7-Oxanorbornane and norbornane mimics of a distorted β-D- mannopyranoside: Synthesis and evaluation as β-mannosidase inhibitors

Article abstract of DOI:10.1002/hlca.200590255

The racemic 7-oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45, and 46 were synthesized and tested as snail β-mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate 9 and furan 10. Esterification provided 11 tha

Full text of DOI:10.1002/hlca.200590255

Helvetica Chimica Acta – Vol. 88 (2005)
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7-Oxanorbornane and Norbornane Mimics of a Distorted b- -
D
Mannopyranoside: Synthesis and Evaluation as b-Mannosidase Inhibitors
by Stephan Buser and Andrea Vasella*
Laboratorium für Organische Chemie, ETH-Hönggerberg, Wolfgang-Pauli Strasse 10, CH-8093 Zürich
The racemic 7-oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45, and 46 were synthesized and
tested as snail b-mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate
9 and furan 10. Esterification provided 11 that underwent an intramolecular Diels–Alder reaction to the 7-oxa-
norbornene 12. Reduction of 12 to 13, desulfonylation, isopropylidenation, and cis-dihydroxylation gave 16. A
second isopropylidenation to 17, followed by debenzylation and a Mitsunobu–Gabriel reaction provided 19 that
was deprotected via 20 to 3. Diels–Alder cycloaddition of furfuryl acetate and maleic anhydride to 21, followed
by alcoholysis of the anhydride, cis-dihydroxylation, isopropylidenation, and Barton decarboxylation gave the
ester 25. Deacetylation to 26 and a Mitsunobu–Gabriel reaction led to 27 that was transformed into the N-
Boc analogue 29, reduced to the alcohol 30, and deprotected to 4. The 1-aminonorbornane 5 was obtained
from Thiele’s Acid 31. Diels–Alder cycloaddition of the cyclopentadiene obtained by thermolysis of the diester
32, methanolysis of the resulting anhydride 33, dihydroxylation, isopropylidenation, Barton decarboxylation,
and Curtius degradation led to the benzyl carbamate 39 that was reduced to the alcohol 40, transformed into
the N-Boc carbamate 41, and deprotected to 5. The alcohol 40 was also transformed into the benzylamine
42, aniline 45, and hydroxylamine 46. Snail b-mannosidase was hardly inhibited by 3, 4, 42, 45, and 46. Only
the amino triol 5 proved a stronger inhibitor. The inhibition by 5 depends on the pH value (at pH 3.5:
Ki =1900 mM; at pH 4.5: Ki =340 mM; at pH 5.5: Ki =110 mM). The results illustrate the strong dependence of
the inhibition by bicyclic mimics upon the precise geometry and orientation of the amino group as determined
by the scaffold. It is in keeping with the hypothesis that the reactive conformation imposed by snail b-manno-
sidase is close to a 1,4B/1S3.
Introduction. – The design, synthesis, and study of glycosidase inhibitors continue to
attract interest, fuelled by the potential of strong and selective glycosidase inhibitors to
act as drugs (e.g., against lysosomal storage disorders such as Gaucher’s disease [1],
influenza [2], HIV [3], hepatitis B [4] and C [5], and diabetes mellitus II [6]), and
their use as tools in the elucidation of the mechanism of action of glycosidases on
the basis of structure–activity relations, kinetic studies, and information provided by
the structure determination of enzyme–inhibitor complexes [7]. Transition-state ana-
logues promise to be most useful. Their design is based upon existent information
about the mechanism of action, and particularly about the transition state of the
rate-determining step, while their study may contribute to a more detailed understand-
ing of the mechanisms of action as summarised in several reviews [8][9]. Partial tran-
sition-state mimics may be thought of as being closer to a point of the reaction coordi-
nate that either precedes, or follows the transition state of interest, and there are rea-
sons to hypothesise that those preceding the rate-determining transition state of the
hydrolysis by retaining b-glycosidases could be more selective. The enzymatic hydrol-
ysis of b- -glycosides involves a conformational change of the substrate to comply with
D
the stereoelectronic requirement of a coplanar orientation of the scissile bond and a
© 2005 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 88 (2005)
doubly occupied, nonbonding orbital of the endocyclic O-atom (nO(5) ꢀs*) [10], and
Davies and co-workers have postulated that all conformations (and among these 1,4B
1
and S3 conformations) that comply with the stereoelectronic requirements are har-
nessed by different glycosidases [11]. We have already shown that the conformationally
biased manno-configured isoquinuclidines 1 and 2 that mimic approximately a 1,4B boat
conformation are selective inhibitors of snail b-mannosidase [12]. While 1 is rather
weak, the benzyl derivative 2 (Ki =1 m ) is a strong and selective inhibitor. The
M
gluco-configured analogues, however, are poor inhibitors of b-glucosidases [13],
while the N-acetylglucosamine analogues are again strong, competitive inhibitors of
bovine kidney and Jack bean hexosaminidases [14]. Considering the inhibition con-
stants of ca. 10ꢀ16
mM for an ideal transition-state mimic that have been derived by Wolf-
enden et al. [15], these isoquinuclidines are still far from closely mimicking the transi-
tion state. While it may indeed not be possible to approach the transition state much
more closely – on account of the lengthening of the scissile bond and the rehybridisa-
tion of the anomeric centre – it appears justified to search for inhibitors derived from
scaffolds that mimic the reactive conformer more closely, particularly considering the
selectivity of the inhibition displayed by the isoquinulidine-derived inhibitors.
Continuing the studies of bicyclic inhibitors1), we wished to modify the length of the
bridge between C(1) and C(4), and to thus modulate the geometry of the boat-like
shape of the inhibitor and the position of the substituents. We planned to synthesise
inhibitors derived from bicyclo[2.2.1]heptanes, or their 7-oxa analogues, depending
on the nature of the substituent at C(1), as 1-amino-7-oxabicyclo[2.2.1]heptanes will
not be sufficiently stable. The cyclohexane ring of these inhibitors should be much
closer to a 1,4B conformation than the one of the above-mentioned isoquinuclidines.
1
)
Tanaka and Bennet [16] synthesised 2,6-anhydro-1-deoxynojirimycin and evaluated it as glycosidase inhib-
itor to evidence the reactive 1,4B conformation of the substrate. Sinay and co-workers [17] synthesised deriv-
¨
atives of 1,4-anhydrogalactofuranose as inhibitors of UDP-galactose mutase to test the hypothesis of a 1,4-
anhydrogalactose intermediate, and Vogel and co-workers [18] evaluated 7-azabicyclo[2.2.1]heptanes as
inhibitors of a series of glycosidases to examine the effect of geometry and rigidity.

Helvetica Chimica Acta – Vol. 88 (2005)
3153
The Diels–Alder cycloadditon provides a favourable access to norbornenes and to
7-oxanorbornenes. Considering the well-known easy reversiblity of the Diels–Alder
cycloaddition to furans, we first opted for an intramolecular Diels–Alder cycloaddition
leading to the amino tetrol 3 (cf. Scheme 1). This introduces a HOCH2 group corre-
sponding to a C(4)ꢀCH2OH substituent of a (branched chain) mannopyranoside,
with unclear consequences on the inhibition. For this reason, we planned to also pre-
pare the amino triol 4 (cf. Scheme 2), a 1,4-anhydromannoheptulose derivative that is
not encumbered by such a HOCH2 group. Finally, considering the important and per-
haps decisive position of the NH2 substituent that is to interact with the catalytic acid of
the mannosidase, we planned to also prepare the 1-aminonorbornane 5 (cf. Scheme 3).
Calculation of the conformation of the isoquinuclidine 2 and the norbornane 5, and
superposition2) of the cyclohexane moieties reveals that the cyclohexane ring of 5
adopts a boat-like shape, whilst the cyclohexane ring of the isoquinuclidine 2 adopts
a conformation that is distorted towards a skew-boat (root-mean-square (rms) devia-
tion 0.139 Å). The distance between the N-atoms amounts to 1.88 Å; the different posi-
tion of the NH2 groups is expected to affect their interaction with the catalytic acid. The
secondary OH groups of the norbornane 5 corresponding to HOꢀC(2) and HOꢀC(3)
of a b- -mannopyranoside are at a slightly different position from those of the isoqui-
D
nuclidine 2 (distance between the O-atoms 0.37 and 0.39 Å, resp.). The position of the
C-atoms of the HOCH2 groups differs by 0.42 Å.
Superposition of the cyclohexane moieties of the isoquinuclidine 2 and the 7-oxa-
norbornane 4 shows an even greater distance between the two NH2 groups (atomic dis-
tance 3.15 Å), while the rms deviation remains almost unchanged (0.168 Å), in agree-
ment with the superposition of the cyclohexane rings of 5 and 2 (rms deviation
0.035 Å).
Synthesis. – Synthesis ofthe 7-Oxanorbornane 3. Epoxidation of allyl phenyl sulfone
(6) by m-CPBA gave the oxirane 7 which was converted to the allyl alcohol 8 (Scheme
1). Jones oxidation [20] gave the sulfonylated acrylic acid 9 in an overall yield of 59%.
The known benzyl ether 10 was obtained from furfuryl alcohol in three steps and in a
yield of 46% according to the procedure of Achmatowicz and Burzynska [21]. Esteri-
fication of the acid 9 with the alcohol 10 under Mukaiyama conditions [22] afforded the
ester 11 (85%), provided that Et3N was slowly added with a syringe pump over a period
of 1 h, complete immediate addition of Et3N resulting in the formation of a black res-
idue. The ester 11 in solution underwent an intramolecular Diels–Alder reaction
already at room temperature, and more rapidly at 408 [23]. The solvent strongly
affected the ratio of product and starting material, benzene leading to the least favour-
able ratio (23 :77) and MeCN to the most favourable one (59 :41), while in kinetically
controlled Diels–Alder reactions the solvent has little influence on product distribution
[24]. The 7-oxanorbornane 12 resulting from the cycloaddition of 11 in MeCN was sep-
arated from 11 by trituration with cyclohexane/AcOEt and isolated in a yield of 64%.
Since 12 in solution was transformed within a few hours at room temperature into a
mixture of product 12 and starting material 11, it was rapidly reduced with DIBAL
2
)
Superposition was carried out using Macromodel V. 6.0 [19]. The structures were minimized with the
PRCG algorithm and using MM3* as the force field.

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Helvetica Chimica Acta – Vol. 88 (2005)
Scheme 1
a) meta-Chloroperbenzoic acid (m-CPBA), ClCH2CH2Cl, 858; 88%. b) 1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU), CH2Cl2, ꢀ108; 89%. c) CrO3, H2SO4, H2O, acetone; 75%. d) 2-Chloro-1-methylpyridinium iodide,
Et3N, CH2Cl2; 85%. e) MeCN, 408; 64%. f) Diisobutylaluminum hydride (DIBAL), toluene; quant. g)
NaHg, Na2HPO4, MeOH; 69%. h) 2,2-Dimethoxypropane, camphorsulfonic acid (CSA), acetone; 88%. i)
OsO4, Me3NO, pyridine, H2O, t-BuOH; 72%. k) 2,2-Dimethoxypropane, CSA, acetone; 97%. l) Pd/C, H2 (6
bar), AcOEt; 90%. m) Phthalimide (PhthNH), Ph3P, diisopropyl azodicarboxylate (DIAD), THF; 93%. n)
NH2NH2 ·H2O, EtOH; 81%. o) 2.5N aq. HCl, 95%.
in toluene to the diol 13 (>98%) which was desulfonylated to 14 (69%) with 2% NaHg
in the presence of Na2HPO4 [25]. Isopropylidenation of 14 yielded 88% of the acetal 15.
Initial attempts to obtain the cis-diol 16 by treating 15 with OsO4 and N-methylmorpho-
line N-oxide (NMO) in acetone [26] led to several side-products which were not char-
acterized, while dihydroxylation with OsO4 and trimethylamine N-oxide in t-BuOH/
H2O containing traces of pyridine [27] led exclusively to the exo-cis-diol 16 (72%)
that was isopropylidenated to the tetracyclic acetal 17 (97%). Hydrogenolytic debenzyl-
ation of 17 in the presence of 10% Pd/C at 6 bar H2 in AcOEt led to the alcohol 18
(90%). Replacement of the primary OH group by phthalimide under Mitsunobu con-

Helvetica Chimica Acta – Vol. 88 (2005)
3155
ditions [28] afforded 19 (93%), and hydrazinolysis provided the amine 20 (81%) which
was further deprotected with 2.5 HCl to give 3 in 95% yield.
N
The formation of the lactone 12 is evidenced by a shift of the C=O IR band from 1782 cmꢀ1 for 11 to 1731
cmꢀ1 for 12, and the replacement of four 1H-NMR signals of 11 at 6.30, 6.40 (J=3.4), 6.84, and 7.76 ppm (J=15.3
Hz) by two signals at 6.65 and 6.73 ppm (J=5.9 Hz), evidencing the (Z)-configuration of the remaining alkenyl
group. The Diels–Alder reaction is also evidenced by the d of the H-atom in a-position to the SO2 group of 12
and 13. Its chemical shift (4.25 and 3.58 ppm, resp.) shows that the corresponding H-atom is not directly bound
to an alkenyl group. The assignment is supported by the spectrum of the product 14 of desulfonylation where this
d is replaced by dds at 1.60 and 1.22 ppm.
That the cis-dihydroxylation of 15 led to the exo-oriented cis-diol is shown by J(10,11)=5.9 and 6.0 Hz; the
expected J(Hexo,Hexo) of the endo-diol is 9–10 Hz [29].
Synthesis ofthe 7-Oxanorbornane 4. The known product 21 [30] of the thermody-
namically controlled Diels–Alder cycloaddition (e.g., [31]) of furfuryl acetate and
maleic anhydride (34%; Scheme 2) was subjected to methanolysis with MeONa in
MeOH. The desired mono-ester 22 was isolated from the mixture of regioisomers in
a yield of 41% by crystallisation from AcOEt. It was dihydroxylated with OsO4 and
NMO [26] to provide the highly polar dihydroxy acid 23 that was isolated as a sponta-
neously crystallising solid by continuous extraction with AcOEt (72%). As recrystalli-
sation of 23 led to considerable loss of material, we isopropylidenated crude 23 to 24
(75%). The corresponding acid chloride was esterified with N-hydroxypyridine-2-thi-
one sodium salt (sodium omadine [32]) in THF to provide the O-acyl thiohydroxamate
that was required for the Barton decarboxylation [33]. Treatment of the thiohydroxa-
mate with Bu3SnH and AIBN in boiling benzene proved most advantageous. However,
the decarboxylation product 25 contained considerable amounts of tin residues even
after purification. They were best removed after deacetylation of 25 to the alcohol
26 that was obtained in pure form in a yield of 62% from 24. Conversion of the alcohol
26 to the phthalimide 27 (94%) [28], followed by hydrazinolysis in EtOH, led to the
amine 28 (76%). It was transformed into the N-Boc-protected amino ester 29 (91%)
and reduced with LiBH4 [34] to the alcohol 30 (82%), which was fully deprotected to
4 (74%) by treatment with 2 aq. HCl.
N
Formation of the anhydride 21 is evidenced by a d at 6.47 ppm (J=5.9 Hz) and a dd at 6.63 ppm (J=5.6, 1.9
Hz), corresponding to the olefinically bonded HꢀC(8) and HꢀC(9). The exo-orientation of the anhydride moi-
ety is supported by J(2,6)=6.9 Hz [29], and confirmed by the absence of a coupling between HꢀC(6) and Hꢀ
C(7). It was only possible to establish the constitution of the product 22 of methanolysis after its decarboxylation
to 25 and transformation to 26. The decarboxylation product of the isomeric monoacid is expected to display a
coupling between HexoꢀC(8) and HꢀC(7); no such coupling was observed for 25. Dihydroxylation of 22 led
exclusively to the desired exo-oriented cis-diol 23. Its configuration was deduced from the absence of a finite
coupling between HꢀC(4) and HꢀC(5), and confirmed by crystal structure analysis3) of 26 (Fig. 1).
Synthesis ofthe 1-Aminonorbornanes 5, 42, 45, and 46. Thiele’s acid 31, first
reported in 1901 [35], appeared to be an advantageous starting material for the synthe-
sis of the title compounds (Scheme 3). For its preparation, we used BuLi in Et2O rather
3
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as depo-
sition No. CCDC-203882. Copies of the data can be obtained, free of charge, on application to the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

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Helvetica Chimica Acta – Vol. 88 (2005)
Scheme 2
a) MeONa, MeOH; 41%. b) OsO4, N-methylmorpholine N-oxide monohydrate (NMO), acetone/H2O 5 :1;
72%. c) 2,2-Dimethoxypropane, Amberlyst 15 (H+ form), acetone; 75%. d) (COCl)2, DMF, CH2Cl2; 1-
hydroxypyridine-2-thione sodium salt, THF; Bu3SnH, 2,2’-azobis[isobutyronitrile] (AIBN), PhH. e) MeONa,
MeOH; 62%. f) PhthNH, PPh3, DIAD; 94%. g) NH2NH2 ·H2O, EtOH; 76%. h) Boc2O, CH2Cl2; 91%. i)
LiBH4, THF; 82%. k) 2N aq. HCl; 74%.
Fig. 1. ORTEP Representation ofthe crystal structure ofthe 7-oxanorbornane 26
than Na in decalin [36][37]. This simplified the preparation of the diacids 31 that were
obtained (crude) in 75% yield. The corresponding di(tert-butyl) esters 32 were obtained
(88%) by treating the diacids with oxalyl chloride and then with t-BuOK in Et2O.
Thiele’s acids 31 and the diesters 32 are mixtures of isomers [37][38]. Considering
that the esters 32 were thermolysed in the next step, we did not separate the isomers.
The resulting cyclopentadiene was collected at ꢀ788 and treated with maleic anhydride
in Et2O [39] whereupon the endo-anhydride 33 precipitated. Recrystallisation provided

Helvetica Chimica Acta – Vol. 88 (2005)
3157
48% of 33. Cycloaddition of the monomer to methyl acrylate led to an inseparable mix-
ture; presumably the cyclopentadiene isomerized prior to its reaction with methyl ac-
rylate. The endo-anhydride 33 was transformed similarly to the 7-oxanorbornene
derived exo-anhydride 21. Methanolysis led to a 1:1 mixture of regioisomeric monoes-
ters that could not be separated by crystallisation. Dihydroxylation of the monoesters
[26] followed by isopropylidenation of the resulting cis-diols led to a mixture of
regioisomers which were readily separated by trituration and crystallisation to give
34 in a yield of 32% from 4 besides a 4 :1 mixture 35/34 of the regioisomeric esters
(39%). Unfortunately, attempts to transform the undesired isomer 35 into the corre-
sponding anhydride followed by methanolysis failed. Decarboxylation of 34 according
to Barton et al. [33] using t-BuSH in PhMe instead of Bu3SnH and AIBN in PhH gave
the endo-monoester 36 (82%) that was epimerized to the exo-isomer 37 by treatment
with MeONa in MeOH (86%). The (tert-butoxy)carbonyl (Boc) group was not
affected. Cleavage of the tert-butyl ester with Me3SiOTf and Et3N [40] gave the carbox-
ylic acid 38 (89%). Its Curtius degradation by treatment with diphenyl phosphorazidate
and Et3N in PhMe at 80–1108 [41] followed by intercepting the isocyanate with benzyl
alcohol (BnOH) in the presence of CuCl [42] yielded 88% of the carbamate 39. The
addition of BnOH to the isocyanate was sluggish, even in the presence of CuCl, and
the addition of t-BnOH failed altogether, illustrating the steric hindrance of the isocy-
anate.
The ester 39 was reduced with LiBH4 [34] to the alcohol 40 (92%). Considering that
traces of Pd compounds may strongly inhibit glycosidases [43], we exchanged the N-
benzyloxycarbonyl (Z) group against the Boc group by transfer hydrogenolysis (cyclo-
hexa-1,4-diene in the presence of Pd/C) followed by treatment of the resulting amine
with Boc2O in EtOH [44] to provide 84% of 41. This carbamate was fully deprotected
with 2 aq. HCl to give the amino triol 5 in 85% yield.
N
To prepare the benzylamino triol 42, we deprotected 40 by transfer hydrogenolysis,
treated the crude amine 43 with PhCHO in PhMe, and reduced the resulting imine
(NaBH4 in MeOH/THF) to 44 (89%; Schemes 3 and 4). Deprotection of 44 with 2
aq. HCl and THF gave 42 (93%) that was characterised as its hydrochloride.
N
In view of the essential interaction of the amino group with the catalytic acid and
the role of the pK value of the inhibitor [9][12][45], we also prepared two less basic
amines, viz. the aniline 45 and the hydroxylamine hydrochloride 46.
For the preparation of the aniline, we protected the primary OH group of 40 by
methoxymethylation to 47 (98%), followed by hydrogenolytic decarbamoylation.
The intermediate amine was not isolated, but phenylated in situ with PhBr in the pres-
ence of [Pd2(dba)3], BINAP, and t-BuOK [46] to yield 75% of the protected aniline 48
(75%) that was deprotected in the usual way by hydrolysis with 2 aq. HCl in MeOH to
N
45 (80%).
For the synthesis of 46, we treated the crude amine 43 with anisaldehyde and oxi-
dised the resulting imine with m-CPBA in ClCH2CH2Cl at 08 to provide a ca. 3 :1 mix-
ture of the diastereoisomeric oxaziridines 49 [47] (78%). They were not separated, but
isomerised [47][48] at 2008 to the (Z)-nitrone 50 (63%) which was hydrolysed with 2
aq. HCl to yield 71% of 46.
N

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Helvetica Chimica Acta – Vol. 88 (2005)
Scheme 3
a) 1.6
M
BuLi in hexane, Et2O; CO2; 75%. b) (COCl)2, cat. DMF, CH2Cl2; t-BuOK, Et2O; 88%. c) 1808;
maleic anhydride, Et2O; 48%. d) MeONa, MeOH; OsO4, NMO, acetone/H2O 5 :1; 2,2-dimethoxypropane,
Amberlyst 15 (H+ form), acetone; 34 (32%) and 35/34 4 :1 (39%). e) (COCl)2, DMF, CH2Cl2; 1-hydroxypyri-
dine-2-thione sodium salt, 4-(dimethylamino)pyridine (DMAP), t-BuSH, PhMe; 82%. f) MeONa, MeOH;
86%. g) Me3SiOTf, Et3N, CH2Cl2; 89%. h) Diphenylphosphoryl azide, Et3N, BnOH, CuCl, PhMe; 88%. i)
LiBH4, THF; 92%. k) Pd/C, H2, EtOH; 75%. l) 1. Pd/C, cyclohexa-1,4-diene; 2. Boc2O, EtOH; 84%. m) 2
N
aq. HCl; 85%.
The endo-orientation of the anhydride moiety of 33 was evidenced by the typical J(6,7) value of 4.7 Hz [29].
The regioselectivity of the anhydride opening could only be determined after the Barton decarboxylation. It is
evidenced by J(8,9exo)=11.2, J(8,9endo)=5.8, and J(7,8)=4.7 Hz of the resulting monoester 36. As expected, Hꢀ
C(7) and HꢀC(8) of the epimerisation product 37 do not couple with each other, similarly as observed for the 7-
oxanorbornane 4. The structure of 37 was established by crystal structure analysis4) (Fig. 2). The transformation
of the ester 38 to the carbamate 39 is evidenced by the 13C(1) signals; the one of 38 resonating at 54.63 ppm, and
the one of 39 at 62.50 ppm. A s at 155.51 ppm further evidences the carbamoyl group.
The structure of the nitrone 50 is evidenced by a new strong IR band at 1604 cmꢀ1, a 13C d at 138.2 ppm for
the C=N bond, and a corresponding 1H s at 7.73 ppm.
Inhibition Studies. – The results of the inhibition study of snail b-mannosidase by
the racemic 7-oxanorbornanes 3 and 4, and the racemic norbornanes 5, 42, 45, and
4
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as depo-
sition No. CCDC-203883. Copies of the data can be obtained, free of charge, on application to the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta – Vol. 88 (2005)
3159
Scheme 4
a) Pd/C, cyclohexa-1,4-diene, EtOH, 608; PhCHO, PhMe, ꢀH2O; NaBH4, MeOH/THF 1:1; 89%. b) 2
N aq.
HCl, THF; 93%. c) Methoxymethyl chloride (MOMCl), Et3N, Bu4NI, THF; 98%. d) Pd/C, H2, EtOH; 15
mol-% 2,2’-bis(diphenylphosphonyl)-1,1’-binaphthalene (BINAP), 8 mol-% [Pd2(dba)3] (dba=dibenzylide-
neacetone), PhBr, PhMe, 1108; 75%. e) 2
N
aq. HCl, MeOH; 80%. f) Pd/C, H2, EtOH; p-MeOꢀC6H4CHO,
MgSO4, CH2Cl2; m-CPBA, ClCH2CH2Cl; 78%. g) 2008; 63%. h) 2
N
aq. HCl; 71%.
46 at pH 3.5, 4.5, and 5.5 are summarised in the Table. At pH 4.5, the 7-oxanorbornanes
3 and 4 inhibited snail b-mannosidase very weakly (IC50 in the m range). A similarly
weak inhibition was displayed by the N-benzylnorbornane 42 (IC50 >1 m ). No inhib-
ition was observed for the N-phenylnorbornane 45 and the hydroxylamine 46 (IC50 >10
). The only inhibitor with a (pH-dependent) inhibition constant in the submillimolar
M
M
m
M
range is the norbornane 5.
The poor inhibition by the 7-oxanorbornanes 3 and 4 suggests that the NH2 group is
too far removed from the catalytic acid. That 3 is a somewhat worse inhibitor than 4
suggests (weak) destabilising interactions due to the additional HOCH2 group.
Similarly as observed for the isoquinuclidine-derived inhibitors [12], the inhibition
strength of 5 depends considerably on the pH value. At pH 3.5, 5 inhibited snail b-man-
nosidase poorly (Ki =1900 m
M
, mixed type, a=2.7). At pH 4.5, Ki was 340 m
M
(mixed
type, a=1.1), and at pH 5.5, Ki was 110 m
M
(mixed type, a=3.1). This pH dependence
suggests that only the free amine 5 binds to the active site of the enzyme. With a pK
value of 8.6, 5 is mostly protonated at the pH optimum of the mannosidase, and thus
not active as inhibitor. The expected Ki value of ca. 50 m
M
at pH 5.5 for the enantiomer
corresponding to -mannose [12] 5 suggests that the pK value of the amine and its
D
proper location are the critical parameters for the inhibition by such bicyclic amines.
That both location and orientation of the NH2 group play a role is evidenced by the

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Helvetica Chimica Acta – Vol. 88 (2005)
Fig. 2. ORTEP Representation ofthe crystal structure ofthe norbornane 37
Table 1. Inhibition of b-Mannosidase from Snail [mM] by the 7-Oxanorbornanes 3 and 4, and the Norbornanes 5,
42, 45, and 46 at 258
Inhibitor (pKHA
)
pH 3.5
pH 4.5
pH 5.5
a
a
3 (8.5)
4 (8.7)
5 (8.6)
42 (8.2)
45 (4.7)
46 (4.9)
)
1800b)
)
a
a
)
1200b)
)
1900c) (a=2.7)
340c) (a=1.1)
1400b)
110c) (a=3.1)
–
–
–
–
–
–
a
)
a
)
a) IC50 >10 m b) IC50. c) Ki.
M.
observation that – in contradistinction to the N-Bn isoquinuclidine 2 – the N-Bn nor-
bornane 42 is a very poor inhibitor of snail b-mannosidase, and this in spite of the oth-
erwise well-established favourable effect of hydrophobic aglycon mimics on the inhib-
ition [12][49]. The poor inhibition by the less basic aniline 45 and hydroxylamine 46 is
in keeping with the hypothesis of an unfavourable location and orientation of the NH2
group by the norbornane scaffold, considering that the loss of activity did not depend
on the polar nature of the N-substituent.
Superposition of C(2)ꢀC(5) and C(5)-O of the ꢀ1 unit of the octa-N-acetylchitooc-
taose in complex with the Serratia marcescens ChiA chitobiase mutant E315Q [50]
where the ꢀ1 unit adopts a 1,4B conformation and of C(2 to 6) of the norbornane 5
shows that the glycosidic C(1)-O of the ꢀ1 unit is rather remote from the NH2
group of 5 (N···O distance 1.19 Å). However, superposition of the ꢀ1 unit (except
for C(1)) in a half-chair conformation with C(2 to 6) of 5 shows that the distance
between the anomeric O- and the N-atom is significantly smaller (N···O distance
0.57 Å). The poor inhibition by the oxanorbornanes and norbornanes is thus in keeping
with the postulate that the reactive conformation of the snail b-mannosidase substrate
is a boat or twist-boat (1,4B or 1S3).

Helvetica Chimica Acta – Vol. 88 (2005)
3161
We thank Dr. B. Schweizer for the determination of the X-ray crystal structures, M. Schneider and D. Man-
ser for the pKHA determinations, Dr. B. Bernet for checking the Exper. Part, and Dr. L. Remen for advice during
the synthesis of 3 and 6–12.
Experimental Part
General. Solvents were distilled before use: THF and toluene from Na/benzophenone, and CH2Cl2 and
MeOH from CaH2. Reactions were run under Ar. Qual. TLC: precoated silica-gel plates (Macherey-Nagel Alu-
gram Sil G/UV254); detection by heating with ‘mostain’ (400 ml of 10% aq. H2SO4, 20 g of (NH4)6Mo7O24 ·H2O,
0.4 g of Ce(SO4)2). Flash chromatography (FC): silica gel Fluka 60 (0.04–0.063 mm). FT-IR: KBr or 2% CHCl3
soln. b-Mannosidase (3.2.1.25, M-9400 as a suspension in acetone, from snail), and 4-nitrophenyl b-D-mannopyr-
anoside were purchased from Sigma and used without any further purification. Normal workup implies pouring
the reaction mixture into a sat. aq. NaHCO3 soln., extracting into the mentioned org. solvent, if necessary wash-
ing with the indicated sat. aq. soln., drying of the org. layer (MgSO4), filtration, and evaporation of the volatiles.
2-[(Phenylsulfonyl)methyl]oxirane (7). A soln. of allyl phenyl sulfone (11.9 g, 65 mmol) in ClCH2CH2Cl (50
ml) was treated with m-CPBA (25 g, 130 mmol), warmed to 858, stirred for 150 min, cooled to 08, treated with
0.2N Na2S2O3 (100 ml), and vigorously stirred for 5 min. The org. layer was separated, and the aq. layer was
extracted with CH2Cl2 (3×50 ml). The combined org. layers were washed with sat. NaHCO3 soln. (100 ml),
and the aq. layer was extracted with CH2Cl2 (3×50 ml). The combined org. layers were dried (MgSO4). Evap-
oration and FC (hexane/Et2O 1:1!0 :1) gave 7 (11.4 g, 88%). Colourless oil. Rf (hexane/Et2O 1:1) 0.61. The
spectral data of 7 are identical to those in [51][52].
3-(Phenylsulfonyl)prop-2-en-1-ol (8). A soln. of 7 (11 g, 82.5 mmol) in CH2Cl2 (100 ml) was cooled to ꢀ108,
treated with a soln. of DBU (12.55 g, 82.5 mmol) in CH2Cl2 (50 ml) over a period of 180 min, warmed to 08, and
treated with 2.5N HCl (150 ml). The org. layer was separated, and the aq. layer was extracted with CHCl3 (5×100
ml). The combined org. layers were dried (MgSO4). Evaporation gave crude 8 (9.9 g, 89%), which was used for
the next reaction without further purification. White solid. Rf (hexane/AcOEt 1:4) 0.53. The spectral data of 8
are identical to those in [51].
(E)-3-(Phenylsulfonyl)prop-2-enoic Acid (9). At 238, a stirred soln. of 8 (5 g, 25.5 mmol) in acetone (200 ml)
was treated dropwise with a soln. of CrO3 (3.78 g, 37.8 mmol) in H2SO4 (4.4 ml) and H2O (12.8 ml) until the col-
our of the mixture remained orange over a period of 15 min. i-PrOH was added until the colour turned green.
After filtration through a short pad of Celite and evaporation, the residue was crystallized from toluene (250 ml)
to give 9 (4.1 g, 75%). White solid. M.p. 1328. IR (CHCl3): 3700–2500m (br.), 1724s, 1448m, 1325s, 1152s, 1085m,
1
1038w, 965w, 822w. H-NMR (300 MHz, CDCl3): 6.83 (d, J=15.3, HꢀC(3)); 7.41 (d, J=15.3, HꢀC(2)); 7.50–
8.00 (m, 5 arom. H); 8.80–9.80 (br. s, COOH). 13C-NMR (75 MHz, CDCl3): 128.70–130.00 (5 arom. CH);
134.91 (C(2)); 138.29 (1 arom. C); 145.64 (C(3)); 168.30 (C=O). EI-MS: 212 (M+). Anal. calc. for C9H8O4S
(212.23): C 50.94, H 3.80, O 30.16, S 15.11; found: C 51.10, H 3.92, O 30.09, S 15.25.
{5-[(Benzyloxy)methyl]furan-2-yl}methyl (E)-3-(Phenylsulfonyl)prop-2-enoate (11). A suspension of 9 (2.1
g, 9.4 mmol), 10 (2 g, 9.4 mmol) and 2-chloro-N-methylpyridinium iodide (2.88 g, 11.3 mmol) in CH2Cl2 (210 ml)
was warmed to 408, treated with Et3N (2.28 g, 22.6 mmol) over a period of 60 min (syringe pump), and cooled to
238. Normal workup (CH2Cl2/NH4Cl) and FC (cyclohexane/AcOEt 4 :1 !3 :1) gave 11 (3.3 g, 85%). Pale yel-
low oil. Rf (cyclohexane/AcOEt 2 :1) 0.60. IR (CHCl3): 3067w, 3034m, 2862w, 1782w, 1731s, 1586w, 1496w,
1448m, 1326s, 1310m, 1295s, 1165s, 1153s, 1085s, 1070m, 1024m, 1008m, 963m. 1H-NMR (300 MHz, CDCl3):
4.46, 4.56 (2s, CH2ꢀC(5’), PhCH2); 5.15 (s, CH2ꢀC(2’)); 6.30, 6.40 (2d, J=3.4, HꢀC(3’), HꢀC(4’)); 6.84 (d,
J=15.3, HꢀC(3)); 7.76 (d, J=15.3, HꢀC(2)); 7.72–7.79 (m, 10 arom. H). 13C-NMR (75 MHz, CDCl3): 59.49
(CH2ꢀC(2’)); 64.03 (CH2ꢀC(5’)); 72.42 (PhCH2); 110.56, 112.60 (C(3’), C(4’)); 128.12–130.67 (10 C); 134.7
(C(2)); 137.94, 138.63 (2 arom. C); 144.08 (C(3)); 148.71, 153.39 (C(2’), C(5’)); 163.39 (C=O); Anal. calc. for
C22H20O6S (412.46): C 64.06, H 4.89, O 23.27, S 7.77; found: C 64.13, H 5.18, O 23.20, S 7.54.
(Æ)-(1RS,5SR,6SR,7RS)-7-[(Benzyloxy)methyl]-6-(phenylsulfonyl)-3,10-dioxatricyclo[5.2.1.01,5]dec-8-en-
4-one (12). A soln. of 11 (5.4 g, 13.1 mmol) in MeCN (70 ml) was kept at 408 for 40 h and evaporated. The res-
idue was triturated at 238 with cyclohexane/AcOEt 1:1, washed with cyclohexane, and filtered to yield 12 as
solid (2.6 g). The filtrate and washings were evaporated. The residue was dissolved in MeCN, kept at 408 for
40 h, evaporated, triturated, and washed with cyclohexane to give further 12 (0.88 g, 64% overall). White
solid. Rf (cyclohexane/AcOEt 3 :1) 0.10. M.p. 1328. IR (CHCl3): 3034w, 1782s, 1448w, 1320s, 1153s, 1085m,
1008m, 907w, 866w, 837w. 1H-NMR (300 MHz, CDCl3): 3.20 (d, J=4.0, HꢀC(5)); 4.12 (d, J=11.5), 4.21 (d,
J=11.8) (CH2ꢀC(7)); 4.25 (d, J=3.7, HꢀC(6)); 4.58, 4.63 (2d, J=11.8, 2 HꢀC(2)); 4.67 (d, J=11.2), 4.76 (d,

3162
Helvetica Chimica Acta – Vol. 88 (2005)
J=11.5) (PhCH2); 6.65, 6.73 (2d, J=5.9, HꢀC(8), HꢀC(9)); 7.25–7.85 (m, 10 arom. H). 13C-NMR (75 MHz,
CDCl3): 51.99 (C(5)); 65.07 (C(6)); 67.64, 69.16 (CH2ꢀC(7), C(2)); 73.93 (PhCH2); 93.31, 94.02 (C(1), C(7));
128.08–129.16, 128.75, 129.80 (9 C); 134.54, 134.81, 136.22 (3 C); 137.69, 139.85 (C(8), C(9)); 172.59 (C=O).
MALDI-MS: 435 ([M+Na]+). Anal. calc. for C22H20O6S (412.46): C 64.06, H 4.89, O 23.27, S 7.77; found: C
64.19, H 5.03, O 23.02, S 7.91.
(Æ)-(1RS,4RS,5SR,6RS)-{4-[(Benzyloxy)methyl]-6-(hydroxymethyl)-5-(phenylsulfonyl)-7-oxabicyclo-
[2.2.1]hept-2-en-1-yl}methanol (13). Neat 12 (1 g, 2.4 mmol) was treated with 1M DIBAL in toluene (10 ml) at 08,
stirred for 15 min, warmed to 238, stirred for 45 min, cooled to 08, treated with sat. aq. NH4Cl soln. (50 ml) and
CHCl3 (50 ml), acidified to pH 1–2 with 2.5 HCl, and stirred at 238 for 2 h. The org. layer was separated, and
N
the aq. layer was extracted with CHCl3 (5×50 ml). The combined org. layers were dried (MgSO4). Evaporation
of the solvent gave crude 13 (1 g, 99%), which was directly used for the next reaction. A small sample was puri-
fied by HPLC. White solid. Rf (AcOEt) 0.40. M.p. 1138. IR (CHCl3): 3479w (br.), 3006w, 2932w, 2875w, 1585w,
1447m, 1307m, 1150s, 1086s, 859w. 1H-NMR (500 MHz, CDCl3): 2.45 (ddd, J=8.7, 4.7, 4.0, HꢀC(6)); 3.00–3.40
(2 br. s, 2 OH ); 3.45 (dd, J=11.1, 3.9, CHꢀC(6); 3.50 (dd, J=11.1, 8.8, CH’ꢀC(6)); 3.58 (d, J=4.9, HꢀC(5));
3.88 (d, J=11.4), 3.95 (d, J=11.5) (CH2ꢀC(1)); 3.96, 4.03 (2d, J=12.4, CH2ꢀC(4)); 4.47 (s, PhCH2); 6.35, 6.57
(2d, J=5.7, HꢀC(2), HꢀC(3)); 7.20–7.90 (m, 10 arom. H). 13C-NMR (125 MHz, CDCl3; assignments based on
a HSQC.GRASP spectrum): 48.32 (d, C(6)); 60.33 (t, CH2ꢀC(1); 62.04 (t, CH2ꢀC(6)); 66.28 (d, C(5)); 67.83 (t,
CH2ꢀC(4)); 73.68 (t, PhCH2); 89.94, 91.15 (2s, C(1), C(4)); 133.89 (d, C(3)); 138.95 (d, C(2)); 127.78, 127.81,
128.19, 128.42, 129.41 (5d); 137.58, 139.66 (2s). MALDI-MS: 439 ([M+Na]+).
(Æ)-(1RS,4RS,6RS)-{4-[(Benzyloxy)methyl]-6-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-en-1-yl}metha-
nol (14). A vigorously stirred suspension of 13 (1.6 g, 3.88 mmol) and Na2HPO4 (4.5 g, 37 mmol) in MeOH (130
ml) was treated at 238 with NaHg 2 :98 (15 g), stirred for 1 h, treated again with NaHg 2 :98 (5 g), stirred for 20
min, and filtered through a short pad of Celite. Normal workup (CHCl3/NH4Cl) and FC (cyclohexane/AcOEt
3 :1!1:1) gave 14 (740 mg, 69%). Colourless oil. Rf (AcOEt) 0.28. IR (CHCl3): 3604w, 3440w, 1601w,
1453m, 1357w, 1333w, 1206s, 1095s, 1042s, 878w, 795w. 1H-NMR (500 MHz, CDCl3): 1.22 (dd, J=11.4, 3.9,
HexoꢀC(5)); 1.60 (dd, J=11.4, 8.2, HendoꢀC(5)); 2.03 (ddt, J=9.6, 8.1, 4.0, HꢀC(6)); 2.90, 3.29 (2 br. s, 2 OH);
3.69 (dd, J=10.8, 9.6, CHꢀC(6)); 3.74 (dd, J=10.8, 4.1, CH’ꢀC(6)); 3.80, 3.86 (2d, J=11.0, CH2ꢀC(1)); 4.05,
4.11 (2d, J=12.2, CH2ꢀC(4)); 4.60, 4.70 (2d, J=12.3, PhCH2); 6.29, 6.38 (2d, J=5.7, HꢀC(2), HꢀC(3));
7.25–7.46 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3; assignments based on a HSQC.GRASP spectrum):
32.94 (t, C(5)); 42.88 (d, C(6)); 61.20 (t, CH2ꢀC(1)); 63.84 (t, CH2ꢀC(6)); 69.58 (t, CH2ꢀC(4)); 73.63 (t,
PhCH2); 88.26, 90.38 (2s, C(1), C(4)); 127.74 (d); 127.79 (2d); 128.43 (2d); 136.68, 137.31 (2d, C(2), C(3));
138.00 (s). MALDI-MS: 299 ([M+Na]+). Anal. calc. for C16H20O4 (276.33): C 69.55, H 7.29; found: C 69.60,
H 7.33.
(Æ)-(1RS,7RS,9RS)-9-[(Benzyloxy)methyl]-4,4-dimethyl-3,5,12-trioxatricyclo[5.4.0.11,9]dodec-10-ene (15).
A soln. of 14 (1.8 g, 6.5 mmol), CSA (72 mg, 0.28 mmol) and 2,2-dimethoxypropane (1.3 g, 12.5 mmol) in ace-
tone (45 ml) was stirred at 238 for 3 h. Normal workup (CH2Cl2/NaHCO3, H2O) and FC (cyclohexane/AcOEt
3 :1) gave 15 (1.8 g, 88%). Colourless oil. Rf (cyclohexane/AcOEt 1:1) 0.75. IR (CHCl3): 3000s, 2915m, 2890w,
1605w, 1503w, 1455m, 1170m, 1080s. 1H-NMR (500 MHz, CDCl3): 1.16 (dd, J=11.5, 3.7, HexoꢀC(8)); 1.37, 1.41
(2s, Me2C(4)); 1.49 (dd, J=11.5, 8.0, HendoꢀC(8)); 1.89 (dddd, J=11.6, 7.9, 4.8, 3.8, HꢀC(7)); 3.59 (dd, J=11.9,
5.1, HꢀC(6)); 3.68 (t, J=11.8, H’ꢀC(6)); 3.85 (d, J=11.7), 3.87 (d, J=11.0) (2 HꢀC(2)); 4.07, 4.23 (2d, J=13.7,
CH2ꢀC(9)); 4.58, 4.67 (2d, J=12.3, PhCH2); 6.12, 6.37 (2d, J=5.7, HꢀC(10), HꢀC(11)); 7.27–7.39 (m, 5 arom.
H). 13C-NMR (125 MHz, CDCl3; assignments based on a HSQC.GRASP spectrum): 23.92, 25.09 (2q, Me2C(4));
32.08 (t, C(8)); 43.71 (d, C(7)); 61.36 (t, CH2ꢀC(9)); 63.72 (t, C(6)); 69.97 (t, C(2)); 73.55 (t, PhCH2); 88.35,
89.93 (2s, C(1), C(9)); 101.64 (s, C(4)); 127.59 (d); 128.34 (2d); 129.29 (2d); 135.81, 137.69 (2d, C(10), C(11));
138.21 (s). MALDI-MS: 339 ([M+Na]+). Anal. calc. for C19H24O4 (316.40): C 72.13, H 7.65; found: C 72.12,
H 7.76.
(Æ)-(1RS,7RS,9RS,10SR,11RS)-9-[(Benzyloxy)methyl]-4,4-dimethyl-3,5,12-trioxatricyclo[5.4.0.11,9]dodec-
ane-10,11-diol (16). A soln. of 15 (500 mg, 1.6 mmol), trimethylamine N-oxide (Me3NO; 530 mg, 4.8 mmol), and
pyridine (120 ml) in H2O (0.9 ml) and t-BuOH (2.3 ml) was treated with OsO4 (10 mg, 0.04 mmol), warmed to
808, stirred for 6 h, cooled to 238, treated with 20% aq. NaHSO3 soln. (18 ml), stirred for 5 min, and treated
with H2O (30 ml). The volatiles were evaporated, and the residue was extracted with AcOEt (1×200 ml,
2×75 ml). The combined org. layers were dried (Na2SO4) and evaporated. Crystallisation from MeOH (5 ml)
and from EtOH (6 ml) gave 16 (406 mg, 72%). White solid. Rf (cyclohexane/AcOEt 1:1) 0.35. M.p. 1308. IR
(CHCl3): 3399m (br.), 2997m, 2937m, 2876m, 1603w, 1455m, 1385m, 1114s, 1073s, 1036m. 1H-NMR (500
MHz, CDCl3): 0.89 (dd, J=12.8, 4.4, HexoꢀC(8)); 1.35, 1.36 (2s, Me2C(4)); 1.52 (dd, J=12.8, 8.7, HendoꢀC(8));
1.86 (ddt, J=11.6, 9.2, 4.6, HꢀC(7)); 3.27 (dd, J=11.9, 5.2, HꢀC(6)); 3.49 (d, J=6.3, HOꢀC(10)); 3.59 (t,

Helvetica Chimica Acta – Vol. 88 (2005)
3163
J=11.8, H’ꢀC(6)); 3.74 (t, J=5.9, HꢀC(10)); 3.94, 3.97 (2d, J=11.0, 2 HꢀC(2)); 4.02 (dd, J=6.0, 3.5, Hꢀ
C(11)); 4.09, 4.13 (2d, J=14.3, 2 CHꢀC(9)); 4.44 (d, J=3.9, HOꢀC(11)); 4.55, 4.69 (2d, J=11.8, PhCH2);
7.31–7.38 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3; assignments based on a HSQC.GRASP spectrum):
23.74, 25.17 (2q, Me2C(4)); 32.25 (t, C(8)); 42.69 (d, C(7)); 60.25 (t, CH2ꢀC(9)); 62.56 (t, C(6)); 70.60 (t,
C(2)); 74.17 (t, PhCH2)); 75.73 (d, C(11)); 76.00 (d, C(10)); 84.23, 88.50 (2s, C(1), C(9)); 101.79 (s, C(4));
127.95 (2d); 128.11 (d); 128.59 (2d); 137.02 (s). MALDI-MS: 373 ([M+Na]+). Anal. calc. for C19H26O6
(350.41): C 65.13, H 7.48; found: C 65.05, H 7.32.
(Æ)-(1RS,7RS,9SR,10SR,14RS)-9-[(Benzyloxy)methyl]-4,4,12,12-tetramethyl-3,5,11,13,15-pentaoxatetracy-
clo[7.5.1.01,7.010,14]tetradecane (17). A suspension of 16 (550 mg, 1.56 mmol), CSA (35 mg), and 2,2-dimethoxy-
propane (411.45 mg, 4.0 mmol) in acetone (14 ml) was stirred for 5 h at 238, and treated with Na2CO3 (60 mg, 0.6
mmol). Normal workup (AcOEt/H2O) and FC (cyclohexane/AcOEt 2 :1) gave 17 (596 mg, 97%). Colourless
oil. Rf (cyclohexane/AcOEt 1:1) 0.54. IR (CHCl3): 3000m, 2938m, 2871m, 1710w, 1604w, 1453w, 1373m,
1266m, 1090s, 1035m, 871w. 1H-NMR (500 MHz, CDCl3): 1.51 (dd, J=13.0, 4.4, HexoꢀC(8)); 1.28, 1.34, 1.36,
1.46 (4s, 2 Me2C); 1.53 (dd, J=13.0, 8.6, irrad. at 1.81!NOE of 4.7%, HendoꢀC(8)); 1.81 (ddt, Jꢁ11.6, 9.0,
4.5, HꢀC(7)); 3.34 (dd, J=12.0, 5.3, irrad. at 1.81 !NOE of 3.8%, HꢀC(6)); 3.59 (t, J=11.8, H’ꢀC(6)); 3.74,
3.94 (2d, J=9.9, 2 HꢀC(2)); 4.05 (s, CH2ꢀC(9)); 4.14 (d, J=5.6, irrad. at 1.81 !NOE of 8.2%, HꢀC(14));
4.31 (d, J=5.6, HꢀC(10)); 6.60 (s, PhCH2); 7.27–7.34 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3; assignments
based on a HSQC.GRASP spectrum): 23.77, 24.99, 25.82, 30.43 (4q, 2 Me2C); 30.43 (t, C(8)); 41.83 (d, C(7));
58.51 (t, CH2ꢀC(9)); 59.59 (t, C(6)); 62.66 (t, C(2)); 68.03 (t, PhCH2); 83.43 (d, C(10)); 83.78 (d, C(14));
85.48, 87.10 (2s, C(1), C(9)); 101.76 (s, C(4)); 112.79 (s, C(12)); 127.52 (d); 127.61 (2d); 128.29 (2d); 138.41
(s). MALDI-MS: 413 ([M+Na]+). Anal. calc. for C22H30O6 (390.48): C 67.67, H 7.74; found: C 67.74, H 7.85.
(Æ)-(1RS,7RS,9SR,10SR,14RS)-9-(Hydroxymethyl)-4,4,12,12-tetramethyl-3,5,11,13,15-pentaoxatetracyclo-
[7.5.1.01,7.010,14]tetradecane (18). Hydrogenation of 17 (270 mg, 0.68 mmol) in AcOEt (3 ml) in the presence of
10% Pd/C (15 mg) at 6 bar for 48 h, filtration through Celite, evaporation, and FC (cyclohexane/AcOEt 1:3)
gave 18 (184 mg, 90%). White solid. Rf (AcOEt) 0.63. M.p. 1438. IR (CHCl3): 3507w (br.), 2999m, 2839m,
1
1728w, 1603w, 1456w, 1384s, 1374s, 1163m, 1108s, 1078s, 1034s, 910m, 870s. H-NMR (400 MHz, CDCl3): 1.23
(dd, J=12.9, 4.4, HexoꢀC(8)); 1.27, 1.35, 1.36, 1.47 (4s, 2 Me2C); 1.42 (dd, J=12.9, 8.5, HendoꢀC(8)); 1.85 (ddt,
J=11.8, 8.5, 4.8, HꢀC(7)); 2.13 (dd, J= 8.7, 3.8, OH); 3.36 (dd, J=12.0, 5.3, HꢀC(6)); 3.60 (t, J=11.8, H’ꢀ
C(6)); 3.88 (dd, J=12.1, 8.6, CHꢀC(9)); 4.06 (s, 2 HꢀC(2)); 4.08 (dd, J=12.1, 3.5, CH’ꢀC(9)); 4.18 (d,
J=5.6, HꢀC(14)); 4.31 (d, J=5.6, HꢀC(10)). 13C-NMR (100 MHz, CDCl3; assignments based on
a
HSQC.GRASP spectrum): 23.78, 24.97, 25.56, 26.09 (4s, 2 Me2C); 29.37 (t, C(8)); 42.04 (d, C(7)); 59.57 (t,
C(2)); 61.27 (t, CH2ꢀC(9)); 62.43 (t, C(6)); 83.81 (d, C(10)); 84.20 (d, C(14)); 86.18, 87.22 (2s, C(1), C(9));
101.86 (s, C(4)); 113.02 (s, C(12)). MALDI-MS: 323 ([M+Na]+). Anal. calc. for C15H24O6 (300.35): C 59.98,
H 8.05; found: C 59.71, H 7.91.
(Æ)-(1RS,7RS,9SR,10SR,14RS)-4,4,12,12-Tetramethyl-9-(phthalimidomethyl)-3,5,11,13,15-pentaoxatetracy-
clo[7.5.1.01,7.010,14]tetradecane (19). A soln. of 18 (160 mg, 0.53 mmol), Ph3P (275 mg, 1.0 mmol), phthalimide
(155 mg, 1.05 mmol), and DIAD (150 mg, 0.8 mmol) in THF (10 ml) was heated to 658 for 4 h, and cooled to
r.t. Normal workup (AcOEt/brine) and FC (cyclohexane/AcOEt 4 :1 !3 :1) gave 19 (211 mg, 93%). Pale yel-
low solid. Rf (cyclohexane/AcOEt 1 :1) 0.57. M.p. 1468. IR (CHCl3): 3030w, 2995w, 2940w, 1777w, 1719s, 1602w,
1469w, 1433w, 1394w. 1H-NMR (500 MHz, CDCl3): 1.13 (dd, J=12.9, 4.4, HexoꢀC(8)); 1.29, 1.33, 1.34, 1.48 (4s, 2
Me2C); 1.41 (dd, J=12.9, 8.5, HendoꢀC(8)); 1.77 (ddt, J=11.6, 8.5, 4.7, HꢀC(7)); 3.29 (dd, J=12.0, 5.3, Hꢀ
C(6)); 3.58 (t, J=11.4, H’ꢀC(6)); 4.02, 4.07 (2d, J=14.0, CH2ꢀC(9)); 4.13 (d, J=5.6, HꢀC(14)); 4.22 (s, 2
HꢀC(2)); 4.30 (d, J=5.6, HꢀC(10)); 7.72–7.74, 7.85–7.87 (2m, 4 arom. H). 13C-NMR (125 MHz, CDCl3;
assignments based on a HSQC.GRASP spectrum): 23.74, 25.02, 26.06, 26.24 (4q, 2 Me2C); 31.20 (t, C(8));
37.06 (t, C(2)); 41.72 (d, C(7)); 59.66 (t, CH2ꢀC(9)); 62.57 (t, C(6)); 83.78 (d, C(10)); 84.32 (d, C(14)); 85.17,
87.03 (2s, C(1), C(9)); 101.81 (s, C(4)); 113.02 (s, C(12)); 123.37, 134.04 (2d, 4 arom. C); 132.04 (s, 2 arom. C);
168.21 (s, 2 C=O); MALDI-MS: 452 ([M+Na]+). Anal. calc. for C23H27NO7 (429.47): C 64.32, H 6.34, N
3.26; found: C 64.21, H 6.42, N 3.43.
(Æ)-(1RS,7RS,9SR,10SR,14RS)-9-(Aminomethyl)-4,4,12,12-tetramethyl-3,5,11,13,15-pentaoxatetracyclo-
[7.5.1.01,7.010,14]tetradecane (20). A soln. of 19 (150 mg, 0.377 mmol) and NH2NH2 ·H2O (72 mg, 1.4 mmol) in
EtOH (15 ml) was stirred for 3 h at 808, kept at 238 for 6 h, filtered, and the filtrate evaporated. FC (CH2Cl2/
MeOH/25% aq. NH3 100 :5 :1) gave 20 (92 mg, 81%). Colourless oil. Rf (CH2Cl2/MeOH/25% aq. NH3
10 :0.5 :0.1) 0.19. IR (CHCl3): 3388w, 2944s, 2937s, 1661w, 1602w, 1456m, 1384s, 1373s, 1109s, 1076s, 1035m.
1H-NMR (400 MHz, CDCl3): 1.07 (dd, J=12.8, 4.3, HexoꢀC(8)); 1.28, 1.35, 1.36, 1.47 (4s, 2 Me2C); 1.45 (dd,
J=12.8, 8.9, HendoꢀC(8)); 1.84 (ddt, J=11.6, 9.5, 4.5, HꢀC(7)); 3.07, 3.17 (2d, J=13.4, CH2ꢀC(9)); 3.35 (dd,
J=12.0, 5.3, HꢀC(6)); 3.56 (t, J=11.8, H’ꢀC(6)); 4.06 (s, 2 HꢀC(2)); 4.15, 4.28 (2d, J=5.7, HꢀC(10), Hꢀ

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Helvetica Chimica Acta – Vol. 88 (2005)
C(14)). 13C-NMR (100 MHz, CDCl3): 23.78, 25.0, 25.69, 26.14 (4q, 2 Me2C); 30.41 (t, C(8)); 41.92 (t, CH2ꢀC(9));
42.19 (d, C(7)); 59.66 (t, C(2)); 62.57 (t, C(6)); 83.82, 86.74 (2d, C(10), C(14)); 86.73, 86.76 (2s, C(1), C(9));
101.82 (s, C(4)); 112.78 (s, C(12)). MALDI-MS: 322 ([M+Na]+). Anal. calc. for C11H10O6 (299.37): C 60.18,
H 8.42, N 4.68; found: C 60.34, H 8.50, N 4.75.
(Æ)-(1RS,2RS,3SR,4SR,6RS)-1-(Aminomethyl)-4,5-bis(hydroxymethyl)-7-oxabicyclo[2.2.1]heptane-2,3-
diol (3). A soln. of 20 (110 mg, 0.36 mmol) in CH2Cl2 (5 ml) was treated with 2.5N aq. HCl (15 ml) and stirred for
15 min. The org. layer was separated, and the aq. layer was washed with CH2Cl2 (2×5 ml). Evaporation of the
aq. layer and FC (Amberlite CG-120, H2O/NH3 1:0 !95 :5) gave 3 (87 mg, 95%). Colourless solid. pK: 8.46. IR
(KBr): 3600–2400s (br.), 1622w, 1504w, 1408w, 1094m, 1035m. 1H-NMR (300 MHz, D2O): 1.24 (dd, J=13.1, 5.0,
HexoꢀC(6)); 1.86 (dd, J=13.1, 8.7, HendoꢀC(6)); 2.06–2.15 (m, HꢀC(5)); 3.39, 3.57 (2d, J=14.0, CH2ꢀC(1));
3.44 (dd, J=10.9, 6.5, CHꢀC(5)); 3.73 (dd, J=10.9, 7.2, CH’ꢀC(5)); 3.89, 4.02 (2d, J=11.8, CH2ꢀC(4)); 4.07,
4.14 (2d, J=6.2, HꢀC(2), HꢀC(3)). 13C-NMR (75 MHz, D2O): 36.30 (t, C(6)); 45.77 (t, CH2ꢀC(1)); 47.78 (d,
C(5)); 63.08, 68.06 (2t, CH2ꢀC(4), CH2ꢀC(5)); 80.34, 83.97 (2d, C(2), C(3)); 89.47, 94.29 (2s, C(1), C(4)).
ESI-MS: 220 ([M+H]+). Anal. calc. for C11H10O6 (219.24): C 49.31, H 7.82, N 6.39; found: C 49.32, H 7.76,
N 6.25.
(Æ)-(1RS,2SR,6RS,7SR)-(3,5-Dioxo-4,10-dioxatricyclo[5.2.1.02,6]dec-8-en-1-yl)methyl Acetate (21) [30]. A
soln. of furfuryl acetate (40 g, 0.28 mol) and maleic anhydride (28 g, 0.28 mol) in Et2O (240 ml) was kept at
258 for 7 d. Evaporation of the solvent and crystallisation from AcOEt gave 21 (23 g, 34%). White solid. Rf (cy-
clohexane/AcOEt 1 :1) 0.26. M.p. 1108 (dec.). IR (CHCl3): 3038w, 1864m, 1789s, 1748s, 1435w, 1396w, 1369w,
1308w, 1154w, 1085m, 1073m, 1046m, 990m, 929s. 1H-NMR (300 MHz, CDCl3): 2.12 (s, AcO); 3.23, 3.34 (2d,
J=6.9, HꢀC(2), HꢀC(6)); 4.54, 4.91 (2d, J=12.8, CH2ꢀC(1)); 5.45 (d, J=1.9, HꢀC(7)); 6.47 (d, J=5.9, Hꢀ
C(9)); 6.63 (dd, J=1.9, 5.6, HꢀC(8)). 13C-NMR (75 MHz, CDCl3): 20.71 (q, Me); 49.67, 51.37 (2d, C(2),
C(6)); 60.69 (t, CH2ꢀC(1)); 82.17 (d, C(7)); 90.64 (s, C(1)); 137.27, 137.87 (2d, C(8), C(9)); 167.66, 169.10,
170.11 (3s, 3 C=O). MALDI-MS: 261 ([M+Na]+). Anal. calc. for C11H10O6 (238.2): C 55.47, H 4.23, O 40.30;
found: C 55.49, H 4.41, O 40.13.
(Æ)-(1RS,2SR,6RS,7SR)-1-(Acetoxymethyl)-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-carbox-
ylic Acid (22). A suspension of 21 (10 g, 42 mmol) in MeOH (170 ml) at 08 was treated with MeONa (2.4 g, 46
mmol), stirred for 30 min, warmed to 258, stirred for 3 h, and evaporated. The residue was treated with sat. aq.
NH4Cl soln. (40 ml) and CH2Cl2 (40 ml), and acidified with 2N aq. HCl to pH 2–3. The org. layer was separated,
and the aq. layer was extracted with CH2Cl2 (7×15 ml). The combined org. layers were dried (MgSO4) and
evaporated. Crystallisation from AcOEt (1×80 ml, 1×50 ml) gave 22 (4.73 g, 41%). White solid. Rf (CH2Cl2/
MeOH/AcOH 10 :0.2 :0.2) 0.30. M.p. 1158 (dec.). IR (CHCl3): 3500–2500m (br.), 1744s, 1436m, 1368m,
1336m, 1044m, 996m, 929m. 1H-NMR (400 MHz, CDCl3): 2.09 (s, AcO); 2.93, 3.04 (2d, J=9.0, HꢀC(2), Hꢀ
C(3)); 3.70 (s, MeO); 4.50, 4.75 (2d, J=12.2, CH2ꢀC(1)); 5.46 (d, J=1.8, HꢀC(4)); 6.38 (d, J=5.7, HꢀC(6));
6.55 (dd, J=5.7, 1.8, HꢀC(5)); 8.02 (br. s, COOH). 13C-NMR (100 MHz, CDCl3): 20.62 (q, Me); 48.34, 49.92
(2d, C(2), C(3)); 52.41 (q, MeO); 61.62 (t, CH2ꢀC(1)); 79.94 (d, C(4)); 89.43 (s, C(1)); 136.91, 137.79 (2d,
C(6), C(7)); 170.69, 171.24, 175.86 (3s, 3 C=O). MALDI-MS: 293 ([M+Na]+). Anal. calc. for C12H14O7
(270.24): C 53.34, H 5.22, O 41.44; found: C 53.27, H 5.36, O 41.32.
(Æ)-(1RS,2SR,3RS,4RS,5RS,6RS)-1-(Acetoxymethyl)-5,6-dihydroxy-3-(methoxycarbonyl)-7-oxabicyclo-
[2.2.1]heptane-2-carboxylic Acid (23). A soln. of 22 (2 g, 7.4 mmol), NMO (1.5 g, 11 mmol), N-methylmorpho-
line (0.75 g, 7.4 mmol), and H2O (4 ml) in acetone (20 ml) was treated at 258 with 2.5% OsO4 in t-BuOH (0.75
ml), stirred for 2 h, treated with 5% aq. NaHSO3 soln. (20 ml), and acidified to pH 2–3 with 2N HCl. The mixture
was continuously extracted for 6.5 h with AcOEt (500 ml) using a 200 ml KutscherꢀSteudel apparatus. Upon
standing at 258, a precipitate was formed, which was filtered off and dried i.v. to give crude 23 (1.63 g, 72%).
For analysis, a small sample was recrystallized in acetone. White solid. M.p. 1788. IR (KBr): 3500–2500s
(br.), 1727s, 1698s, 1463m, 1441m, 1398m, 1356m, 1307s, 1275s, 1249s, 1197s, 1175m, 1093m, 1052m, 1027m.
1H-NMR (300 MHz, (D6)DMSO): 1.98 (s, AcO); 2.97, 3.09 (2d, J=9.7, HꢀC(2), HꢀC(3)); 3.49 (s, MeO);
3.77 (dd, J=12.8, 6.5), 3.84 (dd, J=11.2, 5.9) (HꢀC(5), HꢀC(6)); 4.18, 4.31 (2d, J=10.6, CH2ꢀC(1)); 4.47 (s,
HꢀC(4)); 4.72 (d, J=7.2), 5.18 (d, J=5.6) (2 OH); 12.00–12.20 (br. s, COOH). 13C-NMR (75 MHz,
(D6)DMSO): 20.38 (q, Me); 46.92, 49.19 (2d, C(2), C(3)); 51.36 (s, MeO); 59.72 (t, CH2ꢀC(1)); 71.74, 73.00
(2d, C(5), C(6)); 82.19 (d, C(4)); 87.06 (s, C(1)); 169.48, 170.39, 171.42 (3s, 3 C=O). MALDI-MS: 327
([M+Na]+). Anal. calc. for C12H16O9 (304.25): C 47.37, H 5.30; found: C 47.26, H 5.42.
(Æ)-(1RS,2SR,3RS,4RS,5RS,6RS)-1-(Acetoxymethyl)-8-(methoxycarbonyl)-4,4-dimethyl-3,5,10-trioxatricy-
clo[5.2.1.02,6]decane-9-carboxylic Acid (24). A suspension of 23 (1.3 g, 4.27 mmol), 2,2-dimethoxypropane (11.9
g, 114 mmol) and Amberlyst 15 in acetone (200 ml) was vigorously stirred for 3 h at 238 and filtered through a
short pad of Celite. Evaporation and FC (CH2Cl2/MeOH/AcOH 100 :7:2) gave 24 (1.1 g, 75%). White solid. Rf

Helvetica Chimica Acta – Vol. 88 (2005)
3165
(CH2Cl2/MeOH/AcOH 100 :5 :2) 0.44. M.p. 1628 (subl.). IR (KBr): 3700–2500m (br.), 1744s, 1693s, 1473w,
1437m, 1371m, 1309w, 1067m, 1048m. 1H-NMR (300 MHz, (D6)DMSO): 1.21, 1.33 (2s, Me2C(4)); 1.99 (s,
AcO); 2.93, 3.00 (2d, J=10.0, HꢀC(8), HꢀC(9)); 4.20 (d, J=10.9), 4.27 (d, J=10.5) (CH2ꢀC(1)); 4.30 (d,
J=5.9), 4.37 (d, J=5.3) (HꢀC(2), HꢀC(6)); 4.57 (s, HꢀC(7)); 11.10–11.50 (br. s, COOH). 13C-NMR (75
MHz, (D6)DMSO): 20.36 (q, Me); 25.25, 25.76 (2q, Me2C); 46.24, 48.33 (2d, C(8), C(9)); 51.41 (q, MeO);
59.48 (t, CH2ꢀC(1)); 79.42, 81.20, 81.32 (3d, C(2), C(6), C(7)); 86.01 (s, C(1)); 111.13 (s, C(4)); 169.41, 170.27,
171.37 (3s, 3 C=O). MALDI-MS: 367 ([M+Na]+). Anal. calc. for C15H20O9 (344.32): C 52.33, H 5.85, O
41.82; found: C 52.26, H 6.03, O 41.96.
Methyl (Æ)-(1RS,2RS,6RS,7RS,8RS)-1-(Acetoxymethyl)-4,4-dimethyl-3,5,10-trioxatricyclo[5.2.1.02,6]dec-
ane-8-carboxylate (25). A suspension of 24 (1.5 g, 4.4 mmol) in CH2Cl2 (100 ml) was treated at 238 with DMF
(50 ml, 0.65 mmol) and (COCl)2 (0.83 g, 6.5 mmol), and stirred until the evolution of gas ceased (1.5 h). The res-
idue remaining after evaporation of the volatiles was dissolved in THF (100 ml). The soln. was sheltered from
light, treated with 1-hydroxypyridine-2-thione sodium salt (0.98 g, 6.5 mmol) and DMAP (50 mg), stirred for
1.5 h at 238, and evaporated at 358. A soln. of the residue in benzene (150 ml) was treated with Bu3SnH
(3.8 g, 13 mmol) and AIBN (50 mg), heated to reflux, vigorously stirred for 45 min, treated with additional
Bu3SnH (1 g, 3.7 mmol) and AIBN (50 mg), again stirred for 3 h, cooled to 238, and treated with sat. aq. NH4Cl
soln. (70 ml). The org. layer was separated, treated with sat. aq. NH4Cl soln. (70 ml), vigorously stirred for 1 h,
and filtered through a short pad of Celite. The org. layer was separated, dried (MgSO4), and evaporated. FC
(hexane/AcOEt 3 :1!2 :1) gave crude 25 (1 g), which was used for the next step without further purification.
Rf (cyclohexane/AcOEt 1:1) 0.55.
Methyl (Æ)-(1RS,2RS,6RS,7RS,8RS)-1-(Hydroxymethyl)-4,4-dimethyl-3,5,10-trioxatricyclo[5.2.1.02,6]dec-
ane-8-carboxylate (26). A soln. of crude 25 (1 g) in MeOH (30 ml) was treated with MeONa (40 mg, 0.74
mmol) and stirred for 2 h at 238. Normal workup (CH2Cl2/NH4Cl) and FC (cyclohexane/AcOEt 1:1) gave 26
(703 mg, 62% from 24). White solid. Rf (cyclohexane/AcOEt 1:1) 0.24. M.p. 928. IR (CHCl3): 3520w, 2994m,
1
2954m, 1737s, 1438m, 1384m, 1374m, 1085m, 1043m, 990w, 838w. H-NMR (400 MHz, CDCl3): 1.29, 1.47 (2s,
Me2C(4)); 1.56 (dd, J=13.1, 9.2, HendoꢀC(9)); 2.16 (dd, J=13.0, 4.7, HexoꢀC(9)); 2.25 (br. s, OH); 2.54 (dd,
J=9.2, 4.7, HꢀC(8)); 3.72 (s, MeO); 3.97, 4.11 (2d, J=12.0, CH2ꢀC(1)); 4.28, 4.37 (2d, J=5.6, HꢀC(2), Hꢀ
C(6)); 4.67 (s, HꢀC(7)). 13C-NMR (100 MHz, CDCl3): 25.22, 25.88 (2q, Me2C(4)); 30.09 (t, C(9)); 43.13 (d,
C(8)); 52.39 (s, MeO); 61.17 (t, CH2ꢀC(1)); 81.56, 82.63, 82.95 (3d, C(2), C(6), C(7)); 86.74 (s, C(1)); 112.58
(s, C(4)); 172.80 (s, C=O). MALDI-MS: 281 ([M+Na]+). Anal. calc. for C12H18O6 (258.27): C 55.81, H 7.02,
O 37.17; found: C 55.83, H 7.06, O 36.92.
X-Ray Crystal-Structure Analysis of 26 (CCDC-203882). Crystals were obtained from Et2O by slow evap-
oration at r.t. C12H18O6 (258.27); triclinic P1; a=10.06310(10) Å, b=10.3839(10) Å, c=14.3276(2) Å;
V=1291.43(3) Å3; Dcalc. =1.328 Mg/m3; Z=4; Intensities were measured on a Bruker Nonius KappaCCD dif-
fractometer (graphite monochromator, MoKa, l=0.71073 Å at 202 K). Of the 13736 reflections, 7217 unique
reflections were observed. R=0.068, Rw =0.299. The structure was solved by the direct method with
SHELXL-97 [53].
Methyl (Æ)-(1RS,2RS,6RS,7RS,8RS)-1-(Phthalimidomethyl)-4,4-dimethyl-3,5,10-trioxatricyclo[5.2.1.02,6]-
decane-8-carboxylate (27). A soln. of 26 (250 mg, 0.96 mmol), PPh3 (510 mg, 1.9 mmol), and phthalimide (280
mg, 1.9 mmol) in THF (15 ml) was treated with DIAD (290 mg, 1.4 mmol), heated to reflux for 3 h, and cooled
to 238. Normal workup (CH2Cl2/NH4Cl) and FC (cyclohexane/AcOEt 2 :1!1:1) gave 27 (349 mg, 94%). Pale
yellow foam. Rf (cyclohexane/AcOEt 1:1) 0.48. M.p. 1358. IR (CHCl3): 3008w, 2954w, 1776m, 1718s, 1602w,
1
1468w, 1436m, 1429m, 1398s, 1374m, 1040m, 984w. H-NMR (300 MHz, CDCl3): 1.24, 1.38 (2s, Me2C(4)); 1.53
(dd, J=13.1, 9.0, HendoꢀC(9)); 2.05 (dd, J=13.4, 4.7, HexoꢀC(9)); 2.45 (dd, J=9.0, 4.7, HꢀC(8)); 3.58 (s,
MeO); 4.12 (d, J=14.9), 4.40 (d, J=14.6) (CH2ꢀC(1)); 4.26 (d, J=5.6), 4.39 (d, J=5.7) (HꢀC(2), HꢀC(6));
4.61 (s, HꢀC(7)); 7.69–7.72, 7.83–7.86 (2m, 4 arom. H). 13C-NMR (75 MHz, CDCl3): 25.67, 26.02 (2q, Me2C);
30.71 (t, C(9)); 36.55 (t, CH2ꢀC(1)); 42.89 (d, C(8)); 52.32 (q, MeO); 81.63, 82.79, 83.11 (3d, C(2), C(6), C(7));
86.09 (s, C(1)); 112.63 (s, C(4)); 123.21, 133.78 (2d, 4 arom. C); 131.94 (s, 2 arom. C); 168.07 (s, 2 NꢀC=O);
172.21 (s, OꢀC=O). MALDI-MS: 410 ([M+Na]+). Anal. calc. for C20H21NO7 (387.39): C 62.01, H 5.46, N
3.62; found: C 62.08, H 5.57, N 3.80.
Methyl (Æ)-(1RS,2RS,6RS,7RS,8RS)-1-(Aminomethyl)-4,4-dimethyl-3,5,10-trioxatricyclo[5.2.1.02,6]decane-
8-carboxylate (28). A suspension of 27 (212 mg, 0.55 mmol) and NH2NH2 ·H2O (33 mg, 0.65 mmol) in EtOH
(20 ml) was stirred for 12 h at 238, treated with NH2NH2 ·H2O (20 mg, 0.39 mmol), stirred for 3.5 h, cooled to
08, and filtered. Evaporation and FC (CH2Cl2/MeOH/25% aq. NH3 100 :3 :1!100 :5 :1) of the residue gave
28 (108 mg, 76%). Colourless oil. Rf (CH2Cl2/MeOH/25% NH3 100 :5 :1) 0.25. IR (CHCl3): 3389w, 2992m,
1
2954m, 1736s, 1621w, 1601w, 1455w, 1437m, 1383m, 1374m, 1268m, 1086m, 1042m, 980w, 869w. H-NMR (300

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Helvetica Chimica Acta – Vol. 88 (2005)
MHz, CDCl3): 1.28, 1.46 (2s, Me2C(4)); 1.55 (dd, J=13.1, 9.0, HendoꢀC(9)); 1.65–1.75 (br. s, NH2); 2.08 (dd,
J=2.8, 4.7, HexoꢀC(9)); 2.53 (dd, J=9.0, 4.7, HꢀC(8)); 3.12, 3.40 (2d, J=13.4, CH2ꢀC(1)); 3.71 (s, MeO);
4.27, 4.34 (2d, J=5.6, HꢀC(2), HꢀC(6)); 4.62 (s, HꢀC(7)). 13C-NMR (75 MHz, CDCl3): 25.42, 26.06 (2q, Me2-
C(4)); 30.64 (t, C(9)); 41.31 (t, CH2ꢀC(1)); 43.39 (d, C(8)); 52.47 (q, MeO); 81.32, 82.37, 82.84 (3d, C(2), C(6),
C(7)); 87.52 (s, C(1)); 112.24 (s, C(4)); 172.84 (s, C=O). ESI-MS: 258 ([M+H]+).
Methyl (Æ)-(1RS,2RS,6RS,7RS,8RS)-1-({[(tert-Butoxy)carbonyl]amino}methyl)-4,4-dimethyl-3,5,10-trioxa-
tricyclo[5.2.1.02,6]decane-8-carboxylate (29). A soln. of 28 (62 mg, 0.25 mmol) in CH2Cl2 (5 ml) was treated
with Boc2O (100 mg, 0.45 mmol), stirred for 48 h at 238, and evaporated. FC (cyclohexane/AcOEt 2 :1 !1:1)
gave 29 (78 mg, 91%). White solid. Rf (cyclohexane/AcOEt 1:1) 0.51. M.p. 998. IR (CHCl3): 3453m, 3007m,
2936m, 1710s, 1602m, 1509s, 1455m, 1437m, 1366s, 1106m, 1089m, 1045m, 981w, 932w. 1H-NMR (300 MHz,
CDCl3): 1.25 (s, MeꢀC(4)); 1.42 (s, MeꢀC(4), t-Bu); 1.50 (dd, J=13.1, 9.3, HendoꢀC(9)); 2.09 (dd, J=13.1,
4.7, HexoꢀC(9)); 2.49 (dd, J=9.3, 4.7, HꢀC(8)); 3.55 (dd, J=14.3, 4.7, CHꢀC(1)); 3.69 (s, MeO); 3.70 (dd,
J=14.3, 7.8, CH’ꢀC(1)); 4.17 (d, J=5.6), 4.32 (d, J=5.3) (HꢀC(2), HꢀC(6)); 4.58 (s, HꢀC(7)); 4.89–4.97
(m, NH). 13C-NMR (75 MHz, CDCl3): 25.37, 25.96 (2q, Me2C(4)); 28.41 (q, Me3C); 30.37 (t, C(9)); 39.40 (t,
CH2ꢀC(1)); 43.23 (d, C(8)); 52.35 (q, MeO); 79.28 (s, Me3C); 81.34, 82.51, 82.82 (3d, C(2), C(6), C(7)); 86.30
(s, C(1)); 112.31 (s, C(4)); 156.10 (s, NꢀC=O); 172.55 (s, OꢀC=O). MALDI-MS: 380 ([M+Na]+). Anal.
calc. for C17H27NO7 (357.40): C 57.13, H 7.61, N 3.92; found: C 57.12, H 7.46, N 3.87.
tert-Butyl (Æ)-(1RS,2RS,6RS,7RS,8SR)-{[8-(Hydroxymethyl)-4,4-dimethyl-3,5,10-trioxatricyclo[5.2.1.02,6]-
dec-1-yl]methyl}carbamate (30). A soln. of 29 (33 mg, 0.09 mmol) in THF (6 ml) was treated with a suspension
of 0.5M LiBH4 in THF (1.2 ml), stirred for 5.5 h at 238, treated with 2% aq. NaH2PO4 soln., stirred for 1 h and
extracted with CH2Cl2 (5×5 ml). The combined org. layers were dried (MgSO4) and evaporated. FC (cyclohex-
ane/AcOEt 1 :3) gave 30 (25 mg, 82%). Colourless syrup. Rf (cyclohexane/AcOEt 1:3) 0.30. IR (CHCl3): 3455m,
3019s, 2938s, 1710s, 1510s, 1455w, 1383m, 1289m, 1243m, 1164s, 1090m, 1040w, 971w, 909w, 857w. 1H-NMR (300
MHz, CDCl3): 1.18 (dd, J=13.1, 4.4, HexoꢀC(9)); 1.28, 1.46 (2s, Me2C(4)); 1.39 (dd, J=13.1, 8.1, HendoꢀC(9));
1.43 (s, t-Bu); 1.80–1.90 (m, HꢀC(8), OH); 3.47 (dd, J=10.6, 8.1, CHꢀC(1)); 3.51 (dd, J=10.6, 6.3, CH’ꢀ
C(1)); 3.56 (dd, J=14.3, 5.8, CHꢀC(8)); 3.64 (dd, J=14.3, 7.5, CH’ꢀC(8)); 4.17, 4.31 (2d, J=5.6, HꢀC(2),
HꢀC(6)); 4.30 (s, HꢀC(7)); 5.0 (br. s, NH). 13C-NMR (75 MHz, CDCl3): 25.17, 25.91 (2q, Me2C(4)); 28.42 (q,
Me3C); 30.16 (t, C(9)); 39.75 (t, CH2ꢀC(1)); 40.38 (d, C(8)); 64.20 (t, CH2ꢀC(8)); 79. 29 (s, Me3C); 80.38,
82.72, 83.10 (3d, C(2), C(6), C(7)); 86.00 (s, C(1)); 111.81 (s, C(4)); 156.18 (s, C=O). MALDI-MS: 352
([M+Na]+). Anal. calc. for C16H27NO6 (329.39): C 58.34, H 8.26, N 4.25; found: C 58.50, H 8.33, N 4.07.
(Æ)-(1RS,2RS,6RS,7RS,8SR)-1-(Aminomethyl)-5-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptane-2,3-diol
(4). A soln. of 30 (68 mg, 0.21 mmol) in CH2Cl2 (3 ml) was treated with 2N aq. HCl (15 ml) and stirred for 5 h at
238. The aq. layer was separated and evaporated. FC (Amberlite CG-120, H2O/NH3 1:0 !95 :5) gave 4 (35 mg,
74%). Colourless oil. For analysis, 4 was transformed into its hydrochloride.
Data of 4·HCl: pKHA 8.66. IR (KBr): 3600–2400s (br.), 1623m, 1501m, 1407m, 1294w. 1H-NMR (300 MHz,
D2O): 1.08 (dd, J=12.8, 4.4, HexoꢀC(6)); 1.71 (dd, J=8.6, 12.9, HendoꢀC(6)); 2.01–2.10 (m, HꢀC(5)); 3.38, 3.81
(2d, J=14.0, CH2ꢀC(1)); 3.38–3.42 (m, CH2ꢀC(5)); 4.03, 4.06 (2d, J=6.2, HꢀC(2), HꢀC(3)); 4.24 (s, Hꢀ
C(4)). 13C-NMR (75 MHz, D2O): 32.42 (t, C(6)); 40.20 (t, CH2ꢀC(1)); 41.06 (d, C(5)); 63.80 (t, CH2ꢀC(5));
74.40, 78.46 (2d, C(2), C(3)); 84.01 (d, C(4)); 84.83 (s, C(1)). ESI-MS: 190 ([M+H]+). Anal. calc. for C8H16-
ClNO4 (225.67): C 42.58, H 7.15, N 6.21; found: C 42.90, H 7.63, N 6.00.
3a,4,7,7a-Tetrahydro-4,7-methano-1H-indene-2,5-dicarboxylic Acid (31). A soln. of cyclopenta-1,3-diene
(16.5 g, 250 mmol) in Et2O (700 ml) was treated with 1.6M BuLi in hexane (190 ml, 300 mmol), heated to reflux
for 2 h, cooled to 238, stirred for 14 h, cooled to 08, treated with gaseous CO2 for 0.5 h, warmed to 238, treated
again with gaseous CO2 for 1 h, and then with H2O (500 ml). The org. layer was separated, and the aq. layer was
acidified with 50% aq. H2SO4 soln. (30 ml) to pH 1 and stirred for 3 h. The precipitate was filtered off, triturated
twice with boiling H2O (1×250 ml, 1×200 ml), cooled to r.t., filtered, washed with H2O (30 ml), dried azeotropi-
cally with toluene (500 ml), and filtered. Removal of the residual solvent gave 31 (20.7 g, 75%) as a mixture of
isomers. For analysis, a sample was dissolved in aq. NH3 and precipitated with H2SO4. Light grey solid. M.p. 2108.
IR (KBr): 3600–2400m, 1690s, 1628m, 1602m, 1425m, 1350m, 1295m, 1243m. ESI-MS: 219 ([MꢀH]ꢀ). Anal.
calc. for C12H12O4 (220.23): C 65.45, H 5.49; found: C 65.67, H 5.70.
Di(tert-butyl) 3a,4,7,7a-Tetrahydro-4,7-methano-1H-indene-2,5-dicarboxylate (32). A stirred suspension of
31 (19.5 g, 89 mmol) in CH2Cl2 (200 ml) was treated with DMF (0.2 ml) and (COCl)2 (28.5 g, 225 mmol) until the
evolution of gas ceased. The volatiles were evaporated. A soln. of the residue in Et2O (200 ml) was added drop-
wise to a vigorously stirred suspension of t-BuOK (22 g, 195 mmol) in Et2O (300 ml) at such a rate that a gentle
reflux was maintained throughout the addition. After stirring for 90 min, the soln. was diluted with H2O (500
ml). The org. layer was separated, washed with H2O (400 ml), dried (MgSO4), and filtered through a short

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pad of silica gel. Evaporation and FC (cyclohexane/AcOEt 10 :1) gave 32 (26.1 g, 88%) as a mixture of isomers.
M.p. 49–518. IR (CHCl3): 2981w, 1698s, 1632w, 1601w, 1475w, 1456w, 1393w, 1369m, 1295m. EI-MS: 332.2 (M+).
Anal. calc. for C20H28O4 (332.44): C 72.26, H 8.49; found: C 72.29, H 8.55.
tert-Butyl (Æ)-(1RS,2RS,6RS,7RS)-3,5-Dioxo-4-oxatricyclo[5.2.1.02,6]dec-8-ene-1-carboxylate (33). The
dimeric ester 32 (26 g, 77 mmol) was cracked at 1808, the monoester distilled off i.v. (b.p.22 1098) using a Liebig
cooler, and the distillate was collected at ꢀ788. The distillate was dissolved in cooled (08) Et2O (170 ml), treated
with maleic anhydride (23 g, 234 mmol), and stirred until complete dissolution of maleic anhydride. The soln.
was kept at 238 overnight and filtered. Crystallisation from cyclohexane/AcOEt 1 :1 (250 ml) gave 33 (19.7 g,
48%). Colourless needles. Rf (cyclohexane/AcOEt 1:1) 0.75. M.p. 1558. IR (CHCl3): 3032w, 2984w, 1866m,
1783s, 1725s, 1477w, 1458w, 1394w, 1371w, 1324m, 1279m, 1232m, 1169m, 1137s, 1084s, 917s. 1H-NMR (300
MHz, CDCl3): 1.53 (s, t-Bu); 1.90 (dt, J=8.9, 0.6, HꢀC(10)); 1.99 (dd, J=8.7, 1.6, H’ꢀC(10)); 3.53–3.57 (m,
HꢀC(7)); 3.87 (dd, J=8.4, 4.7, HꢀC(6)); 3.98 (d, J=8.4, HꢀC(2)); 6.33 (dd, J=5.8, 3.0, HꢀC(8)); 5.90 (d,
J=5.9, HꢀC(9)). 13C-NMR (300 MHz, CDCl3): 28.10 (q, Me3C); 46.64, 48.49, 50.19 (3d, C(2), C(6), C(7));
56.93 (t, C(10)); 62.76 (s, C(1)); 82.60 (s, Me3C); 135.42, 135.35 (2d, C(8), C(9)); 169.04, 169.21, 170.35 (3s, 3
C=O). MALDI-MS: 287 ([M+Na]+). Anal. calc. for C14H16O5 (264.28): C 63.63, H 6.10; found: C 63.69, H 6.12.
(Æ)-(1RS,2SR,6RS,7RS,8RS,9RS)-1-[(tert-Butoxy)carbonyl]-8-(methoxycarbonyl)-4,4-dimethyl-3,5-dioxa-
tricyclo[5.2.1.02,6]decane-9-carboxylic Acid (34) and (Æ)-(1RS,2SR,6RS,7RS,8RS,9RS)-1-[(tert-Butoxy)car-
bonyl]-9-(methoxycarbonyl)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]decane-8-carboxylic Acid (35). A soln. of
33 (5 g, 18.9 mmol) in MeOH (100 ml) was cooled to 08, treated with MeONa (1.2 g, 22.2 mmol), stirred for 2
h, warmed to 238, stirred for 1 h, and evaporated. The residue was treated with sat. aq. NH4Cl soln. and CH2Cl2
(100 ml), and acidified to pH 3–4 with 2N HCl. The org. layer was separated, and the aq. layer was extracted with
CH2Cl2 (3×50 ml), dried (MgSO4) and evaporated. A soln. of the residue in acetone (50 ml) was treated with
NMO (3.8 g, 28.1 mmol), N-methylmorpholine (2.1 g, 20.9 mmol), H2O (10 ml), and 2.5% OsO4 in t-BuOH
(1 ml), stirred for 24 h at 238, poured into a soln. of 5% aq. NaHSO3 soln. (150 ml), and stirred for 10 min.
After removal of acetone i.v., the soln. was acidified to pH 2–3 with 2
N HCl and extracted with AcOEt
(1×150 ml, 3×50 ml). The combined org. layers were dried (MgSO4) and evaporated. The residue was dissolved
in AcOEt (150 ml) and washed with 0.04N HCl (3×100 ml). The org. layer was dried (MgSO4) and evaporated.
A soln. of the residue in acetone (100 ml) was treated with 2,2-dimethoxypropane (10 ml) and Amberlyst 15 (H+
form; 10 mg), stirred for 10 h at 238, and filtered. After evaporation of the filtrate, the solid was triturated with
boiling hexane/AcOEt 1:1 (70 ml), and the supernatant was decanted. Recrystallization of the solid in AcOEt
gave 34 (2.2 g, 32%). Evaporation of the mother liquor provided; 35/34 4 :1 (2.7 g, 39%).
Data of 34. White solid. Rf (cyclohexane/AcOEt/AcOH 10 :5 :0.05) 0.27. M.p. 1848 (dec.). IR (CHCl3):
3600–2400m (br.), 1731s, 1664w, 1457w, 1437w, 1384m, 1370m, 1330m, 1265m, 1161s, 1065m, 1046m. 1H-
NMR (300 MHz, CDCl3): 1.28, 1.45 (2s, Me2C(4)); 1.41–1.50 (m, HꢀC(10)); 1.48 (s, t-Bu); 2.21 (dd, J=10.9,
1.6, H’ꢀC(10)); 2.58 (br. d, J=3.7, HꢀC(7)); 3.08 (dd, J=11.7, 3.9, HꢀC(8)); 3.38 (d, J=11.8, HꢀC(9)); 3.66
(s, MeO); 4.57 (d, J=5.3), 4.86 (d, J=5.0) (HꢀC(2), HꢀC(6)). 13C-NMR (75 MHz, CDCl3): 24.37, 25.42 (2q,
Me2C(4)); 28.05 (q, Me3C); 35.76 (t, C(10)); 42.68, 44.74, 47.04 (3d, C(7), C(8), C(9)); 51.77 (q, MeO); 59.18
(s, C(1)); 77.97, 78.66 (2d, C(2), C(6)); 82.57 (s, Me3C); 109.27 (s, C(4)); 170.62, 170.93, 174.09 (3s, 3 C=O).
MALDI-TOF: 393 ([M+Na]+). Anal. calc. for C18H26O8 (370.40): C 58.37, H 7.07; found: C 58.42, H 7.03.
Data of 35. 1H-NMR (300 MHz, CDCl3, 35/34 4 :1): data of 35: 1.28, 1.43 (2s, Me2C(4)); 1.41–1.50 (m, Hꢀ
C(10)); 1.45 (s, t-Bu); 2.16 (br. d, J=9.6, H’ꢀC(10)); 2.56 (br. d, J=3.6, HꢀC(7)); 3.14 (dd, J=12.4, 4.1, Hꢀ
C(8)); 3.35 (d, J=11.8, HꢀC(9)); 3.68 (s, MeO); 4.37 (d, J=5.2), 4.78 (d, J=5.2) (HꢀC(2), HꢀC(6)); 8.4–9.2
(br. s, OH). 13C-NMR (75 MHz, CDCl3, 35/34 4 :1): data of 35: 24.12, 25.22 (2q, Me2C(4)); 27.86 (q, Me3C);
35.48 (t, C(10)); 42.64, 44.71, 47.16 (3d, C(7), C(8), C(9)); 51.88 (q, MeO); 59.24 (s, C(1)); 77.61, 78.23 (2d,
C(2), C(6)); 81.32 (s, Me3C); 108.91 (s, C(4)); 170.47, 170.71, 175.89 (3s, 3 C=O).
tert-Butyl
(Æ)-(1RS,2SR,6RS,7RS,8SR)-8-(Methoxycarbonyl)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]-
decane-1-carboxylate (36). A suspension of 34 (1.5 g, 4.05 mmol) in CH2Cl2 (25 ml) was treated with (COCl)2
(770 mg, 6 mmol) and DMF (10 ml), stirred for 2 h at 238, and evaporated. A soln. of the residue in PhMe (50
ml) was added dropwise over a period of 1 h to a boiling suspension of 1-hydroxypyridine-2-thione sodium
salt (725 mg, 4.8 mmol), t-BuSH (2 g, 21 mmol), and DMAP (20 mg) in toluene (120 ml). The suspension was
stirred for 1 h, and cooled to 238. Normal workup (toluene/H2O) and FC (hexane/AcOEt 10 :1) gave 36 (1.09
g, 82%). White solid. Rf (cyclohexane/AcOEt 3 :1) 0.55. M.p. 1048. IR (CHCl3): 3011w, 1726s, 1601w, 1437w,
1369m, 1328w, 1281m, 1163m, 1104m, 1063m. 1H-NMR (500 MHz, CDCl3): 1.27, 1.43 (2s, Me2C(4)); 1.46 (s,
t-Bu); 1.48 (ddd, J=10.7, 3.1, 1.6, HꢀC(10)); 1.82 (ddd, J=13.3, 5.8, 2.3, HendoꢀC(9)); 1.89 (dd, J=13.3, 11.2,
HexoꢀC(9)); 2.03 (dt, J=10.6, 2.0, H’ꢀC(10)); 2.55–2.56 (br. d, J=4.6, HꢀC(7)); 2.89 (ddd, J=11.2, 5.8, 4.7,
HꢀC(8)); 3.70 (s, MeO); 4.09 (dd, J=5.5, 1.2, HꢀC(6)); 4.25 (dd, J=5.5, 1.6, HꢀC(2)). 13C-NMR (125 MHz,

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Helvetica Chimica Acta – Vol. 88 (2005)
CDCl3): 24.23, 25.42 (2q, Me2C(4)); 28.11 (q, Me3C); 30.67 (t, C(9)); 34.84 (t, C(10)); 41.66, 43.03 (2d, C(7),
C(8)); 51.98 (q, MeO); 56.59 (s, C(1)); 80.69, 82.55 (2d, C(2), C(6)); 80.69 (s, Me3C); 109.38 (s, C(4)); 171.64,
173.47 (2s, 2 C=O). ESI-MS: 327 ([M+H]+). Anal. calc. for C17H26O6 (326.39): C 62.56, H 8.03; found: C
62.61, H 7.93.
tert-Butyl
(Æ)-(1RS,2SR,6RS,7RS,8RS)-8-(Methoxycarbonyl)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]-
decane-1-carboxylate (37). A soln. of 36 (930 mg, 2.85 mmol) in 0.13M MeONa in MeOH (60 ml) was stirred
for 2 d at 238. The mixture was treated with AcOH (1 ml), and evaporated. Normal workup (CH2Cl2/H2O)
and FC (hexane/AcOEt 11:1!10 :1) gave 37 (619 mg) and 36 (251 mg). The recovered 36 was subjected to
0.1M MeONa in MeOH (20 ml) for 2 d. Addition of AcOH (0.3 ml), normal workup (CH2Cl2/H2O) and FC (hex-
ane/AcOEt 11 :1!10 :1) gave 37 (183 mg, 86% overall). White solid. Rf (cyclohexane/AcOEt 3 :1) 0.45. M.p.
998. IR (CHCl3): 3016w, 2974w, 2929w, 1727s, 1600w, 1437w, 1369m, 1158s, 1088m, 1047m, 909w, 865w. 1H-NMR
(400 MHz, CDCl3): 1.28, 1.43 (2s, Me2C(4)); 1.46 (s, t-Bu); 1.58 (ddd, J=10.8, 2.9, 1.4, HꢀC(10)); 1.61 (ddd,
Jꢁ13, 9.0, 2.3, HendoꢀC(9)); 1.89 (ddd, J=11.0, 3.8, 1.5, H’ꢀC(10)); 2.09 (dd, J=13.1, 5.2, HexoꢀC(9)); 2.25
(ddd, J=9.0, 5.2, 1.4, HꢀC(8)); 2.51 (br. s, HꢀC(7)); 3.70 (s, MeO); 4.12 (d, J=5.2, HꢀC(2)); 4.60 (dd,
J=5.5, 1.6, HꢀC(6)). 13C-NMR (100 MHz, CDCl3; assignments based on HSQC.GRASP spectrum): 24.23,
25.38 (2q, Me2C(4)); 28.08 (q, Me3C); 31.51 (t, C(10)); 32.12 (t, C(9)); 41.11 (d, C(8)); 43.84 (d, C(7)); 52.13
(q, MeO); 55.84 (s, C(1)); 80.69 (s, Me3C); 81.58 (d, C(2)); 82.90 (d, C(6)); 110.00 (s, C(4)); 171.56, 174.58 (2s,
2 C=O). ESI-MS: 327 ([M+H]+), 344 ([M+NH4]+). Anal. calc. for C17H26O6 (326.39): C 62.56, H 8.03;
found: C 62.51, H 7.98.
X-Ray Crystal-Structure Analysis of 37 (CCDC-203883). Crystals were obtained from Et2O by slow evap-
oration at r.t. C17H26O6 (326.389); triclinic P1; a=6.22230(10) Å, b=10.7846(2) Å, c=13.6025(3) Å;
V=886.23(3) Å3; Dcalc. =1.223 Mg/m3; Z=2; Intensities were measured on an Bruker Nonius KappaCCD dif-
fractometer (graphite monochromator, MoKa, l=0.71073 Å at 172 K. Of the 10413 reflections, 4663 unique
reflections were observed. R=0.0774; Rw =0.1736. The structure was refined by the direct method with
SHELXL-97 [53].
(Æ)-(1RS,2SR,6RS,7RS,8RS)-8-(Methoxycarbonyl)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]decane-1-car-
boxylic Acid (38). A soln. of 37 (500 mg, 1.5 mmol) and Et3N (190 mg, 1.8 mmol) in CH2Cl2 (20 ml) was treated
with Me3SiOTf (750 mg, 3.4 mmol), stirred for 14 h at 238, treated with NaHCO3 (415 mg, 4.6 mmol) and H2O
(15 ml), stirred for 30 min, acidified to pH 3 with 0.2N aq. HCl, and extracted with CH2Cl2 (3×10 ml). The com-
bined org. layers were dried (MgSO4) and evaporated. FC (cyclohexane/AcOEt/AcOH 100 :50 :0.5 !
100 :75 :0.5) gave 38 (369 mg, 89%). White solid. Rf (cyclohexane/AcOEt/AcOH 10 :5 :0.05) 0.31. M.p. 1538.
IR (CHCl3): 3600–2400m (br.), 1733s, 1451w, 1437w, 1384m, 1376m, 1271m, 1176m, 1076w, 1047m, 946w,
1
863w. H-NMR (400 MHz, CDCl3): 1.32, 1.48 (2s, Me2C(4)); 1.64 (ddd, J=11.1, 4.2, 2.3, HꢀC(10)); 1.68–1.71
(br. d, J=9.4, HendoꢀC(9)); 1.96 (dd, J=11.0, 1.5, H’ꢀC(10)); 2.28 (dd, J=9.3, 5.2, HexoꢀC(9)); 2.27–2.29 (m,
HꢀC(8)); 2.59 (br. s, HꢀC(7)); 3.71 (s, MeO); 4.19 (br. d, J=5.1, HꢀC(6)); 4.28 (dd, J=5.4, 1.6, HꢀC(2)).
13C-NMR (100 MHz, CDCl3; assignments based on HSQC.GRASP spectrum): 24.19, 25.35 (2q, Me2C(4));
32.04 (2t, C(9), C(10)); 40.99 (d, C(8)); 44.12 (d, C(7)); 52.26 (q, MeO); 54.63 (s, C(1)); 81.73 (d, C(6)); 82.30
(d, C(2)); 110.57 (s, C(4)); 174.18, 177.12 (2s, 2 C=O). ESI-MS: 269 ([MꢀH]ꢀ). Anal. calc. for C13H18O6
(270.28): C 57.77, H 6.71; found: C 57.96, H 6.84.
Methyl
(Æ)-(1RS,2SR,6RS,7RS,8RS)-1-{[(Benzyloxy)carbonyl]amino}-4,4-dimethyl-3,5-dioxatricyclo-
[5.2.1.02,6]decane-8-carboxylate (39). A soln. of 38 (250 mg, 0.92 mmol) and Et3N (112 mg, 1.1 mmol) in PhMe
(30 ml) was treated with diphenylphosphoryl azide (DPPA; 305 mg, 1.1 mmol), heated slowly to 1108 within
3 h, treated with BnOH (1 g, 9.2 mmol) and CuCl (15 mg), stirred for 5 h, and cooled to 238. Normal workup
(toluene/H2O), evaporation of the residual BnOH in a bulb-to-bulb apparatus at 608/0.5 Torr, and FC (cyclohex-
ane/AcOEt 3 :1) gave 39 (307 mg, 88%). Pale yellow syrup, which solidified upon standing. Rf (cyclohexane/
AcOEt 1:1) 0.60. M.p. 798. IR (CHCl3): 3442w, 2946w, 1728s, 1509m, 1272m, 1051m. 1H-NMR (500 MHz,
CDCl3): 1.30, 1.45 (2s, Me2C(4)); 1.69–1.74 (m, 2 HꢀC(10)); 1.89 (br. s, HꢀC(8)); 2.31–2.38 (m, 2 HꢀC(9));
2.46 (br. s, HꢀC(7)); 3.69 (s, MeO); 4.18 (d, J=5.5, HꢀC(2)); 4.22 (br. s, HꢀC(6)); 5.05, 5.13 (2d, J=12.3,
PhCH2); 5.28 (br. s, HN); 7.30–7.38 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3): 24.31, 25.42 (2q, Me2C(4));
31.53, 33.24 (2t, C(9), C(10)); 41.53, 41.69 (2d, C(7), C(8)); 52.12 (q, MeO); 62.50 (s, C(1)); 66.57 (t, PhCH2);
80.06, 81.28 (2d, C(2), C(6)); 110.31 (s, C(4)); 128.05, 128.06, 128.18, 128.34, 128.49 (5d); 136.42 (s); 155.51 (s,
NꢀC=O); 174.55 (s, OꢀC=O). ESI-MS: 376 ([M+H]+). Anal. calc. for C20H25NO6 (375.42): C 63.99, H 6.71,
N 3.73; found: C 63.98, H 6.77, N 3.64.
Benzyl (Æ)-(1RS,2RS,6SR,7SR,8SR)-[8-(Hydroxymethyl)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]dec-1-
yl]carbamate (40). A soln. of 39 (250 mg, 0.67 mmol) in THF (25 ml) was treated with LiBH4 (120 mg, 5.5
mmol), stirred for 48 h at 238, treated with 10% aq. NaH2PO4 soln. (20 ml), stirred for 1 h, and extracted

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3169
with CH2Cl2 (1×40 ml, 3×10 ml). The combined org. layers were dried (MgSO4) and evaporated. FC (cyclohex-
ane/AcOEt 1:2) gave 40 (213 mg, 92%). Colourless foam. Rf (cyclohexane/AcOEt 1:2) 0.31. M.p. 47–498. IR
1
(CHCl3): 3619w, 3434w, 2982w, 2929w, 1720s, 1510s, 1457w, 1384w, 1275m, 1164w, 1053s. H-NMR (400 MHz,
CDCl3): 1.45, 1.53 (2s, Me2C(4)); 1.55–1.73 (m, HꢀC(8), 2 HꢀC(9), 2 HꢀC(10), OH); 2.04 (br. s, HꢀC(7));
3.54 (br. s, CH2ꢀC(8)); 4.08 (br. d, J=5.6, HꢀC(6)); 4.16 (br. d, J=5.6, HꢀC(2)); 5.04, 5.09 (2d, J=12.2,
PhCH2); 5.21 (br. s, NH); 7.35–7.58 (m, 5 arom. H). 13C-NMR (100 MHz, CDCl3; assignments based on
HSQC.GRASP spectrum): 24.35, 25.49 (2q, Me2C(4)); 30.76, 31.68 (2t, C(9), C(10)); 39.02, 39.73 (2d, C(7),
C(8)); 62.72 (s, C(1)); 65.54 (t, PhCH2); 66.51 (t, CH2ꢀC(8)); 80.96, 81.84 (2d, C(2), C(6)); 110.19 (s, C(4));
128.07 (d); 128.11 (2d); 128.53 (2d); 136.47 (s); 155.60 (s, C=O). ESI-MS: 348 ([M+H]+). Anal. calc. for C19H25-
NO5 (347.41): C 65.69, H 7.25, N 4.03; found: C 65.56, H 7.22, N 3.97.
tert-Butyl (Æ)-(1RS,2RS,6SR,7SR,8SR)-[8-(Hydroxymethyl)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]dec-
1-yl]carbamate (41). A suspension of 40 (72 mg, 0.21 mmol), 10% Pd/C (80 mg), and cyclohexa-1,4-diene
(160 mg, 2 mmol) in EtOH (1.5 ml) was heated to 708, stirred for 2 h, cooled to 238, treated with Boc2O (67.8
mg, 0.31 mmol), stirred for 20 h, and evaporated. FC (cyclohexane/AcOEt 1:1) gave 41 (55 mg, 84%). Colour-
less foam. Rf (cyclohexane/AcOEt 1:1) 0.18. M.p. 50–528. IR (CHCl3): 3438w, 1709s, 1602m, 1504s, 1368m,
1274m, 1163s, 1017w, 861w. 1H-NMR (500 MHz, CDCl3): 1.30, 1.46 (2s, Me2C(4)); 1.44 (s, t-Bu); 1.42–1.70
(m, HꢀC(8), 2 HꢀC(9), 2 HꢀC(10)); 1.78 (br. s, OH); 2.16 (br. s, HꢀC(7)); 3.50–3.55 (m, CH2ꢀC(8)); 4.03
(dd, J=5.6, 1.3), 4.15 (br. d, J=5.6) (HꢀC(2), HꢀC(6)); 4.93 (br. s, NH). 13C-NMR (125 MHz, CDCl3):
24.33, 25.52 (2q, Me2C(4)); 28.43 (q, Me3C); 30.70, 31.47 (2t, C(9), C(10)); 39.06, 39.69 (2d, C(7), C(8)); 62.53
(s, C(1)); 65.63 (t, CH2ꢀC(8)); 79.31 (s, Me3C); 81.27, 81.77 (2d, C(2), C(6)); 110.07 (s, C(4)); 155.25 (s, C=
O). ESI-MS: 314 ([M+H]+). Anal. calc. for C16H27NO5 (313.39): C 61.32, H 8.68, N 4.47; found: C 61.45, H
8.65, N 4.27.
(Æ)-(1RS,2RS,6SR,7SR,8SR)-1-Amino-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]decane-8-methanol (43). A
suspension of 40 (65 mg, 0.187 mmol) and 10% Pd/C (5 mg) in EtOH (3 ml) was hydrogenated for 2 h at 238
under H2, and filtered. Evaporation of the filtrate and FC (CH2Cl2/NEt3 10 :0 !10 :1) of the residue gave 43
(30 mg, 75%). Colourless oil. Rf (CH2Cl2/MeOH/25% aq. NH3 10 :1 :0.1) 0.34. IR (CHCl3): 3631w, 3373w,
3273m, 2992s, 1667w, 1590w, 1456w, 1383s, 1375s, 1318m, 1272s. 1H-NMR (300 MHz, CDCl3): 1.08–1.16 (m,
HexoꢀC(9), HꢀC(10)); 1.29, 1.44 (2s, Me2C(4)); 1.32–1.35 (m, HendoꢀC(9)); 1.57–1.68 (m, HꢀC(8), H’ꢀ
C(10)); 2.09 (br. s, HꢀC(7)); 2.20 (br. s, NH2, OH); 3.48 (d, J=7.8, CH2ꢀC(8)); 3.73 (dd, J=5.6, 1.3), 4.13
(br. d, J=5.6) (HꢀC(2), HꢀC(6)). 13C-NMR (75 MHz, CDCl3): 24.20, 25.37 (2q, Me2C(4)); 34.47, 34.57 (2t,
C(9), C(10)); 39.33, 40.56 (2d, C(7), C(8)); 62.47 (s, C(1)); 65.11 (t, CH2ꢀC(8)); 82.38, 82.95 (2d, C(2), C(6));
109.52 (s, C(4)). HR-ESI-MS: 214.1431 ([M+H]+, C11H20NO3þ; calc. 214.1443).
(Æ)-(1RS,2RS,6SR,7SR,8SR)-1-Amino-5-(hydroxymethyl)bicyclo[2.2.1]heptane-2,3-diol (5). A soln. of 41
(55 mg, 0.18 mmol) in CH2Cl2 (1 ml) was treated with 2N aq. HCl (5 ml) and stirred for 36 h. The aq. layer
was separated and evaporated. FC (Amberlite CG-120, H2O/NH3 1 :0 !95 :5) gave 5 (25.8 mg, 85%). White
solid. For anal. purpose, 5 was transformed into its HCl salt.
Data of 5·HCl. pKHA 8.60. IR (KBr): 3600–2800s (br.), 1623m, 1507m, 1453w, 1395m, 1307m, 1196m, 1093s,
1048s. 1H-NMR (300 MHz, D2O): 1.31 (dd, J=12.5, 5.0, HexoꢀC(6)); 1.57–1.89 (m, HꢀC(5), HendoꢀC(6), 2 Hꢀ
C(7)); 2.14 (br. s, HꢀC(4)); 3.45 (d, J=7.5, CH2ꢀC(5)); 3.79 (dd, J=6.1, 1.8, HꢀC(3)), 3.94 (br. d, J=5.9, Hꢀ
C(2)). 13C-NMR (75 MHz, D2O): 30.94, 31.50 (2t, C(6), C(7)); 38.25, 42.67 (2d, C(4), C(5)); 61.60 (s, C(1)); 63.81
(d, CH2ꢀC(5)); 72.70, 73.07 (2d, C(2), C(3)). ESI-MS: 174 ([M+H]+). Anal. calc. for C8H16ClNO3·0.5 H2O
(218.68): C 43.94, H 7.84, N 6.41; found: C 43.68, H 7.45, N 6.21.
(Æ)-(1RS,2RS,6SR,7SR,8SR)-[1-(Benzylamino)-4,4-dimethyl-3,5-dioxatricyclo[5.2.1.02,6]dec-8-yl]metha-
nol (44). A suspension of 40 (118 mg, 0.34 mmol), cyclohexa-1,4-diene (272 mg, 3.3 mmol) and 10% Pd/C (100
mg) in EtOH (10 ml) was stirred at 608 for 1 h, filtered through a short pad of Celite, and evaporated. A soln. of
the resulting crude amine 43 in PhCH3 (30 ml) was treated with PhCHO (70 mg, 0.68 mmol). The mixture was
boiled under reflux for 15 h, azeotropically removing H2O with a DeanꢀStark condenser. After evaporation, a
soln. of the residue in MeOH/THF 1:1 (20 ml) was treated with NaBH4 (50 mg, 1.31 mmol) and stirred for 3 h at
238. The mixture was diluted with Et2O (20 ml), treated with 10% aq. NaH2PO4 soln. (10 ml) and stirred for 2 h.
The org. layer was separated. The aq. layer was brought to pH 8 with 2N NaOH and extracted with CH2Cl2 (2×15
ml). The combined org. layers were dried (Na2SO4) and evaporated. FC (AcOEt/aq. NH3 100 :1) afforded 44 (92
mg, 89%). Colourless solid. Rf (AcOEt/aq. NH3 100 :1) 0.20. M.p. 1238. IR (CHCl3): 3512w, 3310w, 2991s, 1605m,
1493w, 1455s, 1317m. 1H-NMR (400 MHz, CDCl3): 1.23 (dd, J=12.5, 5.2, HexoꢀC(9)); 1.32, 1.45 (2s, Me2C(4));
1.32–1.42 (m, HendoꢀC(9), HꢀC(10)); 1.52 (br. d, J=10.2, H’ꢀC(10)); 1.61–1.69 (m, HꢀC(8)); 1.76 (br. s, NH,
OH); 2.13 (br. s, HꢀC(7)); 3.52 (d, J=7.8, CH2ꢀC(8)); 3.71, 3.82 (2d, J=12.4, PhCH2); 4.04 (dd, J=5.6, 1.6),
4.18 (br. d, J=5.6) (HꢀC(2), HꢀC(6)); 7.21–7.37 (m, 5 arom. H). 13C-NMR (100 MHz, CDCl3): 24.31, 25.54

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Helvetica Chimica Acta – Vol. 88 (2005)
(2q, Me2C(4)); 31.32, 32.29 (2t, C(9), C(10)); 39.31, 39.84 (2d, C(7), C(8)); 48.95 (t, PhCH2); 65.77 (t, CH2ꢀ
C(8)); 67.31 (s, C(1)); 80.19, 82.09 (2d, C(2), C(6)); 109.67 (s, C(4)); 126.88 (d); 128.10 (2d); 128.36 (2d);
140.83 (s). ESI-MS: 304 ([M+H]+). Anal. calc. for C18H25NO3 (303.40): C 71.26, H 8.31, N 4.62; found: C
71.54, H 8.52, N 4.61.
(Æ)-(1RS,2RS,3SR,4SR,5SR)-1-(Benzylamino)-5-(hydroxymethyl)bicyclo[2.2.1]heptane-2,3-diol (42).
A
soln. of 44 (67 mg, 0.22 mmol) in THF (0.5 ml) and 2 HCl (5 ml) was stirred for 5 d at 238. Evaporation and
N
FC (Amberlite CG-120, H2O/NH3 1 :0 !95 :5) gave 42 (54 mg, 93%). Colourless oil. pKHA 8.2. For anal. pur-
pose, 42 was transformed into its HCl salt.
Data of 42·HCl. IR (KBr): 3600–2200s (br.), 1960w, 1886w, 1815w, 1668m, 1605m, 1585m, 1497m, 1453s,
1
1383s, 1294s, 1202s. H-NMR (500 MHz, CD3OD): 1.23 (dd, J=12.4, 5.1, HexoꢀC(6)); 1.37 (br. d, J=10.2, Hꢀ
C(7)); 1.47 (br. t, J=12.4, HendoꢀC(6)); 1.55 (br. d, J=10.2, H’ꢀC(7)); 1.68 (br. d, J=7.7, HꢀC(5)); 2.01 (br.
s, HꢀC(4)); 3.39 (d, J=7.7, CH2ꢀC(5)); 3.66, 3.84 (2d, J=11.9, PhCH2); 3.70 (dd, J=6.1, 1.7), 3.81 (dd,
J=6.1, 0.9) (HꢀC(2), HꢀC(3)); 7.23–7.48 (m, 5 arom. H). 13C-NMR (125 MHz, CD3OD): 32.77, 33.04 (2t,
C(6), C(7)); 40.83, 44.24 (2d, C(4), C(5)); 59.96 (t, PhCH2); 66.06 (t, CH2ꢀC(5)); 68.40 (s, C(1)); 73.02, 75.09
(2d, C(2), C(3)); 128.35 (d); 129.61 (4d); 141.01 (s). HR-ESI-MS: 264.1591 ([M+H]+, C15H22NO3þ; calc.
264.160).
Benzyl
(Æ)-(1RS,2RS,6SR,7SR,8SR)-{8-[(Methoxymethoxy)methyl]-4,4-dimethyl-3,5-dioxatricyclo-
[5.2.1.02,6]dec-1-yl}carbamate (47). A soln. of 40 (110 mg, 0.317 mmol), Bu4NI (10 mg), and Et3N (1.46 g, 14.4
mmol) in THF (5 ml) was treated with MOMCl (255 mg, 3.2 mmol). The mixture was stirred for 24 h at 658,
diluted with CHCl3 (10 ml) and H2O (10 ml), and brought to pH 3 with 2N HCl. The layers were separated,
and the aq. layer was extracted with CH2Cl2 (3×5 ml). The combined org. layers were dried (MgSO4) and evapo-
rated. FC (cyclohexane/AcOEt 2 :1) gave 47 (122 mg, 98%). Colourless oil. Rf (cyclohexane/AcOEt 1:1) 0.56.
1
IR (CHCl3): 3437w, 3010m, 2937m, 1721s, 1509s, 1454w, 1384m, 1375m, 1272m. H-NMR (300 MHz, CDCl3):
1.30, 1.45 (2s, Me2C(4)); 1.57–1.83 (m, HꢀC(8), 2 HꢀC(9), 2 HꢀC(10)); 2.19 (br. s, HꢀC(7)); 3.35 (s,
MeOCH2); 3.38–3.48 (m, CH2ꢀC(8)); 4.10, 4.17 (2d, J=5.3, HꢀC(2), HꢀC(6)); 4.59 (br. s, MeOCH2); 5.04,
5.10 (2d, J=12.1, PhCH2); 5.19 (br. s, NH); 7.29–7.37 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 24.44,
25.59 (2q, Me2C(4)); 31.21, 31.88 (2t, C(9), C(10)); 36.64, 40.19 (2d, C(7), C(8)); 55.31 (q, MeOCH2); 62.74 (s,
C(1)); 66.52 (t, CH2ꢀC(8)); 70.52 (t, PhCH2); 80.80, 81.79 (2d, C(2), C(6)); 96.47 (t, MeOCH2); 110.04 (s,
C(4)); 128.0 (3d); 128.43 (2d); 136.35 (s); 155.41 (s, C=O). ESI-MS: 414.2 ([M+Na]+). Anal. calc. for C21H29-
NO6 (391.46): C 64.43, H 7.47, N 3.58; found: C 64.55, H 7.59, N 3.58.
(Æ)-(1RS,2RS,6SR,7SR,8SR)-8-[(Methoxymethoxy)methyl]-4,4-dimethyl-1-(phenylamino)-3,5-dioxatricy-
clo[5.2.1.02,6]decane (48). A suspension of 47 (53 mg, 0.136 mmol) and 10% Pd/C (10 mg) in EtOH (6 ml) was
hydrogenated for 12 h at 238 under H2. After filtration and evaporation, a soln. of the residue in PhMe (6 ml)
was treated with t-BuOK (30 mg, 0.26 mmol), PhBr (45 mg, 0.28 mmol), BINAP (13 mg, 0.021 mmol), and
[Pd2(dba)3] (10 mg, 0.011 mmol). The mixture was kept at reflux for 6 h and evaporated. FC (hexane/AcOEt
2 :1), treatment with activated charcoal (20 mg) in CH2Cl2 (2 ml) for 12 h, and FC (hexane/AcOEt 3 :1) gave
48 (34 mg, 75%). Colourless solid. Rf (cyclohexane/AcOEt 2 :1) 0.32. M.p. 978. IR (CHCl3): 3423w, 3031w,
3010s, 2934s, 2033w, 1940w, 1922w, 1831w, 1726w, 1602s, 1498s. 1H-NMR (300 MHz, CDCl3): 1.32, 1.48 (2s,
Me2C(4)); 1.53–1.64 (m, 2 HꢀC(9)); 1.65–1.73 (m, 2 HꢀC(10)); 1.77–1.86 (m, HꢀC(8)); 2.19 (br. s, Hꢀ
C(7)); 3.37 (s, MeOCH2); 3.46 (dd,Jꢁ12, 9.6), 3.48 (dd, J=13.6, 9.7) (CH2ꢀC(8)); 4.11 (dd, J=5.6, 1.3, Hꢀ
C(6)); 4.21 (d, J=5.6, HꢀC(2)); 4.13 (br. s, NH); 4.63 (s, MeOCH2); 6.74–6.79, 7.13–7.20 (5 arom. H). 13C-
NMR (75 MHz, CDCl3): 24.42, 25.63 (2q, Me2C(4)); 31.89, 32.31 (2t, C(9), C(10)); 37.03, 40.14 (2d, C(7),
C(8)); 55.30 (s, MeOCH2); 65.84 (s, C(1)); 70.61 (t, CH2ꢀC(8)); 81.18, 81.90 (2d, C(2), C(6)); 96.43 (t,
MeOCH2); 109.88 (s, C(4)); 116.83 (2d); 118.68 (d); 128.87 (2d); 146.76 (s). HR-ESI-MS: 334.2009
([M+H]+, C19H28NOþ4 ; calc. 334.2018), 356.1829 ([M+Na]+, C19H27NNaO4þ; calc. 356.1838). Anal. calc. for
C19H27NO4 (333.43): C 68.44, H 8.16, N 4.20; found: C 68.16, H 8.06, N 4.16.
(Æ)-(1RS,2RS,3SR,4SR,5SR)-5-(Hydroxymethyl)-1-(phenylamino)bicyclo[2.2.1]heptane-2,3-diol (45).
A
soln. of 48 (20 mg, 0.06 mmol) in MeOH (4 ml) was treated with 2 HCl (4 ml), stirred for 42 h, and evaporated.
N
FC (Amberlite CG-120, H2O/NH3 1 :0 !95 :5) gave 45 (12 mg, 80%). Colourless solid. pKHA 4.66. IR (KBr):
1
3600–2400s (br.), 1940w, 1924w, 1901w, 1833w, 1818w, 1761w, 1600s, 1509s, 1497s. H-NMR (300 MHz, D2O):
1.25 (dd, J=12.5, 5.0, HexoꢀC(6)); 1.47 (td, J=12.5, 1.9, HendoꢀC(6)); 1.57 (br. d, J=10.3, HꢀC(7)); 1.74 (br.
q, Jꢁ6.5, HꢀC(5)); 2.03 (br. d, J=10.3, H’ꢀC(7)); 2.14 (br. s, HꢀC(4)); 3.31 (d, J=7.2, CH2ꢀC(5)); 3.80,
3.92 (2d, J=5.9, HꢀC(2), HꢀC(3)); 7.44–7.56 (5 arom. H). 13C-NMR (75 MHz, D2O): 33.10 (t, C(6), C(7));
39.17, 41.70 (2d, C(4), C(5)); 64.35 (s, C(1)); 66.28 (d, CH2ꢀC(5)); 72.26, 74.22 (2d, (C(2), C(3)); 118.36 (2d);
120.19 (d); 129.04 (2d); 146.23 (s). HR-ESI-MS: 250.1447 ([M+H]+, C14H20NO3þ; calc. 250.1443), 272.1253
([M+Na]+, C14H19NNaOþ3 ; calc. 250.1296).

Helvetica Chimica Acta – Vol. 88 (2005)
3171
(Æ)-(1RS,2RS,6SR,7SR,8SR)-{1-[3-(4-Methoxyphenyl)oxaziridin-2-yl]-4,4-dimethyl-3,5-dioxatricyclo-
[5.2.1.02,6]dec-8-yl}methanol (49). A suspension of 40 (120 mg, 0.346 mmol) and 10% Pd/C (10 mg) in EtOH (5
ml) was hydrogenated for 4 h at 248 under H2. The mixture was filtered and evaporated. A soln. of the resulting
crude amine 43 in CH2Cl2 (5 ml) and MeOH (1 ml) was treated with anisaldehyde (56 mg, 0.41 mmol) and
MgSO4 (400 mg), stirred for 20 h at 248, filtered, and evaporated. A soln. of the residue in ClCH2CH2Cl (2
ml) at 08 was treated with a previously dried (MgSO4) soln. of m-CPBA (90 mg, 0.51 mmol) in ClCH2CH2Cl
(5 ml), stirred for 75 min, and treated with sat. aq. NaHCO3 soln. The layers were separated, and the aq.
layer was extracted with CH2Cl2 (2×10 ml). The combined org. layers were dried (Na2SO4) and evaporated.
FC (hexane/AcOEt 1:1!1:2) gave 49 (93 mg, 78%) as a diastereoisomeric mixture in a ratio of 68 :32. Colour-
less foam.
Data ofthe 68 :32 Mixture . Rf (cyclohexane/AcOEt 1:2) 0.32. IR (CHCl3): 3612w, 3446w, 3010m, 2936m,
2840m, 1614m, 1518s, 1457w. 1H-NMR (300 MHz, CHCl3): 1.26 (s, 2.04 H), 1.32 (s, 0.96 H), 1.50 (s, 2.04 H),
1.52 (s, 0.96 H) (Me2C(4)); 1.30–1.80 (m, HꢀC(8), 2 HꢀC(9), 2 HꢀC(10)); 2.24 (br. s, 0.32 H), 2.26 (br. s,
0.68 H), (HꢀC(7)); 3.50–3.57 (m, CH2ꢀC(8)); 3.80 (s, MeO); 4.16–4.22 (m, HꢀC(2), HꢀC(6)); 4.87 (s, 0.68
H), 5.01 (s, 0.32 H) (ArCH); 6.87–6.91, 7.32–7.39 (2m, 4 arom. H). 13C-NMR (75 MHz, CDCl3): major and
minor isomer: 24.22, 25.59 (2q, Me2C(4)); 55.40 (q, MeO); 65.36 (t, CH2ꢀC(8)); 110.15 (s, C(4)); 127.00 (s);
128.57 (2d); 160.74 (s); major isomer: 25.16, 32.27 (2t, C(9), C(10)); 37.85, 39.81 (2d, C(7), C(8)); 75.69 (s,
C(1)); 78.27 (d, ArCH); 81.39, 82.17 (2d, C(2), C(6)); 113.92 (2d); minor isomer: 29.10, 31.82 (2t, C(9),
C(10)); 38.84, 40.31 (2d, C(7), C(8)); 74.01 (s, C(1)); 75.34 (d, ArCH); 81.00, 82.22 (2d, C(2), C(6)); 113.81
(2d). HR-ESI-MS: 348.1804 ([M+H]+, C19H26NO5þ; calc. 348.1811), 370.1621 ([M+Na]+, C19H25NNaOþ5 ;
calc. 370.1630).
(Æ)-(1RS,2RS,6SR,7SR,8SR)-8-(Hydroxymethyl)-4,4-dimethyl-1-{[(4-methoxyphenyl)methyl]imino}-3,5-
dioxatricyclo[5.2.1.02,6]decane N-Oxide (50). Neat 49 (123 mg, 0.355 mmol) was heated in a bulb-to-bulb distil-
lation apparatus for 4 min at 2008/0.5 Torr. FC (CH2Cl2/MeOH/Et3N 100 :5 :2) gave 50 (77 mg, 63%). White
powder. Rf (CH2Cl2/MeOH 10 :0.8) 0.50. M.p. 2248 (dec.). IR (KBr): 3369m (br.), 1604s, 1568w, 1510s, 1466w,
1420m, 1382m, 1326m, 1304w, 1206s, 1174s, 1050s. 1H-NMR (300 MHz, CD3OD): 1.32, 1.43 (2s, Me2C(4));
1.49 (dd, J=12.8, 5.3, HexoꢀC(9)); 1.73–1.83 (m, HꢀC(8)); 1.89 (br. d, J=10.0, HꢀC(10)); 2.02 (br. t,
J=12.8, HendoꢀC(9)); 2.14 (br. d, Jꢁ9.3, H’ꢀC(10)); 2.31 (br. s, HꢀC(7)); 3.48–3.51 (m, CH2ꢀC(8)); 3.86 (s,
MeO); 4.33 (d, J=5.6, HꢀC(2)); 4.52 (dd, J=5.6, 1.6, HꢀC(6)); 6.99–7.03, 8.30–8.33 (2m, 4 arom. H). 13C-
NMR (75 MHz, CD3OD): 24.20, 25.37 (2q, Me2C(4)); 31.79, 33.34 (2t, C(9), C(10)); 39.26, 41.36 (2d, C(7),
C(8)); 55.60 (q, MeO); 65.03 (t, CH2ꢀC(8)); 81.08 (s, C(1)); 81.84, 82.87 (2d, C(2), C(6)); 111.25 (s, C(4));
114.48 (2d); 123.53 (s); 132.79 (2d); 138.20 (d, C=N); 163.10 (s). HR-ESI-MS: 348.1801 ([M+H]+,
C19H26NOþ5 ; calc. 348.1811). Anal. calc. for C19H25NO5 (347.41): C 65.69, H 7.25, N 4.03; found: C 65.47, H
7.11, N 3.90.
[(Æ)-(1RS,2RS,3SR,4SR,5SR)-2,3-Dihydroxy-5-(hydroxymethyl)bicyclo[2.2.1]hept-1-yl](hydroxy)ammo-
nium Chloride (46). A suspension of 50 (50 mg, 0.14 mmol) in 2N HCl (2 ml) was stirred for 15 h at 208 and
evaporated. FC (RP-18, H2O !H2O/MeOH 6 :4) gave 46 (23 mg, 71%). Colourless powder. pKHA 4.92. IR
(KBr): 3650–2250s (br.), 1626w, 1453w, 1402m, 1193w, 1050m. 1H-NMR (300 MHz, D2O): 1.42 (dd, J=11.8,
4.4, HexoꢀC(6)); 1.64 (br. d, J=10.6, HꢀC(7)); 1.71–1.88 (m, HꢀC(5), HendoꢀC(6), H’ꢀC(7)); 1.94 (br. s, Hꢀ
C(4)); 3.46 (d, J=7.5, CH2ꢀC(5)); 3.98 (br. s, HꢀC(2), HꢀC(3)). 13C-NMR (75 MHz, D2O): 28.21, 29.02
(C(6), C(7)); 37.62, 42.83 (C(4), C(5)); 63.68 (C(1)); 69.89 (CH2ꢀC(5)); 70.39, 72.74 (C(2), C(3)). HR-ESI-
MS: 190.1071 ([M+H]+, C8H16NOþ4 ; calc. 190.1079), 379.2122 ([2M+H]+, C16H31N2Oþ8 ; calc. 379.2080).
Inhibition ofSnail b-Mannosidase. Inhibition constants were determined in the same way as reported in [27]
at 258 with 0.04M AcOH/AcONa buffer at the indicated pH and with 4-nitrophenyl b-D-mannopyranoside as sub-
strate. The IC50 values were determined at a substrate concentration corresponding to KM.
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Received August 24, 2005