Pyrrolidine N-oxides by stereoselective addition of Grignard and lithium compounds to 4,5-dideoxy-2,3-O-isopropylidene-D-erythro-4-pentenose N-benzyl nitrone and subsequent Cope-House cyclization

Article abstract of DOI:10.1002/1099-0690(200104)2001:7<1293::AID-EJOC1293>3.0.CO;2-4

The addition of Grignard reagents to D-erythro-4-pentenose N-benzyl nitrone 5, which is easily accessible from D-ribose, furnishes ω-unsaturated hydroxylamines that readily undergo Cope-House cyclization to afford pyrrolidine N-oxides. The stereoselectivity of the addition step is altered by either employing organolithium compounds or Lewis acids as complexing agents. The pyrrolidine N-oxides obtained by this sequence serve as key intermediates in the synthesis of 2,5-disubstituted pyrrolidine-3,4-diols (to be discussed in detail separately), both constituting new potential inhibitors of glycosidases.

Full text of DOI:10.1002/1099-0690(200104)2001:7<1293::AID-EJOC1293>3.0.CO;2-4

FULL PAPER
Pyrrolidine N-Oxides by Stereoselective Addition of Grignard and Lithium
Compounds to 4,5-Dideoxy-2,3-O-isopropylidene- -erythro-4-pentenose
D
N-Benzyl Nitrone and Subsequent Cope؊House Cyclization[‡]
Andreas M. Palmer[a] and Volker Jäger*[a]
Dedicated to Professor Günter Helmchen on the occasion of his 60th birthday
Keywords: Grignard addition / CopeϪHouse cyclization / Dihydroxypyrrolidine N-oxides / Dihydroxypyrrolidines /
Glycosidase inhibitors
The addition of Grignard reagents to
N-benzyl nitrone 5, which is easily accessible from
furnishes ω-unsaturated hydroxylamines that readily un-
dergo Cope−House cyclization to afford pyrrolidine N-ox-
ides. The stereoselectivity of the addition step is altered by
either employing organolithium compounds or Lewis acids
D
-erythro-4-pentenose
as complexing agents. The pyrrolidine N-oxides obtained by
this sequence serve as key intermediates in the synthesis of
2,5-disubstituted pyrrolidine-3,4-diols (to be discussed in de-
tail separately), both constituting new potential inhibitors of
glycosidases.
D-ribose,
Introduction
Glycosidase inhibitors hinder the enzymatic hydrolysis of
oligo- and polysaccharides. Such inhibitors are therefore of
considerable interest for the treatment of certain metabolic
disorders, e.g. diabetes or inflammatory processes,[3Ϫ6] and
many efforts have been undertaken to rationalize the char-
acteristics that an effective inhibitor should possess. Two
features seem to be of special relevance:[6Ϫ8] (i) The inhib-
itor should resemble the natural substrate (carbohydrate),
i.e. it should possess several hydroxy groups in a distinct
configuration; (ii) the inhibitor should mimic intermediate
species such as the exo-protonated glycoside A (cf. the pur-
ported pyranosyl cation B),[4] or transition states like C, rel-
evant in the course of the hydrolysis (Figure 1).[9] Thus, it
should contain a basic function to accommodate the posit-
ive charge introduced by protonation.[5Ϫ7]
This concept is derived from many observations, notably
that many potent inhibitors represent polyhydroxypiperid-
ines (1,5-imino derivatives of the natural substrates) or po-
lyhydroxypyrrolidines (1,4-iminoglycitols, ring-contracted
analogues of the natural substrates).[10Ϫ14] Two examples
are depicted in Figure 1: Nojirimycin (D), a potent inhibitor
of several α-glucosidases,[15,16] and 1,4-dideoxy-1,4-imino-
-mannitol (E), which effectively inhibits some α-
mannosidases.[17Ϫ21]
Figure 1. Intermediates and transition states proposed for enzym-
atic cleavage of glycosides. Iminoglycitols as examples of glycosid-
ase inhibitors
[‡]
Synthesis of Glycosidase-Inhibiting Iminopolyols by CopeϪ
The objective of the present work is the synthesis of 2,5-
disubstituted pyrrolidinediols and pyrrolidinediol N-oxides,
classes of compounds that meet the prerequisites outlined
above and that, in our view, might give rise to new struc-
tures with high activities for inhibition, especially of α--
fucosidases: The pyrrolidine N-oxides bring along a nega-
House Cyclization of Unsaturated Hydroxylamines, III. Ϫ
Part II: Ref.[1]
[‡][‡] Ref.[2]
[a]
Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax:(internat) ϩ 49Ϫ711/685-4321
E-mail: jager.ioc@po.uni-stuttgart.de
Eur. J. Org. Chem. 2001, 1293Ϫ1308
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0407Ϫ1293 $ 17.50ϩ.50/0
1293

A. M. Palmer, V. Jäger
FULL PAPER
tively charged oxygen atom, presumably with the capability Results and Discussion
of forming additional hydrogen bonds within the active site
Synthesis of D-erythro-4-Pentenose N-Benzyl Nitrone 5 ؊
A Key Intermediate in the Synthesis of 2- and 2,5-
Substituted Pyrrolidinediols
while retaining the positively charged N-atom (or with N-
hydroxypyrrolidines[22,23] allowing N-protonation to effect
this).
The CopeϪHouse cyclization of unsaturated hy-
droxylamines was expected to offer a convenient approach
to these classes of heterocycles. This transformation was
discovered in 1976 by House and co-workers and was ori-
ginally thought to proceed by a radical pathway.[24,25] In the
early nineties, Ciganek and Oppolzer proved this to be a
concerted process (Scheme 1) with a planar five-membered
transition state involving six electrons.[26Ϫ29] It is, of course,
the reverse of the well-known thermal Cope elimination of
tertiary amine N-oxides, mostly leading to separate ene and
hydroxylamine products.[30,31] Thus, the mechanism of the
CopeϪHouse cyclization,[32,33] which has also been termed
‘‘Cope cyclization’’,[34] ‘‘retro- or reverse-Cope elimina-
tion’’,[27] ‘‘House reaction’’, or ‘‘1,3-azaprotio transfer’’,[32]
resembles that of Alder’s ene reaction.[35] As a consequence,
the cyclization proceeds highly stereoselectively with respect
to the mutual cis-orientation of the N-oxide function and
the newly formed alkyl (methyl) group.
-Ribose (1) was converted into 4,5-dideoxy-2,3-O-isop-
ropylidene--erythro-4-pentenose (4) using a slight modi-
fication of a procedure that had been applied by the groups
of Gallos[41,42] and Paquette[43] (Scheme 2). After protection
of -ribose (1) using 2,2-dimethoxypropane and methanolic
hydrochloric acid,[44] the hydroxy group in 2 was trans-
formed into the iodo compound 3 by means of triphenyl-
phosphane/iodine.[45,46] Ring-opening of 3 to the unsatur-
ated aldehyde 4 by reductive elimination (Boord elimina-
tion) was achieved with n-butyllithium.[22,34,47Ϫ49] The pen-
tenose 4, obtained in 58% overall yield from 1, was
dissolved in dichloromethane and condensed with one
equivalent of N-benzylhydroxylamine, in the presence of
magnesium sulfate as a dehydrating agent,[50] to afford the
analytically pure N-benzyl nitrone 5 in 69% yield.[51] With
this stoichiometric ratio of reactants, three minor by-prod-
ucts were formed and could be isolated by chromatography.
Details of this unexpected formation of 5-azapyranoses are
reported separately.[34,38,39]
Scheme 1. CopeϪHouse cyclization of unsaturated hydroxylamines
The use of unsaturated hydroxylamines derived from en-
antiomerically pure starting materials such as -ribose or
1,2-epoxy-4-pentenols,[34,36,37] combined with the high dias-
tereoselectivity of the CopeϪHouse cyclization, therefore
seemed a promising approach for the stereoselective syn-
thesis of potential glycosidase inhibitors such as iminoglyci-
tol N-oxides and, hence, of the parent polyhydroxypyrrolid-
ines. We have developed four complementary approaches
to obtain such N-oxy-pyrrolidines: (i) The ‘‘epoxypentenol
route’’, involving the nucleophilic addition of hy-
droxylamines with subsequent CopeϪHouse cycliza-
tion;[34,36,38,39] (ii) Bromocyclization of oximes followed by
nucleophilic addition of C-nucleophiles to the intermediate
cyclic nitrone (pyrroline N-oxide);[22,34] and (iii), (iv) Nucle-
ophilic additions to unsaturated oximes and nitrones, re-
spectively, generating alkenylhydroxylamines, which un-
dergo cyclization.[34,38Ϫ40] In the following, details of our
work concerning route (iv), the preparation of hy-
Scheme 2. Synthesis of the N-benzyl nitrone 5 from -ribose (1):
(a) 1. Me2C(OMe)2, MeOH, HCl, acetone, room temp., 21 h; 2.
pyridine; 67%. Ϫ (b) PPh3, imidazole, I2, toluene, 70 °C, 2 h; 87%.
Ϫ (c) nBuLi, THF, Ϫ80 °C, 2 h; quant. Ϫ (d) BnNHOH, MgSO4,
CH2Cl2, room temp., 19 h; 69%
Nucleophilic Addition of Hydride and Grignard Reagents to
Nitrone 5; Cope؊House Cyclization
Nitrones are rather sluggish electrophiles, but additions
droxylamines from -ribose (1) by the addition of a variety of hydride (from sodium borohydride and related agents)
of Grignard or organolithium compounds to respective 4- and particularly of Grignard reagents are well
pentenose nitrones, are described, along with the ensuing precedented.[52Ϫ55] Also, the reduction of oximes to provide
CopeϪHouse cyclization. Transformation of selected prod- N-alkenylhydroxylamines suitable for CopeϪHouse cycliza-
ucts to the parent 2- or 2,5-(di)substituted dihydroxypyrrol- tion is rather common.[25,28,56Ϫ58] However, only in few
idines along with results of the biological evaluation, mainly cases, nitrones were used as starting materials.[26,27,51,57]
concerning fucosidase inhibition, are reported in the next Here, in order to obtain the parent unsaturated hy-
paper of this series.[40]
droxylamine 6, the N-benzyl nitrone 5 was reduced with
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Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
FULL PAPER
1
sodium borohydride in ethanol at 0 °C (Scheme 3). The H urations of these heterocycles were derived from NMR
NMR spectrum of the crude product, taken immediately spectroscopic data as depicted in Scheme 4 (vide infra).
after workup and extraction with chloroform, showed that
As seen from Table 1 (entries 2Ϫ14), the addition of a
the hydroxylamine 6 had been formed, as expected. How- representative set of other Grignard reagents to the nitrone
ever, some conversion of this into the cyclized N-oxides 7 5 was studied likewise and in all cases, after CopeϪHouse
and 8 was already evident, and this was brought to comple- cyclization, led to the respective pyrrolidine N-oxides
tion by allowing the solution to stand at room temperature 11b؊h,k 12b؊k, and 13b,d,g. With ethylmagnesium brom-
for another 16 h. The pyrrolidine N-oxide products were ide and isopropylmagnesium chloride, the 2,3-cis-pyrrolid-
obtained as a 92:8 mixture (93%), from which the major ine N-oxides 12b and 12c were formed preferentially
diastereomer 7 crystallized in 66% yield.
(Table 1, entries 2, 3). When using isobutylmagnesium
bromide, the diastereomeric ratio of the products 11dϪ13d
depended more strongly on the reaction conditions
(Table 1, entries 4 to 6). The question as to whether iso-
merization by Cope elimination/recyclization may occur
was examined by stirring solutions of the pure isomers 11d
and 12d in deuterated chloroform for 6 d at room temper-
ature. The NMR spectra of 11d and 12d remained un-
changed. Thus, it seems that the diastereoselectivity ob-
served depends on the reaction conditions of the nucleo-
philic addition (temperature, time). Similarly, with the other
alkyl cases, a general correlation between the steric demand
of the nucleophile and the diastereoselectivity of the Grig-
nard addition step does not seem to hold.
The reactions of 5 with tert-butyl- or neopentylmagnes-
ium bromide furnished mixtures with two of the expected
pyrrolidine N-oxides, 11e/12e and 11f/12f, respectively, in
rather low yields (Table 1, entries 7 to 9). In the former case,
Scheme 3. Synthesis of the parent pyrrolidine N-oxides 7 and 8 by
reduction of the nitrone 5: (a) NaBH4, EtOH, 0 °C, 4 h; (b) CHCl3,
room temp., 16 h, 93%, 7/8 ϭ 92:8; (c) crystallization; 7: 66%
The fact that only two isomers were formed is in agree- the 2-unsubstituted pyrrolidine N-oxide 7, resulting from
ment with the accepted concerted mechanism.[26Ϫ29] The Grignard reduction, was observed in an approximately
configuration of these pyrrolidine N-oxides 7 and 8 was elu- equal amount; in the latter case the reaction did not go to
cidated from NMR spectroscopic data (vide infra). The di- completion. Again, the diastereomeric ratio observed
astereomeric ratio of 92:8 observed clearly indicates that the strongly depended on the reaction conditions.
acetonide function present at the α- and β-positions to the
double bond causes effective asymmetric induction in the tion of alkyl Grignard reagents to nitrone 5 proceeds with
cyclization step. moderate diastereodifferentation, whereas the
A tentative statement at this point may be that the addi-
For access to 2-substituted 5-methylpyrrolidine-3,4-diols, CopeϪHouse cyclization proceeds highly stereoselectively.
the addition of Grignard reagents proved feasible. A variety The CopeϪHouse cyclization approach to pyrrolidine N-
of reagents was used in order to explore structureϪactivity oxides using the ‘‘nitrone route’’ seems to be of preparative
relationships with regard to the intended tests of fucosidase value mostly with primary and secondary alkyl nucleophiles
inhibition.[40] As indicated in Table 1, most additions oc- for the preceding addition step.
curred readily at low temperatures, typically requiring 2 to
Good yields again were found for the phenyl and vinyl
8 h for completion. The cyclization of the intermediate hy- compounds, from which several of the individual stereoiso-
droxylamines 9 and 10 was then carried out in chloroform mers were isolated. Upon addition of phenylmagnesium
as above; this had been described as the optimum solvent bromide to the nitrone 5, the 2-epimers 11g/12g were ob-
for the CopeϪHouse cyclization.[26,27] In all cases, the con- tained in a diastereomeric ratio of 40:60 (Table 1, entry 10).
version of the unsaturated, acyclic hydroxylamines 9a؊h,k With vinylmagnesium bromide, the similar pair of ste-
and 10a؊k to the pyrrolidine N-oxides 11a؊h,k, 12a؊k reoisomers 11h/12h was found, with a slight preference for
and 13a,b,d,g proceeded smoothly and completely within the formation of 11h, which has the 2-substituent oriented
16 h (Scheme 4).
trans to the acetonide (Table 1, entry 11).
The addition of C-nucleophiles to nitrone 5 and the sub-
The delicate balance of the equilibrium between N-alken-
sequent CopeϪHouse cyclization of the intermediate hy- ylhydroxylamines and pyrrolidine N-oxides, comparable to
droxylamines 9a؊h,k and 10a؊k generate two stereocen- ring-chain tautomerism, became evident in the case of the
ters independently, so that product mixtures with up to four allyl and benzyl compounds: First, Grignard addition at
stereoisomers can be expected. In fact, upon reaction of the low temperature and chloroform treatment at room temper-
nitrone 5 with methylmagnesium bromide in diethyl ether ature for 13 to 16 h led to single stereoisomers of the pyrrol-
three diastereomers, the 2,5-dimethylpyrrolidine N-oxides idine N-oxides 12i and 12j in good yields (47 and 59%; ent-
11a, 12a, and 13a were found (Table 1, entry 1; dr ϭ ries 12, 13 in Table 1). These products, arising from the
38:48:14), which could be separated by MPLC. The config- thermal CopeϪHouse cyclization (‘‘retro-Cope elimina-
Eur. J. Org. Chem. 2001, 1293Ϫ1308
1295

A. M. Palmer, V. Jäger
Table 1. Addition of Grignard/organolithium reagents to N-benzyl nitrone 5 with ensuing CopeϪHouse cyclization
FULL PAPER
Entry
Reagent
Conditions
Products
dr[a]
11/12/13
Yield [%][b]
[°C]
[h]
1
2
MeMgBr
EtMgBr
Ϫ40
Ϫ20 to Ϫ30
Ϫ30
2
3.5
4.75
19
11a/12a/13a
11b/12b/13b
11c/12c
38:48:14
22:67:11
15:85:Ͻ5
27:65:8
78 (11a: 27; 12a: 37)
74 (11b, 12b: 64; 13b: 8)
3
iPrMgCl
48
4
iBuMgBr
0 to room temp.
Ϫ30 to room temp.
Ϫ30 to Ϫ10
Ϫ30
11d/12d/13d
11d/12d/13d
11d/12d/13d
7/11e/12e
11f/12f
74 (11d: 20; 12d: 49)
5
iBuMgBr
8.5
10
46:48:6
87
6
iBuMgBr
26:67:7
not purified[c]
7
tert-BuMgBr
neo-PeMgBr
neo-PeMgBr
PhMgBr
7.5
48
24:76:Ͻ5
50:50:Ͻ5
20:80:Ͻ5
40:60:Ͻ5
67:33:Ͻ5
Ͻ5:Ͼ95:Ͻ5
Ͻ5:Ͼ95:Ͻ5
22:37:41
13:66:21
18:64:18
Ͻ5:Ͼ95:Ͻ5
58:42:Ͻ5
84:16:Ͻ5
84:16:Ͻ5
91:9:Ͻ5
7: 24; 11e/12e: 18
8
room temp.
Ϫ10 to Ϫ30
Ϫ20
12f: 12
9
11
11f/12f
not purified[c]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1
11g/12g/13g
11h/12h
70 (11g: 25; 12g: 41; 13g: 4)
VinylMgBr
Ϫ40
2
91 (11h: 56; 12h: [d]‘‘35’’)
AllylMgBr
Ϫ40
0.75
2
12i
12j
47[e]
BnMgBr
Ϫ30
59[e]
ButenylMgBr
MeMgBr/ZnCl2·Et2O
MeMgBr/Et2AlCl
BnMgBr/Et2AlCl
PhMgBr/Et2AlCl
VinylMgBr/ZnCl2·Et2O
VinylMgBr/Et2AlCl
MeLi
Ϫ20
3.5
6
11k/12k/15
11a/12a/13a
11a/12a/13a
12j
59 (11k: 13; 12k: 23; 15: 23)
Ϫ30 to Ϫ10
Ϫ30
66 (12a: 49)[f]
59
3.25
2.75
3.75
4.25
3.5
4.75
3
Ϫ30 to Ϫ10
Ϫ30
57[e]
11g/12g/13g
11h/12h
76 (11g: 46)
75 (11h: 60)
72
Ϫ30 to Ϫ10
Ϫ30
11h/12h
Ϫ80
11a/12a
58 (11a: 53)
51 (12g: 38)
62
PhLi
VinylLi
Ϫ80
11g/12g/13g
11h/12h
19:81:Ͻ5
71:29:Ͻ5
Ϫ80
5.25
[a]
Diastereomeric ratios are calculated from the 1H and 13C NMR spectra of the crude product. Values Ͻ5 indicate that, although
formation of these isomers is likely (cf. Experimental Section, case 10), characteristic signals of these minor products were not visible in
[b]
the corresponding NMR spectra. Ϫ
Mixtures of diastereomers; yields given in brackets indicate the amount of pure stereoisomer
[c]
isolated after MPLC separation. In entries 15 to 23 only the yield of the major isomer is given. Ϫ Reaction did not go to completion.
[d]
[e]
[f]
Ϫ
Viscous oil, still containing traces of solvent even after thorough drying. Ϫ
Only one pyrrolidine N-oxide was formed. Ϫ
Sample contained approximately 10% of the minor diastereomer 13a.
tion’’) as above, were not stable and, upon prolonged stor-
age at Ϫ25 °C, slowly underwent ring-opening to form the
acyclic isomeric hydroxylamines 14i and 14j (Scheme 5).
This was demonstrated by 1H NMR spectroscopy, when
[D6]DMSO solutions of the N-oxides 12i or 12j were heated
to 80 °C for 15 to 30 min. The spectra showed that quantit-
ative elimination had occurred, which was confirmed by a
preparative run from which the phenyl compound 14j was
isolated in 76% yield. Since the trans orientation of the N-
oxygen atom and the C-2 substituent present in these pyrro-
lidine N-oxides strongly disfavours formation of a planar
transition state as required for the concerted Cope
elimination,[59Ϫ61] this reaction might proceed in an inter-
molecular rather than in an intramolecular fashion, in a
way related to the Hofmann degradation of quaternary am-
monium salts.[31,62]
Scheme 5. Cope elimination of pyrrolidine N-oxides 12i and 12j:
(a) Me2SO, 80 °C, 15Ϫ30 min
Competition of Alkenyl Groups and the Influence of the
Acetonide Group on the Rate of Cyclization
Scheme 4. CopeϪHouse cyclization of the unsaturated hy-
droxylamines 9a؊h,k and 10a؊k generated by Grignard addition
to the nitrone 5: (a) RMgBr or RLi; (b) CHCl3; cf. Table 1
In the case of the vinyl compound, the progress of the
CopeϪHouse cyclization was monitored by 1H NMR spec-
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Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
FULL PAPER
troscopy. It turned out that the reaction rates were different cyclization. However, steric hindrance from the acetonide
for the two diastereomeric hydroxylamines 9h and 10h, with part and additional ring strain to form the fused bicycle
9h reacting faster (15 min after workup: 56% cyclization, dr might oppose this. Based on the experimental results, all
11h/12h ϭ 82:18), and that the reaction was virtually com- these effects seem to balance, and the acetonide group is
plete within 90 min (Ͼ85% cyclization). According to liter- concluded to exhibit only a modest influence on the rate
ature reports, the cyclization of unsaturated hydroxylamines and regioselectivity of the CopeϪHouse cyclization
having alkenyl chains with no alkoxy functional group pro- (Scheme 6).
ceeds to 90% during work-up and goes to completion
within 24 h.[27] Thus, it was of interest to evaluate the effect
Stereoselective Additions to the Nitrone 5 Using
of the isopropylidenedioxy moiety on the cyclization, i.e. to
study the internal competition of this functionalized chain
with an unsubstituted 3-butenyl group. This was possible
with the addition of 3-butenylmagnesium bromide: Two
Organolithium and Grignard Reagents with Lewis Acids
Added
Since the 2-methyl-, 2-phenyl-, and 2-vinylpyrrolidine N-
modes of CopeϪHouse cyclization of the intermediate hy- oxides 11a/12a, 11g, and 11h constitute key intermediates
droxylamines 9k/10k could occur, either involving the but- for access to iminopolyol inhibitors,[40,67Ϫ71] the stereo-
enyl part or the dioxy-butenyl chain (Scheme 6). In fact, selectivity of the addition step was studied further by the
from the reaction with the 3-butenyl Grignard reagent car- use of additional Lewis acids in the Grignard reactions, and
ried out as above, three isomeric pyrrolidine N-oxides 11k, also by employing methyl-, phenyl-, and vinyllithium. For
12k, and 15 were obtained in a ratio of 22:37:41. The mix- both variants, there is ample precedence in the literature
ture was separated by MPLC, and the structures of the indi- concerning nitrone additions[55,72Ϫ76] and, for example, re-
vidual pyrrolidine N-oxides were established by NMR actions with α-oxyimines.[77Ϫ79]
(H,H-COSY). Two of the isomers (11k and 12k, 13% and
Complexation of the nitrone 5 with zinc chloride or di-
23% yield, respectively) resulted from cyclization to the di- ethylaluminium chloride prior to the addition of the methyl
oxybutenyl part, the third isomer 15 (23% yield) constituted Grignard reagent led to somewhat enhanced diastereoselec-
a 3,4-unsubstituted pyrrolidine N-oxide with an intact diox- tivity, up to 13:66:21, and the 2,5-trans isomer 12a was isol-
ybutenyl moiety. The configuration of the latter product 15, ated in 49% yield (Table 1, entries 15 and 16). In the case
a single stereoisomer, has thus far not been deduced.
of the benzyl compound, the addition of diethylaluminium
chloride had no effect on the stereoselectivity of the reac-
tion, and the 2,5-trans-isomer 12j remained the sole product
observed and isolated (57%; Table 1, entry 17).
Switching to methyllithium proved beneficial since this
gave only two products with an increased ratio of 91:9, the
meso-derivative 11a (cis-2,5-dimethyl) being the major
product (Table 1, entry 21). These observations suggest that
organolithium compounds preferentially form the diastere-
omer 11 (2,5-cis) and, on the other hand, that an increase
in the amount of the 2,5-trans isomer 12 formed would re-
sult from pre-complexation of the nitrone 5 with Lewis ac-
ids. Unfortunately, this simple guideline does not hold in
the case of the vinyl and phenyl compounds: In the latter
case, the use of the lithium derivative gave a better propor-
tion (81:19) of the 2,5-trans-diastereomer 12g, whereas the
formation of 2,5-cis-pyrrolidine N-oxide 11g was favoured
in the presence of diethylaluminium chloride (Table 1, ent-
ries 18, 22). When adding vinylmagnesium bromide to the
nitrone 5, pre-complexed with diethylaluminium or zinc
chloride, the major N-oxide product 11h amounted to 84
parts of the two-isomer mixture, and was isolated in 60%
yield (Table 1, entries 19 and 20). Switching from vinylmag-
nesium bromide to vinyllithium did not alter the diastereo-
selectivity of the addition (Table 1, entry 23).
Scheme 6. CopeϪHouse cyclization of the unsaturated hy-
droxylamines 9k/10k derived from nucleophilic addition of 3-but-
enylmagnesium bromide to the nitrone 5: (a) 3-ButenylMgBr, Et2O,
Ϫ20 °C, 3.5 h; (b) CHCl3, room temp., 5 d, isomer ratio 11k/12k/
15 ϭ 22:37:41; (c) MPLC; yields cf. above
Two opposing tendencies need to be considered: The CC
Several models have been proposed by Dondoni, Merino,
double bond bearing an allylic alkoxy function is more elec- and co-workers in order to rationalize the stereochemical
trophilic than that of the unsubstituted butenyl group,[63Ϫ66] outcome of the addition of organometallic C-nucleophiles
and thus should react more readily with the nucleophilic to α-alkoxy nitrones in the presence of Lewis acids.[55,72Ϫ76]
hydroxylamine moiety. Also, the acetonide function serves However, the diastereoselectivities observed here are not
as a clamp and might entropically facilitate the formation satisfactorily explained by any of these and further detailed
of the planar transition state required for the CopeϪHouse studies are necessary.
Eur. J. Org. Chem. 2001, 1293Ϫ1308
1297

A. M. Palmer, V. Jäger
FULL PAPER
Determination of the Configuration and Conformation of
the Pyrrolidine N-Oxides 7, 8 and 11a,b,d-h,k, 12a؊k,
13a,b,g
was based on the crystal structure obtained for the free
meso-pyrrolidinediol N-oxide 16a, as shown below.
Upon addition of methylmagnesium bromide to nitrone
5, and cyclization, three pyrrolidine N-oxides 11a, 12a, and
13a were formed. The NMR spectroscopic data obtained
for these compounds clearly indicated that the two minor
isomers 11a and 13a were meso derivatives (Figure 2).
Reduction of the nitrone 5 with sodium borohydride and
ensuing CopeϪHouse cyclization resulted in the formation
of the 2-epimers 7 and 8 (vide supra). Here, the 2,3-trans
configuration (methyl trans to the acetonide moiety) present
in the major isomer 7 was readily assigned by comparison
Deprotection of one of these meso compounds (11a) was
of the 13C NMR chemical shifts of the 2-methyl groups, accomplished with hydrochloric acid in methanol/water
which for compound 7 appeared significantly downfield (Scheme 7). Recrystallization of this deprotected pyrrolid-
(δ ϭ 11.5 in 7 vs. 8.2 in 8).
ine N-oxide 16a from methanol/diethyl ether yielded crys-
The 1H NMR spectroscopic data, chemical shifts, and tals suitable for X-ray structure determination. The crystal
coupling constants of the pyrrolidine N-oxides obtained in structure of 16a, shown in Figure 3, provided proof of the
this work are collected in Table 2 and Table 3; 13C NMR configuration of the N-oxide 11a as determined above: The
chemical shifts are given in Table 4. In each case, the config- two methyl groups are oriented 2,5-cis and trans to the
uration of the diastereomeric pyrrolidine N-oxides was es- acetonide group. The other meso compound 13a therefore
tablished by comparison of the NMR spectroscopic data constitutes the all-cis isomer which is also concluded from
with those obtained for the 2,5-dimethylpyrrolidine N-ox- the distinct upfield signals for all the carbon atoms con-
ides 11a, 12a, and 13a, in which unambiguous assignment cerned.
Table 2. 1H NMR chemical shifts δ of pyrrolidine N-oxides 11a,b,d,g,h,k, 12a؊k, and 13a,b,g (δ [ppm], 300.1 MHz or 500.1 MHz, CDCl3)
2-H
3-H
4-H
5-H
5-CH3
C(CH3)2
CH2Ph
Others (2-R)
1.69 (CH3)
11a
11b
11d
11g
11h
11k
12a
12b
12c
12d
12e
12f
12g
12h
12i
3.29
3.06
3.24
4.10
3.73
3.17
3.81
3.52
3.36
3.65
3.40
3.61
4.81
4.26
3.61
3.73
4.63
4.68
4.65
5.11
4.83
4.70
4.91
4.89
4.84
4.88
4.94
4.84
5.24
5.09
4.81
4.54
4.63
4.66
4.65
4.80
4.69
4.68
4.63
4.60
4.50
4.61
4.47
4.59
4.80
4.71
4.58
4.47
3.29
3.25
3.27
3.61
3.32
3.26
3.83
3.86
3.87
3.84
3.85
3.87
4.04
3.80
3.87
3.90
1.69
1.68
1.68
1.74
1.70
1.68
1.35
1.27
1.22
1.29
1.21
1.24
1.47
1.43
1.26
1.18
1.28 (6 H)
1.27, 1.28
1.26, 1.27
1.27, 1.38
1.28, 1.32
1.26, 1.28
1.37, 1.64
1.39, 1.68
1.36, 1.68
1.37, 1.67
1.35, 1.70
1.37, 1.68
1.40, 1.67
1.37, 1.61
1.37, 1.69
1.33, 1.74
4.16 (CH2),
7.32, 7.43 (Ph)
4.12, 4.21 (CH2),
7.31, 7.43 (Ph)
4.14, 4.22 (CH2),
7.34, 7.43 (Ph)
3.99, 4.11 (CH2),
7.30, 7.45, 7.99 (2 Ph)
4.13, 4.20 (CH2),
7.34, 7.43 (Ph)
4.14, 4.23 (CH2),
7.31, 7.43 (Ph)
4.20, 4.48 (CH2),
7.38, 7.73 (Ph)
4.25, 4.55 (CH2),
7.37, 7.70 (Ph)
4.44, 4.65 (CH2),
7.37, 7.70 (Ph)
4.26, 4.53 (CH2),
7.36, 7.71 (Ph)
4.75 (CH2),
7.34, 7.74 (Ph)
4.27, 4.50 (CH2),
7.35, 7.68 (Ph)
3.96, 4.52 (CH2),
7.29, 7.41, 7.66, (2 Ph)
4.20, 4.43 (CH2),
7.34, 7.69 (Ph)
4.23, 4.60 (CH2),
7.34, 7.70 (Ph)
4.35, 4.70 (N-CH2),
7.26, 7.36, 7.47,
7.75 (2 Ph)
1.10 (CH3) 1.99Ϫ2.16 (CHaHb),
2.24Ϫ2.34 (CHaHb)
0.97 (CH3), 1.10 (CH3),
1.74 (CHaHb), 1.86 (CH), 2.38 (CHaHb)
[a]
5.58 (CHEHZ), 5.68 (CHEHZ),
6.69 (CH)
2.12, 2.36, 2.45 (CH2CH2),
5.07 (CHEHZ), 5.16 (CHEHZ), 5.92 (CH)
1.52 (CH3)
1.12 (CH3), 2.03 (CHaHb),
2.30 (CHaHb)
1.17 (CH3), 1.55 (CH3),
2.56 (CH)
0.96 (CH3), 1.05 (CH3),
1.79 (CH), 1.97 (CH2)
1.48 [C(CH3)3]
1.08[(CH3)3], 2.00 (CHaHb),
2.16 (CHaHb)
[a]
5.46 (CHEHZ), 5.61 (CHEHZ),
5.99 (CH)
2.74, 2.99 (CHaHb), 5.18 (CHEHZ),
5.31 (CHEHZ), 5.87 (CH)
3.23, 3.55 (2-CH2)[a]
12j
12k
13a
13b
13g
3.65
3.18
3.21
4.22
4.85
4.51
4.70
4.75
4.60
4.51
4.59
4.72
3.89
3.18
3.49
3.58
1.26
1.63
1.58
1.73
1.38, 1.67
1.28, 1.60
1.29, 1.52
1.27, 1.66
4.28, 4.55 (CH2),
7.36, 7.75 (Ph)
4.29 (CH2),
7.34, 7.43 (Ph)
4.52, 4.59 (CH2),
7.43 (Ph)
4.20, 4.76 (CH2),
7.42, 7.95 (2 Ph)
2.10, 2.19, 2.34 (CH2CH2),
5.04 (CHEHZ), 5.13 (CHEHZ), 5.89 (CH)
1.63 (CH3)
1.10 (CH3), 1.94 (CHaHb),
2.46 (CHaHb)
[a]
[a]
Signals of 2-Ph in column CH2Ph.
1298
Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
FULL PAPER
Table 3. H,H-coupling constants of pyrrolidine N-oxides function and to the N-benzyl group, whereas the 5-methyl
11a,b,d,g,h,k, 12a؊k, and 13a,b,g (J [Hz], CDCl3)
group formed by CopeϪHouse cyclization is oriented trans
to the acetonide moiety and cis to the N-oxido group. In
J2,3 J3,4 J4,5 J5,5-Me 2J (CH2Ph)
Other
all other cases, the configuration of the diastereomeric pyr-
rolidine N-oxides was established in a similar way by com-
parison of the NMR spectroscopic data obtained for the
prevailing diastereomers with those obtained for the methyl
compounds (cf. Table 2 to 4).
11a
Ϫ
Ϫ
Ϫ
6.4
Ϫ
14.0
J(2-H,CH3) ϭ 6.4
J(2-H,CHaHb) ϭ 11.3,
J(2-H,CHaHb) ϭ 3.3,
J(CH2CH3) ϭ 7.6
11b 5.5 7.3 6.3 6.3
11d 5.5 n. d. 6.3 6.4
14.0
J(2-H,CHaHb) ϭ 12.0,
J(2-H,CHaHb) ϭ 3.4,
J(CHCH3) ϭ 6.5,
Several trends are obvious when comparing the 13C
NMR spectroscopic data of the diastereomeric pyrrolidine
N-oxides (Table 4). When going from the pyrrolidine N-ox-
ides 11 to their 2-epimers 12, the relationship between 5-
CH3/NO (cis) and 5-CH3/acetonide (trans) is retained,
whereas the orientation between 2-R/NO (cis) and 2-R/ace-
tonide (trans) is reversed. As a consequence, when compar-
J(CHCH3) ϭ 6.8
11g 7.1 7.2 6.1 6.3
11h 6.6 7.1 6.3 6.3
13.8
13.8
J(2-H,CH) ϭ 8.7,
J(CHϭCHEHZ) ϭ 17.8,
J(CHϭCHEHZ) ϭ 10.5
J(2-H,CHaHb) ϭ 11.4,
J(2-H,CHaHb) ϭ 3.0,
J(CHϭCHEHZ) ϭ 10.2,
11k 5.9 7.4 6.5 6.4
14.0
J(CHϭCHEHZ) ϭ 17.2, ing the NMR spectroscopic data of 11a,b,d؊h,k and
2J(CHEHZ) ϭ 1.7
J(2-H,CH3) ϭ 7.2
12a؊k, only a slight change in the chemical shifts of 5-
12a 6.1 7.4 2.0 7.1
12b 5.6 7.4 0.0 7.1
12.2
11.9
CH3, C-5, and C-4 (Ͻ 3 ppm) is observed, whereas signific-
ant changes in the chemical shifts of 2-R, C-2, and C-3
(3Ϫ5 ppm) are apparent. In order to pass from the pyrrolid-
ine N-oxides 11 to their diastereomers 13, the orientation
of both 5-CH3 and 2-R with respect to the acetonide and
the NO-function has to be inverted. Consequently, all ring
carbon atoms and the carbon atoms of the substituents ad-
jacent to the ring in 13a,b,g undergo an upfield shift in the
range of 3 to 5 ppm. Interestingly, the chemical shift of the
N-CH2 part of the benzyl group of the pyrrolidine N-oxides
12a؊k is not affected by the proximity of 2-R, but the car-
bon atoms of the acetonide group give rise to signals dis-
tinctly upfield from those of 11a,b,d؊h,k (2 to 3 ppm).
J(2-H,CHaHb) ϭ 11.8,
J(2-H,CHaHb) ϭ 3.1,
J(CH2CH3) ϭ 7.6
J(2-H,CH) ϭ 10.3,
J(CHCH3) ϭ 6.5,
J(CHCH3) ϭ 6.6
12c 5.4 7.6 0.0 7.5
11.9
12.0
12d 5.7 7.5 1.2 7.5
J(CHCH3) ϭ 6.6,
J(CHCH3) ϭ 6.6
12e 5.5 7.6 0.0 7.5
12f 5.7 7.4 0.0 7.4
Ϫ
12.1
J(2-H,CHaHb) ϭ 11.0,
J(2-H,CHaHb) ϭ 1.5,
2J(CHaHb) ϭ 11.9
12g 5.9 7.4 3.0 7.0
12h 6.3 7.3 3.3 6.9
12.3
12.3
J(2-H,CH) ϭ 9.7,
J(CHϭCHEHZ) ϭ 17.0,
J(CHϭCHEHZ) ϭ 10.3,
2J(CHEHZ) ϭ 1.5
J(2-H,CHaHb) ϭ 12.2,
J(2-H,CHaHb) ϭ 3.4,
2J(CHaHb) ϭ 12.2,
J(CHaHbCH) ϭ 7.5,
J(CHaHbCH) ϭ 6.5,
J(CHϭCHEHZ) ϭ 10.1,
J(CHϭCHEHZ) ϭ 17.1,
2J(CHEHZ) ϭ 1.8
J(2-H,CHaHb) ϭ 12.1,
J(2-H,CHaHb) ϭ 2.6,
2J(CHaHb) ϭ 12.0
J(2-H,CHaHb) ϭ 11.7,
J(2-H,CHaHb) ϭ 2.5,
12i 5.4 7.5 0.8 7.4
11.9
1
In the H NMR spectroscopic data of the pyrrolidine N-
oxides 11a,b,d,g,h,k and 12a؊k significant differences are
also observed: (i) Two of the phenyl protons of 12a؊k are
strongly deshielded (δ ca. 7.7). (ii) In the spectra of 12a؊k,
the diastereotopic methylene protons of the benzyl group
and the methyl groups of the acetonide are clearly differen-
tiated (∆δ ca. 0.3 ppm). (iii) The signals for 2-H and 5-H of
12a؊k experience a net downfield shift relative to those for
2-H and 5-H of 11a,b,d,g,h,k, whereas 5-CH3 in 12a؊k is
12j 5.4 7.4 0.0 7.5
12k 5.7 7.4 0.0 7.4
11.9
12.0
J(CHϭCHEHZ) ϭ 10.2, considerably more shielded than in 11a,b,d,g,h,k. (iv) All
J(CHϭCHEHZ) ϭ 17.1,
coupling constants are of comparable magnitude with the
exception of J4,5 (11b,d,g,h,k: 6.1 to 6.5 Hz; 12a؊k: 0 to
3.3 Hz).
The information derived from these observations was
used to establish suitable starting geometries for molecular
models of the 2,5-dimethylpyrrolidine N-oxides 11a and 12a
as representatives of the structural types 11 and 12. The
energies of these models were minimized by MM2/MOPAC
2J(CHEHZ) ϭ 1.8
13a
Ϫ
Ϫ
Ϫ
6.8
Ϫ
13.7
J(2-H,CH3) ϭ 6.8
J(2-H,CHaHb) ϭ 11.0,
J(2-H,CHaHb) ϭ 3.4,
J(CH2CH3) ϭ 7.5
13b 5.1 7.3 5.3 6.5
13g 5.0 7.1 5.2 6.5
13.7
Consequently, the isomer 12a must have the 2,5-dimethyl calculations: Both pyrrolidine N-oxides 11a and 12a adopt
groups in a trans orientation, as shown by the 13C NMR envelope conformations (Figure 4). In the case of the 2,5-
signals at δ ϭ 9.3 and 13.2; the individual assignment, how- cis-isomer 11a, the ring nitrogen atom is located out of the
ever, is not possible from this. On the other hand, this can plane defined by the ring carbon atoms (1E).[80] This situ-
be done in a reliable way by comparison with the NMR ation is also seen in the crystal structure of 16a. The phenyl
spectroscopic data obtained for the 2-ethyl-5-methylpyrroli- ring and the acetonide protecting group in 11a are oriented
dine N-oxides 11b, 12b, and 13b (cf. Figure 2), where char- symmetrically with respect to a plane (σ) perpendicular to
acteristic shift changes of the 2- and 5-substituent are un- the heterocycle and bisecting the nitrogen atom and the C-
equivocal: In 12a, the 2-methyl group introduced by Grig- 3/C-4 bond. This conformation relates to the fact that for
nard addition is oriented cis to the isopropylidenedioxy all pyrrolidine N-oxides 11 similar chemical shifts were ob-
Eur. J. Org. Chem. 2001, 1293Ϫ1308
1299

A. M. Palmer, V. Jäger
Table 4. 13C NMR chemical shifts of pyrrolidine N-oxides 11a,b,d-h,k, 12a؊k, and 13a,b,g (δ [ppm], 125.8 MHz, CDCl3)
FULL PAPER
C-2
C-3
C-4
C-5
5-CH3
C(CH3)2
CH2Ph
Others (2-R)
11a
11b
11d
72.2
77.4
74.9
82.9
82.2
82.3
82.9
82.9
83.0
72.2
71.8
72.0
11.6
11.2
11.4
24.7, 26.7, 114.5
24.7, 26.8, 114.4
24.9, 26.8, 114.3
65.7 (CH2), 129.4, 129.9,
130.0, 131.0 (Ph)
11.6 (CH3)
66.0 (CH2), 129.3, 129.8,
130.2, 131.3 (Ph)
9.3 (CH3), 19.8 (CH2)
65.8 (CH2), 129.2, 129.9,
130.2, 131.5 (Ph)
70.0 (CH2), 128.2Ϫ132.0 (Ph)
65.8 (CH2), 128.2, 129.1,
131.2, 133.3 (Ph)
21.9 (CH3), 24.4 (CH3),
24.7 (CH), 35.4 (CH2)
29.2 [(CH3)3], 35.0 (C)
30.4 [(CH3)3], 30.4,
11e
11f
79.1
75.1
81.7
82.0
82.0
83.1
71.6
71.3
10.3
11.3
25.7, 27.5, 112.8
24.8, 26.9, 113.9
39.8 (C, CH2)
[a]
11g
80.0
84.2
83.4
73.5
12.0
24.6, 26.8, 114.6
67.3 (CH2), 128.5, 129.1,
129.6, 129.8, 130.2, 131.5,
131.6, 132.2 (2 Ph)
11h
11k
12a
12b
12c
12d
12e
12f
80.1
75.6
74.8
80.5
83.0
77.8
80.3[b]
76.7
83.8
82.2
82.4
77.6
75.7
77.2
76.4
77.5
76.9
77.8
83.6
83.0
82.4
81.3
80.3
81.7
84.5[b]
81.5
83.4
72.3
72.1
70.5
70.0
70.7
70.1
70.8
69.0
71.6
11.9
11.4
13.2
13.7
14.2
13.6
14.6
14.0
13.7
25.0, 27.1, 115.0
24.8, 26.7, 114.5
23.5, 25.3, 112.2
23.1, 25.2, 111.3
23.0, 25.3, 110.8
23.2, 25.3, 111.4
22.9, 25.3, 110.8
23.0, 25.2, 111.0
23.4, 25.4, 112.9
67.2 (CH2), 129.6, 130.2,
130.4, 131.8 (Ph)
123.3 (CH2), 131.8 (CH)
66.0 (CH2), 129.3, 129.9,
130.1, 131.1 (Ph)
26.2, 28.8 (2 CH2),
115.9 (ϭCH2), 137.2 (CH)
9.3 (CH3)
65.3 (CH2), 128.3, 128.8,
131.1, 132.9 (Ph)
66.2 (CH2), 128.2, 128.7,
131.0, 133.3 (Ph)
11.0 (CH3), 16.0 (CH2)
66.0 (CH2), 128.1, 128.7,
131.6, 133.6 (Ph)
20.2 (CH3), 21.7 (CH3),
24.9 (CH)
21.7 (CH3), 24.0 (CH3),
25.6 (CH), 31.2 (CH2)
30.8 [(CH3)3], 35.1 (C)
66.2 (CH2), 128.2, 128.7,
131.4, 133.1 (Ph)
69.1 (CH2), 128.0, 128.7,
131.6, 133.3 (Ph)
66.0 (CH2), 128.1, 128.8,
131.3, 133.4 (Ph)
30.1 [(CH3)3], 30.0,
35.2 (C, CH2)
[a]
12g
66.7 (CH2), 127.8, 128.2,
128.6, 129.4, 130.2, 131.1,
132.6, 132.7 (2 Ph)
12h
12i
12j
82.4
77.4
80.7
78.2
75.9
75.5
83.7
81.4
81.0
72.2
70.1
70.2
13.4
13.6
13.6
24.0, 25.9, 113.5
23.1, 25.2, 111.4
23.1, 25.2, 111.2
66.2 (CH2), 128.4, 128.6,
129.3, 133.2 (Ph)
127.1 (CH), 127.3 (CH2)
66.4 (CH2), 128.2, 128.7,
131.3, 133.3 (Ph)
27.2 (CH2), 118.9 (ϭCH2),
133.0 (CH)
66.7 (N-CH2),
28.8 (2-CH2)[a]
126.8, 128.0, 128.2, 128.6, 128.8,
129.7, 131.2, 133.4, 137.1 (2 Ph)
66.3 (CH2), 128.2, 128.9,
131.1, 133.3 (Ph)
12k
13a
13b
13g
78.5
68.0
74.8
75.6
75.9
79.0
77.3
78.7
81.5
79.0
78.5
79.2
70.0
68.0
69.2
69.0
13.7
8.0
8.1
8.5
23.1, 25.2, 111.5
25.5, 25.9, 113.0
25.0, 25.9, 112.6
25.0, 25.8, 113.1
22.0 (CH2), 30.6 (CH2),
115.7 (ϭCH2), 137.3 (CH)
8.0 (CH3)
68.3 (CH2), 129.3, 129.8,
131.5, 132.9 (Ph)
67.0 (CH2), 129.4, 129.7,
130.2, 131.9 (Ph)
67.3 (CH2), 128.1, 128.4,
129.3, 129.5, 130.0, 130.3,
132.1, 133.5 (2 Ph)
9.8 (CH3), 16.5 (CH2)
[a]
[a]
[b]
Signals of 2-Ph in column CH2Ph. Ϫ Signal assignment may be reversed.
Scheme 7. O-deprotection of the pyrrolidine N-oxide 11a: (a) conc.
HCl, MeOH, H2O (1:8:8), 1 d, room temp.; (b) Dowex 50WX8 (Hϩ
form); 84%
served for both diastereotopic methylene protons of the
benzyl group, and for the carbon atoms C-3 and C-4 (vide
supra). The dihedral angles estimated from this model are
in perfect agreement with the coupling constants J2,3, J3,4
J4,5 (Table 5).
Similarly, for the 2,5-trans isomers 12, an envelope con-
,
Figure 2. Comparison of 13C NMR chemical shifts of 2-methyl-
and 2-ethyl-substituted pyrrolidine N-oxides 11aϪ13a and
11bϪ13b
formation 1E is suggested by the results of the calcula-
1300
Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
FULL PAPER
Figure 3. X-ray structure of the pyrrolidine N-oxide 16a
Table 5. Comparison of the coupling values 3J observed for pyrroli-
dine N-oxides 11a,b,d,g,h,k and 12a؊k with the dihedral angles
calculated for pyrrolidine N-oxides 11a and 12a (MOPAC)
Coupling Protons
Isomer 11
3J [Hz]
Isomer 12
3J [Hz]
δ [°]
δ [°]
2-H, 3-H
3-H, 4-H
4-H, 5-H
5.5 to 7.1
7.1 to 7.4
6.1 to 6.5
139
0
Ϫ139
5.4 to 6.3
7.3 to 7.6
0 to 3.3
Ϫ33
0
Ϫ104
tions.[80] This conformation would result in a perpendicular
orientation (close to 90°) of 4-H and 5-H. Indeed, for all
isomers 12a؊k, coupling values J4,5 in the range of 0 to
3.3 Hz were observed (Table 5). The orientation of the 2-
substituent with respect to the methylene protons of the
benzyl group and to each of the methyl groups of the ace-
tonide part differs considerably, hence the pronounced shift
differences in the NMR signals of these groups. For the
same reason, the C-3 and C-4 show different 13C NMR
chemical shifts.
Figure 4. (a) and (b): Conformation of the pyrrolidine N-oxides
12a and 11a. The phenyl ring and the acetonide group are omitted
for clarity. (c) The side view of the pyrrolidine N-oxide 11a illus-
trates the symmetry of this conformer
and 13 was readily elucidated by analysis of the NMR spec-
troscopic data. Applying simple transformations to these
pyrrolidine N-oxides, a variety of iminopolyols with glycosi-
dase-inhibiting properties is available (to be described in de-
tail in the following paper of this series).[40]
Conclusion
The CopeϪHouse cyclization of unsaturated hy-
droxylamines derived from -ribose offers a quick, efficient,
and stereoselective access to many (1R,2S,3S,4R,5R)- and
(1R,2R,3S,4R,5R)-5-methyl-3,4-dihydroxypyrrolidine N-ox-
ides (allo and -altro/-talo configurations with respect to
1,4-iminoglycitols). Since the side-chain at the 2-position of
the pyrrolidine ring is introduced by nucleophilic addition
of organometallic reagents to nitrone 5, a large variety of
substituents can be attached. Furthermore, by com-
plexation of the nitrone 5 with Lewis acids or the use of
organolithium compounds, in many cases both 2-epimers
are accessible in good yields. The configuration and con-
Experimental Section
General Remarks: Melting points were determined on
a
1
FisherϪJohns 4017 heating block and are uncorrected. Ϫ H and
13C NMR spectra were recorded with Bruker AC 250, ARX 300,
ARX 500 spectrometers using Me4Si as internal standard. Ϫ IR
spectra were recorded with a PerkinϪElmer 283 or a Bruker IFS 28
IR spectrometer. Ϫ Mass spectra and high-resolution mass spectra
(HRMS) were obtained with Finnigan quadrupole-MS 4500 and
Finnigan MAT 95 spectrometers, respectively. Ϫ Optical rotations
were determined with a PerkinϪElmer polarimeter 241MC. Ϫ
CHEM-3D 4.0 was used for molecular modelling (MM2,
formation of the parent pyrrolidine N-oxides 7, 8, 11, 12, MOPAC).[81Ϫ83] Ϫ MPLC separations were carried out using a
Eur. J. Org. Chem. 2001, 1293Ϫ1308 1301

A. M. Palmer, V. Jäger
FULL PAPER
Lewa FL 1 pump; the pyrrolidine N-oxides were monitored at
250 nm using a Knauer 97.00 diode array detector. The columns
(26 cm ϫ 3.2 cm, N ϭ 5000 or 47 cm ϫ 5 cm, N ϭ 11700) were
packed with LiChroprep Si 60 silica gel.[84]
{ref.:[22] [α]2D0 ϭ Ϫ69 (c ϭ 2.08, CH2Cl2)}. Ϫ IR (film): ν˜ ϭ 2988,
1
2936, 1373, 1210, 1194, 1104, 1066, 1018, 956 cmϪ1. Ϫ H NMR
(250.1 MHz, CDCl3): δ ϭ 1.33, 1.49 [2 s, 6 H, C(CH3)2], 3.16 (t,
J
4,5a ϭ 2J5a,5b ϭ 10.0 Hz, 1 H, 5-Ha), 3.29 (dd, J4,5b ϭ 6.3, 2J5a,5b ϭ
10.0 Hz, 1 H, 5-Hb), 3.37 (s, 3 H, OCH3), 4.45 (dd, J4,5a ϭ 10.0,
J4,5b ϭ 6.3 Hz, 1 H, 4-H), 4.63 (d, J2,3 ϭ 5.9 Hz, 1 H, 2-H), 4.77
(d, J2,3 ϭ 5.9 Hz, 1 H, 3-H), 5.06 (s, 1 H, 1-H). Ϫ 13C NMR
(62.9 MHz, CDCl3): δ ϭ 6.7 (C-5), 25.0, 26.4 [C(CH3)2], 55.2
(OCH3), 83.0, 85.3, 87.4 (C-2, C-3, C-4), 109.6 (C-1), 112.6
[C(CH3)2]. Ϫ C9H15O4I (314.1): calcd. C 34.41, H 4.81, I 40.40;
found C 34.46, H 4.81, I 40.18.
Materials: Solvents were purified and dried by standard methods.
For column chromatography, silica gel (40Ϫ63 µm, Merck) was
used, and acidic resin Dowex 50WX8 (Hϩ form) used for ion ex-
change purification was supplied from Fluka. Grignard reagents
were freshly prepared from magnesium and the corresponding alkyl
halide or purchased (Aldrich). MeLi and PhLi were purchased
(Fluka, Acros); vinyllithium was prepared by transmetalation from
tetravinyl tin (Aldrich) and PhLi.[85] The Lewis acids employed
(ZnCl2·Et2O, Et2AlCl) are commercially available (Fluka, Aldrich).
Chloroform (p.a.) used for CopeϪHouse cyclizations was supplied
by Merck.
4,5-Dideoxy-2,3-O-isopropylidene-D-erythro-4-pentenose (4): Fol-
lowing ref.,[22] compound 3 (6.3 g, 20 mmol) was dissolved in dry
THF (90 mL) in a flame-dried flask under nitrogen. The solution
was cooled to Ϫ80 °C and n-butyllithium (1.6  in hexanes,
18.9 mL, 30 mmol) was added over a period of 15 min. The reac-
tion mixture was stirred for 2 h at Ϫ80 °C and then quenched with
NH4Cl (2 g). The mixture was allowed to warm to Ϫ40 °C; water
(50 mL) was added and the aqueous phase extracted with diethyl
ether (3 ϫ 50 mL). The combined organic solutions were dried with
MgSO4 and concentrated in vacuo (since the aldehyde 4 is some-
what volatile, the pressure should be kept above 20 mbar). The al-
dehyde 4 (3.8 g, ‘‘122%’’) was obtained as a colourless oil which
was used without further purification. Ϫ 1H NMR (250.1 MHz,
CDCl3): δ ϭ 1.45, 1.62 [2 s, 6 H, C(CH3)2], 4.42 (dd, J1,2 ϭ 3.1,
J2,3 ϭ 7.5 Hz, 1 H, 2-H), 4.86 (dd, J2,3 ϭ 7.5, J3,4 ϭ 6.8 Hz, 1 H,
Purity of the Pyrrolidine N-Oxides: Correct elemental analyses were
only obtained for the pyrrolidine N-oxides 7, 11a, and 11g. How-
ever, in all cases, spectroscopically pure compounds were obtained.
The hygroscopic properties of amine N-oxides[86Ϫ88] and their cap-
ability to form hydrates[26,27,86Ϫ88] are well described in the literat-
ure, and deviations of the analyses can be explained by the presence
of varying amounts of water. This assumption is confirmed by the
following observations: (a) Several samples gained weight when ex-
posed to air; (b) the presence of water was evident in the 1H NMR
spectra of several pyrrolidine N-oxides, e.g. in the spectrum of 11h
[CDCl3; δ(OH2) ϭ 2.34 (bs, 2 H); compound analyzed for 11h·1.0
H2O]; (c) ‘‘correct’’ analyses are obtained when nonstoichiometric
amounts of water are taken into account (cf. Experimental Sec-
tion), which, however, is ambiguous. Deviations in the elemental
analyses of 12h (viscous oil) and 12i/12j (thermally labile) are due
to the fact that the chromatography solvent (CH2Cl2/MeOH) could
not be completely removed. In all such cases, structures were con-
firmed by HRMS; in many cases, transformations of these hygro-
scopic pyrrolidine N-oxides were performed to yield products with
correct analyses.[40]
3-H), 5.33 (dm, J4,5E ϭ 10.3 Hz, 1 H, 5-HE), 5.47 (dm, J4,5Z
17.1 Hz, 1 H, 5-HZ), 5.77 (ddd, J3,4 ϭ 6.8, J4,5E ϭ 10.3, J4,5Z
ϭ
ϭ
17.1 Hz, 1 H, 4-H), 9.56 (d, J1,2 ϭ 3.1 Hz, 1 H, 1-H). Ϫ 13C NMR
(62.9 MHz, CDCl3): δ ϭ 25.3, 27.4 [C(CH3)2], 79.1, 82.2 (C-2, C-
3), 111.3 [C(CH3)2], 119.7 (C-5), 131.3 (C-4), 200.7 (C-1).
(Z)-4,5-Dideoxy-2,3-O-isopropylidene-D-erythro-4-pentenose
N-
Benzyl Nitrone (5): MgSO4 (6.00 g, 50.0 mmol) was added to a so-
lution of the crude aldehyde 4 [1.90 g, containing ca. 1.56 g
(10.0 mmol) of 4] and N-benzylhydroxylamine (1.23 g, 10.0 mmol)
in CH2Cl2 (60 mL). The suspension was stirred at room temp. for
19 h, then MgSO4 was removed by filtration and washed with
CH2Cl2. The combined filtrates were evaporated to dryness. The
remaining yellowish solid was purified by flash chromatography
(SiO2, ethyl acetate/petroleum ether ϭ 7:3) affording analytically
pure N-benzyl nitrone 5, (1.80 g, 69% based on 3), m.p. 96 °C. Ϫ
Note: Three by-products (tetrahydro-1,2-oxazine derivatives) were
isolated by further separation of the nonpolar fractions by column
chromatography.[34,38,39] Ϫ [α]2D0 ϭ ϩ181 (c ϭ 0.99, CH2Cl2). Ϫ IR
(KBr): ν˜ ϭ 3060, 1595, 1375, 1365, 1250, 1200, 1160, 1140, 1052,
1030 cmϪ1. Ϫ 1H NMR (250.1 MHz, CDCl3,): δ ϭ 1.37, 1.49 [2 s,
6 H, C(CH3)2], 4.80 and 4.88 (2 d, 2J ϭ 13.6 Hz, 2 H, CH2Ph),
4.90 (ddt, J2,3 ϭ 6.9, J3,4 ϭ 6.3, J3,5E ϭ J3,5Z ϭ 1.1 Hz, 1 H, 3-H),
Methyl 2,3-O-Isopropylidene-β-D-ribofuranoside (2): The furanoside
2 (45.5 g, 67%; ref.[44] 70% yield) was prepared from -ribose (1,
50.0 g, 333 mmol) according to ref.[44] Ϫ [α]2D4 ϭ Ϫ77 (c ϭ 1.76,
CHCl3), {ref.:[44] [α]2D5 ϭ Ϫ82 (c ϭ 2, CHCl3)}. Ϫ IR (film): ν˜ ϭ
3460, 2990, 2940, 1375, 1210, 1095, 1045 cmϪ1. Ϫ 1H NMR
(250.1 MHz, CDCl3): δ ϭ 1.32, 1.49 [2 s, 6 H, C(CH3)2], 3.27 (dd,
J5a,OH ϭ 10.0, J5b,OH ϭ 3.2 Hz, 1 H, OH), 3.44 (s, 3 H, OCH3),
3.56Ϫ3.74 (m, 2 H, 5-H), 4.43 (mc, 1 H, 4-H), 4.59 (d, J2,3
ϭ
5.9 Hz, 1 H, 3-H), 4.84 (d, J2,3 ϭ 5.9 Hz, 1 H, 2-H), 4.98 (s, 1 H,
1-H). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 24.7, 26.4 [C(CH3)2],
55.5 (OCH3), 64.0 (C-5), 81.5, 85.8, 88.3 (C-2, C-3, C-4), 110.0 (C-
1), 112.1 [C(CH3)2]. Ϫ C9H16O5 (204.2): calcd. C 52.93, H 7.90;
found C 52.93, H 7.88.
2
5.04 (ddd, J3,5E ϭ 1.1, J4,5E ϭ 10.4, J5E,5Z ϭ 1.8 Hz, 1 H, 5-HE),
5.32 (dd, J1,2 ϭ 5.5, J2,3 ϭ 6.9 Hz, 1 H, 2-H), 5.34 (ddd, J3,5Z
1.1, J4,5Z ϭ 17.1, J5E,5Z ϭ 1.8 Hz, 1 H, 5-HZ), 5.68 (ddd, J3,4
ϭ
Methyl 5-Deoxy-5-iodo-2,3-O-isopropylidene-β-D-ribofuranoside (3):
2
ϭ
For the synthesis of 3, a modification of the procedure given in
ref.[46] was employed: The furanoside 2 (20.0 g, 98 mmol) was dis-
solved in toluene (650 mL). After the addition of imidazole (16.0 g,
235 mmol) and triphenylphosphane (30.9 g, 117 mmol), the solu-
tion was heated to 70 °C. At this temperature, iodine (29.8 g,
117 mmol) was added, and stirring continued for 2 h. The brown
precipitate formed was decanted and the solution was evaporated
to dryness. The remainders were extracted with diethyl ether (3 ϫ
250 mL) and the solvent was evaporated in vacuo to afford a yel-
lowish oil (44.8 g) which was purified by flash chromatography
(SiO2, CH2Cl2). The iodo sugar 3 was obtained as a colourless oil
(26.8 g, 87% yield; ref.[46] 92%). Ϫ [α]2D0 ϭ Ϫ72 (c ϭ 1.95, CH2Cl2),
6.3, J4,5E ϭ 10.4, J4,5Z ϭ 17.1 Hz, 1 H, 4-H), 6.74 (d, J1,2 ϭ 5.5 Hz,
1 H, 1-H), 7.39 (mc, 5 H, C6H5). Ϫ 13C NMR (62.9 MHz, CDCl3):
δ ϭ 24.9, 27.4 [C(CH3)2], 69.2 (CH2Ph), 74.4 (C-2), 78.6 (C-3),
109.5 [C(CH3)2], 117.5 (C-5), 128.9, 129.2, 129.5, 132.3 (C6H5),
132.7 (C-4), 136.5 (C-1). Ϫ C15H19NO3 (261.3): calcd. C 68.94, H
7.32, N 5.36; found C 68.89, H 7.37, N 5.22.
(1S,2R,3R,4S)-N-Benzyl-3,4-O-isopropylidenedioxy-2-
methylpyrrolidine N-Oxide 7: NaBH4 (0.07 g, 1.9 mmol) was added
to an ethanol solution (10 mL) of the N-benzyl nitrone 5 (1.00 g,
3.8 mmol) and the mixture was stirred for 4 h at 0 °C. A solution
of citric acid (10 mL, 0.25 ) was added, then pH 8 was adjusted
1302
Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
by the addition of NaOH (6 ). The aqueous phase was saturated
FULL PAPER
pyrrolidine N-oxides already present. Ϫ 11a (monohydrate): [α]2D0
ϭ
with NaCl and extracted with CHCl3 (3 ϫ 20 mL). The organic 0 (c ϭ 0.56, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3440 (H2O), 3190 (H2O),
solutions were dried with MgSO4, filtered, and then stirred for 16 h
at room temp. to accomplish CopeϪHouse cyclization of 6. After
evaporation of the solvent, a colourless solid remained, identified
as 7 and 8 (dr ϭ 92:8, 0.94 g, 93%). Colourless crystals (m.p.
2980, 1450, 1375, 1365, 1245, 1200, 1145, 1065, 1005 cmϪ1. Ϫ 12a
(monohydrate): [α]2D0 ϭ Ϫ13 (c ϭ 1.03, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ
1
3400 (H2O), 1375, 1195, 985 cmϪ1. Ϫ H and 13C NMR spectro-
scopic data of 11a, 12a, and 13a: see Table 2 to 4. Ϫ C16H23NO3
120Ϫ122 °C) of the major isomer 7 (0.66 g, 66%) were isolated by (277.4): calcd. C 69.29, H 8.36, N 5.05; found for 11a C 64.74, H
crystallization of the crude product from ethyl acetate/heptane
(2:1). Ϫ The intermediate unsaturated hydroxylamine 6 was ob-
served when recording an NMR spectrum immediately after work-
up: 1H NMR (CDCl3, 250.1 MHz): δ ϭ 1.35, 1.45 [2 s, 6 H,
8.39, N 4.63 (correct for M ϩ 1.0 H2O); found for 12a C 65.30, H
8.37, N 4.73 (correct for M ϩ 1.0 H2O).
(b) By Addition of H3CLi: A solution of H3CLi (1.6 , 1.45 mL,
2.3 mmol) was added to a solution of the nitrone 5 (200 mg,
0.77 mmol) in diethyl ether (8 mL) under nitrogen at Ϫ80 °C and
the mixture was kept at this temperature for 4.75 h. Work-up,
CopeϪHouse cyclization in CHCl3 (18 h), and MPLC separation
of the crude product (dr 11a/12a ϭ 91:9) were performed as de-
scribed above, yielding analytically pure 11a in the form of colour-
less crystals (112 mg, 53%, m.p. 121Ϫ123 °C). Ϫ 11a: C16H23NO3
(277.4): calcd. C 69.29, H 8.36, N 5.05; found C 68.98, H 8.44,
N 4.97.
2
C(CH3)2], 2.77 (dd, J1a,1b ϭ 13.2, J1a,2 ϭ 4.3 Hz, 1 H, 1-Ha), 2.85
2
(dd, J1a,1b ϭ 13.2, J1b,2 ϭ 7.2 Hz, 1-Hb), and 2.86 (bs, OH) [to-
gether 2 H], 3.81 and 3.89 (2 d, 2J ϭ 12.9 Hz, 2 H, CH2Ph),
2
4.53Ϫ4.63 (m, 2 H, 2-H, 3-H), 5.20 (dd, J4,5E ϭ 10.3, J5E,5Z
ϭ
2
1.8 Hz, 1 H, 5-HE), 5.31 (dd, J4,5Z ϭ 17.2, J5E,5Z ϭ 1.8 Hz, 1 H,
5-HZ), 5.80 (ddd, J3,4 ϭ 6.9, J4,5E ϭ 10.3, J4,5Z ϭ 17.2 Hz, 1 H, 4-
H), 7.32 (mc, 5 H, C6H5). Ϫ 7: [α]2D0 ϭ Ϫ5 (c ϭ 0.56, CH2Cl2). Ϫ
IR (KBr): ν˜ ϭ 2980, 1445, 1370, 1195, 1145, 1070 cmϪ1. Ϫ 1H
NMR (500.1 MHz, CDCl3): δ ϭ 1.32, 1.40 [2 s, 6 H, C(CH3)2],
1.64 (d, J2,2-Me ϭ 6.4 Hz, 3 H, 2-CH3), 3.36 (quint, J2,2-Me ϭ J2,3 ϭ
6.4 Hz, 1 H, 2-H), 3.40 (dd, J4,5a ϭ 5.6, J5a,5b ϭ 11.1 Hz, 1 H, 5-
Ha), 3.65 (dd, J4,5b ϭ 6.5, J5a,5b ϭ 11.1 Hz, 1 H, 5-Hb), 4.26 and
4.31 (2 d, J ϭ 13.0 Hz, 2 H, CH2Ph), 4.75 (dd, J2,3 ϭ 6.4, J3,4
(c) By Complexation of the Nitrone 5 with Lewis Acids Prior to
Grignard Addition: (i) A solution of ZnCl2·Et2O in CH2Cl2 (2.2 ,
0.42 mL, 0.9 mmol) was added to a suspension of the nitrone 5
(200 mg, 0.77 mmol) in diethyl ether (8 mL) under nitrogen. The
resulting clear solution was stirred for 30 min at Ϫ10 °C, and then
cooled to Ϫ30 °C. H3CMgBr (3.0  in diethyl ether, 1.54 mL,
4.6 mmol) was added. The reaction mixture was kept for 6 h be-
tween Ϫ30 °C and Ϫ10 °C. After work-up, CopeϪHouse cycliza-
tion (16 h in CHCl3 at room temp.), and MPLC separation of the
crude product (dr 11a/12a/13a ϭ 13:66:21) as above, a wax con-
sisting of 12a/13a (109 mg, 49%, dr ϭ 90:10) was isolated and ana-
lyzed as C16H23NO3·(H2O)0.75; (ii) complexation of the nitrone 5
(200 mg, 0.77 mmol) with Et2AlCl (1.0  in hexanes, 0.84 mL,
0.8 mmol) and addition of H3CMgBr (3.0  in diethyl ether,
0.77 mL, 2.3 mmol) was performed as described above. The mix-
ture was stirred for 3.25 h at Ϫ30 °C. After work-up, CopeϪHouse
cyclization, and flash chromatography (SiO2, CH2Cl2/MeOH ϭ
9:1) of the crude product (11a/12a/13a ϭ 18:64:18), an analytically
pure mixture of 11a, 12a, and 13a was isolated (130 mg, 59%, ana-
lyzing for C16H23NO3·(H2O)0.5, dr unchanged).
2
2
2
ϭ
7.0 Hz, 1 H, 3-H), 5.09 (ddd, J3,4 ϭ 7.0, J4,5a ϭ 5.6, J4,5b ϭ 6.5 Hz,
1 H, 4-H), 7.44 (mc, 5 H, C6H5). Ϫ 13C NMR (125.8 MHz, CDCl3):
δ ϭ 10.5 (2-CH3), 23.6, 25.8 [C(CH3)2], 68.7 (CH2Ph), 69.6 (C-5),
72.8 (C-2), 75.2 (C-4), 83.3 (C-3), 113.4 [C(CH3)2], 127.9, 128.7,
129.3, 130.8 (C6H5). Ϫ C15H21NO3 (263.3): calcd. C 68.42, H 8.04,
N 5.32; found C 68.16, H 8.04, N 5.27.
(3S,4R)-2-(N-Benzylhydroxylamino)-3,4-O-isopropylidenedioxy-5-
hexene, (2S)-Isomer 9a or (2R)-Isomer 10a. ؊ N-Benzyl-3,4-O-isop-
ropylidenedioxy-2,5-dimethylpyrrolidine N-Oxides, (2S,3S,4R,5R)-
Isomer 11a, (1S,2R,3S,4R,5R)-Isomer 12a, (2R,3S,4R,5S)-Isomer
13a
(a) By Addition of H3CMgBr: A solution of N-benzyl nitrone 5
(290 mg, 1.11 mmol) in diethyl ether (10 mL) was placed in a flame-
dried flask under nitrogen. At Ϫ40 °C, a solution of H3CMgBr in
diethyl ether (3.0 , 0.57 mL, 1.7 mmol) was added. Within 5 min
a colourless precipitate formed. The reaction mixture was kept at
Ϫ40 °C for 2 h and then quenched by adding NH4Cl (0.3 g) and
ice water (20 mL). The aqueous phase was extracted with diethyl
ether (3 ϫ 20 mL). The combined extracts were dried with MgSO4
and concentrated in vacuo. The residue (290 mg of a yellowish oil)
was dissolved in CHCl3 (10 mL) and the solution stirred for 14 h
at room temp. After evaporation to dryness, the dr of the crude
N-Benzyl-2-ethyl-3,4-O-isopropylidenedioxy-5-methylpyrrolidine N-
Oxides, (1R,2S,3S,4R,5R)-Isomer 11b, (1R,2R,3S,4R,5R)-Isomer
12b, (1S,2R,3S,4R,5S)-Isomer 13b: A suspension of the N-benzyl
nitrone 5 (200 mg, 0.77 mmol) in diethyl ether (8 mL) was treated
with H5C2MgBr (3.0  in diethyl ether, 0.77 mL, 2.3 mmol) at Ϫ30
°C. The reaction mixture was stirred for 3.5 h between Ϫ20 °C and
Ϫ30 °C. After work-up as above, CopeϪHouse cyclization (15.5 h
at room temp., dr of crude material 11b/12b/13b ϭ 22:67:11), and
MPLC separation (10 bar, SiO2, CH2Cl2/MeOH ϭ 9:1), an analyt-
1
product was determined by H and 13C NMR spectroscopy (11a/
12a/13a ϭ 38:48:14) and the diastereomers were separated by
MPLC (10 bar, SiO2, CH2Cl2/MeOH ϭ 9:1). Thus, spectroscop- ically pure mixture of 11b and 12b (148 mg, 64%, dr ϭ 24:76, m.p.
ically pure samples of the pyrrolidine N-oxides 11a (90 mg, 27%, 110Ϫ112 °C), and 13b (18 mg, 8%, m.p. 56Ϫ58 °C) were obtained.
m.p. 109Ϫ110 °C) and 12a (120 mg, 37%, m.p. 97Ϫ100 °C) were Ϫ 11b and 12b (inseparable mixture, dr 24:76): [α]2D0 ϭ Ϫ19 (c ϭ
obtained. The minor isomer 13a (46 mg, 14%) was obtained in a
mixture containing 11a, 12a, and 13a in a ratio of 10:13:77. Ϫ One
of the intermediate hydroxylamines 9a or 10a was observed in the
NMR spectrum of the crude product recorded immediately after
0.54, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3400 (b, H2O), 2960, 1375, 1195,
1030, 1000 cmϪ1. Ϫ C17H25NO3 (291.4): calcd. C 70.07, H 8.65, N
4.81; found C 67.80, H 8.42, N 4.51 (correct for M ϩ 0.5 H2O). Ϫ
MS (EI, 70 eV): m/z (%) ϭ 291.2 (2.7) [Mϩ], 246.2 (25), 200.2 (16),
150.2 (19), 91.1 (100), 18.1 (13). Ϫ HRMS (EI, 70 eV): exact mass
work-up: 1H NMR (CDCl3, 300.1 MHz): δ ϭ 1.10 (d, J1,2
ϭ
7.2 Hz, 3 H, 1-H), 1.40, 1.52 [2 s, 6 H, C(CH3)2], 3.09 (m, 1 H, 2-
calcd. for C17H25NO3: 291.1834; found 291.1834. Ϫ 13b: [α]2D0
ϭ
H), 3.12 (bs, 1 H, OH), 3.87 and 3.99 (2 d, 2J ϭ 13.3 Hz, 2 H, Ϫ12 (c ϭ 0.83, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3400 (b, H2O), 1365,
CH2Ph), 4.33 (dd, J3,4 ϭ 5.7, J4,5 ϭ 9.2 Hz, 1 H, 4-H), 5.22 (d, 1195, 1060, cmϪ1. Ϫ MS (FAB, glycerol): m/z (%) ϭ 292.2 (100)
J5,6E ϭ 10.2 Hz, 1 H, 6-HE), 5.27 (d, J5,6Z ϭ 17.9 Hz, 1 H, 6-HZ),
[MHϩ], 91.0 (18). Ϫ HRMS (FAB, glycerol): exact mass calcd. for
5.89 (ddd, J4,5 ϭ 8.8, J5,6E ϭ 10.0, J5,6Z ϭ 17.1 Hz, 1 H, 5-H), C17H25NO3 ϩ H: 292.1913; found 292.1906. Ϫ H and 13C NMR
1
7.33 (mc, 5 H, C6H5), signal of 3-H hidden by absorptions of the
of 11b, 12b, and 13b: see Table 2 to 4.
Eur. J. Org. Chem. 2001, 1293Ϫ1308
1303

A. M. Palmer, V. Jäger
FULL PAPER
(1R,2R,3S,4R,5R)-N-Benzyl-2-isopropyl-3,4-O-isopropylidenedioxy-
5-methylpyrrolidine N-Oxide (12c): A freshly prepared solution of
iC3H7MgCl (2.3 mmol) in diethyl ether (5 mL) was added at Ϫ30
(200 mg, 0.77 mmol) in diethyl ether (8 mL). The mixture was
stirred for 7.5 h at Ϫ30 °C. Usual work-up, cyclization by stirring
in CHCl3 for 15 h, and flash chromatography (SiO2, CH2Cl2/
°C to a suspension of the N-benzyl nitrone 5 (200 mg, 0.77 mmol) MeOH ϭ 9:1) afforded a mixture of 11e and 12e (dr ϭ 24:76,
in diethyl ether (5 mL). After stirring for 4.75 h, the usual work-
up, CopeϪHouse cyclization by standing at room temp. for 15 h,
and flash chromatography (SiO2, CH2Cl2/MeOH ϭ 9:1) of the
crude product (dr 11c/12c/13c ϭ 15:85:Ͻ5), a colourless solid was
43 mg, 18%) and colourless crystals of 7 (49 mg, 24%), resulting
from Grignard reduction. Attempts to separate 11e and 12e by pre-
parative HPLC resulted in the transformation into new products
not yet fully characterized. Ϫ 1H and 13C NMR spectroscopic data
isolated (115 mg, 48%, m.p. 108 °C, mixture 11c/12c, dr ϭ 12:88). of 11e and 12e: see Table 2 to 4.
Ϫ [α]2D0 ϭ Ϫ14 (c ϭ 0.66, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 2950, 1378,
N-Benzyl-3,4-O-isopropylidenedioxy-5-methyl-2-neopentylpyrrol-
1370, 1195, 1030, 1000 cmϪ1. Ϫ C18H27NO3 (305.4): calcd. C 70.79,
H 8.91, N 4.59; found C 69.70, H 8.78, N 4.43 (correct for M ϩ
0.25 H2O). Ϫ MS (EI, 70 eV): m/z (%) ϭ 305.2 (Ͻ1) [Mϩ], 246.2
(92), 132.2 (18), 91.2 (100), 43.3 (11), 28.1 (18), 18.1 (55). Ϫ HRMS
(EI, 70 eV): exact mass calcd. for C18H27NO3: 305.1991; found
305.1989. Ϫ 1H and 13C NMR spectroscopic data of 12c: see
Table 2 to 4.
idine N-Oxides, (1R,2S,3S,4R,5R)-Isomer 11f, (1R,2R,3S,4R,5R)-
Isomer 12f: (a) The Grignard addition of freshly prepared neo-
C5H11MgBr (2.3 mmol) in diethyl ether (15 mL) to the N-benzyl
nitrone 5 (200 mg, 0.77 mmol) was performed at room temp. as
described above. After a reaction time of 2 d, work-up, and
CopeϪHouse cyclization (CHCl3, 3 d), conversion (66%) and dr
(11f/12f/13f ϭ 50:50:Ͻ5) were estimated from the NMR spectra.
Flash chromatography (SiO2, CH2Cl2/MeOH ϭ 9:1) yielded pure
12f (30 mg of a yellowish solid, 12%, m.p. 62 °C) and a mixture
(31 mg) consisting of 11f, 12f (dr ϭ 70:30), and another two un-
identified products. Ϫ 13C NMR spectroscopic data of 11f: see
Table 4. Ϫ 12f: [α]2D0 ϭ Ϫ22 (c ϭ 0.33, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ
N-Benzyl-2-isobutyl-3,4-O-isopropylidenedioxy-5-methylpyrrolidine
N-Oxides, (1R,2S,3S,4R,5R)-Isomer 11d, (1R,2R,3S,4R,5R)-Isomer
12d: Three variations of the addition of freshly prepared
iC4H9MgBr to N-benzyl nitrone 5 (200 mg, 0.77 mmol) were exam-
ined:
1
2940, 1370, 1195, 1050, 1000 cmϪ1. Ϫ H and 13C NMR spectro-
(a) Addition of the Grignard reagent in diethyl ether (2.3 mmol,
15 mL) at 0 °C, stirring over a period of 19 h at room temp., cyc-
lization in CHCl3. MPLC separation (SiO2, CH2Cl2/MeOH ϭ 9:1)
of the crude product (dr 11d/12d/13d ϭ 27:65:8) afforded pure, col-
ourless, crystalline samples of 11d (50 mg, 20%, m.p. 97Ϫ99 °C)
and 12d (125 mg, 49%, m.p. 112Ϫ113 °C). Ϫ 11d: [α]2D0 ϭ ϩ26 (c ϭ
0.40, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3400 (b, H2O), 3170 (b), 2940,
scopic data: see Table 2 to 4. Ϫ MS (EI, 70 eV): m/z (%) ϭ 333.2
(4.1) [Mϩ], 246.1 (100), 160.1 (12), 132.0 (12), 91.0 (89), 70.0 (10),
57.0 (15), 28.0 (27), 18.0 (47). Ϫ HRMS (EI, 70 eV): exact mass
calcd. for C20H31NO3: 333.2304; found 333.2305.
(b) The reaction was run as described in (a), but with shorter reac-
tion time (11 h) and at lower temperature (Ϫ30 °C and Ϫ10 °C).
After CopeϪHouse cyclization in CHCl3 at room temp. (10.5 h),
the dr of the crude product (11f/12f/13f ϭ 20:80:Ͻ5) and conver-
sion (ca. 32%) were determined from the NMR spectrum.
1460, 1370, 1360, 1245, 1200, 1140, 1060, 1010 cmϪ1
. Ϫ
C19H29NO3 (319.4): calcd. C 71.44, H 9.15, N 4.38; found C 69.29,
H 9.04, N 4.24 (correct for M ϩ 0.5 H2O). Ϫ MS (EI, 70 eV): m/z
(%) ϭ 319.2 (3.4) [Mϩ], 261.2 (10), 246.2 (31), 228.2 (20), 150.1
(51), 91.1 (100). Ϫ HRMS (EI, 70 eV): exact mass calcd. for
C19H29NO3: 319.2147; found 319.2145. Ϫ 12d: [α]2D0 ϭ Ϫ43 (c ϭ
0.46, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3400 (b, H2O), 2940, 1370, 1195,
1025, 1000 cmϪ1. Ϫ C19H29NO3 (319.4): calcd. C 71.44, H 9.15, N
4.38; found C 68.69, H 9.04, N 4.18 (correct for M ϩ 0.67 H2O).
Ϫ MS (EI, 70 eV): m/z (%) ϭ 319.2 (2.4) [Mϩ], 286.2 (12), 246.1
(45), 228.2 (18), 91.1 (100), 41.3 (13), 18.1 (23). Ϫ HRMS (EI,
70 eV): exact mass calcd. for C19H29NO3: 319.2147; found
N-Benzyl-3,4-O-isopropylidenedioxy-5-methyl-2-phenylpyrrolidine
N-Oxides, (1R,2S,3S,4R,5R)-Isomer 11g, (1R,2R,3S,4R,5R)-Isomer
12g, (1S,2R,3S,4R,5S)-Isomer 13g
(a) By Addition of PhMgBr: PhMgBr (3.0  in diethyl ether,
1.15 mL, 3.5 mmol) was added to a suspension of the N-benzyl
nitrone 5 (300 mg, 1.15 mmol) in diethyl ether (15 mL) and the
mixture kept at Ϫ20 °C for 1 h. The usual work-up, CopeϪHouse
cyclization in CHCl3 at room temp. (16 h), and MPLC separation
(SiO2, 10 bar, CH2Cl2/MeOH ϭ 93:7) of the crude product (dr 11g/
12g/13g ϭ 40:60:Ͻ5) afforded colourless crystals of 11g (96 mg,
25%, m.p. 135Ϫ137 °C), 12g (160 mg, 41%, m.p. 45Ϫ47 °C), and
13g (17 mg, 4%, m.p. 123 °C). Ϫ [Note: When kept neat, the pyrrol-
idine N-oxide 12g underwent partial ring opening within several
days to form the unsaturated hydroxylamine 10g (ratio 10g/12g ϭ
33:67). Pure 12g could be recovered by again stirring a CHCl3 solu-
tion of this mixture for 4 d at room temp.] Ϫ Data of the unsatur-
ated hydroxylamine 10g from mixture of 10g/12g: 1H NMR
(300.1 MHz, CDCl3): δ ϭ 1.46, 1.58 [2 s, 6 H, C(CH3)2], 3.88 (d,
1
319.2147. Ϫ H and 13C NMR spectroscopic data of 11d and 12d:
see Table 2 to 4.
(b) iC4H9MgBr (3.1 mmol) was added at Ϫ30 °C to a solution of
5 in diethyl ether (8 mL). The solution was kept for 4.5 h between
Ϫ30 °C and Ϫ10 °C, and was then allowed to warm to room temp.
After a total reaction time of 8.5 h, work-up and CopeϪHouse
cyclization (10.5 h) were performed as above. The crude product
(11d/12d/13d ϭ 46:48:6) was purified by flash chromatography
(SiO2, CH2Cl2/MeOH ϭ 9:1), yielding a colourless oil (214 mg,
87%, 11d/12d ϭ 50:50).
2
J1,2 ϭ 9.7 Hz, 1 H, 1-H), 4.11 and 4.13 (2 d, J ϭ 14.3 Hz, 2 H,
(c) After the addition of iC4H9MgBr (2.3 mmol) in ether (10 mL)
at Ϫ25 °C, the reaction mixture was kept for 10 h between Ϫ30 °C
and Ϫ10 °C. The crude product obtained after workup and
CopeϪHouse cyclization (CHCl3, room temp., 10.5 h), was ana-
lyzed by 1H and 13C NMR spectroscopy: conversion 50%, products
11d/12d/13d dr ϭ 26:67:7.
4
CH2Ph), 4.21 (ddt, J2,3 ϭ 5.7, J3,4 ϭ 7.8, J3,5 ϭ 1.0 Hz, 1 H, 3-
4
2
H), 4.86 (ddd, J3,5Z ϭ 1.0, J4,5Z ϭ 17.1, J5E,5Z ϭ 1.7 Hz, 1 H, 5-
HZ), 4.95 (dd, J1,2 ϭ 9.7, J2,3 ϭ 5.7 Hz, 1 H, 2-H), 5.01 (ddd,
4J3,5E ϭ 0.9, J4,5E ϭ 10.3, 2J5E,5Z ϭ 1.7 Hz, 1 H, 5-HE), 5.69 (ddd,
J3,4 ϭ 7.8, J4,5E ϭ 10.3, J4,5Z ϭ 17.1 Hz, 1 H, 4-H), 7.20Ϫ7.53 (m,
10 H, 2 C6H5). Ϫ 11g: [α]2D0 ϭ ϩ12 (c ϭ 0.56, CH2Cl2). Ϫ IR
N-Benzyl-2-tert-butyl-3,4-O-isopropylidenedioxy-5-methylpyrrol-
idine N-Oxides, (1R,2S,3S,4R,5R)-Isomer 11e, (1R,2R,3S,4R,5R)-
Isomer 12e: tert-C4H9MgBr (2.0  in diethyl ether, 1.15 mL,
(KBr): ν˜ ϭ 2960, 2920, 1440, 1370, 1260, 1195, 1080, 1060 cmϪ1
.
Ϫ C21H25NO3 (339.4): calcd. C 74.31, H 7.42, N 4.13; found C
73.85, H 7.46, N 4.06. Ϫ 12g: [α]2D0 ϭ Ϫ53 (c ϭ 0.52, CH2Cl2). Ϫ
2.3 mmol) was added to a solution of the N-benzyl nitrone 5 IR (KBr): ν˜ ϭ 2960, 2920, 1440, 1370, 1220, 1195, 1150, 1050
1304 Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
cmϪ1. Ϫ MS (FAB, nitrobenzyl alcohol): m/z (%) ϭ 340.2 (100)
FULL PAPER
The mixture was stirred for 45 min at room temp., diluted with
[MHϩ], 212.1 (16), 91.0 (39). Ϫ HRMS (FAB, nitrobenzyl alcohol): diethyl ether (5 mL), cooled to Ϫ80 °C, treated with the N-benzyl
exact mass calcd. for C21H25NO3 ϩ H: 340.1913; found 340.1912.
nitrone 5 (300 mg, 1.15 mmol), and stirred for another 5.25 h at
Ϫ 13g: [α]2D0 ϭ Ϫ74 (c ϭ 0.63, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3400, this temperature. The usual work-up, including CopeϪHouse cyc-
2960, 2920, 1368, 1195, 1100 cmϪ1. Ϫ MS (EI, 70 eV): m/z (%) ϭ lization in CHCl3 at room temp. (18.5 h, dr 11h/12h ϭ 71:29), and
339.2 (8.2) [Mϩ], 308.1 (15), 248.1 (22), 132.0 (75), 91.0 (100), 77.0 column chromatography (SiO2, CH2Cl2/MeOH ϭ 92:8) afforded a
(22), 57.9 (14). Ϫ HRMS (EI, 70 eV): exact mass calcd. for
mixture of 11h/12h (colourless oil, 205 mg, 62%, dr unchanged).
1
C21H25NO3: 339.1834; found 339.1835. Ϫ H and 13C NMR spec-
(c) By Complexation of the Nitrone 5 with Lewis Acids Followed
by Grignard Addition: (i) Complexation of the N-benzyl nitrone 5
(200 mg, 0.77 mmol) with ZnCl2·Et2O (2.2  in diethyl ether,
0.42 mL, 0.9 mmol) [30 min, Ϫ25 °C], subsequent addition of vi-
nylmagnesium bromide (1.0  in THF, 3.90 mL, 3.9 mmol) at Ϫ40
°C with stirring between Ϫ30 °C and Ϫ10 °C for 4.25 h, then cyc-
troscopic data of 11g, 12g, and 13g: see Table 2 to 4.
(b) By Addition of PhLi: A solution of the nitrone 5 (200 mg, 0.77
mmol) in diethyl ether (10 mL) was treated with PhLi (2.0  in
cyclohexane/ether, 1.16 mL, 2.3 mmol) at a temp. of Ϫ80 °C. The
reaction mixture was stirred for 3 h at Ϫ80 °C. The usual work-up
including CopeϪHouse cyclization (16.5 h in CHCl3 at room lization in CHCl3 at room temp. for 11.5 h (dr 11h/12h ϭ 84:16),
temp.) afforded a mixture of 11g, 12g, and 13g (19:81:Ͻ5) which
was separated by MPLC (cf. above). Thus, spectroscopically pure
and MPLC separation (SiO2, 10 bar, CH2Cl2/MeOH ϭ 92:8) af-
forded colourless crystals of 11h [134 mg, 60%, m.p. 67Ϫ69 °C;
samples of 11g (25 mg, 9%, m.p. 134Ϫ136 °C), 12g (100 mg, 38%, analyzed as C17H23NO3·(H2O)0.25]. Ϫ (ii) N-Benzyl nitrone 5
50Ϫ53 °C), and 13g (9 mg, 3%) were obtained.
(200 mg, 0.77 mmol) was treated at Ϫ30 °C with Et2AlCl (1.0  in
hexanes, 0.9 mmol) and, after 45 min vinylmagnesium bromide (1.0
 in THF, 2.31 mL, 2.3 mmol) was added at this temperature. After
stirring for 3.5 h at Ϫ30 °C, work-up, and CopeϪHouse cyclization
(15 h at room temp. in CHCl3) were performed as usual. The crude
product (11h/12h ϭ 84:16) was submitted to flash chromatography
(SiO2, CH2Cl2/MeOH ϭ 92:8) to afford a mixture of 11h and 12h
[163 mg, 72%, analyzes for C17H23NO3·(H2O)0.25].
(c) By Complexation of the Nitrone 5 with Et2AlCl Followed by
Grignard Addition: Et2AlCl (1.0  in hexanes, 0.91 mL, 0.9 mmol)
was added to a solution of the nitrone 5 (200 mg, 0.77 mmol) in
diethyl ether (10 mL). The mixture was stirred for 30 min at Ϫ30
°C, treated with PhMgBr (3.0  in diethyl ether, 0.77 mL,
2.31 mmol), and stirred for another 3 h 45 min. From the usual
work-up and CopeϪHouse cyclization (16.5 h at room temp. in
CHCl3), a crude product consisting of 11g, 12g, and 13g in a dr of
58:42:Ͻ5 was obtained. After MPLC separation (cf. above), analyt-
(1R,2R,3S,4R,5R)-2-Allyl-N-benzyl-3,4-O-isopropylidenedioxy-5-
methylpyrrolidine N-Oxide (12i): A solution of the N-benzyl nitrone
ically pure colourless crystals of 11g (120 mg, 46%, m.p. 139Ϫ140 5 (310 mg, 1.19 mmol) in diethyl ether (10 mL) was treated with
°C), spectroscopically pure crystals of 12g (65 mg, 25%), and oily
13g (12 mg, 5%) were isolated. Ϫ 11g: C21H25NO3 (339.4): calcd.
C 74.31, H 7.42, N 4.13; found C 74.29, H 7.47, N 4.18.
allylmagnesium bromide (1.0  in diethyl ether, 1.72 mL,
1.7 mmol). The mixture was stirred for 45 min at Ϫ40 °C. After
work-up, CopeϪHouse cyclization in CHCl3 at room temp. (16 h),
and MPLC separation (SiO2, 10 bar, CH2Cl2/MeOH ϭ 93:7), a
colourless solid was isolated (12i, 181 mg, 47%) containing some
solvent even after drying over P4O10 at 10Ϫ3 mbar. Since 12i was
found to be thermally labile, no attempts were made to remove
these traces by heating the sample. [Note: The NMR spectra of the
nonpolar fractions obtained during MPLC showed the presence of
the conjugated hydroxylamine 14i (resulting from Cope elimination
of 12i). The hydroxylamine 14i was also formed on prolonged stor-
age of 12i]. Ϫ 1H and 13C NMR spectroscopic data of 12i: see
Table 2 to 4.
N-Benzyl-3,4-O-isopropylidenedioxy-5-methyl-2-vinylpyrrolidine N-
Oxides, (1R,2S,3S,4R,5R)-Isomer 11h, (1R,2R,3S,4R,5R)-Isomer
12h
(a) By Addition of Vinylmagnesium Bromide: Reaction of the N-
benzyl nitrone 5 (200 mg, 0.77 mmol) with vinylmagnesium brom-
ide (1.0  in THF, 1.15 mL, 1.2 mmol) in diethyl ether (8 mL) [2 h,
Ϫ40 °C], CopeϪHouse cyclization in CHCl3 at room temp. for 13 h
(dr 11h/12h ϭ 67:33), and MPLC separation (SiO2, 10 bar, CH2Cl2/
MeOH ϭ 92:8) afforded 11h (131 mg of colourless crystals, 56%,
m.p. 47 °C) and 12h (82 mg of viscous oil, ‘‘35%’’, containing some
solvent not removed by drying). [Note: The major isomer 11h could
be purified by Kugelrohr distillation (10Ϫ3 mbar, 60 °C) and dis-
tilled as the monohydrate. However, the minor diastereomer 12h
was not separated by this method.] Ϫ 11h: [α]2D0 ϭ Ϫ8 (c ϭ 0.15,
CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3650Ϫ3000 (b, H2O), 2970, 1375, 1200,
1150, 1065 cmϪ1. Ϫ C17H23NO3 (289.4): calcd. C 70.56, H 8.01, N
4.84; found C 66.14, H 8.14, N 4.46 (correct for M ϩ 1.0 H2O). Ϫ
(1R,2R,3S,4R,5R)-N,2-Dibenzyl-3,4-O-isopropylidenedioxy-5-
methylpyrrolidine N-Oxide (12j)
(a) By Addition of BnMgBr: Freshly prepared BnMgBr (3.5 mmol)
in diethyl ether (2.5 mL) was added at Ϫ30 °C to a solution of the
N-benzyl nitrone 5 (200 mg, 0.77 mmol) in diethyl ether (8 mL);
cf. methyl case, variant (a). After 2 h at Ϫ30 °C, work-up, and
1
CopeϪHouse cyclization in CHCl3 at room temp. (11.5 h), the H
MS (EI, 70 eV): m/z (%) ϭ 289.2 (1.4) [Mϩ], 170.2 (23), 91.2 (100), and 13C NMR spectra of the crude product showed the presence
43.3 (12), 18.1 (14). Ϫ HRMS (EI, 70 eV): exact mass calcd. for
C17H23NO3: 289.1678; found 289.1678. Ϫ 12h: [α]2D0 ϭ Ϫ51 (c ϭ
0.52, CH2Cl2). Ϫ IR (film): ν˜ ϭ 3365 (b, OH), 2988, 1381, 1209,
of only one pyrrolidine N-oxide 12j and of the unsaturated hy-
droxylamine 14j (85:15). Flash chromatography (SiO2, CH2Cl2/
MeOH ϭ 92:8) afforded 12j (161 mg, 59%, m.p. 66Ϫ69 °C) as a
1099 cmϪ1. Ϫ MS (EI, 70 eV): m/z (%) ϭ 289.2 (3.6) [Mϩ], 273.2 colourless solid. Ϫ [α]2D0 ϭ Ϫ25 (c ϭ 0.51, CH2Cl2). Ϫ IR (KBr):
(16), 170.2 (18), 134.2 (11), 91.2 (100), 43.0 (18), 28.1 (29), 18.1 ν˜ ϭ 2960, 2910, 1445, 1370, 1195, 1035, 1005 cmϪ1. Ϫ 1H and 13C
(21). Ϫ HRMS (EI, 70 eV): exact mass calcd. for C17H23NO3: NMR spectroscopic data of 12j: see Table 2 to 4. Ϫ MS (EI, 70 eV):
289.1678; found 289.1678. Ϫ 1H and 13C NMR spectroscopic data
of 11h and 12h: see Table 2 to 4.
m/z (%) ϭ 353.2 (3.4) [Mϩ], 295.2 (10), 262.2 (36), 246.2 (62), 172.1
(19), 150.1 (39), 146.0 (11), 91.0 (100). Ϫ HRMS (EI, 70 eV): exact
mass calcd. for C22H27NO3: 353.1991; found 353.1995.
(b) By Addition of Vinyllithium: PhLi (2.0  in cyclohexane/ether,
1.73 mL, 3.5 mmol) was added at room temp. to a solution of tetra-
vinyltin (190 mg, 0.84 mmol) in diethyl ether (2.5 mL) which re-
sulted in the immediate formation of a colourless precipitate.[85]
(b) By Complexation of the Nitrone 5 with Et2AlCl Followed by
Grignard Addition: A solution of N-benzyl nitrone 5 (200 mg,
0.77 mmol) in diethyl ether (8 mL) was treated with Et2AlCl [1.0 
Eur. J. Org. Chem. 2001, 1293Ϫ1308
1305

A. M. Palmer, V. Jäger
J2,3 ϭ 8.7, J3,4 ϭ 5.6 Hz, 1 H, 3-H), 4.49 (dd, J3,4 ϭ 5.6, J4,5
8.1 Hz, 1 H, 4-H), 5.08 (d, J7,8E ϭ 10.0 Hz, 1 H, 8-HE), 5.21 (d,
J7,8Z ϭ 16.4 Hz, 1 H, 8-HZ), 5.76 (dd, J4,5 ϭ 8.1, J5,6 ϭ 14.6 Hz,
1 H, 5-H), 6.22 (dd, J5,6 ϭ 14.6, J6,7 ϭ 10.3 Hz, 1 H, 6-H), 6.34
(dt, J6,7 ϭ J7,8E ϭ 10.3, J7,8Z ϭ 16.4 Hz, 1 H, 7-H), 7.25 (mc, 5 H,
C6H5). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 10.5 (C-1), 25.8, 28.4
[C(CH3)2], 59.5 (C-2), 59.9 (CH2Ph), 79.1 (C-4), 79.8 (C-3), 108.9
[C(CH3)2], 118.5 (C-8), 127.1, 128.2, 129.5 (C6H5), 134.7 (C-6),
136.0 (C-7), 138.3 (C6H5).
FULL PAPER
in hexanes, 0.84 mL, 0.8 mmol; cf. methyl case, variant (c)] at Ϫ30
°C. The reaction was continued as described under (a) [reaction
time: 2.75 h between Ϫ10 °C and Ϫ30 °C, crude product with ratio
12j/14j ϭ 83:17], yielding 12j as a colourless solid (154 mg, 57%,
m.p. 66Ϫ69 °C).
ϭ
[Note: As described for the 2-allyl derivative 12i, the solvent was
not completely removed by drying 12j over P4O10 at 10Ϫ3 mbar.
Due to the thermal lability of 12j, no further attempts were made
at this.]
N-Benzyl-2-(3-butene-1-yl)-3,4-O-isopropylidenedioxy-5-methyl-
pyrrolidine N-Oxides, (1R,2S,3S,4R,5R)-Isomer 11k,
(1R,2R,3S,4R,5R)-Isomer 12k, and N-Benzyl-2-(1,2-O-isopropylid-
enedioxy-3-butene-1-yl)-5-methylpyrrolidine N-Oxide (15): Accord-
ing to the standard procedure, the N-benzyl nitrone 5 (200 mg,
0.77 mmol) was added at a temp. of Ϫ20 °C to a solution of freshly
prepared butenylmagnesium bromide (2.3 mmol) in diethyl ether
(10 mL). The mixture was kept for 3.5 h at Ϫ20 °C. The usual
work-up, cyclization in CHCl3 (5 d, dr 11k/12k/15 ϭ 22:37:41), and
MPLC separation (SiO2, 10 bar, CH2Cl2/MeOH ϭ 92:8) afforded
spectroscopically pure samples of 11k (colourless crystals, 33 mg,
13%, m.p. 92Ϫ94 °C), 12k (colourless crystals, 58 mg, 23%, m.p.
108Ϫ110 °C), and 15 (viscous oil, 58 mg, 23%). Ϫ 11k: [α]2D0 ϭ ϩ23
(c ϭ 1.38, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3400 (b, H2O), 2960, 2915,
1445, 1370, 1360, 1245, 1195, 1145, 1070 cmϪ1. Ϫ MS (EI, 70 eV):
m/z (%) ϭ 317.2 (1) [Mϩ], 259.2 (12), 246.2 (18), 150.1 (55), 91.1
(100). Ϫ HRMS (EI, 70 eV): exact mass calcd. for C19H27NO3:
317.1991; found 317.1988. Ϫ 12k: [α]2D0 ϭ Ϫ49 (c ϭ 0.22, CH2Cl2).
Ϫ IR (KBr): ν˜ ϭ 3400 (b, H2O), 2920, 1370, 1195, 1045, 1030, 1000
cmϪ1. Ϫ MS (FAB positive ion, nitrobenzyl alcohol): m/z (%) ϭ
318.2 (100) [MHϩ], 91.0 (16). Ϫ HRMS (FAB positive ion, nitro-
benzyl alcohol): exact mass calcd. for C19H27NO3 ϩ H: 318.2069;
found 318.2065. Ϫ 1H and 13C NMR spectroscopic data of 11k
and 12k: see Table 2 to 4. Ϫ C19H27NO3 (317.4): calcd. C 71.89, H
8.57, N 4.42; found for 11k C 69.78, H 8.54, N 4.31 (correct for M
ϩ 0.5 H2O); found for 12k C 70.06, H 8.48, N 4.23 (correct for M
ϩ 0.5 H2O). Ϫ 15: [α]2D0 ϭ ϩ45 (c ϭ 1.46, CH2Cl2). Ϫ IR (film):
(E)-(2R,3R,4S)-2-(N-Benzylhydroxylamino)-3,4-O-iso-
propylidenedioxy-6-phenyl-5-hexene (14j):
A
solution of 12j
(103 mg, 0.29 mmol) in DMSO was stirred for 30 min at 80 °C.
After removal of the solvent under reduced pressure (50Ϫ60 °C,
0.25 mbar), the residue was purified by flash chromatography
(SiO2, ethyl acetate/petroleum ether ϭ 1:1) yielding 14j (82 mg,
76%) as a colourless oil. Ϫ [α]2D0 ϭ ϩ6 (c ϭ 0.51, CH2Cl2). Ϫ IR
(film): ν˜ ϭ 3407 (b), 2986, 1453, 1371, 1245, 1216, 1064, 1040 cmϪ1
Ϫ 1H NMR (500.1 MHz, CDCl3): δ ϭ 1.09 (d, J1,2 ϭ 6.6 Hz, 3 H,
1-H), 1.43, 1.57 [2 s, 6 H, C(CH3)2], 3.08 (dq, J1,2 ϭ 6.6, J2,3
.
ϭ
2
9.3 Hz, 1 H, 2-H), 3.85 and 4.01 (2 d, J ϭ 13.1 Hz, 2 H, CH2Ph),
4.35 (dd, J2,3 ϭ 9.3, J3,4 ϭ 5.7 Hz, 1 H, 3-H), 4.60 (dd, J3,4 ϭ 5.7,
J4,5 ϭ 9.0 Hz, 1 H, 4-H), 6.09 (s, 1 H, OH), 6.17 (dd, J4,5 ϭ 9.0,
J5,6 ϭ 15.8 Hz, 1 H, 5-H), 6.56 (d, J5,6 ϭ 15.8 Hz, 1 H, 6-H), 7.32
(mc, 10 H, 2 C6H5). Ϫ 13C NMR (125.8 MHz, [D6]DMSO): δ ϭ
10.0 (C-1), 25.8, 28.4 [C(CH3)2], 59.4 (C-2), 59.9 (CH2Ph), 78.4 (C-
4), 78.7 (C-3), 107.6 [C(CH3)2], 126.5 (C-5), 132.5 (C-6), 126.4,
127.7, 128.5, 129.0, 136.2, 139.5 (C6H5). Ϫ C22H27NO3 (353.5):
calcd. C 74.26, H 7.70, N 3.96; found C 71.31, H 7.74, N 3.71
(correct for M ϩ 1.0 H2O).
(2S,3S,4R,5R)-N-Benzyl-3,4-dihydroxy-2,5-dimethylpyrrolidine N-
Oxide (16a): Under argon, 11a (93 mg, 0.31 mmol) was dissolved
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
crude product was purified using a column (5 cm ϫ 1.2 cm) packed
with Dowex 50WX8 (Hϩ form). The resin was first washed with
MeOH (50 mL) and water (50 mL), before 16a was eluted using
NH3 (1 , 50 mL). Concentration in vacuo afforded a colourless
solid (75 mg), which was recrystallized from MeOH/diethyl ether.
This yielded colourless needles of 16a suitable for X-ray analysis
(62 mg, 84%, m.p. 186 °C). Ϫ [α]2D0 ϭ 0 (c ϭ 0.10, MeOH). Ϫ IR
(KBr): ν˜ ϭ 3190 (b, OH), 3050, 2980, 2940, 1495, 1455, 1445, 1430,
1365, 1165, 1135, 1090 cmϪ1. Ϫ 1H NMR (500.1 MHz, MeOD):
δ ϭ 1.57 (d, J2,2-Me ϭ J5,5-Me ϭ 6.4 Hz, 6 H, 2-CH3, 5-CH3), 3.18
(mc, 2 H, 2-H, 5-H), 3.92 (mc, 2 H, 3-H, 4-H), 4.23 (s, 2 H, CH2Ph),
7.47 (mc, 5 H, C6H5). Ϫ 13C NMR (125.8 MHz, MeOD): δ ϭ 11.5
(2-CH3, 5-CH3), 66.1 (CH2Ph), 73.4 (C-2, C-5), 73.5 (C-3, C-4),
130.4, 131.2, 132.9 (C6H5). Ϫ C13H19NO3 (237.3): calcd. C 65.80,
H 8.07, N 5.90; found C 65.66, H 8.10, N 5.91.
1
ν˜ ϭ 3386 (H2O), 2985, 2935, 1380, 1217, 1044 cmϪ1. Ϫ H NMR
(500.1 MHz, CDCl3): δ ϭ 1.51 (d, J5,5-Me ϭ 7.1 Hz, 3 H, 5-CH3),
1.52, 1.67 [2 s, 6 H, C(CH3)2], 1.71 (mc, 3 H, 3-H, 4-Ha), 1.95 (mc,
1 H, 4-Hb), 3.23 (mc, 1 H, 5-H), 3.45 (mc, 1 H, 2-H), 4.25 and 5.05
(2 d, 2J ϭ 13.4 Hz, 2 H, CH2Ph), 4.44 (dd, J1Ј,2Ј ϭ 5.7, J2Ј,3Ј
ϭ
9.0 Hz, 1 H, 2Ј-H), 5.19 (d, J3Ј,4ЈE ϭ 10.0 Hz, 1 H, 4Ј-HE), 5.21 (dd,
J2,1Ј ϭ 9.1, J1Ј,2Ј ϭ 5.7 Hz, 1 H, 1Ј-H), 5.27 (d, J3Ј,4ЈZ ϭ 17.1 Hz, 1
H, 4Ј-HZ), 5.81 (ddd, J2Ј,3Ј ϭ 9.0, J3Ј,4ЈE ϭ 10.0, J3Ј,4ЈZ ϭ 17.1 Hz,
1 H, 3Ј-H), 7.43 (mc, 3 H, C6H5), 7.63 (mc, 2 H, C6H5). Ϫ 13C
NMR (125.8 MHz, CDCl3): δ ϭ 12.3 (5-CH3), 22.1 (C-3), 25.9,
28.4 [C(CH3)2], 27.7 (C-4), 66.9 (C-5), 67.0 (CH2Ph), 68.6 (C-2),
76.4 (C-1Ј), 79.4 (C-2Ј), 110.1 [C(CH3)2], 119.5 (C-4Ј), 128.8, 129.3,
131.5, 132.5 (C6H5), 134.6 (C-3Ј). Ϫ C19H27NO3 (317.4): calcd. C
71.89, H 8.57, N 4.42; found C 67.90, H 8.55, N 4.02 (correct for
M ϩ 1.0 H2O). Ϫ MS (FAB positive ion, nitrobenzyl alcohol): m/z
(%) ϭ 318.2 (100) [MHϩ], 91.0 (28). Ϫ HRMS (FAB positive ion,
nitrobenzyl alcohol): exact mass calcd. for C19H27NO3 ϩ H:
318.2069; found 318.2060.
X-ray Structural Analysis of 16a:[89] C13H19NO3 (237.3), colourless
˚
needle (1.0 mm ϫ 0.1 mm ϫ 0.1 mm), a ϭ 9.890(2) A, b ϭ
3
˚
˚
˚
11.245(2) A, c ϭ 11.377(2) A, V ϭ 1265.3(4) A , T ϭ 293(2) K,
orthorhombic, space group Pnma, Z ϭ 4, K: µ ϭ 0.088 mmϪ1
.
(5E)-(2R,3R,4S)-2-(N-Benzylhydroxylamino)-3,4-O-iso-
propylidenedioxy-5,7-octadiene (14i): An NMR tube containing 12i
(10 mg, 0.03 mmol) dissolved in [D6]DMSO was placed into the
Intensity data were collected using a Nicolet P3 diffractometer with
˚
graphite-monochromated Mo-Kα radiation (0.71073 A). The struc-
ture was solved with direct methods using SHELXS-86.[90] Refine-
ment (full-matrix least-squares) was performed against F2 using
SHELXL-93.[91] 1173 measured reflections in the range of 2.55 to
1
spectrometer and heated to 80 °C. After 15 min, a H NMR spec-
trum was recorded, showing quantitative transformation of 12i into
14i. Ϫ 1H NMR (300.1 MHz, [D6]DMSO, 80 °C): δ ϭ 0.99 (d, 24.99°, 1173 unique reflections and 932 with FO Ͼ 2σ(FO). R1 [FO
J1,2 ϭ 6.5 Hz, 3 H, 1-H), 1.31, 1.42 [2 s, 6 H, C(CH3)2], 2.90 (m, Ͼ 2σ(FO)] ϭ 0.0645, wR2 for all data ϭ 0.1315, GoF ϭ 1.239,
3
2-H), 3.82 and 3.90 (2 d, 2J ϭ 13.8 Hz, 2 H, CH2Ph), 4.27 (dd,
residual electron density: 0.19 e/A .
˚
1306
Eur. J. Org. Chem. 2001, 1293Ϫ1308

Glycosidase-Inhibiting Iminopolyols by CopeϪHouse Cyclization
FULL PAPER
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no. CCDC-147799. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
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[O00423]
1308
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