Lewis acid catalyzed ring-opening reactions of sugar-derived semicyclic N,O-acetals

Article abstract of DOI:10.1002/1522-2675(200211)85:11<3678::AID-HLCA3678>3.0.CO;2-0

N-(Alkoxycarbonyl)-N-glycosides (polyoxygenated semicyclic N.O-acetals) were efficiently synthesized from regular acetyl or methyl glycosides (glucopyranoside, ribofuranoside, arabinofuranoside, and 2-deoxyribofuranoside) and a carbamate by treatment of t

Full text of DOI:10.1002/1522-2675(200211)85:11<3678::AID-HLCA3678>3.0.CO;2-0

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Helvetica Chimica Acta Vol. 85 (2002)
Lewis Acid Catalyzed Ring-Opening Reactions of Sugar-Derived
Semicyclic N,O-Acetals
by Masaharu Sugiura, Hiroyuki Hagio, and Shu Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
(tel: ‡81-3-5841-4790; fax: ‡81-3-5684-0634; e-mail: skobayas@mol.f.u-tokyo.ac.jp)
This paper is dedicated to Professor Dr. Dieter Seebach on the occasion of his 65th birthday
N-(Alkoxycarbonyl)-N-glycosides (polyoxygenated semicyclic N,O-acetals) were efficiently synthesized
from regular acetyl or methyl glycosides (glucopyranoside, ribofuranoside, arabinofuranoside, and 2-
deoxyribofuranoside) and a carbamate by treatment of trimethylsilyl trifluoromethanesulfonate and 4 ä
molecular sieves. It was found that these N-glycosides underwent Lewis acid catalyzed ring-opening reactions
with silylated nucleophiles to give ring-opened amino alcohols with good-to-high diastereoselectivity. The
reactivity order, 2-deoxyribofuranoside
> arabinofuranoside > ribofuranoside > glucopyranoside, was
revealed. Ring-opening reductions were also investigated with silanes or diisobutylaluminium hydride. An
appropriate reducing agent was found to be dependent on the N-glycosides used. A glycosidase inhibitor,
(2S,3R,4R)-2-hydroxymethylpyrrolidine-3,4-diol (7) was synthesized by means of the reactions.
Introduction. N-Glycosides (ˆsemicyclic N,O-acetals with an exocyclic N-atom)
are abundant in nature such as in nucleosides, N-glycopeptides, and glycolipids, and
they play an important role in their biological activities [1]. Although they are often
chemically synthesized via direct N-glycosylation of aza-nucleophiles (for example,
azidotrimethylsilane), N-acylated aza-nucleophiles such as amides are less utilized due
to their low nucleophilicity. Kahne et al. first reported that glycosyl sulfoxides serve as
powerful glycosyl donors toward less reactive nucleophiles, including acetamide, in the
presence of triflic anhydride [2]. However, the most common procedure for the
synthesis of N-acylated- N-glycosides is acylation of glycosylamines [1c]. Meanwhile,
we have recently found that direct N-glycosylation proceeded smoothly in the presence
of trimethylsilyl trifluoromethanesulfonate (Me3SiOTf) and 4-ä molecular sieves (4-ä
MS), when simple monooxygenated glycosyl donors such as 2-methoxy-3-(benzyloxy)-
tetrahydro-2H-pyran and carbamates as N-acylated aza-nucleophiles were used
(Scheme 1) [3]. Moreover, the resulting N-(alkoxycarbonyl)-N-glycosides were found
to undergo Lewis acid catalyzed ring-opening reactions with silylated nucleophiles
(silyl enolates, allylsilanes, and trimethylsilanecarbonitrile) to afford ring-opened
products (1,4- or 1,5-amino alcohols) with high stereoselectivity. Along this line, we
describe herein a further extension of the reactions to that of sugar-derived semicyclic
N,O-acetals, which can afford polyoxygenated amino alcohols as useful intermediates
for the synthesis of biologically important, polyoxygenated, N-containing compounds
such as alkaloids. This report is the first systematic study of Lewis acid catalyzed ring-
opening reactions of N-acyl-N-glycosides, while ring-opening alkylation or reduction of
N-alkyl-N-glycosides including nucleosides with excess Grignard reagents or diisobu-

Helvetica Chimica Acta Vol. 85 (2002)
3679
tylaluminium hydride [4]1) and a Lewis acid promoted ring-opening rearrangement of
N-homoallyl-N-galactoside [6] or anomeric isomerization of nucleosides [7] or N-acyl-
N-glycosides [8] have been reported.
Scheme 1. Preparation and Ring-Opening Reaction of Six-Membered Semicyclic N,O-Acetals
Results and Discussion. At first, we investigated the feasibility of a series of the
reactions with a glucose derivative (Scheme 2). Glucose-derived N-[(benzyloxy)car-
bonyl]-N,O-acetal 2a was obtained in good yield from 1-O-acetyl-2,3,4,6-tetra-O-
benzyl-d-glucose (1a) and benzyl carbamate (H2NZ) according to the procedure that
we described previously (see Scheme 1). Then, 2a was subjected to the conditions of the
Me3SiOTf-catalyzed ring-opening reaction with the silyl enol ether 3B derived from
acetophenone. However, the desired ring-opened product 4aB was obtained in low
yield even after a prolonged reaction time, though good diastereoselectivity was
observed. We speculated that the six-membered pyranose structure of 2a might be
stabilized due to the equatorial substituents at the positions C(2) to C(5) (Fig. 1). Thus,
the assumed reactive intermediate, an acyclic N-acyliminium salt, could not be formed
in sufficient amounts during the reaction2)3).
Scheme 2. Preparation and Ring-Opening Reaction of N-Glucopyranoside 2a
Fig. 1. Ring-opening of N-glucopyranoside 2a
1
)
)
For ring-opening reactions of nucleosides by Grignard reagents or diisobutylaluminium hydride, see [5].
We have proposed the formation of an acyclic N-acyliminium ion as a reactive intermediate for the Lewis
acid catalyzed ring-opening reactions, see [3c].
2
3
)
For a recent review on the chemistry of N-acyliminium ions, see [9].

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Helvetica Chimica Acta Vol. 85 (2002)
Accordingly, we anticipated that furanose-derived N,O-acetals would be more
reactive because the relatively high ring strain could be released by ring opening.
Indeed, it was found that ring-opening reactions of (R)-pantolactone derivative 2b,
which was prepared in high yield from the corresponding 1-(acetyloxy)tetrahydrofuran
1b, with silylated nucleophiles 3A C proceeded smoothly to give syn-amino alcohols
4bA C with good diastereoselectivity (Table 1). The configuration assignment of the
allylation product 4bC was made after conversion to pyrrolidine derivative 5bC
(Scheme 3). An NOE enhancement observed by NMR analysis of 5bC (see Exper.
Part) supported its 2,3-cis configuration, thus establishing the formation of the syn-
product 4bC as the major diastereoisomer. The relative configurations of other
products were tentatively assigned by analogy. The stereochemistry of the reaction is
consistent with our previous observation in reactions of six-membered N,O-acetals [3].
Table 1. Ring-Opening Reactions of a Pantolactone Derivative
Nu-SiMe3 (3)
4b
Time/h
Yield/%
syn/anti
Me2CˆC(OSiMe3)(OMe) (3A)
H2CˆC(OSiMe3)Ph (3B)
H2CˆCHCH2SiMe3 (3C)
4bA Nu ˆ CMe2CO2Me
4bB Nu ˆ CH2COPh
36
16
2072
92
94
91 : 9
90: 10
4bC Nu ˆ CH2CHˆCH2
89 : 11
Scheme 3. Configuration Assignment of Allylation Product syn-4bC by Conversion to 5bC
Next, we set our investigation on the reactions of d-ribose, d-arabinose, and 2-
deoxy-d-ribose derivatives. Formation of the corresponding N,O-acetals 2c e pro-
ceeded in high yields from regular furanosides 1c e, respectively (Scheme 4)4).
Although use of the acetyloxy group as the leaving group is a key to obtain high yields
of ribose and arabinose derivatives 2c and 2d, the methoxy group can be utilized for the
N-glycosylation of the more reactive 2-deoxy-d-ribofuranoside 1e.
4
)
Semicyclic N,O-acetals 2 were obtained as anomeric mixtures (dr 5:5 to 8:2). We have observed that
anomers can be interconverted in the presence of a Lewis acid, see [3c].

Helvetica Chimica Acta Vol. 85 (2002)
Scheme 4. Preparation of N-Furanosides
3681
With furanose-derived N,O-acetals 2c e in hand, Me3SiOTf-catalyzed ring-open-
ing reactions with the silylated nucleophiles 3A C were next examined (Table 2). The
reactions were carried out with a nucleophile (2 equiv.) and a catalytic amount of
Me3SiOTf (0.2 equiv.) in MeCN at low temperature depending on the reactivity of the
nucleophile. In most reactions of ribose and arabinose derivatives 2c and 2d, good
yields of syn-ring-opened products 4cA B and 4dA C, respectively, were obtained
with high diastereoselectivity, while the reaction of deoxyribose derivative 2e with
acetophenone-derived silyl enol ether 3B showed no diastereoselectivity. In contrast to
the high yields obtained from the reactions of 2c with silyl enolates 3A and 3B, no
reaction of 2c with allyltrimethylsilane (3C) was observed. The higher reactivity of
arabinofuranoside 2d than that of ribofuranoside 2c might be attributed to the
differences in ring strain or conformation caused by steric repulsion between
substituents on the furan ring. The syn-configurations of products 4cA and 4dC were
confirmed by 1H-NMR analyses of the corresponding pyrrolidine derivatives 5cA and
5dC (Scheme 5).
The stereochemistry can be rationalized by assuming the a- and b-(benzyloxy)-
chelated transition states TSa and TSb, respectively, for acyclic N-acyliminium
intermediates (Fig. 2). In TSa, the diastereofaces of the iminium ion can be
discriminated efficiently because of the close asymmetric environment created by the
chiral C(a), and therefore, a nucleophile attacks preferentially from the side of the H-
atom to give the syn-adduct (for the reactions of 2b d). On the other hand, in TSb, the
asymmetric environment created by the chiral C(b) is far from the reaction site leading
to low selectivity (for the reaction of 2e). In reactions of a,b-bis(benzyloxy)-
substituted N,O-acetals such as 2c and 2d, chelation by both a- and b-(benzyloxy)
groups might be also possible, though clear evidence in this respect has not been
obtained yet.

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Helvetica Chimica Acta Vol. 85 (2002)
Table 2. Ring-Opening Reactions of Furanose Derivatives
À 408, 12 h
4cA (quant.)a)
syn/anti 93 : 7
À 408, 21 h
4dA (62%)a)
syn/anti 91 : 9
À 408, 16 h
À 408, 37 h
À 408, 9 h
4cB (70%)a)
syn/anti 93 : 7
4dB (77%)a)
syn/anti 93 : 7
4eB (80%)a)
dr 50: 50
08, 23 h
À 308, 39 h
4dC (64%)a)
syn/anti 94 : 6
4cC (0%)a)
a) Product 4: A Nu ˆ CMe2CO2Me; B Nu ˆ CH2COPh; C Nu ˆ CH2CHˆCH2.
Scheme 5. Configuration Assignment of Ring-Opened Products syn-4cA and syn-4dC

Helvetica Chimica Acta Vol. 85 (2002)
3683
Fig. 2. Assumed transition states for the acyclic acyliminium intermediates
The choice of the protective groups at the OH groups of the sugars was also found
to be important for the ring-opening reactions, i.e., O-acetyl-protected ribose-derived
N,O-acetal 2f was unreactive under similar conditions, while the analogous deoxyribose
derivative 2g underwent the reaction with low selectivity (Scheme 6). An electron-
withdrawing substituent at the a-position might retard the formation of the assumed N-
acyliminium intermediate as proposed in glycosylation chemistry [10].
Scheme 6. Ring-Opening Reactions of O-Acetyl-Protected N-Furanosides
We next focused our attention on the ring-opening reduction of 2c and 2d (Table 3).
At first, ribofuranoside 2c was subjected to the conditions with triethylsilane as a
reducing agent and Me3SiOTf as a Lewis acid in MeCN (Entry 1). While 2c remained
unreacted under these conditions, use of chlorodimethylsilane improved the reaction
dramatically to give amino alcohol 4cD in good yield (Entries 2 and 3). Treatment of 2c
with diisobutylaluminium hydride (DIBAL) in THF [5] resulted in a low yield
(Entry 4). On the other hand, arabinofuranoside 2d reacted with triethylsilane to give
4dD in moderate yield besides furan 6 (Entry 5). Other silanes such as chlorodime-
thylsilane and dimethylisopropylsilane were examined, but no remarkable improve-
ment was observed (Entries 6 8). Meanwhile, treatment of 2d with 3 equiv. of DIBAL
in THF provided 4dD in good yield (Entry 9).
Finally, reduction product 4dD was successfully transformed to the glycosidase
inhibitor (2S,3R,4R)-2-(hydroxymethyl)pyrrolidine-3,4-diol (7) (Scheme 7)5). That is,
ring closure of 4dD via mesylation followed by treatment with tBuOK gave pyrrolidine
5
)
For syntheses of 7, see [11].

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Helvetica Chimica Acta Vol. 85 (2002)
Table 3. Ring-Opening Reductions of 2c and 2d
Entry
2
Reagent
Conditions
Yield/%
1
2
3
4
2c
Et3SiH (2.0equiv.), Me 3SiOTf (0.2 equiv.)
Me2ClSiH (2.0equiv.), Me 3SiOTf (0.2 equiv.)
Me2ClSiH (2.0equiv.), Me 3SiOTf (1.0equiv.)
DIBALH (3.0equiv.)
MeCN, 08, 1.5 h ! r.t., 3 h
MeCN, 08, 6 h
MeCN, 0 8, 6 h
THF, À238, 4 h
0
67
76
37
5
6
7
8
9
2d
Et3SiH (2.0equiv.), Me 3SiOTf (0.2 equiv.)
Me2ClSiH (2.0equiv.), Me 3SiOTf (0.2 equiv.)
Me2ClSiH (2.0equiv.), Me 3SiOTf (1.0equiv.)
MeCN, 08, 1.5 h ! r.t., 3 h
52a)
37
59
43
75
MeCN, 08, 11 h
MeCN, 0 8, 9 h
MeCN, 08, 15 h
THF, À238, 4 h
i
Me2 PrSiH (2.0equiv.), Me 3SiOTf (0.2 equiv.)
DIBALH (3.0equiv.)
a) Furan 6 was obtained in 38% yield.
5dD in high yield, and removal of all protective groups was achieved by hydrogenolysis
over Pd/C with hydrochloric acid in EtOH providing the hydrochloride of 7 in high
yield. Although this synthesis is one of the simple applications of our findings,
diastereoselective syntheses of C-glycosides of imino sugars or polyoxygenated
alkaloids utilizing the reactions are possible.
Scheme 7. Synthesis of Glycosidase Inhibitor 7
In summary, we revealed that N-(alkoxycarbonyl)-N-glycosides (polyoxygenated
five-membered semicyclic N,O-acetals) can be directly prepared from the correspond-
ing regular glycosides with a carbamate, and that they undergo Me3SiOTf-catalyzed
ring-opening reactions with silylated nucleophiles to give ring-opened amino alcohols
with good to high diastereoselectivity. The synthetic utility of this reaction was
demonstrated by the synthesis of a glycosidase inhibitor, (2S,3R,4R)-2-(hydroxy-
methyl)pyrrolidine-3,4-diol (7).
This work was partially supported by CREST and SORST, Japan Science Technology Corporation (JST),
and a Grant-in-Aid for Scientific Research from the Japan Society of the Promotion of Sciences (JSPS).

Helvetica Chimica Acta Vol. 85 (2002)
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Experimental Part
1. General. CH2Cl2 was distilled from P2O5, then from CaH2, and dried over molecular sieves 4-ä. MeCN
was distilled from CaH2 and dried over molecular sieves 4-ä. All other solvents and chemical compounds were
purified by standard procedures. Column chromatography (CC): silica gel 60 (Merck). TLC: Wakogel B-5F.
Optical rotations: Jasco P-1010 polarimeter; 10-cm cell. IR Spectra: Jasco FT/IR-610 infrared spectrometer in
cmÀ1 1H- and 13C-NMR Spectra: Jeol JNM-LA300 or JNM-LA400 spectrometer; in CDCl3 unless otherwise
;
noted; d in ppm rel. to SiMe4 as internal standard (d(H) ˆ 0) and CDCl3 as internal standard (d(C) ˆ 77.0); J in
Hz; drˆ diastereoisomer ratio. MS: for high-resolution (HR) Jeol JMX-SX-102A spectrometer; for low-
resolution (EI) Shimazu GCMS-QP5050A spectrometer.
2. N-[(Benzyloxy)carbonyl]-N-glycosides 2 (ˆsemicyclic N,O-acetals with an exocyclic N-atom): General
Procedure: To a suspension of a regular glycoside 1 (1.0equiv.), benzyl carbamate (1.1 equiv.) and 4-ä-
molecular-sieves powder (300 mg/1 mmol of glycoside) in CH2Cl2 (1.0m) was added dropwise trimethylsilyl
trifluoromethanesulfonate (Me3SiOTf; 1.0equiv.) at r.t. The mixture was stirred for 10 to 20min and then
quenched with sat. aq. NaHCO3 soln. After filtration through a Celite pad and extraction of the filtrate with
AcOEt (3Â), the combined org. phase was washed with brine, dried (MgSO4), and evaporated, and the residue
purified by CC (silica gel): 2.
Benzyl (2,3,4,6-Tetra-O-benzyl-d-glucopyranosyl)carbamate (2a). From 1-O-acetyl-2,3,4,6-tetra-O-benzyl-
d-glucopyranose (1a) in 67% yield. Colorless oil: a-d/b-d 35 :65. 1H-NMR (400 MHz, CDCl3): b-d-isomer:
7.35 7.21 (m, 23 H); 7.14 7.10( m, 2 H); 5.15 (d, J ˆ 12.2, 1 H); 5.11 (br.d, J ˆ 10.0, 1 H); 5.06 (d, J ˆ 12.2,
1 H); 4.90( dd, J ˆ 10.0, 8.6, 1 H); 4.89 (d, J ˆ 10.9, 1 H); 4.85 (d, J ˆ 10.9, 1 H); 4.79 (d, J ˆ 11.0, 1 H); 4.76 (d,
J ˆ 11.3, 1 H); 4.67 (d, J ˆ 11.3, 1 H); 4.59 (d, J ˆ 12.2, 1 H); 4.50( d, J ˆ 11.0, 1 H); 4.46 (d, J ˆ 12.2, 1 H);
3.76 3.65 (m, 4 H); 3.49 (br.d, J ˆ 7.6, 1 H); 3.32 (br.t, J ˆ 8.6, 1 H); a-d-isomer: 7.36 7.21 (m, 23 H); 7.14
7.09 ( m, 2 H); 5.62 (t, J ˆ 6.2, 1 H); 5.58 (br.d, J ˆ 6.2, 1 H); 5.16 (d, J ˆ 12.2, 1 H); 5.11 (d, J ˆ 12.2, 1 H); 4.89
(d, J ˆ 11.0, 1 H); 4.79 (d, J ˆ 10.7, 1 H); 4.76 (d, J ˆ 11.0, 1 H); 4.61 (d, J ˆ 12.0, 1 H); 4.58 (s, 2 H); 4.50( d, J ˆ
10.7, 1 H); 4.45 (d, J ˆ 12.2, 1 H); 3.82 3.56 (m, 6 H). 13C-NMR (100 MHz, CDCl3, b-d-isomer 155.5; 138.3;
138.0; 137.8; 137.7; 136.1; 128.44; 128.38; 128.33; 128.31; 128.27; 128.12; 128.06; 127.95; 127.77; 127.69; 127.66;
85.9; 81.7; 80.2; 77.5; 76.2; 75.6; 74.9; 74.7; 73.5; 68.1; 67.0.
Benzyl [(3R)-3-(Benzyloxy)tetrahydro-4,4-dimethylfuran-2-yl]carbamate (2b). From (3R)-3-(benzyloxy)-
tetrahydro-4,4-dimethylfuran-2-yl acetate (1b)6) in 91% yield. Colorless oil. [a]D22 ˆ ‡34.8 (c ˆ 0.345, CHCl3).
IR (film): 3431, 3326, 3064, 3032, 2961, 2871, 1728, 1502, 1224, 1036, 736, 697. 1H-NMR (300 MHz, CDCl3; dr ca.
6 :4): 7.37 7.22 (m, 10H); 5.89 (br. d, J ˆ 9.6, 0.6 H); 5.72 (br. dd, J ˆ 9.6, 5.0, 0.6 H); 5.58 (br. d, J ˆ 9.0,
0.4 H); 5.43 (br. dd, J ˆ 9.0, 4.1, 0.4 H); 5.10 (s, 2 H); 4.66 (br. d, J ˆ 11.7, 0.4 H); 4.57 (d, J ˆ 11.5, 0.6 H); 4.53
(br. d, J ˆ 11.7, 0.4 H); 4.51 (d, J ˆ 11.5, 0.6 H); 3.69 (d, J ˆ 8.1, 0.6 H); 3.64 (d, J ˆ 8.4, 0.4 H); 3.58 (d, J ˆ 8.4,
0.4 H); 3.50 (d, J ˆ 5.0, 0.6 H); 3.45 (br. d, J ˆ 4.1, 0.4 H); 3.39 (d, J ˆ 8.1, 0.6 H); 1.11 (s, 1.2 H); 1.0 8 (s, 1.8 H);
1.06 (s, 1.8 H); 1.04 (s, 1.2 H). 13C-NMR (100 MHz, CDCl3, dr ca. 6 :4): 155.7; 155.3; 137.9; 137.2; 136.2; 136.0;
128.5; 128.4; 128.3; 128.2; 128.10; 128.06; 128.01; 127.9; 127.6; 127.4; 89.1; 87.2; 84.9; 82.7; 78.1; 76.7; 74.3; 72.2;
66.9; 66.8; 42.8; 41.6; 25.2; 24.4; 19.8; 19.5. Anal. calc. for C21H25NO4: C 70.96, H 7.09, N 3.94; found: C 71.01,
H 7.13, N 3.91.
Benzyl (2,3,5-Tri-O-benzyl-d-ribofuranosyl)carbamate (2c). From 2,3,5-tri-O-benzyl-d-ribofuranose 1-
acetate (1c)7) in 89% yield. Colorless oil; dr ca. 7:3. [a]D25 ˆ ‡61.2 (c ˆ 2.295, CHCl3). IR (film): 3417, 3063,
3031, 2925, 2866, 1732, 1505, 1455, 1353, 1239, 1027, 737, 698. 1H-NMR (400 MHz, CDCl3): major isomer: 7.32
7.12 (m, 20H); 6.27 (br. d, J ˆ 9.5, 1 H); 5.64 (dd, J ˆ 9.5, 5.6, 1 H); 5.04 (s, 2 H); 4.58 (d, J ˆ 12.2, 1 H); 4.50( d,
J ˆ 12.2, 1 H); 4.48 (s, 2 H); 4.46 (d, J ˆ 11.9, 1 H); 4.36 (d, J ˆ 11.9, 1 H); 4.16 (ddd, J ˆ 4.2, 3.5, 2.2, 1 H); 3.96
(t, J ˆ 5.1, 1 H); 3.89 (dd, J ˆ 5.1, 2.3, 1 H); 3.38 (dd, J ˆ 10.5, 3.4, 1 H); 3.34 (dd, J ˆ 10.5, 4.6, 1 H); minor
isomer (selected signals): 5.47 (dd, J ˆ 8.9, 5.2, 1 H); 5.03 (s, 2 H); 4.12 (m, 1 H); 3.76 (t, J ˆ 11.1, 1 H); 3.54 (dd,
6
)
Acetate 1b was prepared from (R)-pantolactone in 3 steps including benzylation of the OH group by
benzyl trichloroacetoimidate, reduction by diisobutylaluminium hydride, and acetylation by Ac2O and a
catalytic amount of N,N dimethylpyridine-4-amine in Et3N.
Regular glycosides were prepared from the corresponding sugars according to conventional methods
including a) methyl glycoside formation by treatment with a catalytic amount of acetyl chloride in MeOH,
b) benzylation of OH groups by NaH and benzyl bromide in DMF, c) hydrolysis of the methyl glycoside
with 1n HCl in refluxing dioxane, and d) acetylation of the anomeric OH group by Ac2O and a catalytic
amount of N,N-dimethylpyridin-4-amine in Et3N, see [12].
7
)

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Helvetica Chimica Acta Vol. 85 (2002)
J ˆ 11.1, 4.6, 1 H). 13C-NMR (75 MHz, CDCl3; major isomer: 155.9; 137.8; 137.6; 137.3; 136.3; 128.41; 128.38;
128.35; 128.1; 128.0; 127.9; 127.82; 128.78; 127.7; 127.6; 127.5; 127.4; 81.2; 81.1; 77.8; 76.5; 73.5; 72.48; 72.45; 70.0;
66.7. Anal. calc. for C34H35NO6: C 73.76, H 6.37, N 2.53; found: C 73.44, H 6.34, N 2.51.
Benzyl (2,3,5-Tri-O-benzyl-d-arabinofuranosyl)carbamate (2d). From 2,3,5-tri-O-benzyl-d-arabinofura-
nose 1-acetate (1d)7) in 92% yield. Colorless oil. [a]D26 ˆ ‡2.2 (c ˆ 0.825, CHCl3). IR (film): 3411, 3339, 3087,
3062, 3031, 2922, 2864, 1728, 1509, 1498, 1454, 1215, 1091, 1048, 1028, 738, 697, 459. H-NMR (400 MHz, CDCl3,
dr ca. 1:1): 7.38 7.18 (m, 20H); 5.92 (br. d, J ˆ 10.2, 0.5 H); 5.87 (br. d, J ˆ 10.2, 0.5 H); 5.75 (br. d, J ˆ 10.2,
0.5 H); 5.71 (br. dd, J ˆ 9.9, 5.5, 0.5 H); 5.13 (d, J ˆ 12.2, 0.5 H); 5.10 (s, 1 H); 5.0 8 (d, J ˆ 12.2, 0.5 H); 4.57
4.39 (m, 6 H); 4.34 (ddd, J ˆ 7.6, 5.4, 1.7, 0.5 H); 4.07 3.93 (m, 2 H); 3.89 (s, 0.5 H); 3.59 (dd, J ˆ 9.8, 5.4, 0.5 H);
3.53 (d, J ˆ 3.9, 1 H); 3.48 (dd, J ˆ 9.8, 8.3, 0.5 H). 13C-NMR (75 MHz, CDCl3, dr ca. 1 :1): 155.3; 155.0; 137.9;
137.7; 137.5; 137.0; 136.9; 136.05; 136.02; 136.00; 135.97; 128.38; 128.36; 128.32; 128.30; 128.22; 128.19; 128.08;
128.04; 127.99; 127.93; 127.84; 127.81; 127.74; 127.71; 127.63; 127.58; 127.54; 127.51; 85.5; 84.9; 82.5; 82.2; 81.93;
81.85; 81.2; 80.1; 73.2; 73.1; 72.0; 71.6; 71.5; 71.3; 69.9; 69.7; 66.8. Anal. calc. for C34H35NO6: C 73.76, H 6.37,
N 2.53; found: C 73.67, H 6.36, N 2.50.
Benzyl (3,5-di-O-benzyl-2-deoxy-d-ribofuranosyl)carbamate (2e). From methyl 3,5-di-O-benzyl-2-deoxy-
d-ribofuranoside (1e)7) in 79% yield. Colorless oil. [a]D25 ˆ ‡21.1 (c ˆ 0.435, CHCl3). IR (film): 3409, 3328, 3060,
3032, 2920, 2863, 1727, 1504, 1452, 1357, 1247, 1212, 1078, 741, 697. 1H-NMR (300 MHz, CDCl3; dr ca. 8 :2): 7.40
7.20( m, 15 H); 6.11 (br. d, J ˆ 10.1, 0.8 H); 5.95 (br, 0.2 H); 5.81 (br. dd, J ˆ 9.8, 7.1, 0.8 H); 5.65 (br, 0.2 H);
5.12 (d, J ˆ 12.2, 0.8 H); 5.08 (s, 0.4 H); 5.06 (d, J ˆ 12.2, 0.8 H); 4.54 (d, J ˆ 12.1, 0.8 H); 4.48 4.43 (m, 3.2 H);
4.35 (dd, J ˆ 5.5, 4.5, 0.8 H); 4.28 4.20 (m, 0.4 H); 4.07 (d, J ˆ 5.5, 0.8 H); 3.56 (dd, J ˆ 10.1, 3.1, 0.2 H); 3.45
(dd, J ˆ 10.1, 3.8, 1.0 H); 3.32 (dd, J ˆ 10.1, 6.0, 0.8 H); 2.27 (ddd, J ˆ 13.6, 6.2, 2.7, 0.2 H); 2.18 (apparent dt, J ˆ
13.7, 6.5, 0.8 H); 1.95 (d, J ˆ 13.7, 0.8 H); 1.89 (m, 0.2 H). 13C-NMR (75 MHz, CDCl3; dr ca. 8 :2): 155.3; 137.8;
137.7; 137.4; 136.19; 136.14; 128.36; 128.32; 128.28; 128.24; 128.06; 128.01; 127.9; 127.7; 127.59; 127.53; 127.48;
127.42; 83.0; 82.9; 82.5; 82.4; 80.2; 79.7; 73.5; 73.3; 70.95; 70.91; 70.3; 66.6; 66.5; 38.5; 37.0. Anal. calc. for
C27H29NO5: C 72.46, H 6.53, N 3.13; found: C 72.23, H 6.61, N 3.08.
3. Me3SiOTf-Catalyzed Ring-Opening Reactions of N-Glycosides 2: General Procedure. To a soln. of an N-
glyoside 2 (1 equiv.) and a nucleophile 3 (2 equiv.) in MeCN (0.1m) was added dropwise Me3SiOTf (0.2 equiv.)
at the appropriate temp. After being stirred at that temp. for the time indicated in the schemes or tables, the
mixture was quenched with sat. aq. NaHCO3 soln. and extracted with AcOEt (2Â). The combined org. phase
was washed with brine, dried (MgSO4), and evaporated and the residue purified by prep. TLC to give a ring-
1
opened product 4. The dr of 4 were determined by H-NMR analyses.
Benzyl [(2S,3R,4R,5R)-2,3,4,6-Tetrakis(benzyloxy)-5-hydroxy-1-(2-oxo-2-phenylethyl)hexyl]carbamate
(4aB). Yield 16%. Colorless oil; dr 90:10. 1H-NMR (300 MHz, CDCl3): major isomer: 7.72 (d, J ˆ 7.5, 2 H);
7.52 (t, J ˆ 7.5, 2 H); 7.46 7.10( m, 26 H); 5.30(br. d, J ˆ 9.7, 1 H); 5.09 (s, 2 H); 4.82 (d, J ˆ 11.5, 1 H); 4.74 (d,
J ˆ 11.2, 1 H); 4.68 4.42 (m, 6 H); 4.35 (m, 1 H); 4.05 (m, 1 H); 3.91 (s, 2 H); 3.81 (m, 1 H); 3.70 3.57 ( m,
2 H); 3.08 (dd, J ˆ 17.0, 5.1, 1 H); 2.82 (br. s, 1 H); 2.78 (dd, J ˆ 17.0, 7.9, 1 H); minor isomer (selected signal):
5.83 (d, J ˆ 7.1, 1 H ) . 13C-NMR (100 MHz, CDCl3, major isomer): 197.5; 156.0; 138.3; 138.1; 136.53; 136.46;
133.1; 128.5; 128.44; 128.40; 128.37; 128.30; 128.29; 128.26; 128.16; 128.05; 127.9; 127.74; 127.67; 127.63; 127.56;
79.4; 78.8; 77.5; 77.2; 74.9; 73.4; 71.2; 70.4; 66.9; 48.7; 41.3; 29.7.
Methyl (4R)-4-(Benzyloxy)-3-{[(benzyloxy)carbonyl]amino}-6-hydroxy-2,2,5,5-tetramethylhexanoate
(4bA). Yield 92%. Colorless oil; syn/anti 91:9. [a]2D5 ˆ ‡54.0( c ˆ 0.455, CHCl3). IR (film) 3447, 3089, 3064,
3032, 2952, 2878, 1725, 1507, 1456, 1319, 1265, 1219, 1146, 1056, 735, 697. 1H-NMR (300 MHz, CDCl3): syn-
isomer: 7.36 7.25 (m, 10H); 5.63 ( d, J ˆ 9.0, 1 H); 5.11 (s, 2 H); 4.77 (d, J ˆ 11.3, 1 H); 4.54 (d, J ˆ 11.3, 1 H);
4.12 (d, J ˆ 9.9, 1 H); 3.59 (s, 3 H); 3.51 (s, 1 H); 3.51 (d, J ˆ 11.3, 1 H); 3.36 (d, J ˆ 11.3, 1 H); 2.04 (br. s, 1 H);
1.25 (s, 3 H); 1.20 (s, 3 H); 0 .98 (s, 3 H); 0.911 (s, 3 H); (anti-isomer (selected signals): 5.41 (d, J ˆ 10.3, 1 H);
5.21 (d, J ˆ 12.5, 1 H); 5.14 (d, J ˆ 12.5, 1 H); 4.08 (d, J ˆ 11.0, 1 H); 3.44 (d, J ˆ 11.4, 1 H); 3.30( d, J ˆ 11.4,
1 H). 13C-NMR (75 MHz, CDCl3; syn-isomer): 177.2; 156.4; 138.1; 136.7; 128.44; 128.41; 128.2; 127.6; 127.0; 81.3;
74.4; 69.6; 66.8; 55.9; 52.0; 47.4; 41.4; 24.3; 21.8; 21.6; 21.3. Anal. calc. for C26H35NO6 ¥ 0.15 H2O: C 67.84, H 7.73,
N 3.04; found: C 67.81, H 7.56, N 3.04.
Benzyl [(2R)-2-(Benzyloxy)-4-hydroxy-3,3-dimethyl-1-(2-oxo-2-phenylethyl)butyl]carbamate (4bB).
Yield 94%. Colorless oil; syn/anti 90:10. [ a]2D2 ˆ ‡4.3 (c ˆ 0.645, CHCl3). IR (film): 393, 2923, 2878, 1712,
1598, 1497, 1450, 1294, 1216, 1057, 914, 736, 698. 1H-NMR (400 MHz, CDCl3; syn-isomer): 7.83 (d, J ˆ 7.6, 2 H);
7.56 (t, J ˆ 7.6, 1 H); 7.42 (t, J ˆ 7.6, 2 H); 7.40 7.15 ( m, 10H); 5.56 ( d, J ˆ 8.3, 1 H); 5.08 (s, 2 H); 4.76 (d, J ˆ
11.7, 1 H); 4.49 (d, J ˆ 11.7, 1 H); 4.47 (m, 1 H); 3.60( s, 2 H); 3.43 (dd, J ˆ 11.2, 8.3, 1 H); 3.21 (dd, J ˆ 17.6, 3.2,
1 H); 3.14 (m, 1 H); 2.90( dd, J ˆ 17.6, 10.5, 1 H); 1.05 (s, 3 H); 0.92 (s, 3 H). 13C-NMR (100 MHz, CDCl3; syn-

Helvetica Chimica Acta Vol. 85 (2002)
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isomer): 199.3; 155.3; 138.0; 136.4; 136.1; 133.5; 128.5; 128.4; 128.1; 128.04; 128.00; 82.7; 76.4; 70.2; 66.7; 46.7;
43.4; 41.1; 22.2; 20.6. Anal. calc. for C29H33NO5: C 73.24, H 6.99, N 2.95; found: C 73.00, H 7.11, N 2.83.
Benzyl [1-[(1R)-1-(Benzyloxy)-3-hydroxy-2,2-dimethylpropyl]but-3-enyl]carbamate (4bC). Yield 72%.
Colorless oil; syn/anti 89 :11. [a]2D5 ˆ ‡21.3 (c ˆ 0.200, CHCl3). IR (film): 3439, 3065, 3032, 2962, 2875, 1702,
1499, 1331, 1214, 1053, 1027, 914, 736, 697. 1H-NMR (400 MHz, CDCl3): syn-isomer: 7.37 7.24 (m, 10H); 5.78
(m, 1 H); 5.34 (d, J ˆ 9.0, 1 H); 5.18 5.00 (m, 4 H); 4.73 (d, J ˆ 11.0, 1 H); 4.64 (d, J ˆ 11.0, 1 H); 3.98
(apparent q, J ˆ 8.0, 1 H); 3.56 (d, J ˆ 10.4, 1 H); 3.49 (s, 1 H); 3.29 (d, J ˆ 10.4, 1 H); 2.38 (m, 1 H); 2.26 (m,
1 H); 2.16 (br, 1 H); 1.00 (s, 3 H); 0.88 (s, 3 H); anti-isomer (selected signal): 3.88 (m, 1 H). 13C-NMR
(100 MHz; CDCl3, syn-isomer): 155.7; 138.0; 136.6; 134.7; 128.5; 128.4; 128.0; 127.9; 127.6; 118.0; 83.7; 76.2;
69.9; 66.6; 50.4; 40.4; 40.2; 22.6; 20.8. Anal. calc. for C24H31NO4: C 72.52, H 7.86, N 3.52; found: C 72.26, H 7.88,
N 3.47.
Methyl (4S,5R,6R)-4,5,7-Tris(benzyloxy)-3-{[(benzyloxy)carbonyl]amino}-6-hydroxy-2,2-dimethylhepta-
noate (4cA). Yield quant. Colorless oil; syn/anti 93 :7. [a]2D4 ˆ ‡40.5 (c ˆ 0.135, CHCl3). IR (film): 3447, 3063,
3031, 1725, 1507, 1454, 1218, 1067, 1028, 736, 697. 1H-NMR (400 MHz, CDCl3): syn-isomer: 7.38 7.12 (m, 20 H);
5.65 (d, J ˆ 9.9, 1 H); 5.03 (d, J ˆ 12.2, 1 H); 4.73 (d, J ˆ 11.8, 1 H); 4.68 (d, J ˆ 11.1, 1 H); 4.57 (d, J ˆ 12.2,
1 H); 4.51 (d, J ˆ 12.0, 1 H); 4.45 (d, J ˆ 12.0, 1 H); 4.45 (d, J ˆ 11.8, 1 H); 4.38 (d, J ˆ 11.1, 1 H); 4.29 (d, J ˆ
9.9, 1 H); 3.96 (dddd, J ˆ 8.3, 5.5, 5.4, 3.0, 1 H); 3.91 (d, J ˆ 2.2, 1 H); 3.81 (dd, J ˆ 8.3, 2.2,1 H); 3.68 (dd, J ˆ
9.6, 3.0, 1 H); 3.58 (dd, J ˆ 9.6, 5.5, 1 H); 3.49 (s, 3 H); 2.75 (d, J ˆ 5.4, 1 H); 1.25 (s, 3 H); 1.20 (s, 3 H); anti-
isomer (selected signals): 5.51 (d, J ˆ 10.2, 1 H); 2.60 (d, J ˆ 5.4, 1 H). 13C-NMR (100 MHz, CDCl3; syn-
isomer): 177.1; 156.4; 138.5; 137.8; 137.5; 136.5; 128.37; 128.33; 128.2; 128.1; 128.0; 127.9; 127.74; 127.72; 127.4;
127.3; 78.3; 77.8; 74.0; 73.3; 71.7; 71.1; 69.6; 66.6; 55.8; 51.9; 46.6; 23.9; 21.4. Anal. calc. for C39H45NO8 ¥ 0.23 H2O:
C 70.98, H 6.94, N 2.12; found: C 70.98, H 7.07, N 2.12.
Benzyl [(2S,3R,4R)-2,3,5-Tris(benzyloxy)-4-hydroxy-1-(2-oxo-2-phenylethyl)pentyl]carbamate (4cB).
Yield 70%. Colorless oil; syn/anti 93 :7. [a]2D4 ˆ ‡12.1 (c ˆ 0.105, CHCl3). IR (film): 3430, 3063, 3031, 2918,
2870, 1717, 1684, 1507, 1497, 1454, 1215, 1090, 1071, 1027, 738, 697. 1H-NMR (400 MHz, CDCl3): syn-isomer: 7.84
(d, J ˆ 7.3, 2 H); 7.54 (tt, J ˆ 7.3, 1.2, 1 H); 7.41 (t, J ˆ 7.3, 2 H); 7.36 7.14 (m, 20H); 5.62 (br. d, J ˆ 8.6, 1 H);
5.04 (d, J ˆ 12.2, 1 H); 4.88 (d, J ˆ 12.2,1 H); 4.70( d, J ˆ 11.1, 1 H); 4.66 (d, J ˆ 11.5, 1 H); 4.72 4.59 (m, 1 H,
overlapped), 4.56 (d, J ˆ 11.1, 1 H); 4.55 (d, J ˆ 12.0, 1 H); 4.50 (d, J ˆ 12.0, 1 H); 4.47 (d, J ˆ 11.5, 1 H); 4.12
(m, 1 H); 3.89 (dd, J ˆ 4.6, 1.8, 1 H); 3.84 (dd, J ˆ 6.3, 4.6, 1 H); 3.67 (dd, J ˆ 9.8, 3.4, 1 H); 3.63 (dd, J ˆ 9.8, 5.4,
1 H); 3.26 (dd, J ˆ 16.5, 4.6, 1 H); 3.10(br. s, 1 H); 3.06 ( dd, J ˆ 16.5, 9.0, 1 H); anti-isomer (selected signals):
7.78 (d, J ˆ 8.0, 1 H); 6.03 (br. d, J ˆ 9.0, 1 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 198.8; 155.8; 138.1;
138.0; 137.4; 136.52; 136.42; 133.3; 128.5; 128.44; 128.42; 128.40; 128.38; 128.29; 128.26; 128.22; 128.12; 128.03;
128.00; 127.95; 127.88; 127.78; 127.69; 127.56; 79.2; 78.3; 74.0; 73.4; 73.1; 71.1; 70.8; 66.6; 47.9; 41.6. Anal. calc. for
C42H43NO7 ¥ 0.2 H2O: C 74.47, H 6.46, N 2.07; found: C 74.46, H 6.49, N 2.12.
Benzyl [(2S,3R,4R)-2,3,5-Tris(benzyloxy)-4-hydroxypentyl]carbamate (4cD). Yield 76%. Colorless oil.
1H-NMR (300 MHz, (D6)DMSO, 808): 7.36 7.21 (m, 20H); 6.74 (br. s, 1 H); 5.03 (s, 2 H); 4.66 (d, J ˆ 11.3,
1 H); 4.58 (d, J ˆ 11.7, 1 H); 4.57 (d, J ˆ 11.3, 1 H); 4.53 (d, J ˆ 11.7, 1 H); 4.50( d, J ˆ 12.4, 1 H); 4.46 (d, J ˆ
12.4, 1 H); 3.91 3.81 (m, 2 H); 3.69 (dd, J ˆ 6.2, 3.6, 1 H); 3.61 (dd, J ˆ 10.1, 3.6, 1 H); 3.52 (dd, J ˆ 10.1, 6.0,
1 H); 3.46 (ddd, J ˆ 14.1, 5.5, 4.2, 1 H); 3.33 (ddd, J ˆ 14.1, 6.4, 6.4, 1 H). 13C-NMR (75 MHz, (D6)DMSO, 808):
155.8; 138.43; 138.36; 138.28; 137.0; 127.8; 127.66; 127.63; 127.61; 127.17; 127.13; 127.08; 127.05; 127.01; 126.80;
126.75; 79.9; 78.0; 72.5; 72.1; 71.8; 71.0; 69.3; 64.9; 40.8 Anal. calc. for C 34H37NO6 ¥ 0.28 H2O: C 72.83, H 6.75,
N 2.49; found: C 72.83, H 6.67, N 2.45.
Methyl (4R,5R,6R)-4,5,7-Tris(benzyloxy)-3-{[(benzyloxy)carbonyl]amino}-6-hydroxy-2,2-dimethylhepta-
noate (4dA). Yield 62%. Colorless oil; syn/anti 91:9. [a]2D5 ˆ À33.4 (c ˆ 0.050, CHCl3). IR (film): 3443, 3063,
3031, 2950, 2869, 1719, 1507, 1454, 1250, 1217, 1148, 1100, 1052, 1028, 735, 697. 1H-NMR (400 MHz, CDCl3); syn-
isomer: 7.38 7.10( m, 20H); 5.86 ( d, J ˆ 10.5, 1 H); 5.14 (d, J ˆ 12.4, 1 H); 5.10( d, J ˆ 12.4, 1 H); 4.90( d, J ˆ
10.7,1 H); 4.65 (d, J ˆ 11.0, 1 H); 4.56 (d, J ˆ 12.0, 1 H); 4.50 (d, J ˆ 12.0, 1 H); 4.45 (d, J ˆ 11.0, 1 H); 4.34 (d,
J ˆ 10.7, 1 H); 4.04 (d, J ˆ 10.7, 1 H); 3.93 (m, 1 H); 3.89 (d, J ˆ 7.0, 1 H); 3.72 3.56 (m, 3 H); 3.30( s, 3 H); 2.82
(d, J ˆ 5.4, 1 H); 1.23 (s, 3 H); 1.21 (s, 3 H); anti-isomer (selected signals): 5.54 (d, J ˆ 11.0, 1 H); 2.41 (d, J ˆ 4.6,
1 H). 13C-NMR (100 MHz, CDCl3, syn-isomer): 176.4; 156.8; 138.10; 138.05; 137.99; 137.8; 136.5; 128.5; 128.3;
128.23; 128.17; 128.11; 128.07; 127.9; 127.8; 127.61; 127.58; 127.4; 78.7; 77.8; 74.5; 73.9; 72.2; 70.9; 70.8; 66.9; 59.1;
51.7; 45.2; 23.7; 23.4. Anal. calc. for C39H45NO8: C 71.43, H 6.92, N 2.14; found: C 71.16, H 7.03, N 2.09.
Benzyl [(2R,3R,4R)-2,3,5-Tris(benzyloxy)-4-hydroxy-1-(2-oxo-2-phenylethyl)pentyl]carbamate (4dB).
Yield 77%. Colorless oil; syn/anti 93 :7. [a]2D5 ˆ ‡7.6 (c ˆ 0.880, CHCl3). IR (film): 3437, 3063, 3031, 2909,
2868, 1716, 1683, 1597, 1497, 1454, 1215, 1071, 1027, 737, 698. 1H-NMR (400 MHz, CDCl3); syn-isomer: 7.81 (d,
J ˆ 7.3, 2 H); 7.53 (tt, J ˆ 7.3, 1.2, 1 H); 7.40( t, J ˆ 7.3, 2 H); 7.36 7.13 (m, 20H); 5.50(br. d, J ˆ 9.0, 1 H); 5.09

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Helvetica Chimica Acta Vol. 85 (2002)
(d, J ˆ 12.2, 1 H); 5.02 (d, J ˆ 12.2, 1 H); 4.79 (d, J ˆ 11.2, 1 H); 4.66 (d, J ˆ 11.2, 1 H); 4.57 (d, J ˆ 11.2, 1 H);
4.56 (d, J ˆ 11.9, 1 H); 4.51 (d, J ˆ 11.2, 1 H); 4.50( d, J ˆ 11.9, 1 H); 4.56 4.46 (m, 1 H, overlapped), 4.05 (m,
1 H); 3.92 (dd, J ˆ 6.3, 2.3, 1 H); 3.75 (t, J ˆ 6.3, 1 H); 3.72 (dd, J ˆ 9.6, 3.6, 1 H); 3.67 (dd, J ˆ 9.6, 6.0, 1 H);
3.23 (dd, J ˆ 16.9, 4.5, 1 H); 3.01 (dd, J ˆ 16.9, 8.6, 1 H); 2.86 (br. d, J ˆ 5.1, 1 H); anti-isomer (selected signals):
6.00 (br. d, J ˆ 8.3, 1 H); 3.60( dd, J ˆ 9.6, 5.4, 1 H); 3.57 (dd, J ˆ 9.6, 4.6, 1 H); 3.41 (dd, J ˆ 17.5, 5.1, 1 H); 2.97
(dd, J ˆ 17.5, 6.8, 1 H). 13C-NMR (100 MHz, CDCl3; syn-isomer): 198.2; 155.9; 138.2; 138.0; 137.8; 136.45;
136.37; 133.2; 128.5; 128.41; 128.36; 128.35; 128.30; 128.12; 128.08; 127.92; 127.87; 127.84; 127.65; 127.60; 80.2;
78.8; 75.0; 74.4; 73.3; 71.1; 70.7; 66.8; 49.2; 41.3. Anal. calc. for C 42H43NO7: C 74.87, H 6.43, N 2.08; found:
C 74.58, H 6.53, N 2.11.
Benzyl {1-[(1R,2R,3R)-1,2,4-Tris(benzyloxy)-3-hydroxybutyl]but-3-enyl}carbamate (4dC). Yield 64%.
Colorless oil; syn/anti 94 :6. [a]2D6 ˆ ‡10.2 (c ˆ 0.275, CHCl3). IR (film): 3438, 3064, 3031, 2916, 2865, 1718,
1497, 1454, 1213, 1092, 1028, 736, 698. 1H-NMR (300 MHz, CDCl3): syn-isomer: 7.36 7.19 (m, 20H); 5.66 ( ddt,
J ˆ 17.1, 10.1, 7.1, 1 H); 5.23 (d, J ˆ 9.5, 1 H); 5.10( d, J ˆ 12.2, 1 H); 5.02 (d, J ˆ 12.2, 1 H); 4.99 (br. d, J ˆ 10.1,
1 H); 4.95 (br. d, J ˆ 17.1, 1 H); 4.82 (d, J ˆ 11.0, 1 H); 4.68 (d, J ˆ 11.2, 1 H); 4.56 (d, J ˆ 12.1, 1 H); 4.54 (d, J ˆ
11.0, 1 H); 4.51 (d, J ˆ 12.1, 1 H); 4.49 (d, J ˆ 11.2, 1 H); 4.07 4.01 (m, 2 H); 3.70 3.58 ( m, 4 H); 2.73 (d, J ˆ
5.9, 1 H); 2.39 2.15 (m, 2 H); anti-isomer (selected signals): 5.92 (d, J ˆ 9.7, 1 H); 3.10( d, J ˆ 6.8, 1 H).
13C-NMR 75 MHz, CDCl3; syn-isomer): 156.2; 138.3; 138.04; 137.97; 136.5; 134.6; 128.5; 128.4; 128.3; 128.1;
127.9; 127.8; 127.7; 127.6; 117.7; 80.0; 79.7; 74.9; 74.6; 73.3; 71.3. 70.7; 66.7; 51.9; 38.0. Anal. calc. for C37H41NO6:
C 74.60, H 6.94, N 2.35; found: C 74.30, H 6.95, N 2.35.
Benzyl [(2R,3R,4R)-2,3,5-Tris(benzyloxy)-4-hydroxypentyl]carbamate (4dD). Yield 75%. Colorless oil.
[a]2D5 ˆ À2.4 (c ˆ 0.655, CHCl3). IR (film): 3426, 3350, 3063, 3031, 2925, 2868, 1718, 1514, 1497, 1454, 1399, 1337,
1
1253, 1069, 1028, 737, 698. H-NMR (300 MHz, CDCl3: 7.38 7.25 (m, 20 H); 5.05 (s, 2 H); 4.85 (br. t, J ˆ 5.8,
1 H); 4.60( d, J ˆ 11.4, 1 H); 4.58 (d, J ˆ 11.4, 1 H); 4.54 (d, J ˆ 11.4, 1 H); 4.53 (d, J ˆ 11.4, 1 H); 4.52 (s, 2 H);
3.99 (ddt, J ˆ 7.1, 6.0, 4.6, 1 H); 3.78 (ddd, J ˆ 5.5, 5.3, 3.5, 1 H); 3.63 (d, J ˆ 4.6, 2 H); 3.61 (dd, J ˆ 7.1, 3.5, 1 H);
3.50( ddd, J ˆ 14.3, 5.8, .5.5, 1 H); 3.31 (ddd, J ˆ 14.3, 5.8, 5.3, 1 H); 2.83 (d, J ˆ 6.0, 1 H). 13C-NMR (75 MHz,
CDCl3): 156.4; 137.8; 137.6; 136.6; 128.5; 128.4; 128.3; 128.00; 127.96; 127.82; 127.8; 78.0; 77.1; 73.5; 73.4; 72.6;
70.9. 70.3; 66.5; 40.9. Anal. calc. for C34H37NO6 ¥ 0 .28 HO: C 72.83, H 6.75, N 2.49; found: C 72.83, H 6.67, N 2.45.
2
Benzyl [(3S,4R)-3,5bis(benzyloxy)-4-hydroxy-1-(2-oxo-2-phenylethyl)pentyl]carbamate (4eB). Yield
80%. Colorless oil; dr 50 :50. [a]25 ˆ ‡0.6 (c ˆ 0.785, CHCl3). IR (film): 3416, 3063, 3031, 2915, 2867, 1716,
D
1678, 1597, 1580, 1497, 1453, 1253, 1216, 1094, 1071, 1027, 752, 698. 1H-NMR (400 MHz, CDCl3, dr 50:50): 7.90
(d, J ˆ 7.3, 1 H); 7.88 (d, J ˆ 7.3, 1 H); 7.54 (tt, J ˆ 7.3, 1.2, 0.5 H); 7.53 (tt, J ˆ 7.3, 1.2, 0.5 H); 7.42 (t, J ˆ 7.3, 1 H);
7.40( t, J ˆ 7.3, 1 H); 7.36 7.18 (m, 15 H); 5.80(br. d, J ˆ 8.0, 0.5 H); 5.64 (br. d, J ˆ 8.3, 0.5 H); 5.05 (s, 2 H);
4.57 (d, J ˆ 11.0, 0.5 H); 4.53 (d, J ˆ 11.0, 0.5 H); 4.51 (s, 1 H); 4.50( s, 1 H); 4.46 (s, 1 H); 4.42 4.26 (m, 1 H);
3.99 3.89 (m, 1 H); 3.65 (ddd, J ˆ 9.5, 4.6, 2.4, 0.5 H); 3.62 3.52 (m, 2.5 H); 3.40(br. d, J ˆ 17.0, 1 H); 3.09 (dd,
J ˆ 17.1, 6.6, 0.5 H); 3.01 (dd, J ˆ 17.1, 6.6, 0.5 H); 2.89 (m, 0.5 H); 2.62 (m, 0.5 H); 2.07 1.85 (m, 1.5 H); 1.76
(ddd, J ˆ 14.9, 9.6, 3.3, 0.5 H). 13C-NMR (100 MHz, CDCl3, dr 50:50): 198.90; 198.85; 155.9; 155.8; 137.9;
137.81; 137.77; 137.72; 136.67; 136.66; 136.5; 136.4; 133.2; 128.55; 128.54; 128.40; 128.38; 128.35; 128.31; 128.09;
128.05; 128.03; 127.95; 127.93; 127.87; 127.80; 127.78; 127.75; 127.73; 127.70; 127.68; 77.2; 76.8; 73.4; 73.3; 72.6;
71.6; 71.5; 70.9; 70.8; 66.5; 66.4; 46.1; 46.6; 42.9; 42.5; 34.4; 33.8. Anal. calc. for C35H37NO6: C 74.05, H 6.57,
N 2.47; found: C 73.84, H 6.80, N 2.42.
4. Cyclization via the Mesylation/tBuOK-Treatment Sequence. General Procedure [13]. To a soln. of 4
(1.0equiv.) and Et 3N (2.2 equiv.) in CH2Cl2 (0.1m) was added dropwise methanesulfonyl chloride (2.0equiv.) at
r.t. The mixture was stirred at r.t. for 2 2.5 h. After dilution with AcOEt, the org. layer was washed with brine,
dried (MgSO4) and evaporated. The residue was diluted with dry THF (0.1m) and treated with tBuOK
(2.0equiv.) at r.t. The mixture was stirred at r.t. for 15 h, quenched with sat. aq. NH 4Cl soln., and extracted with
AcOEt (3Â). The combined org. phase was dried (MgSO4) and evaporated and the residue purified by prep.
TLC (hexane/AcOEt 2 :1): 5.
(2R,3R)-2-Allyl-3-(benzyloxy)-1-[(benzyloxy)carbonyl]-4,4-dimethylpyrrolidine (5bC). From 4bC in 88%
yield. Colorless oil; single isomer. 1H-NMR (300 MHz, (D6)DMSO, 508): 7.35 7.24 (m, 2 Ph); 5.78 (br. m,
CHˆCH2); 5.09 (d, J ˆ 12.8, 1 H, PhCH2OCO); 5.03 (d, J ˆ 12.8, 1 H; PhCH2OCO); 4.95 (br. d, J ˆ 9.7,
CHˆCH2); 4.58 (d, J ˆ 11.5, 1 H, PhCH2OÀC(3)); 4.51 (d, J ˆ 11.5, 1 H, PhCH2OÀC(3)); 3.99 (br. dt, J ˆ 5.7,
6.8 1 H; HÀC(2)); 3.62 (d, J ˆ 5.7, HÀC(3)); 3.24 (br. d, J ˆ 10.2, HbÀC(5)); 3.07 (d, J ˆ 10.2, HaÀC(5)); 2.67
2.40( m, CH2CHˆCH2); 1.07 (s, MeaÀC(4)); 0.93 (s, MebÀC(4)). NOE: see Table 4. 13C-NMR (75 MHz,
(D6)DMSO, 508): 154.5; 138.1; 136.9; 135.9; 128.1; 128.0; 127.5; 127.24; 127.21; 115.9; 85.1; 73.4; 65.7; 60.3; 56.7;
54.6; 30.4; 25.0; 20.1.

Helvetica Chimica Acta Vol. 85 (2002)
Table 4. 1H-NOE Enhancements of 5bC
3689
Irradiated H
Enhancements/%
HÀC(2)
HÀC(3)
Mea
HÀC(3) (7.9), Meb (3.6)
HÀC(2) (7.8), Mea (3.4), Meb (3.2), PhCH2OÀC(3) (6.9)
HÀC(3) (1.0), HaÀC(5) (1.6), PhCH2OÀC(3) (1.1), Meb (2.5)
Meb
HÀC(2) (1.4), HÀC(3) (2.4), HbÀC(5) (2.6), Mea (2.0)
HaÀC(5)
Mea (3.2)
Meb (1.9)
HbÀC(5)
(2S,3R,4R,5S)-5-Allyl-3,4-bis(benzyloxy)-1-[(benzyloxy)carbonyl]-2-[(benzyloxy)methyl]pyrrolidine
(5dC). From 4dC in 91% yield. Colorless oil; single isomer. 1H-NMR (300 MHz, (D6)DMSO, 808): 7.36 7.16
(m, 20H, 4 Ph); 5.77 ( m, CHˆCH2); 5.07 (s, PhCH2OCO); 4.96 4.82 (m, CHˆCH2), 4.66 (d, J ˆ 11.9, 1 H,
PhCH2OÀC(4)); 4.60( d, J ˆ 11.9, 1 H, PhCH2OÀC(4)); 4.60( s, 2 H, PhCH2OCH2); 4.40 4.32 ( m, HÀC(3),
PhCH2OÀC(3)); 4.18 (dd, J ˆ 8.8, 7.9, HÀC(4)); 4.07 3.96 (m, HÀC(2), HÀC(5)); 3.76 (br. s, 1 H;
PhCH2OCH2); 3.52 (br. d, J ˆ 9.2, 1 H; PhCH2OCH2); 2.54 (m, 1 H; PhCH2OCH2); 2.25 (m, 1 H;
CH2CHˆCH2). NOE: see Table 5. 13C-NMR (75 MHz, (D6)DMSO, 808): 153.4; 138.2; 138.1; 136.4; 135.4;
127.9; 127.77; 127.72; 127.44; 127.37; 127.04; 126.99; 126.94; 126.79; 126.70; 116.6; 80.25; 80.11; 72.2; 71.99; 71.96;
65.7; 55.8; 55.7; 30.1.
Table 5. 1H-NOE Enhancements of 5dC
Irradiated H
Enhancements/%
HÀC(2), HÀC(5)
HÀC(3), PhCH2OÀC(3)
HÀC(4)
HÀC(3) and/or PhCH2OÀC(3) (2.8), HÀC(4) (1.7), HbÀC(1') (1.9)
HÀC(2) (4.1), HÀC(4) (1.3), HaÀC(1') (0.9), PhCH2OCH2 (1.7)
HÀC(3) (2.1), HÀC(5) (7.0), PhCH2OÀC(4) (4.8)
HÀC(3) and/or PhCH2OÀC(3) (9.0), HbÀC(1') (10.3)
HÀC(3) and/or PhCH2OÀC(3) (6.0)
HaÀC(1')
HbÀC(1')
PhCH2OÀC(4), PhCH2OCH2
HÀC(2) or HÀC(5) (1.2), HÀC(3) and/or
PhCH2OÀC(3) (4.0), HÀC(4) (0.7)
(2S,3R,4R)-3,4-Bis(benzyloxy)-1-[(benzyloxy)carbonyl]-2-[(benzyloxy)methyl]pyrrolidine (5dD). From
4dD in 82% yield. Colorless oil. [a]2D5 ˆ À7.7 (c ˆ 0.430, CHCl3). IR (film): 3063, 3031, 2931, 2867, 1702, 1496,
1454, 1414, 1356, 1207, 1095, 1027, 913, 735, 697. 1H-NMR (300 MHz, (D6)DMSO, 508): 7.37 7.19 (m, 4 Ph); 5.08
(d, J ˆ 12.9, 1 H, PhCH2OCO); 5.03 (d, J ˆ 12.9, 1 H, PhCH2OCO); 4.61 (s, PhCH2OÀC(3)); 4.56 (d, J ˆ 12.2,
1 H, PhCH2OÀC(4)); 4.51 (d, J ˆ 12.2, 1 H, PhCH2OÀC(4)); 4.42 (s, PhCH2OCH2); 4.23 (ddd, J ˆ 6.4, 6.4, 4.5,
HÀC(4)); 4.18 4.09 (m, HÀC(2), HÀC(3)); 3.72 3.63 (m, PhCH2OCH2); 3.56 (dd, J ˆ 11.3, 6.4, HaÀC(5));
3.34 (dd, J ˆ 11.3, 4.5, HbÀC(5)). NOE: see Table 6. 13C-NMR (125 MHz, (D6)DMSO, 808): 154.0; 138.1;
137.92; 137.86; 136.5; 127.9; 127.77; 127.71; 127.3; 127.11; 127.09; 127.04; 127.02; 126.99; 126.81; 126.76; 81.2; 79.0;
72.2; 71.7; 70.6; 66.3; 65.7; 57.4; 49.1. Anal. calc. for C34H35NO5: C 75.95, H 6.56, N 2.61; found: C 76.04, H 6.74,
N 2.53.

3690
Helvetica Chimica Acta Vol. 85 (2002)
Table 6. 1H-NOE Enhancements of 5dD
Irradiated H
Enhancements/%
HÀC(2), HÀC(3)
HÀC(4)
CH2(1') (5.2), PhCH2OÀC(3) (3.2)
HaÀC(5) (8.1), PhCH2OÀC(4) (4.6), PhCH2OÀC(3) (4.6)
HbÀC(5) (24.7), HÀC(4) (7.8)
HaÀC(5)
HbÀC(5)
HaÀC(5) (18.0), HÀC(4) (1.8), PhCH2OÀC(4) (1.2)
HÀC(2) (5.3), PhCH2OÀC(3) (1.8), PhCH2OCH2 (3.9)
HÀC(3) (4.0), HÀC(4) (0.9)
CH2(1')
PhCH2OÀC(3)
PhCH2OÀC(4)
PhCH2OCH2
HÀC(3) (1.2), HÀC(4) (4.0)
CH2(1') (2.0)
5. (2R,3R,4S,5R)-3,4-Bis(benzyloxy)-1-[(benzyloxy)carbonyl]-2-[(benzyloxy)methyl]-5-[(1-methoxycar-
bonyl)-1-methylethyl]pyrrolidine (5cA). To a suspension of 4cA (21.9 mg, 0.033 mmol) and 4-ä molecular
sieves powder (activated in a domestic microwave oven; 43 mg) in CH2Cl2 (0.66 ml) was added pyridinium
chlorochromate (21.3 mg, 3 equiv.) at r.t. After being stirred at r.t. for 2 h, Celite and AcOEt were added to the
mixture. The resulting suspension was filtered through a short column (silica gel, washing with AcOEt), and the
filtrate evaporated. The residue was dissolved in dry MeCN (2 ml) and treated with Et3SiH (19 ml, 3 equiv.) and
Me3SiOTf (18 ml, 3 equiv.) at 08. After 20min, the mixture was quenched with sat. aq. NaHCO 3 soln. and
extracted with AcOEt (3Â). The combined org. phase was washed with brine, dried (MgSO4), and evaporated,
and the residue purified by prep. TLC (hexane/AcOEt 3 :1) to give 5cA (15.8 mg, 72%). Colorless oil; single
isomer. 1H-NMR (300 MHz, (D6)DMSO, 808): 7.36 7.17 (m, 20H, 4 Ph); 5.11 ( d, J ˆ 12.5, 1 H, PhCH2OCO);
4.87 (d, J ˆ 12.5, 1 H, PhCH2OCO); 4.66 (d, J ˆ 11.5, 1 H, PhCH2OÀC(4)); 4.64 (d, J ˆ 6.7, HÀC(5)); 4.60( d,
J ˆ 11.8, 1 H, PhCH2OÀC(3)); 4.55 (d, J ˆ 11.8, 1 H, PhCH2OÀC(3)); 4.45 (d, J ˆ 11.5, 1 H, PhCH2OÀC(4));
4.32 (dd, J ˆ 6.7, 5.1, HÀC(4)); 4.29 (s, PhCH2OCH2); 4.07 (dd, J ˆ 5.1, 4.2, HÀC(3)); 3.93 3.83 (m, HÀC(2),
HaÀC(1')); 3.46 (dd, J ˆ 9.2, 1.2, HbÀC(1')); 3.41 (s, MeO); 1.21 (s, Mea of CMe2CO2Me); 1.13 (s, Meb of
CMe2CO2Me). NOE: see Table 7. 13C-NMR (75 MHz, (D6)DMSO, 808): 176.3; 154.5; 137.9; 137.8; 136.2; 127.9;
127.8; 127.75; 127.68; 127.5; 127.4; 127.2; 127.04; 126.99; 126.95; 126.88; 79.0; 76.6; 71.99; 71.93; 71.6; 67.1; 65.6;
63.4; 62.2; 50.7; 44.9; 24.1; 22.5.
Table 7. 1H-NOE Enhancements of 5cA
Irradiated
Enhancements/%
HÀC(3)
HÀC(4) (7.2), HÀC(5) (3.9), PhCH2OÀC(3) (5.8)
HbÀC(1') (14.2), PhCH2OCH2 (2.3)
HÀC(3) (6.6), HÀC(5) (9.8)
HÀC(2), HaÀC(1')
HÀC(4)
HÀC(5)
HÀC(4) (5.2)
HbÀC(1')
HÀC(2) and/or HaÀC(1') (21.0), PhCH2OCH2 (3.0)
HÀC(4) (1.1), HÀC(5) (1.1), PhCH2OÀC(4) (1.3)
HÀC(5) (1.7)
Mea of CMe2CO2Me
Meb of CMe2CO2Me
6. (2S,3R,4R)-2-(Hydroxymethyl)pyrrolidine-3,4-diol Hydrochloride (7 ¥ HCl). A suspension of 5dD
(36.8 mg), 10% Pd/C (20 mg), and 2n HCl (0.5 ml) in EtOH (1.5 ml) was stirred under 1 atm of H2 at r.t. for

Helvetica Chimica Acta Vol. 85 (2002)
3691
24 h. After removal of H2, the mixture was filtered through a Celite pad with EtOH. Evaporation of the filtrate
gave almost pure 7 ¥ HCl (13.8 mg). [a]2D5 ˆ À3.4 (c ˆ 0.070, H2O). 1H-NMR (300 MHz, D2O; dioxane (d 3.70)
as internal standard): 4.29 (br. d, J ˆ 4.4, 1 H); 4.23 (br. s, 1 H); 3.98 3.76 (m, 3 H); 3.57 (dd, J ˆ 13.0, 4.7, 1 H);
3.21 (d, J ˆ 13.0, 1 H). 13C-NMR (75 MHz, D2O; dioxane (d 67.40) as internal standard): 75.15; 63.84; 58.08;
51.35.
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Received June 6, 2002