Preparation and biological evaluation of pyrrolidinediols and pyrrolidine N-oxides from D-ribose using the nitrone approach

Article abstract of DOI:10.1002/1099-0690(200107)2001:13<2547::AID-EJOC2547>3.0.CO;2-H

The transformation of 3,4-isopropylidenedioxy-5-methylpyrrolidine 1-oxides with various 2-substituents into the free diols and, by reduction, into the corresponding pyrrolidinediols (iminoglycitols) is described. The pyrrolidine N-oxides were derived from

Full text of DOI:10.1002/1099-0690(200107)2001:13<2547::AID-EJOC2547>3.0.CO;2-H

FULL PAPER
Preparation and Biological Evaluation of Pyrrolidinediols and Pyrrolidine
N-Oxides from
-Ribose Using the Nitrone Approach[‡] [‡‡]
D
Andreas M. Palmer[a] and Volker Jäger*[a]
Keywords: CopeϪHouse cyclization / 3,4-Dihydroxypyrrolidine 1-oxides / 2,5-Disubstituted 3,4-dihydroxypyrrolidines /
Glycosidase inhibitors / Structure-activity relationships
The transformation of 3,4-isopropylidenedioxy-5-methylpyr- as described earlier. The biological activity of these com-
rolidine 1-oxides with various 2-substituents into the free di-
ols and, by reduction, into the corresponding pyrrolidinediols while all the tested pyrrolidine N-oxides proved inactive,
(iminoglycitols) is described. The pyrrolidine N-oxides were
some of the new iminopolyols showed moderate activity
derived from -ribose via unsaturated hydroxylamines, with -fucosidases and α- -glucosidases, with Ki values
against α-
of 30−40 µ
pounds with respect to glycosidase inhibition was examined;
D
L
D
the key steps of nitrone addition and Cope−House cyclization
M.
Introduction
(see Figure 1). The piperidine 1-deoxy--fuconojirimycin
(DFJ, B), the imino analogue of the natural substrate, is
the most potent inhibitor known so far, displaying highly
selective, competitive inhibition.[31Ϫ34]
Many polyhydroxypyrrolidines (1,4-iminoglycitols) ex-
hibit biological activity towards glycosidases, inhibiting the
enzymatic
degradation
of
oligosaccharides
and
polysaccharides.[3Ϫ14] This is explained by their ability to
mimic the exo-protonated glycoside or transition states ad-
opted by the natural substrate in the course of the
hydrolysis.[13Ϫ21]
Glycosidases are also responsible for the catabolism of
glycoproteins.[22] Since the ligand-receptor interaction be-
tween glycoconjugates located on the cell surface and cer-
tain proteins regulates important biological processes[23]
Ϫ
such as cell-cell recognition,[24] inflammation[25] and cell in-
fection[24] Ϫ glycosidase inhibitors might also constitute
powerful tools in the treatment of certain diseases.[15,22Ϫ27]
In particular, inhibitors of fucosidases might be of thera-
peutic value, since the α--fucopyranosyl fragment A (6-de-
oxy--galacto) is present in numerous oligosaccharides and
glycoconjugates.[25,28,29] Recognition of the α--fucoside
moiety in these glycoconjugates by specific lectins is of great
importance for pathological modifications of normal cell
behaviour, such as tumour growth, formation of meta-
stases[30] or exaggerated leukocyte recruitment during in-
flammatory diseases.[25] High activity of fucosidases and en-
richment of fucosyl-containing structures in cancer cells has
been observed.[28]
Consequently, much effort has been devoted towards the
synthesis and structure-activity analysis of fucosidase inhib-
itors, and a variety of such compounds have been found
Figure 1. α--Fucopyranoside (6-deoxy--galacto, A) and fucosid-
ase inhibitors BϪK; Ki values refer to inhibition of α--fucosidase
derived from either [a]bovine epididymis or [b]bovine kidney
[‡]
Synthesis of Glycosidase-Inhibiting Iminopolyols by CopeϪ
House Cyclization of Unsaturated Hydroxylamines, IV. Ϫ
In contrast to DFJ (B) and related piperidine inhibitors,
where epimers often show a total loss of inhibitory activity,
polyhydroxypyrrolidine inhibitors retain their activity and
a variety of configurations is tolerated (Figure 1). Wong
and co-workers have developed a chemo-enzymatic syn-
Part III, II and I: See ref.[2]
[‡‡]
See Ref.[1]
[a]
Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: (internat.) ϩ 49-(0)711/685-4321
E-mail: jager.ioc@po.uni-stuttgart.de
Eur. J. Org. Chem. 2001, 2547Ϫ2558
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0713Ϫ2547 $ 17.50ϩ.50/0
2547

A. M. Palmer, V. Jäger
FULL PAPER
thesis for the iminopolyols DϪF and have interpreted the
(i) We were interested in the preparation of various 3,4-
differing activities in terms of lower steric demand, as com- dihydroxypyrrolidine 1-oxides 15Ϫ20 (R ϭ H, Me, vinyl,
pared to that of the six-membered counterparts.[35] Re- Ph), in order to test the hypothesis that these compounds
cently, several highly active pyrrolidines and N-hydroxy- might constitute a new class of glycosidase inhibitors.[36]
pyrrolidines have been found both in our group[36Ϫ38] and This idea relates to the fact that these N-oxide structures
by Defoin and co-workers.[39,40] These iminopolyols GϪK not only show all properties necessary for effective glycosid-
constitute the most powerful fucosidase inhibitors of the ase inhibition Ϫ that is, (i) a basic heteroatom that may be
pyrrolidine series known so far, and likewise show that the protonated and mimic the intermediates occurring in the
imine J, and its hydrogensulfite adduct K, or lipophilic course of the hydrolysis, and (ii) ring substituents analogous
groups at the 2-position are more effective than the ‘‘usual’’ to those in the natural substrate Ϫ but also possess an addi-
hydroxymethyl substituent (cf. D, E, F). Concerning the tional function (N-oxy) that might produce improved hy-
configuration, the most active pyrrolidine structures in drogen bonding with the respective amino acids of the
terms of fucosidase inhibition exhibit the ‘‘natural’’ all-cis active site of the enzyme.
orientation of the substituents at positions 3, 4, and 5.[37Ϫ40]
(ii) In order to determine the inhibitory activity of
In the preceding paper of this series, we have presented (3S,4R,5R)-3,4-dihydroxy-5-methylpyrrolidines, we sought
stereoselective syntheses of 3,4-dihydroxypyrrolidine 1-ox- access to compounds 21Ϫ31, bearing a variety of 2-sub-
ides such as 9Ϫ14 (Scheme 1), taking advantage of substitu- stituents: R ϭ H (parent), R ϭ methyl, vinyl, phenyl (lipo-
ent variation in the nitrone addition step and of the philic), R ϭ hydroxymethyl, carboxy (hydrogen donor-ac-
CopeϪHouse cyclization of the corresponding unsaturated ceptor properties), methoxycarbonyl (electron-withdrawing,
hydroxylamines 3Ϫ8 derived from -ribose (1, still lipophilic). It was intended to synthesize both 2-epi-
Scheme 1).[41] Since this reaction gives access to 4,5-trans- mers of the 2-methyl- and 2-carboxypyrrolidines 22 and 23
pyrrolidine 1-oxides (e.g., 9Ϫ14), it provides a valuable tool (30 and 31, respectively), in order to evaluate the influence
with which to address the question of whether this all-cis of the orientation of these substituents on both the activity
relationship is a necessary prerequisite for fucosidase inhibi- and the selectivity of glycosidase inhibition. The prepara-
tion, as well as for further evaluation of 2-substituents.
tion of the N-debenzylated analogues 26 and 27 [R ϭ H,
(2S)-methyl] was also planned, to estimate the contribution
of this lipophilic group to the biological activity of these
compounds.
Results and Discussion
Preparation of 3,4-Dihydroxy-5-methylpyrrolidine 1-Oxides
15؊20 and Pyrrolidines 21؊27 with Lipophilic 2-
Substituents
The acetonide protecting groups in the pyrrolidine N-ox-
ides 9Ϫ14[41] were removed using aqueous hydrochloric acid
in methanol (Scheme 2). The 3,4-dihydroxypyrrolidine 1-
oxides 15Ϫ20 were obtained as hydrochlorides, each in the
form of an oil. After purification using acidic ion exchange
resin (Dowex 50WX8, Hϩ form), however, crystalline
samples of the pyrrolidine N-oxides 15Ϫ20 were isolated.
The reduction of the pyrrolidine N-oxides 9Ϫ13 was ef-
fected with acid-activated zinc dust and is summarized in
Scheme 1. Synthesis of pyrrolidine N-oxides 9Ϫ14 from -ribose
(1) using nitrone addition/CopeϪHouse cyclization as key steps[41]
Here, we report on our findings concerning the trans-
formation of these pyrrolidine N-oxides into new candidates
for glycosidase inhibition assays (Figure 2) and on the re-
sults of these biological tests:
Figure 2. Pyrrolidine N-oxides 15Ϫ20 and pyrrolidinediols 21Ϫ31:
target structures and new candidates for glycosidase inhibition as-
says
Scheme 2. Preparation of 3,4-dihydroxy-5-methylpyrrolidine 1-ox-
ides 15Ϫ20 [(2S) derivatives: 2,3-trans; (2R) derivatives: 2,3-cis;
numbering does not apply to 9 and 15]
2548
Eur. J. Org. Chem. 2001, 2547Ϫ2558

Preparation and Biological Evaluation of Pyrrolidinediols and Pyrrolidine N-Oxides
FULL PAPER
Scheme 3; the corresponding, analytically pure 3,4-isoprop- the resulting pyrrolidine N-oxide, and cleavage of the furyl
ylidenedioxypyrrolidines 32Ϫ36 were obtained in 49Ϫ84% moiety using ruthenium trichloride/sodium periodate.[47Ϫ50]
yield.
Route (i): Several cyanide sources (sodium cyanide, di-
ethylaluminium cyanide, lithium cyanide) were employed to
effect this addition to the nitrone 2.[41] In each case, how-
ever, a complex reaction mixture resulted. When lithium cy-
anide was used, the amide 37 Ϫ probably formed by the
known ‘‘Beckmann’’ rearrangement of nitrones[51] Ϫ and
the lactam 38 were isolated in place of the expected 2-
cyanopyrrolidine 1-oxide L (Scheme 5).
Scheme 3. Reduction of pyrrolidine N-oxides 9Ϫ13 [(2S) derivat-
ives: 2,3-trans; (2R) derivatives: 2,3-cis; reverse numbering for 9, 32]
For preparation of the free iminopolyols, the acetonide
groups on the above N-benzylpyrrolidines 32Ϫ36 were first
removed with aqueous hydrochloric acid in methanol, fur-
nishing the 3,4-dihydroxypyrrolidines 21Ϫ25 as hydro-
chlorides (Scheme 4). The iminopolyols 22, 24, and 25 were
obtained as pure and crystalline hydrochloride salts from 2-
propanol/diethyl ether; the diols 21 and 23 were purified
using acidic ion exchange resin Dowex 50WX8. Next, the
N-benzyl groups on the pyrrolidines 21 and 22 were split
off by hydrogenation with Pearlman’s catalyst,[42] to give 26
and 27, respectively (Scheme 4).
Scheme 5. Target structures with a hydrophilic 2-substituent 28Ϫ31
and first attempt (i); addition of lithium cyanide to the nitrone 2:
(a) LiCN, CH2Cl2, Ϫ20 °C, 5 h; (b) CHCl3, room temp., 5 d
Scheme 4. Deprotection of iminopolyols 32Ϫ36: (a) conc. HCl/
MeOH/H2O (1:8:8), room temp., 2Ϫ16 h; 21 and 23 purified with
Dowex 50WX8 (Hϩ form); (b) H2 (4 bar), Pd(OH)2/C, MeOH,
room temp., 2Ϫ4 d; compound 26: subsequent addition of HBr
(48%). Ϫ Numbering does not apply to 21, 26 and 32. Ϫ 22, 24,
25, and 27 isolated as hydrochloride, 26 as hydrobromide salt.
Route (ii): Addition of α-furyllithium to the N-benzyl
nitrone 2[41] with ensuing CopeϪHouse cyclization of the
intermediate unsaturated hydroxylamine afforded the pyr-
rolidine N-oxide 39 in high yield (89%) and with good se-
lectivity [(2S)/(2R) ϭ 92:8]. After zinc reduction of 39 to
produce the N-benzylpyrrolidine 40, none of the minor iso-
mer could be detected. The furyl ring of the pyrrolidine 40
was cleaved with ruthenium tetroxide, generated in situ us-
Preparation of 3,4-Dihydroxy-5-methylpyrrolidines with
Hydrophilic 2-Substituents
The synthesis of the known fucosidase inhibitor 28[43,44] ing a standard system consisting of ruthenium trichloride
and of the proline derivatives 29[45] and 30 turned out to be and sodium periodate.[47Ϫ50] However, the cyclic lactam 38
more complicated. Moreover, the 2-epimer 31 was unexpec- was formed rather than the expected proline derivative M
tedly obtained instead of 30. The two most obvious strat- (Scheme 6).
egies for the synthesis of 29 and 30 were pursued first:
After these approaches had failed, the 2-vinylpyrrolidine
(i) Nucleophilic addition of cyanide to the N-benzyl 35 was selected as an alternative starting material. From
nitrone 2, followed by CopeϪHouse cyclization of the inter- this, the iminopolyol 28 and the proline derivative 29 should
mediate unsaturated hydroxylamine (cf. Scheme 1).[41]
be readily accessible through a sequence of bis(hydroxyl-
(ii) The use of the furyl ring as a carboxy equivalent,[46] ation), lead tetraacetate cleavage of the diol 41, and reduc-
by addition of furyllithium to the nitrone 2,[41] reduction of tion/oxidation of the corresponding aldehyde (Scheme 7).
Eur. J. Org. Chem. 2001, 2547Ϫ2558
2549

A. M. Palmer, V. Jäger
FULL PAPER
Scheme 6. Attempted preparation of the proline derivative M by
nucleophilic addition of furyllithium to the nitrone 2: (a) α-furylLi,
THF, Ϫ80 °C, 75 min; (b) CHCl3, room temp., 17 h, 89% [92:8]; (c)
Zn, HOAc, room temp., 22 h, 75%; (d) RuCl3·H2O, NaIO4, CCl4,
CH3CN, H2O, room temp., 1 h, 43% of lactam 38
Scheme 7. Synthesis of the 2-hydroxymethylpyrrolidine 28: (a)
OsO4, N-methylmorpholine N-oxide, acetone/H2O, room temp.,
4.5 d, 83%; (b) H2 (4 bar), Pd(OH)2/C, MeOH, room temp., 3 d,
quant.; (c) BnOCOCl, Na2CO3, dioxane/water, room temp., 2.5 h,
79%; (d) Pb(OAc)4, K2CO3, CH2Cl2, room temp., 1 h; (e) NaBH4,
The first step proceeded as expected, to give a mixture of EtOH, 0 °C, 4 h, 77% for two steps; (f) H2 (1 bar), Pd/C, MeOH,
diastereomeric diols 41 (dr 60:40) in 83% yield. However,
the N-benzyl-protected aldehyde obtained in the next step,
room temp., 5.5 h, 91%; (g) MeOH, HCl (1.5 ), room temp., 17 h,
then Dowex 50WX8 (Hϩ form), quant.
by cleavage of the diol 41 with lead tetraacetate, turned out
to be labile, and it was deemed necessary to replace the N-
benzyl group by the more electron-poor benzyloxycarbonyl
group. This was achieved by catalytic hydrogenation and
treatment of the resulting pyrrolidine 42 with benzyl chloro-
formate. Indeed, lead tetraacetate cleavage followed by so-
dium borohydride reduction of the Z-protected diol 43 af-
forded the pyrrolidine 45[44] in good yield. Both protecting
groups of 45 were removed, firstly by hydrogenolysis to give
46 and subsequently with aqueous hydrochloric acid in
methanol (Scheme 7). This afforded the fucosidase inhibitor
28 in 91% yield. The synthesis reported here thus comprises
13 steps and proceeds in 10.2% overall yield. In another
synthesis of 28, recently reported by Defoin and co-workers,
sorbaldehyde dimethylacetal was used as starting material
and an overall yield of 9.5% (13 steps) was reported.[43,44]
In order to secure the proline derivatives, the interme-
diate aldehyde 44 was oxidized to the carboxylic acid 47
with sodium chlorite (Scheme 8).[52,53] 3,4-Dihydroxy-5-
methyl--proline (29) was then obtained by N,O-deprotec-
tion as above, by catalytic debenzylation of 47 to give 48,
followed by hydrolysis. The amino acid 29, isolated as a
spectroscopically pure hydrochloride, proved very hygro-
scopic (as seen with many of these iminopolyols), and was
characterized by HRMS analysis. The route from -ribose
(1) to 29 takes 13 steps, with a 9.5% overall yield.
Scheme 8. Synthesis of the dihydroxyproline derivatives 29 and 31:
(a) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, room
temp., 5.5 h, 78% 47 based on the diol 43; (b) H2 (1 bar), Pd/C,
MeOH, room temp., 4 h, quant.; (c) HCl (0.7 ), room temp., 4 h,
quant.; (d) CH2N2, MeOH, 67% based on the diol 43; (e) 1 bar
H2, Pd/C, room temp., 3 h, quant.; (f) MeOH/HCl (gas), room
temp., 2.5 h, crude product with 30/31 ϭ 29:71, 57% of 31 after
crystallization; 29, 30, and 31 isolated as hydrochloride salt
In order to obtain the methyl ester of 29, the protected
imino acid 47 was treated with diazomethane (Scheme 8). dihydroxyproline esters 30 and 31 were obtained in a 29:71
1
The Z-protecting group in the resulting methyl ester 49 was ratio, as seen by H and 13C NMR analysis. A sample of
removed by catalytic hydrogenation and the resulting pyrro- the major epimer 31, containing 6% of 30, was isolated by
lidine acetonide 50 was treated with dry hydrogen chloride recrystallization from isopropyl alcohol (57% yield). Thus,
in methanol. This caused acetal cleavage as expected, but for the overall sequence from -ribose to 31, an overall yield
also Ϫ surprisingly Ϫ partial epimerization at C-2. After of 4.9% over 14 steps is stated. A different approach to the
a reaction time of 2.5 h at room temp., the two epimeric racemic 3,4-dihydroxy-5-methylproline (Ϯ)-29 was pub-
2550
Eur. J. Org. Chem. 2001, 2547Ϫ2558

Preparation and Biological Evaluation of Pyrrolidinediols and Pyrrolidine N-Oxides
FULL PAPER
lished recently by Defoin and co-workers (9 steps, 8.8% to- ture of the group at C-2 affects both the selectivity and the
tal yield).[45]
strength of inhibition. Thus, the biological activity of the
iminopolyols 22 (2-CH3) and 25 (2-Ph), with 2,3-trans con-
figurations, against certain α--glucosidases is lost when the
lipophilic 2-residue is replaced by a polar group such as
hydroxymethyl (28) or carboxy (29). In contrast, iminopoly-
ols with 2,3-cis configurations and bearing either a lipo-
philic group such as 2-methyl (23) or a polar 2-substituent
such as methoxycarbonyl (as seen in 31) inhibit α--fucosid-
ases to a weak to moderate extent.
No strict rule can be derived from these observations,
though, as can be seen from the inhibition patterns of the
iminopolyols 28 (2-hydroxymethyl; α--fucosidase inhibi-
tion) and 24 (2-vinyl; no activity). Nevertheless, it is note-
worthy that the iminopolyols examined here show weak to
moderate biological activity despite possessing the ‘‘wrong’’
-configuration [(R)-5-methyl] as compared to the natural
α--fucoside substrates. This supports the assumption that
the configurational prerequisites for pyrrolidine inhibitors
are less strict than those observed in the piperidine
series.[15,35] However, the fact that the presence of the (5R)
configuration in the new structures ( series) is responsible
for a considerable loss of activity against α--fucosidases
compared to the structures C and GϪK, with ‘‘correct’’ 5-
methyl group orientations ( series), can clearly be seen by
comparison of the Ki values of the 5-epimers D[35] (1.4 µ)
and 28[44] (83Ϫ120 µ).
Glycosidase Inhibition Assays
The biological activity of the compounds obtained here
[the hydroxypyrrolidine N-oxides 15Ϫ20 (cf. Scheme 2) and
the iminopolyols 21Ϫ29, 31 (cf. Schemes 4, 7, 8)] was exam-
ined in glycosidase inhibition assays.[54,55] Each candidate
was incubated with a set of 24 different enzymes. In order
to evaluate the inhibitory activity, the rates of enzymatic
cleavage of p-nitrophenyl glycoside (‘‘substrate’’) were de-
termined in the absence and in the presence of 1 m of the
potential inhibitor.[54,55] If a significant decrease in the rate
of hydrolysis was observed, the inhibition activity of the
compound was quantified by determination of IC50 and Ki
values. The new compounds showing significant activity (Ͼ
70% inhibition) are included in Table 1.
Table 1. Inhibition activity of the 2-substituted iminopolyols ob-
tained against various glycosidases (candidates 15Ϫ20, 21, 24, 26,
27 and 29 were found to be inactive)
Conclusion
In summary, transformations of a series of (1R,3S,
4R,5R)-1-benzyl-3,4-isopropylidenedioxy-5-methylpyrro-
lidine 1-oxides Ϫ obtained by CopeϪHouse cyclization of
[a]
Enzyme sources: yeast, maltase (y. m.); baker’s yeast (b. y.);
[b]
bovine kidney (b. k.); E. coli (E. c.); bovine epididymis (b. e.). Ϫ
In the presence of 1 m of inhibitor.
unsaturated hydroxylamines derived from -ribose[41]
Ϫ
into pyrrolidinediol structures of biological interest are re-
ported. New syntheses of the known fucosidase inhibitor
28 and the 3,4-dihydroxy-5-methylproline derivative 29 have
been developed. All the iminopolyols prepared in the course
of this work were screened in glycosidase inhibition assays.
Whereas none of the pyrrolidine N-oxides exhibited any ac-
tivity, several of the iminopolyols turned out to be weak to
moderate glycosidase inhibitors, with Ki values in the range
from 30 to 500 µ. This supports the assumption that the
configurational limitations affecting pyrrolidinepolyol in-
hibitors are less rigid than those for piperidinepolyol inhib-
itors. The (5R) configuration present in all structures of this
series seems to impede effective inhibition of α--fucosid-
ases. Nevertheless, as far as the 2-substituents are con-
cerned, a distinct increase in activity is once again seen with
a 2-methoxycarbonyl group (cf. ref.[37]).
On the basis of these results, it is now possible to draw
some conclusions as to structure-activity relationships:
(a) Since none of the pyrrolidine N-oxides 15Ϫ20 tested
showed significant inhibition, it appears that the N-oxide
function impedes activity. These observations are consistent
with results reported by Wong and co-workers, indicating
that the N-oxides of 1-deoxynojirimycin, 1,6-dideoxynojiri-
mycin and castanospermine are weaker inhibitors than their
N-methyl analogues.[56] This is explained by the ability of
the N-oxide function to participate in intramolecular H-
bonding and to interact in a repulsive manner with the
carboxylate group of the enzyme; both are assumed to pre-
vent the formation of a stable enzyme-inhibitor complex.[56]
(b) Comparison of the biological activities of the trans-
2,3-dimethylpyrrolidines 22, with an N-benzyl substituent,
and of 27, without one, suggests that the presence of an N-
benzyl group might be useful, since compound 22 displays
some activity (Ki in the 0.5 m range) with two α-glycosid-
ases, while the debenzyl compound 27 shows none.
Experimental Section
General Remarks: Melting points were determined with a Fisher
Johns 4017 heating block and are uncorrected. Ϫ 1H and 13C NMR
spectra were recorded with Bruker AC 250, ARX 300, or ARX 500
(c) A substituent in the 2-position of the heterocycle
seems to be crucial (the 2-unsubstituted pyrrolidines 21 and
26 were inactive). Furthermore, the configuration and na- spectrometers using SiMe4 as internal standard. C,H-COSY spec-
Eur. J. Org. Chem. 2001, 2547Ϫ2558 2551

A. M. Palmer, V. Jäger
FULL PAPER
tra were recorded for the assignment of 13C NMR signals. Ϫ IR 500.1 MHz): δ ϭ 1.48 (d, J2,2-Me ϭ 6.4 Hz, 3 H, 2-CH3), 3.37 (dq,
spectra were recorded with a PerkinϪElmer 283 or a Bruker IFS 28 2,3 ϭ 8.8, J2,2-Me ϭ 6.4 Hz, 1 H, 2-H), 3.48 (d, J4,5 ϭ 6.4 Hz, 2 H,
IR spectrometer. Ϫ Mass spectra and high-resolution mass spectra 5-H), 4.08 (dd, J2,3 ϭ 8.8, J3,4 ϭ 6.4 Hz, 1 H, 3-H), 4.33 (s, 2 H,
J
(HRMS) were measured with Finnigan Quadrupol-MS 4500/Finni-
gan MAT 95 mass spectrometers, respectively. Ϫ Optical rotations
CH2Ph), 4.37 (qu, J3,4 ϭ J4,5 ϭ 6.4 Hz, 1 H, 4-H), 7.45 (mc, 3 H,
C6H5), 7.55 (mc, 2 H, C6H5). Ϫ 13C NMR (MeOD, 125.8 MHz):
were determined with a PerkinϪElmer polarimeter 241MC. Ϫ A δ ϭ 11.0 (2-CH3), 67.0 (C-4), 70.5 (CH2Ph), 73.3 (C-5), 74.7 (C-
Parr (Moline, IL/USA) shaking apparatus was used for catalytic
hydrogenation.
2), 75.1 (C-3), 129.8, 130.8, 131.5, 133.4 (C6H5). Ϫ C12H17NO3
(223.3): calcd. C 64.55, H 7.67, N 6.27; found C 64.32, H 7.61,
N 6.24.
Materials: Solvents were purified and dried by standard
methods.[57] For column chromatography, silica gel (40Ϫ63 µm,
Merck) was used. Dowex 50WX8 acidic resin used for ion exchange
purification was supplied by Fluka and was activated with HCl (1
) prior to use. Commercial reagents were used throughout.
(2S,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-2,5-dimethylpyrrolidine
1-
Oxide (16): Deprotection of 10·H2O (93 mg, 0.31 mmol)[41] and
purification as described for the preparation of 15 yielded 75 mg
of a colourless solid, which was recrystallized from MeOH/diethyl
ether. The free diol 16 (62 mg, 84%) was obtained in the form of
colourless needles, m.p. 186 °C (decomp.). Ϫ Optically inactive
(meso compound). Ϫ IR (KBr): ν˜ ϭ 3190 (br., OH), 3050, 2980,
(1S,2R,3R,4S)-1-Benzyl-3,4-dihydroxy-2-methylpyrrolidine 1-Oxide
(15): Compound 9·H2O (200 mg, 0.71 mmol)[41] was dissolved un-
der nitrogen in a mixture of water (2 mL), MeOH (2 mL) and conc.
HCl (0.25 mL). The clear solution was stirred for 1 d at room temp.
The solvent was removed under reduced pressure, and the crude
product, a colourless oil, was purified using 5 g of Dowex 50WX8
(Hϩ form, by treatment of the resin with 1  HCl and removal of
2940, 1495, 1455, 1445, 1430, 1365, 1165, 1135, 1090 cmϪ1. Ϫ H
1
and 13C NMR spectroscopic data for 16: see Tables 2Ϫ4. Ϫ
C13H19NO3 (237.3): calcd. C 65.80, H 8.07, N 5.90; found C 65.66,
H 8.10, N 5.91.
excess acid by washing with water). The resin was charged with (1S,2R,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-2,5-dimethylpyrroli-
15·HCl, dissolved in MeOH, and first washed with 50-mL portions
dine 1-Oxide (17): Deprotection of 11·H2O (88 mg, 0.30 mmol)[41]
each of MeOH and water, before elution of 15 with 1  NH3 and purification as described for the preparation of 15 yielded a
(100 mL). Concentration in vacuo afforded 158 mg of a colourless colourless solid (63 mg), which was recrystallized from MeOH/di-
solid, which was recrystallized from MeOH/diethyl ether to give
colourless crystals of 15 (112 mg, 71%), m.p. 172 °C (decomp.). Ϫ
[α]2D0 ϭ ϩ17 (c ϭ 0.28, MeOH). Ϫ IR (KBr): ν˜ ϭ 3220 (br., OH),
ethyl ether. Colourless crystals of 17 (45 mg, 63%) were obtained;
m.p. 149Ϫ151 °C (decomp.). Ϫ [α]2D0 ϭ Ϫ11 (c ϭ 0.13, MeOH). Ϫ
IR (KBr): ν˜ ϭ 3600Ϫ2300 (OH), 1485, 1450, 1170, 1120 cmϪ1. Ϫ
2960, 2910, 1445, 1140, 1125, 1090 cmϪ1. Ϫ 1H NMR (MeOD, 1H and 13C NMR spectroscopic data for 17: see Tables 2Ϫ4. Ϫ
Table 2. 1H NMR chemical shifts δ of pyrrolidine N-oxides 16Ϫ20, 39, 1-Bn-3,4-isopropylidenedioxypyrrolidines 33Ϫ36, 40, 1-Z-3,4-
isopropylidenedioxypyrrolidines 45, 47, 49, 3,4-isopropylidenedioxypyrrolidines 46, 48, 50, O-deprotected iminopolyols 22Ϫ25, and N,O-
deprotected pyrrolidinediols 27Ϫ31 (δ [ppm]; 250.1, 300.1 or 500.1 MHz)
[a]
Arrangement of compounds according to substance class (pyrrolidine N-oxide/pyrrolidine) and protecting group pattern for better
[b]
[c]
[d]
[e]
[f]
[g]
comparison. Ϫ In MeOD. Ϫ In CDCl3. Ϫ
In [D6]DMSO. Ϫ Measured at 353 K. Ϫ In C6D6. Ϫ Measured at 347 K. Ϫ
[h]
[i]
Major conformer, ratio 86:14 at 347 K. Ϫ NMR-spectroscopic data of the hydrochloride.
2552
Eur. J. Org. Chem. 2001, 2547Ϫ2558

Preparation and Biological Evaluation of Pyrrolidinediols and Pyrrolidine N-Oxides
FULL PAPER
Table 3. H,H-coupling constants J of pyrrolidine N-oxides 16Ϫ20, 39, 1-Bn-3,4-isopropylidenedioxypyrrolidines 33Ϫ36, 40, 1-Z-3,4-
isopropylidenedioxypyrrolidines 45, 47, 49, 3,4-isopropylidenedioxypyrrolidines 46, 48, 50, O-deprotected iminopolyols 22Ϫ25, and N,O-
deprotected pyrrolidinediols 27Ϫ31 (J [Hz])
[a]
Arrangement of compounds according to substance class (pyrrolidine N-oxide/pyrrolidine) and protecting group pattern for better
[b]
[c]
[d]
[e]
[f]
[g]
comparison. Ϫ In MeOD. Ϫ In CDCl3. Ϫ
In [D6]DMSO. Ϫ Measured at 353 K. Ϫ In C6D6. Ϫ Measured at 347 K. Ϫ
[h]
Data of the hydrochloride.
C13H19NO3 (237.3): calcd. C 65.80, H 8.07, N 5.90; found C 65.49, Tables 2Ϫ4. Ϫ MS (Auto-CI, positive ion): m/z (%) ϭ 300.2 (100)
H 8.22, N 5.79.
[MHϩ], 284.1 (13), 212.1 (22), 132.1 (13), 91.0 (65). Ϫ HRMS
(Auto-CI, positive ion): exact mass calcd. for C18H21NO3 ϩ H:
300.1600; found 300.1592.
(1R,2S,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-5-methyl-2-vinylpyrroli-
dine 1-Oxide (18): Deprotection of 12 (200 mg, 0.69 mmol),[41] puri-
fication and recrystallization (cf. preparation of 15) afforded col-
ourless crystals of 18 (98 mg, 57%), m.p. 151Ϫ152 °C (decomp.) Ϫ
[α]2D0 ϭ ϩ13 (c ϭ 0.53, MeOH). Ϫ IR (KBr): ν˜ ϭ 3240, 2920, 1440,
(2R,3R,4S)-1-Benzyl-3,4-isopropylidenedioxy-2-methylpyrroli-
dine (32): A solution of the crude pyrrolidine N-oxide 9 (330 mg,
1.25 mmol, containing 8% of the 2-epimer)[41] in 6 mL of acetic
acid was prepared under nitrogen in a heated flask. Activated Zn
dust (1.23 g, 19 mmol) was added over a period of 45 min and the
reaction mixture was stirred for 2.5 h at room temp. The mixture
was filtered and the residue was washed with acetic acid. The fil-
trate was concd. in vacuo, diluted with water (10 mL), cooled to 0
°C and made basic (pH Ͼ 9) using 6  NaOH. The aqueous phase
was extracted with CH2Cl2 (3 ϫ 20 mL). The organic phase was
dried with MgSO4 and concentrated to dryness. Flash chromato-
graphy (SiO2; petroleum ether/ethyl acetate, 9:1) afforded pure 32
(colourless oil, 174 mg, 56% yield based on 2). Additionally, 16 mg
(5%) of the 2-epimer was obtained. Ϫ [α]2D0 ϭ Ϫ63 (c ϭ 0.55,
CH2Cl2). Ϫ IR (film): ν˜ ϭ 2967, 2932, 2801, 1454, 1379, 1252,
1209, 1160, 1077, 1059 cmϪ1. Ϫ 1H NMR (CDCl3, 500.1 MHz):
1130, 1080 cmϪ1. Ϫ H and 13C NMR spectroscopic data for 18:
see Tables 2Ϫ4. Ϫ C14H19NO3 (249.3): calcd. C 67.45, H 7.68, N
5.62; found C 67.02, H 7.59, N 5.54.
1
(1R,2S,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-5-methyl-2-phenylpyr-
rolidine 1-Oxide (19): Deprotection of 13 (60 mg, 0.18 mmol),[41]
purification using acidic resin, and recrystallization from MeOH/
diethyl ether as described for 15 afforded colourless crystals of 19
(43 mg, 81%), m.p. 178Ϫ179 °C (decomp.). Ϫ [α]2D0 ϭ ϩ30 (c ϭ
0.51, MeOH). Ϫ IR (KBr): ν˜ ϭ 3200 (OH), 2940, 2910, 1442, 1140,
1125, 1080, 1040 cmϪ1. Ϫ 1H and 13C NMR spectroscopic data for
19: see Tables 2Ϫ4. Ϫ C18H21NO3 (299.4): calcd. C 72.22, H 7.07,
N 4.68, found. C 71.52, H 7.08, N 4.63.
(1R,2R,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-5-methyl-2-phenylpyr- δ ϭ 1.15 (d, J2,2-Me ϭ 6.4 Hz, 3 H, 2-CH3), 1.31, 1.52 [2 s, 6 H,
2
rolidine 1-Oxide (20): Deprotection of 14 (65 mg, 0.19 mmol)[41] C(CH3)2], 2.48 (dd, J4,5a ϭ 3.9, J5a,5b ϭ 10.3 Hz, 1 H, 5-Ha), 2.76
and purification using acidic resin afforded the pyrrolidinediol N-
(dq, J2,2-Me ϭ 6.4, J2,3 ϭ 4.1 Hz, 1 H, 2-H), 3.03 (dd, J4,5b ϭ 6.1,
2
oxide 20 (39 mg, 68%), m.p. 147Ϫ148 °C (decomp.) (Ͼ 90% purity 2J5a,5b ϭ 10.3 Hz, 1 H, 5-Hb), 3.38 and 3.89 (2 d, J ϭ 13.1 Hz, 2
1
according to H NMR). Ϫ [α]2D0 ϭ Ϫ40 (c ϭ 0.38, MeOH). Ϫ IR
H, CH2Ph), 4.24 (dd, J2,3 ϭ 4.1, J3,4 ϭ 6.9 Hz, 1 H, 3-H), 4.62
(KBr): ν˜ ϭ 3240 (b), 1485, 1445, 1355, 1195, 1140, 1120, 1080 (ddd, J3,4 ϭ 6.9, J4,5a ϭ 3.9, J4,5b ϭ 6.1 Hz, 1 H, 4-H), 7.24, 7.30
cmϪ1. Ϫ 1H and 13C NMR spectroscopic data for 20: see
(2mc, 5 H, C6H5). Ϫ 13C NMR (CDCl3, 125.8 MHz): δ ϭ 14.9 (2-
Eur. J. Org. Chem. 2001, 2547Ϫ2558
2553

A. M. Palmer, V. Jäger
FULL PAPER
Table 4. 13C NMR chemical shifts δ of pyrrolidine N-oxides 16Ϫ20, 39, 1-Bn-3,4-isopropylidenedioxypyrrolidines 33Ϫ36, 40, 1-Z-3,4-
isopropylidenedioxypyrrolidines 45, 47, 49, 3,4-isopropylidenedioxypyrrolidines 46, 48, 50, O-deprotected iminopolyols 22Ϫ25, and N,O-
deprotected pyrrolidinediols 27Ϫ31 (δ [ppm]; 62.9, 75.5 or 125.8 MHz)
[a]
Arrangement of compounds according to substance class (pyrrolidine N-oxide/pyrrolidine) and protecting group pattern for better
[b]
[c]
[d]
[e]
[f]
comparison. Ϫ
C6D6. Ϫ
In MeOD. Ϫ Assignment may be reversed. Ϫ
Signal assignment based on C,H-COSY. Ϫ In CDCl3. Ϫ In
[g]
[h]
[i]
[j]
[k]
Acquisition at 347 K. Ϫ
In [D6]DMSO. Ϫ Acquisition at 353 K. Ϫ Major conformer, ratio 86:14 at 347 K. Ϫ
NMR-spectroscopic data of the hydrochloride.
CH3), 25.2, 27.1 [C(CH3)2], 56.4 (CH2Ph), 57.9 (C-5), 63.7 (C-2), scribed for 32; compound 12 (60 mg, 0.20 mmol),[41] acetic acid
77.8 (C-4), 86.3 (C-3), 112.7 [C(CH3)2], 126.9, 128.3, 128.7, 138.7 (3 mL), Zn (0.27 g, 4 mmol), addition time 20 min, reaction time 1
(C6H5). Ϫ C15H21NO2 (247.3): calcd. C 72.84, H 8.56, N 5.66;
d at room temp. Workup as above and flash chromatography (SiO2;
found C 72.60, H 8.49, N 5.59.
petroleum ether/ethyl acetate, 4:1) afforded pure 35 as a colourless
oil (47 mg, 84%). Ϫ [α]2D0 ϭ Ϫ1 (c ϭ 0.42, CH2Cl2). Ϫ IR (film):
(2S,3S,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-2,5-dimethylpyr-
rolidine (33): This compound was prepared as described for 32;
compound 10·H2O (159 mg, 0.54 mmol),[41] acetic acid (10 mL), Zn
(0.70 g, 11 mmol), addition time 40 min, reaction time 1 d at room
temp. Workup and flash chromatography as above afforded analyt-
ically pure 33 (colourless oil, 96 mg, 69%); optically inactive (meso
compound). Ϫ IR (film): ν˜ ϭ 3423 (b), 2967, 2930, 1379, 1229,
1073 cmϪ1. Ϫ 1H and 13C NMR spectroscopic data for 33: see
Tables 2Ϫ4. Ϫ C16H23NO2 (261.4): calcd. C 73.53, H 8.87, N 5.36;
found C 73.59, H 8.97, N 5.37.
1
ν˜ ϭ 2980, 2930, 1454, 1380, 1247, 1209, 1071 cmϪ1. Ϫ H and 13
C
NMR spectroscopic data for 35: see Tables 2Ϫ4. Ϫ C17H23NO2
(273.4): calcd. C 74.69, H 8.48, N 5.12; found C 74.97, H 8.52,
N 5.08.
(2S,3S,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-5-meth-
yl-2-phenylpyrrolidine (36): This compound was prepared as de-
scribed for 32; compound 13 (119 mg, 0.35 mmol),[41] acetic acid
(8 mL), Zn (0.46 g, 7 mmol), addition time 45 min, reaction time
16 h at room temp. Workup and flash chromatography as above
afforded analytically pure 36 as colourless crystals (88 mg, 77%),
m.p. 63 °C. Ϫ [α]2D0 ϭ ϩ13 (c ϭ 0.66, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ
2960, 2940, 2900, 2800, 1440, 1370, 1360, 1235, 1190, 1170, 1140,
(2R,3S,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-2,5-dimethylpyr-
rolidine (34): This compound was prepared as described for 32;
compound 11·H2O and its 5-epimer (116 mg, 0.39 mmol, dr
85:15),[41] acetic acid (5 mL), Zn (0.52 g, 8 mmol), addition time 30
min, reaction time 1 d at room temp. Workup as described above
and flash chromatography (SiO2; petroleum ether/ethyl acetate, 4:1)
afforded 34 as a spectroscopically pure, colourless oil with a some-
what deviating analysis (50 mg, 49%) and another fraction con-
taining equal amounts of 34 and its 5-epimer (29 mg, 28%). Ϫ [α]D20
ϭ Ϫ43 (c ϭ 2.09, CH2Cl2). Ϫ IR (film): ν˜ ϭ 2977, 2932, 1377,
1209, 1160, 1056 cmϪ1. Ϫ 1H and 13C NMR spectroscopic data for
34: see Tables 2Ϫ4. Ϫ C16H23NO2 (261.4): calcd. C 73.53, H 8.87,
N 5.36; found C 72.33, H 8.81, N 5.23.
1
1075, 1045 cmϪ1. Ϫ H and 13C NMR spectroscopic data for 36:
see Tables 2Ϫ4. Ϫ C21H25NO2 (323.4): calcd. C 77.99, H 7.79, N
4.33; found C 77.95, H 7.89, N 4.25.
(2R,3R,4S)-1-Benzyl-3,4-dihydroxy-2-methylpyrrolidine (21): The ace-
tonide 32 (85 mg, 0.34 mmol) was dissolved under nitrogen in a
mixture of MeOH (2 mL), water (2 mL) and conc. HCl (0.25 mL).
The colourless reaction mixture was stirred for 16 h at room temp.
Concentration to dryness and purification of the crude product
using Dowex 50WX8 acidic resin (cf. preparation of 15) afforded
spectroscopically pure 21 with deviating elemental analysis (colour-
(2S,3S,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-5-meth- less oil, 63 mg, 88%). Ϫ [α]2D0 ϭ Ϫ50 (c ϭ 0.56, MeOH). Ϫ IR
yl-2-vinylpyrrolidine (35): This compound was prepared as de-
(film): ν˜ ϭ 3387, 2963, 2927, 1125 cmϪ1. Ϫ 1H NMR (MeOD,
2554
Eur. J. Org. Chem. 2001, 2547Ϫ2558

Preparation and Biological Evaluation of Pyrrolidinediols and Pyrrolidine N-Oxides
FULL PAPER
300.1 MHz): δ ϭ 1.22 (J2,2-Me ϭ 6.2 Hz, 3 H, 2-CH3), 2.27 (dd,
ν
˜ ϭ 3320 (b), 3260, 2960, 2760, 1595, 1445, 1410, 1360, 1250, 1125,
2
J4,5a ϭ 5.4, J5a,5b ϭ 10.4 Hz, 1 H, 5-Ha), 2.47 (dq, J2,3 ϭ 7.2, 1105, 1075, 1045 cmϪ1. Ϫ 1H NMR (MeOD, 500.1 MHz): δ ϭ 1.43
2
J
2,2-Me ϭ 6.2 Hz, 1 H, 2-H), 3.13 (dd, J4,5b ϭ 6.3, 2J5a,5b ϭ 10.4 Hz, (d, J2,2-Me ϭ 6.9 Hz, 3 H, 2-CH3), 3.21 (dd, J4,5a ϭ 2.2, J5a,5b
ϭ
2
2
1 H, 5-Hb), 3.32 and 3.98 (2 d, J ϭ 12.4 Hz, 2 H, CH2Ph), 3.52 12.7 Hz, 1 H, 5-Ha), 3.49 (dd, J4,5b ϭ 4.5, J5a,5b ϭ 12.7 Hz, 1 H,
(dd, J2,3 ϭ 7.2, J3,4 ϭ 6.3 Hz, 1 H, 3-H), 4.01 (dt, J3,4 ϭ J4,5b 5-Hb), 3.53 (dq, J2,3 ϭ 8.3, J2,2-Me ϭ 6.9 Hz, 1 H, 2-H), 3.85 (dd,
6.3, J4,5a ϭ 5.4 Hz, 1 H, 4-H), 7.27 (mc, 5 H, C6H5). Ϫ 13C NMR
J2,3 ϭ 8.3, J3,4 ϭ 4.2 Hz, 1 H, 3-H), 4.26 (ddd, J3,4 ϭ 4.2, J4,5a
ϭ
ϭ
(MeOD, 75.5 MHz): δ ϭ 17.8 (2-CH3), 59.9 (CH2Ph), 61.1 (C-5), 2.2, J4,5b ϭ 4.5 Hz, 1 H, 4-H). Ϫ 13C NMR (MeOD, 125.8 MHz):
65.7 (C-2), 69.9 (C-4), 78.9 (C-3), 129.0, 129.9, 131.1, 139.7 (C6H5). δ ϭ 15.4 (2-CH3), 50.6 (C-5), 58.2 (C-2), 70.7 (C-4), 77.7 (C-3). Ϫ
Ϫ MS (FAB, positive ion): m/z (%) ϭ 208.1 (100) [MHϩ], 192.1 C5H11NO2·HBr (198.1): calcd. C 30.32, H 6.11, N 7.07; found C
(10), 91.0 (48). Ϫ HRMS (FAB, positive ion): exact mass calcd. for
C12H17NO2 ϩ H: 208.1338; found 208.1339. Ϫ C12H17NO2 (207.3):
calcd. C 69.54, H 8.27, N 6.76; found C 68.18, H 8.22, N 6.54.
30.66, H 6.15, N 7.00.
(2S,3S,4R,5R)-3,4-Dihydroxy-2,5-dimethylpyrrolidine Hydrochlo-
ride (27·HCl): The N-benzyl group of 22·HCl (32 mg, 0.12 mmol)
was removed by catalytic hydrogenation as described for 26.[42]
After a reaction time of 4 d and workup as above, the crude prod-
uct, a colourless oil (22 mg), was crystallized from 2-propanol/di-
ethyl ether (1:1). This afforded colourless needles of pure 27·HCl
(18 mg, 87%), m.p. 133 °C. Ϫ optically inactive (meso compound).
Ϫ IR (KBr): ν˜ ϭ 3300 (br., OH), 2960, 2870, 2770, 2670, 2450,
1560, 1415, 1130, 1095, 1055, 1000 cmϪ1. Ϫ 1H and 13C NMR
spectroscopic data for 27·HCl: see Tables 2Ϫ4. Ϫ C6H13NO2·HCl
(167.6): calcd. C 43.00, H 8.42, N 8.36; found C 42.54, H 8.41,
N 8.04.
(2S,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-2,5-dimethylpyrroli-
dine Hydrochloride (22·HCl): Compound 33 (30 mg, 0.11 mmol)
was deprotected as described for 21 (reaction time: 2 h). Concentra-
tion to dryness afforded a pale yellow solid (35 mg), which was
recrystallized from MeOH/diethyl ether (1:6) and gave colourless
crystals of pure 22·HCl (27 mg, 91%), m.p. 177Ϫ178 °C; optically
inactive (meso compound). Ϫ IR (KBr): ν˜ ϭ 3420, 3140, 2900,
2585, 1440, 1415, 1375, 1320, 1120, 1095, 1060, 1045, 1000 cmϪ1
.
Ϫ 1H and 13C NMR spectroscopic data for 22·HCl: see Tables 2Ϫ4.
Ϫ C13H19NO2·HCl (257.8): calcd. 60.58, H 7.82, N 5.43; found
60.21, H 7.73, N 5.30.
(2R,3R)-N-Benzyl-2,3-isopropylidenedioxy-4-penteneamide
(37) and (3R,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-5-methylpyrrol-
idin-2-one (38): A solution of the nitrone 2 (200 mg, 0.77 mol)[41] in
dry CH2Cl2 (8 mL) was treated at Ϫ20 °C with lithium cyanide (0.5
 in DMF, 2.30 mL, 1.2 mmol). Stirring was continued for 5 h; the
reaction mixture turned red and a precipitate was formed. After addi-
tion of ammonium chloride (0.18 g) and water (10 mL), the mixture
was extracted with CH2Cl2 (4 ϫ 10 mL). The combined organic
phases were washed with water (2 ϫ 10 mL) and dried with MgSO4.
The residue obtained upon concentration in vacuo (219 mg) was dis-
solved in chloroform and stirred for 5 d at room temp. to effect
CopeϪHouse cyclization of the assumed intermediate hy-
droxylamine. After removal of the solvent, the crude product was
purified by column chromatography (SiO2, ethyl acetate) yielding
150 mg of yellow oil that was rechromatographed (SiO2; petroleum
ether/ethyl acetate, 4:1, then 1:1). In this way, samples of the amide
37, an analytically pure solid (63 mg, 31%), m.p. 33 °C, and of the
lactam 38 (yellow oil, still containing impurities, 61 mg, ca. 30%) were
obtained. Ϫ Amide 37: [α]2D0 ϭ ϩ18 (c ϭ 0.41, CH2Cl2). Ϫ IR (KBr):
(2R,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-2,5-dimethylpyrroli-
dine (23): Deprotection of 34 (37 mg, 0.14 mmol) as described
above (reaction time: 3 h), and purification of the crude product
using Dowex 50WX8 acidic resin (5 g, application of 23·HCl dis-
solved in MeOH; washing with 70 mL each of MeOH and water;
elution of 23 with 140 mL of 1  NH3) afforded spectroscopically
pure 23 (27 mg, 87%, pale yellow oil). Ϫ [α]2D0 ϭ Ϫ27 (c ϭ 0.63,
MeOH). Ϫ IR (film): ν˜ ϭ 3386, 2976, 1627, 1453, 1390 cmϪ1. Ϫ
1H and 13C NMR spectroscopic data for 23: see Tables 2Ϫ4.
(2S,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-5-methyl-2-vinylpyr-
rolidine Hydrochloride (24·HCl): Deprotection of 35 (139 mg,
0.51 mmol) as described for 21 (reaction time: 3 h) and crystalliza-
tion of the crude product from 2-propanol afforded colourless crys-
tals of pure 24·HCl (107 mg, 78%), m.p. 183Ϫ184 °C. Ϫ [α]2D0
ϭ
Ϫ13 (c ϭ 0.53, MeOH). Ϫ IR (KBr): ν˜ ϭ 3320 (OH), 2910,
1
2760Ϫ2500, 1420, 1380, 1320, 1270, 1125, 1095, 1050 cmϪ1. Ϫ H
and 13C NMR spectroscopic data for 24·HCl: see Tables 2Ϫ4. Ϫ
C14H19NO2·HCl (269.8): calcd. C 62.33, H 7.47, N 5.19; found C
62.28, H 7.50, N 5.12.
1
ν˜ ϭ 3280 (b), 2970, 1665 (CO), 1525, 1205, 1080, 1030 cmϪ1. Ϫ H
NMR (CDCl3, 500.1 MHz): δ ϭ 1.40, 1.54 [2 s, C(CH3)2, 6 H], 4.41
2
and 4.53 (2 dd, J ϭ 15.0, JCH,NH ϭ 6.0 Hz, 2 H, CH2Ph), 4.68 (d,
(2S,3S,4R,5R)-1-Benzyl-3,4-dihydroxy-5-methyl-2-phenylpyrro-
lidine Hydrochloride (25·HCl): Deprotection of 36 (59 mg,
0.18 mmol) was performed as described for the preparation of 21.
Crystallization of the crude product from 2-propanol/diethyl ether
yielded colourless crystals of pure 25·HCl (56 mg, 96%), m.p.
181Ϫ183 °C. Ϫ [α]2D0 ϭ Ϫ16 (c ϭ 0.34, MeOH). Ϫ IR (KBr): ν˜ ϭ
3320, 2460, 1415, 1320, 1135, 1125, 1040 cmϪ1. Ϫ 1H and 13C
J2,3 ϭ 7.7 Hz, 1 H, 2-H), 4.89 (dd, J2,3 ϭ 7.7, J3,4 ϭ 6.6 Hz, 1 H, 3-
2
H), 5.26 (dd, J4,5E ϭ 10.3, J5E,5Z ϭ 1.6 Hz, 1 H, 5-HE), 5.42 (dd,
2
J4,5Z ϭ 17.0, J5E,5Z ϭ 1.6 Hz, 1 H, 5-HZ), 5.79 (ddd, J3,4 ϭ 6.6,
J4,5E ϭ 10.3, J4,5Z ϭ 17.0 Hz, 1 H, 4-H), 6.82 (mc, 1 H, NH), 7.28,
7.34 (2 mc, 5 H, C6H5). Ϫ 13C NMR (CDCl3, 125.8 MHz): δ ϭ 25.1,
27.6 [C(CH3)2], 43.2 (CH2Ph), 78.5 (C-2), 78.9 (C-3), 110.5
[C(CH3)2], 119.1 (C-5), 128.0, 128.1, 129.1, 138.2 (C6H5), 133.2 (C-
4), 168.8 (CO). Ϫ MS (EI, 70 eV): m/z (%) ϭ 261.1 (26) [Mϩ], 246.2
(11), 203.1 (100), 127.1 (37), 106.1 (31), 91.0 (82), 69.0 (60), 59.0 (34),
43.0 (18), 28.0 (18). Ϫ HRMS (EI, 70 eV): exact mass calcd. for
C15H19NO3: 261.1365; found 261.1361. Ϫ C15H19NO3 (261.3): calcd.
C 68.94, H 7.32, N 5.36; found C 68.90, H 7.26, N 5.39. Ϫ Lactam
38: 1H NMR spectroscopic data identical to those given below.
NMR spectroscopic data for 25·HCl: see Tables 2Ϫ4.
Ϫ
C18H21NO2·HCl (319.8): calcd. C 67.60, H 6.93, N 4.38; found C
67.50, H 6.94, N 4.25.
(2R,3R,4S)-3,4-Dihydroxy-2-methylpyrrolidine Hydrobromide (26·
HBr): A solution of 21 (104 mg, 0.50 mmol) in MeOH (5 mL) was
treated with Pearlman’s catalyst [20% Pd(OH)2 on charcoal, 20 mg]
and was hydrogenated at a pressure of 4 bar.[42] After 2 d, the cata-
lyst was removed by centrifugation and washed with MeOH. The (1R,2S,3S,4R,5R)-1-Benzyl-2-(2-furyl)-3,4-isopropylidene-
crude product obtained from the combined solutes was treated with dioxy-5-methylpyrrolidine 1-Oxide (39): A solution of furan (0.17 mL,
48% HBr (0.25 mL) and crystallized from MeOH/diethyl ether
2.3 mmol) in THF (10 mL) was placed under nitrogen in a flame-
(1:1), yielding pale-brown crystals of pure 26·HBr (49 mg, 50%,
dried flask. After butyllithium (1.6  in hexanes, 1.50 mL, 2.4 mmol)
m.p. 126Ϫ128 °C). Ϫ [α]2D0 ϭ ϩ45 (c ϭ 0.41, MeOH). Ϫ IR (KBr): had been added at Ϫ80 °C, the solution was stirred for 2 h at 0 °C.
Eur. J. Org. Chem. 2001, 2547Ϫ2558
2555

A. M. Palmer, V. Jäger
FULL PAPER
At this point, the nitrone 2 (200 mg, 0.77 mmol)[41] in THF (10 mL) 60:40). Ϫ [α]2D0 ϭ Ϫ2 (c ϭ 0.59, CH2Cl2). Ϫ C17H25NO4 (307.4):
was added over a period of 30 min at Ϫ80 °C. Stirring was continued calcd. C 66.43, H 8.20, N 4.56; found C 66.41, H 8.32, N 4.62.
for 75 min and the reaction mixture was then quenched with ammo-
(2S,3S,4R,5R)-2-(1Ј,2Ј-Dihydroxyethyl)-3,4-isopropylidene-
dioxy-5-methylpyrrolidine (42): A solution of 41 (343 mg, 1.12 mmol)
nium chloride (0.20 g) and water (10 mL). The aqueous phase was
extracted with diethyl ether (4 ϫ 10 mL). The organic phases were
in MeOH (10 mL) was hydrogenated with Pearlman’s catalyst [70 mg,
dried with MgSO4 and concentrated in vacuo. The residual orange
20% Pd(OH)2 on charcoal, 4 bar H2].[42] After 3 d, the catalyst was
oil (340 mg) was dissolved in chloroform (10 mL) and stirred for 17 h
removed by centrifugation and washed with MeOH. The MeOH
at room temp. After removal of the solvent, the crude product (39
and its 2-epimer, dr 92:8) was purified by column chromatography
phases were combined and concentrated to dryness, yielding analytic-
ally pure 42 (243 mg, 100%, dr 60:40), m.p. 62Ϫ63 °C. Ϫ [α]2D0 ϭ ϩ1
(SiO2; CH2Cl2/MeOH, 98:2, then 92:8). The pyrrolidine N-oxide 39
(c ϭ 0.97, MeOH). Ϫ C10H19NO4 (217.3): calcd. C 55.28, H 8.81, N
was obtained as a colourless oil containing 6Ϫ8% of the 2-epimer
6.45; found C 55.32, H 8.73, N 6.29.
(224 mg, 89%). Ϫ [α]2D0 ϭ Ϫ127 (c ϭ 0.51, CH2Cl2). Ϫ IR (film): ν˜ ϭ
3385, 2988, 1382, 1209, 1097, 1021 cmϪ1. Ϫ 1H and 13C NMR spec-
(2S,3S,4R,5R)-1-Benzyloxycarbonyl-2-(1Ј,2Ј-dihydroxyethyl)-
troscopic data for 39: see Tables 2Ϫ4. Ϫ MS (EI, 70 eV): m/z (%) ϭ
329.1 (28) [Mϩ], 271.1 (10), 202.0 (13), 150.0 (16), 91.0 (100). Ϫ
HRMS (EI, 70 eV): exact mass calcd. for C19H23NO4: 329.1627;
found 329.1619.
3,4-isopropylidenedioxy-5-methylpyrrolidine (43): Na2CO3 (49 mg,
0.46 mmol) and benzyloxycarbonyl chloride (86 mg, 71 µL,
0.50 mmol) were added to a solution of the pyrrolidine 42 (100 mg,
0.46 mmol, dr 60:40) in 10 mL of dioxane/water, 1:1. After the reac-
tion mixture had been stirred for 2.5 h at room temp., it was con-
centrated in vacuo, diluted with water (5 mL), and extracted with
ethyl acetate (3 ϫ 10 mL). The organic solution was dried with
MgSO4 and concentrated to dryness. The crude product (200 mg)
was purified by flash chromatography (SiO2; ethyl acetate), af-
fording pure 43 as a colourless oil (127 mg, 79%, dr 60:40). Ϫ
C18H25NO6 (351.4): calcd. C 61.53, H 7.17, N 3.99; found C 61.20,
H 7.19, N 3.93.
(2S,3S,4R,5R)-1-Benzyl-2-(2-furyl)-3,4-isopropylidene-
dioxy-5-methylpyrrolidine (40): As described for 32; Zn dust (0.81 g,
12 mmol) added over 30 min to 39 (204 mg, 0.62 mmol, with ca. 8%
of the 2-epimer) in acetic acid (10 mL); reaction time 22 h at room
temp. Workup and chromatography (SiO2; petroleum ether/ethyl
acetate, 9:1) afforded the 2-(2-furyl)pyrrolidine 40 (146 mg, 75%) as a
spectroscopically pure stereoisomer. Note: The pyrrolidine 40 proved
sensitive towards oxidation by air and, after NMR measurement, was
immediately subjected to the next step. Ϫ 1H and 13C NMR spectro-
scopic data for 40: see Tables 2Ϫ4.
(2S,3S,4R,5R)-1-Benzyloxycarbonyl-2-hydroxymethyl-3,4-
isopropylidenedioxy-5-methylpyrrolidine (45): K2CO3 (704 mg,
5.09 mmol) was added to a solution of the pyrrolidine 43 (180 mg,
0.51 mmol, dr 60:40) in CH2Cl2 (5 mL). The resulting suspension
was treated with a solution of lead tetraacetate (85%, 321 mg,
0.62 mmol) in CH2Cl2 (10 mL) to give a yellow mixture, which was
stirred for 1 h at room temp., filtered, and concentrated in vacuo.
The resulting colourless oil (44, 175 mg) was dissolved in ethanol
(6 mL) and NaBH4 (39 mg, 1.03 mmol) was added at 0 °C. After
2.5 h, another portion of NaBH4 (40 mg) was added. After 1.5 h
at 0 °C, the reaction was quenched by addition of an aqueous solu-
tion of citric acid (0.25 , 8 mL). The solution was neutralized
using 6  NaOH, concentrated by rotary evaporation until most of
the ethanol was removed, and extracted with CHCl3 (3 ϫ 20 mL).
The organic phase was dried with MgSO4 and concentrated to dry-
ness. The residue was purified by flash chromatography (SiO2; pet-
roleum ether/ethyl acetate, 1:1) to give pure 45 as a colourless oil
(3R,4R,5R)-1-Benzyl-3,4-isopropylidenedioxy-5-methylpyrroli-
din-2-one (38): A solution of the acetonide 40 (129 mg, 0.41 mmol)
in CCl4 (2 mL), acetonitrile (2 mL), and water (3 mL) was treated
with sodium periodate (1.32 g, 6.2 mmol) and RuCl3·H2O (5 mg).[50]
The solution turned dark, with formation of a colourless precipitate
and gas evolution (carbon dioxide). After vigorous stirring for 1 h,
the reaction mixture was extracted with CH2Cl2 (4 ϫ 10 mL). The
organic solutes were dried with MgSO4 and concentrated in vacuo.
The residue was dissolved in diethyl ether and filtered through Celite.
Column chromatography of the crude material obtained upon con-
centration of the filtrate (SiO2; ethyl acetate/petroleum ether, 7:3) af-
forded colourless crystals of the pure lactam 38 (46 mg, 43%), m.p.
83Ϫ84 °C. Ϫ [α]2D0 ϭ ϩ69 (c ϭ 0.51, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ
2970, 2950, 2910, 1685 (CO), 1420 cmϪ1. Ϫ 1H NMR (CDCl3,
500.1 MHz): δ ϭ 1.18 (d, J5,5-Me ϭ 6.9 Hz, 3 H, 5-CH3), 1.36, 1.43
[2 s, 6 H, C(CH3)2], 3.53 (qu, J5,5-Me ϭ 6.9 Hz, 1 H, 5-H), 3.95 and
(126 mg, 77%). Ϫ [α]2D0 ϭ ϩ13 (c ϭ 0.52, CH2Cl2) {ref.[44] [α]2D0
ϭ
ϩ13 (c ϭ 1.0, CHCl3)} Ϫ IR (film): ν˜ ϭ 3458 (br., OH), 2986,
2938, 1694, 1681, 1454, 1415, 1380, 1359, 1329, 1241, 1213, 1064
cmϪ1 (identical with the data given in ref.[44]). Ϫ 1H and 13C NMR
spectroscopic data for 45: see Tables 2Ϫ4 (for NMR spectroscopic
data in CDCl3, 333 K, see ref.[44]). Ϫ C17H23NO5 (321.4): calcd. C
63.54, H 7.21, N 4.36; found C 63.41, H 7.25, N 4.34.
2
5.03 (2 d, J ϭ 15.1 Hz, 2 H, CH2Ph), 4.33 (d, J3,4 ϭ 5.7 Hz, 1 H,
3-H or 4-H), 4.76 (d, J3,4 ϭ 5.7 Hz, 1 H, 4-H or 3-H), 7.33 (mc, 5
H, C6H5). Ϫ 13C NMR (CDCl3, 125.8 MHz): δ ϭ 17.6 (5-CH3), 25.8,
27.2 [C(CH3)2], 44.1 (CH2Ph), 56.2 (C-5), 77.2, 78.8 (C-3, C-4), 112.3
[C(CH3)2], 127.7, 128.0, 128.7, 135.4 (C6H5), 170.7 (CO).
Ϫ
C15H19NO3 (261.3): calcd. C 68.94, H 7.33, N 5.36; found C 68.75,
H 7.36, N 5.36.
(2S,3S,4R,5R)-2-Hydroxymethyl-3,4-isopropylidenedioxy-5-
methylpyrrolidine (46): Removal of the Z group was achieved by
hydrogenation (1 bar) of a solution of 45 (108 mg, 0.34 mmol) in
MeOH (5 mL), using Pd catalyst (40 mg, 10% Pd on charcoal).
After a reaction time of 5.5 h, the catalyst was removed by centrifu-
gation and washed with MeOH. Concentration of the MeOH solu-
tion under reduced pressure afforded the acetonide 46 (63 mg, 91%)
(2S,3S,4R,5R)-1-Benzyl-2-(1Ј,2Ј-dihydroxyethyl)-3,4-isopropylid-
enedioxy-5-methylpyrrolidine (41):
A solution of 35 (200 mg,
0.73 mmol) in 8 mL of acetone/water (1:1) was treated with N-mor-
pholine N-oxide (NMO, 110 mg, 0.81 mmol) and OsO4 (0.5 mL of a
solution of 10 mg/mL OsO4 in tert-butyl alcohol, 0.03 equiv.). The
reaction mixture was stirred for 1 d at room temp., then treated with
a further portion of NMO (110 mg) and OsO4 solution (0.5 mL).
1
as a colourless oil. Ϫ H and 13C NMR spectroscopic data for 46:
see Tables 2Ϫ4.
After a total reaction time of 4.5 d, Na2SO3 (0.4 g) and silica gel (2S,3S,4R,5R)-3,4-Dihydroxy-2-hydroxymethyl-5-methyl-
(1 g) were added and the heterogeneous mixture was concentrated in pyrrolidine (28): Compound 46 (55 mg, 0.27 mmol) was dissolved
vacuo. Flash chromatography (SiO2, ethyl acetate) yielded the pure under argon in a mixture of MeOH (3 mL), water (3 mL), and
diol 41 as a mixture of epimers (colourless oil, 187 mg, 83%, dr
conc. HCl (0.45 mL). The colourless solution was stirred for 17 h at
2556
Eur. J. Org. Chem. 2001, 2547Ϫ2558

Preparation and Biological Evaluation of Pyrrolidinediols and Pyrrolidine N-Oxides
room temp. Concentration to dryness afforded a brown oil (58 mg), hol): exact mass calcd. for C6H11NO4 ϩ H: 162.0766; found
FULL PAPER
which was purified using Dowex 50WX8 (1 g, cf. purification of
15). The crude 28·HCl in MeOH was loaded onto the resin, this
was washed with MeOH (50 mL) and water (50 mL), and the pyr-
rolidine 28 was then eluted with 1  NH3 (50 mL). Removal of the
solvent under reduced pressure yielded 40 mg (0.27 mmol, 100%)
of the iminopolyol 28, a spectroscopically pure, pale yellow solid
162.0762.
( 2 R , 3 S, 4 R , 5 R ) - 1 - B e n z y l ox yc a r b o ny l - 3 , 4 - i s o p ro py -
lidenedioxy-5-methylproline Methyl Ester (49): The carboxylic acid
47 was prepared from 43 (169 mg, 0.48 mmol) as described above.
The crude product of 47 was dissolved in MeOH (5 mL) and
treated with a 0.7  solution of diazomethane in ether[58,59] until
the yellow colour persisted. After concentration in vacuo, the crude
ester was purified by flash chromatography (SiO2; petroleum ether/
ethyl acetate, 7:3) yielding the protected proline 49 (112 mg, 67%)
as an analytically pure, colourless oil. Ϫ [α]2D0 ϭ Ϫ19 (c ϭ 0.15,
CH2Cl2). Ϫ IR (film): ν˜ ϭ 2987, 2952, 1753 (CO), 1707 (CO), 1412,
1207, 1063 cmϪ1. Ϫ 1H and 13C NMR spectroscopic data of 49:
see Tables 2Ϫ4. Ϫ MS (EI, 70 eV): m/z (%) ϭ 349.1 (14) [Mϩ],
290.1 (15), 246.1 (25), 91.1 (100), 28.1 (17), 18.0 (28). Ϫ C18H23NO6
(349.4): calcd. C 61.88, H 6.64, N 4.01; found C 61.66, H 6.64,
N 3.99.
with deviating analysis, m.p. 97Ϫ100 °C (ref.:[43,44] oil). Ϫ [α]2D0
ϭ
Ϫ1 (c ϭ 1.50, MeOH) {ref.[43,44] [α]2D0 ϭ Ϫ2 (c ϭ 1.0, MeOH)}. Ϫ
IR (KBr): ν˜ ϭ 3364 (br., OH), 2964, 2930, 1455, 1416, 1372, 1328,
1108 cmϪ1. Ϫ 1H and 13C NMR spectroscopic data for 28: see
Tables 2Ϫ4 (for NMR spectroscopic data in D2O cf. ref.[44]). Ϫ MS
(Auto-CI): m/z (%) ϭ 148.1 (16) [MHϩ], 116.0 (100), 87.1 (22), 69.0
(68), 60.1 (10), 54.0 (14). Ϫ HRMS (Auto-CI): exact mass calcd.
for C6H13NO3 ϩ H: 148.0974; found 148.0974. Ϫ C6H13NO3
(147.2): calcd. C 48.96, H 8.90, N 9.52; found C 46.97, H 8.68,
N 8.71.
(2R,3S,4R,5R)-3,4-Isopropylidenedioxy-5-methylproline Methyl Ester
(50): Pd catalyst (10% Pd on charcoal, 30 mg) was added to a solu-
tion of the Z-proline derivative 49 (148 mg, 0.42 mmol) in MeOH
(10 mL). The mixture was hydrogenated (1 bar) over a period of
3 h. The catalyst was removed by centrifugation and washed with
MeOH. The combined MeOH phases were concentrated, yielding
the proline ester 50 as a colourless oil (90 mg, 100%). Ϫ 1H and
13C NMR spectroscopic data for 50: see Tables 2Ϫ4.
(2R,3S,4R,5R)-1-Benzyloxycarbonyl-3,4-isopropylidene-
dioxy-5-methylproline (47): Lead tetraacetate cleavage of 43
(204 mg, 0.58 mmol) was performed as reported for 45, yielding 44
(176 mg) as a colourless oil. This was dissolved in tert-butyl alcohol
(2.5 mL) and 2-methyl-2-butene (1.5 mL).[53] An aqueous solution
(0.75 mL) of NaClO2 (79 mg, 0.87 mmol) and NaH2PO4 (105 mg,
0.87 mmol) was added over a period of 40 min. The reaction mix-
ture was stirred for 5.5 h at room temp. and the pH was then ad-
justed to Ͼ 8 using 6  NaOH. After most of the solvent had been
removed in vacuo, water (15 mL) was added. The aqueous phase
was extracted with diethyl ether (3 ϫ 15 mL) and the pH was ad-
justed to 2 by addition of 1  HCl. The organic phase collected on
extraction of the aqueous phase with diethyl ether (3 ϫ 15 mL)
was dried with MgSO4 and concentrated to dryness. The proline
derivative 47 was isolated as a colourless resin (152 mg, 78%). Ϫ
[α]2D0 ϭ ϩ15 (c ϭ 1.90, CH2Cl2). Ϫ IR (film): ν˜ ϭ 3660Ϫ2350 (br.,
COOH), 1753 (CO), 1708 (CO), 1419, 1356, 1212, 1064 cmϪ1. Ϫ
1H and 13C NMR spectroscopic data of 47: see Tables 2Ϫ4. Ϫ
C17H21NO6 (335.4): calcd. C 60.89, H 6.31, N 4.18; found C 60.27,
H 6.39, N 4.02.
(2S,3S,4R,5R)-3,4-Dihydroxy-5-methylproline Methyl Ester Hydro-
chloride (31·HCl): A solution of the proline derivative 50 (25 mg,
0.12 mmol) in MeOH (3.5 mL) was treated with MeOH saturated
with HCl gas (0.5 mL) and stirred for 2.5 h at room temp. The
residue obtained on concentration to dryness (ratio of 2-epimers
30/31 ϭ 29:71) was crystallized from 2-propanol (1 mL), yielding
almost analytically pure proline ester hydrochloride 31·HCl (14 mg,
57%, 30/31 ϭ 6:94), m.p. 189Ϫ191 °C. Ϫ [α]2D0 ϭ ϩ19 (c ϭ 0.24,
MeOH). Ϫ IR (KBr): ν˜ ϭ 2970, 2930, 2880, 1740 (CO), 1435, 1265,
1220, 1112, 1100, 1085 cmϪ1. Ϫ 1H and 13C NMR spectroscopic
data for 31·HCl: see Tables 2Ϫ4. Ϫ MS (FAB, positive ion, nitro-
benzyl alcohol): m/z (%) ϭ 176.1 (100) [MHϩ], 116.0 (10). Ϫ
HRMS (FAB, positive ion, nitrobenzyl alcohol): exact mass calcd.
for C7H13NO4 ϩ H: 176.0923; found 176.0919. Ϫ C7H13NO4·HCl
(211.6): calcd. C 39.72, H 6.67, N 6.62; found C 39.09, H 6.49,
N 6.18.
(2R,3S,4R,5R)-3,4-Isopropylidenedioxy-5-methylproline (48): The Z
group was removed from 47 (75 mg in 5 mL of MeOH, 0.22 mmol)
by catalytic hydrogenation (1 bar, 25 mg of 10% Pd on charcoal).
After a reaction time of 4 h, the catalyst was removed by centrifu-
gation and washed with MeOH (10 mL) and water (10 mL). The
combined solutions were concentrated, yielding spectroscopically
pure, colourless crystals of 48 (45 mg, 100%), m.p. 238Ϫ240 °C
(decomp.). Ϫ [α]2D0 ϭ Ϫ34 (c ϭ 1.08, MeOH). Ϫ 1H and 13C NMR
spectroscopic data for 48: see Tables 2Ϫ4.
Acknowledgments
We are grateful to ‘‘Landesgraduiertenförderung Baden-Württem-
berg’’, the ‘‘Fonds der Chemischen Industrie’’, the ‘‘Bundesminis-
terium für Bildung, Wissenschaft, Forschung und Technologie’’,
and ‘‘COST D13’’ for financial support (scholarships to A. M. P.
and travel grants). We would like to thank Prof. Dr. P. Vogel and
Dr. S. Picasso (University of Lausanne) for excellent and long-
standing cooperation in the field of glycosidase inhibition. Further-
more, we are grateful to Dr. P. Hilgers, who made the performance
of the bioassays at the University of Stuttgart possible and to Ms.
I. Kienzle for determining the biological activity of the pyrrolidines
described in this work.
(2R,3S,4R,5R)-3,4-Dihydroxy-5-methylproline Hydrochloride (29·
HCl): Conc. HCl (0.25 mL) was added under nitrogen to an aque-
ous solution (4 mL) of 48 (52 mg, 0.26 mmol). After the colourless
solution had been stirred for 4 h at room temp., it was concentrated
to dryness. Drying over P4O10 afforded 51 mg (100%) of spectro-
scopically pure 29·HCl. The extremely hygroscopic solid deli-
quesced when exposed to air [ref.:[45] racemic mixture of neutral 29,
m.p. 115Ϫ116 °C (decomp.)]. Ϫ [α]2D0 ϭ 0 (c ϭ 0.24, MeOH). Ϫ IR
(film): ν˜ ϭ 3680Ϫ2250 (br., COOH, NH, OH), 1732 (CO), 1626,
1392, 1233, 1126, 1075 cmϪ1. Ϫ 1H and 13C NMR spectroscopic
data for 29·HCl: see Tables 2Ϫ4 (for NMR spectroscopic data of
neutral 29 cf. ref.[45]) Ϫ C6H11NO4·HCl (197.6): calcd. C 36.47, H
6.12, N 7.09; found C 34.91, H 6.04, N 6.31 [correct for
M·HCl·(H2O)0.5]. Ϫ MS (FAB, positive ion, glycerol): m/z (%) ϭ
162.1 (100) [MHϩ]. Ϫ HRMS (FAB, positive ion, nitrobenzyl alco-
[1]
Part of the planned Dissertation of A. M. Palmer, Stuttgart. Ϫ
Presented at the 17th ICHC, Vienna, August 1999 (Abstr. PO-
439), and at the 2000 Lausanne Workshop on Glycomimetics
(COST D13), Lausanne, May 2000 (Abstr. 4).
[2]
Part III: ref.[41]; part II: A. M. Palmer, V. Jäger, Synlett 2000,
10, 1405Ϫ1407; to be considered part I in this series: ref.[36]
R. Müller, T. Leibold, M. Pätzel, V. Jäger, Angew. Chem. 1994,
[3]
Eur. J. Org. Chem. 2001, 2547Ϫ2558
2557

A. M. Palmer, V. Jäger
FULL PAPER
[31]
[32]
106, 1305Ϫ1308; Angew. Chem. Int. Ed. Engl. 1994, 33,
1295Ϫ1298.
V. Jäger, R. Müller, T. Leibold, M. Hein, M. Schwarz, M.
Fengler, L. Jaroskova, M. Pätzel, P.-Y. LeRoy, Bull. Soc. Chim.
Belg. 1994, 103, 491Ϫ507.
V. Jäger, W. Hümmer, Angew. Chem. 1990, 102, 1182Ϫ1183;
Angew. Chem. Int. Ed. Engl. 1990, 29, 1171Ϫ1173.
W. Hümmer, E. Dubois, T. Gracza, V. Jäger, Synthesis 1997,
634Ϫ642.
G. W. J. Fleet, A. N. Shaw, S. V. Evans, L. E. Fellows, J. Chem.
Soc., Chem. Commun. 1985, 841Ϫ842.
G. W. J. Fleet, S. Petursson, A. L. Campbell, R. A. Mueller, J.
R. Behling, K. A. Babiak, J. S. Ng; M. G. Scaros, J. Chem.
Soc., Perkin Trans. 1 1989, 665Ϫ666.
H. Paulsen, M. Matzke, B. Orthen, R. Nuck, W. Reutter, Lie-
bigs Ann. Chem. 1990, 953Ϫ963.
B. Winchester, C. Barker, S. Baines, G. S. Jacob, S. K.
Namgoong, G. Fleet, Biochem. J. 1990, 265, 277Ϫ282.
Y.-F. Wang, D. P. Dumas, C.-H. Wong, Tetrahedron Lett. 1993,
34, 403Ϫ406.
[4]
[33]
[34]
[35]
[36]
[5]
[6]
[7]
V. Jäger, T. Gracza, E. Dubois, T. Hasenöhrl, W. Hümmer, U.
Kautz, B. Kirschbaum, A. Lieberknecht, L. Remen, D. Shaw,
U. Stahl, O. Stephan in Organic Synthesis via Organometallics
OSM 5 (Eds.: G. Helmchen, J. Dibo, D. Flubacher, B. Wiese),
Vieweg, Braunschweig, 1997, p. 331Ϫ360.
V. Wehner, V. Jäger, Angew. Chem. 1990, 102, 1180Ϫ1182; An-
gew. Chem. Int. Ed. Engl. 1990, 29, 1169Ϫ1171.
F.-M. Kieß, P. Poggendorf, S. Picasso, V. Jäger, Chem. Com-
mun. 1998, 119Ϫ120.
V. Jäger, R. Öhrlein, V. Wehner, P. Poggendorf, B. Steuer, J.
Raczko, H. Griesser, F.-M. Kieß, A. Menzel, Enantiomer 1999,
4, 205Ϫ228.
S. V. Evans, L. E. Fellows, T. K. M. Shing, G. W. J. Fleet,
Phytochem. 1985, 24, 1953Ϫ1955.
C.-H. Wong, L. Provencher, J. A. Porco Jr., S.-H. Jung, Y.-F.
Wang, L. Chen, R. Wang, D. H. Steensma, J. Org. Chem. 1995,
60, 1492Ϫ1501.
G. Legler, Adv. Carbohydr. Chem. Biochem. 1990, 48, 319Ϫ384.
M. L. Sinnott, Chem. Rev. 1990, 90, 1171Ϫ1202.
B. Winchester, G. W. J. Fleet, Glycobiology 1992, 2, 199Ϫ210.
D. A. Winkler, G. Holan, J. Med. Chem. 1989, 32, 2084Ϫ2089.
P. Ermert, A. Vasella, M. Weber, K. Rupitz, S. G. Withers,
Carbohydr. Res. 1993, 250, 113Ϫ128.
T. D. Heightman, A. T. Vasella, Angew. Chem. 1999, 111,
794Ϫ815; Angew. Chem. Int. Ed. 1999, 38, 750Ϫ770.
D. L. Zechel, S. G. Withers, Acc. Chem. Res. 2000, 33, 11Ϫ18.
Carbohydrate Mimics Ϫ Concepts and Methods (Ed.: Y. Chap-
leur), Wiley-VCH, Weinheim, 1998.
E. J. Hehre, Adv. Carbohydr. Chem. Biochem. 1999, 55,
265Ϫ310.
G. W. Jourdian in New Comprehensive Biochemistry (Eds.: A.
Neuberger, L. L. M. van Deenen), vol. 30 (‘‘Glycoproteins and
Disease’’) (Eds.: J. Montreuil, J. F. G. Vliegenthart, H.
Schachter), Elsevier, Amsterdam, 1996, p. 3Ϫ54.
R. A. Dwek, Chem. Rev. 1996, 96, 683Ϫ720.
A. Varki, Glycobiology 1993, 3, 97Ϫ130.
A. Giannis, Angew. Chem. 1994, 106, 188Ϫ191; Angew. Chem.
Int. Ed. Engl. 1994, 33, 178Ϫ180.
E. Truscheit, W. Frommer, B. Junge, L. Müller, D. D. Schmidt,
W. Wingender, Angew. Chem. 1981, 93, 738Ϫ755; Angew.
Chem. Int. Ed. Engl. 1981, 20, 744Ϫ761.
A. D. Elbein, R. J. Molyneux in Imino Sugars as Glycosidase
Inhibitors: Nojirimycin and Beyond (Ed.: A. E. Stütz), Wiley-
VCH, Weinheim, 1999, p. 216Ϫ252.
H. M. Flowers, Adv. Carbohydr. Chem. Biochem. 1981, 39,
279Ϫ345.
T. K. Lindhorst, M. Ludewig, J. Thiem, J. Carbohydr. Chem.
1998, 17, 1131Ϫ1149.
V. Jäger, L. Bierer, H.-Q. Dong, A. M. Palmer, D. Shaw, W.
Frey, J. Heterocycl. Chem. 2000, 37, 455Ϫ465.
L. Bierer, Dissertation, Universität Stuttgart, 1999.
L. Bierer, V. Jäger, manuscript in preparation.
[37]
[38]
[39]
[8]
`
´
M. Joubert, These Doctorale, Universite de Haute-Alsace,
Mulhouse, 2000.
[9]
[40]
M. Joubert, A. Defoin, C. Tarnus, J. Streith, Synlett 2000,
1366Ϫ1368.
A. M. Palmer, V. Jäger, Eur. J. Org. Chem., 2001, 1293Ϫ1308.
R. C. Bernotas, R. V. Cube, Synth. Comm. 1990, 20,
1209Ϫ1212.
[10]
[41]
[42]
[11]
[43]
[44]
[45]
[46]
ˆ
cf. A. Defoin, Th. Sifferlen, J. Streith, I. Dosbaa, M.-J. Fogli-
etti, Tetrahedron: Asymmetry 1997, 8, 363Ϫ366.
[12]
cf. T. Sifferlen, A. Defoin, J. Streith, D. Le Noue¨n, C. Tarnus,
I. Dosbaa, M.-J. Foglietti, Tetrahedron 2000, 56, 971Ϫ978.
cf. J. B. Behr, A. Defoin, N. Mahmood, J. Streith, Helv. Chim.
ˆ
[13]
Acta 1995, 78, 1166Ϫ1177.
[14]
A. I. Meyers, General Heterocyclic Chemistry Series, vol. 3
(‘‘Heterocycles in Organic Synthesis’’) (Eds.: E. C. Taylor, A.
Weissberger), Wiley & Sons, New York, 1974.
[15]
[16]
[47]
P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J.
Org. Chem. 1981, 46, 3936Ϫ3938.
R. Franz, Dissertation, Universität Würzburg, 1984.
V. Jäger, R. Franz, W. Schwab, B. Häfele, D. Schröter, D.
Schäfer, W. Hümmer, E. Guntrum, B. Seidel in Studies in Or-
ganic Chemistry, vol. 35 (‘‘Chemistry of Heterocyclic Com-
[17]
[48]
[49]
[18]
[19]
[20]
´
´
´
pounds’’) (Eds.: J. Kovac, P. Zalupsky), Elsevier, Amsterdam,
1988, p. 58Ϫ75.
[21]
[50]
cf. M. T. Nun˜ez, V. S. Martin, J. Org. Chem. 1990, 55,
1928Ϫ1932.
F. Kröhnke, Justus Liebigs Ann. Chem. 1957, 604, 203Ϫ207.
B. O. Lindgren, T. Nilsson, Acta Chim. Scand. 1973, 27,
888Ϫ890.
G. A. Kraus, B. Roth, J. Org. Chem. 1980, 45, 4825Ϫ4830.
A. Brandi, S. Cicchi, F. M. Cordero, R. Frignoli, A. Goti, S.
Picasso, P. Vogel, J. Org. Chem. 1995, 60, 6806Ϫ6812.
P. Hilgers, Dissertation, Universität Stuttgart, 2000.
T. Kajimoto, K. K.-C. Liu, R. L. Pederson, Z. Zhong, Y. Ichi-
kawa, J. A. Porco, Jr., C.-H. Wong, J. Am. Chem. Soc. 1991,
113, 6187Ϫ6196.
H. G. Becker, W. Berger, G. Domschke, E. Fanghänel, J. Faust,
M. Fischer, F. Gentz, K. Gewald, R. Gluch, R. Mayer, K.
Müller, D. Pavel, H. Schmidt, K. Schollberg, K. Schwetlick, E.
Seiler, G. Zeppenfeld, Organikum, 20th ed., Wiley-VCH,
Weinheim, 1999.
[51]
[52]
[22]
[53]
[54]
[23]
[24]
[55]
[56]
[25]
[26]
[57]
[27]
[28]
[58]
[59]
Th. J. De Boer, H. J. Backer, Org. Synth., Coll. Vol. 4 1963,
250Ϫ253.
[29]
M. Hudlicky, J. Org. Chem. 1980, 45, 5377Ϫ5378.
Received December 22, 2000
[30]
S. Hakomori, Adv. Cancer Res. 1989, 52, 257.
[O00657]
2558
Eur. J. Org. Chem. 2001, 2547Ϫ2558