Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Article abstract of DOI:10.1016/S0040-4020(02)01660-5

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cycliz

Full text of DOI:10.1016/S0040-4020(02)01660-5

Tetrahedron 59 (2003) 1293–1299
Asymmetric synthesis of (1)-1-deoxynojirimycin and
(1)-castanospermine
*
Peter Somfai, Patrice Marchand, Staffan Torsell and Ulf M. Lindstrom
¨
Organic Chemistry, Department of Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden
Received 27 September 2002; revised 27 November 2002; accepted 19 December 2002
Abstract—Asymmetric total syntheses of (þ)-1-deoxynojirimycin (1) and (þ)-castanospermine (2) are described. Starting from diene 3, the
required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of
amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (þ)-Deoxynojirimicyn
(1) was obtained in 36% yield over 11 steps from diene 3, while (þ)-castanospermine (2) was achieved in 13% after 19 steps from the same
starting material. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
biological activities of compounds 1 and 2, as well as
derivatives thereof, there is a current interest in developing
stereocontrolled syntheses of these alkaloids.
(þ)-Deoxynojirimycin (1) and (þ)-castanospermine (2) are
naturally occurring polyhydroxylated alkaloids known as
aza-sugars. Several structurally related congeners are
known, of which some are shown in Figure 1. (þ)-
Castanospermine (2) was first isolated as the major alkaloid
component from the seeds of Castanospermum australe,1
and later of the dried pod of Alexa leiopetala,2 and was
found to be a powerful inhibitor of a- and b-glucosi-
dases,3–6 while (þ)-1-deoxynojirimycin (1) was extracted
from the roots of mulberry trees7 and also inhibits
a-glucosidases I and II.8 In addition, compounds 1 and 2
also show promising anitiviral9 and anticancer properties.9,
10 It has also been found that derivatives of 1 and 2 exhibit
interesting biological properties.8,11 Due to the interesting
To date several syntheses of compounds 18 and 211 have
been described. Due to their highly oxygenated architecture
and structural relationship with natural sugars, a number of
the developed routes have made clever use of the intrinsic
chirality of various carbohydrate precursors, mainly glucose
and sorbose. As a result, however, these routes are limited
by their lack of stereochemical flexibility. So far only few
methods have been developed that allow for control of the
absolute and relative stereochemistry of the contiguous
stereocenters required for alkaloids 1 and 2. To date, one of
the more flexible and efficient entries to various poly-
hydroxylated indolizidine alkaloids is based on the use of
tandem [4þ2]/[3þ2] cycloaddition of nitroalkenes,
developed by Denmark and co-workers.12 This strategy
has been used for the preparation of several hydroxylated
indolizidine and pyrrolizidine alkaloids.
We previously reported an enatioselective synthesis of 1 (14
steps, 20% overall yield) in which a regio- and stereo-
selective opening of vinylepoxide 4, itself prepared from 3,
was used to secure piperidine 5 (Scheme 1).13 Conversion of
5 into aldehyde 6, which was then reduced and deprotected
to give (þ)-1-deoxynojirimycine (1), was uneventful. At the
outset, it was also planned to use derivative 5 or 6 as
intermediate for the preparation of (þ)-castanospermine (2).
All attempts, however, to realize this goal proved
unsuccessful. Protection of the hydroxyl moiety in 6 to
give 8 failed, most likely due to a facile retro aldol reaction.
To circumvent this, 5 was converted into 7, but then
oxidation of 7 into 8 proved to be unacceptably slow and
low yielding. The problems with this approach resided in the
Figure 1. Examples of naturally occurring polyhydroxylated alkaloids.
Keywords: amino alcohols; asymmetric synthesis; alkaloids.
*
Corresponding author. Tel.: þ46-8-7906960; fax: þ46-8-7912333;
e-mail: somfai@kth.se
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01660-5

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P. Somfai et al. / Tetrahedron 59 (2003) 1293–1299
expected diol 9 in 80% yield and 97% ee,17 which was
easily improved to 99.5% ee by a single recrystallization.18
The diol moiety in 9 was protected as an acetonide to give
1019 (97%) and subsequent DIBAL reduction of the ester
functionality yielded allylic alcohol 11 (93%). Epoxidation
of 11 using the catalytic Sharpless epoxidation resulted in
poor yield of 12,20 but could be realized by utilizing the
stoichiometric protocol to afford 12 in 80% yield and high
diastereoselectivity (de.95%). As noted previously, epoxi-
dation of substrates similar to 11 using (þ)-tartrate esters
constitutes a mis-matched combination and, indeed, sub-
jecting 11 to m-CPBA gave 12 and its diastereomer in 50%
de favoring the unwanted diastereomer.21 Protection of the
hydroxyl group in 12 as a TBDPS ether then gave 13 (97%).
Removal of the PMB group yielded 14 (92%), the primary
hydroxyl group of which was activated towards nucleophilic
attack by conversion into mesylate 15 (100%). Somewhat
surprisingly, 15 proved to be inert when subjected to
benzylamine and the starting material was recovered.
Instead, mesylate 15 could be converted into azide 16
(91%) without opening of the epoxide, and then reduced to
amine 17 using Staudinger conditions (83%). Subjecting 17
to refluxing EtOH resulted in a smooth and quantitative
cyclization into piperidine derivative 18. As expected, only
the product derived from a 6-endo-tet cyclization was
detected; the corresponding 5-exo-tet process being dis-
favored since it would produce a trans-fused bicyclo[3.3.0]-
nonane type of system.22
Scheme 1.
difficulties encountered in preparing aldehyde 8 and it was
decided to develop an alternative approach from diene 3
towards alkaloids 1 and 2. Herein are detailed the results
from this effort.
Concomitant removal of both the silyl and acetonide
protecting groups in key intermediate 18 by aq. HCl in
refluxing EtOH then gave (þ)-1-deoxynojirimycin (1) in
quantitative yield, its physical data being in accordance with
literature values.23 By this reaction sequence 1 was obtained
in 11 steps and 36% overall yield from diene 3.
2. Results and discussion
2.1. Synthesis of (1)-1-deoxynojirimycin (1)
Formation of the four contiguous stereocenters required for
1 can be achieved by asymmetric dihydroxylation of diene 3
followed by epoxidation (Scheme 2). It has previously
been shown that the enantioselectivity obtained in asym-
metric dihydroxylation of 6-hydroxyhexa-2,4-dienoic acid
derivatives is sensitive to the nature of the hydroxyl
protecting group.13–15 For reasons of orthogonality with
other projected protecting groups, the p-methoxybenzyl
ether 3 was selected as a suitable starting material.16
Dihydroxylation of this material using AD-mix-a led to the
2.2. Synthesis of (1)-castanospermine (2)
In order to proceed with the synthesis of (þ)-castano-
spermine (2) and avoid the problems encountered in our
earlier route it was necessary to protect both the secondary
hydroxyl and amine functionalities in 18. Initial attempts to
benzylate the hydroxyl group in 18 using standard basic
conditions resulted in partial migration of the silyl group,24
Scheme 2. (a) AD-mix-a, CH3SO2NH2, t-BuOH, H2O, 80%l; (b) 2-methoxypropene, p-TsOH (cat.), DMF, 97%; (c) DIBAL, 2788C, CH2Cl2, 93%; (d) (þ)-
DIPT, Ti(Oi-Pr)4, t-BuOOH, CH2Cl2, 2208C, 80%; (e) t-BuPh2SiCl, Et3N, DMAP, CH2Cl2, 97%; (f) DDQ, CH2Cl2, H2O, 92%; (g) MsCl, i-Pr2EtN, CH2Cl2,
100%; (h) NaN3, DMF, 708C, 91%; (i) Ph3P, THF, H2O, 83%; (j) EtOH, K, 100%; (k) HCl (37%), MeOH, 100%.

P. Somfai et al. / Tetrahedron 59 (2003) 1293–1299
1295
11 steps and (þ)-castanospermine (2) was obtained in 19
steps and 13% overall yield starting from the same diene.
4. Experimental27
4.1. Data for compounds
4.1.1. (E)-Ethyl (4S,5S)-4,5-dihydroxy-6-(4-methoxy-
benzyloxy)-hex-2-enoate (9). To a stirred solution of AD-
mix-a (5.0 g), K2OsO4·2H2O (0.011 g, 0.03 mmol), and
methanesulfonamide (0.344 g, 3.62 mmol) in t-BuOH–H2O
(36 mL, 1:1), was added 3 (1.0 g, 3.62 mmol) at 08C. After
stirring at 08C for 46 h, Na2SO3 (5.7 g) was added. The
mixture was stirred for an additional l2 h at rt and then
diluted with EtOAc (40 mL). The phases were separated and
the aqueous phase was extracted with EtOAc (2£20 mL).
The combined organic phases were washed with 2 M KOH.
Drying (MgSO4), filtration and concentration, followed by
flash chromatography (pentane–EtOAc 2:1) of the residue
afforded diol 9 (0.90 g, 80%) as white crystals in 97% ee.
One recrystallization (i-PrOH–hexane) afforded .99.5%
Scheme 3. (a) KHMDS (2.2 equiv.), BnBr (3 equiv.), THF, 2788C, 82%;
(b) BnBr (1.3 equiv.), K2CO3 (2.6 equiv.), CH3CN, K, 97%; (c) n-Bu4NF,
THF, rt, 100%; (d) (COCl)2, DMSO, Et3N, CH2Cl2, 2788C, 93%;
(e) CH2CHCH2SiMe3, TiCl4, CH2Cl2, 265 to 2608C, 71%; (f) OsO4,
NMO, t-BuOH–THF–H2O (10:3:1); (g) NaIO4, NaHCO3, THF–H2O
(1:1), 84% (2 steps); (h) H2, Pd/C, then TFA, 81%.
1
ee. Mp 65–668C; H NMR (400 MHz, CDCl3) d 7.25 (d,
J¼8.8 Hz, 2H), 6.90 (m, 3H), 6.14 (dd, J¼15.7, 1.8 Hz, 1H),
4.49 (m 2H), 4.38 (dt, 1H, J¼4.5, 1.8 Hz, 1H), 4.20 (q,
J¼7.2 Hz, 2H), 3.82 (s, 3H), 3.76 (m, 1H), 3.61 (m, 2H),
1.29 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
166.0, 159.4, 145.8, 129.4 (2C), 129.2 (2C), 122.4, 113.9,
73.4, 72.1, 71.9, 71.2, 60.5, 55.3, 14.3; IR (film) 3428, 2933,
2871, 2360, 1716, 1513, 1249 cm21; [a]D¼224.2 (c 1.08,
CHCl3); HRMS (CI) calcd for C16H22O6 (M): 310.1416,
found: 310.1422.
while acid catalyzed methods only gave degradation of the
starting material (Scheme 3). This was eventually resolved
by using KHMDS and BnBr in THF at 2788C, which
yielded compound 19 (82%). Protection of the amine
moiety gave 20 (97%) and removal of the silyl group
afforded primary alcohol 21 (100%), which was converted
to aldehyde 22 (93%) by a Swern oxidation. Introduction of
the final stereocenter required for 2 by a Sakurai reaction on
aldehyde 22 proved more problematic than anticipated.25
Subjecting 22 to TiCl4 and allyltrimethylsilane at 2788C
gave no reaction, while higher temperatures resulted in what
appeared to be concomitant addition to the carbonyl group
and removal of the acetonide. Other Lewis acids examined
did not promote the addition while the use of allylmagne-
sium chloride gave 23 in 1:1 diastereoselectivity. After
careful optimization 23 could be obtained in reasonable
yield and excellent diastereoselectivity by addition of TiCl4
to a mixture of 22 and allyltrimethylsilane at 2658C and
stirring the resultant mixture at this temperature 15 h (71%,
.95% de). Completion of the synthesis was then straight-
forward. Dihydroxylation of 23 gave the corresponding triol
as a mixture of diastereomers that upon treatment with
NaIO4 resulted in the somewhat labile aldehyde 24 (84%, 2
steps). Finally, reductive amination of this material
followed by acidic workup gave (þ)-castanospermine (2)
in 81% yield.26
4.1.2. (E)-Ethyl 3-[(4S,5S)-5-(4-methoxybenzyloxy-
methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]prop-2-enoate
(10). To a solution of 9 (0.100 g, 0.32 mmol) in DMF
(8 mL) was added 2-methoxypropene (0.121 mL,
1.29 mmol) and a few crystals of p-TsOH. The mixture
was stirred over night after which it was poured into Et2O
(20 mL) and washed with water and then brine. Drying
(MgSO4), filtration and concentration, followed by flash
chromatography (heptane–EtOAc 8:1) of the residue
afforded acetonide 10 (0.108 mg, 97%) as a colorless oil.
1H NMR (400 MHz, CDCl3) d 7.27 (m, 2H), 6.89 (m, 3H),
6.09 (dd, J¼15.7, 1.4 Hz, 1H), 4.54 (s, 2H), 4.41 (m, 1H),
4.21 (q, J¼7.1 Hz, 2H), 3.95 (dt, J¼8.4, 4.7 Hz, 1H), 3.82
(s, 3H), 3.66 (d, J¼4.7 Hz, 2H), 1.46 (s, 3H), 1.44 (s, 3H),
1.30 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
166.4, 159.7, 144.5, 130.2, 129.8, 123.0, 114.3, 110.6, 80.0,
77.9, 73.7, 69.4, 61.0, 55.7, 27.4, 27.1, 14.7; IR (film) 2987,
2935, 2360, 1720, 1513, 1249 cm21; [a]D¼222.8 (c 1,
CHCl3); HRMS (CIþ) calcd for C19H26O6 (M): 350.1729,
found: 350.1734.
3. Conclusion
4.1.3. (E)-3-[(4S,5S)-5-(4-Methoxybenzyloxymethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl]prop-2-en-1-ol (11). To
In conclusion, we have developed a route to (þ)-1-
deoxynojirimycin (1) that also allows for the preparation
of (þ)-castanospermine (2). The required stereochemistry
was introduced by a sequential use of the Sharpless
asymmetric dihydroxylation and epoxidation reactions,
while the remaining stereocenter in 2 was created by a
highly selective Sakurai reaction. Starting from diene 3,
(þ)-1-deoxynojirimycin (1) was prepared in 36% yield over
a
solution of 10 (4.30 g, 12.3 mmol) in CH2Cl2 (40 mL) at
2788C was added DIBAL (4.8 mL, 27.0 mmol). After 0.5 h
at 2788C the reaction was carefully quenched by dropwise
addition of MeOH before the cooling bath was removed.
The reaction mixture was then poured into aq. Rochelle salt.
The phases were separated and the aqueous phase was
extracted twice with CH2Cl2. Drying (MgSO4), filtration,

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P. Somfai et al. / Tetrahedron 59 (2003) 1293–1299
concentration and flash chromatography (heptane–EtOAc
1
1:1) afforded 11 (3.70 g, 93%) as a colorless oil. H NMR
73.7, 70.1, 63.4, 56.1, 55.7, 55.3, 27.4, 27.2, 27.0, 19.6; IR
(film) 2923, 2861, 1624, 1527, 1263, 1111 cm21
;
(400 MHz, CDCl3) d 7.26 (br d, J¼8.7 Hz, 2H), 6.88 (br d,
J¼8.7 Hz, 2H), 5.92 (ddt, J¼15.5, 5.0, 0.6 Hz, 1H), 5.71
(ddt, J¼15.5, 7.4, 1.6 Hz, 1H), 4.52 (s, 2H), 4.24 (t,
J¼7.9 Hz, 1H), 4.13 (br s, 2H), 3.90 (m, 1H), 3.80 (s, 3H),
3.56 (m, 2H), 1.83 (br s, 1H), 1.44 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 159.7, 134.6, 130.4, 129.8, 128.1,
114.2, 109.8, 80.5, 79.0, 73.6, 69.5, 63.0, 55.7, 27.4; IR
[a]D¼215 (c 0.7, CHCl3); HRMS (CI-CH4) calcd for
C33H41O6Si (M2H): 561.2672, found: 561.2666.
4.1.6. (4S,5R)-5-[(2R,3R)-3-(t-Butyldiphenylsilanyloxy-
methyl)-oxiranyl]-2,2-dimethyl-1,3-dioxolan-4-
yl]methanol (14). To a solution of 13 (1.08 g, 1.921 mmol)
in CH2Cl2 (30 mL) and H2O (1.2 mL) at 08C was added
DDQ (480 mg, 2.114 mmol) in portions. The resultant
mixture was stirred at rt for 3 h and then sat. NaHCO3
(10 mL) was added. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (3£50 mL). The
combined organic layers were dried over Na2SO4 and
concentrated. The residual oil was purified by flash
chromatography (pentane–EtOAC 3:1) to give 14
(780 mg, 92%) as a slightly yellow oil. 1H NMR
(400 MHz, CDCl3) d 7.70 (m, 4H), 7.45 (m, 6H), 4.05 (dt,
J¼8.7, 3.5 Hz, 1H), 3.85 (m, 4H), 3.62 (m, 1H), 3.13 (dt,
J¼3.5, 2.3 Hz, 1H), 3.01 (dd, J¼4.8, 2.3 Hz, 1H), 1.85 (dd,
J¼8.3, 4.8 Hz, 1H), 1.50 (s, 6H), 1.10 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 134.7, 134.3. 132.2, 132.1, 128.9,
126.9, 126.9, 109.0, 77.2, 75.5, 62.2, 60.6, 54.4, 53.8, 26.1,
25.8, 25.5, 18.3; IR (film) 3402, 2930, 2875, 1652, 1256,
1124 cm21; [a]D¼213.2 (c 0.22, CHCl3); HRMS (FABþ)
calcd for C25H34O5SiNa (MþNa): 465.2073, found:
465.2075.
(film) 3423, 2987, 2869, 2360, 1513, 1247 cm21
;
[a]D¼27.3 (c 0.66, CHCl3); HRMS (CIþ) calcd for
C17H23O5 (M2H): 307.1546, found: 307.1564.
4.1.4. (2R,3R)-3-[(4S,5R)-5-(4-Methoxybenzyloxy-
methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]oxiranylmetha-
nol (12). To
a solution of Ti(Oi-Pr)4 (0.034 mL,
0.116 mmol) in CH2Cl2 (1.0 mL) at 2208C was added
(þ)-diisopropyl tartrate (0.031 mL, 0.145 mmol). After
stirring for 10 min, 11 (0.030 g, 0.097 mmol, in 1 mL
CH2Cl2) was added. After stirring for 20 min at 2208C
t-BuOOH (5.2 M in toluene; 0.037 mL, 0.194 mmol) was
added and the resultant mixture was stored in a freezer at
2208C over night. The reaction was quenched by addition
of sat. aq. Na2SO4 (0.5 mL) and Et2O (1 mL). The resultant
mixture was stirred for 1 h at rt after which it was filtered
through a pad of Celitew. The filtrate was diluted with Et2O
(5 mL) and stirred for 20 min with 1 M NaOH (2 mL). The
phases were separated and the aqueous phase was extracted
twice with Et2O. The combined organic phases were washed
with brine, dried (MgSO4) and concentrated. Flash
chromatography (heptane–EtOAc 1:1) of the residue
afforded 12 (0.025 g, 80%) as a colorless oil in .95% de.
1H NMR (400 MHz, CDCl3) d 7.24 (d, J¼8.6 Hz, 2H), 6.88
(dd, J¼8.7 Hz, 2H), 4.50 (s, 2H), 4.13 (m, 1H), 3.85 (d,
J¼2.1 Hz, 1H), 3.81 (s, 3H), 3.76 (dd, J¼8.0, 4.7 Hz, 1H),
3.66 (dd, J¼10.0, 4.8 Hz, 1H), 3.54 (dd, J¼9.9, 5.6 Hz, 2H),
3.08 (m, 2H), 1.92 (br s, 1H), 1.41 (s, 6H). 13C NMR
(100 MHz, CDCl3) d 159.2, 129.6, 129.4, 113.7, 109.9,
78.7, 76.5, 73.3, 69.7, 60.6, 55.7, 55.3, 54.6, 27.0, 26.6; IR
(film) 3448, 1513, 1249, 1087 cm21; [a]D¼211.4 (c 0.51,
CHCl3); HRMS (CIþ) calcd for C17H23O6 (M2H):
323.1495, found: 323.1499.
4.1.7. (4S,5R)-5-[(2R,3R)-3-(-t-Butyldiphenylsilanyloxy-
methyl)-oxiranyl]-2,2-dimethyl-1,3-dioxolan-4-
yl)methanesulfonate (15). To a solution of 14 (720 mg,
1.63 mmol) in CH2Cl2 (35 mL) at 08C was added i-Pr2EtN
(994 mL, 5.705 mmol) and CH3SO2Cl (315 mL,
4.075 mmol). The resultant mixture was stirred over night
at rt and then poured into aq. NaHCO3. The phases were
separated and the aqueous phase extracted with CH2Cl2.
The combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. Remaining by-products were
removed under vacuum (oil pump, 608C) to give 15
(859 mg, 100%) as a slightly yellow oil. 1H NMR
(400 MHz, CDCl3) d 7.70 (m, 6H), 7.40 (m, 4H), 4.39
(dd, J¼11.3, 4.5 Hz, 1H), 4.35 (dd, J¼11.3, 3.9 Hz, 1H),
4.16 (dt, J¼8.1, 3.2 Hz, 1H), 3.89 (dd, J¼8.3, 4.8 Hz, 1H),
3.85 (t, J¼4.0 Hz, 2H), 3.20 (dt, J¼3.52, 2.3 Hz, 1H), 3.08
(s, 3H), 3.01 (dd, J¼4.6, 2.3 Hz, 1H), 1.30 (s, 6H), 1.10 (s,
9H); 13C NMR (CDCl3, 100 MHz) d 134.5, 132.1, 132.1,
128.9, 126.9, 109.8, 74.4, 67.0, 61.5, 54.6, 53.1, 36.8, 26.05,
25.8, 25.7, 18.3; IR (film) 2932, 2858, 1472, 1360, 1259,
1177, 1112 cm21; [a]D¼213.2 (c 1, CHCl3); HRMS
(FABþ) calcd for C26H36O7SSiNa (MþNa): 543.1849,
found: 543.1852.
4.1.5. t-Butyl-[3-(2R,3R)-((4S,5R)-5-(4-methoxybenzyl-
oxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)oxiranyl-
methoxy]diphenylsilane (13). To a solution of Et3N
(1.8 equiv., 2.01 mL, 14.46 mmol) in CH2Cl2 (50 mL) was
added DMAP (5 mol%,48 mg) and TBDPSCl (3.134 mL,
12.05 mmol). After 5 min 12 (2.595 g, 8.03 mmol) in
CH2Cl2 (10 mL) was added. The resultant mixture was
stirred at rt for 16 h, then poured into sat. NaHCO3 and the
phases were separated. The aqueous phase was extracted
with CH2Cl2 (2£50 mL). The combined organic phases
were washed with brine, dried (Na2SO4) and concentrated.
Flash chromatography (heptane–EtOAc 6:1) of the residue
gave 13 (4.402 g, 97%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.69 (m, 4H), 7.43 (m, 6H), 7.22 (d,
J¼8.6 Hz, 2H), 6.87 (d, J¼8.3 Hz, 2H), 4.51 (m, 2H), 4.12
(dt, J¼8.0, 5.0 Hz, 1H), 3.81 (m, 1H), 3.80 (s, 3H), 3.77 (dd,
J¼8.0, 5.3 Hz, 1H), 3.72 (m, 1H), 3.60 (dd, J¼15.4, 5.0 Hz,
2H), 3.09 (m, 1H), 3.00 (dd, J¼5.3, 2.3 Hz, 1H), 1.5 (s, 6H),
1.1 (s, 9H); 13C NMR (100 MHz, CDCl3) d 160.7, 136.0,
135.9, 133.6, 133.5, 130.2, 129.9, 128.2, 114.2, 110.4, 78.9,
4.1.8. (4S,5R)-5-((2R,3R)-3-(t-Butyldiphenylsilanyloxy-
methyl)-oxiranyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methylazide (16). Compound 15 (1.02 g, 1.96 mmol)
was dissolved in DMF (30 mL) and NaN3 (156.6 mg,
2.255 mmol) was added. The flask was then sealed and
warmed to 808C over night. The solution was then cooled to
rt and the DMF was removed under reduced pressure. The
residue was taken up in Et2O–H2O (50 mL, 1:1), the phases
were separated and the aqueous phase extracted with Et2O
(3£50 mL). The combined organic layers were washed with
H2O, dried (MgSO4) and concentrated. The residual oil was

P. Somfai et al. / Tetrahedron 59 (2003) 1293–1299
1297
purified by flash chromatography (pentane–EtOAc 35:10)
to give 16 (802 mg, 91%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.58 (m, 4H), 7.34 (m, 6H), 3.98 (dt,
J¼8.1, 4.3 Hz, 1H), 3.74 (m, 3H), 3.48 (dd, J¼13.1, 4.3 Hz,
1H), 3.23 (dd, J¼13.1, 4.5 Hz, 1H), 3.05 (dt, J¼3.8, 2.0 Hz,
1H), 2.86 (dd, J¼4.8, 2.3 Hz, 1H), 1.37 (s, 3H), 1.34 (s, 3H),
0.98 (s, 9H); 13C NMR (100 MHz, CDCl3) d 136.0, 135.9,
133.4, 133.5, 130.3, 128.2, 110.9, 77.9, 76.9, 63.4, 55.8,
54.8, 51.8, 27.3, 27.1, 27.0, 19.6; IR (film) 2930, 2861,
2097, 1444, 1375, 1250, 1118 cm21; [a]D¼228.9 (c 0.95,
CHCl3); HRMS (FABþ) calcd for C25H33N3O4SiNa
(MþNa): 490.2138, found: 490.2134.
(ddd, J¼12.2, 9.5, 5.1 Hz, 1H), 3.59 (t, J¼9.5 Hz, 1H), 3.52
(t, J¼9.5 Hz, 1H), 3.48 (dd, J¼12.2, 5.1 Hz, 1H), 317 (ddd,
J¼3.1, 5.2, 9.5 Hz, 1H) 2.95 (t, J¼12.2 Hz, 1H); 13C NMR
(125 MHz, D2O) d 79.1, 70.9, 70.1, 62.9, 60.9, 49.0;
[a]D¼þ46.9 (c 0.11, H2O) [lit.23 [a]D¼þ47.1 (c 0.17,
H2O)].
4.1.12. (3aS,6R,7aS,7R)-5-Benzyl-6-(t-butyldiphenyl-
silanyloxymethyl)-2,2-dimethyl-hexahydro-1,3-di-
oxolo[4,5-c]pyridin-7-ol (19). To a stirred solution of 18
(18.2 mg, 0.041 mmol) and benzyl bromide (14.7 mL,
0.124 mmol) in THF (1 mL) at 2788C was added
KHMDS (70.5 mL, 1.23 M in THF). The reaction mixture
was stirred at 2788C for 2 h and then allowed to slowly
warm to rt over night. The reaction was quenched by
addition of aq. Na2CO3 (2 mL) and the resultant mixture
was extracted twice with Et2O. The combined organic
phases were dried (MgSO4), concentrated and flash
chromatographed (Et2O–pentane 3:7) to give 19 (18 mg,
82%) as a slightly yellow oil. 1H NMR (400 MHz, CDCl3) d
7.64 (m, 4H), 7.40–7.15 (m, 11H), 4.87 (d, J¼11.4 Hz, 1H),
4.47 (d, J¼11.4 Hz, 1H), 3.98 (dd, J¼9.95, 3.9 Hz, 1H),
3.91 (dd, J¼9.95, 2.6 Hz, 1H), 3.62 (t, J¼9.1 Hz, 1H), 3.51
(t, J¼8.9 Hz, 1H), 3.35 (m, 2H), 2.72 (dt, J¼11.5, 2.04 Hz,
1H), 2.47 (dt, J¼11.5, 2.63 Hz, 1H), 1.49 (s, 3H), 1.45 (s,
3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) d 138.9,
136.0, 133.6, 130.2, 128.6, 128.2, 128.0, 127.8, 110.5, 85.2,
78.0, 76.9, 72.3, 63.4, 60.87, 47.2, 27.4, 27.3, 27.3, 19.8; IR
4.1.9. (4S,5R)-5-((2R,3R)-3-(t-Butyldiphenylsilanyloxy-
methyl)-oxiranyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methylamine (17). To a solution of 16 (800 mg,
1.713 mmol) in THF–H2O (25 mL, 10:1) was added Ph3P
(516 mg, 1.97 mmol) and the resultant mixture was stirred
at rt over night. The solvents were then removed and the
residue was purified by flash chromatography (EtOAc!
EtOAc–MeOH–NH4OH 9:1:0.1) to give 17 (632 mg, 83%)
as a slightly yellow oil. 1H NMR (400 MHz, CDCl3) d 7.60
(m, 4H), 7.44 (m, 6H), 3.87 (ddd, J¼9.7, 6.3, 3.8 Hz, 1H),
3.75 (d, J¼4.0 Hz, 2H), 3.61 (dd, J¼8.0, 4.8 Hz, 1H), 3.05
(dt, J¼3.8, 2.3 Hz, 1H), 2.89 (dd, J¼4.8, 2.3 Hz, 1H), 2.87
(dd, J¼13.6, 3.8 Hz, 1H), 2.75 (dd, J¼13.6, 6.3 Hz, 1H),
2.40 (bs, 2H), 1.34 (s, 3H), 1.33 (s, 3H), 0.90 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 136.0, 135.9, 133.4, 133.5,
130.3, 128.2, 110.9, 77.9, 76.9, 63.4, 55.8, 54.8, 51.8, 27.3,
27.1, 27.0, 19.6; IR (film) 2962, 1471, 1429, 1114, 1105,
1100 cm21; [a]D¼223 (c 0.2, CHCl3); HRMS (EIþ) calcd
for C25H35NO4Si (M): 441.2335, found: 441.2346.
(film) 2956, 2931, 1429, 1380, 1232, 1112, 1083 cm21
;
[a]D¼þ25.4 (c 1.01, CHCl3); HRMS (EIþ) calcd for
C32H41NO4Si (M): 531.2805, found: 531.2816.
4.1.13. (3aS,6R,7aS,7R)-5-Benzyl-7-benzyloxy-6-(t-
butyldiphenylsilanyloxymethyl)-2,2-dimethyl-hexa-
hydro-1,3-dioxolo[4,5-c]pyridine (20). To a solution of 19
(140 mg, 0.253 mmol) in CH3CN (3 mL) was added benzyl
bromide (40.6 mL, 0.343 mmol) and K2CO3 (94.8 mg,
0.685 mmol, dried and powdered). The resultant hetero-
geneous solution was heated at reflux for 5 h. After cooling
to rt the solids were filtered off and the solvents removed.
Flash chromatography (pentane–Et2O 9:1) of the residue
gave 20 (153 mg, 97%) as an oil. 1H NMR (400 MHz,
CDCl3) d 7.65 (m, 6H), 7.52 (m, 2H), 7.40–7.10 (m, 12H),
4.85 (d, J¼11.4 Hz, 1H), 4.45 (d, J¼11.4 Hz, 1H), 4.34 (d,
J¼13.8 Hz, 1H), 4.12 (dd, J¼10.1, 1.0 Hz, 1H), 4.01 (dd,
J¼10.1, 3.8 Hz, 1H), 3.65 (t, J¼8.6 Hz, 1H), 3.47 (m, 2H),
3.39 (d, J¼13.8 Hz, 1H), 3.12 (dd, J¼10.5, 3.1 Hz, 1H),
2.50 (dd, J¼7.3, 2.2 Hz, 1H), 2.18 (dt, J¼9.8, 4.8 Hz, 1H),
1.41 (s, 3H), 1.43 (s, 3H), 0.95 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 138.9, 138.3, 135.7, 135.6, 133.3, 133.2, 129.5,
128.7, 128.1, 128.1, 127.8, 127.6, 127.6, 127.5, 127.3,
126.8, 110.5, 84.9, 75.8, 73.7, 72.2, 66.7, 62.24, 57.07, 52.5,
26.94, 26.9, 26.8, 19.2; IR (film) 3068, 2931, 2858, 1454,
1380, 1232, 1110 cm21; [a]D¼þ5.7 (c 1.99, CHCl3);
HRMS (EIþ) calcd for C39H47NO4Si (M): 621.3274,
found: 621.3278.
4.1.10. (3aS,6R,7aS,7R)-6-(t-Butyldiphenylsilanyloxy-
methyl)-2,2-dimethyl-hexahydro-1,3-dioxolo[4,5-c]pyri-
din-7-ol (18). A solution of 17 (630 mg, 1.428 mmol) in
EtOH (50 mL) was heated to reflux for 65 h. The solvents
were then removed and the residue was dissolved in
Et2O. The organic phase was washed with aq. Na2CO3,
dried (Na2SO4) and the solvents were removed. Flash
chromatography of the residue (pentane–EtOAc
1:1!EtOAc) gave 18 (567 mg, 90%) as a slightly yellow
1
oil. H NMR (400 MHz, CDCl3) d 7.60 (m, 4H), 7.35 (m,
6H), 3.83 (dd, J¼10.1, 4.0 Hz, 1H), 3.79 (dd, J¼10.1,
4.0 Hz, 1H), 3.70 (t, J¼8.9 Hz, 1H), 3.33 (t, J¼8.9 Hz, 1H),
3.27 (m, 2H), 2.67 (dd, J¼12.6, 11.3 Hz, 1H), 2.47 (dt,
J¼8.6, 4.0 Hz, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.00 (s, 9H);
13C NMR (100 MHz, CDCl3) d 135.9, 133.2, 130.4, 128.3,
110.9, 84.4, 76.6, 72.2, 64.0, 61.4, 47.1, 27.3, 27.1, 19.6; IR
(film) 2888, 2858, 1428, 1228, 1114, 1080, 1027 cm21
;
[a]D¼þ9 (c 0.8, CHCl3); HRMS (CIþ) calcd for
C25H35NO4Si (M): 441.2335, found: 441.2331.
4.1.11. (1)-1-Deoxynojirimycin (1). To 18 (47 mg,
0.106 mmol) in MeOH (1 mL) was added HCl (37%,
1 mL) and the resultant mixture was stirred at 708C for 4 h.
After cooling to rt, the mixture was diluted with EtOH
(1 mL) and 10 mL of CH3CN (10 mL) followed by removal
of the solvents. The residual oil was purified by flash
chromatography (CHCl3–MeOH 1:1) to give the known
1·HCl salt (17 mg, 100%) as white crystals. Mp 201–2028C
4.1.14. (3aS,6R,7aS,7R)-(5-Benzyl-7-benzyloxy-2,2-
dimethyl-hexahydro-[1,3]dioxolo[4,5-c]pyridin-6-
yl)methanol (21). To
a solution of 20 (150 mg,
0.241 mmol) in THF (6 mL) was added n-Bu4NF·2H2O
(133 mg, 0.411 mmol) in one portion. The reaction mixture
was then stirred at rt for 14 h followed by removal of the
1
(lit.23 202–2048C); H NMR (500 MHz, D2O) d 3.95 (dd,
J¼11.7, 3.1 Hz, 1H), 3.88 (dd, J¼11.7, 5.1 Hz, 1H), 3.78

1298
P. Somfai et al. / Tetrahedron 59 (2003) 1293–1299
solvents. Flash chromatography (pentane–Et2O 3:2) of the
residue gave 21 (92 mg, 100%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) d 7.39–7.22 (m, 10H), 4.94 (d,
J¼11.3 Hz, 1H), 4.64 (d, J¼11.3 Hz, 1H), 4.08 (d,
J¼9.1 Hz, 1H), 3.98 (t, J¼11.9 Hz, 1H), 3.92 (t,
J¼11.3 Hz, 1H), 3.8 (t, J¼8.8 Hz, 1H), 3.4 (m, 3H), 3.22
(dd, J¼10.0, 3.6 Hz, 1H), 2.48 (d, J¼9.1 Hz, 1H), 2.41 (d,
J¼6.8 Hz, 1H), 2.32 (t, J¼9.9 Hz, 1H), 1.43 (s, 6H); 13C
NMR (125 MHz, CDCl3) d 138.3, 137.1, 129.1, 128.5,
128.4, 127.8, 127.5, 111.1, 84.2, 75.8, 73.7, 72.9, 64.8, 64.7,
58.0, 57.1, 52.7, 27.0, 26.8; IR (film) 3440, 1641, 1454,
1382, 1230, 1153, 1074 cm21; [a]D¼þ21.0 (c 0.4, CHCl3);
HRMS (CIþ) calcd for C23H30NO4 (MþH): 384.2175,
found: 384.2171.
1H), 3.53 (t, J¼9.0 Hz, 1H), 3.46 (m, 1H), 3.19 (dd, J¼10.5,
4.2 Hz, 1H), 2.69 (dd, J¼8.2, 3.3 Hz, 1H), 2.40 (m, 1H),
2.34 (t, J¼10.4 Hz, 1H), 2.05 (m, 1H), 1.46 (s, 3H), 1.44 (s,
3H); 13C NMR (100 MHz, CDCl3) d 138.8, 137.9, 136.3,
129.2, 129.0, 128.9, 128.8, 128.5, 127.6, 117.1, 111.5, 84.6,
77.9, 74.0, 72.8, 71.4, 67.4, 58.7, 53.6, 38.8, 27.4, 27.3; IR
(film) 3450, 2985, 1640 cm21; [a]D¼þ37.5 (c 2.50,
CHCl3); HRMS (FABþ) calcd for C26H34NO4 (MþH):
424.2488, found: 424.2484.
4.1.17. (3S)-3-((3aS,6R,7aS,7R)-5-Benzyl-7-benzyloxy-
2,2-dimethylhexahydro-1,3-dioxolo[4,5-c]pyridin-6-yl)-
3-hydroxypropionaldehyde (24). To a solution of 23
(54 mg, 0.127 mmol) in t-BuOH–THF–H2O (2 mL,
10:3:1) was added NMO (29 mg, 0.254 mmol) and OsO4
(cat.). After stirring at rt for 3 h sat. Na2SO3 (1 mL) was
added and the resultant mixture was stirred for 1 h. The
mixture was extracted with Et2O (3£5 mL) and the
combined organic phases were dried (MgSO4). Removal
of the solvents gave a residue that was filtered through a
plug of silica to give the corresponding diol (48 mg) as a 1:1
mixture of diastereomers (1H NMR). This mixture was not
further purified but taken on to the next step.
4.1.15. (3aS,6S,7aS,7R)-5-Benzyl-7-benzyloxy-2,2-
dimethyl-hexahydro-1,3-dioxolo[4,5-c]pyridine-6-car-
baldehyde (22). To a solution of DMSO (59 mL,
0.783 mmol) in CH2Cl2 (4 mL) at 2788C was added
(COCl)2 (28 mL, 0.392 mmol). After stirring for 15 min at
2788C 15 min 21 (100 mg, 0.261 mmol) in CH2Cl2 (1 mL)
was added. The resultant solution was then stirred
2788C!2408C for 4 h. and then recooled to 2788C before
addition of Et3N (145.3 mL, 1.044 mmol). The resultant
pale yellow solution was warmed to rt and stirred for 1 h
before it was quenched by addition of sat. NaCO3 (5 mL).
The phases were separated, the aqueous phase extracted
with Et2O (2£15 mL) and the combined organic layers were
washed with brine, dried (MgSO4) and concentrated. The
residual oil was dissolved in Et2O, the organic phase was
washed with H2O, then triturated with pentane (25% V/V)
and finally washed with H2O (10 mL). This process was
repeated thrice and then the organic phase was dried
(MgSO4) and concentrated to give crude 22 (92 mg, 93%) as
a colorless oil. Compound 22 can be stored at 2208C for a
short period of time but was normally taken on directly to
the subsequent step. 1H NMR (400 MHz, CDCl3) d 9.49 (d,
J¼4.5 Hz, 1H), 7.38–7.19 (m, 10H), 4.84 (d, J¼11.8 Hz,
1H), 4.61 (d, J¼11.8 Hz, 1H), 3.82 (t, J¼8.8 Hz, 1H), 3.78
(d, J¼13.7 Hz, 1H), 3.55 (dt, J¼9.1, 3.9 Hz, 1H), 3.45 (d,
J¼6.6 Hz, 1H), 3.42 (d, J¼13.7 Hz, 1H), 3.19 (dd, J¼9.9,
3.8 Hz, 1H), 2.97 (dd, J¼8.7, 4.5 Hz, 1H), 2.23 (t,
J¼9.8 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 199.4, 137.5, 136.0, 129.0, 128.3,
128.2, 128.0, 127.7, 127.5, 111.4, 83.5, 74.1, 72.9, 72.2,
59.3, 52.0, 31.0, 27.0, 26.9.
To the diol from above (53 mg) in THF–H2O (1 mL, 1:1)
was added NaHCO3 (44 mg, 0.525 mmol) and NaIO4
(45 mg, 0.210 mmol). After stirring at rt for 3 h the mixture
was poured into Et2O–H2O, the phases were separated and
the aqueous phase extracted with Et2O (2£5 mL). The
combined organic phases were dried (MgSO4) and con-
centrated. Flash chromatography (pentane–EtOAc 4:1) of
the residue gave 24 (45 mg, 84% from 24) as a colorless oil.
1H NMR (400 MHz, CDCl3) d 9.54 (br s, 1H), 7.40–7.19
(m, 10H), 4.93 (d, J¼11.4 Hz, 1H), 4.71 (m, 1H), 4.69 (d,
J¼11.4 Hz, 1H), 3.95 (m, 1H), 3.94 (d, J¼14.4 Hz, 1H),
3.81 (br t, J¼8.7 Hz, 1H), 3.69 (d, J¼14.4 Hz, 1H), 3.52 (br
t, J¼8.7 Hz, 1H), 3.47 (m, 1H), 3.20 (dd, J¼10.5, 4.0 Hz,
1H), 2.72 (dd, J¼8.7, 3.4 Hz, 1H), 2.56 (br d, J¼16.3 Hz,
1H), 2.41 (t, J¼10.5 Hz, 1H), 2.36 (ddd, J¼16.3, 9.8,
2.5 Hz, 1H), 1.47 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 201.7, 138.4, 137.5, 129.1, 129.0, 128.9, 128.7,
128.7, 127.8, 111.6, 84.4, 73.8, 72.8, 67.0, 66.9, 58.3, 53.8,
48.0, 27.3, 27.2; IR (film): 3459, 2985, 1725 cm21
;
[a]D¼þ44.5 (c 2.50, CHCl3).
4.1.18. (1)-Castanospermine (2). A mixture of 24 (37 mg
0.087 mmol) and 10% Pd/C (5 mg) in EtOAc (3 mL) was
stirred at rt under H2 for 24 h. The mixture was then filtered
through Celitew and the solvents were evaporated. The
residue was taken up in TFA–H2O (2 mL, 8:1) and stirred rt
for 10 h. Removal of the solvents gave a white solid that was
recrystallized from CH2Cl2–MeOH (3:1) to give the 2·TFA
4.1.16. (1S)-1-((3aS,6S,7aS,7R)-5-Benzyl-7-benzyloxy-
2,2-dimethylhexahydro-1,3-dioxolo[4,5-c]pyridin-6-yl)-
but-3-en-1-ol (23). To a solution of aldehyde 22 (73 mg,
0.19 mmol) and allyltrimethylsilane (0.120 mL, 0.95 mmol)
in CH2Cl2 (4 mL) was added TiCl4 (1 M in CH2Cl2;
0.20 mL, 0.20 mmol) at 2658C. After 15 h at 2788C, a
saturated solution of NH3 in EtOH (0.2 mL) was added and
the reaction mixture allowed to attain rt. The mixture was
poured into Et2O (5 mL) and H2O (5 mL). The organic
phase was washed with brine and then dried (Na2SO4).
Flash chromatography (pentane–EtOAc 20:1!15:1) gave
1
salt (23 mg, 89%) as white crystals. Mp 174–1768C; H
NMR (500 MHz, D2O) d 4.65 (m, 1H), 3.83, (m, 2H), 3.74
(m, 1H), 3.67 (m, 1H), 3.55 (br t, J¼9.2 Hz, 1H), 3.15 (m,
2H), 2.95 (br t, J¼11.5 Hz, 1H), 2.52 (m, 1H), 2.05 (m, 1H);
13C NMR (125 MHz, D2O) d 79.7, 74.1, 70.6, 70.4, 69.2,
55.5, 54.6, 34.4; [a]D¼þ54.7 (c 0.25, H2O); IR (KBr) 3368,
2841, 1673 cm21; HRMS (FABþ) calcd for C8H16NO4
(2þH): 190.1079, found:190.1082.
1
23 (57 mg, 71%) as an oil. H NMR (400 MHz, CDCl3) d
7.41–7.20 (m, 10H), 5.81 (m, 1H), 5.04 (m, 1H), 4.99 (m,
1H), 4.91 (d, J¼11.5 Hz, 1H), 4.69 (d, J¼11.5 Hz, 1H), 4.08
(br d, J¼8.4 Hz, 1H), 4.01 (d, J¼13.9 Hz, 1H), 3.84 (dd,
J¼8.3, 0.8 Hz, 1H), 3.73 (br s, 1H), 3.58 (d, J¼13.9 Hz,
The 2·TFA salt (23 mg, 0.076 mmol) from above was
subjected ion-exchange chromatography (Dowex 1-X, OH2

P. Somfai et al. / Tetrahedron 59 (2003) 1293–1299
1299
9. Sunkara, P. S.; Bowlin, T. L.; Liu, P. S.; Sjoerdsma, A.
Biochem. Biophys. Res. Commun. 1987, 148, 206–210.
10. Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R. Cancer
Res. 1988, 48, 1091–1094.
form, 100–200 mesh, H2O). Removal of the solvents
followed by lyophilization gave 2 (13 mg, 81% from 24) as
white crystals. Mp 209–2118C dec (lit.28 mp 212–2158C);
1H NMR (500 MHz, D2O) d 4.41 (dd, J¼7.2, 4.4, 1.7 Hz,
1H), 3.61 (ddd, J¼10.4, 9.3, 5.1 Hz, 1H), 3.60 (br t,
J¼9.6 Hz, 1H), 3.33 (t, J¼9.1 Hz, 1H), 3.18 (dd, J¼5.1 Hz,
1H), 3.09 (td, J¼9.1, 2.2 Hz, 1H), 2.34 (dddd, J¼14.2, 9.4,
7.3, 2.4 Hz, 1H), 2.22 (q, J¼9.1 Hz, 1H), 2.06 (t,
J¼10.7 Hz, 1H), 2.02 (dd, J¼9.8, 4.4 Hz, 1H), 1.71 (dtd,
J¼14.2, 8.8, 1.8 Hz, 1H); 13C NMR (125 MHz, D2O) d
81.8, 74.2, 72.9, 72.4, 71.8, 58.2, 54.4, 35.5; [a]D¼þ82.4 (c
0.35, H2O) [lit.28 [a]D¼þ76.8 (c 0.1, H2O)].
11. Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045–4066.
12. Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999,
121, 3046–3056.
¨
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Acknowledgements
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0.5 mL/min.
This work was supported financially by the Swedish
Research Council. We are grateful to Mr Jan Blid for
assistance with NMR measurements.
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