Synthesis of imino sugar scaffolds for the generation of glycosidase inhibitor libraries

FULL PAPER

Synthesis of Imino Sugar Scaffolds for the Generation

of Glycosidase Inhibitor Libraries

Barbara La Ferla,^[a]Piergiuliano Bugada,^[a]Laura Cipolla,^[a]Francesco Peri,^[a]and

Francesco Nicotra*^[a]

Dedicated to the memory of Professor Christian Pedersen

Keywords: Carbohydrates / Glycosidase inhibitors / Imino sugars / Libraries / Scaffolds

We have synthesized imino sugar scaffolds bearing two

points of diversity — the stereocenters located in α positions

sugar analogues having both α and β structures and of both

and stereochemistry. Different derivatives have been pre-

D

L

relative to the nitrogen atom — and three points of ortho- pared from the scaffolds we obtained. The carboxymethyl

gonal derivatization — a carboxylic function, the primary hy-

droxy group, and the ring nitrogen atom. The key steps in

the synthetic approach are the chain elongation of aldehyde

5 with the formation of an α,β-unsaturated ester, the Michael

addition of an amine, and the final cyclization. This strategy

leads to the preparation of different N-substituted imino

group was coupled to the amino function of different amino

acids to afford compounds 30−34, while the selectively ac-

cessible primary hydroxy group has been substituted with an

azido group to afford compounds 24−26.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2004)

Introduction

The significant role that carbohydrates play in a variety

of biological processes, particularly cellϪcell and

cellϪpathogen recognition phenomena, has stimulated

great interest in compounds that interfere in carbohydrate

metabolism and in carbohydrate-based recognition

phenomena. In this context, great efforts have been devoted

to the synthesis of glycomimetics,^[1]such as imino sugars^[2]

and C-glycosides,^[3]which can act as inhibitors of carbo-

hydrate processing enzymes and/or as stable analogues of

glycidic entities. In particular, imino sugars, in which the

ring oxygen atom of the natural sugar is replaced by a nitro-

gen atom that, when protonated, assumes a positive charge,

mimic the oxonium ion transition state of glycosidases and,

therefore, act as competitive inhibitors. The natural imino

sugar nojirimycin (1; Figure 1), discovered in 1966 as the

first glucose mimic,^[4]has shown inhibitory activity towards

α- and β-glucosidases,^[2,4]but because of the lability of the

hemiaminal function, chemists’ interest shifted to the stable,

and even more powerful, inhibitor, 1-deoxynojirimycin

(DNJ, 2) and to a variety of its derivatives.^[2]The multitude

of publications on the synthesis of imino sugars reported

so far outlines the growing interest in finding inhibitors that

have improved activities and specificities. Particular atten-

Figure 1. Natural imino sugars

tion has been devoted to the preparation of numerous N-

alkylated derivatives of 1-deoxynojirimycin;^[5]indeed, the

presence of a lipophilic appendage on the nitrogen atom

strongly enhances the biological activity.^[6]In addition, the

design and synthesis of imino sugar C-glycosides^[7]has at-

tracted attention since α-homonojirimycin (3), first synthe-

sized by Liu^[8]and thereafter isolated from a natural

source,^[9]has proven to be a potent and, more significantly,

selective inhibitor of α-glycosidases from the mouse gut and

human intestine. In addition, properly functionalized and

protected imino sugar C-glycosides could be useful building

blocks for the synthesis of more complex imino sugar con-

jugates.

[a]

Department of Biotechnology and Biosciences,

University of Milano Bicocca

Since the rational design of specific inhibitors is fre-

quently difficult, in part because of the lack of information

regarding the structures of most enzymes’ active sites, we

Piazza della Scienza 2, 20126 Milano, Italy

Fax: (internat.) ϩ 39-02-64484535

E-mail: francesco.nicotra@unimib.it

Eur. J. Org. Chem. 2004, 2451Ϫ2470

DOI: 10.1002/ejoc.200300805

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2451

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

believed that the synthesis of an imino sugar library could obtained imino sugars present three points for orthogonal

represent a better strategy in the search for specificity. An derivatization: the carboxylic group, the primary hydroxy

interesting example of a ‘‘dynamic’’ library of imino sugars, group, and the ring nitrogen atom.

reported by Vogel et al.,^[10]is based on the imines obtained

Formation of the α,β-Unsaturated Ester and Michael

Addition of the Amino Group

from an imino sugar bearing a carboxaldehyde function

and different amines. Recently, Wong et al.,^[11]in search of

selective α-fucosidase inhibitors, reported the synthesis of a

library of fuconojirimycin derivatives generated from a sin-

gle core structure. We aimed, instead, to generate a library

from imino sugar scaffolds having various points of diver-

sity, functional groups, and orthogonal protections. While

contemplating the kind of diversity sites that should be in-

troduced into our library, we considered some structural

features of previously cited imino sugars that have been

proven to correlate with and to enhance the inhibitory po-

tency and enzyme selectivity: the presence of an alkyl chain

on the ring nitrogen atom and the presence of a substituent

at C(1).

The synthetic strategy, outlined in Scheme 2, starts from

aldehyde 5 and requires, as key reactions, elongation to

form α,β-unsaturated esters, the introduction of an amino

group by Michael addition, and, finally, the cyclization. Al-

dehyde 5,^[12]obtained from commercially available 2,3,4,6-

tetra-O-benzyl--glucopyranose,

was

treated

with

[(ethoxycarbonyl)- and (benzyloxycarbonyl)methylene]tri-

phenylphosphorane (Scheme 2) to afford the α,β-unsatu-

rated esters 6 and 7. It is noteworthy that, in a combina-

torial approach, the use of different stabilized ylides allows

the introduction of different substituents at C(1).

The Michael acceptors 6 and 7 represent key intermedi-

ates for the introduction of a range of substituted amines

and, thus, affords, once again in a combinatorial fashion,

different N-substituted imino sugars as final products. We

used butylamine, allylamine, and benzylamine — the latter

two to permit deprotection of the amino group for further

derivatization. The Michael addition afforded two dia-

stereoisomers 8 [(3S) configuration] and 9 [(3R) configura-

tion], whose ratios are listed in Table 1. The configuration

at the newly formed stereocenter was determined, by ¹H

NMR coupling constants and the NOESY 1D experiments

discussed below, only after cyclization.

To allow easy derivatization at these positions, we chose

to synthesize imino-C-glycosides having a carboxylic func-

tion; this unit allows further elongation/derivatization by

well-established peptide synthesis procedures.

Results and Discussion

Retrosynthetic Scheme

We planned a retrosynthesis (Scheme 1) that allows imino

sugars to be obtained having a methylenecarboxylic ap-

pendage at C(1) for further elongation. Furthermore, the

synthesis allows the preparation of analogues of both α-

and β-glycosides and both the  and  series of sugars. The

Since we were interested in the production of both dia-

stereoisomers, no chelating agent or chiral auxiliaries were

adopted to improve the diastereoselectivity. We rationalize

the predominance of the (S) product over the (R) one in

Table 1. Products of the Michael addition

Compound RЈNH₂Products 8, 9 8/9 ratio Yield [%]

6

7

allyl

8a, 9a

8b, 9b

8c, 9c

8d, 9d

63:37

60:40

50 (8), 30 (9)

33 (8), 19 (9)^[a]

50 (8), 30 (9)

43 (8), 28 (9)

benzyl

butyl

allyl

[a]

Scheme 1

28% of the starting material was recovered.

Scheme 2. Reagents and conditions: i) PPh₃ϭCHCOOR, toluene, reflux; ii) RЈNH₂RЈ ϭ All, Bu, Bzl; iii) PTSOH, CH₃CN, H₂O, reflux;

iv) TBDPSiCl, imidazole, CH₂Cl₂; v) FmocCl, Na₂CO₃, dioxane/H₂O; vi) PCC, CH₂Cl₂; vii) piperidine, DMF; viii) CH₂Cl₂, Na₂SO₄,

AcOH, NaBH(OAc)₃

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Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

terms of a slightly more favorable nucleophilic attack from configurations of the C(2) stereocenter formed during the

the less hindered side of the double bond, according to the Michael addition and at C(6).

Cram transition state model depicted in Figure 2. The two

The values of the coupling constants (J_5,4ϭ 9.5, J_4,3ϭ

diastereoisomers obtained from the conjugate additions 9.5, and J_3,2ϭ 8.4 Hz) of compound 18d (Figure 4) are in-

were readily separated by flash chromatography.

dicative for a trans-diaxial disposition of the protons,

which, thus, indicates a ⁴C₁conformation; moreover, the

diaxial disposition of C(2)-H/C(3)-H allows us to determine

the absolute (S) configuration of the C(2) center. In ad-

dition, the coupling constant J_5,6ϭ 5.9 Hz indicates an

equatorial disposition of the C-6ϪH proton and conse-

quently the (S) absolute configuration at the C(6) center.

This data are supported by monodimensional NOE differ-

ence experiments and are confirmed by bidimensional

NOESY; a strong NOE was observed between C(2)-H/C(4)-

H while NOEs were absent for C(2)-H/C(6)-H and C(4)-H/

Figure 2. Diastereoselection of the conjugate addition

C(6)-H. In compound 19d, the coupling constants J_5,6

ϭ

4

9.6, J_5,4ϭ 9.6, and J_4,3ϭ 9.5 Hz are indicative of a C₁

conformation and a trans-diaxial disposition of the C(3)-H/

C(4)-H, C(4)-H/C(5)-H, and C(5)-H/C(6)-H units; the latter

disposition is also indicative of the absolute (R) configura-

tion at C-6. In a similar manner, J_3,2ϭ 5.2 Hz is diagnostic

of the equatorial disposition of C(2)-H and the absolute (R)

configuration at C(2). Moreover, an NOE was found be-

tween C(4)-H and C(6)-H. The absolute configurations of

the C(2) and C(6) centers of the other compounds were

determined similarly. The stereochemical outcome of the

newly formed stereocenter C(6) of products 18 and 19 is

somehow correlated to the configuration of the carbon

atom bearing the amine in precursors 16 and 17. As out-

lined in Table 2, the cyclization affords, as the major prod-

ucts, compounds having the substituent at C(6) positioned

trans with respect to the one at C(2) (Entries 1, 3Ϫ8). The

only compound that behaves differently is 16b (Entry 2),

which afforded as its major product the imino sugar 18b

that has its C(2) and C(6) substituents in a cis configura-

tion. In this compound, the coupling constants J_3,4ϭ 9.6,

and J_3,2ϭ 8.4 Hz confirm a trans-diaxial disposition of the

C(2)-H/C(3)-H and C(3)-H/C(4)-H units, which, thus, indi-

cates an absolute (S) configuration of the C(2) center, and

an NOE between the C(2)-H and C(6)-H protons indicates

the axial disposition of the C(6)-H unit and, consequently,

the (R) configuration at C(6).

Cyclization

To obtain their cyclic imino sugar structures, the open

chain compounds 8 and 9 can by cyclized by nucleophilic

attack of the amino group on an electrophilic center at

C(7). We performed this cyclization by intramolecular re-

ductive amination, which requires oxidation of the second-

ary hydroxy group at C(7). To perform this transformation,

the isopropylidene protecting groups of compounds 8 and 9

were hydrolyzed (p-toluenesulfonic acid or camphorsulfonic

acid, MeCN/H₂O, reflux) and the products were treated

with tert-butyldiphenylsilyl chloride (imidazole, CH₂Cl₂) to

protect the primary hydroxy groups selectively. Oxidation of

the free hydroxy groups of compounds 12 and 13 required

protection of the secondary amino groups to avoid their

oxidation to the corresponding N-oxides. Therefore, com-

pounds 12 and 13 were converted into the Fmoc derivatives

14 and 15 and then treated with PCC to afford the ketones

16 and 17. Finally, cleavage of the Fmoc protecting group

and immediate intramolecular reductive amination, per-

formed using NaBH(OAc)₃under acidic conditions (1,2-

dichloroethane, Na₂SO₄, AcOH) afforded the imino sugars

18 and 19 (Figure 3) in variable yields [40Ϫ98% for the last

1

three steps (Table 2)]. H NMR spectroscopic analysis on

the cyclized products allowed us to determine the absolute

Table 2. Stereochemical outcome of the reductive amination

Entry

Substrate

C(2)/C(6),

trans/cis ratio

Major

product

Yield

[%]^[a]

1

2

3

4

5

6

7

8

16a

16b

16c

16d

17a

17b

17c

17d

95:5

18a

18b

18c

18d

19a

19b

19c

19d

82

65

45

55

98

40

68

55

20:80

100:0

95:5

85:25

95:5

87:13

^[a]Yield of the isolated major product; calculated from the alcohols

14/15.

Figure 3. Cyclization major products

Eur. J. Org. Chem. 2004, 2451Ϫ2470

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FULL PAPER

Figure 4. NOE correlations

Derivatization

Imino sugars 18a, 19a, and 19c (major isomers) were de-

protected at their primary hydroxy groups by treatment

with tetrabutylammonium fluoride to afford compounds

20, 21, and 22, respectively (Scheme 3); these free primary

hydroxy groups can be derivatized or modified. These com-

pounds were converted into the corresponding azides 23,

24, and 25 by transformation to the intermediate mesylates

and subsequent treatment with sodium azide. Furthermore,

compounds 20, 21, and 22 were converted into the corre-

sponding carboxylic acids 26Ϫ28 to allow easy derivatiz-

ation of the ‘‘anomeric’’ appendage. We coupled com-

pounds 26 and 27 with different amino acids under typical

peptide coupling conditions (HBTU, HOBT, DIPEA,

DMF) to obtain the iminoglycosyl amino acids 29Ϫ33

(50Ϫ78% yield), which, to the best of our knowledge, are

among only a few examples^[13,14]of imino sugars linked to

amino acids.

Scheme 3. Reagents and conditions: i) TBAF, THF; ii) MsCl, Py,

CH₂Cl₂; iii) NaN₃, DMF; iv) LiOH, MeOH/H₂O/THF; v) HBTU,

HOBT, DIPEA, DMF, Xaa

derivatization or modification of the hydroxy group at C(2);

e.g., the formation of mimics of N-acetylglucosamine. De-

benzylation of compound 20 afforded a mixture of the de-

Deprotection

Compound 22 was debenzylated by performing catalytic sired N-propyl derivative 34 and the deallylated compound

hydrogenation with Pd(OH)₂/C in acidic methanol, afford- 38; this problem, which is due to partial deallylation caused

ing the deprotected imino sugar 35 (Scheme 4). Not surpris- by the palladium catalyst, was overcome by hydrogenation

ingly, compound 35, in D₂O, spontaneously began to con- of 20 using Raney nickel as catalyst, which afforded pure

vert into its corresponding lactone 41 in the NMR tube, as compound 34. Compounds 38 and 39 were obtained from

1

evidenced by the H NMR spectroscopic signals of the lac- 20 and 21 by deallylation with [Pd(PPh₃)₄] and dimethyl-

tone, the most significant of which are those of the C(3)-H barbituric acid (DMBA) and subsequent debenzylation

unit, shifted downfield from δ ϭ 3.62 to 4.33 ppm, and the [Pd(OH)₂/C, H₂, MeOH, AcOH)]. Compound 18b was de-

C(2)-H proton, which shifts from δ ϭ 3.75 to 4.05 ppm, silylated (TBAF, THF) at the primary hydroxy group and

with respect to 35. Compound 41 can be used for selective debenzylated to afford the carboxylic acid 40.

Scheme 4. Reagents and conditions: i) Pd(PPh₃)₄, DMBA; ii) H₂, Pd(OH)₂/C, AcOH, MeOH; iii) Raney Ni, MeOH, H₂; iv) TBAF, THF

2454

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Generation of Glycosidase Inhibitor Libraries

FULL PAPER

2

11.5 Hz, 1 H, CHPh), 4.56 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.58

Conclusion

2

(d, J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.66 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

CHPh), 4.76 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.79 (d, J_H,H

ϭ

A ductile strategy for the synthesis of imino sugar librar-

ies is described. The stereochemical outcome of the Michael

addition and of the cyclization by reductive amination gen-

erates two points of diversity that determine the absolute

configurations at the C(2) and C(6) centers (α or β;  or

) of the final imino sugars. Although the stereochemical

outcome of the cyclization depends on the stereochemistry

obtained in the Michael addition, we observed, in the case

of the Michael adduct having a (S) configuration, that the

result can be reversed by changing the substituent at the

nitrogen atom from butyl or allyl to benzyl.

The imino sugars obtained according to this strategy pre-

sent different sites for ready derivatization. In particular,

the carboxylic function at the ‘‘anomeric’’ substituent al-

lows further elongation; for instance, we functionalized it

by coupling with amino acids. The selectively deprotected

primary hydroxy group, which allows elongation at the

‘‘non-reducing’’ end of the sugar mimic, was converted into

azide functions, i.e., masked precursors of the amino

groups. Furthermore, with proper choice of the primary

amine employed in the Michael reaction, the amino group

of the ring nitrogen atom also can be varied or deprotected

to allow further derivatization.

3

11.2 Hz, 1 H, CHPh), 6.04 [d, J_H,Hϭ 15.8 Hz, 1 H, C(2)-H], 6.93

[dd, ³J_H,Hϭ 15.8, ³J_H,Hϭ 5.9 Hz, 1 H, C(3)-H], 7.29Ϫ7.37 (m, 15

H, HAr) ppm. ¹³C NMR: δ ϭ 14.71 (OCH₂CH₃), 25.31 [(CH₃)₂C],

26.93 [(CH₃)₂C], 60.88, 66.12 [C(8), OCH₂CH₃], 72.20, 74.43, 75.19

(3 CH₂Ph), 77.28, 78.78, 79.31, 81.66 [C(4), C(5), C(6), C(7)], 108.4

[(CH₃)₂C], 123.4 [C(2)], 127.8Ϫ128.6 (CHAr), 137.8, 138.1, 138.4

(3 CqAr), 144.7 [C(3)], 166.0 [C(1)] ppm. MS (MALDI-TOF):

m/z ϭ 584 [M ϩ Na]^ϩ, 600 [M ϩ K]^ϩ. C₃₄H₄₀O₇(560.7): calcd. C

72.83, H 7.19; found C 72.53, H 7.17.

Benzyl (2E,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-7,8-bis(isopropylid-

enoxy)-2-octenoate (7): Aldehyde 5 (385 mg, 0.78 mmol) was dis-

solved in toluene (2 mL) and [(benzyloxycarbonyl)methylene]tri-

phenylphosphorane (480 mg, 1.5 equiv.) dissolved in toluene

(2 mL) was added. The reaction mixture was heated at 80 °C. After

7 h, the solvent was evaporated under reduced pressure and purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 9:1)

afforded compound 7 (473 mg, 98% yield) as a colorless oil. [α]²_D⁰

ϭ

ϩ6.3 (c ϭ 0.9, CHCl₃). ¹H NMR: δ ϭ 1.26 [s, 3 H, (CH₃)₂C], 1.41

[s, 3 H, (CH₃)₂C], 3.64 [dd, ³J_H,Hϭ 6.4, ³J_H,Hϭ 4.0 Hz, 1 H, C(5)-

3

2

H], 3.84 [t, J_H,Hϭ 4.0 Hz, 1 H, C(6)-H], 3.93 [dd, J_H,Hϭ 8.4,

³J_H,Hϭ 6.8 Hz, 1 H, C(8a)-H], 4.00 [br. t, 1 H, C(8b)-H], 4.17 [dt,

3

³J_H,Hϭ 6.8, J_H,Hϭ 4.0 Hz, 1 H, C(7)-H], 4.28 [dt, J_H,Hϭ 6.4,

2

⁴J_H,Hϭ 1.2 Hz, 1 H, C(4)-H], 4.42 (d, J_H,Hϭ 11.6 Hz, 1 H,

2

CHPh), 4.56 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.59 (d, J_H,H

ϭ

2

11.2 Hz, 1 H, CHPh), 4.65 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.76

2

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.79 (d, J_H,Hϭ 11.6 Hz, 1 H,

2

CHPh), 5.15 (d, J_H,Hϭ 12.4 Hz, 1 H, CHPh), 5.19 (d, J_H,H

ϭ

Experimental Section

12.4 Hz, 1 H, CHPh), 6.09 [dd, ³J_H,Hϭ 16.2, ⁴J_H,Hϭ 1.2 Hz, 1 H,

3

C(2)-H], 7.00 [dd, J_H,Hϭ 16.2, J_H,Hϭ 6.4 Hz, 1 H, C(3)-H],

7.22Ϫ7.38 (m, 20 H, HAr) ppm. ¹³C NMR: δ ϭ 25.32 [(CH₃)₂C],

26.94 [(CH₃)₂C], 66.16, 66.71, 72.30, 74.43, 75.20 [C(8), 4 CH₂Ph],

77.38, 78.78, 79.30, 81.65 [C(4), C(5), C(6), C(7)], 108.5 [(CH₃)₂C],

122.9 [C(2)], 128.0Ϫ128.8 (CHAr), 136.0, 137.8, 138.0, 138.4 (4

CqAr), 145.5 [C(3)], 165.8 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ

645 [M ϩ Na]^ϩ, 661 [M ϩ K]^ϩ. C₃₉H₄₀O₇(620.7): calcd. C 75.22,

H 6.80; found C 75.15, H 6.62.

General Remarks: All solvents were dried with molecular sieves, for

at least 24 h prior to use. Thin layer chromatography (TLC) was

performed on silica gel 60 F₂₅₄plates (Merck) with detection using

UV light when possible, or by charring with a solution of concd.

H₂SO₄/EtOH/H₂O (5:45:45) or a solution of (NH₄)₆Mo₇O₂₄(21 g),

Ce(SO₄)₂(1 g), concd. H₂SO₄(31 mL) in water (500 mL). Flash

column chromatography was performed on silica gel 230Ϫ400

1

mesh (Merck). H and ¹³C NMR spectra were recorded at 25 °C

with a Varian Mercury 400 MHz instrument using CDCl₃as the

solvent unless otherwise stated. Chemical shift assignments, re-

ported in ppm, are referenced to the corresponding solvent peaks.

Mass spectra were recorded with a MALDI2 Kompakt Kratos in-

strument, using gentisic acid (DHB) as the matrix. Optical ro-

tations were measured at room temperature using a Krüss P3002

electronic polarimeter and are reported in units of 10^Ϫ1

Ethyl (3S,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-

bis(isopropylidenoxy)octanoate (8a) and Ethyl (3R,4S,5R,6R,7R)-3-

(Allylamino)-4,5,6-tris(benzyloxy)-7,8-bis(isopropylidenoxy)-

octanoate (9a): Compound 6 (725 mg, 1.29 mmol) was dissolved in

allylamine (1.94 mL, 25.86 mmol, 12 equiv.) and the reaction mix-

ture was stirred at room temperature for 5 d. The excess allylamine

was evaporated under reduced pressure and the residue was puri-

fied by flash chromatography (petroleum ether/ethyl acetate, 9:1)

deg·cm²·g^Ϫ1

PerkinϪElmer Series II Analyzer 2400.

.

Elemental analyses were performed using

a

to yield 8a and 9a (652 mg, 82%, 8a/9a, 63:37) as colorless oils. 8a:

3

Ethyl (2E,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-7,8-bis(isopropylid-

[α]²_D⁰ϭ Ϫ3.5 (c ϭ 0.8, CHCl₃). ¹H NMR: δ ϭ 1.22 (t, J_H,H

ϭ

enoxy)-2-octenoate (6): Aldehyde 5 (1.574 g, 3.74 mmol) was dis- 7.1 Hz, 3 H, OCH₂CH₃), 1.30 [s, 3 H, (CH₃)₂C], 1.42 [s, 3 H,

solved in toluene (20 mL) and [(ethoxycarbonyl)methylene]triphen-

ylphosphorane (2.18 g, 5.61 mmol, 1.5 equiv.) was added. The reac- 14.0, J_H,Hϭ 5.9 Hz, 1 H, CHCHϭCH₂), 3.02 (dd, J_H,Hϭ 14.0,

(CH₃)₂C], 2.46Ϫ2.57 [m, 2 H, C(2a)-H, C(2b)-H], 2.95 (dd, ²J_H,Hϭ

3

2

tion mixture was stirred at 80 °C for 6 h. The solvent was evapo-

rated under reduced pressure and the residue was purified by flash

chromatography (petroleum ether/ethyl acetate, 9:1) to provide

compound 6 (1.50 g, 86%, de 100%) as a colorless oil. [α]²_D⁰ϭ ϩ4.7

³J_H,Hϭ 5.9 Hz, 1 H, CHCHϭCH₂), 3.15 [m, 1 H, C(3)-H], 3.69

[dd, ³J_H,Hϭ 7.3, ³J_H,Hϭ 3.5 Hz, 1 H, C(5)-H], 3.84 [br. t, ³J_H,Hϭ

3

3.7 Hz, 1 H, C(6)-H], 3.92 [dd, J_H,Hϭ 7.1, J_H,Hϭ 3.1 Hz, 1 H,

C(4)-H], 3.95 [dd, ²J_H,Hϭ 8.2, ³J_H,Hϭ 6.6 Hz, 1 H, C(8a)-H], 4.04

1

3

(c ϭ 0.4, CHCl₃). H NMR: δ ϭ 1.29 [s, 3 H, (CH₃)₂C], 1.31 (t,

[m, 1 H, C(8b)-H], 4.08 (q, J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃), 4.21

³J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.40 [s, 3 H, (CH₃)₂C], 3.64 [dd, [ddd, ³J_H,Hϭ 6.7, ³J_H,Hϭ 6.7, ³J_H,Hϭ 4.3 Hz, 1 H, C(7)-H], 4.61

3

2

³J_H,Hϭ 6.2, J_H,Hϭ 3.6 Hz, 1 H, C(5)-H], 3.84 [br. t, J_H,H

ϭ

(d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.63 (d, J_H,Hϭ 11.1 Hz, 1 H,

2

3

2

3.9 Hz, 1 H, C(6)-H], 3.92 [dd, J_H,Hϭ 8.1, J_H,Hϭ 6.7 Hz, 1 H,

CHPh), 4.64 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.80 (d, J_H,Hϭ

2

C(8a)-H], 4.00 [br. t, 1 H, C(8b)-H], 4.12Ϫ4.20 [m, 3 H, C(7)-H, 11.4 Hz, 1 H, CHPh), 4.82 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.86

OCH₂CH₃], 4.27 [t, ³J_H,Hϭ 6.2 Hz, 1 H, C(4)-H], 4.41 (d, ²J_H,Hϭ (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.97 [dd, J_H,Hϭ 10.3, J_H,H

ϭ

2

3

4

Eur. J. Org. Chem. 2004, 2451Ϫ2470

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2455

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

1.4 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.01 (dd, J_H,Hϭ 17.2, J_H,H

3

4

ϭ

108.5 [(CH₃)₂C], 127.8Ϫ128.6 (CHAr), 138.4, 138.6, 138.7, 140.5

3

1.6 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.70 [ddt, J_H,Hϭ 17.0, (4 CqAr), 172.7 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 669 [M ϩ

³J_H,Hϭ 10.3, ³J_H,Hϭ 5.9 Hz, 1 H, CH₂CHϭCH₂], 7.25Ϫ7.34 (m, H]^ϩ, 691 [M ϩ Na]^ϩ. C₄₁H₄₉NO₇(667.8): calcd. C 73.74, H 7.40,

15 H, HAr) ppm. ¹³C NMR: δ ϭ 14.68 (OCH₂CH₃), 25.34 N 2.10; found C 74.00, H 7.21, N 2.03. 9b: [α]²_D⁰ϭ ϩ0.7 (c ϭ 1.1,

1

3

[(CH₃)₂C], 26.97 [(CH₃)₂C], 36.20 (ϪCH₂CHϭCH₂), 49.87 [C(2)], CHCl₃). H NMR: δ ϭ 1.15 (t, J_H,Hϭ 7.0 Hz, 3 H, OCH₂CH₃),

2

56.20 [C(3)], 60.72, 66.35 [C(8), CH₂CH₃], 74.49, 74.91, 75.32 (3

CH₂Ph), 77.32, 79.38, 79.46, 81.28 [C(4), C(5), C(6), C(7)], 108.5 15.2, J_H,Hϭ 7.0 Hz, 1 H, C(2a)-H], 2.65 [dd, J_H,Hϭ 15.2,

[(CH₃)₂C], 115.7 (CH₂CHϭCH₂), 127.8Ϫ128.6 (CHAr), 137.2

³J_H,Hϭ 4.5 Hz, 1 H, C(2b)-H], 3.02Ϫ3.08 [m, 1 H, C(3)-H],

(CH₂CHϭCH₂), 138.4, 138.5, 138.7 (3 CqAr), 172.7 [C(1)] ppm. 3.62Ϫ3.68 (m, 2 H, CH₂Ph), 3.80 [br. d, 1 H, C(4)-H], 3.88Ϫ4.00

1.31 [s, 3 H, (CH₃)₂C], 1.45 [s, 3 H, (CH₃)₂C], 2.49 [dd, J_H,Hϭ

3

2

MS (MALDI-TOF): m/z ϭ 619 [M ϩ H]^ϩ, 641 [M ϩ Na]^ϩ, 657

[m, 5 H, C(8a)-H, C(8b)-H, CHPh, OCH₂CH₃], 4.18Ϫ4.24 [m, 2

2

[M ϩ K]^ϩ. C₃₇H₄₇NO₇(617.8): calcd. C 71.94, H 7.67, N 2.27; H, C(5)-H, C(7)-H], 4.50 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.57

2

found C 71.72, H 7.65, N 2.26. 9a: [α]²_D⁰ϭ ϩ5.7 (c ϭ 1.8, CHCl₃).

(d, J_H,Hϭ 11.7 Hz, 1 H, CHPh), 4.61Ϫ4.69 (m, 2 H, 2 CHPh),

¹H NMR: δ ϭ 1.08 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃); 1.21 [s, 3 4.80Ϫ4.89 (m, 2 H, 2 CHPh), 7.20Ϫ7.38 (m, 20 H, HAr) ppm. ¹³

C

3

2

H, (CH₃)₂C], 1.35 [s, 3 H, (CH₃)₂C], 2.37 [dd, J_H,Hϭ 14.3,

NMR: δ ϭ 14.63 (OCH₂CH₃), 25.37 [(CH₃)₂C], 27.03 [(CH₃)₂C],

36.20 [C(2)], 55.14 [C(3)], 51.30, 60.76, 65.93, 66.71, 74.19, 75.25

³J_H,Hϭ 6.9 Hz, 1 H, C(2a)-H], 2.49 [dd, J_H,Hϭ 14.8, J_H,H

ϭ

2

3

5.2 Hz, 1 H, C(2b)-H], 3.00Ϫ3.05 [m, 2 H, C(3)-H, CHCHϭCH₂],

[C(8), 4 CH₂Ph, OCH₂CH₃], 77.27, 78.97, 81.02, 81.89 [C(4), C(5),

2

3

3.28 (dd, J_H,Hϭ 13.9, J_H,Hϭ 5.8 Hz, 1 H, CHCHϭCH₂), C(6), C(7)], 108.2 [(CH₃)₂C], 128.3Ϫ136.3 (CHAr), 138.6, 138.7,

3

3.72Ϫ3.77 [m, 2 H, C(4)-H, C(6)-H], 3.82Ϫ3.84 [m, J_H,Hϭ 5.1, 1

138.9, 140.5 (4 CqAr), 172.4 [C(1)] ppm. MS (MALDI-TOF):

3

H, C(8a)-H], 3.88 (q, J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃), 3.96 [dd, m/z ϭ 669 [M ϩ H]^ϩ, 691 [M ϩ Na]^ϩ, 707 [M ϩ K]^ϩ. C₄₁H₄₉NO₇

²J_H,Hϭ 8.2, ³J_H,Hϭ 7.0 Hz, 1 H, C(8b)-H], 4.07 [dd, ³J_H,Hϭ 8.1, (667.8): calcd. C 73.74, H 7.40, N 2.10; found C 73.98, H 7.12,

3

³J_H,Hϭ 2.2 Hz, 1 H, C(5)-H], 4.16 (br. t, J_H,Hϭ 7.0, J_H,H

ϭ

N 2.32.

2

4.3 Hz, 1 H, C(7)-H]], 4.47 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.56

2

Ethyl (3S,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-3-(butylamino)-7,8-

bis(isopropylidenoxy)octanoate (8c) and Ethyl (3R,4S,5R,6R,7R)-

4,5,6-Tris(benzyloxy)-3-(butylamino)-7,8-bis(isopropylidenoxy)-

octanoate (9c): Compound 6 (350 mg, 0.62 mmol) was dissolved in

butylamine (913 mg, 12.48 mmol) under an inert gas and the reac-

tion mixture was stirred at room temperature for 8 h. The excess

butylamine was evaporated under reduced pressure and then the

residue was purified by flash chromatography (petroleum ether/

ethyl acetate, 9:1) to yield 8c and 9c (324 mg, 84%; 8c/9c ϭ 63:37)

as colorless oils. 8c: [α]²_D⁰ϭ ϩ3.4 (c ϭ 1.7, CHCl₃). ¹H NMR: δ ϭ

(d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.57 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

CHPh), 4.74 (d, J_H,Hϭ 11.3 Hz, 2 H, 2 CHPh), 4.78 (d, J_H,H

ϭ

11.2 Hz, 1 H, CHPh), 5.00 [dd, ³J_H,Hϭ 10.2, ⁴J_H,Hϭ 1.7 Hz, 1 H,

3

4

CH₂CHϭCH₂(cis)], 5.10 [dd, J_H,Hϭ 17.2, J_H,Hϭ 1.7 Hz, 1 H,

CH₂CHϭCH₂(trans)], 5.72Ϫ5.82 (m, H, CH₂CHϭCH₂),

1

7.12Ϫ7.28 (m, 15 H, HAr) ppm. ¹³C NMR: δ ϭ 14.62 (OCH₂CH₃),

25.29 [(CH₃)₂C], 27.00 [(CH₃)₂C], 30.14 (ϪCH₂CHϭCH₂), 49.99

[C(2)], 55.21 [C(3)], 60.77, 66.45 [C(8), OCH₂CH₃], 74.29, 75.16,

75.24 (3 CH₂Ph), 77.51, 77.51, 78.91, 80.77 [C(4), C(5), C(6), C(7)],

108.3 [(CH₃)₂C], 116.7 (CH₂CHϭCH₂), 127.7Ϫ129.1 (CHAr),

137.2 (CH₂CHϭCH₂), 138.5, 138.6, 138.8 (3 CqAr), 172.4 [C(1)]

ppm. MS (MALDI-TOF): m/z ϭ 619 [M ϩ H]^ϩ, 641 [M ϩ Na]^ϩ,

657 [M ϩ K]^ϩ. C₃₇H₄₇NO₇(617.8): calcd. C 71.94, H 7.67, N 2.27;

found C 71.75, H 7.64, N 2.28.

3

0.81 [t, J_H,Hϭ 6.9 Hz, 3 H, (CH₂)₃CH₃], 1.22 (t, J_H,Hϭ 7.1 Hz,

3 H, OCH₂CH₃), 1.16Ϫ1.28 (m, 4 H, CH₂CH₂CH₃), 1.30 [s, 3 H,

(CH₃)₂C], 1.43 [s,

3 H, (CH₃)₂C], 2.29Ϫ2.37 [m, 2 H,

NCH₂(CH₂)₂CH₃], 2.48Ϫ2.53 [m,

2 H, C(2a)-H, C(2b)-H],

3.10Ϫ3.14 [m, 1 H, C(3)-H], 3.67 [dd, ³J_H,Hϭ 7.2, ³J_H,Hϭ 3.6 Hz,

3

Ethyl (3S,4S,5R,6R,7R)-3-(Benzylamino)-4,5,6-tris(benzyloxy)-7,8-

1 H, C(5)-H], 3.87 [br. t, J_H,Hϭ 3.8 Hz, 1 H, C(6)-H], 3.92 [dd,

bis(isopropylidenoxy)-octanoate (8b) and Ethyl (3R,4S,5R,6R,7R)-3- ³J_H,Hϭ 6.6, J_H,Hϭ 3.6 Hz, 1 H, C(4)-H], 3.95 [dd, J_H,Hϭ 8.2,

3

(Benzylamino)-4,5,6-tris(benzyloxy)-7,8-bis(isopropylidenoxy)-

octanoate (9b): Under an inert gas, compound (779 mg,

³J_H,Hϭ 6.6 Hz, 1 H, C(8a)-H], 4.03Ϫ4.10 [m, 3 H, OCH₂CH₃,

C(8b)-H], 4.23 [dt, ³J_H,Hϭ 6.7, ³J_H,Hϭ 4.2 Hz, 1 H, C(7)-H], 4.61

6

2

1.39 mmol) was dissolved in benzylamine (500 µL, 3.6 equiv.) and (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.62 (d, J_H,Hϭ 11.1 Hz, 1 H,

2

the reaction mixture was stirred for 7 d. Excess benzylamine was

evaporated under reduced pressure and then purification by flash

chromatography (petroleum ether/ethyl acetate, 8:2) afforded pure

compound 8b (303 mg, 33% yield) as a yellow oil and a mixture of

9b and 6, which was separated by flash chromatography (toluene/

ethyl acetate, 9:1) to afford 9b (177 mg, 19% yield) as a yellow oil

CHPh), 4.63 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.78, (d, J_H,Hϭ

2

11.1 Hz, 1 H, CHPh), 4.81 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.88

(d, J_H,Hϭ 11.4 Hz, 1 H, CHPh, 7.27Ϫ7.38 (m, 15 H, HAr) ppm.

2

¹³C NMR: δ ϭ 14.45, 14.67 [N(CH₂)₃CH₃, OCH₂CH₃], 20.79

(CH₂CH₂CH₂CH₃), 25.30 [(CH₃)₂C], 26.94 [(CH₃)₂C], 30.14

(CH₂CH₂CH₂CH₃), 36.44 [C(2)], 47.37 (CH₂CH₂CH₂CH₃), 57.11

[C(3)], 60.66, 66.27 [OCH₂CH₃, C(8)], 74.55, 74.87, 75.28 (3

and unchanged 6 (222 mg). 8b: [α]²_D⁰ϭ Ϫ15.0 (c ϭ 1.6, CHCl₃). ¹H

3

NMR: δ ϭ 1.11 (t, J_H,Hϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.15 [s, 3 H, CH₂Ph), 77.38, 79.38, 79.45, 81.35 [C(4), C(5), C(6), C(7)], 108.4

(CH₃)₂C], 1.20 [s, 3 H, (CH₃)₂C], 2.52Ϫ2.59 [m, 2 H, C(2a)-H, [(CH₃)₂C], 127.8Ϫ128.5 (CHAr), 138.4, 138.5, 138.7 (3 CqAr),

3

C(2b)-H], 3.19Ϫ3.22 [m, 1 H, C(3)-H], 3.42 (d, J_H,Hϭ 12.8 Hz, 1

172.8 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 634 [M ϩ H]^ϩ.

H, CHPh), 3.49 (d, ³J_H,Hϭ 12.8 Hz, 1 H, CHPh), 3.60 [dd, ³J_H,Hϭ C₃₈H₅₁NO₇(633.8): calcd. C 72.01, H 8.11, N 2.21; found C 72.24,

3

1

7.2, J_H,Hϭ 3.6 Hz, 1 H, C(5)-H], 3.74 [br. t, 1 H, C(6)-H], 3.84 H 8.38, N 2.01. 9c: [α]²_D⁰ϭ Ϫ0.4 (c ϭ 1.0, CHCl₃). H NMR: δ ϭ

2

3

[dd, J_H,Hϭ 8.4, J_H,Hϭ 6.8 Hz, 1 H, C(8a)-H], 3.90Ϫ3.94 [m, 1

H, C(4)-H], 3.92 [dd, J_H,Hϭ 8.4, J_H,Hϭ 6.8 Hz, 1 H, C(8b)-H],

3.94Ϫ4.40 (m, 2 H, OCH₂CH₃), 4.13 [dt, J_H,Hϭ 6.8, J_H,H

4.4 Hz, 1 H, C(7)-H], 4.49 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.51 NCH(CH₂)₂CH₃], 2.58 [dd, J_H,Hϭ 14.8, J_H,Hϭ 5.4 Hz, 1 H,

0.91 [t, ³J_H,Hϭ 7.2 Hz, 3 H, N(CH₂)₃CH₃], 1.16 (t, ³J_H,Hϭ 7.1 Hz,

3 H, OCH₂CH₃), 1.26Ϫ1.41 (m, 4 H, CH₂CH₂CH₃), 1.29 [s, 3 H,

(CH₃)₂C], 1.43 [s, 3 H, (CH₃)₂C], 2.35Ϫ2.45 [m, 2 H, C(2a)-H,

2

3

ϭ

2

3

2

(d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 4.56 (d, J_H,Hϭ 11.6 Hz, 1 H, C(2b)-H], 2.68Ϫ2.74 [m, 1 H, NCH(CH₂)₂CH₃], 3.01Ϫ3.05 [m, 1

2

3

CHPh), 4.70 (d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 4.72 (br. d, 2 H, 2

H, C(3)-H], 3.79 [dd, J_H,Hϭ 8.2, J_H,Hϭ 2.2 Hz, 1 H, C(4)-H],

CHPh), 7.00Ϫ7.24 (m, 20 H, HAr) ppm. ¹³C NMR: δ ϭ 14.72 3.84 [dd, J_H,Hϭ 3.8, J_H,Hϭ 2.9 Hz, 1 H, C(6)-H], 3.93 [dd,

3

(OCH₂CH₃), 25.40 [(CH₃)₂C], 27.00 [(CH₃)₂C], 36.30 [C(2)], 56.78 ²J_H,Hϭ 7.7, J_H,Hϭ 6.7 Hz, 1 H, C(8a)-H], 3.97 (q, J_H,H

[C(3)], 51.45, 60.75, 66.41, 74.55, 74.90, 75.34 [C(8), 4 CH₂Ph, 7.1 Hz, 2 H, OCH₂CH₃), 4.06 [br. t, 1 H, C(8b)-H], 4.14 [dd,

OCH₂CH₃], 77.33, 79.46, 79.51, 81.34 [C(4), C(5), C(6), C(7)], ³J_H,Hϭ 8.2, J_H,Hϭ 2.6 Hz, 1 H, C(5)-H], 4.24 [dt, J_H,Hϭ 4.4,

ϭ

3

2456

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

74.27, 75.19, 77.36 [C(8), 4 CH₂Ph], 77.53, 78.88, 80.79, 81.98

[C(4), C(5), C(6), C(7)], 108.3 [(CH₃)₂C], 116.1 (CH₂CHϭCH₂),

127.6Ϫ128.8 (CH₂CHϭCH₂, CHAr), 135.9Ϫ138.6 (CqAr), 172.2

2

³J_H,Hϭ 4.2 Hz, 1 H, C(7)-H], 4.55 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

CHPh), 4.64 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.66 (d, J_H,H

ϭ

11.3 Hz, 1 H, CHPh), 4.82, (d, ²J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.83

2

(d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.85 (d, J_H,Hϭ 11.2 Hz, 1 H, [C(1)] ppm.. MS (MALDI-TOF): m/z ϭ 680 [M ϩ H]^ϩ, 702 [M ϩ

CHPh), 7.26Ϫ7.40 (m, 15 H, HAr) ppm. ¹³C NMR: δ ϭ 14.53, Na]^ϩ, 718 [M ϩ K]^ϩ. C₄₂H₄₉NO₇(679.9): calcd. C 74.20, H 7.26,

14.64 [N(CH₂)₃CH₃, OCH₂CH₃], 20.93 (CH₂CH₂CH₂CH₃), 25.29

[(CH₃)₂C], 26.99 [(CH₃)₂C], 33.14 (CH₂CH₂CH₂CH₃), 36.58 [C(2)],

47.28 (CH₂CH₂CH₂CH₃), 56.17 [C(3)], 60.69, 66.42 [OCH₂CH₃,

C(8)], 74.27, 75.16, 75.22 (3 CH₂Ph), 77.56, 78.98, 80.91, 81.77

[C(4), C(5), C(6), C(7)], 108.2 [(CH₃)₂C], 127.6Ϫ128.5 (CHAr),

138.7, 138.8, 138.9 (3 CqAr), 172.6 [C(1)] ppm. MS (MALDI-

TOF): m/z ϭ 634 [M ϩ H]^ϩ. C₃₈H₅₁NO₇(633.8): calcd. C 72.01,

H 8.11, N 2.21; found C 72.36, H 8.33, N 2.12.

N 2.06; found C 74.10, H 7.51, N 1.90.

Ethyl (3S,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-di-

hydroxyoctanoate (10a): Compound 8a (359 mg, 0.58 mmol) was

dissolved in CH₃CN (3 mL) and H₂O (100 µL) was added. The

reaction solution was acidified using PTSA and then stirred at 60

°C for 20 min. The mixture was neutralized using NaHCO₃(satu-

rated solution), the two layers were separated, and the aqueous

layer was extracted with ethyl acetate (3 ϫ 5 mL); the combined

organic layers were dried with Na₂SO₄. The solvent was evaporated

under reduced pressure and the residue was purified by flash chro-

matography (petroleum ether/ethyl acetate, 5:5) yielding 10a

(267 mg, 80%) as a colorless oil. [α]²_D⁰ϭ Ϫ7.1 (c ϭ 0.7, CHCl₃). ¹H

NMR: δ ϭ 1.21 (t, ³J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 2.50Ϫ2.53 [m,

Benzyl (3S,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-

bis(isopropylidenoxy)octanoate (8d) and Benzyl (3R,4S,5R,6R,7R)-

3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-bis(isopropylidenoxy)-

octanoate (9d): Under an inert gas, compound

7 (353 mg,

0.566 mmol) was dissolved in allylamine (424 µL, 10 equiv.) and

then the reaction mixture was stirred for 72 h. The excess allyla-

mine was evaporated under reduced pressure and then purification

by flash chromatography (petroleum ether/ethyl acetate, 8:2) af-

forded pure compounds 8d (163 mg, 42% yield) and 9d (110 mg,

29% yield) as yellowish oils. 8d: [α]²_D⁰ϭ Ϫ2.1 (c ϭ 2.9, CHCl₃). ¹H

2

3

2 H, C(2a)-H, C(2b)-H], 3.05 (dd, J_H,Hϭ 13.9, J_H,Hϭ 6.0 Hz, 1

2

3

H, CHCHϭCH₂), 3.14 (dd, J_H,Hϭ 13.9, J_H,Hϭ 5.8 Hz, 1 H,

3

CHCHϭCH₂), 3.32 [dd, J_H,Hϭ 10.9, J_H,Hϭ 6.5 Hz, 1 H, C(3)-

2

3

H], 3.66 [dd, J_H,Hϭ 11.4, J_H,Hϭ 4.4 Hz, 1 H, C(8a)-H], 3.70

[dd, J_H,Hϭ 7.7, J_H,Hϭ 4.0 Hz, 1 H, C(6)-H], 3.74 [dd, J_H,H

11.4, J_H,Hϭ 3.4 Hz, 1 H, C(8b)-H], 3.84 [t, J_H,Hϭ 4.1 Hz, 1 H,

C(5)-H], 3.88 [br. dd, J_H,Hϭ 7.8, J_H,Hϭ 4.2 Hz, 1 H, C(7)-H],

3

2

ϭ

3

NMR: δ ϭ 1.10 [s, 3 H, (CH₃)₂C], 1.13 [s, 3 H, (CH₃)₂C],

2

3

2.44Ϫ2.53 [m, 2 H, C(2a)-H, C(2b)-H], 2.85 [br.dd, 1 H, J_H,H

ϭ

3

2

3

14.0, J_H,Hϭ 8.0 Hz, 1 H, CHCHϭCH₂], 2.91 [br. dd, J_H,H

ϭ

3.92 [br. t, J_H,Hϭ 4.8 Hz, 1 H, C(4)-H], 4.06 (q, J_H,Hϭ 7.1 Hz,

14.0, ³J_H,Hϭ 5.6 Hz, 1 H, CHCHϭCH₂], 3.05Ϫ3.11 [m, 1 H, C(3)-

2

2 H, OCH₂CH₃), 4.58 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.61 (d,

3

²J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.63 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

H,], 3.59 [dd, J_H,Hϭ 7.2, J_H,Hϭ 3.2 Hz, 1 H, C(5)-H], 3.73 [br.

t, ³J_H,Hϭ 4.0 Hz, 1 H, C(6)-H], 3.82Ϫ3.87 [m, 2 H, C(8a)-H, C(4)-

H], 3.92 [dd, ²J_H,Hϭ 8.0, ³J_H,Hϭ 6.8 Hz, 1 H, C(8b)-H], 4.12 [dt,

2

CHPh), 4.67 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.70 (d, J_H,H

11.2 Hz, 1 H, CHPh), 4.76 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 5.01

ϭ

2

3

2

³J_H,Hϭ 6.8, J_H,Hϭ 4.4 Hz, 1 H, C(7)-H], 4.50 (br. d, J_H,H

ϭ

3

4

[dd, J_H,Hϭ 10.2, J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.07

2

[dd, ³J_H,Hϭ 17.1, ⁴J_H,Hϭ 1.7 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.76

11.6 Hz, 3 H, 3 CHPh), 4.68 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh),

4.69 (d, ²J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.73 (d, J_H,Hϭ 11.6 Hz, 1

2

3

(ddt, J_H,Hϭ 17.1, J_H,Hϭ 10.3, J_H,Hϭ 5.9 Hz, 1 H, CH₂CHϭ

CH₂), 7.25Ϫ7.36 (m, 15 H, HAr) ppm. ¹³C NMR: δ ϭ 14.64

(OCH₂CH₃), 36.20 [C(2)], 50.24 (ϪCH₂CHϭCH₂), 56.12 [C(3)],

60.79, 63.92 [C(8), OCH₂CH₃], 71.95, 77.01, 78.98, 79.71 [C(4),

C(5), C(6), C(7)], 73.58, 74.42, 74.44 (3 CH₂Ph), 116.1 (CH₂CHϭ

CH₂), 128.0Ϫ128.8 (CHAr), 137.0 (CH₂CHϭCH₂), 137.8, 137.9,

138.2 (3 CqAr), 172.7 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 579

[M ϩ H]^ϩ, 601 [M ϩ Na]^ϩ, 617 [M ϩ K]^ϩ. C₃₄H₄₃NO₇(577.7):

calcd. C 70.69, H 7.50, N 2.42; found C 70.44, H 7.47, N 2.43.

H, CHPh), 4.85 [dd, J_H,Hϭ 12.0, ⁴J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭ

3

4

CH₂(cis)], 4.89 [dd, J_H,Hϭ 19.2, J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭ

CH₂(trans)], 4.95 (d, J_H,Hϭ 12.4 Hz, 1 H, CHPh), 4.98 (d,

2

²J_H,Hϭ 12.4 Hz, 1 H, CHPh), 5.53Ϫ5.62 (m, 1 H, CH₂CHϭCH₂),

7.22Ϫ7.38 (m, 20 H, HAr) ppm. ¹³C NMR: δ ϭ 25.33 [(CH₃)₂C],

26.95 [(CH₃)₂C], 30.14 [C(2)], 49.80 (CH₂CHϭCH₂), 56.39 [C(3)],

66.40, 66.58, 74.46, 74.94, 75.26 [C(8), 4 CH₂Ph], 77.28, 77.35,

79.36, 81.19 [C(4), (5), (6), (7)], 108.4 [(CH₃)₂C], 108.5 (CH₂CHϭ

CH₂), 127.8Ϫ128.7 (CH₂CHϭCH₂, CHAr), 136.1, 138.3, 138.5,

138.6 (4 CqAr), 172.4 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 680

Ethyl (3S,4S,5R,6R,7R)-3-(Benzylamino)-4,5,6-tris(benzyloxy)-7,8-

[M ϩ H]^ϩ, 702 [M ϩ Na]^ϩ, 718 [M ϩ K]^ϩ. C₄₂H₄₉NO₇(679.9): dihydroxyoctanoate (10b): Compound 8b (108 mg, 0.16 mmol) was

calcd. C 74.20, H 7.26, N 2.06; found C 73.98, H 7.33, N 1.80. 9d:

dissolved in CH₃CN (2 mL); H₂O (300 µL) and PTSA (95 mg, 0.3

[α]²_D⁰ϭ ϩ3.2 (c ϭ 1.5, CHCl₃). ¹H NMR: δ ϭ 1.30 [s, 3 H, equiv.) were added. The reaction mixture was heated to 70 °C for

2

3

(CH₃)₂C], 1.44 [s, 3 H, (CH₃)₂C], 2.49 [dd, J_H,Hϭ 15.6, J_H,H

ϭ

3 h. After cooling to room temp., the reaction mixture was diluted

2

3

7.6 Hz, 1 H, C(2a)-H], 2.61 [dd, J_H,Hϭ 15.6, J_H,Hϭ 5.2 Hz, 1 with EtOAc, washed with a saturated solution of NaHCO₃, dried

H, C(2b)-H], 3.07Ϫ3.12 [m, 2 H, C(3)-H, CHCHϭCH₂], 3.35 [br. with Na₂SO₄, and filtered; the solvent was evaporated under re-

2

3

dd, J_H,Hϭ 14.0, J_H,Hϭ 5.6 Hz, 1 H, CHCHϭCH₂], 3.81Ϫ3.85 duced pressure. Purification by flash chromatography (petroleum

[m, 2 H, C(5)-H, C(6)-H], 3.94 [dd, ²J_H,Hϭ 8.0, ³J_H,Hϭ 6.4 Hz, 1

ether/ethyl acetate, 1:1) afforded pure compound 10b (98 mg, 97%

2

3

1

H, C(8a)-H], 4.05 [dd, J_H,Hϭ 8.4, J_H,Hϭ 7.2 Hz, 1 H, C(8b)- yield) as a colorless oil. [α]²_D⁰ϭ Ϫ7.8 (c ϭ 1.8, CHCl₃). H NMR:

H], 4.15 [dd, ³J_H,Hϭ 8.0, ³J_H,Hϭ 2.4 Hz, 1 H, C(4)-H], 4.23Ϫ4.27

δ ϭ 1.17 (t, J_H,Hϭ 7.0 Hz, 3 H, OCH₂CH₃), 2.48Ϫ2.50 [m, 2 H,

3

2

[m, 1 H, C(7)-H], 4.50 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.64 (d, C(2a)-H, C(2b)-H], 3.30Ϫ3.36 [m, 1 H, C(3)-H], 3.50Ϫ3.65 [m, 5

²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.65 (d, J_H,Hϭ 11.6 Hz, 1 H, H, C(7)-H, C(8a)-H, C(8b)-H, 2 CHPh], 3.70Ϫ3.75 [m, 2 H, C(5)-

2

CHPh), 4.81 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.82 (d, J_H,H

ϭ

H, C(6)-H], 3.86Ϫ3.88 [m, 1 H, C(4)-H], 3.93Ϫ4.03 (m, 2 H,

2

11.2 Hz, 1 H, CHPh), 4.83 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.91

OCH₂CH₃), 4.47 (s, 2 H, CH₂Ph), 4.49 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

(d, J_H,Hϭ 12.4 Hz, 1 H, CHPh), 4.97 (d, J_H,Hϭ 12.4 Hz, 1 H, CHPh), 4.56 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.58 (d, J_H,H

ϭ

3

4

2

CHPh), 5.07 [dd, J_H,Hϭ 10.0, J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭ

11.2 Hz, 1 H, CHPh), 4.64 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh),

3

4

CH₂(cis)], 5.16 [dd, J_H,Hϭ 17.2, J_H,Hϭ 2.0 Hz, 1 H, CH₂CHϭ

7.00Ϫ7.24 (m, 20 H, HAr) ppm. ¹³C NMR: δ ϭ 14.68 (OCH₂CH₃),

CH₂(trans)], 5.78Ϫ5.88 (m, 1 H, CH₂CHϭCH₂), 7.22Ϫ7.38 (m, 20 36.25 [C(2)], 56.47 [C(3)], 51.79, 60.83, 63.92, 73.94, 74.39, 74.41

H, HAr) ppm. ¹³C NMR: δ ϭ 25.30 [(CH₃)₂C], 27.01 [(CH₃)₂C], [C(8), 4 CH₂Ph, OCH₂CH₃], 71.99, 77.09, 79.07, 79.73 [C(4), C(5),

30.15 [C(2)], 50.00 (CH₂CHϭCH₂), 55.22 [C(3)], 66.45, 66.60,

www.eurjoc.org

C(6), C(7)], 128.0Ϫ128.7 (CHAr), 137.8, 137.9, 138.3, 140.4 (4

2457

Eur. J. Org. Chem. 2004, 2451Ϫ2470

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

CqAr), 172.7 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 628 [M ϩ Ethyl (3R,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-

H]^ϩ, 650 [M ϩ Na]^ϩ, 666 [M ϩ K]^ϩ. C₃₈H₄₅NO₇(627.8): calcd. C dihydroxyoctanoate (11a): The same procedure was used as that for

72.70, H 7.23, N 2.23; found C 72.35, H 7.15, N 2.01.

the synthesis of 10a, starting from 9a (213 mg, 0.34 mmol). Purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 5:5)

afforded 11a (170 mg, 85%) as a colorless oil. [α]²_D⁰ϭ ϩ3.2 (c ϭ

Ethyl (3S,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-3-(butylamino)-7,8-

dihydroxyoctanoate (10c): The same procedure was used as that for

the synthesis of 10a, starting from 8c (1.98 g, 3.20 mmol). Purifi-

cation by flash chromatography (petroleum ether/EtOAc, 1:1) af-

forded 10c (1.34 g, 72%) as colorless oil. [α]²_D⁰ϭ Ϫ5.1 (c ϭ 1.0,

CHCl₃). ¹H NMR: δ ϭ 0.85 [t, ³J_H,Hϭ 7.1 Hz, 3 H, N(CH₂)₃CH₃],

3

0.9, CHCl₃). ¹H NMR: δ ϭ 1.21 (t, J_H,Hϭ 7.1 Hz, 3 H,

2

3

OCH₂CH₃), 2.51 [dd, J_H,Hϭ 15.3, J_H,Hϭ 6.1 Hz, 1 H, C(2a)-

2

3

H], 2.59 [dd, J_H,Hϭ 15.4, J_H,Hϭ 6.9 Hz, 1 H, C(2b)-H], 3.09

(dd, J_H,Hϭ 13.9, ³J_H,Hϭ 5.7 Hz, 1 H, CHCHϭCH₂), 3.26Ϫ3.33

2

[m, 2 H, C(3)-H, CHCHϭCH₂], 3.65Ϫ3.69 [m, 2 H, C(8a)-H, C(5)-

2

3

H], 3.75 [dd, J_H,Hϭ 11.4, J_H,Hϭ 3.7 Hz, 1 H, C(8b)-H], 3.88

3

1.27 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.25Ϫ1.38 (m, 4 H,

3

[dd, J_H,Hϭ 6.7, J_H,Hϭ 2.7 Hz, 1 H, C(6)-H], 3.92 [dd, J_H,H

7.7, J_H,Hϭ 3.8 Hz, 1 H, C(4)-H], 4.05 (q, J_H,Hϭ 7.1 Hz, 2 H,

ϭ

CH₂CH₂CH₃), 2.36Ϫ2.42 [m, 1 H, CH(CH₂)₂CH₃], 2.47Ϫ2.58 [m,

3

3 H, C(2a)-H, C(2b)-H, CH(CH₂)₂CH₃], 3.30 [dd, J_H,Hϭ 10.9,

3

OCH₂CH₃), 4.27 [dd, J_H,Hϭ 6.4, J_H,Hϭ 3.2 Hz, 1 H, C(7)-H],

2

3

³J_H,Hϭ 5.9 Hz, 1 H, C(3)-H], 3.68 [dd, J_H,Hϭ 11.5, J_H,H

ϭ

4.56 (d, ²J_H,Hϭ 11.8 Hz, 1 H, CHPh), 4.59 (d, J_H,Hϭ 12.2 Hz, 1

2

3

4.5 Hz, 1 H, C(8a)-H], 3.72 [dd, J_H,Hϭ 8.0, J_H,Hϭ 4.5 Hz, 1 H,

H, CHPh), 4.67 (d, ²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.68 (d, ²J_H,Hϭ

2

3

C(6)-H], 3.75 [dd, J_H,Hϭ 11.4, J_H,Hϭ 3.5 Hz, 1 H, C(8b)-H],

2

11.5 Hz, 1 H, CHPh), 4.71 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.83

(d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 5.07 [dd, J_H,Hϭ 10.2, J_H,H

1.2 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.16 [dd, J_H,Hϭ 17.2, J_H,H

3

3.85 [br. t, J_H,Hϭ 4.2 Hz, 1 H, C(5)-H], 3.90 [dd, J_H,Hϭ 7.9,

2

3

4

ϭ

³J_H,Hϭ 4.2 Hz, 1 H, C(7)-H], 3.92 [br. t, J_H,Hϭ 5.0 Hz, 1 H,

3

4

ϭ

C(4)-H], 4.06 (q, ³J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃), 4.60 (d, ²J_H,Hϭ

3

1.7 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.83 (ddt, J_H,Hϭ 17.0,

³J_H,Hϭ 10.3, ³J_H,Hϭ 5.9 Hz, 1 H, CH₂CHϭCH₂), 7.26Ϫ7.34 (m,

15 H, HAr) ppm. ¹³C NMR: δ ϭ 14.68 (OCH₂CH₃), 36.01 [C(2)],

49.96 (ϪCH₂CHϭCH₂), 54.62 [C(3)], 60.87, 64.27 [OCH₂CH₃,

C(8)], 73.44, 74.30, 74.91 (3 CH₂Ph), 72.11, 76.83, 78.59, 80.27

[C(4), C(5), C(6), C(7)], 116.3 (CH₂CHϭCH₂), 127.9Ϫ128.7

(CHAr), 136.8 (CH₂CHϭCH₂), 138.0, 138.0, 138.5 (3 CqAr), 172.7

[C(1)] ppm. MS (MALDI-TOF): m/z ϭ 579 [M ϩ H]^ϩ, 601 [M ϩ

Na]^ϩ, 617 [M ϩ K]^ϩ. C₃₄H₄₃NO₇(577.7): calcd. C 70.69, H 7.50,

N 2.42, O 19.39; found C 70.83, H 7.48, N 2.38.

2

11.3 Hz, 1 H, CHPh), 4.62 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.64

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.67 (d, J_H,Hϭ 11.4 Hz, 1 H,

CHPh), 4.71 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.76 (d, J_H,H

11.3 Hz, 1 H, CHPh), 7.30Ϫ7.35 (m, 15 H, HAr) ppm. ¹³C NMR:

14.47, 14.65 [CH₂(CH₂)₂CH₃, OCH₂CH₃], 20.84

2

ϭ

δ

ϭ

(CH₂CH₂CH₂CH₃), 32.82 (CH₂CH₂CH₂CH₃), 36.84 [C(2)], 47.66

(CH₂CH₂CH₂CH₃), 57.25 [C(3)], 60.75, 64.00 [OCH₂CH₃, C(8)],

73.91, 74.42, 74.45 (3 CH₂Ph), 71.93, 77.34, 79.00, 79.84 [C(4),

C(5), C(6), C(7)], 127.9Ϫ128.7 (CHAr), 137.8, 137.9, 138.3 (3

CqAr), 172.8 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 595 [M ϩ

H]^ϩ. C₃₅H₄₇NO₇(593.8): calcd. C 70.80, H 7.98, N 2.36; found C

70.94, H 7.95, N 2.35.

Ethyl (3R,4S,5R,6R,7R)-3-(Benzylamino)-4,5,6-tris(benzyloxy)-7,8-

dihydroxyoctanoate (11b): Same procedure as that used for 10b,

starting from 9b (81 mg, 0.12 mmol). Purification by flash chroma-

tography (petroleum ether/ethyl acetate, 1:1) afforded pure com-

pound 11b (60 mg, 79% yield) as a yellow oil. 11b [α]²_D⁰ϭ ϩ3.0

Benzyl (3S,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-

dihydroxyoctanoate (10d): Compound 8d (158 mg, 0.23 mmol) was

dissolved in CH₃CN (2 mL); H₂O (300 µL) and CSA (5 mg, 0.1

equiv.) were added. The reaction mixture was heated to 70 °C for

6 h. After cooling to room temp., the reaction mixture was diluted

with EtOAc, washed with a saturated solution of NaHCO₃, dried

with Na₂SO₄, and filtered; the solvent was evaporated under re-

duced pressure. Purification by flash chromatography (petroleum

ether/ethyl acetate, 4:6) afforded pure compound 10d (130 mg, 88%

3

(c ϭ 1.6, CHCl₃). ¹H NMR: δ ϭ 1.19 (t, J_H,Hϭ 7.1 Hz, 3 H,

2

3

OCH₂CH₃), 2.57 [dd, J_H,Hϭ 15.3, J_H,Hϭ 6.5 Hz, 1 H, C(2a)-

2

3

H], 2.63 [dd, J_H,Hϭ 15.36, J_H,Hϭ 6.7 Hz, 1 H, C(2b)-H],

3.26Ϫ3.29 [m, 1 H, C(3)-H], 3.56 [dd, ³J_H,Hϭ 7.7, ³J_H,Hϭ 3.37 Hz,

2

3

1 H, C(6)-H], 3.62 [dd, J_H,Hϭ 11.4, J_H,Hϭ 4.7 Hz, 1 H, C(8a)-

2

H], 3.64 (d, J_H,Hϭ 12.9 Hz, 1 H, CHPh), 3.70 [dd, J_H,Hϭ 11.4,

³J_H,Hϭ 3.6 Hz, 1 H, C(8b)-H], 3.83Ϫ3.92 [m, 3 H, C(4)-H, C(7)-

yield) as a colorless oil. [α]²_D⁰ϭ Ϫ9.1 (c ϭ 1.8, CHCl₃). H NMR:

1

3

H, CHPh], 4.00Ϫ4.05 (m, 2 H, OCH₂CH₃), 4.29 [dd, J_H,Hϭ 6.5,

δ ϭ 2.43Ϫ2.50 [m, 2 H, C(2a)-H, C(2b)-H], 2.94 [dd, 1 H, ²J_H,Hϭ

³J_H,Hϭ 3.3 Hz, 1 H, C(5)-H], 4.48 (d, J_H,Hϭ 11.3 Hz, 1 H,

2

3

2

14.0, J_H,Hϭ 5.6 Hz, 1 H, CHCHϭCH₂], 3.04 [dd, J_H,Hϭ 14.0,

CHPh), 4.54 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.58 (d, J_H,H

11.1 Hz, 1 H, CHPh), 4.67 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.74

ϭ

³J_H,Hϭ 6.0 Hz, 1 H, CHCHϭCH₂], 3.23Ϫ3.27 [m, 1 H, C(3)-H],

2

3

2

3.55 [dd, J_H,Hϭ 11.3, J_H,Hϭ 4.4 Hz, 1 H, C(8a)-H], 3.59 [dd,

(d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.81 (d, J_H,Hϭ 11.1 Hz, 1 H,

CHPh), 7.20Ϫ7.40 (m, 20 H, HAr) ppm. ¹³C NMR: δ ϭ 14.64

(OCH₂CH₃), 30.14 [C(2)], 54.83 [C(3)], 51.36, 60.88, 64.21, 73.42,

74.18, 74.81 [C(8), 4 CH₂Ph, OCH₂CH₃], 71.91, 76.82, 78.15, 80.00

[C(4), C(5), C(6), C(7)], 127.3Ϫ128.7 (CHAr), 137.8, 137.9, 137.9,

138.3 (4 CqAr), 172.7 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 628

[M ϩ H]^ϩ, 650 [M ϩ Na]^ϩ, 666 [M ϩ K]^ϩ. C₃₈H₄₅NO₇(627.8):

calcd. C 72.70, H 7.23, N 2.23; found C 72.95, H 7.24, N 2.42.

³J_H,Hϭ 8.0, J_H,Hϭ 4.0 Hz, 1 H, C(6)-H], 3.63 [dd, J_H,Hϭ 8.0,

3

2

³J_H,Hϭ 3.6 Hz, 1 H, C(8b)-H], 3.72 [dd, J_H,Hϭ 5.2, J_H,H

ϭ

3

4.0 Hz, 1 H, C(5)-H], 3.74Ϫ3.78 [m, 1 H, C(7)-H,], 3.81Ϫ3.84 [m, 1

H, C(4)-H], 4.45 (d, ²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.48 (d, ²J_H,Hϭ

2

11.2 Hz, 1 H, CHPh), 4.50 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.54

2

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.58 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

3

CHPh), 4.62 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.91 [d, J_H,H

ϭ

10.2 Hz, 1 H, CH₂CHϭCH₂(cis)], 4.94 (s, 2 H, CH₂Ph), 4.89 [d,

3

³J_H,Hϭ 16.0 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.63 [ddt, J_H,H

ϭ

Ethyl (3R,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-3-(butylamino)-7,8-

dihydroxyoctanoate (11c): The same procedure was used as that for

the synthesis of 10a, starting from 9c (1.419 g, 2.29 mmol). Purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 5:5)

16.0, ³J_H,Hϭ 10.2, ³J_H,Hϭ 5.6 Hz, 1 H, CH₂CHϭCH₂], 7.22Ϫ7.38

(m, 20 H, HAr) ppm. ¹³C NMR: δ ϭ 36.13 [C(2)], 50.18 (CH₂CHϭ

CH₂), 56.25 [C(3)], 63.93, 66.62, 73.89, 74.38, 74.52 [C(8), 4

CH₂Ph], 71.92, 76.89, 78.97, 79.71 [C(4), C(5), C(6), C(7)], 116.2 afforded 11c (1.147 g, 86%) as a colorless oil. [α]²_D⁰ϭ ϩ5.4 (c ϭ

(CH₂CHϭCH₂), 128.0Ϫ128.7 (CH₂CHϭCH₂, CHAr), 136.0, 0.2, CHCl₃). ¹H NMR: δ ϭ 0.90 [t, J_H,Hϭ 7.3 Hz, 3 H,

3

137.6, 137.7, 138.2 (4 CqAr), 172.4 [C(1)] ppm. MS (MALDI-

TOF): m/z ϭ 640 [M ϩ H]^ϩ, 662 [M ϩ Na]^ϩ. C₃₉H₄₅NO₇(639.8): (m, 4 H, CH₂CH₂CH₃), 2.36Ϫ2.43 [m, 1 H, NCH(CH₂)₂CH₃],

calcd. C 73.22, H 7.09, N 2.19; found C 73.58, H 7.39, N 1.90. 2.54Ϫ2.58 [m, 2 H, C(2a)-H, C(2b)-H], 2.60Ϫ2.69 [m, 1 H,

N(CH₂)₃CH₃], 1.23 (t, ³J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.26Ϫ1.44

2458

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

NCH(CH₂)₂CH₃], 3.26 [dt, ³J_H,Hϭ 6.2, ³J_H,Hϭ 2.5 Hz, 1 H, C(3)-

²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.55 (d, J_H,Hϭ 11.5 Hz, 1 H,

2

3

2

H], 3.68 [dd, J_H,Hϭ 7.5, J_H,Hϭ 3.8 Hz, C(5)-H], 3.69 [dd, CHPh), 4.56 (d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.68 (d, J_H,H

ϭ

3

2

²J_H,Hϭ 10.5, J_H,Hϭ 4.4 Hz, 1 H, C(8a)-H], 3.77 (dd, J_H,H

ϭ

11.1 Hz, 1 H, CHPh), 4.74 (d, J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.86

11.4, ³J_H,Hϭ 2.7 Hz, 1 H, C(8b)-H], 3.88 [dd, ³J_H,Hϭ 6.4, ³J_H,Hϭ [dd, J_H,Hϭ 10.2, J_H,Hϭ 1.6, 1 H, CH₂CHϭCH₂(cis)], 4.92 [dd,

3

4

3

4

2.2 Hz, 1 H, C(6)-H], 3.93 [dd, J_H,Hϭ 7.8, J_H,Hϭ 3.8 Hz, 1 H, ³J_H,Hϭ 17.2, J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.61

3

C(4)-H], 4.06 (q, J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃), 4.27 [dd,

(ddt, J_H,Hϭ 17.1, J_H,Hϭ 10.3, J_H,Hϭ 5.8 Hz, 1 H, CH₂CHϭ

³J_H,Hϭ 6.00, 2.8 Hz, 1 H, C(7)-H], 4.59 (d, J_H,Hϭ 10.8 Hz, 1 H, CH₂), 7.04Ϫ7.35 (m, 21 H, HAr), 7.55Ϫ7.60 (m, 4 H, HAr) ppm.

2

CHPh), 4.61 (d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 4.70 (d, J_H,H

ϭ

¹³C NMR:

δ ϭ 14.70 (OCH₂CH₃), 19.79 [(CH₃)₃C], 27.40

[(CH₃)₃C], 36.16 [C(2)], 49.96 (CH₂CHϭCH₂), 55.91 [C(3)], 60.68,

65.27 [OCH₂CH₃, C(8)], 73.56, 75.01, 75.06 (3 CH₂Ph), 71.89,

2

11.3 Hz, 1 H, CHPh), 4.77 (s, 2 H, 2 CHPh), 4.84 (d, J_H,H

ϭ

11.3 Hz, 1 H, CHPh), 7.29Ϫ7.35 (m, 15 H, CHAr) ppm. ¹³C NMR

(100.57 MHz, CDCl₃, 25 °C): δ ϭ 14.53, 14.68 [N(CH₂)₃CH₃, 77.66, 79.36, 80.39 [C(4), C(5), C(6), C(7)], 115.9 (CH₂CHϭCH₂),

OCH₂CH₃), 20.94 (CH₂CH₂CH₂CH₃), 32.96 (CH₂CH₂CH₂CH₃), 127.8Ϫ130.0 (CHAr), 133.3, 133.4 (2 CqAr), 135.9 (CH₂CHϭ

47.27 [C(2)], 55.57 [C(3)], 60.83, 64.38 [OCH₂CH₃, C(8)], 73.43, CH₂), 138.2, 138.3, 138.8 (3 CqAr), 172.7 [C(1)] ppm. MS

74.27, 74.84 (3 CH₂Ph), 72.16, 76.94, 78.67, 80.38 [C(4), C(5), C(6), (MALDI-TOF): m/z ϭ 817 [M ϩ H]^ϩ, 839 [M ϩ Na]^ϩ, 855 [M ϩ

C(7)], 127.9Ϫ128.8 (CHAr), 138.0, 138.5, 138.5 (3 CqAr), 172.8 K]^ϩ. C₅₀H₆₁NO₇Si (816.1): calcd. C 73.59, H 7.53, N 1.72; found

[C(1)] ppm. MS (MALDI-TOF): m/z ϭ 595 [M ϩ H]^ϩ. C₃₅H₄₇NO₇C 73.37, H 7.55, N 1.71.

(593.8): calcd. C 70.80, H 7.98, N 2.36; found C 70.90, H 8.00,

N 2.36.

Ethyl (3S,4S,5R,6R,7R)-3-(Benzylamino)-4,5,6-tris(benzyloxy)-8-

[(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate (12b): Compound

10b (98 mg, 0.16 mmol) was dissolved in dry CH₂Cl₂(2 mL) under

an inert gas. Imidazole (42 mg, 4 equiv.) and TBDPSCl (80 µL, 2

equiv.) were added. After 2 h, the reaction mixture was quenched

with MeOH (2 drops), diluted with H₂O, and extracted with

CH₂Cl₂. The organic layer was dried with Na₂SO₄and filtered and

then the solvent was evaporated under reduced pressure. Purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 8:2)

Benzyl (3R,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-7,8-

dihydroxyoctanoate (11d): Same procedure as that used for 10d,

starting from 9d (110 mg, 0.16 mmol); purification by flash

chromatography (petroleum ether/ethyl acetate, 1:1 to 4:6) afforded

pure compound 11d (83 mg, 81% yield) as a yellowish oil. [α]²_D⁰

ϩ5.7 (c ϭ 1.1, CHCl₃). H NMR (400 MHz, CDCl₃, 25 °C): δ ϭ

ϭ

1

2

3

2.54 [dd, J_H,Hϭ 15.4, J_H,Hϭ 6.0 Hz, 1 H, C(2a)-H], 2.64 [dd,

²J_H,Hϭ 15.6, ³J_H,Hϭ 6.7 Hz, 1 H, C(2b)-H], 3.06 [br. dd, J_H,Hϭ afforded pure compound 12b (130 mg, 96% yield). [α]²_D⁰ϭ Ϫ17.5

2

13.8, ³J_H,Hϭ 5.8 Hz, 1 H, CHCHϭCH₂], 3.25Ϫ3.32 [m, 1 H, C(3)-

(c ϭ 1.3, CHCl₃). H NMR: δ ϭ 1.14 [s, 9 H, (CH₃)₃C], 1.23 (t,

1

H], 3.63Ϫ3.67 [m, 2 H, C(6)-H, C(8a)-H], 3.73 [dd, J_H,Hϭ 11.4, ³J_H,Hϭ 7.0 Hz, 3 H, OCH₂CH₃), 2.55Ϫ2.66 [m, 2 H, C(2a)-H,

2

³J_H,Hϭ 3.7 Hz, 1 H, C(8b)-H], 3.86Ϫ3.91 [m, 2 H, C(4)-H, C(7)-

C(2b)-H], 3.25Ϫ3.39 [m, 1 H, C(3)-H], 3.59 (d, J_H,Hϭ 13.1 Hz, 1

2

3

2

H], 4.23 [dd, J_H,Hϭ 6.4, J_H,Hϭ 3.5 Hz, 1 H, C(5)-H], 4.54 (d, H, CHPh), 3.65 (d, J_H,Hϭ 13.1 Hz, 1 H, CHPh), 3.80Ϫ4.20 [m,

²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.63 (d, J_H,Hϭ 11.2 Hz, 1 H, 5 H, C(5)-H, C(6)-H, C(7)-H, C(8a)-H, C(8b)-H], 4.00Ϫ4.15 [m, 3

2

CHPh), 4.67 (s, 2 H, CH₂Ph), 4.78 (d, J_H,Hϭ 11.2 Hz, 1 H, H, C(4)-H, OCH₂CH₃], 4.51 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh),

2

CHPh), 5.00 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 5.03 (d, J_H,H

ϭ

4.57 (d, ²J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.68 (d, J_H,Hϭ 11.0 Hz, 1

11.3 Hz, 1 H, CHPh), 5.05 [dd, J_H,Hϭ 10.2, J_H,Hϭ 1.3 Hz, 1 H, CHPh), 4.73 (d, ²J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.79 (d, ²J_H,Hϭ

3

2

3

2

H, CH₂CHϭCH₂(cis)], 5.11 [d, J_H,Hϭ 17.2 Hz, 1 H, CH₂CHϭ

11.0 Hz, 1 H, CHPh), 4.88 (d, J_H,Hϭ 11.5 Hz, 1 H, CHPh),

CH₂(trans)], 5.75Ϫ5.82 [m, 1 H, CH₂CHϭCH₂], 7.20Ϫ7.40 (m, 20 7.20Ϫ7.80 (m, 30 H, HAr) ppm. ¹³C NMR: δ ϭ 14.71 (OCH₂CH₃),

H, HAr) ppm. ¹³C NMR (100.57 MHz, CDCl₃, 25 °C): δ ϭ 35.81 19.76 [(CH₃)₃C], 27.42 [(CH₃)₃C], 36.22 [C(2)], 56.47 [C(3)], 51.54,

[C(2)], 49.91 (CH₂CHϭCH₂), 54.80 [C(3)], 64.24, 66.73, 73.43, 60.72, 65.30, 73.56, 74.98, 75.04 [C(8), 4 CH₂Ph, OCH₂CH₃],

74.19, 74.79 [C(8), 4 CH₂Ph], 72.06, 76.69, 78.36, 79.93 [C(4), C(5), 71.95, 77.71, 79.54, 80.40 [C(4), C(5), C(6), C(7)], 126.9Ϫ135.9

C(6), C(7)], 116.3 (CH₂CHϭCH₂), 128.0Ϫ130.0 (CH₂CHϭCH₂,

(CHAr), 133.3, 133.4, 138.2, 138.3, 138.8, 140.6 (CqAr), 172.8

CHAr), 135.9, 137.8, 137.9, 138.3 (4 CqAr), 172.3 [C(1)] ppm. MS [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 867 [M ϩ H]^ϩ, 889 [M ϩ

(MALDI-TOF): m/z ϭ 640 [M ϩ H]^ϩ. C₃₉H₄₅NO₇(639.8): calcd. Na]^ϩ, 905 [M ϩ K]^ϩ. C₅₄H₆₃NO₇Si (866.2): calcd. C 74.88, H 7.33,

C 73.22, H 7.09, N 2.19; found C 72.95, H 7.12, N 2.01.

N 1.62; found C 74.53, H 7.12, N 1.78.

Ethyl

(3S,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-8-

Ethyl

(3S,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-3-(butylamino)-8-

[(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate

(12a): 10a [(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate (12c): The same

(267 mg, 0.46 mmol) was dissolved in CH₂Cl₂(3 mL) and then tert-

butyldiphenylsilyl chloride (TBDPSCl) (191 mg, 0.69 mmol, 1.5

procedure was used as that for the synthesis of 12a, starting from

10b (1.59 g, 2.74 mmol). Purification by flash chromatography

equiv.) and imidazole (94 mg, 1.39 mmol, 3 equiv.) were added. The (petroleum ether/ethyl acetate, 9:1) afforded 12c (1.86 g, 83%) as a

1

reaction mixture was stirred at room temperature for 6 h before

colorless oil. [α]²_D⁰ϭ Ϫ10.0 (c ϭ 0.7, CHCl₃). H NMR: δ ϭ 0.84

CH₃OH (500 µL) and H₂O (3 mL) were added. The two layers were [t, ³J_H,Hϭ 7.0 Hz, 3 H, N(CH₂)₃CH₃], 1.13 [s, 9 H, (CH₃)₃C], 1.23

3

separated, the aqueous layer was extracted with CH₂Cl₂(3 ϫ

3 mL), and the combined organic layers were dried with Na₂SO₄.

The solvent was evaporated under reduced pressure and the residue

was purified by flash chromatography (petroleum ether/ethyl acet-

(t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.20Ϫ1.32 (m, 4 H,

CH₂CH₂CH₃), 2.35Ϫ2.42 [m, 2 H, CH₂(CH₂)₂CH₃], 2.50 [dd,

²J_H,Hϭ 15.4, J_H,Hϭ 7.7 Hz, 1 H, C(2a)-H], 2.56 [dd, J_H,H

ϭ

3

2

15.4, ³J_H,Hϭ 4.8 Hz, 1 H, C(2b)-H], 3.23 [dt, ³J_H,Hϭ 7.1, ³J_H,Hϭ

ate, 9:1) yielding 12a (350 mg, 93%) as a colorless oil. [α]²_D⁰ϭ Ϫ11.8

4.1 Hz, 1 H, C(3)-H], 3.83Ϫ4.04 [m, 6 H, C(4)-H, C(5)-H, C(6)-H,

1

3

(c ϭ 1.2, CHCl₃). H NMR (400 MHz, CDCl_3,25 °C): δ ϭ 1.00 C(7)-H, C(8a)-H, C(8b)-H], 4.08 (q, J_H,Hϭ 7.1 Hz, 2 H,

3

2

[s, 9 H, (CH₃)₃C], 1.11 (t, J_H,Hϭ 7.0 Hz, 3 H, OCH₂CH₃), OCH₂CH₃), 4.55 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.61 (d,

2

2.35Ϫ2.48 [m, 2 H, C(2a)-H, C(2b)-H], 2.87Ϫ2.98 (m, 2 H,

²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.67 (d, J_H,Hϭ 11.5 Hz, 1 H,

2

CHCHϭCH₂), 3.13Ϫ3.17 [m, 1 H, C(3)-H], 3.69Ϫ3.86 [m, 5 H, CHPh), 4.68 (d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.80 (d, J_H,H

ϭ

C(5)-H, C(6)-H, C(7)-H, C(8a)-H, C(8b)-H], 3.91 [dd, ³J_H,Hϭ 7.4, 11.0 Hz, 1 H, CHPh), 4.85 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh),

2

³J_H,Hϭ 3.8 Hz, 1 H, C(4)-H], 3.96 (q, J_H,Hϭ 7.0 Hz, 2 H, 7.18Ϫ7.45 (m, 21 H, CHAr), 7.68Ϫ7.72 (m, 4 H, CHAr) ppm. ¹³

C

3

2

OCH₂CH₃), 4.42 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.47 (d, NMR:

δ

ϭ

14.50, 14.70 [N(CH₂)₃CH₃, OCH₂CH₃], 19.78

Eur. J. Org. Chem. 2004, 2451Ϫ2470

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2459

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

[(CH₃)₃C], 20.85 (CH₂CH₂CH₂CH₃), 27.40 [(CH₃)₃C], 32.95

73.29, 74.86, 75.32 (3 CH₂Ph), 72.12, 77.31, 79.42, 81.22 [C(4),

(CH₂CH₂CH₂CH₃), 36.36 [C(2)], 47.47 (CH₂CH₂CH₂CH₃), 56.94 C(5), C(6), C(7)], 116.1 (CH₂CHϭCH₂), 127.7Ϫ130.0 (CHAr),

[C(3)], 60.61, 65.30 [OCH₂CH₃, C(8)], 72.98, 73.53, 75.03 (3 133.4, 133.6 (2 CqAr), 135.7Ϫ137.3 (CHAr), 138.4, 138.5, 138.9 (3

CH₂Ph), 71.90, 77.77, 79.40, 80.51 [C(4), C(5), C(6), C(7)], CqAr), 172.6 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 817 [M ϩ

127.8Ϫ130.0 (CHAr), 133.3, 133.4 (2 CqAr), 135.8, 135.9 (CHAr),

138.2, 138.4, 138.9 (3 CqAr), 172.9 [C(1)] ppm. MS (MALDI-

TOF): m/z ϭ 833 [M ϩ H]^ϩ, 855 [M ϩ Na]^ϩ. C₅₁H₆₅NO₇Si

(832.2): calcd. C 73.61, H 7.87, N 1.68; found C 73.46, H 7.88,

N 1.67.

H]^ϩ, 839 [M ϩ Na]^ϩ, 855 [M ϩ K]^ϩ. C₅₀H₆₁NO₇Si (816.1): calcd.

C 73.59, H 7.53, N 1.72; found C 73.39, H 7.51, N 1.74.

Ethyl (3R,4S,5R,6R,7R) 3-(Benzylamino)-4,5,6-tris(benzyloxy)-8-

[(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate (13b): Same pro-

cedure as that used for the synthesis of 12b, starting from 11b

(72 mg, 0.11 mmol). Purification by flash chromatography (petro-

leum ether/ethyl acetate, 9:1) afforded pure compound 13b (83 mg,

87% yield) as a colorless oil. [α]²_D⁰ϭ 0.0 (c ϭ 2.3, CHCl₃). ¹H

Benzyl

(3S,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-8-

[(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate (12d): Compound

10d (105 mg, 0.16 mmol) was dissolved in dry CH₂Cl₂(2 mL) un-

der an inert gas. Imidazole (33 mg, 3 equiv.) and TBDPSCl (45

µL, 1.5 equiv.) were added. After 2.5 h, the reaction mixture was

quenched with MeOH (2 drops), diluted with H₂O, and extracted

with CH₂Cl₂. The organic layer was dried with Na₂SO₄and filtered

and then the solvent was evaporated under reduced pressure. Purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 8:2)

afforded pure compound 12d (137 mg, 96% yield) as a colorless oil.

[α]²_D⁰ϭ Ϫ8.4 (c ϭ 2.1, CHCl₃). ¹H NMR: δ ϭ 1.10 [s, 9 H,

(CH₃)₃C], 2.52Ϫ2.62 [m, 2 H, C(2a)-H, C(2b)-H], 2.87Ϫ3.17 (m, 2

H, -CH₂CHϭCH₂), 3.24Ϫ3.29 [m, 1 H, C(3)-H], 3.76Ϫ3.88 [m, 4

H, C(5)-H, C(6)-H, C(8a)-H, C(8b)-H], 3.93Ϫ3.97 [m, 1 H, C(7)-

3

NMR: δ ϭ 1.09 [s, 9 H, (CH₃)₃C], 1.75 (t, J_H,Hϭ 7.1 Hz, 3 H,

2

3

OCH₂CH₃), 2.54 [dd, J_H,Hϭ 15.0, J_H,Hϭ 7.7 Hz, 1 H, C(2a)-

2

3

H], 2.65 [dd, J_H,Hϭ 15.0, J_H,Hϭ 5.2 Hz, 1 H, C(2b)-H],

3.21Ϫ3.26 [m, 1 H, C(3)-H], 3.62 (d, ²J_H,Hϭ 13.0 Hz, 1 H, CHPh),

3

3.69 [dd, J_H,Hϭ 7.8, J_H,Hϭ 2.3 Hz, 1 H, C(6)-H], 3.79 [dd,

²J_H,Hϭ 10.4, J_H,Hϭ 5.4 Hz, 1 H, C(8a)-H], 3.85Ϫ3.92 [m, 3 H,

3

C(4)-H, C(8b)-H, CHPh], 3.96Ϫ4.04 [m, 3 H, C(7)-H, OCH₂CH₃],

4.42 (d, ²J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.42Ϫ4.46 [m, 1 H, C(5)-H],

2

4.48 (d, ²J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.58 (d, J_H,Hϭ 11.2 Hz, 1

H, CHPh), 4.72 (d, ²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.81 (d, ²J_H,Hϭ

2

11.3 Hz, 1 H, CHPh), 4.90 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh),

7.15Ϫ7.80 (m, 30 H, HAr) ppm. ¹³C NMR: δ ϭ 14.65 (OCH₂CH₃),

19.77 [(CH₃)₃C], 27.38 [(CH₃)₃C], 36.32 [C(2)], 55.43 [C(3)], 60.75,

65.59, 73.27, 74.84, 75.24 [C(8), 4 CH₂Ph, OCH₂CH₃], 71.99,

77.56, 79.26, 81.24 [C(4), C(5), C(6), C(7)], 127.1Ϫ135.9 (CHAr),

133.4, 133.5, 138.3, 138.6, 138.9, 140.6 (CqAr), 172.6 [C(1)] ppm.

MS (MALDI-TOF): m/z ϭ 867 [M ϩ H]^ϩ, 889 [M ϩ Na]^ϩ.

C₅₄H₆₃NO₇Si (866.2): calcd. C 74.88, H 7.33, N 1.62; found C

74.84, H 7.19, N 1.43.

3

H], 4.01 [dd, J_H,Hϭ 7.2, J_H,Hϭ 3.6 Hz, 1 H, C(4)-H], 4.48 (d,

²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.53 (d, J_H,Hϭ 11.2 Hz, 1 H,

CHPh), 4.62 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.63 (d, J_H,H

11.2 Hz, 1 H, CHPh), 4.75 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.81

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.93 [dd, J_H,Hϭ 10.2, J_H,H

2

ϭ

2

3

4

ϭ

1.6 Hz, 1 H, CH₂CHϭCH₂(cis)], 4.97Ϫ5.03 [m, 2 H, CHPh,

2

CH₂CHϭCH₂(trans)], 5.05 (d, J_H,Hϭ 12.4 Hz, 1 H, CHPh),

5.61Ϫ5.73 (m, 1 H, CH₂CHϭCH₂), 7.12Ϫ7.72 (m, 30 H, HAr)

ppm. ¹³C NMR: δ ϭ 19.76 [(CH₃)₃C], 27.38 [(CH₃)₃C], 36.03

[C(2)], 49.88 (CH₂CHϭCH₂), 56.04 [C(3)], 60.79, 65.26, 66.51,

73.53, 74.95 [C(8), 4 CH₂Ph], 71.89, 75.05, 77.68, 81.35 [C(4), C(5),

C(6), C(7)], 127.8Ϫ130.0 (CH₂CHϭCH₂, CHAr), 133.2, 133.4,

136.2, 138.0, 138.0, 138.2, 138.7 (CqAr), 135.8Ϫ135.9 (CHAr),

172.4 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 879 [M ϩ H]^ϩ.

C₅₅H₆₃NO₇Si (878.2): calcd. C 75.22, H 7.23, N 1.59; found C

75.02, H 7.51, N 1.80.

Ethyl

(3R,4S,5R,6R,7R)-4,5,6-Tris(benzyloxy)-3-(butylamino)-8-

[(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate (13c): Same pro-

cedure as that used for the synthesis of 12a, starting from 11c

(175 mg, 0.30 mmol). Purification by flash chromatography (petro-

leum ether/ethyl acetate, 8:2) afforded 13c (233 mg, 93%) as a color-

less oil. [α]²_D⁰ϭ ϩ9.5 (c ϭ 0.4, CHCl₃). ¹H NMR: δ ϭ 0.90 [t,

³J_H,Hϭ 7.2 Hz, 3 H, N(CH₂)₃CH₃], 1.13 [s, 9 H, (CH₃)₃C], 1.22

3

(t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.26Ϫ1.48 (m, 4 H,

2

3

CH₂CH₂CH₃), 2.37 [ddd, J_H,Hϭ 10.8, J_H,Hϭ 8.1, J_H,H

ϭ

Ethyl

(3R,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-8-

2

3

6.1 Hz, 1 H, NCH(CH₂)₂CH₃], 2.52 [dd, J_H,Hϭ 14.8, J_H,H

ϭ

(tert-butyldiphenylsilyl)oxy-7-hydroxyoctanoate (13a): Same pro-

cedure as that used for the synthesis of 12a, starting from 11a

(164 mg, 0.284 mmol). Purification by flash chromatography

(petroleum ether/ethyl acetate, 9:1) afforded 13a (222 mg, 96%) as

2

3

7.4 Hz, 1 H, C(2a)-H], 2.62 [dd, J_H,Hϭ 15.0, J_H,Hϭ 5.5 Hz, 1

H, C(2b)-H], 2.69 [ddd, ²J_H,Hϭ 10.9, ³J_H,Hϭ 8.1, ³J_H,Hϭ 6.0 Hz,

1 H, NCH(CH₂)₂CH₃], 3.22Ϫ3.25 [m, 1 H, C(3)-H], 3.87Ϫ4.09 [m,

7 H, C(4)-H, C(5)-H, C(6)-H, C(8a)-H¸ C(8b)-H, OCH₂CH₃], 4.41

[dd, J_H,Hϭ 7.9, J_H,Hϭ 2.5 Hz, 1 H, C(7)-H], 4.57 (d, J_H,H

11.2 Hz, 1 H, CHPh), 4.62 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.66

1

a colorless oil. [α]²_D⁰ϭ ϩ4.0 (c ϭ 0.7, CHCl₃). H NMR: δ ϭ 1.15

3

2

ϭ

3

[s, 9 H, [(CH₃)₃C], 1.22 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 2.54

2

3

2

[dd, J_H,Hϭ 15.0, J_H,Hϭ 7.6, 1 H, C(2a)-H], 2.62 [dd, J_H,H

ϭ

2

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.75 (d, J_H,Hϭ 11.1 Hz, 1 H,

CHPh), 4.81 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.93 (d, J_H,H

3

2

15.1, J_H,Hϭ 5.4 Hz, 1 H, C(2b)-H], 3.11 (dd, J_H,Hϭ 13.9,

2

ϭ

³J_H,Hϭ 5.8 Hz, 1 H, CHCHϭCH₂), 3.26Ϫ3.30 [m, 1 H, C(3)-H],

11.2 Hz, 1 H, CHPh), 7.23Ϫ7.45 (m, 21 H, CHAr), 7.69Ϫ7.73 (m,

4 H, CHAr) ppm. ¹³C NMR: δ ϭ 14.57, 14.70 [N(CH₂)₃CH₃,

OCH₂CH₃], 19.80 [(CH₃)₃C], 20.97 (CH₂CH₂CH₂CH₃), 27.41

[(CH₃)₃C], 30.17 (CH₂CH₂CH₂CH₃), 36.35 [C(2)], 56.14 [C(3)],

60.72, 65.39 [OCH₂CH₃, C(8)], 73.24, 74.78, 75.28 (3 CH₂Ph),

72.22, 77.24, 79.48, 81.40 [C(4), C(5), C(6), C(7)], 127.7Ϫ129.9

(CHAr), 133.4, 133.6 (2 CqAr), 135.9, 135.9 (CHAr), 138.5, 138.6,

139.0 (3 CqAr), 172.7 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 833

[M ϩ H]^ϩ, 855 [M ϩ Na]^ϩ, 871 [M ϩ K]^ϩ. C₅₁H₆₅NO₇Si (832.2):

calcd. C 73.61, H 7.87, N 1.68; found C 73.51, H 7.85, N 1.68.

2

3

3.36 (dd, J_H,Hϭ 13.9, J_H,Hϭ 5.9 Hz, 1 H, CHCHϭCH₂),

3.86Ϫ4.18 [m, 7 H, C(4)-H, C(5)-H, C(6)-H, C(8a)-H, C(8b)-H,

3

OCH₂CH₃], 4.44 [dd, J_H,Hϭ 7.9, J_H,Hϭ 2.4 Hz, 1 H, C(7)-H],

4.54 (d, ²J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.63 (d, J_H,Hϭ 11.1 Hz, 1

2

H, CHPh), 4.65 (d, ²J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.76 (d, ²J_H,Hϭ

2

11.1 Hz, 1 H, CHPh), 4.84 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.96

(d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 5.08 [dd, J_H,Hϭ 10.2, J_H,H

1.6 Hz, 1 H, CH₂CHϭCH₂(cis)] 5.20 [dd, J_H,Hϭ 17.1, J_H,H

1.7 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.87 (ddt, J_H,Hϭ 17.2,

³J_H,Hϭ 10.3, ³J_H,Hϭ 5.8 Hz, 1 H, CH₂CHϭCH₂), 7.23Ϫ7.47 (m,

21 H, HAr), 7.71Ϫ7.78 (m, 4 H, HAr) ppm. ¹³C NMR: δ ϭ 14.71

2

3

4

ϭ

3

4

ϭ

3

Benzyl (3R,4S,5R,6R,7R)-3-(Allylamino)-4,5,6-tris(benzyloxy)-8-

(OCH₂CH₃), 19.83 [(CH₃)₃C], 27.10 [(CH₃)₃C], 36.32 [C(2)], 50.00 [(tert-butyldiphenylsilyl)oxy]-7-hydroxyoctanoate (13d): Same pro-

(ϪCH₂CHϭCH₂), 55.34 [C(3)], 60.80, 65.43 [OCH₂CH₃, C(8)], cedure as that used for the synthesis of 12d, starting from 11d

2460

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

(73 mg, 0.11 mmol). Purification by flash chromatography (petro-

was evaporated under reduced pressure. Purification by flash chro-

leum ether/ethyl acetate, 8:2) afforded pure compound 13d (78 mg, matography (petroleum ether/ethyl acetate, 9:1) afforded pure com-

78% yield) as a colorless oil. 13d: [α]²_D⁰0 (c ϭ 0.4, CHCl₃). ¹H

pound 14b (132 mg, 81% yield) as a colorless oil. [α]²_D⁰ϭ Ϫ16.0

2

NMR: δ ϭ 0.99 [s, 9 H, (CH₃)₃C], 2.43 [dd, J_H,Hϭ 15.2, ³J_H,Hϭ (c ϭ 0.9, CHCl₃). ¹H NMR: δ ϭ 1.02Ϫ1.18 [m, 12 H, (CH₃)₃C,

2

3

7.3 Hz, 1 H, C(2a)-H], 2.50 [dd, J_H,Hϭ 15.2, J_H,Hϭ 5.6 Hz, 1

OCH₂CH₃), 2.68Ϫ2.79 [m, 1 H, C(2a)-H], 2.80Ϫ2.85 [m, 1 H,

C(2b)-H], 3.65Ϫ3.80 [m, 2 H CH₂(Fmoc)], 3.80Ϫ4.00 [m, 4 H,

H, C(2b)-H], 2.93 [dd, ²J_H,Hϭ 13.8, ³J_H,Hϭ 5.7 Hz, 1 H, CHCHϭ

CH₂], 3.11Ϫ3.15 [m, 1 H, C(3)-H], 3.19 [dd, ²J_H,Hϭ 13.8, ³J_H,Hϭ C(8a)-H, C(8b)-H, OCH₂CH₃], 4.02Ϫ4.18 [m, 2 H, C(6)-H, C(7)-

5.9 Hz, 1 H, CHCHϭCH₂], 3.70 [dd, ³J_H,Hϭ 7.8, ³J_H,Hϭ 6.5 Hz,

H], 4.20Ϫ4.38 [CH(Fmoc)], 4.38Ϫ4.78 [m, 9 H, C(4)-H, C(5)-H, 7

1 H, C(6)-H], 3.74Ϫ3.75 [m, 2 H, C(8a)-H, C(8b)-H], 3.80 [dd, CHPh], 4.82Ϫ4.96 [m, 2 H, C(3)-H, CHPh], 6.98Ϫ7.80 (m, 38 H,

3

³J_H,Hϭ 7.8, J_H,Hϭ 2.3 Hz, 1 H, C(4)-H], 3.85Ϫ3.89 [m, 1 H,

HAr) ppm. ¹³C NMR: δ ϭ 14.44 (OCH₂CH₃), 19.79 [(CH₃)₃C],

27.42 [(CH₃)₃C], 30.18 [C(2)], 47.59 [C(3)], 60.84, 65.44, 67.46,

C(7)-H], 4.27 [dd, J_H,Hϭ 7.9, ³J_H,Hϭ 2.8 Hz, 1 H, C(5)-H], 4.40

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.43 (d, J_H,Hϭ 11.2 Hz, 1 H, 67.88, 74.22, 74.67, 74.71 [C(8),

CHPh), 4.48 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.59 (d, J_H,H

11.2 Hz, 1 H, CHPh), 4.67 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.77

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.84 (d, J_H,Hϭ 11.3 Hz, 1 H, 144.0, 144.1 (CqAr), 156.5 [CϭO (Fmoc)], 171.6 [C(1)] ppm. MS

CHPh), 4.89 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.91 [dd, J_H,H

10.2, J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.02 [dd, J_H,H

3

2

4

CH₂Ph, OCH₂CH₃,

2

ϭ

CH₂(Fmoc)], 72.35, 72.35, 77.88, 80.22 [C(4), C(5), C(6), C(7)],

120.1Ϫ135.9 (CHAr), 133.3, 133.5, 138.3, 138.4, 138.7, 141.4,

2

3

ϭ

(MALDI-TOF): m/z ϭ 1111 [M ϩ Na]^ϩ, 1127 [M ϩ K]^ϩ.

C₆₉H₇₃NO₉Si (1088.4): calcd. C 76.14, H 6.76, N 1.29; found C

4

3

ϭ

4

17.2, J_H,Hϭ 1.6 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.64Ϫ5.73 [m, 1 75.88, H 6.91, N 1.11.

H, CH₂CHϭCH₂], 7.05Ϫ7.60 (m, 30 H, HAr) ppm. ¹³C NMR:

Ethyl

(3S,4S,5R,6R,7R)-3-{Butyl[(9H-fluoren-9-yl)methoxycarb-

δ

ϭ 19.83 [(CH₃)₃C], 27.45 [(CH₃)₃C], 36.29 [C(2)], 50.01

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7-

hydroxyoctanoate (14c): Same procedure as that used for the syn-

thesis of 14a, starting from 12c (529 mg, 0.64 mmol). Purification

by flash chromatography (petroleum ether/ethyl acetate, 8:2) af-

forded 14c (650 mg, 97%) as a colorless oil. [α]²_D⁰ϭ Ϫ6.0 (c ϭ 1.2,

(CH₂CHϭCH₂), 55.35 [C(3)], 65.40, 66.64, 73.27, 74.83, 75.24

[C(8), 4 CH₂Ph], 72.11, 77.31, 79.34, 81.20 [C(4), C(5), C(6), C(7)],

116.1 (CH₂CHϭCH₂), 127.7Ϫ128.7 (CHAr), 130.0 (CH₂CHϭ

CH₂), 133.4, 133.6, 136.0, 138.4, 138.5, 138.9 (CqAr), 135.8Ϫ135.9

(CHAr), 172.4 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 879 [M ϩ

H]^ϩ, 901 [M ϩ Na]^ϩ. C₅₅H₆₃NO₇Si (878.2): calcd. C 75.22, H 7.23,

N 1.59; found C 75.39, H 7.12, N 1.80.

1

CHCl₃). H NMR: δ ϭ 0.73 [br. t, 3 H, N(CH₂)₃CH₃], 0.79Ϫ0.95

3

(m, 4 H, CH₂CH₂CH₃), 1.13 [s, 9 H, (CH₃)₃C], 1.17 (t, J_H,H

ϭ

7.1 Hz, 3 H, OCH₂CH₃), 2.73Ϫ3.08 [m, 4 H, C(2a)-H, C(2b)-H,

NCH₂(CH₂)₂CH₃], 3.70Ϫ4.20 [m, 11 H, C(4)-H, C(5)-H, C(6)-H,

Ethyl

(3S,4S,5R,6R,7R)-3-{Allyl[(9H-fluoren-9-yl)methoxycarb-

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7- C(7)-H, C(8a)-H, C(8b)-H, CHFmoc, CH₂Fmoc, OCH₂CH₃],

hydroxyoctanoate (14a): 12a (413 mg, 0.51 mmol) was dissolved in

dioxane (3 mL) and then FmocCl (200 mg, 0.76 mmol, 1.5 equiv.)

dissolved in dioxane (1 mL) was added. Na₂CO₃(10% aqueous

sol., 1.3 mL) was added and after 2 h the solvent was evaporated

4.44Ϫ4.70 [m, 6 H, C(3)-H, 5 CHPh), 4.85 (br. d, ²J_H,Hϭ 11.3 Hz,

1 H, CHPh), 7.23Ϫ7.41 (m, 25 H, CHAr), 7.71Ϫ7.77 (m, 8 H,

CHAr) ppm. ¹³C NMR: δ ϭ 14.61 [N(CH₂)₃CH₃, OCH₂CH₃),

19.79 [(CH₃)₃C], 23.89 (CH₂CH₂CH₂CH₃), 27.41 [(CH₃)₃C], 27.43

under reduced pressure. The crude product was dissolved in ethyl (CH₂CH₂CH₂CH₃), 30.06, 32.03 [C(2), CH₂CH₂CH₂CH₃], 47.84

acetate (5 mL) and then the solution washed with H₂O (2 ϫ 5 mL) [C(3)], 60.80, 65.45, 66.73, 73.00, 73.10, 74.68 [C(8), OCH₂CH₃,

and dried with Na₂SO₄. The solvent was evaporated under reduced CH₂Fmoc, 3 CH₂Ph], 72.47, 72.99, 73.39, 77.71, 79.77 [C(4), C(5),

pressure and the residue was purified by flash chromatography

(petroleum ether/ethyl acetate, 8:2) yielding 14a (488 mg, 90%) as

a colorless oil. [α]²_D⁰ϭ Ϫ10.5 (c ϭ 1.4, CHCl₃). ¹H NMR: δ ϭ

1.08Ϫ1.18 [m, 12 H, (CH₃)₃C, OCH₂CH₃], 2.72Ϫ2.80 [m, 2 H,

CH₂CHϭCH₂], 2.82Ϫ3.00 [m, 2 H, C(2a)-H, C(2b)-H], 3.60Ϫ4.20,

4.38Ϫ4.78 [2m, 17 H, C(3)-H, C(4)-H, C(5)-H, C(6)-H, C(7)-H,

C(8a)-H, C(8b)-H, 5 CHPh, OCH₂CH₃, CH-Fmoc, CH₂-Fmoc),

4.79Ϫ5.00 (m, 3 H, CHPh, CH₂CHϭCH₂), 5.47Ϫ5.58 (m, 1 H,

CH₂CHϭCH₂), 7.05Ϫ7.38 (m, 25 H, CHAr), 7.52Ϫ7.79 (m, 8 H,

CHAr) ppm. ¹³C NMR: δ ϭ 14.63 (OCH₂CH₃), 19.82 [(CH₃)₃C],

27.45 [(CH₃)₃C], 30.21, 34.00 [C(2), CH₂CHϭCH₂], 47.76 [C(3)],

60.89, 65.47, 67.47, 74.23, 74.73, 74.74 [C(8), 3 CH₂Ph, OCH₂CH₃,

CH₂-Fmoc], 50.75, 72.37, 74.73, 77.77, 80.05 [C(4), C(5), C(6),

C(7), CH-Fmoc], 116.3 (CH₂CHϭCH₂), 120.3Ϫ130.0 (CHAr),

133.4, 133.5 (CqAr), 139.9 (CH₂CHϭCH₂), 138.3Ϫ144.4 (CqAr),

156.2 (CϭO Fmoc), 171.6 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ

1061 [M ϩ Na]^ϩ, 1077 [M ϩ K]^ϩ. C₆₅H₇₁NO₉Si (1038.4): calcd.

C 75.19, H 6.89, N 1.35; found C 74.96, H 6.90, N 1.35.

C(6), C(7), CHFmoc], 127.2Ϫ141.6 (CHAr, CqAr), 172.1 [C(1)]

ppm. MS (MALDI-TOF): m/z ϭ 1077 [M ϩ Na]^ϩ, 1093 [M ϩ

K]^ϩ. C₆₆H₇₅NO₉Si (1054.4): calcd. C 75.18, H 7.17, N 1.33; found

C 74.98, H 7.18, N 1.36.

Benzyl (3S,4S,5R,6R,7R)-3-{Allyl[(9H-fluoren-9-yl)methoxycarb-

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7-

hydroxyoctanoate (14d): Compound 12d (110 mg, 0.13 mmol) was

dissolved in dioxane (700 µL) and then a 10% aqueous solution of

Na₂CO₃(407 µL, 2.6 equiv.) and a solution of FmocCl (39 mg, 1.2

equiv.) in dioxane (300 µL) were added. After 30 min, the reaction

mixture was diluted with H₂O and extracted with EtOAc. The or-

ganic layer was dried with Na₂SO₄and filtered and then the solvent

was evaporated under reduced pressure. Purification by flash chro-

matography (petroleum ether/ethyl acetate, 85:15) afforded pure

compound 14d (115 mg, 84% yield) as a colorless oil. [α]²_D⁰ϭ Ϫ11.2

(c ϭ 2.0, CHCl₃). ¹H NMR: δ ϭ 1.05 [s, 9 H, (CH₃)₃C], 2.83Ϫ3.00

[m, 2 H, C(2a)-H, C(2b)-H], 3.60Ϫ4.21 [m, 10 H, C(3)-H, C(4)-H,

C(5)-H, C(6)-H, C(7)-H, C(8a)-H, C(8b)-H, CHPh -CH₂CHϭ

CH₂], 4.35Ϫ4.88 [m, 7 H, 4 CHPh, CH₂(Fmoc), CH(Fmoc)],

Benzyl (3S,4S,5R,6R,7R)-3-{Benzyl[(9H-fluoren-9-yl)methoxycarb-

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7- 4.70Ϫ4.88 [m, 3 H, CHPh, CH₂CHϭCH₂], 4.90Ϫ5.20 [m, 2 H,

hydroxyoctanoate (14b): Compound 12b (130 mg, 0.15 mmol) was

dissolved in dioxane (600 µL) then a 10% aqueous solution of

2 CHPh], 7.02Ϫ7.80 (m, 38 H, HAr) ppm.¹³C NMR: δ ϭ 19.77

[(CH₃)₃C], 27.40 [(CH₃)₃C], 34.20 [C(2)], 47.70 [C(3)], 60.81, 65.42,

Na₂CO₃(488 µL, 2.6 equiv.) and a solution of FmocCl (47 mg, 1.2 66.74, 67.45, 74.17, 74.70 [C(8), 4 CH₂Ph, CH₂CHϭCH₂], 72.34,

equiv.) in dioxane (300 µL) were added. After 30 min, the reaction

mixture was diluted with H₂O and extracted with EtOAc. The or-

ganic layer was dried with Na₂SO₄and filtered and then the solvent

72.34, 80.01, 80.19 [C(4), C(5), C(6), C(7)], 116.3 (CH₂CHϭCH₂),

125.2Ϫ130.0 (CH₂CHϭCH₂, CHAr), 133.3, 133.5, 138.2, 138.3,

138.6, 141.5, 144.1, 144.3 (CqAr), 156.1 [CϭO (Fmoc)], 171.4

Eur. J. Org. Chem. 2004, 2451Ϫ2470

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2461

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

[C(1)] ppm. MS (MALDI-TOF): m/z ϭ 1123 [M ϩ Na]^ϩ, 1139 [M

47.80 [C(3)], 60.88, 67.35, 71.90, 74.03, 76.00 [C(8), OCH₂CH₃, 3

ϩ K]^ϩ. C₇₀H₇₃NO₉Si: calcd. C 76.40, H 6.69, N 1.27; found C CH₂Ph], 73.20, 77.63, 77.63, 79.60 [C(4), C(5), C(6), C(7)],

76.20, H 6.77, N 1.60.

127.2Ϫ141.6 (CHAr, CqAr), 172.1 [C(1)] ppm. MS (MALDI-

TOF): m/z ϭ 1077 [M ϩ Na]^ϩ, 1093 [M ϩ K]^ϩ. C₆₆H₇₅NO₉Si

(1054.4): calcd. C 75.18, H 7.17, N 1.33; found C 75.21, H 7.15,

N 1.32.

Ethyl

(3R,4S,5R,6R,7R)-3-{Allyl[(9H-fluoren-9-yl)methoxycarb-

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7-

hydroxyoctanoate (15a): Same procedure as that used for the syn-

thesis of 14a, starting from 13a (350 mg, 0.43 mmol). Purification

by flash chromatography (petroleum ether/ethyl acetate, 8:2) af-

Benzyl (3R,4S,5R,6R,7R)-3-{Allyl[(9H-fluoren-9-yl)methoxycarb-

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7-

hydroxyoctanoate (15d): Same procedure as that used for the syn-

thesis of 14d, starting from 13d (71 mg, 0.08 mmol). Purification

by flash chromatography (petroleum ether/ethyl acetate, 85:15) af-

forded pure compound 15d (87 mg, 98% yield) as a yellowish oil.

[α]²_D⁰ϭ ϩ28.9 (c ϭ 1.8, CHCl₃). ¹H NMR: δ ϭ 1.03 [s, 9 H,

(CH₃)₃C], 2.54Ϫ2.67 [m, 2 H, C(2a)-H, C(2b)-H], 4.13 [br. t, 1 H,

C(4)-H], 3.62Ϫ4.38 [m, 10 H, C(5)-H, C(6)-H, C(7)-H, C(8a)-H,

C(8b)-H, CH₂CHϭCH₂, CH₂(Fmoc), CH(Fmoc)], 4.21 (d,

²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.47Ϫ4.53 (m, 3 H, 3 CHPh),

4.53Ϫ4.61 [m, 1 H, C(3)-H], 4.65 (d, ²J_H,Hϭ 11.1 Hz, 1 H, CHPh),

4.73 (d, ²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.81 [br. d, ³J_H,Hϭ 11.1 Hz,

forded 15a (400 mg, 96%) as a colorless oil. [α]²_D⁰ϭ ϩ32.8 (c ϭ 0.8,

CHCl₃). ¹H NMR: δ ϭ 1.12 [s, 9 H, (CH₃)₃C], 1.18 (t, J_H,H

ϭ

3

7.1 Hz, 3 H, OCH₂CH₃), 2.18Ϫ2.22 [m, 1 H, C(2a)-H], 2.60Ϫ2.80

[m, 1 H, C(2b)-H], 3.73Ϫ4.48 [m, 14 H, C(4)-H, C(5)-H, C(6)-H,

C(7)-H, C(8a)-H, C(8b)-H, NCH₂CHϭCH₂, CH₂Fmoc, CHFmoc,

OCH₂CH_3,CHPh], 4.56Ϫ4.72 [m, 4 H, 3 CHPh, C(3)-H], 4.76 (br.

d, 1 H, CHPh), 4.85 (br. d, 1 H, CHPh), 4.90Ϫ5.00 (m, 2 H,

CH₂CHϭCH₂), 5.64Ϫ5.78 (m, 1 H, CH₂CHϭCH₂), 7.23Ϫ7.39 (m,

25 H, CHAr), 7.56Ϫ7.76 (m, 8 H, CHAr). ¹³C NMR: δ ϭ 14.67

(OCH₂CH₃), 19.83 [(CH₃)₃C], 27.41 [(CH₃)₃C], 30.17, 35.71 [C(2),

CH₂CHϭCH₂], 47.67 [C(3)], 60.89,65.02, 67.93, 74.19, 74.19, 75.86

[C(8), OCH₂CH₃, CH₂Fmoc, 3 CH₂Ph], 71.51, 77.63, 77.63, 79.52

[C(4), C(5), C(6), C(7)], 116.7 (CH₂CHϭCH₂), 120.2Ϫ128.0

(CHAr), 133.3, 133.5 (2 CqAr), 135.9 (CH₂CHϭCH₂), 138.7,

141.5, 144.2 (3 CqAr), 157.0 (CϭOFmoc), 170.9 [C(1)] ppm. MS

(MALDI-TOF): m/z ϭ 1061 [M ϩ Na]^ϩ, 1077 [M ϩ K]^ϩ.

C₆₅H₇₁NO₉Si: calcd. C 75.19, H 6.89, N 1.35; found C 74.98, H

6.87, N 1.36.

3

1 H, CH₂CHϭCH₂(cis)], 4.82 [br. d, J_H,Hϭ 16.3 Hz, 1 H,

2

CH₂CHϭCH₂(trans)], 4.88 (d, J_H,Hϭ 12.2 Hz, 1 H, CHPh), 4.93

2

(d, J_H,Hϭ 12.2 Hz, 1 H, CHPh), 5.51Ϫ5.61 [m, 1 H, CH₂CHϭ

CH₂], 7.05Ϫ7.60 (m, 38 H, HAr) ppm. ¹³C NMR: δ ϭ 19.81

[(CH₃)₃C], 27.41 [(CH₃)₃C], 35.52 [C(2)], 47.67 [C(3)], 61.00, 65.03,

66.71, 67.89, 74.15, 75.87 [C(8), 4 CH₂Ph, CH₂CHϭCH₂], 71.54,

77.58, 77.73, 79.43 [C(4), C(5), C(6), C(7)], 116.6 (CH₂CHϭCH₂),

127.7Ϫ128.7 (CHAr), 129.9 (CH₂CHϭCH₂), 135.6Ϫ135.9

(CHAr), 133.3, 133.5, 138.6, 141.5, 141.5, 144.3 (CqAr), 157.3 [Cϭ

O (Fmoc)], 170.7 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 1123 [M

ϩ Na]^ϩ, 1139 [M ϩ K]^ϩ. C₇₀H₇₃NO₉Si (1100.4): calcd. C 76.40,

H 6.69, N 1.27; found C 76.05, H 6.73, N 1.39.

Benzyl (3R,4S,5R,6R,7R)-3-{Benzyl[(9H-fluoren-9-yl)methoxycarb-

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7-

hydroxyoctanoate Acid (15b): Same procedure as that used for the

synthesis of 14b, starting from 13b (60 mg, 0.07 mmol). Purification

by flash chromatography (toluene/ethyl acetate, 95:5) afforded pure

compound 15b (61 mg, 81% yield) as a yellowish oil. [α]²_D⁰ϭ ϩ41.8

(c ϭ 0.5, CHCl₃). ¹H NMR: δ ϭ 0.80Ϫ1.08 [m, 12 H, (CH₃)₃C,

OCH₂CH₃], 2.10Ϫ2.18 [m, 1 H, C(2a)-H], 2.44Ϫ2.54 [m, 1 H,

C(2b)-H], 3.62Ϫ3.95, 3.96Ϫ4.15, 4.20Ϫ4.38 [3m, 13 H, C(3)-H,

C(4)-H, C(5)-H, C(6)-H, C(7)-H, C(8a)-H, C(8b)-H, CH₂(Fmoc),

CH(Fmoc), CHPh, OCH₂CH₃], 4.40Ϫ4.62 [m, 6 H, 6 CHPh],

4.76Ϫ4.80 (m, 1 H, CHPh), 7.05Ϫ7.75 (m, 38 H, HAr) ppm. ¹³C

NMR: δ ϭ 14.56 (OCH₂CH₃), 19.71 [(CH₃)₃C], 27.36 [(CH₃)₃C],

35.85 [C(2)], 47.59 [C(3)], 60.84, 65.08, 68.00, 73.13, 73.26, 74.21,

75.13 [C(8), 4 CH₂Ph, OCH₂CH₃, CH₂(Fmoc)], 71.58, 77.81,

79.23, 80.93 [C(4), C(5), C(6), C(7)], 120.2Ϫ135.9 (CHAr), 133.2,

133.2, 137.9, 138.1, 138.2, 138.3, 141.4, 144.1 (CqAr), 166.0 [CϭO

(Fmoc)], 170.9 [C(1)] ppm. MS (MALDI-TOF): m/z ϭ 1111 [M ϩ

Na]^ϩ, 1127 [M ϩ K]^ϩ. C₆₉H₇₃NO₉Si (1088.4): calcd. C 76.14, H

6.76, N 1.29; found C 76.03, H 6.55, N 1.30.

Ethyl [(2S,3S,4R,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-{[(tert-but-

yldiphenylsilyl)oxy]methyl}piperidin-2-yl]acetate (18a): Compound

14a (418 mg, 0.40 mmol) was dissolved in CH₂Cl₂(4 mL) under an

inert gas, and added to

a flask containing PCC (345 mg,

1.60 mmol, 4 equiv.), previously dried with powdered molecular si-

˚

eves (4 A). After 12 h, the reaction mixture was filtered through

silica gel (petroleum ether/ethyl acetate, 9:1) to remove the PCC.

The solvent was then evaporated, crude 16a was dissolved in dry

DMF (3 mL) under an inert gas, and piperidine (600 µL) was ad-

ded. After 20 min, the solvent was evaporated under reduce press-

ure. The crude product was dissolved in dry 1,2-dichloroethane

(10 mL) under an inert gas and then Na₂SO₄(2.17 g, 15.32 mmol,

40 equiv.), AcOH (230 mg, 3.83 mmol, 10 equiv.), and NaB-

H(OAc)₃(324 mg, 1.53 mmol, 4 equiv.) were added. After 6 h, the

reaction mixture was neutralized using NaHCO₃(satd. solution);

Ethyl

(3R,4S,5R,6R,7R)-3-{Butyl[(9H-fluoren-9-yl)methoxycarb- the two layers were separated, the aqueous layer was extracted with

onyl]amino}-4,5,6-tris(benzyloxy)-8-[(tert-butyldiphenylsilyl)oxy]-7- CH₂Cl₂(3 ϫ 10 mL) and the combined organic layers were dried

hydroxyoctanoate (15c): Same procedure as that used for the syn-

thesis of 14c, starting from 13c (158 mg, 0.19 mmol). Purification

by flash chromatography (petroleum ether/ethyl acetate, 8:2) af-

forded 15c (180 mg, 90%) as a colorless oil. [α]²_D⁰ϭ ϩ25.3 (c ϭ 1.2,

with Na₂SO₄. The solvent was evaporated under reduced pressure

and the residue was purified by flash chromatography (petroleum

ether/ethyl acetate, 15:1) yielding 18a [263 mg, 82% for the three

steps) as a colorless oil. The (6R) stereoisomer was detectable only

1

CHCl₃). ¹H NMR: δ ϭ 0.67 [t, ³J_H,Hϭ 6.9 Hz, 3 H, N(CH₂)₃CH₃], by TLC]. [α]²_D⁰ϭ Ϫ52.3 (c ϭ 1.0, CHCl₃). H NMR: δ ϭ 1.10 [s,

3

1.04Ϫ1.08 [m, 12 H, (CH₃)₃C, OCH₂CH₃], 0.77Ϫ1.17 (m, 4 H,

9 H, (CH₃)₃C], 1.15 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 2.48 (dd,

CH₂CH₂CH₃), 2.14Ϫ2.18 [m, 1 H, C(2a)-H], 2.62Ϫ2.64 [m, 1 H, ²J_H,Hϭ 15.1, J_H,Hϭ 7.3 Hz, 1 H, CHCO₂Et), 2.77 (dd, J_H,H

ϭ

3

2

3

C(2b)-H], 2.85Ϫ2.87 [m, 1 H, NCH(CH₂)₂CH₃], 3.00Ϫ3.13 [m, 1 15.0, J_H,Hϭ 5.0 Hz, 1 H, CHCO₂Et), 3.24Ϫ3.26 [m, 1 H, C(6)-

H, NCH(CH₂)₂CH₃], 3.61Ϫ4.70 [m, 18 H, C(3)-H, C(4)-H, C(5)- H], 3.28 (dd, J_H,Hϭ 15.3, J_H,Hϭ 5.6 Hz, 1 H, CHCHϭCH₂),

H, C(6)-H, C(7)-H, C(8a)-H, C(8b)-H, CH₂(Fmoc), CH(Fmoc), 6 3.38Ϫ3.42 (m, 1 H, CHCHϭCH₂), 3.41 [dd, J_H,Hϭ 9.4, J_H,H

2

3

ϭ

CHPh, OCH₂CH₃], 7.11Ϫ7.47 (m, 25 H, CHAr), 7.61Ϫ7.66 (m, 8 8.7 Hz, 1 H, C(3)-H], 3.76Ϫ3.82 [m, 2 H, C(2)-H, C(5)-H],

3

H, CHAr) ppm. ¹³C NMR: δ ϭ 14.69 [N(CH₂)₃CH₃, OCH₂CH₃), 3.88Ϫ4.10 (m, 2 H, CH₂OTBDPS), 4.01 (q, J_H,Hϭ 7.0 Hz, 2 H,

3

19.87 [(CH₃)₃C], 20.89 (CH₂CH₂CH₂CH₃), 23.41 (CH₂CH₂CH₂- OCH₂CH₃), 4.12 [dd, J_H,Hϭ 9.1, J_H,Hϭ 8.7 Hz, 1 H, C(4)-H],

2

CH₃), 27.47 [(CH₃)₃C], 30.20, 35.80 [C(2), CH₂CH₂CH₂CH₃],

4.57 (s, 2 H, CHPh), 4.64 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.68

2462

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

2

(d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.90 (d, J_H,Hϭ 10.7 Hz, 1 H, After 2 h, the solvent was evaporated under reduce pressure. The

2

CHPh), 4.98 (d, J_H,Hϭ 11.7 Hz, 1 H, CHPh), 5.00Ϫ5.05 (m, 2

crude product was dissolved in dry 1,2-dichloroethane (1 mL) un-

der an inert gas and then Na₂SO₄(159 mg, 1.12 mmol, 40 equiv.),

3

H, CH₂CHϭCH₂), 5.69 (ddt, J_H,Hϭ 17.1, ³J_H,Hϭ 10.3, ³J_H,H

ϭ

5.8 Hz, 1 H, CH₂CHϭCH₂), 7.21Ϫ7.43 (m, 21 H, CHAr), AcOH (16.8 mg, 0.28 mmol, 10 equiv.), and NaBH(OAc)₃(24 mg,

7.75Ϫ7.78 (m, 14.67 0.112 mmol, 4 equiv.) were added. The reaction mixture was stirred

4

H, CHAr) ppm. ¹³C NMR:

δ ϭ

(OCH₂CH₃), 19.58 [(CH₃)₃C], 27.36 [(CH₃)₃C], 36.60 (CH₂CO₂Et), overnight and then neutralized by adding NaHCO₃(satd. solu-

51.66 (CH₂CHϭCH₂), 57.29, 58.72 [C(2), C(6)], 60.69 tion); the two layers were separated, the aqueous layer was ex-

(OCH₂CH₃), 72.95, 74.84, 75.58 (3 CH₂Ph), 79.11, 81.29, 84.16 tracted with CH₂Cl₂(3 ϫ 3 mL), and the combined organic layers

[C(3), C(4), C(5)], 116.8 (CH₂CHϭCH₂), 127.5Ϫ129.8 (CHAr),

133.4, 133.5 (2 CqAr), 136.0 (CH₂CHϭCH₂), 138.7, 138.9, 139.0 duced pressure and the residue was purified by flash chromatogra-

(3 CqAr), 172.2 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 799 [M phy (petroleum ether/ethyl acetate, 9:1) yielding 18c (10 mg, 45%)

were dried with Na₂SO₄. The solvent was evaporated under re-

1

ϩ H]^ϩ821 [M ϩ Na]^ϩ. C₅₀H₅₉NO₆Si (798.1): calcd. C 75.25, H as a colorless oil. [α]²_D⁰ϭ Ϫ15.0 (c ϭ 1.1, CHCl₃). H NMR: δ ϭ

7.45, N 1.76; found C 75.33, H 7.21, N 1.80.

0.90 [t, ³J_H,Hϭ 7.2 Hz, 3 H, N(CH₂)₃CH₃], 1.11 [s, 9 H, (CH₃)₃C],

3

1.17 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.27Ϫ1.31 (m, 4 H,

2

3

Ethyl [(2S,3S,4R,5R,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-6-{[(tert-

CH₂CH₂CH₃), 2.48 (dd, J_H,Hϭ 15.1, J_H,Hϭ 7.3 Hz, 1 H,

CHCO₂Et), 2.54Ϫ2.63 [m, 1 H, NCH(CH₂)₂CH₃], 2.70Ϫ2.75 [m,

butyldiphenylsilyl)oxy]methyl}piperidin-2-yl]acetate (18b): Com-

pound 14b (117 mg, 0.11 mmol) was dissolved in dry CH₂Cl₂

(4 mL) under an inert gas, and added to a flask containing PCC

(48 mg, 2 equiv.) previously dried with powdered molecular sieves

2

3

1 H, NCH(CH₂)₂CH₃], 2.76 (dd, J_H,Hϭ 15.1, J_H,Hϭ 5.0 Hz, 1

3

H, CHCO₂Et), 3.27 [td, J_H,Hϭ 5.5, J_H,Hϭ 3.1 Hz, 1 H, C(6)-

H], 3.39 [dd, ³J_H,Hϭ 9.8, ³J_H,Hϭ 8.4 Hz, 1 H, C(3)-H], 3.63 [ddd,

˚

³J_H,Hϭ 10.0, J_H,Hϭ 7.3, ³J_H,Hϭ 5.0 Hz, 1 H, C(2)-H], 3.78 [dd,

3

(4 A). After 12 h, more PCC (24 mg, 1 equiv.) was added and then,

³J_H,Hϭ 9.6, J_H,Hϭ 5.8 Hz, 1 H, C(5)-H], 3.95 [dd, J_H,Hϭ 9.6,

³J_H,Hϭ 8.4 Hz, 1 H, C(4)-H], 3.97Ϫ4.11 (m, 2 H, OCH₂TBDPS),

4.01 (q, ³J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃), 4.64 (d, ²J_H,Hϭ 13.4 Hz,

3

after 1 h, the mixture was concentrated and filtered through silica

gel (petroleum ether/ethyl acetate, 9:1) to remove PCC and molecu-

lar sieves. The solvent was then evaporated and the crude product

was dissolved in dry DMF (1 mL) under an inert gas. Piperidine

(10 µL) was added and the reaction mixture was stirred for 3 h.

The solvent was evaporated under reduced pressure without heat-

ing and then the crude product was dried in vacuo for 3 h. This

material was dissolved in dry 1,2-dichloroethane (3 mL) under an

inert gas and then Na₂SO₄(632 mg, 40 equiv.), AcOH (63 µL, 10

equiv.), and NaBH(OAc)₃(94 mg, 4 equiv.) were added in sequence.

The reaction mixture was stirred overnight before being neutralized

with a saturated solution of NaHCO₃, extracted with CH₂Cl₂,

dried with Na₂SO₄, and filtered; the solvent was evaporated under

reduced pressure. Purification by flash chromatography (toluene)

afforded compound 18b (75 mg, 81% for the three steps) as a mix-

ture of diastereoisomers [(6R)/(6S) ϭ 8:2, determined by NMR

spectroscopy] as a colorless oil. [α]²_D⁰ϭ Ϫ16.8 (c ϭ 2.3, CHCl₃).

¹H NMR: δ ϭ 1.02Ϫ1.08 [m, 12 H, (CH₃)₃C, OCH₂CH₃], 2.54 (dd,

²J_H,Hϭ 14.8, ³J_H,Hϭ 7.6 Hz, 1 H, CHCOOEt), 2.84 (dd, ²J_H,Hϭ

2

1 H, CHPh), 4.66 (s, 2 H, 2 CHPh), 4.70 (d, J_H,Hϭ 10.7 Hz, 1

H, CHPh), 4.91 (d, ²J_H,Hϭ 10.6 Hz, 1 H, CHPh), 4.99 (d, ²J_H,Hϭ

11.3 Hz, 1 H, CHPh), 7.26Ϫ7.38 (m, 21 H, HAr), 7.77Ϫ7.79 (m, 4

H, HAr) ppm. ¹³C NMR: δ ϭ 14.57, 14.64 [N(CH₂)₃CH₃,

OCH₂CH₃], 19.57 [(CH₃)₃C], 20.76 (CH₂CH₂CH₂CH₃), 27.29

[(CH₃)₃C], 31.81 (CH₂CH₂CH₂CH₃), 36.69 (CH₂CO₂Et), 48.10

(CH₂CH₂CH₂CH₃) 57.35, 59.33 [C(2), C(6)], 60.63, 60.72

(CH₂OTBDPS, OCH₂CH₃), 73.08, 74.94, 75.54 (3 CH₂Ph), 79.43,

81.45, 84.25 [C(3), C(4), C(5)], 127.6Ϫ129.8 (CHAr), 133.5, 133.6

(2 CqAr), 135.9, 136.0 (CHAr), 138.7, 138.9, 138.97 (3 CqAr),

172.3 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 815 [M ϩ H]^ϩ.

C₅₁H₆₃NO₆Si (814.1): calcd. C 75.24, H 7.80, N 1.72; found C

75.33, H 7.69, N 1.70.

Benzyl

[(2S,3S,4R,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-{[(tert-

butyldiphenylsilyl)oxy]methyl}piperidin-2-yl]acetate (18d): Com-

pound 14d (100 mg, 0.09 mmol) was dissolved in dry CH₂Cl₂

(5 mL) under an inert gas, and added to a flask containing PCC

(293 mg, 1.5 equiv.) previously dried with powdered molecular si-

3

14.8, J_H,Hϭ 4.4 Hz, 1 H, CHCOOEt), 3.06Ϫ3.12 [m, 1 H, C(6)-

H], 3.53 [dd, ³J_H,Hϭ 9.6, ³J_H,Hϭ 8.4 Hz, 1 H, C(3)-H], 3.78Ϫ3.84

[m, 4 H, C(2)-H, C(5)-H, CHOTBDPS, CHPh], 3.85Ϫ410 [m, 5 H,

˚

2

eves (4 A). After 2 h, the mixture was concentrated and filtered

C(4)-H, CHOTBDPS, CHPh, OCH₂CH₃], 4.37 (d, J_H,H

ϭ

2

through silica gel (petroleum ether/ethyl acetate, 8:2) to remove

PCC and molecular sieves. The solvent was then evaporated and

the crude product was dissolved in dry DMF (2 mL) under an inert

gas. Piperidine (100 µL) was added and the reaction mixture was

stirred for 3 h. The solvent was evaporated under reduced pressure

without heating and the crude product was dried in vacuo for 3 h.

The material was dissolved in dry 1,2-dichloroethane (2 mL) under

an inert gas and then Na₂SO₄(392 mg, 40 equiv.), AcOH (40 µL,

10 equiv.), and NaBH(OAc)₃(59 mg, 4 equiv.) were added in se-

quence. The reaction mixture was stirred overnight before it was

neutralized with a saturated solution of NaHCO₃, extracted with

CH₂Cl₂, dried with Na₂SO₄, and filtered; the solvent was evapo-

11.2 Hz, 1 H, CHPh), 4.42 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.65

2

(d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.69 (d, J_H,Hϭ 10.7 Hz, 1 H,

2

CHPh), 4.89 (d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 5.00 (d, J_H,H

ϭ

11.2 Hz, 1 H, CHPh), 7.19Ϫ7.80 (m, HAr) ppm. ¹³C NMR: δ ϭ

14.57 (OCH₂CH₃), 19.57 [(CH₃)₃C], 27.33 [(CH₃)₃C], 31.00

(CH₂COOEt), 57.03, 58.52 [C(2), (6)], 52.12, 60.75, 65.94, 72.58,

75.03, 75.64 (CH₂OTBDPS, 4 CH₂Ph, OCH₂CH₃), 78.72, 81.39,

84.43 [C(3), C(4), C(5)], 126.5Ϫ136.0 (CHAr), 132.5, 133.3, 133.5,

138.4, 138.9, 140.1 (CqAr), 172.0 (CϭO) ppm. MS (MALDI-

TOF): m/z ϭ 849 [M ϩ H]^ϩ. C₅₄H₆₁NO₆Si (848.2): calcd. C 76.47,

H 7.25, N 1.65; found C 76.12, H 7.00, N 1.70.

Ethyl [(2S,3S,4R,5R,6S)-1-Butyl-3,4,5-tris(benzyloxy)-6-{[(tert-but- rated under reduced pressure. Purification by flash chromatography

yldiphenylsilyl)oxy]methyl}piperidin-2yl]acetate (18c): Compound

14c (30 mg, 0.028 mmol) was dissolved in CH₂Cl₂(4 mL) under an

inert gas, and added to a flask containing PCC (24 mg, 0.11 mmol,

(petroleum ether/ethyl acetate, 9:1) afforded pure compound 18d

(42 mg, 55% yield for the three steps) as a colorless oil. The (6R)

stereoisomer was detectable only by TLC. [α]²_D⁰ϭ Ϫ9.0 (c ϭ 1.5,

1

2

˚

4 equiv.), previously dried with powdered molecular sieves (4 A).

CHCl₃). H NMR: δ ϭ 1.09 [s, 9 H, (CH₃)₃C], 2.45 (dd, J_H,Hϭ

3

2

After 3 h, the reaction mixture was filtered through silica gel (petro-

leum ether/ethyl acetate, 8:2) to remove PCC. The solvent was eva-

porated and then the crude product was dissolved in dry DMF

(0.25 mL) under an inert gas and piperidine (2.5 µL) was added.

15.1, J_H,Hϭ 7.2 Hz, 1 H, CHCOOBn), 2.71 (dd, J_H,Hϭ 15.1,

³J_H,Hϭ 5.2 Hz, 1 H, CHCOOBn), 3.12Ϫ3.19 [m, 2 H, C(6)-H,

CHCHϭCH₂), 3.26 [dd, J_H,Hϭ 14.3, J_H,Hϭ 6.4 Hz, 1 H,

CHCHϭCH₂], 3.35 [dd, J_H,Hϭ 9.5, J_H,Hϭ 8.4 Hz, 1 H, C(3)-

2

3

Eur. J. Org. Chem. 2004, 2451Ϫ2470

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2463

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

2

H], 3.67 [dd, ³J_H,Hϭ 9.5, ³J_H,Hϭ 5.9 Hz, 1 H, C(5)-H], 3.72Ϫ3.78 H], 3.73Ϫ3.83 (m, 2 H, CH₂OTBDPS), 3.94 (d, J_H,Hϭ 12.4 Hz,

2

3

2

[m, 1 H, C(2)-H], 3.84 (dd, J_H,Hϭ 11.1, J_H,Hϭ 8.0 Hz, 1 H, 1 H, CHPh), 3.97 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.13 (d,

2

3

2

CHOTBDPS), 3.93 (dd, J_H,Hϭ 11.1, J_H,Hϭ 5.0 Hz, 1 H, ²J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.26 (d, J_H,Hϭ 11.2 Hz, 1 H,

3

2

CHOTBDPS), 4.05 [t, J_H,Hϭ 9.5 Hz, 1 H, C(4)-H], 4.45 (d,

CHPh), 4.42 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.68 (d, J_H,Hϭ

²J_H,Hϭ 11.7 Hz, 1 H, CHPh), 4.49 (d, J_H,Hϭ 11.7 Hz, 1 H, 11.2 Hz, 1 H, CHPh), 4.74 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh),

2

CHPh), 4.53 (d, J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.58 (d, J_H,H

ϭ

6.80Ϫ7.40 (m, HAr) ppm. ¹³C NMR: δ ϭ 14.26 (OCH₂CH₃), 19.53

2

10.7 Hz, 1 H, CHPh), 4.79 (d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.84 [(CH₃)₃C], 27.34 [(CH₃)₃C], 30.28 (CH₂COOEt), 54.39, 61.01 [C(2),

2

(d, J_H,Hϭ 12.3 Hz, 1 H, CHPh), 4.88 (d, J_H,Hϭ 11.5 Hz, 1 H,

C(6)], 52.81, 60.24, 62.68, 72.09, 74.73, 75.33 (CH₂OTBDPS, 4

CH₂Ph, OCH₂CH₃), 78.78, 80.00, 83.96 [C(3), C(4), C(5)],

2

CHPh), 4.87Ϫ4.92 (m, 2 H, CH₂CHϭCH₂), 4.99 (d, J_H,H

ϭ

12.3 Hz, 1 H, CHPh), 5.50Ϫ5.57 (m, 1 H, CH₂CHϭCH₂), 127.0Ϫ129.9 (CHAr), 133.3, 133.4, 138.7, 139.3, 139.6, 140.3

7.19Ϫ7.80 (m, 30 H, HAr) ppm. ¹³C NMR: δ ϭ 19.55 [(CH₃)₃C], (CqAr), 172.0 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 849 [M ϩ

27.32 [(CH₃)₃C], 36.51 (CH₂COOBn), 51.82 (CH₂CHϭCH₂),

H]^ϩ. C₅₄H₆₁NO₆Si (848.2): calcd. C 76.47, H 7.25, N 1.65; found

57.33, 58.74 [C(2), C(6)], 60.95, 66.49, 72.95, 74.75, 75.52 C 76.58, H 7.13, N 1.76.

(CH₂OTBDPS, 4 CH₂Ph), 79.12, 81.21, 84.04 [C(3), C(4), C(5)],

Ethyl

[(2R,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-1-butyl-6-{[(tert-

116.8 (CH₂CHϭCH₂), 127.4Ϫ129.8, (CHAr), 133.3, 133.4, 136.2,

138.6, 138.9, 139.0 (CqAr), 136.0Ϫ136.1 (CHAr), 171.9 (CϭO)

ppm. MS (MALDI-TOF): m/z ϭ 861 [M ϩ H]^ϩ. C₅₅H₆₁NO₆Si

(860.2): calcd. C 76.80, H 7.15, N 1.63; found C 76.51, H 6.95,

N 1.33.

butyldiphenylsilyl)oxy]methyl}piperidin-2yl]acetate (19c): Same pro-

cedure as that used for the synthesis of 18c, starting from 15c

(80.7 mg, 0.077 mmol) to afford 19c (43 mg, 68% for the three

steps). The (6S) stereoisomer was detectable only by TLC. [α]²_D⁰

ϭ

1

3

ϩ16.9 (c ϭ 0.7, CHCl₃). H NMR: δ ϭ 0.93 [t, J_H,Hϭ 7.2 Hz, 3

H, N(CH₂)₃CH₃], 1.13 [s, 9 H, (CH₃)₃C], 1.22 (t, J_H,Hϭ 7.1 Hz,

3

Ethyl [(2R,3S,4R,5R,6R)-1-Allyl-3,4,5-tris(benzyloxy)-6-{[(tert-but-

yldiphenylsilyl)oxy]methyl}piperidin-2yl]acetate (19a): Same pro-

cedure as that used for the synthesis of 18a, starting from 15a

(184 mg, 0.18 mmol). Purification by flash chromatography (petro-

3 H, OCH₂CH₃), 1.48Ϫ1.51 (m, 4 H, CH₂CH₂CH₃), 2.52 (dd,

²J_H,Hϭ 15.1, J_H,Hϭ 5.9 Hz, 1 H, CHCO₂Et), 2.56Ϫ2.63 [m, 1

3

H, NCH(CH₂)₂CH₃], 2.67 (dd, ²J_H,Hϭ 15.2, ³J_H,Hϭ 6.5 Hz, 1 H,

3

leum ether/ethyl acetate, 15:1) afforded 19a (140 mg, 98% for the

CHCO₂Et), 2.72 [ddd, J_H,Hϭ 9.9, J_H,Hϭ 4.1, J_H,Hϭ 2.5 Hz,

three steps) as a colorless oil. [α]²_D⁰ϭ ϩ21.6 (c ϭ 0.5, CHCl₃). H 1 H, C(6)-H], 2.80Ϫ2.89 [m, 1 H, NCH(CH₂)₂CH₃], 3.55 [dd,

1

3

NMR: δ ϭ 0.98 [s, 9 H, (CH₃)₃C], 1.07 (t, J_H,Hϭ 7.1 Hz, 3 H, ³J_H,Hϭ 9.8, J_H,Hϭ 8.3 Hz, 1 H, C(5)-H], 3.73 [dd, J_H,Hϭ 9.6,

2

3

OCH₂CH₃), 2.46 (dd, J_H,Hϭ 15.1, J_H,Hϭ 6.2 Hz, 1 H,

³J_H,Hϭ 9.6 Hz, 1 H, C(4)-H], 3.75 [dd, J_H,Hϭ 9.5, J_H,Hϭ 5.2,

H, C(3)-H], 3.91Ϫ4.14 [m, H, C(2)-H, OCH₂CH₃,

CHCO₂Et), 2.67 [dd, J_H,Hϭ 9.9, J_H,Hϭ 2.4 Hz, 1 H, C(6)-H], CH₂OTBDPS), 4.50 (d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.64 (d,

2

3

CHCO₂Et), 2.62 (dd, J_H,Hϭ 15.2, J_H,Hϭ 6.6 Hz, 1 H,

1

5

3

2

3

2

3.13 (dd, J_H,Hϭ 14.4, J_H,Hϭ 6.7 Hz, 1 H, -CHCHϭCH₂), 3.37

²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.73 (d, J_H,Hϭ 11.3 Hz, 1 H,

2

3

2

(dd, J_H,Hϭ 14.4, J_H,Hϭ 5.6 Hz, 1 H, -CHCHϭCH₂), 3.46 [dd, CHPh), 4.77 (d, J_H,Hϭ 10.5 Hz, 1 H, CHPh), 4.90 (d, J_H,H

ϭ

³J_H,Hϭ 9.7, J_H,Hϭ 8.3 Hz, 1 H, C(5)-H], 3.60 [dd, J_H,Hϭ 8.9, 10.9 Hz, 1 H, CHPh), 4.97 (d, J_H,Hϭ 10.6 Hz, 1 H, CHPh),

3

2

³J_H,Hϭ 8.2 Hz, 1 H, C(4)-H], 3.65 [dd, J_H,Hϭ 9.5, J_H,Hϭ 5.0, 7.24Ϫ7.26 (m, 21 H, CHAr), 7.66Ϫ7.77 (m, 4 H, CHAr) ppm. ¹³

1 H, C(3)-H], 3.94Ϫ3.80 [m, 5 H, OCH₂CH₃, CH₂OTBDPS, C(2)- NMR: 14.64, 14.78 [N(CH₂)₃CH₃, OCH₂CH₃], 19.82

[(CH₃)₃C], 21.01 (CH₂CH₂CH₂CH₃), 27.48 [(CH₃)₃C], 29.23

11.2 Hz, 1 H, CHPh), 4.60 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.66 (CH₂CH₂CH₂CH₃), 31.28 (CH₂CO₂Et), 48.87 (CH₂CH₂CH₂CH₃),

C

3

δ

ϭ

2

H], 4.40 (d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.48 (d, J_H,H

ϭ

2

(d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.79 (d, J_H,Hϭ 10.9 Hz, 1 H,

CHPh), 4.79 (d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.84 (d, J_H,H

10.9 Hz, 1 H, CHPh), 4.99 [d, J_H,Hϭ 15.4 Hz, CH₂CHϭ

54.54, 61.33 [C(2), C(6)], 60.73, 62.51, 72.83, 75.11, 75.87

(CH₂OTBDPS, OCH₂CH₃, 3 CH₂Ph), 78.68, 80.45, 84.22 [C(3),

C(4), C(5)], 127.6Ϫ129.9 (CHAr), 133.5, 133.6 (2 CqAr), 136.0,

2

ϭ

3

CH₂(trans)], 5.00 [d, J_H,Hϭ 11.6 Hz, 1 H, CH₂CHϭCH₂(cis)], 136.0 (CHAr), 138.7, 138.7, 139.0 (3 CqAr), 173.2 (CϭO) ppm.

5.64 (ddt, ³J_H,Hϭ 11.6 Hz, 1 H, CH₂CHϭCH₂), 6.95Ϫ7.36 (m, 21 MS (MALDI-TOF): m/z ϭ 815 [M ϩ H]^ϩ. C₅₁H₆₃NO₆Si (814.1):

H, HAr), 7.43Ϫ7.64 (m, 4 H, HAr) ppm. ¹³C NMR: δ ϭ 14.61

(OCH₂CH₃), 19.79 [(CH₃)₃C], 27.44 [(CH₃)₃C], 30.17 (CH₂CO₂Et),

52.27 (CH₂CHϭCH₂), 54.59 [C(2)], 60.38 [C(6)], 60.66

(OCH₂CH₃), 72.66, 75.14, 75.90 (3 CH₂Ph), 78.49, 80.03, 84.08

[C(3), C(4), C(5)], 117.0 (CH₂CHϭCH₂), 127.6Ϫ132.5 (CHAr),

133.3, 133.5 (2 CqAr), 135.9 (CH₂CHϭCH₂), 138.6, 138.6, 138.9

(3 CqAr), 172.8 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 799 [M

ϩ H]^ϩ821 [M ϩ Na]^ϩ. C₅₀H₅₉NO₆Si (798.1): calcd. C 75.25, H

7.45, N 1.76; found C 75.22, H 7.49, N 1.75.

calcd. C 75.24, H 7.80, N 1.72; found C 75.41, H 7.55, N 1.69.

Benzyl [(2R,3S,4R,5R,6R)-1-Allyl-3,4,5-tris(benzyloxy)-6-{[(tert-

butyldiphenylsilyl)oxy]methyl}piperidin-2-yl]acetate (19d): Same

procedure as that used for the synthesis of 18d, starting from 15d

(69 mg, 0.06 mmol). Purification by flash chromatography (tolu-

ene/ethyl acetate, 95:5) afforded two diastereoisomeric compounds

19d (32 mg, 62% global yield for the three steps) in the ratio (6R)/

(6S) ϭ 7:1. Major Isomer (6R): [α]²_D⁰ϭ ϩ16.6 (c ϭ 1.2, CHCl₃).

2

¹H NMR: δ ϭ 1.06 [s, 9 H, (CH₃)₃C], 2.50 (dd, J_H,Hϭ 15.1,

Ethyl [(2R,3S,4R,5R,6R)-1-Benzyl-3,4,5-tris(benzyloxy)-6-{[(tert-

butyldiphenylsilyl)oxy]methyl}piperidin-2-yl]acetate (19b): Same

procedure as that used for the synthesis of 18b, starting from 15b

(63 mg, 0.06 mmol). Purification by flash chromatography (tolu-

³J_H,Hϭ 5.9 Hz, 1 H, CHCOOBn), 2.68 (dd, ²J_H,Hϭ 15.1, ³J_H,Hϭ

7.8 Hz, 1 H, CHCOOBn), 2.71Ϫ2.74 [m, 1 H, C(6)-H], 3.18 [dd,

3

²J_H,Hϭ 14.6, J_H,Hϭ 6.8 Hz, 1 H, CHCHϭCH₂], 3.45 [dd,

²J_H,Hϭ 14.6, ³J_H,Hϭ 5.2 Hz, 1 H, CHCHϭCH₂], 3.54 [t, ³J_H,Hϭ

3

ene) afforded two diastereoisomeric compounds 19b (28 mg, 57% 9.6 Hz, 1 H, C(5)-H], 3.69 [t, J_H,Hϭ 9.5 Hz, 1 H, C(4)-H], 3.74

global yield for the three steps) in the ratio (6R)/(6S) ϭ 7:3. Major

[dd, ³J_H,Hϭ 9.5, ³J_H,Hϭ 5.2 Hz, 1 H, C(3)-H], 3.89 (br. d, ²J_H,Hϭ

1

2

3

Isomer (6R): [α]²_D⁰ϭ ϩ16.3 (c ϭ 2.0, CHCl₃). H NMR: δ ϭ 0.80

11.4 Hz, 1 H, CHOTBDPS), 3.95 (dd, J_H,Hϭ 11.4, J_H,Hϭ

(t, 3 H, OCH₂CH₃), 0.85 [s, 9 H, (CH₃)₃C], 2.21 (dd, ²J_H,Hϭ 14.8,

³J_H,Hϭ 5.6 Hz, 1 H, CHCOOEt), 2.41 (dd, ²J_H,Hϭ 14.8, ³J_H,Hϭ

4.5 Hz, 1 H, CHOTBDPS), 3.95Ϫ4.00 [m, 1 H, C(2)-H], 4.47 (d,

2

²J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.55 (d, J_H,Hϭ 11.2 Hz, 1 H,

2

6.8 Hz, 1 H, CHCOOEt), 2.64Ϫ2.66 [m, 1 H, C(6)-H], 3.38 [t, CHPh), 4.64 (d, J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.72 (d, J_H,H

ϭ

³J_H,Hϭ 9.2 Hz, 1 H, C(5)-H], 3.41Ϫ3.54 [m, 3 H, C(3)-H, C(4)-H, 10.7 Hz, 1 H, CHPh), 4.85 (d, J_H,Hϭ 12.3 Hz, 1 H, CHPh), 4.86

2

CHPh], 3.56Ϫ3.64 (m, 2 H, OCH₂CH₃), 3.65Ϫ3.72 [m, 1 H, C(2)-

(d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.91 (d, J_H,Hϭ 10.7 Hz, 1 H,

2464

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

2

CHPh), 4.96 (d, J_H,Hϭ 12.3 Hz, 1 H, CHPh), 5.04Ϫ5.07 (m, 2

10.9 Hz, 1 H, CHPh), 4.97 (d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 5.17

3

H, CH₂CHϭCH₂), 5.65Ϫ5.75 (m, 1 H, CH₂CHϭCH₂), 7.00Ϫ7.40 [d, J_H,Hϭ 10.3 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.20 [d, J_H,H

ϭ

(m, 30 H, HAr) ppm. ¹³C NMR: δ ϭ 19.76 [(CH₃)₃C], 27.41 16.7 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.81 (ddt, J_H,Hϭ 16.8,

[(CH₃)₃C], 29.45 (CH₂COOBn), 51.28 (CH₂CHϭCH₂), 54.70,

³J_H,Hϭ 10.3, ³J_H,Hϭ 6.1 Hz, 1 H, CH₂CHϭCH₂), 7.30Ϫ7.34 (m,

60.43 [C(2), C(6)], 62.01, 66.55, 72.71, 75.10, 75.87 (CH₂OTBDPS, 15 H, CHAr) ppm. ¹³C NMR: δ ϭ 14.64 (OCH₂CH₃), 30.74

4 CH₂Ph), 78.44, 80.10, 83.94 [C(3), C(4), C(5)], 117.1 (CH₂CHϭ (CH₂CO₂Et), 51.16 (CH₂CHϭCH₂), 55.43, 59.65 [C(2), C(6)],

CH₂), 127.6Ϫ128.6, (CHAr), 129.9 (CH₂CHϭCH₂), 133.3, 133.4, 59.63, 60.88 (CH₂OH, OCH₂CH₃), 72.85, 75.56, 72.75 (3 CH₂Ph),

3

136.1, 138.5, 138.6, 138.9 (CqAr), 135.5Ϫ135.6 (CHAr), 172.6 (Cϭ

78.29, 79.25, 83.45 [C(3), C(4), C(5)], 117.6 (CH₂CHϭCH₂),

O) ppm. MS (MALDI-TOF): m/z ϭ 861 [M ϩ H]^ϩ. C₅₅H₆₁NO₆Si 127.8Ϫ128.7 (CHAr), 136.1 (CH₂CHϭCH₂), 138.3, 138.4, 138.8 (3

(860.2): calcd. C 76.80, H 7.15, N 1.63; found C 76.81, H 7.30, CqAr), 172.5 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 561 [M ϩ

N 1.88.

H]^ϩ, 583 [M ϩ Na]^ϩ, 599 [M ϩ K]^ϩ. C₃₄H₄₁NO₆(559.7): calcd. C

72.96, H 7.38, N 2.50; found C 72.99, H 7.36, N 2.49.

Ethyl [(2S,3S,4R,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetate (20): Compound 18a (140 mg,

Ethyl [(2R,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-1-butyl-6-(hydroxy-

0.18 mmol) was dissolved in THF (1 mL) and TBAF (0.35 mmol, methyl)piperidin-2-yl]acetate (22): The reaction was carried out as

2 equiv., 1  in THF, 350 µL) was added. The reaction mixture

was stirred at room temperature for 8 h and then more TBAF

(0.09 mmol, 0.5 equiv., 1  in THF, 90 µL) was added. After 4 h,

the reaction mixture was quenched with buffer phosphate (pH ϭ

described in the preparation of 20, starting from 19c (376 mg,

0.46 mmol) to afford 22 (228 mg, 86%) as a colorless oil. [α]²_D⁰

ϭ

1

3

ϩ7.6 (c ϭ 1.1, CHCl₃). H NMR: δ ϭ 0.93 [t, J_H,Hϭ 7.3 Hz, 1

3

H, N(CH₂)₃CH₃], 1.22 (t, J_H,Hϭ 7.2 Hz, 3 H, OCH₂CH₃),

7; 3 mL), the two layers were separated, the aqueous layer was ex- 1.40Ϫ1.48 (m,

4

H, CH₂CH₂CH₃), 2.44Ϫ2.52 [m,

1

H,

2

3

tracted with ethyl acetate (3 ϫ 3 mL), and the combined organic

layers were dried with Na₂SO₄. The solvent was evaporated under

reduced pressure and the residue was purified by flash chromatog-

NCH(CH₂)₂CH₃], 2.49 (dd, J_H,Hϭ 15.0, J_H,Hϭ 7.5 Hz, 1 H,

CHCO₂Et), 2.57 [dd, J_H,Hϭ 13.2, J_H,Hϭ 6.1 Hz, 1 H,

NCH(CH₂)₂CH₃], 2.66 (dd, J_H,Hϭ 15.0, J_H,Hϭ 5.9 Hz, 1 H,

2

3

2

3

raphy (petroleum ether/ethyl acetate, 8:2) yielding 20 (81 mg, 83%) CHCO₂Et), 2.74Ϫ2.80 [m, 1 H, C(6)-H], 3.55 [dd, J_H,Hϭ 9.8,

as a colorless oil. [α]²_D⁰ϭ Ϫ24.3 (c ϭ 0.9, CHCl₃). H NMR: δ ϭ

³J_H,Hϭ 8.3 Hz, 1 H, C(5)-H], 3.68Ϫ3.82 (m, 1 H, CHOH), 3.71

1

3

2

3

1.23 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 2.37 (dd, J_H,Hϭ 15.5, [dd, J_H,Hϭ 9.3, J_H,Hϭ 8.2 Hz, 1 H, C(4)-H], 3.75 [dd, J_H,H

ϭ

3

³J_H,Hϭ 7.4 Hz, 1 H, CHCO₂Et), 2.86Ϫ2.91 (m, 1 H, CHCO₂Et), 9.4, J_H,Hϭ 5.3 Hz, 1 H, C(3)-H], 3.82Ϫ3.85 [m, 2 H, C(2)-H,

2

3

2.97 (dd, J_H,Hϭ 13.8, J_H,Hϭ 8.2 Hz, 1 H, CHCHϭCH₂), 3.33 CHOH), 4.03Ϫ4.10 (m, 2 H, OCH₂CH₃), 4.62 (d, ²J_H,Hϭ 10.7 Hz,

3

2

[ddd, J_H,Hϭ 10.2, J_H,Hϭ 6.4, J_H,Hϭ 6.2 Hz, 1 H, C(6)-H],

1 H, CHPh), 4.66 (d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.69 (d,

2

3.38Ϫ3.40 [m, 2 H, C(2)-H, C(3)-H], 3.44 (dd, J_H,Hϭ 13.8, ²J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.81 (d, J_H,Hϭ 10.8 Hz, 1 H,

³J_H,Hϭ 4.2 Hz, 1 H, CHCHϭCH₂), 3.72Ϫ3.83 [m, 3 H, C(4)-H, CHPh), 4.92 (d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.96 (d, J_H,H

CH₂OH], 3.87 [dd, ³J_H,Hϭ 9.7, ³J_H,Hϭ 6.2 Hz, 1 H, C(5)-H], 4.11 10.8 Hz, 1 H, CHPh), 7.30Ϫ7.34 (m, 15 H, HAr) ppm. ¹³C NMR:

14.51, 14.62 [N(CH₂)₃CH₃, OCH₂CH₃], 20.86

H, CHPh), 4.63 (s, 2 H, CH₂Ph), 4.79 (d, J_H,Hϭ 10.5 Hz, 1 H, (CH₂CH₂CH₂CH₃), 30.54, 31.25 (CH₂CH₂CH₂CH₃, CH₂CO₂Et),

ϭ

2

3

2

(q, J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃), 4.55 (d, J_H,Hϭ 10.9 Hz, 1

δ

ϭ

2

CHPh), 4.91 (d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.92 (d, J_H,H

ϭ

47.65 (CH₂CH₂CH₂CH₃), 54.94, 60.02 [C(2), C(6)], 59.54, 60.92

(CH₂OH, OCH₂CH₃), 73.04, 75.64, 75.77 (3 CH₂Ph), 75.77, 78.53,

10.5 Hz, 1 H, CHPh), 5.02 [br. d, ³J_H,Hϭ 17.1 Hz, 1 H, CH₂CHϭ

CH₂(trans)], 5.05 [br. d, ³J_H,Hϭ 10.5 Hz, 1 H, CH₂CHϭCH₂(cis)], 79.43 [C(3), C(4), C(5)], 127.8Ϫ128.7 (CHAr), 138.3, 138.8, 138.8

5.51Ϫ5.61 (m, 1 H, CH₂CHϭCH₂), 7.25Ϫ7.34 (m, 15 H, HAr) (3 CqAr), 172.7 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 577 [M

ppm. ¹³C NMR: δ ϭ 14.66 (OCH₂CH₃), 34.60 (CH₂CO₂Et), 50.02 ϩ H]^ϩ, 599 [M ϩ Na]^ϩ. C₃₅H₄₅NO₆(575.7): calcd. C 73.02, H

(ϪCH₂CHϭCH₂), 53.49, 57.65 [C(2), C(6)], 56.94, 61.18

(OCH₂CH₃, CH₂OH), 73.25, 75.54, 76.16 (3 CH₂Ph), 77.47, 79.13,

84.98 [C(3), C(4), C(5)], 117.9 (CH₂CHϭCH₂), 127.9Ϫ128.7

(CHAr), 136.3 (CH₂CHϭCH₂), 138.0, 138.2, 138.7 (3 CqAr), 171.8

(CϭO) ppm. MS (MALDI-TOF): m/z ϭ 561 [M ϩ H]^ϩ, 583 [M

ϩ Na]^ϩ, 599 [M ϩ K]^ϩ. C₃₄H₄₁NO₆(559.7): calcd. C 72.96, H

7.38, N 2.50; found C 73.00, H 7.36, N 2.49.

7.88, N 2.43; found C 73.29, H 7.61, N 2.20.

Ethyl [(2S,3S,4R,5R,6S)-1-Allyl-6-(azidomethyl)-3,4,5-tris(benzyl-

oxy)piperidin-2-yl]acetate (23): Compound 20 (91 mg, 0.163 mmol)

was dissolved in dry CH₂Cl₂(1 mL) and pyridine (77 mg,

0.98 mmol, 6 equiv.) and MsCl (56 mg, 0.49 mmol, 3 equiv.) were

added. The mixture was stirred at room temperature for 6 h, then

H₂O (2 mL) was added. The two layers were separated, the aqueous

layer was extracted with CH₂Cl₂(3 ϫ 2 mL), and the combined

organic layers were dried with Na₂SO₄. The solvent was evaporated

Ethyl [(2R,3S,4R,5R,6R)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetate (21): Same procedure as that used for

the synthesis of 20, starting 19a (735 mg, 0.92 mmol). Purification under reduced pressure and then the crude product was dissolved

by flash chromatography (petroleum ether/ethyl acetate, 8:2) af-

in DMF (1.5 mL); NaN₃(16 mg, 0.25 mmol, 1.5 equiv.) was added

and the mixture was stirred at 80 °C for 4 h. H₂O (5 mL) was ad-

forded 21 (375 mg, 73%) as a colorless oil. [α]²_D⁰ϭ ϩ29.9 (c ϭ 1.2,

1

3

CHCl₃). H NMR: δ ϭ 1.23 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), ded, the mixture was extracted with ethyl acetate (4 ϫ 5 mL), and

2.53 (dd, ²J_H,Hϭ 15.0, ³J_H,Hϭ 7.1 Hz, 1 H, CHCO₂Et), 2.69 (dd,

the combined organic layers were dried with Na₂SO₄. The solvent

²J_H,Hϭ 15.0, ³J_H,Hϭ 6.1 Hz, 1 H, CHCO₂Et), 2.84 [ddd, ³J_H,Hϭ was evaporated under reduced pressure and the crude product was

9.5, ³J_H,Hϭ 4.7, ³J_H,Hϭ 4.4, 1 H, C(6)-H], 3.24 (dd, ²J_H,Hϭ 14.4,

purified by flash chromatography (petroleum ether/ethyl acetate,

³J_H,Hϭ 6.1 Hz, 1 H, CHCHϭCH₂), 3.31 (dd, J_H,Hϭ 14.4, 9:1) to afford 23 (45 mg, 47%) as a colorless oil. [α]²_D⁰ϭ ϩ3.0 (c ϭ

2

³J_H,Hϭ 6.3 Hz, 1 H, CHCHϭCH₂), 3.59 [dd, ³J_H,Hϭ 9.5, ³J_H,Hϭ 1.7, CHCl₃). ¹H NMR: δ ϭ 1.21 (t, J_H,Hϭ 7.1 Hz, 3 H,

3

2

3

8.3 Hz, 1 H, C(5)-H], 3.71Ϫ3.78 [m, 3 H, C(3)-H, C(4)-H, CHOH], OCH₂CH₃), 2.35 (dd, J_H,Hϭ 14.0, J_H,Hϭ 10.4 Hz, 1 H,

2

3

2

3

3.84 (dd, J_H,Hϭ 11.8, J_H,Hϭ 3.7 Hz, 1 H, CHOH), 3.95 [dd, CHCO₂Et), 2.75 (dd, J_H,Hϭ 14.0, J_H,Hϭ 5.2 Hz, 1 H,

3

2

3

³J_H,Hϭ 11.4, J_H,Hϭ 6.8 Hz, 1 H, C(2)-H], 4.02 (q, J_H,H

ϭ

CHCO₂Et), 3.11 (dd, J_H,Hϭ 14.2, J_H,Hϭ 4.5 Hz, 1 H, CHN₃),

2

3

7.1 Hz, 2 H, OCH₂CH₃), 4.61 (d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 3.21Ϫ3.31 (m, 3 H, CH₂CHϭCH₂, CHN₃), 3.47 [br. d, J_H,H

ϭ

4.64 (d, ²J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.69 (d, J_H,Hϭ 11.3 Hz, 1

10.0 Hz, 1 H, C(3)-H], 3.77 [dd, J_H,Hϭ 11.1, J_H,Hϭ 4.4 Hz, 1

2

3

H, CHPh), 4.81 (d, ²J_H,Hϭ 10.8 Hz, 1 H, CHPh), 4.93 (d, ²J_H,Hϭ H, C(6)-H], 3.93Ϫ4.16 [m, 5 H, C(2)-H, OCH₂CH₃, C(4)-H, C(5)-

Eur. J. Org. Chem. 2004, 2451Ϫ2470

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2465

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

FULL PAPER

H], 4.34 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 4.49 (d, J_H,H

2

ϭ

ppm. ¹³C NMR: δ ϭ 14.55, 14.60 [N(CH₂)₃CH₃, OCH₂CH₃],

2

12.6 Hz, 1 H, CHPh), 4.56 (d, J_H,Hϭ 11.7 Hz, 1 H, CHPh), 4.62

20.98,

29.44,

30.69

(CH₂CO₂Et,

CH₂CH₂CH₂CH₃,

2

(d, J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.71 (d, J_H,Hϭ 11.6 Hz, 2 H,

CH₂CH₂CH₂CH₃), 48.44, 49.32 (CH₂N₃, CH₂CH₂CH₂CH₃),

2 CHPh), 5.07 [d, J_H,Hϭ 10.0 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.13 54.83, 58.75 [C(2), C(6)], 60.89 (OCH₂CH₃), 72.93, 75.63, 75.72 (3

3

[d, J_H,Hϭ 17.2 Hz, 1 H, CH₂CHϭCH₂(trans)], 5.62Ϫ5.68 (m, 1 CH₂Ph), 78.96, 79.87, 83.63 [C(3), C(4), C(5)], 127.8Ϫ128.7

H, CH₂CHϭCH₂), 7.25Ϫ7.34 (m, 15 H, CHAr) ppm. ¹³C NMR: (CHAr), 138.3, 138.4, 138.8 (3 CqAr), 172.7 (CϭO) ppm. MS

δ

ϭ

14.73 (OCH₂CH₃), 30.15 (CH₂CO₂Et), 38.64, 50.15

(MALDI-TOF): m/z ϭ 602 [M ϩ H]^ϩ, 624 [M ϩ Na]^ϩ, 640 [M ϩ

(ϪCH₂CHϭCH₂, CH₂N₃), 55.34, 61.04 [C(2), C(6)], 60.47 K]^ϩ. C₃₅H₄₄N₄O₅(600.8): calcd. C 69.98, H 7.38, N 9.33; found C

(OCH₂CH₃), 72.55, 72.60, 73.10 (3 CH₂Ph), 78.37, 80.00, 85.18 70.12, H 7.45, N 9.59.

[C(3), C(4), C(5)], 116.7 (CH₂CHϭCH₂), 127.7Ϫ128.8 (CHAr),

[(2S,3S,4R,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxymethyl)-

137.16 (CH₂CHϭCH₂), 137.7, 137.9, 138.0 (3 CqAr), 172.3 (Cϭ

piperidin-2-yl]acetic Acid (26): Compound 20 (100 mg, 0.18 mmol)

O) ppm. MS (MALDI-TOF): m/z ϭ 586 [M ϩ H]^ϩ, 608 [M ϩ

was dissolved in a mixture of THF/CH₃OH/H₂O (1:1:1; 1.5 mL)

Na]^ϩ. C₃₄H₄₀N₄O₅(584.7): calcd. C 69.84, H 6.90, N 9.58; found

and then LiOH (42 mg, 0.27 mmol, 1.5 equiv.) was added. The mix-

C 70.01, H 6.95, N 9.39.

ture was stirred at room temperature for 3 h and then acidified with

HCl (5%). The two layers were separated; the aqueous layer was

extracted with ethyl acetate (3 ϫ 3 mL) and the combined organic

layers were dried with Na₂SO₄. The solvent was evaporated under

reduced pressure and the residue was purified by flash chromatog-

Ethyl [(2R,3S,4R,5R,6R)-1-Allyl-6-(azidomethyl)-3,4,5-tris(benzyl-

oxy)piperidin-2-yl]acetate (24): The reaction was carried out as de-

scribed for the preparation of 23, starting from 21 (94 mg,

0.17 mmol) to afford 24 (50 mg, 51%) as a colorless oil. [α]²_D⁰

Ϫ8.3 (c ϭ 0.9, CHCl₃). H NMR (400 MHz, CDCl₃, 25 °C): δ ϭ

ϭ

raphy (petroleum ether/ethyl acetate, 1:9) yielding 26 (90 mg, 94%)

as an amorphous solid. [α]²_D⁰ϭ Ϫ21.4 (c ϭ 1.1, CHCl₃). ¹H NMR

(CD₃COCD₃): δ ϭ 2.60Ϫ2.66 (m, 1 H, CHCO₂H), 2.80Ϫ2.83 (m,

1 H, CHCO₂H), 3.26Ϫ3.36 (m, 1 H, CHCHϭCH₂), 3.40Ϫ3.96 [m,

8 H, C(2)-H, C(3)-H, C(4)-H, C(5)-H, C(6)-H, CH₂OH, CHCHϭ

1

3

2

1.21 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 2.47 (dd, J_H,Hϭ 15.2,

³J_H,Hϭ 5.6 Hz, 1 H, CHCO₂Et), 2.63 (dd, J_H,Hϭ 15.3, J_H,H

ϭ

2

3

6.7 Hz, 1 H, CHCO₂Et), 2.88 [dt, J_H,Hϭ 9.3, J_H,Hϭ 3.0 Hz, 1

H, C(6)-H], 3.17 (dd, ²J_H,Hϭ 13.9, ³J_H,Hϭ 7.2 Hz, 1 H, CHCHϭ

CH₂), 3.45 (dd, ²J_H,Hϭ 13.9, ³J_H,Hϭ 5.6 Hz, 1 H, CHCHϭCH₂),

3.65 (dd, ³J_H,Hϭ 9.1, ³J_H,Hϭ 8.5 Hz, 1 H, CHN₃), 3.69Ϫ3.76 [m,

2 H, C(3)-H, C(4)-H], 3.79 [dd, ³J_H,Hϭ 12.5, ³J_H,Hϭ 2.8 Hz, 1 H,

2

CH₂], 4.64Ϫ4.69 (m, 3 H, 3 CHPh), 4.77 (d, J_H,Hϭ 11.0 Hz, 1

H, CHPh), 4.85 (d, ²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.89 (d, ²J_H,Hϭ

3

11.4 Hz, 1 H, CHPh), 5.07 [d, J_H,Hϭ 10.0 Hz, 1 H, CH₂CHϭ

3

CH₂(cis)], 5.17 [d, J_H,Hϭ 17.2 Hz, 1 H, CH₂CHϭCH₂(trans)],

3

C(5)-H], 3.95Ϫ3.98 (m, 1 H, CHN₃), 4.03 (q, J_H,Hϭ 7.1 Hz, 2 H,

5.66Ϫ5.79 (m, 1 H, CH₂CHϭCH₂), 7.20Ϫ7.42 (m, 15 H, CHAr)

ppm. ¹³C NMR (CD₃COCD₃): δ ϭ 32.19 (CH₂CO₂H), 50.15,

53.92, 56.88, 57.42 [C(2), C(6), CH₂CHϭCH₂, CH₂OH], 57.46,

72.60, 74.58 74.99, 77.33, 79.06 [C(3), C(4), C(5), 3 CH₂Ph], 117.2

(CH₂CHϭCH₂), 127.5Ϫ129.0 (CHAr), 136.9 (CH₂CHϭCH₂),

138.8, 138.98, 139.4 (3 CqAr), 173.2 (CϭO) ppm. MS (MALDI-

TOF): m/z ϭ 533 [M ϩ H]^ϩ. C₃₂H₃₇NO₆(531.6): calcd. C 72.29,

H 7.01, N 2.63; found C 72.31, H 7.04, N 2.61.

OCH₂CH₃), 4.08 [dd, J_H,Hϭ 11.7, ³J_H,Hϭ 5.0 Hz, 1 H, C(2)-H],

3

4.58 (d, ²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.68 (d, J_H,Hϭ 10.6 Hz, 1

2

H, CHPh), 4.71 (d, ²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.80 (d, ²J_H,Hϭ

2

10.8 Hz, 1 H, CHPh), 4.98 (d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.99

(d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 5.19 [d, J_H,Hϭ 10.0 Hz, 1 H,

CH₂CHϭCH₂(cis)], 5.22 [d, J_H,Hϭ 16.7 Hz, 1 H, CH₂CHϭ

2

3

CH₂(trans)], 5.88 (dddd, J_H,Hϭ 17.3, J_H,Hϭ 10.1, J_H,Hϭ 7.2,

³J_H,Hϭ 5.5 Hz, CH₂CHϭCH₂), 7.28Ϫ7.35 (m, 15 H, CHAr) ppm.

¹³C NMR: δ ϭ 14.59 (OCH₂CH₃), 29.24 (CH₂CO₂Et), 43.27

(ϪCH₂CHϭCH₂), 50.00 (CH₂N₃), 54.93, 59.07 [C(2), C(6)], 60.82

(OCH₂CH₃), 72.73, 75.74, 75.87 (3 CH₂Ph), 78.89, 80.20, 83.26

[C(3), C(4), C(5)], 118.1 (CH₂CHϭCH₂), 127.7Ϫ128.7 (CHAr),

135.5 (CH₂CHϭCH₂), 138.4, 138.9, 138.9 (3 CqAr), 172.5 (CϭO)

ppm. MS (MALDI-TOF): m/z ϭ 586 [M ϩ H]^ϩ, 608 [M ϩ Na]^ϩ,

624 [M ϩ K]^ϩ. C₃₄H₄₀N₄O₅(584.7): calcd. C 69.84, H 6.90, N

9.58; found C 69.98, H 6.99, N 9.38.

[(2R,3S,4R,5R,6R)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetic Acid (27): Same procedure as that used

for the synthesis of 26, starting from 21 (86 mg, 0.15 mmol). Purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 1:9)

afforded 27 (77 mg, 97%) as an amorphous solid. [α]²_D⁰ϭ Ϫ11.7

1

(c ϭ 0.2, CHCl₃). H NMR (400 MHz, CD₃COCD₃): δ ϭ 3.03 (t,

3

dd, J_H,Hϭ 16.8, J_H,Hϭ 9.3 Hz, 1 H, CHCO₂H), 3.33Ϫ3.36 (m,

1 H, CHCO₂H), 3.80Ϫ4.31 [m, 8 H, C(3)-H, C(4)-H, C(5)-H, C(6)-

H, CH₂OH, CH₂CHϭCH₂], 4.37Ϫ4.39 [m, 1 H, C(2)-H], 4.54 (d,

²J_H,Hϭ 11.2 Hz, 1 H, CHPh), 4.60Ϫ4.68 (m, 4 H, 4 CHPh), 4.70

Ethyl [(2R,3S,4R,5R,6R)-6-(Azidomethyl)-3,4,5-tris(benzyloxy)-1-

butylpiperidin-2-yl]acetate (25): The reaction was carried out as de-

scribed in the preparation of 23, starting from compound 22 (67 mg

2

3

(d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 5.29 [d, J_H,Hϭ 18.6 Hz, 1 H,

3

CH₂CHϭCH₂(trans)], 5.33 [d, J_H,Hϭ 10.3 Hz, 1 H, CH₂CHϭ

mg, 0.12 mmol) to afford 25 (54 mg, 77%) as a colorless oil. [α]²_D⁰

ϭ

CH₂(cis)], 6.02Ϫ6.12 (m, 1 H, CH₂CHϭCH₂), 7.21Ϫ7.32 (m, 15

H, CHAr) ppm. ¹³C NMR (100.57 MHz, CD₃COCD₃, 25 °C): δ ϭ

30.17 (CH₂CO₂OH), 50.21, 53.33, 54.03, 57.95 [C(2), C(6), -

CH₂CHϭCH₂, CH₂OH], 64.12, 72.53, 73.14 73.76, 74.52, 74.90

[C(3), C(4), C(5), 3 CH₂Ph], 124.3 (CH₂CHϭCH₂), 127.8Ϫ129.3

(CHAr), 137.9 (CH₂CHϭCH₂), 170.8 (CϭO) ppm. MS (MALDI-

TOF): m/z ϭ 533 [M ϩ H]^ϩ, 555 [M ϩ Na]^ϩ. C₃₂H₃₇NO₆(531.6):

calcd. C 72.29, H 7.01, N 2.63; found C 72.27, H 7.00, N 2.61.

1

3

Ϫ7.7 (c ϭ 1.2, CHCl₃). H NMR: δ ϭ 0.96 [t, J_H,Hϭ 7.3 Hz, 3

3

H, N(CH₂)₃CH₃], 1.22 (t, J_H,Hϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.32

3

(q, J_H,Hϭ 7.4 Hz, 2 H, CH₂CH₂CH₃), 1.40Ϫ1.60 (m, 2 H,

CH₂CH₂CH₃), 2.40Ϫ2.50 [m, 2 H, NCH(CH₂)₂CH₃, CHCO₂Et],

2.59Ϫ2.66 [m, 2 H, NCH(CH₂)₂CH₃, CHCO₂Et], 2.74 [ddd,

3

³J_H,Hϭ 9.8, J_H,Hϭ 4.5, J_H,Hϭ 2.9 Hz, 1 H, C(6)-H], 3.48 [dd,

³J_H,Hϭ 9.8, ³J_H,Hϭ 8.6 Hz, 1 H, C(5)-H], 3.54 (dd, ²J_H,Hϭ 13.4,

³J_H,Hϭ 4.8 Hz, 1 H, CHN₃), 3.64 (dd, J_H,Hϭ 13.5, J_H,H

ϭ

2

3

3.0 Hz, 1 H, CHN₃), 3.70 [dd, J_H,Hϭ 9.7, J_H,Hϭ 8.5 Hz, 1 H,

[(2R,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-1-butyl-6-(hydroxy-

C4)-H], 3.76 [dd, J_H,Hϭ 9.7, J_H,Hϭ 5.3 Hz, 1 H, C(3)-H], methyl)piperidin-2-yl]acetic Acid (28): Same procedure as that used

3

3.94Ϫ4.02 [m, 1 H, C(2)-H], 4.06 (q, J_H,Hϭ 7.1 Hz, OCH₂CH₃),

for the synthesis of 26, starting from 22 (19 mg, 0.033 mmol). Puri-

4.60 (d, ²J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.62 (d, J_H,Hϭ 11.2 Hz, 1 fication by flash chromatography (petroleum ether/ethyl acetate,

2

H, CHPh), 4.70 (d, ²J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.80 (d, ²J_H,Hϭ 1:9) afforded 22 (18 mg, 100%) as an amorphous solid. [α]²_D⁰

ϭ

2

10.8 Hz, 1 H, CHPh), 4.98 (d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.99

Ϫ12.5 (c ϭ 1.1, CHCl₃). ¹H NMR (CD₃COCD₃): δ ϭ 0.73 [t,

2

(d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 7.28Ϫ7.39 (m, 15 H, CHAr) ³J_H,H

ϭ 7.4 Hz, 3 H, N(CH₂)₃CH₃], 1.07Ϫ1.23 (m, 4 H,

2466  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org

Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

brine (5 mL) and dried with Na₂SO₄. The solvent was evaporated

2

3

CH₂CH₂CH₃), 2.81 (dd, J_H,Hϭ 17.3, J_H,Hϭ 5.3 Hz, 1 H,

CHCO₂H), 2.90Ϫ3.01 [m, 3 H, CHCO₂H, NCH₂(CH₂)₂CH₃], under reduced pressure and the residue was purified by flash chro-

3.53Ϫ4.00 [m, 7 H, C(2)-H, C(3)-H, C(4)-H, C(5)-H, C(6)-H, matography (petroleum ether/EtOAc 6:4) yielding 30 (35 mg, 78%)

2

CH₂OH], 4.55 (d, J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.56 (d, J_H,H

ϭ

as a colorless oil. [α]²_D⁰ϭ Ϫ14.5 (c ϭ 0.9, CHCl₃). ¹H NMR

2

3

11.2 Hz, 1 H, CHPh), 4.61 (d, J_H,Hϭ 11.5 Hz, 1 H, CHPh), 4.62

(d, J_H,Hϭ 11.3 Hz, 1 H, CHPh), 4.69 (d, J_H,Hϭ 11.3 Hz, 1 H,

(CD₃COCD₃) δ ϭ 0.93 [d, J_H,Hϭ 6.8 Hz, 3 H, (CH₃)₂C], 0.94 [d,

2

³J_H,Hϭ 6.8 Hz, 3 H, (CH₃)₂C], 2.09Ϫ2.14 [m, 1 H, CH(CH₃)₂],

2

3

CHPh), 4.72 (d, J_H,Hϭ 11.4 Hz, 1 H, CHPh), 7.14Ϫ7.24 (m, 15 2.64 (dd, J_H,Hϭ 16.1, J_H,Hϭ 10.3 Hz, 1 H, CHCONH), 2.82

H, CHAr) ppm. ¹³C NMR (CD₃COCD₃):

[N(CH₂)₃CH₃], 20.20 (CH₂CH₂CH₂CH₃),

δ

ϭ

13.63 (dd, J_H,Hϭ 16.4, J_H,Hϭ 3.6 Hz, 1 H, CHCONH), 3.23 (dd,

2

3

29.90 ²J_H,Hϭ 14.0, J_H,Hϭ 8.1 Hz, 1 H, CHCHϭCH₂), 3.31 (br. d,

3

(CH₂CH₂CH₂CH₃), 34.60, 48.84, 55.88, 56.92, 58.57 [CH₂CO₂H, ³J_H,Hϭ 8.8 Hz, 1 H, CHOH), 3.36Ϫ3.42 [m, 1 H, C(6)-H],

C(2), C(6), NCH₂(CH₂)₂CH₃, CH₂OH], 64.01, 72.95, 74.12 75.97, 3.47Ϫ3.54 [m, 2 H, C(2)-H, C(3)-H], 3.62Ϫ3.65 (m, 1 H, CHCHϭ

77.76, 79.37 [C(3), C(4), C(5), 3 CH₂Ph], 126.6Ϫ129.0 (CHAr),

CH₂), 3.67 (s, 3 H, OCH₃), 3.73Ϫ3.79 [m, 1 H, C(4)-H], 3.94 [dd,

3

138.4, 138.5, 138.8 (3 CqAr), 172.5 (CϭO) ppm. MS (MALDI- ³J_H,Hϭ 9.5, J_H,Hϭ 6.0 Hz, 1 H, C(5)-H], 4.40 (dd, J_H,Hϭ 8.2,

TOF): m/z ϭ 549 [M ϩ H]^ϩ, 571 [M ϩ Na]^ϩ. C₃₃H₄₁NO₆(547.7): ³J_H,Hϭ 5.7 Hz, 1 H, NHCHCO₂CH₃), 4.63 (d, J_H,Hϭ 10.9 Hz,

calcd. C 72.37, H 7.55, N 2.56; found C 72.33, H 7.56, N 2.55.

2

1 H, CHPh), 4.69 (d, J_H,Hϭ 11.7 Hz, 2 H, 2 CHPh), 4.79 (d,

2

²J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.87 (d, J_H,Hϭ 11.0 Hz, 1 H,

2

3

{2-[(2S,3S,4R,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetyl}glycine tert-Butyl Ester (29): Com-

pound 26 (80 mg 0.15 mmol) was dissolved in DMF (2 mL) and

then H-Gly-OtBu·AcOH (86 mg, 0.45 mmol, 3 equiv.), HBTU

(171 mg, 0.45 mmol, 3 equiv.), HOBt (57 mg, 0.42 mmol, 2.8

equiv.), and DIPEA (96 mg, 0.75 mmol, 5 equiv.) were added. The

mixture was stirred at room temperature for 3 h and then water

(3 mL) was added. The aqueous layer was extracted with ethyl acet-

ate (3 ϫ 5 mL) and the combined organic layers were back-ex-

tracted with brine and dried with Na₂SO₄. The solvent was evapo-

rated under reduced pressure and the residue was purified by flash

chromatography (petroleum ether/ethyl acetate, 6:4) yielding 29

(71 mg, 73%) as a colorless oil. [α]²_D⁰ϭ Ϫ12.8 (c ϭ 1.6, CHCl₃). ¹H

NMR (CD₃COCD₃): δ ϭ 1.44 [s, 9 H, (CH₃)₃C], 2.58 (dd, ²J_H,Hϭ

CHPh), 4.93 (d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 5.07 [d, J_H,H

ϭ

3

10.1 Hz, CH₂CHϭCH₂(cis)], 5.19 [d, J_H,Hϭ 16.4 Hz, 1 H,

CH₂CHϭCH₂(trans)], 5.71Ϫ5.81 (m, H, CH₂CHϭCH₂),

1

3

7.29Ϫ7.36 (m, 15 H, CHAr), 7.86 (d, J_H,Hϭ 8.1 Hz, 1 H, NH)

ppm. ¹³C NMR (CD₃COCD₃): δ ϭ 23.35, 24.24 [(CH₃)₂C], 36.23

[CH(CH₃)₂], 39.49 (CH₂CONH), 54.93, 62.18 (CH₂OH,

-

CH₂CHϭCH₂), 56.72, 58.89, 62.77, 63.05 [C(2), C(6), OCH₃,

NHCHCO], 77.72, 80.02, 80.39 (3 CH₂Ph), 82.76, 84.69, 89.85

[C(3), C(4), C(5)], 122.0 (CH₂CHϭCH₂), 132.6Ϫ133.6 (CHAr),

142.6 (CH₂CHϭCH₂), 144.1, 144.2, 144.7 (3 CqAr), 176.2, 177.4

(2 CϭO) ppm. MS (MALDI-TOF): m/z ϭ 646 [M ϩ H]^ϩ, 668 [M

ϩ Na]^ϩ. C₃₈H₄₈N₂O₇(644.8): calcd. C 70.78, H 7.50, N 4.34; found

C 70.71, H 7.65, N 4.30.

3

2

{2-[(2S,3S,4S,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetyl}phenylalanine tert-Butyl Ester (31):

Compound 26 (32 mg 0.06 mmol) was dissolved in DMF (500 µL)

and then -Phe-OtBu·HCl (93 mg, 0.361 mmol, 6 equiv.), HBTU

(137 mg, 0.361 mmol, 6 equiv.), HOBt (45 mg, 0.336 mmol, 5.8

equiv.), and DIPEA (78 mg, 0.60 mmol, 10 equiv.) were added. The

mixture was stirred at room temperature for 3 h and then water

(3 mL) was added. The aqueous layer was extracted with ethyl acet-

ate (3 ϫ 5 mL) and the combined organic layers were back-ex-

tracted with brine (5 mL) and dried with Na₂SO₄. The solvent was

evaporated under reduced pressure and the residue was purified by

flash chromatography (petroleum ether/ethyl acetate, 6:4) to yield

31 (31 mg, 70%) as a colorless oil. [α]²_D⁰ϭ ϩ12.4 (c ϭ 0.7, CHCl₃).

¹H NMR (CD₃COCD₃): δ ϭ 1.36 [s, 9 H, (CH₃)₃C], 2.56 (dd,

²J_H,Hϭ 16.3, ³J_H,Hϭ 10.3 Hz, 1 H, CHCONH), 2.77 (dd, ²J_H,Hϭ

15.9, J_H,Hϭ 10.3 Hz, 1 H, CHCONH), 2.79 (dd, J_H,Hϭ 16.1,

³J_H,Hϭ 3.7 Hz, 1 H, CHCONH), 3.18 (dd, J_H,Hϭ 14.2, J_H,H

ϭ

2

3

8.2 Hz, 1 H, CHCHϭCH₂), 3.32 (dd, ²J_H,Hϭ 9.6, ³J_H,Hϭ 2.1 Hz,

1 H, CHOH), 3.39 [m, 1 H, C(6)-H], 3.45Ϫ3.52 [m, 2 H, C(2)-H,

3

C(3)-H], 3.61 (dd, J_H,Hϭ 14.2, J_H,Hϭ 4.4, 1 H, CHCHϭCH₂),

3.68Ϫ3.79 [m, H, C(4)-H, CHOH], 3.80Ϫ3.84 [m, H,

NHCH₂CO₂tBu], 3.94 [dd, ³J_H,Hϭ 9.5, ³J_H,Hϭ 6.1 Hz, 1 H, C(5)-

H], 4.64 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.65 (d, J_H,H

11.6 Hz, 1 H, CHPh), 4.69 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.79

(d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.79 (d, J_H,Hϭ 11.1 Hz, 1 H,

CHPh), 4.88 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.92 (d, J_H,H

11.1 Hz, 1 H, CHPh), 5.04 [d, J_H,Hϭ 9.9 Hz, 1 H, CH₂CHϭ

CH₂(cis)], 5.16 [dd, J_H,Hϭ 17.1, J_H,Hϭ 0.7 Hz, 1 H, CH₂CHϭ

2

ϭ

2

ϭ

3

4

3

CH₂(trans)], 5.78 (ddt, J_H,Hϭ 18.1, J_H,Hϭ 10.0, J_H,Hϭ 8.1,

³J_H,Hϭ 4.4 Hz, 1 H, CH₂CHϭCH₂), 7.24Ϫ7.40 (m, 15 H, CHAr),

3

7.86 (t, J_H,Hϭ 5.6 Hz, 1 H, NH) ppm. ¹³C NMR (CD₃COCD₃):

3

16.5, J_H,Hϭ 3.7 Hz, 1 H, CHCONH), 2.98Ϫ3.04 (m, 2 H,

2

3

CH₂Ph), 3.15 (dd, J_H,Hϭ 14.3, J_H,Hϭ 8.2 Hz, 1 H, CHCHϭ

CH₂), 3.35Ϫ3.50 [m, 3 H, C(2)-H, C(3)-H, C(6)-H], 3.52Ϫ3.57 (m,

1 H, CHCHϭCH₂), 3.72Ϫ3.77 [m, 2 H, C(4)-H, CHOH], 3.86 (br.

δ ϭ 32.93 [(CH₃)₃C], 39.52 [(CH₃)₃C], 47.10 (CH₂CONH), 54.93,

61.91 (NHCH₂COtBu, CH₂CHϭCH₂), 58.74, 62.93 [C(2), C(6)],

77.72, 79.96, 80.41, 86.11 (CH₂OH, 3 CH₂Ph), 82.82, 84.70, 89.98

[C(3), C(4), C(5)], 121.6 (CH₂CHϭCH₂), 132.6Ϫ133.6 (CHAr),

143.0 (CH₂CHϭCH₂), 144.4, 144.5, 144.7 (3 CqAr), 174.4, 176.3

(2 CϭO) ppm. MS (MALDI-TOF): m/z ϭ 646 [M ϩ H]^ϩ, 668 [M

ϩ Na]^ϩ. C₃₈H₄₈N₂O₇(644.8): calcd. C 70.78, H 7.50, N 4.34; found

C 70.66, H 7.36, N 4.49.

3

t, J_H,Hϭ 10.5 Hz, 1 H, CHOH), 3.92 [dd, J_H,Hϭ 9.5, J_H,H

ϭ

6.0 Hz, 1 H, C(5)-H], 4.58Ϫ4.62 (m, 1 H, NHCHCO₂tBu), 4.62 (d,

2

²J_H,Hϭ 11.0, 1 H, CHPh), 4.65 (d, J_H,Hϭ 11.6 Hz, 1 H, CHPh),

4.69 (d, ²J_H,Hϭ 11.6 Hz, 1 H, CHPh), 4.78 (d, ²J_H,Hϭ 11.1 Hz, 1

H, CHPh), 4.86 (d, ²J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.92 (d, ²J_H,Hϭ

3

11.1 Hz, 1 H, CHPh), 5.00 [d, J_H,Hϭ 10.1 Hz, 1 H, CH₂CHϭ

3

{2-[(2S,3S,4S,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetyl}valine Methyl Ester (30): Compound 26

(37 mg 0.07 mmol) was dissolved in DMF (700 µL) and then -

Val-OMe·HCl (70 mg, 0.42 mmol, 6 equiv.), HBTU (159 mg,

CH₂(cis)], 5.14 [d, J_H,Hϭ 17.2 Hz, 1 H, CH₂CHϭCH₂(trans)],

5.60Ϫ5.70 (m, 1 H, CH₂CHϭCH₂), 7.28Ϫ7.33 (m, 15 H, HAr),

3

7.90 (d, J_H,Hϭ 7.5 Hz, 1 H, NH) ppm. ¹³C NMR (CD₃COCD₃):

δ

ϭ 32.80 [(CH₃)₃C], 39.38 [(CH₃)₃C], 43.30, 55.00, 62.10

0.42 mmol, 6 equiv.), HOBt (53 mg, 0.392 mmol, 5.6 equiv.), and (CH₂CHϭCH₂, CH₂Ph, CH₂CONH), 58.74, 59.77, 63.06 [C(2),

DIPEA (90 mg, 0.70 mmol, 10 equiv.) were added. The mixture

was stirred at room temperature for 3 h and then water (3 mL) was

added. The aqueous layer was extracted with ethyl acetate (3 ϫ

5 mL) and the combined organic layers were back-extracted with

C(6), NHCHCO₂tBu], 77.72, 79.97, 80.35, 86.34 (CH₂OH, 3

CH₂Ph), 82.83, 84.74, 89.77 [C(3), C(4), C(5)], 121.7 (CH₂CHϭ

CH₂), 131.9Ϫ134.6 (CHAr), 142.7 (CqAr), 142.8 (CH₂CHϭCH₂),

144.1, 144.2, 144.7 (3 CqAr), 175.8, 176.2 (2 CϭO) ppm. MS:

Eur. J. Org. Chem. 2004, 2451Ϫ2470

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2467

B. La Ferla, P. Bugada, L. Cipolla, F. Peri, F. Nicotra

m/z ϭ 736 [M ϩ H]^ϩ, 758 [M ϩ Na]^ϩ, 774 [M ϩ K]^ϩ. C₄₅H₅₄N₂O₇39.15 [(CH₃)₃C], 41.85 (CH₂CONH), 51.47, 59.14 (NHCH₂COtBu,

FULL PAPER

(734.9): calcd. C 73.54, H 7.41, N 3.81; found C 73.22, H 7.48,

N 3.93.

CH₂CHϭCH₂), 54.28, 59.81 [C(2), C(6)], 72.08, 74.57, 74.86, 80.76

(CH₂OH, 3 CH₂Ph), 78.05, 78.75, 80.95 [C(3), C(4), C(5)], 117.0

(CH₂CHϭCH₂), 124.4Ϫ128.9 (CHAr), 138.9 (CH₂CHϭCH₂),

138.9, 139.2, 139.4 (3 CqAr), 169.1, 171.6 (2 CϭO) ppm. MS

(MALDI-TOF): m/z

C₃₈H₄₈N₂O₇(644.8): calcd. C 70.78, H 7.50, N 4.34; found C 70.62,

H 7.39, N 4.51.

{2-[(2S,3S,4R,5R,6S)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy-

methyl)piperidin-2-yl]acetyl}alanine tert-Butyl Ester (32): Com-

pound 26 (52 mg 0.098 mmol) was dissolved in DMF (700 µL) and

then -Ala-OtBu·HCl (107 mg, 0.587 mmol, 6 equiv.), HBTU

(223 mg, 0.587 mmol, 6 equiv.), HOBt (74 mg, 5.6 mmol, 5.6

equiv.), and DIPEA (127 mg, 0.980 mmol, 10 equiv.) were added.

The mixture was stirred at room temperature for 3 h and then water

(3 mL) was added. The aqueous layer was extracted with ethyl acet-

ate (3 ϫ 5 mL) and the combined organic layers were back-ex-

tracted with brine (5 mL) and dried with Na₂SO₄. The solvent was

evaporated under reduced pressure and the residue was purified by

flash chromatography (petroleum ether/ethyl acetate, 6:4) to yield

32 (32 mg, 50%) as a colorless oil. [α]²_D⁰ϭ Ϫ10.6 (c ϭ 0.4, CHCl₃).

ϭ 646 [M ϩ ϩ

H]^ϩ, 668 [M Na]^ϩ.

Ethyl [(2S,3S,4R,5R,6S)-3,4,5-Trihydroxy-6-(hydroxymethyl)-1-pro-

pylpiperidin-2-yl]acetate (34): Compound 20 (15 mg, 0.027 mmol)

was dissolved in CH₃OH (1 mL); a suspension of Raney nickel

(0.1 mg/ mL) (5 mL) was added and the reaction mixture was

stirred under H₂for 3 h. The catalyst was filtered through a pad of

Celite (eluting with CH₃OH) and then the solvent was evaporated

under reduced pressure to afford pure compound 34 (8 mg, quant.

yield) as an amorphous solid. [α]²_D⁰ϭ Ϫ35.5 (c ϭ 0.8, H₂O). ¹H

NMR (D₂O): δ ϭ 0.67 (br. t, 3 H, NCH₂CH₂CH₃), 1.10 (t, ³J_H,Hϭ

7.0 Hz, 3 H, OCH₂CH₃), 1.15Ϫ1.32 (m, 2 H, NCH₂CH₂CH₃), 2.35

3

¹H NMR: δ ϭ 1.35 (d, J_H,Hϭ 7.0 Hz, 3 H, CHCH₃), 1.47 [s, 9

2

H, (CH₃)₃C], 2.31Ϫ2.37 (m, 1 H, CHCONH), 2.89 (dd, J_H,H

ϭ

2

3

(ddd, J_H,H

NCHCH₂CH₃), 2.43Ϫ2.54 (m, 2 H, NCHCH₂CH₃, CHCOOEt),

ϭ 14.1, J_H,Hϭ 8.8, J_H,Hϭ 5.3 Hz, 1 H,

3

2

15.7, J_H,Hϭ 2.3 Hz, 1 H, CHCONH), 3.03 (dd, J_H,Hϭ 13.7,

³J_H,Hϭ 8.6 Hz, 1 H, CHCHϭCH₂), 3.37Ϫ3.39; 3.45Ϫ3.48;

3.68Ϫ3.92 [3m, 8 H, C(2)-H, C(3)-H, C(4)-H, C(5)-H, C(6)-H,

CH₂OH, CHCHϭCH₂], 4.43Ϫ4.47 (m, 1 H, NHCHCO₂tBu), 4.55

2

3

2.70 (dd, J_H,Hϭ 16.2, J_H,Hϭ 5.1 Hz, 1 H, CHCOOEt), 2.98

3

[ddd, J_H,Hϭ 10.5, J_H,Hϭ 5.3, J_H,Hϭ 1.6 Hz, 1 H, C(2)-H],

3.09Ϫ3.14 [m, 1 H, C(6)-H], 3.20 [dd, ³J_H,Hϭ 10.5, ³J_H,Hϭ 9.1 Hz,

2

(d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.63 (s, 2 H, CH₂Ph), 4.78 (d,

3

1 H, C(3)-H], 3.30 [br. t, J_H,Hϭ 9.9 Hz, 1 H, C(4)-H], 3.61 (d,

²J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.88 (d, J_H,Hϭ 11.1 Hz, 1 H,

2

³J_H,Hϭ 7.2 Hz, 2 H, CH₂OH), 3.75 [dd, J_H,Hϭ 9.9, J_H,H

ϭ

3

2

3

CHPh), 4.91 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 5.03 [d, J_H,H

ϭ

3.8 Hz, 1 H, C(5)-H], 3.97Ϫ4.08 (m, 2 H, OCH₂CH₃) ppm. ¹³C

NMR (D₂O): δ ϭ 11.03, 13.64 (NCH₂CH₂CH₃, OCH₂CH₃), 22.15

(NCH₂CH₂CH₃), 35.15 (CH₂COOEt), 48.88, 55.20, 55.97, 60.40,

62.28, 69.19, 71.96, 75.32 [C(2), C(3), C(4), C(5), C(6), CH₂OH,

OCH₂CH₃, NCH₂CH₂CH₃], 174.9 (CϭO) ppm. MS (MALDI-

TOF): m/z ϭ 292 [M ϩ H]^ϩ, 314 [M ϩ Na]^ϩ, 330 [M ϩ K]^ϩ.

C₁₃H₂₅NO₆(291.3): calcd. C 53.59, H 8.65, N 4.81; found C 53.80,

H 8.00, N 4.99.

3

18.4 Hz, 1 H, CH₂CHϭCH₂(cis)], 5.07 [d, J_H,Hϭ 11.3 Hz, 1 H,

CH₂CHϭCH₂(trans)], 5.63Ϫ5.73 (m, H, CH₂CHϭCH₂),

1

7.28Ϫ7.35 (m, 15 H, HAr) 7.64 (d, ³J_H,Hϭ 6.6 Hz, 1 H, NH) ppm.

¹³C NMR: δ ϭ 19.25 (CHCH₃), 28.35 [(CH₃)₃C], 34.60 [(CH₃)₃C],

49.06, 53.68, 58.07 [C(2), C(6), NHCHCO], 49.83, 57.76

(ϪCH₂CHϭCH₂, CH₂OH), 73.18, 75.61, 75.97 (3 CH₂Ph), 76.85,

79.28, 84.44 [C(3), C(4), C(5)], 118.3 (CH₂CHϭCH₂), 127.9Ϫ129.2

(CHAr), 136.1 (CH₂CHϭCH₂), 137.9, 137.9, 138.6 (3 CqAr),

170.2, 173.1 (2 CϭO) ppm. MS: m/z ϭ 660 [M ϩ H]^ϩ, 682 [M ϩ

Na]^ϩ, 698 [M ϩ K]^ϩ. C₃₉H₅₀N₂O₇(658.8): calcd. C 71.10, H 7.65,

N 4.25; found C 71.36, H 7.44, N 4.20.

Ethyl [(2R,3S,4R,5R,6R)-N-Butyl-3,4,5-trihydroxy-6-(hydroxymeth-

yl)piperidin-2-yl)acetate (35): Compound 22 (20 mg, 0.035 mmol)

was dissolved in CH₃OH (5 mL); a catalytic amount of Pd(OH)₂

and acetic acid (1 mL) were added and then the reaction mixture

{2-[(2R,3S,4R,5R,6R)-1-Allyl-3,4,5-tris(benzyloxy)-6-(hydroxy- was stirred under H₂overnight. The catalyst was filtered through

methyl)piperidin-2-yl]acetyl}glycine tert-Butyl Ester (33): Com- a pad of Celite (eluting with CH₃OH) and then the solvent was

pound 27 (49 mg 0.09 mmol) was dissolved in DMF (1 mL) and evaporated under reduced pressure to afford pure compound 35

then H-Gly-OtBu·AcOH (536 mg, 0.28 mmol, 3 equiv.), HBTU

(6 mg, 60% yield) as an amorphous solid. ¹H NMR (D₂O): δ ϭ

(105 mg, 0.28 mmol, 3 equiv.), HOBt (35 mg, 0.26 mmol, 2.8 0.75 [t, ³J_H,Hϭ 7.0 Hz, 3 H, N(CH₂)₃CH₃], 1.10 (t, ³J_H,Hϭ 6.9 Hz,

equiv.), and DIPEA (79 µL, 0.46 mmol, 5 equiv.) were added. The

3

H, OCH₂CH₃), 1.08Ϫ1.22 [m,

2 H, N(CH₂)₂CH₂CH₃],

mixture was stirred at room temperature for 3 h and then water

1.22Ϫ1.52 (m, 2 H, NCH₂CH₂CH₂CH₃), 2.40Ϫ2.58 [m, 4 H, C(6)-

(2 mL) was added. The aqueous layer was extracted with ethyl acet- H, NCH₂(CH₂)₂CH₃, CH₂COOEt], 2.78Ϫ2.85 [m,

1

H,

3

ate (3 ϫ 5 mL) and the combined organic layers were back-ex-

tracted with brine and dried with Na₂SO₄. The solvent was evapo-

rated under reduced pressure and the residue was purified by flash

chromatography (petroleum ether/ethyl acetate, 6:4) to yield 33

NCH₂(CH₂)₂CH₃]], 3.30 [br. t, J_H,Hϭ 9.6 Hz, 1 H, C(5)-H], 3.39

[t, J_H,Hϭ 9.6 Hz, 1 H, C(4)-H], 3.62 (dd, J_H,Hϭ 9.6, J_H,H

5.9 Hz, 1 H, C(3)-H], 3.70Ϫ3.80 [m, 3 H, C(2)-H, CH₂OH], 4.01

(q, ³J_H,Hϭ 6.9 Hz, 2 H, OCH₂CH₃) ppm. ¹³C NMR (100.57 MHz,

D₂O, 25 °C): δ ϭ 13.53, 13.57 [N(CH₂)₃CH₃, OCH₂CH₃], 20.51

[N(CH₂)₂CH₂CH₃], 28.31 (NCH₂CH₂CH₂CH₃), 50.34, 56.99,

3

ϭ

1

(33 mg, 56%) as a colorless oil. [α]²_D⁰ϭ ϩ5.2 (c ϭ 1.0, CHCl₃). H

NMR (CD₃COCD₃): δ ϭ 1.44 [s, 9 H, (CH₃)₃C], 2.64Ϫ2.66 (m, 2

H, CH₂CONH), 3.53Ϫ3.54 (m, 2 H, CH₂CHϭCH₂), 3.62 [dd, 57.27, 57.67, 59.85, 62.49, 68.82, 74.64, 81.34 [C(2), C(3), C(4),

³J_H,Hϭ 9.2, ³J_H,Hϭ 8.3 Hz, 1 H, C(5)-H], 3.72 (dd, ²J_H,Hϭ 17.7, C(5), C(6), CH₂OH, OCH₂CH₃, NCH₂(CH₂)₂CH₃, CH₂COOEt],

³J_H,Hϭ 5.5 Hz, 1 H, NHCHCO₂tBu), 3.77Ϫ3.92 [m, 5 H, C(3)-H,

178.7 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 306 [M ϩ H]^ϩ, 328

2

C(4)-H, CH₂OH, NHCHCO₂tBu], 4.60 (d, J_H,Hϭ 11.5 Hz, 1 H, [M ϩ Na]^ϩ. Selected data for the lactonized form 41: ¹H NMR

2

CHPh), 4.66 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.73 (d, J_H,H

ϭ

(D₂O): δ ϭ 0.75 [t, ³J_H,Hϭ 7.0 Hz, 3 H, N(CH₂)₃CH₃], 1.10Ϫ1.30

[m, 2 H, N(CH₂)₂CH₂CH₃], 1.30Ϫ1.60 (m, 2 H, NCH₂CH₂CH₂-

CH₃), 2.38Ϫ2.54 [m, 3 H, C(6)-H, NCH(CH₂)₂CH₃, CHCOOEt],

2

11.5 Hz, 1 H, CHPh), 4.77 (d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.88

2

(d, J_H,Hϭ 11.1 Hz, 1 H, CHPh), 4.93 (d, J_H,Hϭ 11.1 Hz, 1 H,

CHPh), 5.00 [dd, J_H,Hϭ 10.3, J_H,Hϭ 1.8 Hz, 1 H, CH₂CHϭ 2.68Ϫ2.78 [m, 2 H, NCH(CH₂)₂CH₃, CHCOOEt], 3.35 [t, ³J_H,Hϭ

3

4

3

4

3

CH₂(cis)], 5.22 [dd, J_H,Hϭ 17.2, J_H,Hϭ 1.9 Hz, 1 H, CH₂CHϭ

9.4 Hz, 1 H, C(5)-H], 3.52 [br. t, J_H,Hϭ 9.2 Hz, 1 H, C(4)-H],

CH₂(trans)], 5.88 (ddt, ³J_H,Hϭ 17.1, ³J_H,Hϭ 10.3, ³J_H,Hϭ 6.2 Hz, 3.75Ϫ3.80 (m, 2 H, CH₂OH), 4.00Ϫ4.08 [m, 1 H, C(2)-H], 4.34

1 H, CH₂CHϭCH₂), 7.26Ϫ7.38 (m, 15 H, CHAr), 7.71Ϫ7.77 (m, [dd, ³J_H,Hϭ 8.9, ³J_H,Hϭ 8.1 Hz, 1 H, C(3)-H] ppm. MS (MALDI-

1 H, NH) ppm. ¹³C NMR (CD₃COCD₃): δ ϭ 31.66 [(CH₃)₃C], TOF): m/z ϭ 282 [M ϩ Na]^ϩ.

2468

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2451Ϫ2470

Generation of Glycosidase Inhibitor Libraries

FULL PAPER

Ethyl [(2S,3S,4R,5R,6S)-3,4,5-Tris(benzyloxy)-6-(hydroxymethyl)- 3.75Ϫ3.88 (m, 1 H, CHOH), 3.97Ϫ4.60 (m, 2 H, OCH₂CH₃) ppm.

piperidin-2-yl]acetate (36): Compound 20 (79 mg, 0.14 mmol) was

¹³C NMR (D₂O): δ ϭ 13.57, 13.59 (OCH₂CH₃), 35.47, 36.81

dissolved in degassed CH₂Cl₂(700 µL). Dimethylbarbituric acid (CH₂COOEt), 50.62, 55.71, 56.27, 57.16, 57.43, 62.32, 66.55, 69.56,

(77 mg, 0.49 mmol, 3.5 equiv.) and Pd(PPh₃)₄(3.2 mg, 2.8 µmol,

0.02 equiv.) were added and the mixture was stirred for 2 h at 35

°C. The solution was neutralized with NaHCO₃(satd. solution)

and the two layers were separated. The aqueous layer was extracted

with CH₂Cl₂(3 ϫ 3 mL) and the combined organic layers were

dried with Na₂SO₄. The solvent was evaporated under reduced

pressure and the residue purified by flash chromatography (petro-

leum ether/ethyl acetate, 1:1) to yield 36 (72 mg, 99%) as a colorless

oil. [α]²_D⁰ϭ Ϫ29.5 (c ϭ 0.3, CHCl₃). ¹H NMR: δ ϭ 1.15 (t, ³J_H,Hϭ

71.02, 72.47, 73.88, 74.18, 74.29 [C(2), C(3), C(4), C(5), C(6),

CH₂OH, OCH₂CH₃], 173.7, 174.3 (CϭO) ppm. MS (MALDI-

TOF): m/z ϭ 250 [M ϩ H]^ϩ, 272 [M ϩ Na]^ϩ. C₁₀H₁₉NO₆(249.3):

calcd. C 48.19, H 7.68, N 5.62; found C 47.95, H 7.81, N 5.39.

Ethyl [(2R,3S,4R,5R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)piper-

idin-2-yl]acetate (39): Compound 37 (36 mg, 0.069 mmol) was dis-

solved in CH₃OH (5 mL); a catalytic amount of Pd(OH)₂and

acetic acid (1 mL) were added and the reaction mixture was stirred

under H₂overnight. The catalyst was filtered through a Celite pad

(eluent CH₃OH) and then the solvent was evaporated under re-

duced pressure to afford pure compound 39 (17 mg, 98% yield) as

an amorphous solid. [α]²_D⁰ϭ 0.0 (c ϭ 0.8, H₂O). Major conformer:

2

3

7.1 Hz, 1 H, OCH₂CH₃), 2.23 (dd, J_H,Hϭ 16.4, J_H,Hϭ 8.7 Hz,

2

3

1 H, CHCO₂Et), 2.71 (dd, J_H,Hϭ 16.3, J_H,Hϭ 3.2 Hz, 1 H,

3

CHCO₂Et), 3.01 [ddd, J_H,Hϭ 9.3, J_H,Hϭ 9.0, J_H,Hϭ 3.2 Hz,

1 H, C(2)-H], 3.12 [br. t, J_H,Hϭ 9.0 Hz, 1 H, C(3)-H], 3.22Ϫ3.30

3

¹H NMR (D₂O): δ ϭ 1.10 (t, J_H,Hϭ 7.0 Hz, 3 H, OCH₂CH₃),

3

[m, 1 H, C(6)-H], 3.62 [t, J_H,Hϭ 9.3 Hz, 1 H, C(4)-H], 3.68 [dd,

2.57 (dd, ²J_H,Hϭ 17.4, ³J_H,Hϭ 8.2 Hz, 1 H, CHCOOEt), 2.91 (dd,

²J_H,Hϭ 17.4, ³J_H,Hϭ 3.7 Hz, 1 H, CHCOOEt), 3.29 [br. t, ³J_H,Hϭ

9.2 Hz, 1 H, C(3)-H], 3.45Ϫ3.62 [m, 3 H, C(2)-H, C(4)-H, C(5)-

³J_H,Hϭ 9.3, J_H,Hϭ 5.8 Hz, 1 H, C(5)-H], 3.72 (br. d, J_H,H

ϭ

3

7.9 Hz, 2 H, CH₂OH), 4.02 (q, J_H,Hϭ 7.1 Hz, 2 H, OCH₂CH₃),

4.48 (d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.58 (s, 2 H, CH₂Ph), 4.69

(d, J_H,Hϭ 10.7 Hz, 1 H, CHPh), 4.82 (d, J_H,Hϭ 10.9 Hz, 1 H,

2

3

H], 3.70Ϫ3.80 [m, 3 H, CH₂OH, C(6)-H], 4.03 (q, J_H,Hϭ 7.0 Hz,

2

2 H, OCH₂CH₃) ppm. ¹³C NMR (D₂O): δ ϭ 13.52 (OCH₂CH₃),

34.18 (CH₂COOEt), 51.11, 55.22, 56.87, 62.72, 68.79, 71.45, 72.60

[C(2), C(3), C(4), C(5), C(6), CH₂OH, OCH₂CH₃], 172.3 (CϭO)

ppm. MS (MALDI-TOF): m/z ϭ 250 [M ϩ H]^ϩ, 272 [M ϩ Na]^ϩ.

C₁₀H₁₉NO₆(249.3): calcd. C 48.19, H 7.68, N 5.62; found C 48.02,

H 7.94, N 5.45.

2

CHPh), 4.83 (d, J_H,Hϭ 10.8 Hz, 1 H, CHPh), 7.13Ϫ7.43 (m, 15

H, HAr) ppm. ¹³C NMR:

δ ϭ 14.64 (OCH₂CH₃), 36.67

(CH₂CO₂Et), 50.18, 54.95 [C(2), C(6)], 58.41, 61.17 (CH₂OH,

OCH₂CH₃), 73.19, 75.43, 75.91 (3 CH₂Ph), 81.62, 82.49, 83.61

[C(3), C(4), C(5)], 127.9Ϫ132.3 (CHAr), 138.2, 138.3, 138.7 (3

CqAr), 172.5 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 521 [M ϩ

H]^ϩ, 543 [M ϩ Na]^ϩ, 559 [M ϩ K]^ϩ. C₃₁H₃₇NO₆(519.6): calcd. C

71.65, H 7.18, N 2.70; found C 71.31, H 6.99, N 2.90.

[(2S,3S,4R,5R,6S)-3,4,5-Trihydroxy-6-(hydroxymethyl)-1-propyl-

piperidin-2-yl]acetic Acid (40): Compound 18b (100 mg,

0.161 mmol) was dissolved in CH₃OH/CH₂Cl₂(5:3, 8 mL); a cata-

lytic amount of Pd(OH)₂and acetic acid (1 mL) were added and

the reaction mixture was stirred under H₂overnight. The catalyst

was filtered through a pad of Celite (eluent CH₃OH) and then the

solvent was evaporated under reduced pressure to afford pure com-

pound 40 (17 mg, 98% yield) as an amorphous solid. [α]²_D⁰ϭ Ϫ62.5

Ethyl [(2R,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-(hydroxymethyl)-

piperidin-2-yl]acetate (37): The reaction was carried out as de-

scribed for the preparation of 36, starting from 21 (15 mg,

0.027 mmol) to afford 37 (14 mg, 100%) as a colorless oil. [α]²_D⁰

ϭ

3

Ϫ9.4 (c ϭ 1.0, CHCl₃). ¹H NMR: δ ϭ 1.15 (t, J_H,Hϭ 7.1 Hz,

2

3

3 H, OCH₂CH₃), 2.50 (dd, J_H,Hϭ 16.1, J_H,Hϭ 10.2 Hz, 1 H,

3

(c ϭ 0.4, H₂O). ¹H NMR (D₂O): δ ϭ 0.83 [t, J_H,Hϭ 7.0 Hz, 3 H,

2

3

CHCO₂Et), 2.63 (dd, J_H,Hϭ 16.1, J_H,Hϭ 4.01 Hz, 1 H,

CHCO₂Et), 2.78Ϫ2.84 [m, 1 H, C(6)-H], 3.29 [br. t, ³J_H,Hϭ 9.0 Hz,

1 H, C(5)-H], 3.52Ϫ3.63 [m, 4 H, C(3)-H, C(4)-H, CH₂OH],

3.68Ϫ3.73 [m, 1 H, C(2)-H], 3.98Ϫ4.70 (m, 2 H, OCH₂CH₃), 4.53

N(CH₂)₃CH₃], 1.45Ϫ1.59 [m, 1 H, NCH₂CHCH₃], 1.60Ϫ1.73 [m,

1 H, NCH₂CH₂CH₃], 2.50Ϫ2.61 (m, 1 H, CHCOOH), 2.70Ϫ2.81

(m,

1 H, CHCOOH), 2.92Ϫ3.07 (m, 1 H, NCHCH₂CH₃),

3.09Ϫ3.29 (m, 1 H, NCHCH₂CH₃), 3.43Ϫ3.64 [m, 3 H, C(2)-H,

C(5)-H, C(6)-H], 3.74Ϫ3.98 [m, 4 H, C(3)-H, C(4)-H, CH₂OH]

2

(d, J_H,Hϭ 11.0 Hz, 1 H, CHPh), 4.56 (s, 2 H, CH₂Ph), 4.68 (d,

²J_H,Hϭ 10.9 Hz, 1 H, CHPh), 4.82 (d, J_H,Hϭ 11.0 Hz, 1 H,

2

ppm. ¹³C NMR (D₂O):

δ ϭ 9.94 [N(CH₂)₂CH₃], 19.12

2

CHPh), 4.83 (d, J_H,Hϭ 10.9 Hz, 1 H, CHPh), 7.13Ϫ7.43 (m, 15

(NCH₂CH₂CH₃), 32.00 (CH₂COOH), 49.07, 54.62, 56.98, 61.62,

66.49, 68.68, 73.38 [C(2), C(3), C(4), C(5), C(6), CH₂OH,

NCH₂CH₂CH₃], 177.0 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ

264 [M ϩ H]^ϩ, 286 [M ϩ Na]^ϩ. C₁₁H₂₁NO₆(263.3): calcd. C 50.18,

H 8.04, N 5.32; found C 50.46, H 8.34, N 5.50.

H, CHAr) ppm. ¹³C NMR: δ ϭ 14.64 (OCH₂CH₃), 30.15

(CH₂CO₂Et), 51.09, 55.05 [C(2), C(6)], 60.97, 62.89 (CH₂OH,

OCH₂CH₃), 72.91, 75.32, 75.69 (3 CH₂Ph), 79.51, 80.80, 82.72

[C(3), C(4), C(5)], 127.9Ϫ132.3 (CHAr), 138.3, 138.4, 138.8 (3

CqAr), 172.7 (CϭO) ppm. MS (MALDI-TOF): m/z ϭ 521 [M ϩ

H]^ϩ, 543 [M ϩ Na]^ϩ, 559 [M ϩ K]^ϩ. C₃₁H₃₇NO₆(519.6): calcd. C

71.65, H 7.18, N 2.70; found C 71.30, H 7.05, N 2.88.

Acknowledgments

This work was supported in part by the European Community’s

Human Potential Programme under contract HPRN-CT-2002-

00173 (GLYCIDIC SCAFFOLDS) and, in part, by the Combi-

gen Project.

Ethyl [(2S,3S,4R,5R,6S)-3,4,5-Trihydroxy-6-(hydroxymethyl)piperi-

din-2-yl]acetate (38): Compound 36 (24 mg, 0.046 mmol) was dis-

solved in CH₃OH (4 mL); a catalytic amount of Pd(OH)₂and

acetic acid (1 mL) were added and the reaction mixture was stirred

under H₂overnight. The catalyst was filtered through a Celite pad

(eluent CH₃OH) and then the solvent was evaporated under re-

duced pressure to afford pure compound 38 (10 mg, 87% yield)

as an amorphous solid. Compound 38 exists as a mixture of two

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2470

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Eur. J. Org. Chem. 2004, 2451Ϫ2470

Article Doi

Synthesis of imino sugar scaffolds for the generation of glycosidase inhibitor libraries

DOI: 10.1002/ejoc.200300805

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