Syntheses and Glycosidase Inhibitory Activities of 2-(Aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol Derivatives

Article abstract of DOI:10.1002/hlca.200490078

New 2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol derivatives were synthesized from (5S)-5-[(trityloxy)methyl]pyrrolidin-2-one (6) (Schemes 1 and 2) and their inhibitory activities toward 25 glycosidases assayed (Table). The influence of the confi

Full text of DOI:10.1002/hlca.200490078

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Helvetica Chimica Acta Vol. 87 (2004)
Syntheses and Glycosidase Inhibitory Activities of 2-(Aminomethyl)-5-
(hydroxymethyl)pyrrolidine-3,4-diol Derivatives
by Florence Popowycz, Sandrine Gerber-Lemaire*, Catherine Sch¸tz, and Pierre Vogel
Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology, EPFL-BCH,
CH-1015 Lausanne
New 2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol derivatives were synthesized from (5S)-5-
[(trityloxy)methyl]pyrrolidin-2-one (6) (Schemes 1 and 2) and their inhibitory activities toward 25 glycosidases
assayed (Table). The influence of the configuration of the pyrrolidine ring on glycosidase inhibition was
evaluated. (2R,3R,4S,5R)-2-[(benzylamino)methyl]-5-(hydroxymethyl)pyrrolidine-3,4-diol ((‡)-21) was found
to be a good and selective inhibitor of a-mannosidase from jack bean (Ki ˆ 1.2 mm) and from almond (Ki ˆ
1.0 mm). Selectivity was lost for the non-benzylated derivative (2R,3R,4S,5R)-2-(aminomethyl)-5-(hydroxy-
methyl)pyrrolidine-3,4-diol ((‡)-22) which inhibited a-galactosidases, b-galactosidases, b-glucosidases, and a-
N-acetylgalactosaminidase as well.
Introduction.
Enzymes that are involved in the synthesis and processing of
oligosaccharides, such as glycosidases and glycosyltransferases, are important catalysts
for the specific assembly of oligosaccharide structures on proteins [1] and sphingolipids
[2]. The design and preparation of selective inhibitors of these enzymes [3] is of high
interest, as these molecules can be used to modulate cellular functions. Moreover they
may provide potential drugs in new therapeutic strategies [4]. In particular,
swainsonine (1), a natural inhibitor of Golgi a-mannosidase II containing a 4-amino-
4-deoxymannofuranoside unit [5], reduces certain tumors and hematological dysfunc-
tions [6] (Fig.). Nevertheless, some side effects resulted in limitations for the
development of this compound in medicinal treatments. The search for new a-
mannosidase inhibitors that might be used as antimetastatic agents is an important field
of investigation, and some synthetic analogues of swainsonine have also shown
interesting properties [7]. Recently, we reported that (2R,3R,4S) and (2S,3R,4S)-2-
(aminomethyl)pyrrolidine-3,4-diol derivatives, such as 3a and 4, are selective and
competitive inhibitors of a-mannosidases [8].
Inspired by the work of Saotome and co-workers [9], we wondered whether the
introduction of a hydroxymethyl substituent at the C(5) position of the pyrrolidine ring
could enhance the enzymatic inhibitory activity of our aromatic derivatives. We report
here the syntheses and inhibitory activities toward glycosidases of 2-(aminomethyl)-5-
(hydroxymethyl)pyrrolidine-3,4-diol derivatives 5.
Results and Discussion. Following the procedure reported by Ikota and co-
workers [10], the semi-protected lactam 6 was converted to the diastereoisomeric
alcohols (À)-9 and (À)-10 via the allylic alcohols 7, which were obtained as a mixture of
unseparable diastereoisomers (Scheme 1). Mesylation of the secondary alcohols 7

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801
Figure. Swainsonine (1) and synthetic analogues as a-mannosidase inhibitors. Ki for a-mannosidase from jack
bean.
followed by treatment with tBuOK induced cyclization to give the protected
pyrrolidines 8 in 50% yield. Ozonolysis of the olefin moiety and reductive treatment
of the resulting aldehydes afforded (À)-9 and (À)-10 in 29 and 43% yields, respectively.
The major stereoisomer (À)-10 was first oxidized under Swern conditions [11] and
submitted to reductive amination in the presence of benzylamine to generate the
protected diamine (À)-11 in 77% yield. Acidic hydrolysis of all the protective groups
afforded (À)-12 in quantitative yield. The corresponding free diamino derivative (À)-
13 was obtained after cleavage of the benzyl group and treatment with HCl. It was
possible to generate the related enantiomers by transformation of the tritylated
alcohol. For this purpose, alcohol (À)-10 was silylated under classical conditions
(tBuMe2SiOTf, 2,6-lutidine (ˆ2,6-dimethylpyridine), 08), and Birch reduction of the
resulting bis-ether allowed rapid and efficient removal of the trityl protecting group.
All other attempts (HCOOH, TsOH, ZnBr2, Me2SiCl/phenol, H2/Pd(OH)2) failed to
give the semiprotected derivative (‡)-14. Following the procedure described before,
the benzylamino derivative (‡)-12 and the corresponding diamino derivative (‡)-13
were obtained via (‡)-15 in 68 and 51% yield, respectively (starting from (‡)-14).
To generate other stereoisomers of this family, alcohol (À)-9 was protected as a silyl
ether ( ! (À)-16) and submitted to Birch reduction (Scheme 2). However, the so-
formed alcoholate intermediate readily cyclized at the carbamate moiety to provide the
bicyclic derivative (À)-17 in excellent yield1). In the case of the isomer derived from
(À)-10, the bulky trityl and tert-butyldimethylsilyl groups are located on the same face
of the pyrrolidine ring so that the carbamate group may be pushed down on the
opposite face of the ring. As a result, the cyclization was not observed within the
reaction time. For isomer (À)-9, it was necessary to turn to a methoxymethyl (MOM)
protective group ( ! (À)-18) to avoid this side reaction and to isolate the free alcohol
1
)
Such derivatives are often observed in the multi-step synthesis of pyrrolidine derivatives [12].

Scheme 1. Synthesis of(2 S,3S,4R,5R)- and (2R,3R,4S,5S)-2-(Aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol Derivatives
Tr ˆ Ph3C, Boc ˆ tBuOC(O), Bn ˆ PhCH2, TBS ˆ tBuMe2Si

Helvetica Chimica Acta Vol. 87 (2004)
803
(À)-19 in 76% yield. Oxidation under Swern conditions followed by reductive
amination in the presence of benzylamine afforded, after appropriate deprotection of
the intermediate (À)-20, the benzylamino derivative (‡)-21 and the diamino derivative
(‡)-22.
Scheme 2. Synthesis of(2 R,3R,4S,5R)-2-(Aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol Derivatives
Tr ˆ Ph3C, Boc ˆ tBuOC(O), TBS ˆ tBuMe2Si, MOM ˆ MeOCH2, Bn ˆ PhCH2
Compounds (À)-12, (À)-13, (‡)-12, (‡)-13, (‡)-21, and (‡)-22 were tested for their
inhibitory activities toward 25 commercially available glycosidases2), and the results
were compared with the activities of the previously reported inhibitors 3. The data are
summarized in the Table for galactosidases, glucosidases, mannosidases, and one a-N-
acetylgalactosaminidase. Our derivatives did not show any inhibitory activity at 1m m
concentration toward a-l-fucosidases from bovine epididymis and from human
placenta, b-mannosidase from Helix pomatia, b-xylosidase from Aspergillus niger,
and b-N-acetylglucosaminidases from jack bean and from bovine epididymis A and B.
2
)
For detailed experimental conditions, see [13].

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Helvetica Chimica Acta Vol. 87 (2004)
Table. Inhibitory Activities of3,4-Dihydroxy-5-(hydroxymethyl)-2-yl Derivatives. Percentage of inhibition at
1 mm concentration, IC50 and Ki in mm, optimal pH. All inhibitions are competitive, except when indicated. M ˆ
mixed-type inhibition, n.i. ˆ no inhibition at 1m m concentration.
3a
3b
(À)-12 (‡)-12 (À)-13 (‡)-13 (‡)-21
(‡)-22
a-Galactosidase:
coffee bean
Aspergillus niger
E. coli
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
72%
n.i.
n.i.
92%
n.i.
n.i.
100%
44%
63%
b-Galactosidase:
E. coli
bovine liver
Aspergillus niger
Aspergillus orizae
jack bean
24%
26%
n.i.
n.i.
n.i.
92%
n.i.
24%
60%
76%
n.i.
45%
n.i.
n.i.
37%
n.i.
59%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
97%
n.i.
n.i.
n.i.
n.i.
n.i.
30%
n.i.
n.i.
n.i.
83%
86%
n.i.
43%
40%
b-Glucosidase:
almond
68%
97%
93%
n.i.
n.i.
51%
41%
31%
40%
36%
n.i.
41%
58%
99%
97%
Caldocellum saccharolyticum n.i.
a-Mannosidase:
jack bean
almond
92%
81%
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
100%
97%
97%
IC50 ˆ 60 IC50 ˆ 170
IC50 ˆ 6.2
Ki ˆ 1.2(M)
98%
Ki ˆ 7.4
Ki ˆ 53
69%
51%
21%
IC50 ˆ 230 IC50 ˆ 1000
IC50 ˆ 4.5
Ki ˆ 71
Ki ˆ 1.0
a-N-Acetylgalactosaminidase:
chicken liver
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
99%
99%
IC50 ˆ 2.3
Ki ˆ 24
As we already observed for the aminopyrrolidinediol 3b, derivatives that bear a
primary amino group at the lateral side chain are moderate to strong inhibitors of a
wide range of enzymes. In particular, aminopyrrolidinediol (‡)-22 is a strong inhibitor
of a-galactosidase from coffee bean (100% inhibition at 1mm), b-glucosidases from
almond and Caldocellum saccharolyticum (99% and 97% at 1mm), a-mannosidase
from jack bean and almond (each 97% at 1mm), and a-N-acetylgalactosaminidase from
chicken liver (99% at 1mm). This lack of selectivity is probably due to the small size of
the pyrrolidine derivative that can enter the active site of various enzymes without any
specificity due to its flexibility. Introduction of an aromatic substituent at the primary
amino group resulted in significative enhancement of the enzymatic selectivity, in
particular for the (2R,3R,4S,5R) derivative (‡)-21 that appeared to be the most
promising inhibitor of this study. This compound demonstrated competitive inhibition
(LineweaverÀBurk plots) of a-mannosidase from almond (IC50 ˆ 4.5 mm, Ki ˆ 1 mm)
and a-N-acetylgalactosaminidase from chicken liver (IC50 ˆ 2.3 mm, Ki ˆ 24 mm) and
mixed-type inhibition of a-mannosidase from jack bean (IC50 ˆ 6.2 mm, Ki ˆ 1.2 mm). In
comparison with derivative 3a, which has no substituent at C(5) of the pyrrolidine ring,
we observed not only enhancement of the inhibitory activity toward a-mannosidases
(increase of a factor 70 for the inhibition of a-mannosidase from almond), but also
found good inhibition of a-N-acetylgalactosaminidase.

Helvetica Chimica Acta Vol. 87 (2004)
805
These inhibitions can result from the different conformations adopted by the
pyrrolidine ring that can either mimic a galactopyranoside or a mannopyranoside
(Scheme 3). In derivative 3a, the absence of a hydroxymethyl group at C(5) resulted in
a complete loss of the binding to galactosidases. As expected, we also observed that the
absolute configuration of the stereogenic centers of the pyrrolidine ring has a crucial
influence on the inhibitory activities as the other isomers (À)-12 and (‡)-12 exhibited
poor or no inhibition toward the glycosidases tested.
Scheme 3. Possible Conformations Adopted by the Pyrrolidine Ring
Conclusions. We have synthesized polysubstituted five-membered iminoalditols
from (5S)-5-[(trityloxy)methyl]pyrrolidin-2-one (6) with various configurations. Eval-
uation of their inhibitory activities toward glycosidases demonstrated that only the
(2R,3R,4S,5R) derivative exhibits interesting properties with strong inhibiton of a-
mannosidases and a-N-acetylgalactosaminidase due to the different conformations that
can adopt the pyrrolidine ring. Moreover, the introduction of a hydroxymethyl
substituent at C(5) of the pyrrolidine ring led to significative enhancement of the
inhibitory activity toward a-mannosidases in comparison with the nonsubstituted
derivative. Exchange of the benzyl group in (‡)-21 for other aromatic systems might
lead to better a-mannosidase inhibitors.
This work was supported by the Swiss National Science Foundation (Grant N8 2100-063567.00/1) and the
¬
¬
Office Federal de l×Enseignement et de la Recherche (COST D13/0001/99).
Experimental Part
General. All commercially available reagents (Fluka, Aldrich) were used without further purification.
Solvents were dried by standard methods. Light petroleum ether refers to the fraction boiling at 40 608. Liquid/
solid flash chromatography (FC): silica-gel 60 (Merck No. 9385; 240 400 mesh). TLC: Merck silica-gel 60F254
plates; detection by UV light, Pancaldi reagent ((NH4)6MoO4, Ce(SO4)2, H2SO4, H2O) or KMnO4. IR Spectra:
Perkin-Elmer 1420 spectrometer. Optical rotations: Jasco DIP-370 polarimeter; [a]D in 10À1 deg cm2 gÀ1
.
1H-NMR Spectra: Bruker ARX-400 spectrometer, at 400 MHz; d(H) in ppm rel. to the solvent×s residual signal
(CHCl3, d(H) 7.278; CH3OD, d(H) 3.31) as internal reference, J in Hz; all 1H assigments were confirmed by 2D-
COSY-45 and 2D-NOESYexperiments. 13C-NMR Spectra: same instrument as for 1H but at 100.6 MHz; d(C) in
ppm rel. to the solvent×s signal (CDCl3, d(C) 77.08; CD3OD, d(C) 49.2) as internal reference, J in Hz; all 13C

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Helvetica Chimica Acta Vol. 87 (2004)
assignments were confirmed by 2D-HMQC. MS: Nermag R 10-10C, chemical ionization (NH3) mode; m/z
(amu) (% rel. to base peak). Elemental analyses: Ilse Beetz, D-96301Kronach.
tert-Butyl (3aS,4S,6R,6aR)-4-[(Benzylamino)methyl]-tetrahydro-2,2-dimethyl-6-[(trityloxy)methyl]-5H-
[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((À)-11). To a soln. of oxalyl chloride (81 ml, 0.94 mmol, 1.15 equiv.)
in CH2Cl2 (4 ml), cooled to À788, was added DMSO (140 ml, 1.97 mmol, 2.4 equiv.). After 20 min, alcohol (À)-
10 (446 mg, 0.82 mmol, 1equiv.) in anh. CH 2Cl2 (8 ml) was added dropwise. After 20 min, Et3N (571 ml,
4.1mmol, 5 equiv.) was added, and the mixture was warmed to À308 for 20 min. The mixture was poured into
H2O (15 ml) and extracted with CH2Cl2 (3 Â 20 ml). The combined extract was washed with brine (20 ml), dried
(MgSO4), and evaporated to afford a pale yellow oil. Sodium triacetoxyborohydride (243 mg, 1.15 mmol,
1.4 equiv.) was added portionwise to a stirred soln. of the crude aldehyde (0.82 mmol, 1 equiv.) and benzylamine
(0.82 mmol, 1equiv.) in 1,2-dichloroethane (8 ml). After stirring at r.t. overnight, the soln. was poured into sat.
aq. NaHCO3 soln. (10 ml) and extracted with CH2Cl2 (3 Â 10 ml). The combined org. extract was dried
(MgSO4) and evaporated. FC (silica gel, AcOEt/light petroleum ether 1:1) afforded ( À)-11 (400 mg, 77% (2
25
25
25
25
25
steps)). Colorless oil. [a] ˆ À28, [a] ˆ À31, [a] ˆ À35, [a] ˆ À57, [a] ˆ À69 (c ˆ 0.37, CH2Cl2). UV
589
577
546
435
405
(MeCN) 271 (33000), 214 (31560). IR (film): 3445, 3060, 2980, 2935, 1690, 1490, 1450, 1395, 1215, 1160, 1130,
1065, 1000, 900, 870, 755, 700. 1H-NMR (400 MHz, CDCl3): 7.47 7.25 (m, 20 arom. H); 4.70 4.62 (m,
HÀC(3a), HÀC(6a)); 4.17 (m, HÀC(6)); 4.04 3.84 (m, HÀC(4)); 3.65 3.52 (m, PhCH2); 3.38 3.04 (m, 2
HÀC(1'')); 2.74 (dd, 3J(1',4) ˆ 4.7, 2J ˆ 11.7, 1 HÀC(1')); 2.67 2.54 (m, 1 HÀC(1')); 1.49 (s, Me2C); 1.38 (s, tBu):
1.36 (s, Me2C). 13C-NMR (101 MHz, CDCl3): 154.3 (s, NCOO); 143.6 (s, arom. C); 140.4 (s, arom. C); 128.8,
128.3, 128.0, 127.8, 127.1, 126.8 (6d, arom. C); 111.6 (s, Me2CO); 86.4 (s, Ph3C); 83.2, 82.3 (2d, C(3a), C(6a)); 79.8
(s, Me3CO); 64.6 (2d, C(4), C(6)); 63.2 (t, C(1'')); 53.6 (t, PhCH2); 51.1 (t, C(1')); 28.3 (q, Me3C); 27.3 (q, Me);
‡
25.5 (q, Me). CI-MS (NH3): 635 (100, [M ‡ H] ), 391 (10), 335 (4), 243 (91), 198 (25), 128 (68), 91 (27,
‡
PhCH2 ). Anal. calc. for C40H46N2O5 (634.85): C 75.68, H 8.09, N 4.41; found: C 75.74, H 8.07, N 4.38.
(2S,3S,4R,5R)-2-[(Benzylamino)methyl]-5-(hydroxymethyl)pyrrolidine-3,4-diol ((À)-12). A soln. of (À)-
11 (48 mg, 7.561¥ 10 À5 mol) in CF3COOH (4 ml) and H2O (0.5 ml) was stirred at r.t. for 45 min. Evaporation and
25
25
FC (silica gel, MeCN/NH4OH soln. 4 :1) afforded (À)-12 (19 mg, 100%). Pale yellow oil. [a] ˆ À4, [a]
ˆ
589
577
25
25
25
À5, [a] ˆ À5, [a] ˆ À9, [a] ˆ À1 2 (c ˆ 0.59, H2O). UV (MeCN): 260 900), 206 (6600). IR (film): 3210,
435
435
405
1695, 1680, 1650, 1435, 1200, 1135. 1H-NMR (400 MHz, MeOD): 7.48 7.36 (m, 5 arom. H); 4.07 (s, PhCH2); 3.99
(dd, J(4,3) ˆ 5.1, 3J(4,5) ˆ 5.1, HÀC(4)); 3.85 (dd, J(3,4) ˆ 5.1, 3J(3,2)) ˆ 5.2, HÀC(3)); 3.71( dd, J(1'',5)) ˆ
4.0, 2J ˆ 11.3, 1 HÀC(1'')); 3.63 (dd, 3J(1'',5) ˆ 4.7, 2J ˆ 11.3, 1 HÀC(1'')); 3.43 (m, HÀC(2)); 3.35 (m, HÀC(5));
3.08 (dd, 3J(1',2) ˆ 4.7, 2J ˆ 12.7, 1 HÀC(1')); 2.89 (dd, 3J(1',2)) ˆ 8.5, 2J ˆ 12.7, 1 HÀC(1')). 13C-NMR (101 MHz,
MeOD): 137.2 (s, arom. C), 131.1 (d, 1J(C,H) ˆ 159, 2 arom. C), 130.8 (d, 1J(C,H) ˆ 161, 2 arom. C), 130.4 (d,
1J(C,H) ˆ 161, arom. C), 75.9 (d, 1J(C,H) ˆ 143, C(3)); 74.1 (d, 1J(C,H) ˆ 148, C(4)), 66.5 (d, 1J(C,H) ˆ 141,
C(5)), 63.3 (t, 1J(C,H) ˆ 143, C(1'')); 62.3 (d, 1J(C,H) ˆ 142, C(2)), 54.2 (t, 1J(C,H) ˆ 140, PhCH2), 51.2 (t,
3
3
3
1J(C,H) ˆ 141, C-(1')). CI-MS (NH3): 253 (100, [M ‡ H] ), 221 (6), 163 (3), 146 (10), 132 (58), 120 (71), 115
‡
‡
(67), 91(56, PhCH 2 ).
(2S,3S,4R,5R)-2-(Aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol ((À)-13).
A
soln. of (À)-11
(104 mg, 0.16 mmol) and 10% Pd(OH)2/C (20 mg) in MeOH (3 ml) was stirred at r.t. for 12 h. The mixture
was filtered through a pad of Celite and evaporated: pale oil (68 mg, 76%). This crude intermediate was stirred
at r.t. for 30 min in a 4m aq. HCl soln. (2.5 ml). Evaporation and FC (silica gel, MeCN/NH4OH soln. 4 :1)
25
25
25
25
afforded (À)-13 (20 mg, 100%). Pale yellow oil. [a] ˆ À4, [a] ˆ À5, [a] ˆ À7, [a] ˆ À1 3 c( ˆ 0.26,
589
577
546
435
H2O). UV(MeCN): 295 (1300), 260 (1280), 212 (3200). IR (film): 3500 3000, 1650, 1455, 1205, 800, 700.
1H-NMR (400 MHz, D2O): 4.33 (dd, J(3,4) ˆ 5.0, J(3,2) ˆ 7.6, HÀC(3)); 4.29 (dd, J(4,5) ˆ 3.7, J(4,3) ˆ 5.0,
3
3
3
3
HÀC(4)); 3.97 (dd, 3J(1'',5) ˆ 3.4, J ˆ 12.0, 1 HÀC(1'')); 3.92 3.83 (m, 1 HÀC(1''), HÀC(2), HÀC(5)); 3.57
2
(AB, 2 HÀC(1')). 13C-NMR (101 MHz, D2O): 75.0 (d, 1J(C,H) ˆ 148, C(3)); 72.6 (d, 1J(C,H) ˆ 154, C(4)); 68.6
(d, 1J(C,H) ˆ 149, C(5)); 61.1 (d, 1J(C,H) ˆ 148, C(2)); 60.6 (t, 1J(C,H) ˆ 146, C(1'')); 41.0 (t, 1J(C,H) ˆ 146,
‡
C(1')). CI-MS (NH3): 163 (6, [M ‡ H] ), 146 (8), 132 (100), 115 (11), 84 (9).
tert-Butyl (3aS,4S,6R,6aR)-4-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}tetrahydro-6-(hydroxymethyl)-2,2-
dimethyl-5H-[1,3]dioxolo[4,5-c] pyrrole-5-carboxylate ((‡)-14). To a soln. of (À)-10 (503 mg, 0.92 mmol) in
CH2Cl2 (15 ml), cooled to 08, were added 2,6-lutidine (267 ml, 2.30 mmol, 2.5 equiv.) and tBuMe2SiOTf (296 ml,
1.29 mmol, 1.4 equiv.). After stirring for 10 min at 08, the mixture was diluted with CH2Cl2 (20 ml) and poured
into sat. aq. NaHCO3 soln. (20 ml). The aq. layer was extracted with CH2Cl2 (3 Â 20 ml). The combined extract
was washed with brine (10 ml), dried (MgSO4), and evaporated. FC (silica gel, Et2O/light petroleum ether 1:9)
afforded intermediate fully protected pyrrolidine (354 mg, 58%) as a colorless oil.
Metallic Na (185 mg, 8.0 mmol, 15 equiv.) was added to liq. NH3 (10 ml; condensed at À788). A soln. of the
fully protected pyrrolidine (354 mg, 0.54 mmol) in THF (5 ml) was added dropwise. After stirring at À788 for

Helvetica Chimica Acta Vol. 87 (2004)
807
20 min, solid NH4Cl was added, and the mixture was allowed to warm up to r.t. The residue was diluted with
MeOH, filtrated on a pad of Celite, and evaporated. Purification by FC (silica gel, AcOEt/light petroleum ether
25
25
25
25
1:4) afforded (‡)-14 (211 mg, 94%). Colorless oil. [a] ˆ ‡10, [a] ˆ ‡1 1 ,a][ ˆ ‡13, [a] ˆ ‡22,
589
577
546
435
25
[a] ˆ ‡25 (c ˆ 0.75, CH2Cl2). UV (MeCN): 285 (20700). IR (film): 3445, 2935, 2885, 2860, 1695, 1675, 1470,
405
1
1395, 1335, 1255, 1215, 1175, 1110, 1065, 1005, 975, 940, 840, 780. H-NMR (400 MHz, CDCl3): 4.81 4.71( m,
HÀC(3a)); 4.68 4.54 (m, HÀC(6a)); 4.40 3.58 (m, HÀC(4), HÀC(6), 2 HÀC(1'), 2 HÀC(1'')); 1.51 (s,
t
Me2C); 1.48 (s, Bu); 1.36 (s, Me2C); 0.93 (s, Me3CSi); 0.12 (s, Me2Si). 13C-NMR (101 MHz, CDCl3): 154.1
(NCOO); 111.5 (Me2CO); 82.1, 81.6, 81.5, 80.9 (C(3a), C(6a)); 80.7, 80.3 (Me CO); 66.7, 66.3, 65.8, 64.8, 63.9,
3
63.6, 63.1(C(4), C(6), C(1 '), C(1'')); 28.4 (tBu); 27.6 (Me2C); 26.0 (Me3CSi); 25.5 (Me2C); 18.6 (Me3CSi); À5.5,
‡
À5.6 (Me2Si). CI-MS (NH3): 418 (18, [M ‡ H] ), 362 (15), 318 (56), 304 (45), 260 (29), 228 (11), 202 (55), 172
(100), 116 (7), 75 (28). Anal. calc. for C20H39NO6Si (417.65): C 57.52, H 9.41, N 3.35; found C 57.56, H 9.54,
N 3.44.
tert-Butyl (3aR,4R,6S,6aS)-4-[(Benzylamino)methyl]-6-{{[(tert-butyl)dimethylsilyl]oxy}methyl}tetrahy-
dro-2,2-diemethyl-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((‡)-15). As described for (À)-11, with oxalyl
chloride (23 ml, 0.26 mmol, 1.15 equiv.), CH2Cl2 (1.5 ml), DMSO (39 ml, 0.55 mmol, 2.4 equiv.), (‡)-14 (94 mg,
0.23 mmol), CH2Cl2 (2.5 ml), and Et2N (160 ml, 1.15 mmol, 5 equiv.). Workup with H2O (1 0 ml), CHCl2 (3 Â
2
10 ml), and brine (10 ml). Then with sodium triacetoxyborohydride (68 mg, 0.32 mmol, 1.4 equiv.), crude
aldehyde (0.23 mmol), benzylamine (25 ml, 0.23 mmol), and 1,2-dichloroethane (3 ml) (12 h). Workup with sat.
aq. NaHCO3 soln. (5 ml) and CH2Cl2 (3  5 ml). FC (silica gel, AcOEt/light petroleum ether 1:4) afforded ( ‡)-
25
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25
15 (1:1 mixutre of rotamers a and b; 79 mg, 68% (2 steps)). Colorless oil. [a] ˆ ‡22, [a] ˆ ‡22, [a]
ˆ
589
577
546
25
25
‡25, [a] ˆ ‡33, [a] ˆ ‡34 (c ˆ 0.49, CH2Cl2). UV (MeCN) 270 (4100), 208 (9030). IR (film): 3335, 2955,
435
405
2930, 2860, 1695, 1470, 1455, 1395, 1335, 1255, 1215, 1175, 1115, 1065, 975, 835, 780, 735, 700. 1H-NMR
(400 MHz, CDCl3): 7.34 7.24 (m, 5 arom. H); 4.69 (m, HÀC(3a)); 4.60 (m, HÀC(6a)); 4.02 3.55 (m, HÀC(4),
HÀC(6), PhCH2, 2 HÀC(1'')); 2.87 2.60 (m, 2 HÀC(1')); 1.47 (s, tBu); 1.40 (s, Me2C); 1.34 (s, Me2C); 0.89 (s,
Me3CSi); 0.04, 0.03 (2 s, Me). 13C-NMR (101 MHz, CDCl3): 154.5 (s, NCOO); 140.4 (s, arom. C); 128.3 (d,
1J(C,H) ˆ 159, 2 arom. C); 128.0 (d, 1J(C,H) ˆ 160, 2 arom. C); 126.9 (d, 1J(C,H) ˆ 158, arom. C); 111.5 (s,
Me2CO); 83.7 (d, 1J(C,H) ˆ 153, C(6a)a); 83.2 (d, 1J(C,H) ˆ 156, C(6a)b); 81.9 (d, 1J(C,H) ˆ 151, C(3a)b); 81.1
1
1
1
(d, J(C,H) ˆ 157, C(3a)a); 79.9 (s, Me3CO); 66.0, 64.7 (2d, J(C,H) ˆ 144, J(C,H) ˆ 142, C(4), C(6)); 63.2 (t,
1J(C,H) ˆ 142, C(1'')b); 62.7 (t, 1J(C,H) ˆ 144, C(1'')a), 53.7 (t, 1J(C,H) ˆ 132, PhCH2); 51.2 (t, 1J(C,H) ˆ 136,
C(1')), 28.4 (q, 1J(C,H) ˆ 126, Bu); 27.4 (q, 1J(C,H) ˆ 127, Me2C); 26.0 (q, 1J(C,H) ˆ 125, Me3CSi); 25.5 (q,
t
1J(C,H) ˆ 126, Me2C); 18.4 (s, Me3CSi); À5.4 (q, 1J(C,H) ˆ 120, Me2Si). CI-MS: 507 (100, [M ‡ H] ), 449 (1),
‡
228 (3), 154 (9), 120 (42), 91 (11).
tert-Butyl (3aS,4R,6R,6aR)-4-{{(tert-Butyl)dimethylsilyl]oxy}methyl}tetrahydro-2,2-dimethyl-6-[(tritylox-
y)methyl]-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((À)-16). As described for (‡)-14 with alcohol (À)-9
(574 mg, 1.05 mmol), CH2Cl2 (17 ml), 2,6-lutidine (305 ml, 2.63 mmol, 2.5 equiv.), and tBuMe2Si (338 ml,
25
1.47 mmol, 1.4 equiv.) (omitting the Na/NH3 treatment) (À)-16 (631mg, 91%). Colorless oil. [ a] ˆ À60,
589
25
25
25
25
[a] ˆ À63, [a] ˆ À68, [a] ˆ À114, [a] ˆ À134 (c ˆ 0.59, CH2Cl2). UV (MeCN) 262 (2200), 210
577
546
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405
(28300). IR (film): 3435, 2955, 2855, 1695, 1450, 1370, 1255, 1215, 1165, 1085, 1000, 840, 755, 705. 1H-NMR
(400 MHz, CDCl3): 7.42 7.24 (m, 15 arom. H); 4.87 4.48 (m, HÀC(3a), HÀC(6a), 1H ÀC(1')); 4.15 4.05 (m,
HÀC(4), HÀC(6)); 3.87 (m, 1 HÀC(1')); 3.36 3.04 (m, 2 HÀC(1'')); 1.53 (s, Me2C); 1.49 (s, Me2C); 1.34 (s,
tBu); 0.94 (s, Me3CSi); 0.11 (s, Me2Si). 13C-NMR (101 MHz, CDCl3): 154.3 (NCOO); 143.6 (arom. C); 128.6,
127.9, 127.1 (arom C); 111.5 (Me2CO); 86.5 (Ph3CO); 80.3 (C(3a), C(6a)); 80.2 (Me3CO); 65.0, 63.6 (C(4),
C(6)); 63.5 (C(1'')); 60.5 (C(1')); 28.4 (tBu); 26.5 (Me2C); 25.9 (Me3CSi); 25.0 (Me2C); 18.5 (Me3CSi); À5.5 (q,
‡
Me2CSi). CI-MS (NH3): 660 (7, [M ‡ H] ), 286 (5), 243 (100), 165 (16), 105 (7). Anal. calc. for C39H53NO6Si
(659.98): C 70.98, H 8.09, N 2.12; found: C 70.91, H 8.03, N 2.09.
(3aR,3bR,8R,8aS)-8-{{[(tert-Butyl)dimethylsilyl]oxy}methyl}tetrahydro-4H,6H-[1,3]dioxolo[3,4]pyrro-
lo[1,2-c]oxazol-6-one ((À)-17). As described for (‡)-14 (omitting the tBuMe2SiO Tf/2,6-lutidine treatment)
with Na (42 mg, 1.84 mmol, 15 equiv.), NH3 (5 ml), (À)-16 (81mg, 0.12 mmol), and THF (2 ml) (NH 4Cl (0.5 g)
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25
25
25
for workup): (À)-17 (39 mg, 91%). [a] ˆ À9, [a] ˆ À1 1 ,a[] ˆ À14, [a] ˆ À25, [a] ˆ À30 (c ˆ 0.37,
589
577
546
435
405
CH2Cl2). UV (MeCN): 334 (470), 206 (3700). IR (film): 3500, 2930, 2855, 1765, 1705, 1470, 1395, 1255, 1215,
1080, 840, 775. 1H-NMR (400 MHz, CDCl3): 4.91( dd, 3J(8a,3a) ˆ 6.4, 3J(8a,8)) ˆ 6.4, HÀC(8a)); 4.56 (dd,
3J(4,3b) ˆ 8.3, J ˆ 9.4, HÀC(4)); 4.47 (dd, J(3a,8a) ˆ 6.4, J(3a,3b) ˆ 6.3, HÀC(3a)); 4.32 (dd, J(4,3b) ˆ 3.4,
2
3
3
3
2J ˆ 9.4, HÀC(4)); 4.17 (m, HÀC(8)); 3.93 (m, HÀC(3b)); 3.89 (dd, 3J(1',8) ˆ 6.6, 2J ˆ 10.5, HÀC(1')); 3.75 (dd,
3J(1',8) ˆ 7.2, J ˆ 10.5, HÀC(1')); 1.53 (s, Me2C); 1.33 (s, Me2C); 0.91( s, Me3CSi); 0.09 (s, Me2Si). 13C-NMR
2
(101 MHz, CDCl3): 160.3 (s, NCOO); 114.8 (s, Me2CO); 84.5 (d, 1J(C,H) ˆ 154, C(3a)); 81.2 (d, 1J(C,H) ˆ 158,
C(8a)); 66.8 (d, 1J(C,H) ˆ 153, C(4)); 62.9 (d, 1J(C,H) ˆ 152, C(3b)); 61.3 (d, 1J(C,H) ˆ 144, C(8)); 60.7 (t,

808
Helvetica Chimica Acta Vol. 87 (2004)
1J(C,H) ˆ 145, C(1')); 27.0 (q, 1J(C,H) ˆ 127, Me2C); 25.8 (q, 1J(C,H) ˆ 125, Me3CSi); 25.0 (q, 1J(C,H) ˆ 127,
‡
Me2C); 18.3 (s, Me3CSi); À5.5 (q, 1J(C,H) ˆ 119, Me2Si). CI-MS (NH3): 344 (28, [M ‡ H] ), 328 (7), 304 (1),
286 (37), 243 (18), 228 (22), 198 (25), 184 (44), 154 (79), 142 (100), 129 (61), 89 (6), 75 (28). Anal. calc. for
C16H29NO5Si (343.51): C 55.95, H 8.51 ; found: C 56.10, H 8.52.
tert-Butyl (3aS,4R,6R,6aR)-Tetrahydro-4-[(methoxymethoxy)methyl]-2,2-dimethyl-6-[(trityloxy)methyl]-
5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (À)-18. To a soln. of (À)-9 (104 mg, 0.19 mmol) in CH2Cl2
(3 ml), cooled to 08, were added N-ethyldiisopropylamine (196 ml, 1.14 mmol, 6 equiv.) and MeOCH2Cl
(58 ml, 0.76 mmol, 4 equiv.). The mixture was allowed to warm to r.t. for 12 h. The soln. was diluted with CH2Cl2
(5 ml) and washed with 1m HCl. The aq. layer was extracted with CH2Cl2 (3 Â 5 ml) and the combined org.
extract dried (MgSO4) and evaporated. FC (silica gel (AcOEt/light petroleum ether 1:4)) afforded (À)-18
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25
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25
(78 mg, 62%). Colorless oil. [a] ˆ À53, [a] ˆ À55, [a] ˆ À63, [a] ˆ À106, [a] ˆ À123 (c ˆ 0.56,
589
577
546
435
405
CH2Cl2). UV (MeCN): 260 (2020), 212 (25500). IR (film): 3060, 2980, 1700, 1600, 1490, 1450, 1370, 1250, 1210,
1155, 1045. 1H-NMR (400 MHz, CDCl3): 7.42 7.12 (m, 15 arom. H); 4.95 (m, HÀC(6a)); 4.72 (AB, OCH2O);
4.50 (m, HÀC(3a)); 4.36 3.80 (m, HÀC(4), HÀC(6), 2 HÀC(1')); 3.46 (m, 1 HÀC(1'')); 3.42 (s, MeO); 3.12
(m, 1 HÀC(1'')); 1.60 (s, Me2C); 1.53 (s, Me2C); 1.35 (s, Bu). 13C-NMR (101 MHz, CDCl3): 154.3 (NCOO);
t
143.5 (arom. C); 128.5, 128.0, 127.2 (arom. C); 111.2 (Me2CO); 97.1(OCH O); 81.4 (C(3a)); 80.3 (Me3CO);
2
80.0 (C(6a)); 65.3 (C(4)); 63.7 (C(1')); 63.5 (C(1'')); 61.6 (C(6)); 55.2 (MeO); 28.4 (tBu); 26.0 (Me2C), 24.8
‡
(Me2C). CI-MS (NH3): 590 (2, [M ‡ H] ), 527 (0.4), 348 (3), 292 (2), 243 (100), 216 (48), 165 (63). Anal. calc.
for C35H43NO7 (589.76): C 71.28, H 7.35; found: C 71.64, H 7.69.
tert-Butyl (3aR,4R,6R,6aS)-Tetrahydro-4-(hydroxymethyl)-6-[(methoxymethoxy)methyl]-2,2-dimethyl-
5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((À)-19). As described for (À)-17, with Na (198 mg, 8.6 mmol,
30 equiv.), NH3 (10 ml), (À)-18 (169 mg, 0.29 mmol), and THF (4 ml) (NH4Cl (0.8 g) for workup): (À)-19
25
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25
25
25
(76 mg, 76%). Colorless oil. [a] ˆ À65, [a] ˆ À70, [a] ˆ À77, [a] ˆ À130, [a] ˆ À153 (c ˆ 0.46,
589
577
546
435
405
CH2Cl2). UV (MeCN): 271 (780), 198 (6670). IR (film): 3460, 2980, 1695, 1660, 1455, 1370, 1250, 1210, 1040.
1H-NMR (400 MHz, CDCl3): 4.81( dd, J(6a,3a) ˆ 6.3, J(HÀ6a,6) ˆ 6.2, HÀC(6a)); 4.67 (AB, OCH2O); 4.47
3
3
(br. s, HÀC(3a)); 4.10 3.86 (m, HÀC(4), HÀC(6), HÀC(1')); 3.81( t, 3J(1'',6) ˆ 9.3, HÀC(1'')); 3.74 (dd,
3J(1',4) ˆ 4.8, 2J ˆ 11.4, HÀC(1')); 3.40 (s, MeO); 1.55 (s, Me2C); 1.49 (s, Bu); 1.38 (s, Me2C). 13C-NMR
t
(101 MHz, CDCl3): 154.3 (s, NCOO); 111.5 (s, Me2CO); 96.7 (t, 1J(C,H) ˆ 165, OCH2O); 80.9 (d, 1J(C,H) ˆ 158,
1
1
1
C(3a)); 80.2 (s, Me3CO); 78.5 (d, J(C,H) ˆ 153, C(6a)); 65.4 (d, J(C,H) ˆ 146, C(4)); 64.9 (t, J(C,H) ˆ 147,
C(1')); 62.9 (t, 1J(C,H) ˆ 145, C(1'')); 60.4 (d, 1J(C,H) ˆ 144, C(6)); 55.2 (q, 1J(C,H) ˆ 142, MeO); 28.4 (q,
1J(C,H) ˆ 127, tBu); 26.0 (q, 1J(C,H) ˆ 127, Me2C); 24.8 (q, 1J(C,H) ˆ 127, Me2C). CI-MS (NH3): 349 (11), 348
‡
(6, [M ‡ H] ), 216 (10), 202 (2), 185 (13), 172 (100), 154 (7), 126 (5), 85 (2). Anal. calc. for C16H29NO7 (347.43):
C 55.32, H 8.41; found: C 55.30, H 8.32.
tert-Butyl (3aR,4R,6R,6aS)-4-[(Benzylamino)methyl]tetrahydro-6-[(methoxymethoxy)methyl]-2,2-di-
methyl-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((À)-20). As described for (À)-11, with oxalyl chloride
(22 ml, 0.25 mmol, 1.15 equiv.), CH2Cl2 (1.5 ml), DMSO (37 ml, 0.52 mmol, 2.4 equiv.), (À)-19 (76 mg,
0.22 mmol, 1equiv.), CH 2Cl2 (2.5 ml), and Et3N (152 ml, 1.09 mmol, 5 equiv.). Workup with H2O (1 0 ml),
CH2Cl2 (3 Â 10 ml), and brine (10 ml). Then with sodium triacetoxyborohydride (65 mg, 0.31 mmol, 1.4 equiv.),
crude aldehyde (0.22 mmol), benzylamine (24 ml, 0.23 mmol, 1equiv.), and 1,2-dichloroethane (2 ml) (12 h).
Workup with sat. aq. NaHCO3 soln. (5 ml) and CH2Cl2 (3 Â 5 ml): (À)-20 (55 mg, 57% (2 steps)). Pale yellow
25
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25
oil. [a] ˆ À65, [a] ˆ À70, [a] ˆ À79, [a] ˆ À133, [a] ˆ À160 (c ˆ 0.62, CH2Cl2). UV (MeCN): 261
589
577
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405
(2530), 207 (17000). IR (film): 3340, 2980, 2935, 1700, 1495, 1455, 1370, 1280, 1245, 1165, 1115, 1050, 1000.
1H-NMR (400 MHz, MeOD): 7.37 7.24 (m, 5 arom. H); 4.83 (dd, 3J(6a,3a) ˆ 6.0, 3J(6a,6) ˆ 5.9, HÀC(6a)); 4.67
(m, HÀC(3a)); 4.63 (s, OCH2O); 4.31 3.83 ( m, 2 HÀC(1'')); 3.86 (m, HÀC(6)); 3.80 3.74 (m, HÀC(4),
PhCH2); 3.38 (s, MeO); 2.70 (m, 2 HÀC(1')); 1.48 (s, Me2C); 1.35 (s, tBu, Me2C). 13C-NMR (101 MHz, MeOD):
157.1 (s, NCOO); 142.0 (s, arom. C); 130.3 (d, 1J(C,H) ˆ 160, 4 arom. C); 129.0 (d, J(C,H) ˆ 161, arom. C);
1
113.3 (s, Me2CO); 98.7 (t, 1J(C,H) ˆ 161, OCH2O); 83.7 (d, 1J(C,H) ˆ 159, C(3a)); 82.4 (s, Me3CO); 81.7 (d,
1J(C,H) ˆ 160, C(6a)); 66.7 (d, 1J(C,H) ˆ 152, C(4)); 66.3 (d, 1J(C,H) ˆ 147, C(1'')); 62.7 (d, 1J(C,H) ˆ 140,
C(6)); 56.4 (q, 1J(C,H) ˆ 135, MeO); 55.4 (t, 1J(C,H) ˆ 134, PhCH2); 50.4 (t, C(1')); 29.5 (q, 1J(C,H) ˆ 127,
Me3C); 27.3, 25.9 (2q, 1J(C,H) ˆ 127, Me2C). CI-MS (NH3): 437 (2, [M ‡ H] ), 375 (1), 216 (2), 184 (7), 143 (2),
‡
‡
120 (33), 91 (100, PhCH2 ). Anal. calc. for C23H36N2O6 (436.57): C 63.28, H 8.31; found: C 63.38, H 8.36.
(2R,3R,4S,5R)-2-[(Benzylamino)methyl]-5-(hydroxymethyl)pyrrolidine-3,4-diol ((‡)-21). As described
for (À)-12, with (À)-20 (24 mg, 5.497 ¥ 10À5 mol), CF3COOH (2 ml), and H2O (0.25 ml) (30 min): (‡)-21
25
25
25
25
(14 mg, 100%). Colorless oil. [a] ˆ ‡6, [a] ˆ ‡7, [a] ˆ ‡8, [a] ˆ ‡1 4 c(ˆ 0.64, MeOH). UV
589
577
546
435
(MeCN): 266 (640), 198 (2400). IR (film): 3280, 2920, 1655, 1580, 1460, 795. 1H-NMR (400 MHz, D2O): 7.53
7.47 (m, 5 arom. H); 4.21( dd, 3J(4,3) ˆ 4.0, 3J(4,5) ˆ 3.7, HÀC(4)); 4.05 (s, PhCH2); 3.99 (dd, 3J(3,4)) ˆ 4.0,

Helvetica Chimica Acta Vol. 87 (2004)
809
3J(3,2)) ˆ 8.2, HÀC(3)); 3.85 (dd, 3J(1'',5) ˆ 6.6, 2J ˆ 11.5, 1 HÀC(1'')); 3.71( dd, 3J(1'',5)) ˆ 6.6, 2J ˆ 11.5, 1
3
2
3
HÀC(1'')); 3.36 (m, HÀC(2), HÀC(5)); 3.08 (dd, J(1',2) ˆ 4.4, J ˆ 12.5, 1 HÀC(1')); 2.93 (dd, J(1',2) ˆ 9.0,
2J ˆ 12.5, 1 HÀC(1')). 13C-NMR (101 MHz, D2O): 134.2 (arom. C); 131.6 (2 arom. C); 131.4 (2 arom. C); 130.9
(arom. C); 78.3 (C(3)); 74.3 (C(4)); 62.5, 60.8 (C(2), C(5), C(1'')); 54.6 (PhCH2); 53.1(C(1 ')). ESI-MS: 253.34.
(2R,3R,4S,5R)-2-(Aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol ((‡)-22). As described for (À)-13,
with (À)-20 (110 mg, 0.250 mmol), 10% Pd(OH)2/C (20 mg), and MeOH (5 ml). Then with the pale yellow oily
intermediate (86 mg, 100%) and 4m HCl (5 ml) (1h). ( ‡)-22 (40 mg, 100%). Colorless oil.
Data ofIntermediate tert-Butyl (3aR,4R,6R,6aS)-4-(Aminomethyl)tetrahydro-6-[(methoxymethoxy)meth-
25
25
25
25
yl]-2,2-dimethyl-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate: [a] ˆ À80, [a] ˆ À80, [a] ˆ À92, [a]
ˆ
589
577
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25
À154, [a] ˆ À182 (c ˆ 0.46, CH2Cl2). UV (MeCN): 263 (640), 198 (9050). IR (film): 3380, 2980, 2935, 1695,
405
1455, 1370, 1280, 1245, 1210, 1165, 1115, 1050, 1000. 1H-NMR (400 MHz, MeOD): 4.82 (m, HÀC(6a)); 4.67 (m,
HÀC(3a)); 4.64 (s, OCH2O); 4.36 4.11 (m, 2 HÀC(1'')); 3.90 (m, HÀC(6)); 3.79 (dd, J(4,3) ˆ 9.1, 3J(4,1') ˆ
3
9.2, HÀC(4)); 3.39 (s, MeO); 2.84 (m, 2 HÀC(1')); 1.50 (s, Me2C, Bu); 1.37 (s, Me2C). 13C-NMR (101 MHz,
t
MeOD): 156.9 (s, NCOO); 113.5 (s, Me2CO); 98.6 (t, 1J(C,H) ˆ 161, OCH2O); 83.0 (d, 1J(C,H) ˆ 146, C(3a));
81.6 (s, Me3CO); 81.5 (d, 1J(C,H) ˆ 158, C(6a)); 66.8 (t, 1J(C,H) ˆ 141, C(1'')); 66.7 (d, 1J(C,H) ˆ 156, C(4));
1
1
1
1
62.4 (d, J(C,H) ˆ 142, C(6)); 56.4 (q, J(C,H) ˆ 136, MeO); 43.4 (t, J(C,H) ˆ 148, C(1')); 29.7 (q, J(C,H) ˆ
127, Me3C); 27.3, 25.9 (2q, 1J(C,H) ˆ 127, Me2C). CI-MS (NH3): 347 (1, [M ‡ H] ), 291(2), 241(6), 216 (22),
‡
184 (100), 154 (24), 126 (17), 98 (42), 84 (24). Anal. calc. for C16H30N2O6 (346.44): C 55.47, H 8.73; found:
C 55.71, H 8.69.
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Data for (‡)-22: [a] ˆ ‡17, [ a] ˆ ‡28, [a] ˆ ‡34, [a] ˆ ‡59, [a] ˆ ‡71( c ˆ 0.13, H2O). UV
589
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435
405
(MeCN): 269 (605), 260 (605), 202 (270). IR (film): 3600 2980, 1680, 1630, 1455, 1435, 1200, 800, 700. 1H-NMR
(400 MHz, D2O): 4.42 (m, HÀC(4)); 4.37 (dd, 3J(3,4)) ˆ 3.7, 3J(3,2)) ˆ 9.5, HÀC(3)); 4.11 4.00 (m, HÀC(5), 2
HÀC(1'')); 3.90 (m, HÀC(2)); 3.61( m, 2 HÀC(1')). 13C-NMR (101 MHz, D2O): 76.6 (d, 1J(C,H) ˆ 142, C(3));
71.9 (d, 1J(C,H) ˆ 157, C(4)); 65.4 (d, 1J(C,H) ˆ 151, C(5)); 59.9 (t, 1J(C,H) ˆ 141, C(1'')); 59.4 (d, 1J(C,H) ˆ 144,
1
C(2)); 41.5 (t, J(C,H) ˆ 142, C(1')). EI-MS: 163.38.
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Received October 16, 2003