Am. Chem. Soc. 1998, 120, 7429.
Exp er im en ta l Section
Gen er a l Meth od s. Solvent purification, spectral analyses,
and workup procedures were performed as described in the
Supporting Information and elsewhere.38 The chemical shifts
(36) (a) Armstrong, R. W.; DeMattei, J . A. Tetrahedron Lett. 1991,
32, 5749. (b) Woo, K. C.; J ones, K. Tetrahedron Lett. 1991, 32, 6949.
(c) Zhang, R.; Brownewell, F.; Madalengoitia, J . S. Tetrahedron Lett.
1999, 40, 2707.
(37) (a) Shin, C.-G.; Nakamura, Y.; Yamada, Y.; Yonezawa, Y.;
Umemura, K.; Yoshimura, Bull. Chem. Soc. J pn. 1995, 68, 3151. (b)
Pu¨schl, A., Boesen T., Zuccarello G.; Dahl, O.; Pitsch, S., Nielsen P. E.
J . Org. Chem. 2001, 66, 707.
J . Org. Chem, Vol. 69, No. 22, 2004 7561

Langlois and Le Nguyen
in 1H NMR (300 MHz) and 13C NMR (75.0 MHz) spectra are
given in ppm relative, respectively, to CHCl3 at 7.27 ppm and
to the middle line of CDCl3 at 77.14 ppm, or as otherwise
indicated.
was added under argon to a solution of 11 (340.0 mg, 1.96
mmol) in dry CH2Cl2, stirred at 0 °C. After 10 min, methane-
sulfonyl chloride (230 µL, 2.35 mmol) was added, and the
mixture was stirred at 0 °C for 2 h. The volatile constituents
were evaporated at rt under reduced pressure, and the residue
was purified by chromatography (eluent: CH2Cl2-CH3OH 95:
(()-2-N,N-Dim et h yla m in om et h yl-2-m et h oxyca r b on -
ylp yr r olid in -5-on e ((()-5). LiHMDS (1 M in THF, 0.88 mL,
0.88 mmol) was added under argon to a solution of methyl
pyroglutamate (60.0 mg, 0.42 mmol) in THF (2.1 mL) cooled
at -78 °C. The mixture was stirred for 1.5 h during which
time the temperature was allowed to reach -20 to -10 °C,
and then it was cooled again to -60 °C before the addition of
Eschenmoser’s salt (94 mg, 0.5 mmol). The mixture was stirred
at -60 °C for 0.5 h and at -60 to -20 °C for 1 h. After addition
of saturated solutions of NH4Cl (1 mL) and NaHCO3 (1 mL)
the product was rapidly extracted with CH2Cl2. The crude
product obtained after usual workup was purified by prepara-
tive TLC (eluent: CH2Cl2-CH3OH-NH4OH 92:8:0.1) affording
compound 5 (68.5 mg, 82%) as colorless crystals. Mp: 73 °C.
IR: 3220, 2952, 2828, 2778, 1737, 1699, 1456, 1265. MS (ESI,
CH3OH) m/z: 223 [(MNa)+, 100], 201 (MH)+. 1H NMR (300
MHz, CDCl3) δ: 6.64 (broad s), 3.75 (s, 3H), 2.86 (d, 1H, J )
13.4 Hz), 2.51 (d, 1H, J ) 13.4 Hz), 2.34 (m, 3H), 2.24 (s, 6H),
2.02 (m, 1H). 13C NMR (75.0 MHz, CD3OD δ ) 49.00 ppm)
δ: 180.2, 175.2, 68.3, 66.9, 53.0, 47.7, 30.7, 30.3. HRMS (ESI,
CH3OH): calcd for C9H17N2O3 (MH)+ 201.1239, found 201.1272.
When some hydrolysis of 5 occurred during the extraction
step, the aqueous layer could be acidified with CF3CO2H,
evaporated to dryness at 30 °C, and treated with CH2N2 in
Et2O to recover 5.
5) affording 13 as a colorless oil (422 mg, 86%). [R]24 ) +8.1
D
(c 0.98, CHCl3). IR: 3425, 3024, 3006, 2957, 1747 (sh), 1711,
1367, 1350. MS (ESI, CH3OH) m/z: 274 [(MNa+), 100]. 1H
NMR (300 MHz, CDCl3) δ: 6.84 (broad s, 1H), 4.54 (d, 1H, J
) 10.0 Hz), 4.24 (d, 1H, J ) 10.0 Hz), 3.81 (s, 3H), 3.05 (s,
3H), 2.41 (3 m, 3H), 2.16 (m, 1H). 13C NMR (75.0 MHz, CDCl3)
δ: 177.0, 171.5, 72.1, 64.6, 53.6, 37.8, 29.1, 27.7. HRMS (ESI,
CH3OH): calcd for C8H13NO6SNa (MNa)+ 274.0361, found
274.0371.
(S)-2-Azid om e t h yl-2-m e t h oxyca r b on ylp yr r olid in -5-
on e (14). Sodium azide (520 mg, 8.0 mmol) was added under
argon to a solution of 13 (400.0 mg, 1.6 mmol) in DMF (5.0
mL). The mixture was stirred at 65 °C for 72 h. The solvent
was evaporated at the same temperature, and the residue was
purified by chromatography (eluent: EtOAc) to give 14 (287
mg, 91%) as colorless crystals. Mp: 80 °C. [R]24 ) +34.4 (c
D
1.29, CHCl3). IR: 3426, 3005, 2956, 2928, 2111, 1745 (sh),
1710, 1404, 1334. MS (ESI, CH3OH) m/z: 419 (2MNa)+, [221
1
(MNa)+, 100], 199 (MH)+. H NMR (300 MHz, CDCl3) δ: 6.41
(broad s, 1H), 3.86 (d, 1H, J ) 12.5 Hz), 3.83 (s, 3H), 3.48 (d,
1H, J ) 12.5 Hz), 2.43 (2 m, 2H), 2.35 (m, 1H), 2.10 (m, 1H).
13C NMR (75.0 MHz, CDCl3) δ: 176.9, 172.3, 65.3, 58.0, 53.4,
29.4, 28.7. Anal. Calcd for C7H10N4O3: C, 42.42; H, 5.09.
Found: C, 42.51; H, 5.16.
(()-2-N,N-Dim eth yla m in om eth yl-5-oxop yr r olid in e-2-
ca r boxylic Acid (6). The methyl ester 5 in H2O was changed
into the corresponding carboxylic acid 6. MS (ESI, H2O + CH3-
CN): 225 (MK)+, 209 (MNa)+, 187 [(MH)+, 100]. 1H NMR (300
MHz, D2O δ ) 4.65 ppm) δ: 3.49 (d, 1H, J ) 13.7 Hz), 3.31 (d,
1H, J ) 13.7 Hz), 2.78 (s, 6H), 2.34 (m, 2H), 2.20 (m, 1H),
2.04 (m, 1H). 13C NMR (75.0 MHz, D2O, CD3OD δ ) 49.00
ppm) δ: 182.5, 178.2, 65.3, 64.3, 45.5, 32.4, 29.1. HRMS (ESI,
H2O + CH3CN): calcd for C8H14N2O3Na (MNa)+ 209.0902,
found 209.0935.
(S)-2-Am in om et h yl-2-m et h oxyca r b on ylp yr r olid in -5-
on e (15), Hyd r och lor id e. To a solution of 14 (150.0 mg, 0.758
mmol) in CH3OH (3.0 mL), was added 10% Pd/C (20.0 mg),
and the mixture was stirred under hydrogen (1 atm) for 18 h
at room temperature. The catalyst was filtered off on Celite
and washed with CH3OH. After evaporation to dryness, the
residue was disolved in 0.1 N HCl and gave rise to the
hydrochloride salt after evaporation (157.9 mg, 100%) as
colorless crystals. Mp: 158 °C. [R]23D ) -26.3 (c 2.02, CH3OH).
MS (ESI, CH3OH)) m/z: 173 [MH)+, 100]. 1H NMR (300 MHz,
D2O δ ) 4.65 ppm) δ: 3.72 (s, 3H), 3.37 (d, 1H, J ) 15.9 Hz),
3.32 (d, 1H, J ) 15.9 Hz), 2.44 (m, 3H), 2.17 (m, 1H). 13C NMR
(75.0 MHz, D2O, CD3OD δ ) 49.00 ppm) δ: 182.5, 173.9, 67.5,
54.8, 44.6, 30.0, 29.2. HRMS (ESI, CH3OH): calcd for C7H13N2O3
(MH)+ 173.0926, found 173.0926.
(S)-2-Hyd r oxym eth ylglu ta m ic Acid (10) a n d (S)-Meth -
yl 2-Hyd r oxym eth ylp yr oglu ta m a te (11). Acid ic Hyd r oly-
sis of Nitr ile 9. To powdered nitrile 9 (767 mg, 3.36 mmol)
under argon was added 6 N hydrochloric acid (70.0 mL), and
the mixture was stirred at 50 °C until dissolution and then
heated at 115 °C for 20 h. After being cooled at rt, the reaction
mixture was diluted with water and Et2O was added. The
aqueous layer was extracted with Et2O, and each organic layer
was washed twice with water. Evaporation of aqueous layers
provided crude diacid hydrochloride as pale yellow crystals
which were washed with a mixture Et2O-EtOH 9:1 to give
HMG hydrochloride (10, HCl, 705.5 mg, 98%).9,10 (S)-2-
Hydr oxym eth yl-2-m eth oxycar bon ylpyr r olidin -5-on e (11).
A solution of diazomethane in ether was added by parts over
2 h to a suspension of this dried diacid hydrochloride (652.0
mg, 3.0 mmol) in methanol (25.0 mL). The mixture was stirred
at rt for 18 h and evaporated under reduced pressure. The
residue was purified by chromatography (eluent: CH2Cl2-
MeOH 93:7) to give (S)-2-hydroxymethyl-2-methoxycarbon-
ylpyrrolidin-5-one 11 (346 mg, 67%) and N-methylated de-
rivative 12 (54 mg, ∼10%) as white crystals. Compound 11.
Mp: 132 °C. [R]D: +37 (c 0.45, CHCl3). IR: 3426, 2987, 1736,
1700. MS (ESI, CH3OH) m/z: 196 [(MNa)+, 100]. 1H NMR (300
MHz, CDCl3) δ: 6.49 (broad s, 1H), 3.99 (d, 1H, J ) 11.6 Hz),
3.79 (s, 3H), 3.65 (d, 1H, J ) 11.6 Hz), 2.42 (m, 2H), 2.29 (m,
1H), 2.12 (m, 1H). 13C NMR (75.0 MHz, CDCl3) δ: 178.5, 173.5,
67.8, 67.6, 53.0, 29.9, 27.2. HRMS (ESI, CH3OH): calcd for
C7H11NO4Na (MNa)+ 196.0586, found 196.0607.
(S)-2-N,N-Dim et h yla m in om et h yl-2-m et h oxyca r b on -
ylp yr r olid in -5-on e ((S)-5). Formaldehyde (37% w/v in water,
44 µL) and 10% Pd/C (7.0 mg) were added to a solution of 15,
h yd r och lor id e (63.0 mg, 0.3 mmol) in water (5.0 mL). The
mixture was stirrred under hydrogen (45-50 psi) for 24 h. The
catalyst was filtered off and washed with CH3OH, and the
solution was evaporated to dryness under vacuum. To the
residue in CH2Cl2 (5 mL) was added some drops of saturated
aqueous solution of NaHCO3, and the mixture was stirred at
rt for few minutes and dried over MgSO4. Evaporation to
dryness afforded (S)-5 (38.2 mg, 64%) as white crystals. Mp:
77 °C. [R]23 ) +24 (c 1.01, CHCl3). HRMS (ESI, CH3OH):
D
calcd for C9H17N2O3 (MH)+ 201.1239, found 201.1256. Spec-
troscopic data were identical to those of (()-5.
(S)-2-Meth oxycar bon yl-2-(N,N,N-tr im eth ylam m on iu m -
m eth yl)p yr r olid in -5-on e Iod id e ((S)-16). F r om (S)-2-N,N-
Dim eth yla m in o Der iva tive (S)-5. Iodomethane (0.3 mL), 4.8
mmol) was added to a solution of (S)-5 (32.0 mg, 0.16 mmol)
in THF (2.4 mL), and the mixture was stirred for 40 h at rt.
The solvent and excess of reagent were evaporated under
reduced pressure. The residue was washed several times with
CH2Cl2 to provide trimethylammonium iodide as white crystals
(47 mg, 86%). F r om (S)-2-Am in om eth yla ted Der iva tive 15.
Diisopropylethylamine (73 µL, 0.42 mmol) and iodomethane
(262 µL, 4.2 mmol) were successively added to a solution of
15 (24.2 mg, 0.14 mmol) in THF (2.1 mL). The mixture was
stirred at rt for 40 h. After evaporation to dryness, the white
(S)-2-Met h a n esu lfon yloxym et h yl-2-m et h oxyca r b on -
ylp yr r olid in -5-on e (13). Triethylamine (0.50 mL, 3.59 mmol)
(38) Mota, A. J .; Chiaroni, A.; Langlois, N. Eur. J . Org. Chem. 2003,
4187.
7562 J . Org. Chem., Vol. 69, No. 22, 2004

Diastereoselective Synthesis of Deoxydysibetaine
solid was washed with CH2Cl2. Trimethylammonium iodide
provide the diacide as hydrochloride (728 mg, >100%). A
solution of diazomethane in ether was added by parts to a
suspension of this diacid (700.0 mg, 2.95 mmol) in methanol
(30.0 mL) over 2 h. The mixture was stirred at rt for 18 h and
evaporated under reduced pressure. The residue was purified
by chromatography (eluent: CH2Cl2-CH3OH 9:1) to give
(2S,4S)-4-hydroxy-2-hydroxymethyl-2-methoxycarbonylpyrro-
lidin-5-one 29 (328.5 mg, 59%) and N-methylated derivative
30 (36.2 mg, 6%) as white solids. (2S,4S)-4-Hyd r oxy-2-
h yd r oxym eth yl-2-m eth oxyca r bon ylp yr r olid in -5-on e 29:
[R]24D ) -18.3 (c 0.73, CH3OH). IR: 3299 (broad), 2956, 1701,
1436, 1306. MS (ESI, CH3OH) m/z: 212 (MNa)+. 1H NMR (300
MHz, D2O δ ) 4.65 ppm) δ: 4.35 (dd, 1H, J ) J ′ ) 8.6 Hz),
3.83 (d, 1H, J ) 11.7 Hz), 3.66 (s, 3H), 3.56 (d, 1H, J ) 11.7
Hz), 2.63 (dd, 1H, J ) 13.5, 8.6 Hz), 1.84 (dd, 1H, J ) 13.5,
8.6 Hz). 13C NMR (75.0 MHz, D2O, CD3OD δ ) 49.00 ppm) δ:
179.6, 175.2, 69.2, 66.6, 65.6, 54.4, 36.5. HRMS (ESI, CH3-
OH): calcd for C7H11NO5Na (MNa)+ 212.0535, found 212.0540
(100).
(S)-16 was obtained as white crystals (45.0 mg, 94%). [R]24
)
D
-12.5 (c 0.77, CH3OH). MS (ESI, CH3OH) m/z: 215 (M+, 100).
1H NMR (300 MHz, D2O δ ) 4.65 ppm) δ: 4.10 (d, 1H, J ) 16
Hz), 3.80 (s, 3H), 3.77 (d, 1H, J ) 16 Hz), 3.11 (s, 9H), 2.60-
2.32 (3 m, 3H), 2.21 (m, 1H). 13C NMR (75.0 MHz, D2O, CD3-
OD δ ) 49.00 ppm) δ: 182.1, 173.6, 70.7, 64.5, 55.7, 55.3, 33.5,
29.3. HRMS (ESI, H2O + CH3CN): calcd for C10H19N2O3 (M)+
215.1396, found 215.1421.
(S)-2-Car boxylate-2-(N,N,N-tr im eth ylam on iu m m eth yl)-
p yr r olid in e-5-on e (S)-2: (S)-Deoxyd ysibeta in e (2). Resine
Dowex 550A (HO- form, 327 mg) was added to a solution of
(S)-16 (46.7 mg, 0.137 mmol) in dry methanol (2.0 mL). The
mixture was stirred at 55 °C for 12 h and cooled, and the resin
was filtered off and washed with methanol. Evaporation to
dryness gave rise to (S)-deoxydysibetaine 2 as white crystals
(29.5 mg, 100%).6
Under the same conditions, (()-2 was prepared from (()-
16 (85%), which was obtained by N-methylation of (()-5 (73%).
(2S,4S)-4-Hyd r oxy-2-m eth oxyca r bon yl-2-(m eth ylsu lfo-
n ylm eth yl)p yr r olid in -5-on e (31). A solution of mesyl chlo-
ride (67 µL, 0.87 mmol) was slowly added to a solution of 29
(151.2 mg, 0.8 mmol) in pyridine (7.5 mL) cooled at 0 °C. The
mixture was stirred at the same temperature for 0.5 h before
the addition of methanol. After being stirred for additional 0.25
h, the solvents were evaporated under vacuum at rt and the
products were separated by preparative TLC (eluent: EtOAc,
then CH2Cl2-CH3OH 95:5) to afford (2S,4S)-4-hydroxy-2-
methoxycarbonyl-2-(methylsulfonylmethyl)pyrrolidin-5-one 31
(80 mg, 38%), (2S,4S)-2-hydroxymethyl-2-methoxycarbonyl-4-
methylsulfonyloxypyrrolidin-5-one 32 (17.4 mg, 8%), and
dimesylate 33 (14.5 mg, 3%), together with starting diol 29
(61.8 mg, 41%). (2S,4S)-4-Hyd r oxy-2-m eth oxyca r bon yl-2-
(m eth ylsu lfon ylm eth yl)pyr r olidin -5-on e 31: [R]24D ) -20.7
(c 0.41, CHCl3). IR: 3335, 1713, 1436, 1354, 1245, 1174. MS
(ESI, CH3OH) m/z: 290 [(MNa)+, 100]. 1H NMR (300 MHz,
CDCl3) δ: 6.97 (broad s, 1H), 4.63 (d, 1H, J ) 10.1 Hz), 4.42
(dd, 1H, J ) 8.5, 7.5 Hz), 4.35 (d, 1H, J ) 10.1 Hz), 3.83 (s,
3H), 3.09 (s, 3H), 2.71 (dd, 1H, J ) 13.8, 8.5), 2.08 (dd, 1H, J
) 13.8, 7.5 Hz). 13C NMR (75.0 MHz, CDCl3): δ 176.9, 171.0,
71.9, 68.2, 62.3, 53.7, 37.7, 36.3. HRMS (ESI, CH3OH): calcd
for C8H13O7NSNa (MNa)+ 290.0310, found 290.0316 (100).
(2S,4S)-2-Azid om et h yl-4-h yd r oxy-2-m et h oxyca r b on -
ylp yr r olid in -5-on e (34). Sodium azide (75 mg, 1.15 mmol)
was added to a solution of monomesylate 31 (61.0 mg, 0.23
mmol) in DMF (0.6 mL), and the mixture was stirred at rt for
72 h. The solvent was evaporated under vacuum, and the
product was purified by preparative TLC (eluent: EtOAc) to
give methyl 2-azidomethyl-4-hydroxypyroglutamate 34 (27.0
mg, 70%) as white crystals. Mp ) 118 °C. [R]24D ) +1.0 (c 0.65,
CH3OH). IR: 3277, 2917, 2111, 1738 (sh), 1710, 1436, 1278.
MS (ESI, CH3OH) m/z: 237 [(MNa)+, 100)]. 1H NMR (300
MHz, CDCl3) δ: 6.39 (broad s, 1H), 4.38 (dd, 1H, J ) 8.6, 7.8
Hz), 3.98 (d, 1H, J ) 12.1 Hz), 3.84 (s, 3H), 3.53 (d, 1H, J )
12.1 Hz), 3.12 (broad, OH), 2.70 (dd, 1H, J ) 13.8, 7.9 Hz),
2.03 (dd, 1H, J ) 13.8, 7.7 Hz). 13C NMR (75.0 MHz, D2O, CD3-
OD δ ) 49.0 ppm) δ: 179.6, 174.5, 69.1, 66.0, 57.0, 54.6, 37.6.
HRMS (ESI, CH3OH): calcd for C7H10N4O4Na (MNa)+ 237.0600,
found 237.0592.
(5R)-5-Cya n o-7-h yd r oxy-2-p h en yl-3-oxa -1-a za [3.3.0]-
bicycloocta n e-8-on es (26) a n d (27). With 2-P h en ylsu lfo-
n yl-3-p h en yloxa zir id in e. A solution of KHMDS in toluene
(0.5 M, 0.8 mL, 0.4 mmol) was added dropwise under argon to
a stirred solution of nitrile 9 (72.5 mg, 0.32 mmol) at -78 °C.
The mixture was stirred for 1 h at - 78 °C, and a solution of
2-phenylsulfonyl-3-phenyloxaziridine (101.0 mg, 0.39 mmol)
in THF (0.8 mL) was added. The mixture was stirred for 45
min before addition of a saturated aqueous solution of NH4Cl
and was then allowed to warm to rt. After extraction with CH2-
Cl2 and usual workup, the crude product was purified by
preparative TLC (eluent: CH2Cl2-CH3OH 93.5:6.5) to give two
diastereomers 26 (less polar: 31.2 mg, 40%) and 27 (9.2 mg,
11.9%) as white crystals. With MoOP H. A solution of KHMDS
in toluene (0.5 M, 18.0 mL, 9.0 mmol) was added dropwise
under argon to a stirred solution of nitrile 9 (1.00 g, 4.38 mmol)
in anhydrous THF (44.0 mL) at - 78 °C. The mixture was
stirred for 10 min at - 78 °C, the cooling bath was removed
for 10 min, and the mixture was cooled again at -78 °C before
the addition of MoOPH (2.80 g, 6.45 mmol) at once. After being
stirred for 2 h at the same temperature, a saturated aqueous
solution of NH4Cl (20 mL) was added, and the mixture was
allowed to reach rt and was extracted with EtOAc. After usual
workup, the product was purified by chromatography (eluent:
CH2Cl2-CH3OH 97:3) affording two diastereomers 26 and 27
(867 mg, 81%) (7S: 7R ) 80:1). (5R,7S)-5-Cya n o-7-h yd r oxy-
2-p h en yl-3-oxa -1-a za bicyclo[3.3.0]octa n -8-on e 26 (856 mg,
80%). Mp: 75 °C. [R]24 ) +60.3 (c 0.68, CHCl3). IR: 3346,
D
3022, 2877, 1736. MS (ESI, CH3OH) m/z: 511.0 (2MNa)+, 266.9
1
(MNa)+. H NMR (300 MHz, CDCl3) δ: 7.53 (m, 2H), 7.43 (m,
3H), 6.32 (s, 1H), 4.93 (dd, 1H, J ) 11.1, 7.9 Hz), 4.56 (d, 1H,
J ) 9.3 Hz), 3.92 (d, 1H, J ) 9.3 Hz), 3.56 (broad s, 1H), 3.17
(dd, 1H, J ) 13.0, 7.9 Hz), 2.29 (dd, 1H, J ) 13.0, 11.1 Hz).
13C NMR (75.0 MHz, CDCl3) δ: 176.4, 135.4, 129.9, 128.9,
126.7, 119.0, 89.6, 76.2, 71.5, 57.6, 40.3. Anal. Calcd for
C
13H12N2O3 : C, 63.92; H, 4.95; N, 11.47. Found: C, 63.43; H,
5.01; N, 11.47. (5R,7R)-5-Cya n o-7-h yd r oxy-2-p h en yl-3-oxa -
1-a za bicyclo[3.3.0]octa n -8-on e 27 (11 mg, 1%). Mp: 159 °C.
[R]24 ) +129.5 (c 0.26, CHCl3). IR: 3774, 2920, 2856, 1715,
D
1455, 1360, 1343. MS (ESI, CH3OH) m/z: 283 (MK)+, 267
[(MNa)+, 100], 245 (MH)+. 1H NMR (300 MHz, CDCl3) δ: 7.56
(m, 2H), 7.40 (m, 3H), 6.27 (s, 1H), 4.58 (d, 1H, J ) 9.0 Hz),
4.53 (dd, 1H, J ) 6.6, 2.0 Hz), 3.75 (d, 1H, J ) 9.0 Hz), 2.73
(dd, 1H, J ) 14.5, 2.0 Hz), 2.53 (dd, 1H, J ) 14.5, 6.6 Hz). 13C
NMR (75.0 MHz, CDCl3): δ 176.0, 135.8, 129.9, 129.1, 126.8,
119.5, 89.9, 76.2, 73.9, 60.6, 38.8.
(2S,4S)-2-Am in om eth yl-4-h yd r oxy-2-m eth oxyca r bon -
ylp yr r olid in -5-on e (35) a n d (2S,4S)-2-N,N-Dim eth yla m i-
n om et h yl-4-h yd r oxy-2-m et h oxyca r b on ylp yr r olid in -5-
on e (36). To azide 34 (22.4 mg, 0.105 mmol) in dry CH3OH
(0.9 mL) was added 10% Pd/C (3.5 mg), and the mixture was
stirred under hydrogen (1 atm) for 19 h at rt. The catalyst
was filtered off on Celite and washed with dry CH3OH and
then dry CH3OH containing some amounts of NH3. Evapora-
tion to dryness provided the labile aminomethyl derivative 35
(18.7 mg, 95%). 1H NMR (300 MHz, D2O δ ) 4.65 ppm) δ: 4.31
dd, 1H, J ) J ′ ) 8.3 Hz), 3.63 (s, 3H), 2.95 (d, 1H, J ) 13.8
Hz), 2.83 (d, 1H, J ) 13.8 Hz), 2.64 (dd, 1H, J ) 13.6, 8.3 Hz),
1.82 (dd, 1H, J ) 13.6, 8.3 Hz). N-Dim eth yla tion to 36.
(2S,4S)-4-Hyd r oxy-2-h yd r oxym eth yl-2-m eth oxyca r bo-
n ylp yr r olid in -5-on e (29) fr om 26. Hyd r olysis of 26 w ith
6 N HCl. HCl (6 N, 80.0 mL) was added under argon to the
hydroxylated lactam 26 (750.0 mg, 3.07 mmol), the mixture
was stirred at 40 °C until complete dissolution, and the
solution was heated at 110 °C for 72 h. After being washed
with Et2O, the aqueous layer was evaporated to dryness to
J . Org. Chem, Vol. 69, No. 22, 2004 7563

Langlois and Le Nguyen
Formaldehyde (37%w/v in water, 6.0 µL and 10% Pd/C (2.0
mg) were added to a solution of 35, h yd r och lor id e (10.2 mg,
0.045 mmol) in water (2 mL). The mixture was stirrred under
hydrogen (45 psi) for 48 h. The catalyst was filtered off on
Celite and washed with H2O, and the solution was evaporated
to dryness under vacuum. To the residue in EtOAc (5 mL) was
added dried NaHCO3, and the mixture was stirred at rt for 5
min and filtered. Evaporation to dryness afforded rather
unstable 36 (10.0 mg, 100%) which was immediately converted
into its trimethylammonium iodide 37.
-30 °C for 10 min, and then it was cooled again at -78 °C
before the addition of MoOPH (124.9 mg, 0.288 mmol). After
additional stirring at the same temperature for 1.75 h, the
mixture was allowed to reach -45 °C for 0.25 h before the
addition of aqueous saturated solution of NH4Cl. The product
was extracted with EtOAc and the organic layer was washed
rapidly with cooled water. Usual workup and purification by
preparative TLC (eluent: EtOAc, then Et2O) gave rise to rather
unstable (2S*,4R*)-1-tert-butoxycarbonyl-2-N,N-dimethylami-
nomethyl-4-hydroxy-2-methoxycarbonylpyrrolidin-5-one 39
(66%) together with diastereomer 40 (8%), 3-oxo derivative 41
(3%), and starting product (6%). 39. IR (film): 3389, 2978,
2929, 2856, 1789, 1745, 1714. MS (ESI, CH3OH) m/z: 339
(MNa)+, 239 (100), 217. 1H NMR (300 MHz, CDCl3) δ: 4.86
(dd, 1H, J ) J ′) 7.5 Hz), 3.74 (s, 3H), 3.09 (d, 1H, J ) 11.2
Hz), 2.96 (d, 1H, J ) 11.2 Hz), 2.58 (dd, 1H, J ) 10, 7.5 Hz),
2.28 (s, 6H), 2.06 (dd, 1H, J ) 10, 7.5 Hz). 13C NMR (75.0 MHz)
δ: 175.1, 171.8, 148.9, 84.3, 68.8, 67.13, 61.4, 52.5, 48.1, 37.8,
28.3. HRMS (ESI, CH3OH): calcd for C14H24N2O6Na (MNa)+
339.1532, found 339.1530.
(2S,4S)-4-Hyd r oxy-2-m eth oxyca r bon yl[(N,N,N-tr im e-
t h yla m m on iu m )m et h yl]p yr r olid in -5-on e Iod id e (37).
F r om (2S,4S)-2-N,N-Dim eth yla m in om eth yl-4-h yd r oxy-2-
m eth oxyca r bon ylp yr r olid in -5-on e 36. Iodomethane (0.12
mL, 1.93 mmol) was added to a solution of 36 (10.0 mg, 0.046
mmol) in THF (1.2 mL), and the mixture was stirred for 24 h
at rt before a second addition of iodomethane (0.04 mL). After
being stirred for an additional 24 h, the solvent and excess of
reagent were evaporated under reduced pressure. The residue
was washed several times with CH2Cl2 to provide trimethy-
lammonium iodide 37 as a white solid (13.9 mg, 84%). [R]24
(2S*,4R*)-4-Hyd r oxy-2-m eth oxyca r bon yl-[N,N,N-tr im -
et h yla m m on iu m )m et h yl]p yr r olid in -5-on e Iod id e (43).
(2S*,4R*)-2-N,N-Dim eth ylam in om eth yl-4-h ydr oxy-2-m eth -
oxyca r bon ylp yr r olid in -5-on e 42 (Tr iflu or oa ceta te). A
solution of CF3CO2H in dry CH2Cl2 (10% v/v, 0.162 mL) was
added to a solution of 39 (26.1 mg, 0.08 mmol) in dry CH2Cl2
and the mixture was stirred at 34 °C for 23 h. Evaporation to
dryness at room temperature afforded N-deprotected 42 as its
trifluoroacetate (27.5 mg, 100%). MS (ESI, H2O) m/z: 239
D
) -9.6 (c 0.3, CH3OH). 1H NMR (300 MHz, D2O δ ) 4.65 ppm)
δ: 4.29 (dd, 1H, J ) 8.3, 5.8 Hz), 4.05 (d, 1H, J ) 15.0 Hz),
3.80 (d, 1H, J ) 15.0 Hz), 2.63 (dd, 1H, J ) 14.4, 8.3 Hz), 2.06
(dd, 1H, J ) 14.4, 5.8 Hz). Dir ectly fr om (2S,4S)-2-Am i-
n om et h yl-4-h yd r oxy-2-m et h oxyca r b on ylp yr r olid in -5-
on e 35. Iodomethane (55 µL, 0.88 mmol) was added to a
solution of 35 (8.2 mg, 0.044 mmol) in THF (0.66 mL). The
mixture was stirred at rt for 16 h before the addition of
diisopropylethylamine (14 µL, 0.08 mmol) and iodomethane
(27 µL), and the mixture was stirred for an additional 24 h.
After evaporation to dryness, the residue was washed 6 times
with small amounts of CH2Cl2 to give trimethylammonium
1
[(MNa)+, 100], 217 (MH)+. H NMR (300 MHz, D2O δ ) 4.65
ppm) δ: 4.40 (dd, 1H, J ∼ J ′∼ 8 Hz), 3.75 (masked d, 1H, J )
14.5 Hz), 3.74 (s, 3H), 3.43 (d, 1H, J ) 14.5 Hz), 2.78 (broad s,
6H), 2.58 (dd, 1H, J ) 14, 8 Hz), 2.15 (dd, 1H, J ) 14, 8.8 Hz).
HRMS (ESI, H2O): calcd for C9H16N2O4Na (MNa)+ 239.1008,
found 239.1009. N-Meth yla tion to 43. Diisopropylethylamine
(16 µL) and iodomethane (75 µL) were successively added to a
solution of trifluoroacetate 42 (12.0 mg, 0.036 mmol) in dry
THF (0.6 mL). The mixture was stirred at rt for 46 h, and
volatile constituents were evaporated under reduced pressure
at rt. The residue was washed several times with small
amounts of CH2Cl2 and dried to provide trimethylammonium
1
iodide 37 (comparison of H NMR) as a white solid (9.5 mg,
61%).
Dysibeta in e (1). Resine Dowex 550A (HO- form, 92 mg)
was added to a solution of 37 (11.9 mg, 0.33 mmol) in methanol
(1.0 mL). The mixture was stirred at 55 °C for 14 h and cooled
to rt, and the resine was filtered off and washed with
methanol. Evaporation to dryness gave rise to dysibetaine 1
as white solid (7.2 mg, 100%). [R]24D ) -6.1 (c 0.15, H2O); [lit.4a
[R]D ) -7.1 (c 0.26, H2O)]. MS (ESI, H2O + CH3CN) m/z: 255
(MK)+, 239 (MNa)+, 217 [(MH)+, 100]. 1H NMR (300 MHz, D2O
δ ) 4.65 ppm) δ: 4.25 (dd, 1H, J ) 7.9, 5.4 Hz), 3.94 (d, 1H,
J ) 14.0 Hz), 3.64 (d, 1H, J ) 14.0 Hz), 3.11 (s, 9H), 2.59 (dd,
1H, J ) 13.9, 7.9 Hz), 1.90 (dd, 1H, J ) 13.9, 5.4 Hz).13C NMR
(75.0 MHz, D2O, CD3OD δ ) 49.00 ppm) δ: 179.6, 176.8, 73.0,
69.0, 64.1, 55.6, 42.3: identical to described data.4a HRMS
(ESI): calcd for C9H16N2O4Na (MNa)+ 239.1008, found 239.1008.
(()-1-ter t-Bu toxycar bon yl-2-N,N-dim eth ylam in om eth yl-
2-m eth oxyca r bon ylp yr r olid in -5-on e (38). To a stirred
solution of (()-5 (186.2 mg, 0.93 mmol) in CH3CN (9.3 mL)
were successively added under argon DMAP (117.4 mg, 0.96
mmol) and (Boc)2O (303.8 mg, 1.39 mmol). After the mixture
was stirred at rt for 3 h, the solvent was evaporated under
reduced pressure at 30 °C. The residue was purified by
chromatography (eluent: EtOAc) providing N-Boc derivative
38 as a colorless oil (209.5 mg, 75%). IR: 2979, 2953, 2871,
2826, 2775, 1793, 1744, 1716, 1458, 1370, 1315, 1291, 1155.
1
iodide 43 as a white solid (9.2 mg, 71%). H NMR (300 MHz,
D2O δ ) 4.65 ppm) δ: 4.48 (dd, 1H, J ) 9.6, 7.8 Hz), 4.08 (d,
1H, J ) 14.0 Hz), 3.76 (s, 3H), 3.64 (d, 1H, J ) 14.0 Hz), 3.05
(s, 9H), 2.60 (dd, 1H, J ) 14.0, 7.8 Hz), 2.16 (dd, 1H, J ) 14.0,
9.6 Hz). 13C NMR (75.0 MHz, D2O) δ: 178.4, 171.9, 69.5, 66.8,
54.5, 54.3, 41.1.
(()-4-epi-Dysibeta in e (3). Resine Dowex 550A (HO- form,
58 mg) was added to a solution of 43 (8.8 mg, 0.025 mmol) in
dry methanol (1.0 mL). The mixture was stirred at 55 °C for
24 h and cooled, and the resin was filtered off and washed
with methanol. Evaporation to dryness gave rise to racemic
4-epi-dysibetaine 3 as a white solid (5.3 mg, 100%). MS (ESI,
H2O + CH3CN) m/z: 239 (MNa)+, 144 (100). 1H NMR (300
MHz, D2O δ ) 4.65 ppm) δ: 4.46 (dd, 1H, J ) 10.0, 7.9 Hz),
3.93 (d, 1H, J ) 14.0 Hz), 3.48 (d, 1H, J ) 14.0 Hz), 3.02 (s,
9H), 2.51 (dd, 1H, J ) 13.3, 7.9 Hz), 1.96 (dd, 1H, J ) 13.3,
10.0 Hz) identical to described data for (2S,4R)-4-epi-dysi-
betaine.4a
1
MS (ESI, CH3CN) m/z: 323 (MNa)+, 264, 201 (100). H NMR
(300 MHz, CDCl3) δ: 3.73 (s, 3H), 3.11 (d, 1H, J ) 14.6 Hz),
2.90 (d, 1H, J ) 14.6 Hz), 2.78 (m, 1H), 2.54 (m, 1H), 2.28 (s,
6H), 2.28 (masked m, 1H), 2.01 (m, 1H), 1.49 (m, 9H). 13C NMR
(75.0 MHz, CDCl3) δ: 174.8, 173.0, 149.4, 83.7, 69.2, 61.6, 52.4,
48.2, 31.5, 28.0, 27.0. HRMS (ESI, CH3CN): calcd for
Ack n ow led gm en t. We are grateful to Professor J .-
Y. Lallemand, Director of ICSN, for a grant (B.K.L.N.).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 7-9, 16, 2, 17-22, 24, 25, and 28,
spectral data of 12, 17-22, 24, 25, 30, 32, 33, 40, and 41, and
1H NMR spectra of compounds 5-7, 11, 13, 14, 16-27, 29,
31, 39, and 42. This material is available free of charge via
the Internet at http://pubs.acs.org.
C
14H24O5N2Na (MNa)+ 323.1583, found 323.1554.
(2S*,4R*)-1-ter t-Bu t oxyca r b on yl-2-N,N-d im et h yla m i-
n om et h yl-4-h yd r oxy-2-m et h oxyca r b on ylp yr r olid in -5-
on e (39). A solution of KHMDS (0.5 M in toluene, 0.85 mL,
0.425 mmol) was added under argon to a stirred solution of
dried 38 (57.8 mg, 0.193 mmol) in anhydrous THF (1.90 mL)
at -78 °C. The mixture was stirred at -78 °C for 0.5 h and at
J O040216+
7564 J . Org. Chem., Vol. 69, No. 22, 2004