Synthesis and transformations of [1,2-O-isopropylidene-α-D-erythro (and α-D-ribo)furanose]-3-spiro-3′-(4′-amino-5′H- 2′,3′-dihydroisothiazole-1′,1′-dioxide) derivatives

Tetrahedron 60 (2004) 4709–4727

Synthesis and transformations of [1,2-O-isopropylidene-a-D-

erythro (and a-^D-ribo)furanose]-3-spiro-3⁰-(4⁰-amino-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) derivatives

a

Albert Nguyen Van Nhien, Laura Domınguez,^b,cCyrille Tomassi,^aM. Rosario Torres,^d

´

b

Christophe Len,^aDenis Postel^aand Jose Marco-Contelles

,

*

´

a

´

Laboratoire des Glucides, Universite de Picardie Jules Verne, Faculte des Sciences, 33, rue Saint Leu, 80039 Amiens, France

Laboratorio de Radicales Libres (Instituto de Quımica Organica General, CSIC), C/Juan de la Cierva, 3, 28006 Madrid, Spain

´

b

´

c

´ ´ ´ ´ ´

Seccion de Sıntesis Organica e Imagen Molecular por Resonancia Magnetica, Instituto Universitario de Investigacion, UNED,

Senda del Rey, 9, 28040 Madrid, Spain

´ ´

CAI difraccion de Rayos-X, Facultad de CC. Quımicas, Universidad Complutense de Madrid, 28040 Madrid, Spain

d

Received 4 December 2003; revised 19 February 2004; accepted 19 March 2004

Abstract—The carbanion-mediated sulfonamide cyclisations (CSIC protocols) of glyco-a-sulfonamidonitriles derived from readily

available uloses 1A and 1B have been investigated using different bases (potassium carbonate, cesium carbonate, LDA and n-BuLi). As ₀a

result, a series of enantiomerically pure [1,2-O-isopropylidene-a-^D-erythro (and a-D-ribo)furanose]-3-spiro-3⁰-(4⁰-amino-5⁰H-2⁰,3 -

dihydroisothiazole-1⁰,1⁰-dioxide) derivatives have been prepared and isolated in good yields.

1. Introduction

sulfonamide, or sulfoxide or sulfone) intermolecular

coupling) and intramolecular (carbanion-mediated

sulfonate (or sulfonamide, or sulfoxide or sulfone) intra-

molecular cyclization) conversions.³Recently, we have

shown⁴that alkyl and benzylsulfonates, other than mesy-

lates, may also act as the active methylene group in the

CSIC reaction to give the corresponding substituted

4-amino-g-sultones, and that the CSIC conditions can be

successfully applied to many alkylsulfonyl nitriles in which

the SO₂group may be attached to either an oxygen or a

nitrogen atom.⁴

The reactivity of carbanions¹stabilized by sulfur containing

functional groups, one of the most useful and recognized

tools for carbon–carbon bond formation in organic

synthesis, has been largely reviewed and summarized.²

Conversely, the literature regarding related carbanions

derived from alkanesulfonates and alkanesulfonamides is

relatively scarce.^2dFrom a synthetic perspective it has been

shown that different bases (n-BuLi, DBU, etc.) are able to

abstract protons from the a-position to sulfur atom in

alkanesulfonates (sulfonamides) to give anions that react

with different electrophiles, such as alkyl halides,

sulfonates, either carbonyl compounds (ketones, esters),

nitriles and aromatic activated substrates, in inter-, and

intramolecular conversions, to yield substituted alkane-

sulfonates, alkanesulfonamides and different types of

heterocyclic ring systems (Chart 1, Eq. 1 and 2).

However, the development and application of the CSIC

reaction with alkanesulfonamides located on mono-

saccharide backbones has never been undertaken. Our

interest in carbohydrate chemistry, especially that pertain-

ing to glyco-a-aminonitriles⁵encouraged us to extend our

investigations into the CSIC reaction. Very recently, one of

us investigated this approach and solved this problem,

showing a convenient access to a novel range of precursors

for the synthesis of new (aza)nucleosides.⁶Herein we report

in full, our studies on the glycoaminocyanation and

cyclisation steps to afford the target enantiomerically pure

[1,2-O-isopropylid₀ene-a-^D-eryth₀ro(and a-D-ribo)fura-

n₀ose]-3-spiro-3⁰-(4 -amino-5⁰H-2 ,3⁰-dihydroisothiazole-

1 ,1⁰-dioxide) derivatives using synthetic routes which

started from either ^D-xylose or D-glucose. These compounds

should be exploited as key intermediates in our current

project for the synthesis of new azanucleosides.

We have named, typiﬁed and reviewed these types of

transformations as CSIC reactions, by taking the initials of

the keywords that describe and deﬁne the process for

both intermolecular (carbanion-mediated sulfonate (or

Keywords: Carbanion; Sulfonamidonitrile; Organic synthesis; Glyco-a-

aminonitrile; CSIC.

*

Corresponding authors. Tel.: þ33-3-22-82-75-70; fax: þ33-3-22-82-75-

68 (D.P.); tel.: þ34-91-562-29-00; fax: þ34-91-564-48-53 (J.M.-C.);

e-mail addresses: denis.postel@sc.u-picardie.fr; iqoc21@iqog.csic.es

doi:10.1016/j.tet.2004.03.063

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A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

Chart 1. CSIC reaction.

2. Results and discussion

acetone at reﬂux, in the presence of potassium carbonate,

gave the N-methylated (3Ac), N-benzylated (3Ad) and the

N-allylated (3Ae) derivatives in 99, 66 and 56% yields,

respectively (Chart 2).

2.1. Synthesis of the precursors and CSIC reactions

At the outset of our project we selected the uloses 1A⁷and

1B⁸(Chart 2) with 5-O-trityl and 5,6-O-isopropylidene

protecting groups, respectively, known to be readily cleaved

under mild conditions.

Similarly, compound 3Ab, under the same standard

N-alkylation conditions, afforded the expected derivatives

3Af–g in moderate to good chemical yields (31–85%).

Very interestingly, during the N-allylation of compound

3Ab, after 17 h at rt, in addition to the expected sulfonamide

3Ah, a second product (4Af) was isolated in 18% yield, and

identiﬁed as the CSIC resulting molecule from compound

3Ah. This result suggested that we could possibly perform

in situ CSIC reactions on the N-alkylated intermediates,

using prolonged reaction times. In fact, we were very

satisﬁed to see that compound 3Ab gave the N-methylated

(4Ad, 95%), N-benzylated (4Ae, 68%), and the N-allylated

(4Af, 14%) CSICproducts (Chart 2), respectively, after 2

days reaction time, from low to excellent chemical yields.

Strecker conditions, using NH₃–MeOH and Ti(OiPr)₄as the

Lewis acid,⁵applied to the protected erythro-pentofuranos-

3-ulose derivative 1A,⁷followed by TMSCN addition gave

stereoselectively the a-aminonitrile 2A (Chart 2) in 96%

yield. Compound 2A on treatment with methanesulfonyl or

benzylsulfonyl chloride, in pyridine, using catalytic

amounts DMAP, afforded the key methanesulfonamido-

nitrile 3Aa (92%) and the benzylsulfonamidonitrile 3Ab

(93%), respectively (Chart 2). The reaction of precursor

3Aa with methyl iodide, benzylbromide or allyl bromide in

Chart 2.

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4711

Alternatively, treatment of the N-alkylated methanesulfon-

2.2. Acid hydrolyis of the CSIC products

amide (3Ac–e) and N-alkylated benzylsulfonamides

(3Af–h), with cesium carbonate (1 equiv.), in acetonitrile

as solvent, at reﬂux, in 1–3 h, cleanly afforded compounds

4Aa–c (46–95%) and 4Ad–f (48–89%), respectively

(Chart 2) (see Section 4).

For our current synthetic purposes, it was of interest to

investigate the acid hydrolysis of compounds 4A,B. Using

aqueous acetic acid at 40 8C for 1–5 h, products 4A(B)a,

4A(B)b and 4A(B)g gave the alcohols (5A(B)a–c),

obtained after selective hydrolysis of the trityl or the 5,6-

isopropylidene groups (Scheme 1). Only one diastereo-

isomer was detected and isolated. These products were

possibly the result of the nucleophilic attack of the free

hydroxyl group onto the protonated enamine moiety. The

absolute conﬁguration at the quaternary, new formed

stereocenter was tentatively assigned as shown, assuming

that the nucleophilic attack of the hydroxyl group could only

proceed from the rear face of the enamine.

We have also investigated the direct CSIC reaction on the

nitrogen unprotected precursors 3Aa and 3Ab. After some

experimentation we found that n-BuLi or freshly prepared

LDA were the bases of choice for this transformation.

Accordingly, reaction of sulfonamides 3Aa and 3Ab with

n-BuLi (3 equiv.) (or with LDA, 3 equiv.) at 210 8C, in dry

THF, provided the new CSIC reaction products 4Ag and

4Ah, respectively, in 98 and 76% yields (Chart 2).

Next, we investigated similar reactivity and experimental

methods on related 5,6-isopropylidene containing sub-

strates, starting with the ketone 1B.⁸These protocols

allowed us to prepare the CSIC ^D-ribo-3⁰-spiro derivatives

4Ba–h, via the corresponding N-alkylated sulfonamides

3Ba–h, using as the key intermediate a-aminonitrile 2B

(Chart 2) (see Section 4).

Very interestingly, the analogous 5⁰-phenyl substituted

derivatives 4A(B)d, 4A(B)e and 4A(B)h, under the same

conditions, afforded alcohols 6A(B)a–c (Scheme 2) in good

chemical yields, as the only detected products. In no case,

we observed similar tetracyclic products as in the hydrolysis

of compounds lacking the phenyl ring moiety (see above). It

seems that in these substrates the electrons on the enamine

nitrogen atom are more delocalized in resonance electronic

structures involving the phenyl ring, preventing the

intramolecular attack of the hydroxyl group onto the

protonated enamine.

All new compounds showed analytical and spectroscopic

data in good agreement with the proposed structures (see

below).

Scheme 1. Acid hydrolysis of compounds 4A(B)a,b,g.

Scheme 2. Acid hydrolysis of compounds 4A(B)d,e,h.

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A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

Scheme 3. Acetylation of compounds 5Aa,b.

The structures of products 5 (Scheme 1) and 6 (Scheme 2)

have been established by their analytical and spectroscopic

data, and after some chemical manipulation.

previously observed by one of us in similar N-acylated-2,3-

dihydroisothiazole derivatives,^4band gives support to this

structural assignment, conﬁrmed by the mass spectra and

the elemental analyses.

After acetylation, compounds 5Aa and 5Ab afforded

monoacetate derivatives 7a/8a, and 7b/8b, respectively

(Scheme 3). Compounds 7a,b are the monoacetylated

derivatives on the aminal precursors, while products 8a,b

are the monoacetylated sugar at hydroxyl group in the

derivatives where the dihydroisothiazole ring system has

been recovered after base-promoted tetrahydrofuran ring

opening.

In Scheme 5, we propose a possible mechanism for the

formation of compounds 8a,b (Eq. 1). Pyridine promoted

abstraction of the acidic Ha-proton in the sulfonamide

moiety, followed by ring opening the tetrahydrofuran and

intramolecular acetyl migration from the acetamido group

to the resulting alkoxy group at C5, via intermediates

I–1/I–3, should give the transacetylated compounds 8a,b.

The reason why these enamines are not further acetylated

remains obscure for us, and work is currently now in

progress in laboratory to ﬁnd an explanation for this

apparently anomalous reactivity. However, note that

compounds 6Ba,b with a phenyl group at C5⁰, upon

acetylation, only afforded diacetylated derivatives 12a,b in

good yield (Scheme 6), showing that in this case the

nitrogen in the enamine moiety is also reluctant to undergo

acetylation.

The acetylation of alcohol 5Ba for 4 h afforded only

monoacetate 9 (84%). When the reaction was prolonged for

15 h, only product 10 (60%) was isolated. Finally,

acetylation of compound 5Ba, during 3 days, gave

1

compounds 10 (70%) and 11 (14, 86% pure by H NMR

analysis) (Scheme 4). These results suggest that in the long-

term acetylation of alcohol 5Ba the key intermediate is the

monoacetyl [C6(O)-acetyl] derivative 9, that gives the bis-

acetyl [N-acetyl, C6(O)-acetyl] compound 10, the precursor

for the dihydroisothiazole derivative 11, after base-

promoted tetrahydrofuran ring opening followed by acetyl-

ation of the resulting free hydroxyl group (Scheme 4).

We think that in the case of product 10, after similar base-

promoted tetrahydrofuran ring opening, the exclusive

intramolecular acetyl migration, from the acetyl group

bound at O–C6 to the resulting secondary alkoxy species at

C-5 in intermediate (I–4), can be explained as shown in

Scheme 5 (Eq. 2). In fact, simple inspection with molecular

models suggests that a possible intermediate (I–5) leading

to primary alkoxy group (I–6) is not so sterically

constrained, as an analogous intermediate involving the

acetyl migration from the acetamido group attached to the

spiro heterocyclic ring system. Final intermolecular acetyl-

ation process should afford compound 11.

Summarising these results obtained in the acetylation

reactions, we were very surprised to see that in the

acetylation of compounds 5Aa (Scheme 3) and 5Ba

(Scheme 4), the resulting minor products 8a,b (12%),

compared with 11 (14%), were not acetylated at the nitrogen

on the enamine moiety. A careful analysis of the ¹H and ¹³

C

NMR spectra revealed, for instance, that compound 8a was

actually a monoacetate (2.12 ppm, 3H (CH₃COO); 21.1

(CH₃COO) and 171.0 (CH₃COO) ppm) with a free NH₂

(4.63, s, 2H) group bound to a double bond (H-C5⁰:

5.62 ppm; C4⁰(151.1 ppm); C5⁰(95.0 ppm)), in an enamime

moiety, while compound 11 has three acetyl groups (2.21,

2.09, 2.07 ppm) with an acetamido₀(7.65 ppm, br s,

CH₃CONH) group bound to carbon C4 (C4⁰(140.1 ppm)-

C5⁰(108.5 ppm)). The shift to lower ﬁeld for C5⁰has been

2.3. Structural analysis and stereochemical

considerations

Although the structural analysis of the products obtained in

this work has been achieved by extensive NMR spectro-

scopyic analysis, the assignments of the chemical shifts for

Scheme 4. Long-term acetylation of compound 5Ba.

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4713

Scheme 5.

1

involved in the ring closure based on the fact that the H

NMR spectrum of 5Bb displayed a signal for OH as a triplet

(J¼5.9 Hz) at 4.71 ppm, that exchangeable with D₂O; in

addition, selective irradiation of this signal clearly change

the multiplets at 3.16 ppm (H-6a) and 3.00 ppm (H-6b) in

two doublet of doublets typical of the AB part of an ABX

1

system. Similar observations were also made on the H

NMR spectra of compounds 5Ba and 5Bc. This is only

possible for a structure with the O–C5 oxygen involved in

the aminal moiety.

Final conﬁrmation regarding the whole structure on these

compounds (5Ba–c), and the absolute conﬁguration at the

new stereocenter at C-4⁰were obtained by X-ray analysis of

a suitable crystal from of 5Bc (Fig. 1).

Scheme 6. Acetylation of compounds 6Ba,b.

protons and carbons are based on a comparison of spectro-

scopic data previously reported by us^5,6and others.⁹

Regarding the different substrates obtained by acid

hydrolysis from the CSIC products, in Chart 3 we have

shown some of typical chemical shifts observed in the NMR

spectra.

The X-ray molecular structure of compound 5Bc, shows that

the absolute conﬁguration at C4⁰is S, as previously

suggested (Fig. 1). The N· · ·O and O· · ·O distances in the

˚

range 2.883(2)–3.121(3) A and the N· · ·H· · ·O and

O· · ·H· · ·O angles in the range 117(2)–174(2)8 are in

accordance with the formation of four strong hydrogen

bonds, two of which are intramolecular and the other two,

Particularly, for compounds 5Ba–c (Scheme 1), we have

excluded that the primary hydroxyl group at C-6 could be

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A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

Chart 3.

Figure 1. ORTEP view of the molecular unit of 5Bc, showing intramolecular hydrogen bonds as dotted lines.

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4715

˚

Table 1. Hydrogen bonds for 5Bc (A and 8)

3. All of the N-substituted alkylsulfonamides (3) reacted

efﬁciently using cesium carbonate as base in acetonitrile,

to give the CSIC products (4) in yields ranging from 46 to

99%.

4. n-BuLi (or LDA, in THF, at 210 8C) was found to be the

most effective base promoting CSIC reactions in

secondary alkylsufonamides with minimum by-product.

5. The acid hydrolysis of the CSIC adducts 4 gave tetracyclic

aminal derivatives implementing the formation of fused

tertrahydrofuranringsbynucleophilicattackoftheC-5free

hydroxyl group onto the protonated enamine moiety.

D–H· · ·A

d(D–H)

d(H· · ·A)

d(D· · ·A)

,(DHA)

N(2)–H(2A)· · ·O(7)

N(2)–H(2B)· · ·O(6)#1

N(2⁰)–H(2⁰)· · ·O(6)#2

O(6)–H(6)· · ·O(4)

0.84(2)

0.91(3)

0.81(3)

0.87(3)

2.65(3)

2.15(3)

2.23(3)

2.06(3)

3.121(3)

3.054(3)

3.001(3)

2.883(2)

117(2)

174(2)

160(2)

158(2)

Symmetry transformations used to generate equivalent atoms: #1 x21, y, z;

#2 2xþ2, y21/2, 2zþ1/2.

intermolecular, whose details are given in Table 1 The

intermolecular bonds are extending in two directions giving

rise to the formation of folder layers of molecules running to

the ‘ab’ crystal plane (Fig. 2).

4. Experimental

4.1. Materials and methods

Melting points were determined on a digital melting-point

apparatus (Electrothermal) and are uncorrected. Optical

rotations were recorded in CHCl₃, MeOH, acetone or

DMSO with a digital polarimeter DIP-370 (JASCO) using a

1 dm cell. ¹H NMR and ¹³C NMR spectra were recorded in

CDCl₃, acetone-d6, Me₂SO-d6 or MeOD-d3 (internal

Me₄Si), respectively, at 300.13 MHz and at 75.47 MHz

(Bruker Avance-300). TLC was performed on Silica F254

(Merck) and detection by UV light at 254 nm or by charring

with phosphomolybdic–H₂SO₄reagent. Column chroma-

tography was effected on Silica Gel 60 (Merck, 230 mesh).

Acetone, hexane and diethyl ether were distilled before use.

Bases and solvents were used as supplied. MeOH–NH₃is

methanol saturated (7 N) with ammonia gas at room

temperature. Elemental analyses have been carried out in

Madrid (IQOG, CSIC reaction). ¹³C NMR resonances have

been assigned by using standard NMR (DEPT, COSY,

HMBQ, HMBC) experiments. Compounds have been

recrystallized from ethyl acetate–hexane mixtures. FTIR

spectra were obtained on a AVATARe 320 neat on KBr

plate or using ATR and are reported in cm²¹. Mass spectral

data were acquiered on a WATERS Micromass ZQ

Figure 2. Crystal packing of 5Bc.

Based on this analysis, and by comparison of the close

relationship between the spectroscopic data for 5Bc with

those observed for the analogues 5Ba and 5Bb (Chart 3), we

conﬁrmed the previously assigned structures for these

compounds (Scheme 1).

spectrometer or

spectrometer.

a WATERS Micromass Q-TOFF

4.2. General method for the synthesis of sulfonamides

(A)

3. Conclusions

In summary, we have demonstrated that differently a-

sulfonamidonitriles derived from commercial carbohydrates

are key intermediates in the CSIC reaction leading to useful

building blocks incorporating the [1,2-O-isopropylidene-a-

D-erythro ₀(and a-D-ribo)furanose]-3-spiro-3⁰-(5⁰H-4⁰-

amino-2⁰,3 -dihydroisothiazole-1⁰,1⁰-dioxide) structural and

functional moiety, and we conclude that:

Methylsulfonyl (or benzylsulfonyl chloride) (3 equiv.) was

added dropwise to a solution of the aminonitrile and DMAP

(0.5 equiv.) in dry pyridine. The reaction mixture was

stirred at rt until the disappearance of the aminonitrile

(2–30 h). Then water and EtOAc were added. The organic

layer was separated, dried over Na₂SO₄and evaporated to

dryness. The crude product was puriﬁed by ﬂash

chromatography.

1. Reﬂuxing of the secondary methanesulfonamides

[3Aa(Ba)] with potassium carbonate as base in acetone,

in the presence of the appropriate electrophilic agents,

gave the N-alkylated products in good yields (56–99%).

2. Under comparable conditions as described above, the

benzylsulfonamides [3Ab(Bb)] gave mixtures of

N-alkylated and the desired CSIC products in short

reaction times. However, extended reaction times in

excess of 24 h enabled the CSIC reaction products to be

isolated exclusively in good yield.

4.3. General method for the synthesis for the N-

alkylation of sulfonamides (B)

To a solution of sulfonamide and K₂CO₃(1.5 equiv.), in

acetone, was added MeI, BnBr or AllBr (2 equiv.).

The mixture was reﬂuxed until complete reaction

(45 min–28 h). The mixture was ﬁltered through a silica

pad and evaporated to dryness. The residue was puriﬁed by

ﬂash chromatography.

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A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4.4. General method for the one-pot CSIC procedure

using K₂CO₃(C)

H-4), 3.80 (dd, J_5a,5b¼9.7 Hz, 1H, H-5b), 3.54 (dd, 1H,

H-5a), 2.04 (s, 2H, NH₂), 1.58 (s, 3H, CH₃), 1.38 (s, 3H,

CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 143.3, 128.6–127.4

[18 C, OC(C₆H₅)₃], 118.5 (CN), 113.4 [OC(CH₃)₂], 103.9

(C-1), 87.9 [OC(C₆H₅)₃], 83.2 (C-2), 79.9 (C-4), 63.3 (C-5),

62.3 (C-3), 26.5 (CH₃), 26.4 (CH₃); MS (APCIþ) m/z

479.33 [MþNa]^þ, 495.26 [MþK]^þ, 935.44 [2MþNa]^þ.

Anal. Calcd for C₂₈H₂₈N₂0₄(456.43 g/mol): C, 73.66; H,

6.18; N, 6.14. Found: C, 73.55; H, 6.07; N, 6.01.

To a solution of the sulfonamidonitriles and K₂CO₃

(1.5 equiv.), in acetone, was added MeI, BnBr or AllBr

(2 equiv.). The mixture was reﬂuxed until complete reaction

(17 h–48 h). The mixture was ﬁltered through Celite and

evaporated to dryness. The residue was puriﬁed by ﬂash

chromatography.

4.5. General method for the CSIC reaction using Cs₂CO₃

(D)

4.8.2. 3-Amino-3-C-cyano-3-deoxy-1,2-O-isopropyli-

dene-3-N-methanesulfonyl-5-O-trityl-a-^D-ribofuranose

(3Aa). Following the general method (A), CH₃SO₂Cl

(0.37 mL, 3.3 mmol) was added dropwise to a solution of

2A (500 mg, 1.1 mmol) and DMAP (60 mg, 0.55 mmol) in

dry pyridine (2.75 mL). The reaction mixture was stirred at

room temperature for 5 h. The crude product was submitted

to ﬂash chromatography (EtOAc/petroleum ether, 2:8) to

yield 3Aa (540 mg, 92%) as a colourless solid: mp 223–

224 8C; [a]²_D⁶227 (c 1.39, CHCl₃); IR (ATR) n 3299, 1381,

Cs₂CO₃(1 equiv.) was added to a solution of the

sulfonamidonitriles in CH₃CN. The mixture was reﬂuxed

until complete reaction and then was ﬁltered through Celite

and evaporated to dryness. The residue was puriﬁed by ﬂash

chromatography.

4.6. General method for the CSIC reaction using n-BuLi

(E)

1

1332, 1150, 1054, 879, 751, 704 cm²¹; H NMR (CDCl₃,

300 MHz) d 7.41–7.30 [m, 15H, OC(C₆H₅)₃], 5.86 (d,

J_1,2¼3.6 Hz, 1H, H-1), 5.61 (s, 1H, NH), 5.07 (d, 1H, H-2),

3.91 (dd, J_5a,4¼8.8 Hz, J_4,5b¼4.8 Hz, 1H, H-4), 3.79 (dd,

J_5b,5a¼10.1 Hz, 1H, H-5a), 3.61 (dd, 1H, H-5b), 3.05 (s, 3H,

SO₂CH₃), 1.52 (s, 3H, CH₃), 1.25 (s, 3H, CH₃); ¹³C NMR

(CDCl₃, 75 MHz) d 142.7, 128.4–127.6 [18 C, OC(C₆H₅)₃],

115.7 (CN), 114.0 [OC(CH₃)₂], 104.3 (C-1), 88.6

[OC(C₆H₅)₃], 82.4 (C-2), 77.8 (C-4), 63.2 (C-3), 62.7

(C-5), 42.9 (SO₂CH₃), 26.6 (CH₃), 26.3 (CH₃); MS

(APCIþ) m/z 557.26 [MþNa]^þ. Anal. Calcd for

C₂₉H₃₀N₂0₆S (534.18 g/mol): C, 65.15; H, 5.66; N, 5.24;

S, 6.00. Found: C, 64.98; H, 5.61; N, 5.22; S, 6.06.

To a solution of the sulfonamidonitrile in dry THF, n-BuLi

(3 equiv., 1.6 M or 2.5 M in hexane) was added. The

reaction mixture was stirred for 5 min–20 min at –10 8C.

Water and HCl 1 M were added until pH 6. Then, ethyl

acetate was added. The organic layer was separated and

dried over Na₂SO₄. The solvent was removed under vacuum

and the residue was puriﬁed by ﬂash chromatography

(EtOAc/petroleum ether).

4.7. General method for the acid hydrolysis of acetals (F)

Acetic acid and water (6:4, v/v) were added, and the

reaction mixture was stirred at 40 8C for 1 h 10 min–5 h

20 min. Then the solvent was evaporated to dryness and the

residue was puriﬁed by ﬂash chromatography (EtOAc/

petroleum ether) to give the products as indicated.

4.8.3. 3-Amino-3-C-cyano-3-deoxy-1,2-O-isopropyli-

dene-3-N-phenylmethanesulfonyl-5-O-trityl-a-^D-ribo-

furanose (3Ab). Following the general method (A), 2A

(4.0 g, 8.76 mmol), DMAP (0.53 g, 4.38 mmol), C₆H₅CH₂-

SO₂Cl (3.34 g, 17.52 mmol) in pyridine (25 mL) for 2 h

gave, after ﬂash chromatograpy (EtOAc/petroleum ether,

2:8), compound 3Ab (5.0 g, 93%) as a colourless solid: mp

97–99 8C; [a]²_D⁴240 (c 0.47, CHCl₃); IR (ATR) n 3299,

4.8. General method for acetylations (G)

Pyridine and Ac₂O (1:1, v/v) were added to the compound.

The reaction mixture was stirred at room temperature. After

complete reaction, the solvent was evaporated to dryness

and the residue was puriﬁed by ﬂash chromatography

eluting with mixtures of hexane/EtOAc.

1

1337, 1162, 1064, 900, 778, 704 cm²¹; H NMR (CDCl₃,

300 MHz) d 7.42–7.29 (m, 20H, 4£C₆H₅), 5.92 (d,

J_1,2¼3.6 Hz, 1H, H-1), 5.16 (s, 1H, H-2), 5.10 (d, 1H,

NH), 4.53 (d, J_A,B¼13.8 Hz, 1H, H-A, SO₂CH₂C₆H₅), 4.34

(d, 1H, H-B, SO₂CH₂C₆H₅), 3.86 (dd, J_5a,4¼5.2 Hz,

J_5a,5b¼10.3 Hz, 1H, H-5a), 3.70 (dd, 1H, H-4), 3.59 (dd,

J_5b,4¼7.3 Hz, 1H, H-5b), 1.59 (s, 3H, CH₃), 1.41 (s, 3H,

CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 143.2–127.9 (24 C,

4£C₆H₅), 116.2 (CN), 114.4 [OC(CH₃)₂], 104.8 (C-1), 89.1

[OC(C₆H₅)₃], 82.6 (C-2), 78.5 (C-4), 63.3 (C-5), 63.1 (C-3),

60.6 (SO₂CH₂C₆H₅), 27.0 (CH₃), 26.8 (CH₃); MS (APCIþ)

m/z 633.45 [MþNa]^þ, 649.37 [MþK]^þ, 1243.58

[2MþNa]^þ, 1259.50 [2MþK]^þ. Anal. Calcd for

C₃₅H₃₄N₂0₆S (610.21 g/mol): C, 68.83; H, 5.61; N, 4.59;

S, 5.25. Found: C, 69.04; H, 5.75; N, 4.68; S, 5.40.

4.8.1. 3-Amino-3-C-cyano-3-deoxy-1,2-O-isopropyli-

dene-5-O-trityl-a-^D-ribofuranose

(2A).

Ti(OiPr)₄

(4.18 mL, 13.9 mmol) was added to a solution of ulose 1A

(5 g, 11.6 mmol) and NH₃(16.6 mL, NH₃in MeOH 7 N) in

MeOH (23.4 mL). The reaction mixture was stirred at rt for

5 h, then TMSiCN (1.55 mL, 11.6 mmol) was added and the

mixture stirred for 12 h. Water (5 mL) and EtOAc were

added until oxidation of the titanium residue was complete.

The solvent was evaporated to dryness and the crude

product was puriﬁed by ﬂash chromatography (EtOAc/

petroleum ether, 15:85) to yield compound 2A (5.8 g, 96%)

as a colourless solid: mp 163–167 8C; [a]²_D⁵229 (c 1.20,

CHCl₃); IR (ATR) n 1479, 1441, 1370, 1205, 1079, 1020,

4.8.4. 3-Amino-3-C-cyano-3-deoxy-1,2-O-isopropyli-

dene-3-N-methanesulfonyl-3-N-methyl-5-O-trityl-a-^D-

ribofuranose (3Ac). Following the general method (B), a

solution of 3Aa (0.75 g, 1.40 mmol) in acetone (22 mL) was

treated with K₂CO₃(0.29 g, 2.10 mmol) and CH₃I

1

870, 747, 706 cm²¹; H NMR (CDCl₃, 300 MHz) d 7.50–

7.39 [m, 15H, OC(C₆H₅)₃], 5.91 (d, J_1,2¼3.6 Hz, 1H, H-1),

4.70 (d, 1H, H-2), 3.86 (dd, J_4,5a¼7.3 Hz, J_4,5b¼5.4 Hz, 1H,

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4717

(0.17 mL, 2.80 mmol). The reaction mixture was reﬂuxed

for 2 h to yield, after ﬂash chromatography (EtOAc),

compound 3Ac (0.77 g, 99%) as a colorless oil: [a]²_D⁶þ10

(c 2.01, CHCl₃); IR (ATR) n 1450, 1349, 1220, 1159, 1034,

88.0 [OC(C₆H₅)₃], 84.3 (C-2), 78.3 (C-4), 67.0 (C-3), 64.1

(C-5), 50.3 (NCH₂CHvCH₂), 41.6 (SO₂CH₃), 26.9 (CH₃),

26.7 (CH₃); MS (APCIþ) m/z 597.4 [MþNa]^þ, 613.4

[MþK]^þ. Anal. Calcd for C₃₂H₃₄N₂0₆S (574.21 g/mol): C,

66.88; H, 5.96; N, 4.87; S, 5.58. Found: C, 66.59; H, 5.66;

N, 4.58; S, 5.31.

1

958, 709 cm²¹; H NMR (CDCl₃, 300 MHz) d 7.37–7.16

[m, 15H, OC(C₆H₅)₃] 5.79 (d, J_1,2¼3.8 Hz, 1H, H-1), 4.99

(d, 1H, H-2), 4.48 (dd, J_4,5a¼4.1 Hz, J_4,5b¼5.8 Hz, 1H,

H-4), 3.68 (dd, J_5a,5b¼10.7 Hz, 1H, H-5b), 3.38 (dd, 1H,

H-5a), 2.81 (s, 3H, SO₂CH₃), 2.8 (s, 3H, NCH₃), 1.47 (s, 3H,

CH₃), 1.23 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

142.8, 128.4–127.2 [18 C, OC(C₆H₅)₃], 115.3 (CN), 113.0

[OC(CH₃)₂], 103.0 (C-1), 87.5 [OC(C₆H₅)₃], 84.1 (C-2),

77.6 (C-4), 65.7 (C-3), 63.0 (C-5), 39.7 (SO₂CH₃), 34.4

(NCH₃), 26.2 (CH₃), 26.1 (CH₃); MS (APCIþ) m/z 571.30

[MþNa]^þ, 587.42 [MþK]^þ. Anal. Calcd for C₃₀H₃₂N₂0₆S

(548.20 g/mol): C, 65.67; H, 5.88; N, 5.11; S, 5.84. Found:

C, 65.82; H, 6.10; N, 5.23; S, 5.68.

4.8.7. 3-Amino-3-C-cyano-3-deoxy-1,2-O-isopropyli-

dene-3-N-methyl-3-N-phenylmethanesulfonyl-5-O-

trityl-a-^D-ribofuranose (3Af). Following the general

method (B), 3Ab (0.80 g, 1.31 mmol), K₂CO₃(0.27 g,

1.96 mmol), MeI (0.16 mL, 2.62 mmol) in acetone (20 mL)

for 1 h 20 min gave, after ﬂash chromatography (EtOAc/

petroleum ether, 2:8), compound (3Af) (0.70 g, 85%) as a

yellow solid: mp 89–91 8C; [a]²_D⁹þ37 (c 0.50, CHCl₃); IR

(ATR) n 1490, 1441, 1353, 1216, 1153, 1032, 883,

1

698 cm²¹; H NMR (CDCl₃, 300 MHz) d 7.54–7.30 (m,

20H, 4£C₆H₅), 5.97 (d, J_1,2¼3.9 Hz, 1H, H-1), 5.16 (d, 1H,

H-2), 4.55 (dd, J_4,5a¼6.9 Hz, J_4,5b¼2.5 Hz, 1H, H-4), 4.36

(s, 2H, SO₂CH₂C₆H₅), 3.89 (dd, J_5a,5b¼10.9 Hz, 1H, H-5a),

3.50 (dd, 1H, H-5b), 2.46 (s, 3H, NCH₃), 1.63 (s, 3H, CH₃),

1.39 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 143.7–

127.8 (24 C, 4£C₆H₅), 115.9 (CN), 113.7 [OC(CH₃)₂],

103.7 (C-1), 88.2 [OC(C₆H₅)₃], 85.1 (C-2), 78.5 (C-4), 66.0

(C-3), 64.0 (C-5), 60.3 (SO₂CH₂C₆H₅), 36.1 (NCH₃), 26.9

(CH₃), 26.8 (CH₃); MS (APCIþ) m/z 647.36 [MþNa]^þ,

663.35 [MþK]^þ, 1271.53 [2MþNa]^þ. Anal. Calcd for

C₃₆H₃₆N₂0₆S (624.23 g/mol): C, 69.21; H, 5.81; N, 4.48; S,

5.13. Found: C, 68.95; H, 5.73; N, 4.64; S, 5.30.

4.8.5. 3-Amino-3-N-benzyl-3-C-cyano-3-deoxy-1,2-O-

isopropylidene-3-N-methanesulfonyl-5-O-trityl-a-^D-

ribofuranose (3Ad). Following the general method (B), a

solution of 3Aa (0.39 g, 0.74 mmol) in acetone (10 mL) was

treated with K₂CO₃(0.15 g, 1.11 mmol) and BnBr

(0.17 mL, 1.49 mmol). The reaction was reﬂuxed for 19 h

to yield after ﬂash chromatography (EtOAc/petroleum

ether, 2:8), compound 3Ad (0.31 g, 66%) as a white solid:

mp 66–68 8C; [a]²_D⁴þ21 (c 0.26, CHCl₃); IR (ATR) n 1441,

1352, 1154, 1029, 747, 699 cm²^{1 1}H NMR (CDCl₃,

;

300 MHz) d 7.52–7.31 (m, 20H, 4£C₆H₅), 5.95 (d,

J_1,2¼3.8 Hz, 1H, H-1), 5.16 (d, 1H, H-2), 4.66 (dd, J_4,5a

¼

5.5 Hz, J_4,5b¼1.9 Hz, 1H, H-4), 4.43 (d, J_A,B¼16.5 Hz, 1H,

H-B, NCH₂C₆H₅), 4.13 (d, 1H, H-A, NCH₂C₆H₅), 3.81 (dd,

J_5a,5b¼11.2 Hz, 1H, H-5a), 3.58 (dd, 1H, H-5b), 2.82 (s, 3H,

SO₂CH₃), 1.33 (s, 6H, 2£CH₃); ¹³C NMR (CDCl₃, 75 MHz)

4.8.8. 3-Amino-3-N-benzyl-3-C-cyano-3-deoxy-1,2-O-

isopropylidene-3-N-phenylmethanesulfonyl-5-O-trityl-

a-^D-ribofuranose (3Ag). Following the general method

(B), 3Ab (0.60 g, 0.98 mmol), K₂CO₃(0.20 g, 1.47 mmol),

BnBr (0.23 mL, 1.96 mmol) in acetone (30 mL) for 4 h

gave, after ﬂash chromatography (EtOAc/petroleum ether,

1.5:8.5) compound (3Ag) (215 mg, 31%) as a colourless oil

and unreacted 3Ab (255 mg, 42%). 3Ag: [a]²_D⁹þ28 (c 0.30,

CHCl₃); IR (ATR) n 2959, 2915, 1490, 1447, 1348, 1145,

d

143.4–136.2, 129.2–127.8 [24 C, OCH₂C₆H₅,

OC(C₆H₅)₃], 116.4 (CN), 113.7 [OC(CH₃)₂], 103.4 (C-1),

88.1 [OC(C₆H₅)₃], 84.8 (C-2), 78.9 (C-4), 67.3 (C-3), 64.5

(C-5), 51.3 (NCH₂C₆H₅), 41.4 (SO₂CH₃), 26.9 (CH₃), 26.4

(CH₃); MS (APCIþ) m/z 647.27 [MþNa]^þ, 663.26

[MþK]^þ. Anal. Calcd for C₃₆H₃₆N₂0₆S (624.23 g/mol):

C, 69.21; H, 5.81; N, 4.48; S, 5.13. Found: C, 69.68; H, 5.80;

N, 4.60; S, 5.39.

1085, 1041, 899, 733, 697 cm²¹

;

¹H NMR (CDCl₃,

300 MHz) d 7.56–7.33 (m, 25H, 5£C₆H₅), 5.94 (d, J_1,2

¼

3.8 Hz, 1H, H-1), 5.16 (d, 1H, H-2), 4.72 (dd, J_4,5a¼5.9 Hz,

J_4,5b¼1.3 Hz, 1H, H-4), 4.37 (d, J_A,B¼13.6 Hz, 1H, H-A,

SO₂CH₂C₆H₅), 4.23 (d, 1H, H-B, SO₂CH₂C₆H₅), 4.14 (d,

J_A,B¼16.6 Hz, 1H, H-A, NCH₂C₆H₅), 3.82 (m, 2H, H-5a,

H-B, NCH₂C₆H₅), 3.63 (dd, J_5a,5b¼11.1 Hz, 1H, H-5b),

1.34 (s, 3H, CH₃), 1.19 (s, 3H, CH₃); ¹³C NMR (CDCl₃,

75 MHz) d 143.6–127.5 (30 C, 5£C₆H₅), 116.6 (CN), 113.7

[OC(CH₃)₂], 103.3 (C-1), 88.1 (OC(C₆H₅)₃), 84.9 (C-2),

78.6 (C-4), 67.2 (C-3), 64.9 (C-5), 60.2 (SO₂CH₂C₆H₅),

52.4 (NCH₂C₆H₅), 26.8 (CH₃), 26.1 (CH₃); MS (APCIþ)

m/z 723.4 [MþNa]^þ, 739.4 [MþK]^þ. Anal. Calcd for

C₄₂H₄₀N₂0₆S (700.26 g/mol): C, 71.98; H, 5.75; N, 4.00; S,

4.58. Found: C, 70.68; H, 6.80; N, 4.60; S, 4.69.

4.8.6. 3-N-Allyl-3-amino-3-C-cyano-3-deoxy-1,2-O-iso-

propylidene-3-N-methanesulfonyl-5-O-trityl-a-^D-ribo-

furanose (3Ae). Following the general method (B), a

solution of 3Aa (1.50 g, 2.80 mmol) in acetone (30 mL) was

treated with K₂CO₃(0.58 g, 4.20 mmol) and AllBr

(0.48 mL, 5.60 mmol). The reaction was reﬂuxed for 24 h

to yield, after ﬂash chromatography (EtOAc/petroleum

ether,1.5:8.5), compound 3Ae (0.90 g, 56%) as a white

solid: mp 167–168 8C; [a]³_D⁰þ5 (c 0.51, CHCl₃); IR (ATR)

1

n 1485, 1447, 1353, 1159, 1043, 866, 749, 707 cm²¹; H

NMR (CDCl₃, 300 MHz) d 7.51–7.31 (m, 15H, 3£C₆H₅),

5.94 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.70 (m, 1H, NCH₂-

CHvCH₂), 5.14 (m, 2H, NCH₂CHvCH₂), 5.07 (d, 1H,

H-2), 4.70 (dd, J_4,5a¼5.6 Hz, J_4,5b¼2.7 Hz, 1H, H-4), 3.87

(m, 1H, H-A, NCH₂CHvCH₂), 3.79 (dd, J_5a,5b¼10.9 Hz,

1H, H-5a), 3.74 (m, 1H, H-B, NCH₂CHvCH₂), 3.46 (dd,

1H, H-5b), 2.98 (s, 3H, SO₂CH₃), 1.63 (s, 3H, CH₃), 1.39 (s,

3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 143.3–127.8

(18C, 3£C₆H₅), 135.4 (NCH₂CHvCH₂), 118.6 (NCH₂-

CHvCH₂), 116.2 (CN), 113.8 [OC(CH₃)₂], 103.6 (C-1),

4.8.9. 3-N-Allyl-3-amino-3-C-cyano-3-deoxy-1,2-O-iso-

propylidene-5-O-trityl-3-N-phenylmethanesulfonyl a-^D-

ribofuranose (3Ah). Following the general method (B),

3Ab (0.4 g, 0.65 mmol), K₂CO₃(0.13 g, 0.98 mmol), AllBr

(0.11 mL, 1.31 mmol) in acetone (20 mL) for 17 h gave,

after ﬂash chromatography (EtOAc/petroleum ether, 3:7)

product (3Ah) (211 mg, 49%) as a white solid and 1,2-O-

isopropylidene-5-O-trityl-a-^D-erythro-pentofuranose-3-

4718

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

spiro-3⁰-(2⁰-N-allyl-4⁰-amino-5⁰-phenyl-5⁰H-2⁰,3⁰-dihydro-

isothiazole-1⁰,1⁰-dioxide) (4Af) (73 mg, 18%). 3Ah: mp

97–99 8C; [a]³_D²þ33 (c 0.53, CHCl₃); IR (ATR) n 2921,

4.8.11. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-2⁰-N-benzyl-5⁰-

phenyl-5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Ae).

Following the general method (C), 3Ab (500 mg,

0.82 mmol), K₂CO₃(170 mg, 1.22 mmol) and BnBr

(0.19 mL, 1.63 mmol) in acetone (20 mL) for 48 h gave,

after ﬂash chromatography (EtOAc/petroleum ether, 3:7),

compound 4Ae (394 mg, 68%) as a white solid: mp 98–

100 8C; [a]³_D¹þ91 (c 0.50, CHCl₃); IR (ATR) n 1649, 1490,

¹H NMR (CDCl₃, 300 MHz) d 7.31–7.10 (m, 10H,

2£C₆H₅), 5.95 (d, J_1,2¼3.8 Hz, 1H, H-1), 4.84 (d, 1H,

H-2), 4.75 (s, 2H, NCH₂C₆H₅), 4.50 (s, 2H, NH₂), 4.38 (dd,

J_4,5a¼2.6 Hz, J_4,5b¼4.2 Hz, 1H, H-4), 3.28 (dd,

J_5a,5b¼11.6 Hz, 1H, H-5a), 3.02 (dd, 1H, H-5b), 1.71 (s,

3H, CH₃), 1.42 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

147.6 (C-4⁰), 143.5–126.9 (30 C, 5£C₆H₅), 113.8

[OC(CH₃)₂], 108.0 (C-5⁰), 104.3 (C-1), 88.1 [OC(C₆H₅)₃],

85.2 (C-2), 76.2 (C-4), 70.2 (C-3), 60.4 (C-5), 44.8

(NCH₂C₆H₅), 26.9 (CH₃), 26.3 (CH₃); MS (APCIþ) m/z

723.39 [MþNa]^þ, 739.31 [MþK]^þ, 1423.54 [2MþNa]^þ.

Anal. Calcd for C₄₂H₄₀N₂0₆S (700.26 g/mol): C, 71.98; H,

5.75; N, 4.00; S, 4.58. Found: C, 71.65; H, 5.37; N, 4.40; S,

4.43.

2356, 1447, 1348, 1151, 1085, 1036, 871, 751, 698 cm²¹

;

¹H NMR (CDCl₃, 300 MHz) d 7.53–7.34 (m, 20H,

4£C₆H₅), 5.97 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.58 (m, 1H,

NCH₂CHvCH₂), 5.13 (d, 1H, H-2), 5.02 (d, J_A,b¼8.2 Hz,

1H, NCH₂CHvCH₂), 4.99 (d, J_B,b¼9.9 Hz, 1H, NCH₂-

CHvCH₂), 4.77 (dd, J_4,5a¼6.4 Hz, J_4,5b¼1.8 Hz, 1H, H-4),

4.42 (d, J_A,B¼13.7 Hz, 1H, H-A, SO₂CH₂C₆H₅), 4.37 (d,

1H, H-B, SO₂CH₂C₆H₅), 3.82 (dd, J_5a,5b¼10.9 Hz, 1H,

H-5a), 3.47 (m, 3H, H-5b, NCH₂CHvCH₂), 1.66 (s, 3H,

CH₃), 1.41 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

143.6–127.8 (24 C, 4£C₆H₅), 136.3 (NCH₂CHvCH₂),

117.8 (NCH₂CHvCH₂), 116.3 (CN), 113.8 [OC(CH₃)₂],

103.6 (C-1), 87.9 [OC(C₆H₅)₃], 84.5 (C-2), 78.3 (C-4), 66.8

(C-3), 64.5 (C-5), 60.3 (SO₂CH₂C₆H₅), 51.6 (NCH₂-

CHvCH₂), 26.8 (CH₃), 26.7 (CH₃); MS (APCIþ) m/z

673.5 [MþNa]^þ, 689.5 [MþK]^þ. Anal. Calcd for

C₃₈H₃₈N₂0₆S (650.25 g/mol): C, 70.13; H, 5.89; N, 4.30;

S, 4.93. Found: C, 69.95; H, 5.76; N, 4.29; S, 4.68. 4Af: oil;

[a]³_D²þ66 (c 0.30, CHCl₃); IR (ATR) n 3474, 3353, 2921,

1652, 1448, 1274, 1164, 1079, 909, 876, 733, 703 cm²¹; ¹H

NMR (CDCl₃, 300 MHz) d 7.36 (m, 20H, 4£C₆H₅), 5.93 (d,

J_1,2¼3.9 Hz, 1H, H-1), 5.83 (m, 1H, NCH₂CHvCH₂), 5.21

(dd, J_A,b¼17.3 Hz, J_A,B¼1.3 Hz, 1H, NCH₂CHvCH₂),

5.05 (dd, J_B,b¼10.1 Hz, 1H, NCH₂CHvCH₂), 4.73 (d, 1H,

H-2), 4.68 (dd, J_4,5a¼2.5 Hz, J_4,5b¼5.6 Hz, 1H, H-4), 4.41

(s, 2H, NH₂), 4.15 (d, J_H,b¼6.5 Hz, 2H, NCH₂CHvCH₂),

3.48 (dd, J_5a,5b¼11.3 Hz, 1H, H-5a), 3.36 (dd, 1H, H-5b),

1.69 (s, 3H, CH₃), 1.39 (s, 3H, CH₃); ¹³C NMR (CDCl₃,

75 MHz) d 146.6 (C-4⁰), 143.6–126.8 (24 C, 4£C₆H₅),

135.6 (NCH₂CHvCH₂), 118.1 (NCH₂CHvCH₂), 113.7

[OC(CH₃)₂], 108.2 (C-5⁰), 104.2 (C-1), 88.1 [OC(C₆H₅)₃],

84.8 (C-2), 76.0 (C-4), 69.8 (C-3), 61.1 (C-5), 44.8

(NCH₂CHvCH₂), 26.7 (CH₃), 26.3 (CH₃); MS (APCIþ)

m/z 673.3 [MþNa]^þ, 689.2 [MþK]^þ. Anal. Calcd for

C₃₈H₃₈N₂0₆S (650.25 g/mol): C, 70.13; H, 5.89; N, 4.30; S,

4.93. Found: C, 69.05; H, 8.04; N, 4.00; S, 4.27.

1447, 1364, 1271, 1211, 1151, 1030, 871, 751, 700 cm²¹

;

4.8.12. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(2⁰-N-allyl-4⁰-amino-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Af). Follow-

ing the general method (C), 3Ab (300 mg, 0.49 mmol),

K₂CO₃(0.10 g, 0.73 mmol) and AllBr (0.08 mL,

0.98 mmol) in acetone (20 mL) for 47 h gave, after ﬂash

chromatography (EtOAc/petroleum ether, 4.5:5.5),

compound 4Af (45 mg, 14%).

4.8.13. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-2⁰-N-methyl-5⁰H-

2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Aa). Following

the general method (D), Cs₂CO₃(0.18 g, 0.56 mmol) was

added to a solution of 3Ac (0.31 g, 0.56 mmol) in CH₃CN

(5 mL). The reaction mixture was reﬂuxed for 3 h then

evaporated to dryness. The residue was puriﬁed by ﬂash

chromatography (EtOAc/petroleum ether, 6:4) to give 4Aa

(0.28 g, 90%) as a colourless solid: mp 158–160 8C; [a]_D²⁶

þ13 (c 1.01, CHCl₃); IR (ATR) n 1638, 1254, 1210, 1117,

;

¹H NMR (CDCl₃,

4.8.10. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-2⁰-N-allyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Ad). Follow-

ing the general method (C), 3Ab (200 mg, 0.33 mmol),

K₂CO₃(67 mg, 0.49 mmol) and MeI (0.04 mL, 0.65 mmol)

in acetone (10 mL) for 43 h gave, after ﬂash chromato-

graphy (EtOAc/petroleum ether, 5.5:4.5), compound 4Ad

(194 mg, 95%) as a white solid: mp 231–232 8C; [a]²_D⁸þ28

(c 0.15, CHCl₃); IR (ATR) n 3447, 3353, 2921, 1655, 1441,

1073, 1024, 871, 706, 682 cm²¹

300 MHz) d 7.45–7.28 [m, 15H, OC(C₆H₅)₃], 5.84 (d,

J_1,2¼3.9 Hz, 1H, H-1), 5.43 (s, 1H, H-5⁰), 4.60 (d, 1H, H-2),

4.52 (t, J_4,5¼5,1 Hz, 1H, H-4), 4.38 (s, 2H, NH₂), 3.40 (d,

2H, H-5), 2.77 (s, 3H, NCH₃), 1.64 (s, 3H, CH₃), 1.34 (s,

3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 151.9 (C-4⁰),

143.2, 128.5–127.1 [18 C, OC(C₆H₅)₃], 113.0 [OC(CH₃)₂],

103.4 (C-1), 93.2 (C-5⁰), 87.4 [OC(C₆H₅)₃], 84.2 (C-2), 74.8

(C-4), 70.4 (C-3), 60.9 (C-5), 26.4 (NCH₃), 26.0 (CH₃), 25.8

(CH₃); MS (APCIþ) m/z 571.24 [MþNa]^þ. Anal. Calcd for

C₃₀H₃₂N₂0₆S (548.20 g/mol): C, 65.67; H, 5.88; N, 5.11; S,

5.84. Found: C, 65.48; H, 5.67; N, 5.14; S, 5.61.

1

1260, 1145, 1054, 866, 760, 699 cm²¹; H NMR (CDCl₃,

300 MHz) d 7.47–7.33 (m, 20H, 4£C₆H₅), 5.94 (d,

J_1,2¼3.9 Hz, 1H, H-1), 4.72 (d, 1H, H-2), 4.67 (dd,

J_4,5a¼3.2 Hz, J_4,5b¼5.8 Hz, 1H, H-4), 4.40 (s, 2H, NH₂),

3.54 (dd, J_5a,5b¼11.2 Hz, 1H, H-5a), 3.38 (dd, 1H, H-5b),

2.94 (s, 3H, NCH₃), 1.68 (s, 3H, CH₃), 1.37 (s, 3H, CH₃);

¹³C NMR (CDCl₃, 75 MHz) d 146.5 (C-4⁰), 143.7–126.9

(24 C, 4£C₆H₅), 113.6 [OC(CH₃)₂], 107.8 (C-5⁰), 104.2

(C-1), 88.2 [OC(C₆H₅)₃], 85.0 (C-2), 75.4 (C-4), 69.6 (C-3),

61.5 (C-5), 27.4 (NCH₃), 26.6 (CH₃), 26.4 (CH₃); MS

(APCIþ) m/z 647.43 [MþNa]^þ, 663.41 [MþK]^þ, 1271.59

[2MþNa]^þ, 1287.58 [2MþK]^þ. Anal. Calcd for

C₃₆H₃₆N₂0₆S (624.23 g/mol): C, 69.21; H, 5.81; N, 4.48;

S, 5.13. Found: C, 68.04; H, 6.21; N, 5.00; S, 5.04.

4.8.14. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-2⁰-N-benzyl-5⁰H-

2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Ab). Following

the general method (D), Cs₂CO₃(0.15 g, 0.47 mmol) was

added to a solution of 3Ad (0.29 g, 0.47 mmol) in CH₃CN

(10 mL). The reaction mixture was reﬂuxed for 3 h then

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4719

evaporated to dryness. The residue was puriﬁed by ﬂash

chromatography (EtOAc/petroleum ether, 7:3) to give 4Ab

(0.14 g, 46%) as a yellow oil: [a]²_D⁴þ65 (c 1.36, CHCl₃); IR

(ATR) n 2926, 2362, 1633, 1271, 1110, 1074, 877, 740,

reﬂuxed for 1 h then evaporated to dryness. The residue was

puriﬁed by ﬂash chromatography (EtOAc/petroleum ether,

3:7) to give 4Ae (50 mg, 48%).

1

606 cm²¹; H NMR (CDCl₃, 300 MHz) d 7.32 [m, 20H,

4.8.18. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(2⁰-N-allyl-4⁰-amino-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Af). Follow-

ing the general method (D), Cs₂CO₃(26.3 mg, 0.08 mmol)

was added to a solution of 3Ah (52.6 mg, 0.08 mmol) in

CH₃CN (5 mL). The reaction mixture was reﬂuxed for

45 min then evaporated to dryness. The residue was puriﬁed

by ﬂash chromatography (EtOAc/petroleum ether, 3:7) to

give 4Af (47.2 mg, 89%).

C₆H₅, OC(C₆H₅)₃], 5.86 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.44 (s,

1H, H-5⁰), 4.71 (d, 1H, H-2), 4.58 (d, J_A,B¼15,2 Hz, 1H,

H-A, NCH₂C₆H₅), 4.51 (d, 1H, H-B, NCH₂C₆H₅), 4.42 (s,

2H, NH₂), 4.36 (dd, J_4,5a¼2.7 Hz, J_4,5b¼5.7 Hz, 1H, H-4),

3.21 (dd, J_5a,5b¼11.4 Hz, 1H, H-5a), 3.11 (dd, 1H, H-5b),

1.67 (s, 3H, CH₃), 1.39 (s, 3H, CH₃); ¹³C NMR (CDCl₃,

75 MHz) d 152.9 (C-4⁰), 143.2, 137.5, 129.2–127.6 [24 C,

OCH₂C₆H₅, OC(C₆H₅)₃], 113.8 [OC(CH₃)₂], 104.1 (C-1),

94.9 (C-5⁰), 88.2 [OC(C₆H₅)₃], 84.9 (C-2), 76.1 (C-4), 71.5

(C-3), 60.6 (C-5), 44.9 (NCH₂C₆H₃), 26.8 (CH₃), 26.3 (CH₃);

MS (APCIþ) m/z 647.32 [MþNa]^þ, 663.32 [MþK]^þ. Anal.

Calcd for C₃₆H₃₆N₂0₆S (624.23 g/mol): C, 69.21; H, 5.81; N,

4.48; S, 5.13. Found: C, 69.44; H, 5.57; N, 4.37; S, 5.43.

4.8.19. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-5⁰H-2⁰,3⁰-dihydro-

isothiazole-1⁰,1⁰-dioxide) (4Ag). Following the general

method (E), n-BuLi (9 mL, 13 mmol, 1.6 M in hexane)

was added to a solution of 3Aa (200 mg, 3.7 mmol) in THF

(30 mL). The reaction mixture was stirred for 10 min at

210 8C. The crude was puriﬁed by ﬂash chromatography

(EtOAc/petroleum ether, 1:1) to give 4Ag (2.24 g, 98%) as a

colourless solid: mp 93–95 8C; [a]²_D⁵þ15 (c 1.21, CHCl₃);

4.8.15. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(2⁰-N-allyl-4⁰-amino-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (4Ac). Following the

general method (D), Cs₂CO₃(11 mg, 0.34 mmol) was

added to a solution of 3Ae (200 mg, 0.34 mmol) in

CH₃CN (5 mL). The reaction mixture was reﬂuxed for 1 h

20 min then evaporated to dryness. The residue was puriﬁed

by ﬂash chromatography (EtOAc/petroleum ether, 4.5:5.5)

to give 4Ac (190 mg, 95%) as a white solid: mp 115–

117 8C; [a]²_D⁹þ55 (c 0.51, CHCl₃); IR (ATR) n 3452, 3353,

1

IR (ATR) n 1633, 1277, 1216, 1125, 1063, 705 cm²¹; H

NMR (CDCl₃, 300 MHz)

d

7.40–7.23 (m, 15H,

OC(C₆H₅)₃), 5.86 (d, J_1,2¼4.0 Hz, 1H, H-1), 5.22 (s, 1H,

CHSO₂), 4.85 (s, 1H, NH), 4.48 (d, 1H, H-2), 4.46 (s, 1H,

NH₂), 4.00 (t, J_4,5¼4.8 Hz, 1H, H-4), 3.48 (d, 2H, H-5), 1.51

(s, 3H, CH₃), 1.31 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz)

d 152.1 (C-4⁰), 143.3, 128.6–127.2 [18 C, OC(C₆H₅)₃],

113.5 [OC(CH₃)₂], 103.7 (C-1), 94.1 (C-5⁰), 87.6

[OC(C₆H₅)₃], 81.8 (C-2), 79.3 (C-4), 69.3 (C-3), 60.5

(C-5), 26.4 (CH₃), 26.1 (CH₃); MS (APCIþ) m/z 557.20

[MþNa]^þ. Anal. Calcd for C₂₉H₃₀N₂0₆S (534.18 g/mol): C,

65.15; H, 5.66; N, 5.24; S, 6.00. Found: C, 65.06; H, 5.85;

N, 5.05; S, 6.20.

2921, 1644, 1452, 1266, 1211, 1123, 1078, 866, 705 cm²¹

;

¹H NMR (CDCl₃, 300 MHz) d 7.47–7.30 (m, 15H,

3£C₆H₅), 5.85 (d, J_1,2¼3.9 Hz, 1H, H-1), 5.75 (m, 1H,

NCH₂CHvCH₂), 5.35 (s, 1H, H-5⁰), 5.19 (d, J_A,b¼17.3 Hz,

1H, NCH₂CHvCH₂), 5.03 (d, J_B,b¼10.2 Hz, 1H, NCH₂-

CHvCH₂), 4.58 (d, 1H, H-2), 4.52 (m, 3H, H-4, NH₂), 3.95

(d, J¼6.5 Hz, 2H, NCH₂CHvCH₂), 3.41 (dd, J_4,5a¼7.2 Hz,

J_5a,5b¼11.1 Hz, 1H, H-5a), 3.33 (dd, J_4,5b¼2.6 Hz, 1H,

H-5b), 1.66 (s, 3H, CH₃), 1.36 (s, 3H, CH₃); ¹³C NMR

(CDCl₃, 75 MHz) d 152.2 (C-4⁰), 143.7–127.7 (18 C,

3£C₆H₅), 135.3 (NCH₂CHvCH₂), 118.3 (NCH₂-

CHvCH₂), 113.6 [OC(CH₃)₂], 104.1 (C-1), 94.2 (C-5⁰),

87.8 [OC(C₆H₅)₃], 84.5 (C-2), 76.0 (C-4), 71.3 (C-3), 61.5

(C-5), 44.8 (NCH₂CHvCH₂), 26.6 (CH₃), 26.4 (CH₃); MS

(APCIþ) m/z 597.1 [MþNa]^þ. Anal. Calcd for

C₃₂H₃₄N₂0₆S (574.21 g/mol): C, 66.88; H, 5.96; N, 4.87;

S, 5.58. Found: C, 66.94; H, 6.15; N, 4.69; S, 5.39.

4.8.20. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-5⁰-phenyl-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (4Ah). Following the

general method (E), n-BuLi (0.98 mL, 2.45 mmol, 2.5 M

in hexane) was added to a solution of 3Ab (500 mg,

0.81 mmol) in THF (10 mL). The reaction mixture was

stirred for 20 min at 210 8C. The crude was puriﬁed by ﬂash

chromatography (EtOAc/petroleum ether, 7:3) to give 4Ah

(380 mg, 76%) as a colourless solid: mp 98–100 8C; [a]_D²⁵

þ38 (c 0.19, CHCl₃); IR (ATR) n 1649, 1479, 1447, 1266,

1140, 1068, 860, 701 cm²¹; ¹H NMR (CDCl₃, 300 MHz) d

7.38 (m, 20H, 4£C₆H₅), 6.04 (d, J_1,2¼3.9 Hz, 1H, H-1),

5.12 (s, 1H, NH), 4.69 (d, 1H, H-2), 4.47 (s, 1H, NH₂), 4.19

(dd, J_4,5a¼3.3 Hz, J_4,5b¼5.2 Hz, 1H, H-4), 3.64 (dd,

J_5b,5a¼11.3 Hz, 1H, H-5a), 3.54 (dd, 1H, H-5b), 1.61 (s,

3H, CH₃), 1.41 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

147.0 (C-4⁰), 143.3–127.1 (24 C, 4£C₆H₅), 114.0

[OC(CH₃)₂], 108.1 (C-5⁰), 104.4 (C-1), 88.3 [OC(C₆H₅)₃],

82.5 (C-2), 80.1 (C-4), 68.1 (C-3), 60.8 (C-5), 26.9 (CH₃),

26.6 (CH₃); MS (APCIþ) m/z 633.32 [MþNa]^þ, 649.31

[MþK]^þ, 1243.45 [2MþNa]^þ. Anal. Calcd for

C₃₅H₃₄N₂0₆S (610.21 g/mol): C, 68.83; H, 5.61; N, 4.59;

S, 5.25. Found: C, 69.01; H, 5.90; N, 4.61; S, 5.40.

4.8.16. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-2⁰-N-methyl-5⁰-

phenyl-5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Ad).

Following the general method (D), Cs₂CO₃(0.19 g,

6.05 mmol) was added to a solution of 3Af (378 mg,

6.05 mmol) in CH₃CN (5 mL). The reaction mixture was

reﬂuxed for 1 h then evaporated to dryness. The residue was

puriﬁed by ﬂash chromatography (EtOAc/petroleum ether,

5.2:4.8) to give 4Ad (279 mg, 73%).

4.8.17. 1,2-O-Isopropylidene-5-O-trityl-a-^D-erythro-

pentofuranose-3-spiro-3⁰-(4⁰-amino-2⁰-N-benzyl-5⁰-

phenyl-5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Ae).

Following the general method (D), Cs₂CO₃(48 mg,

0.15 mmol) was added to a solution of 3Ag (105 mg,

0.15 mmol) in CH₃CN (5 mL). The reaction mixture was

4.8.21. 3-Amino-3-C-cyano-3-deoxy-1,2:5,6-di-O-isopro-

pylidene-a-^D-allofuranose (2B). Likewise, 1B (5 g,

4720

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

19.3 mmol), NH₃(27.6 mL, NH₃in MeOH 7 N), Ti(OiPr)₄

(6.96 mL, 23.2 mmol) and TMSiCN (2.57 mL, 19.3 mmol)

in MeOH (12.4 mL), gave after ﬂash chromatography

(EtOAc/petroleum ether, 15:85) compound 2B (7.1 g,

98%) as a colourless solid: mp 79–82 8C; [a]²_D⁵þ5 (c 1.2,

CHCl₃); IR (ATR) n 3386, 2986, 2932, 1375, 1215, 1164,

1076, 1022, 840 cm²¹; ¹H NMR (CDCl₃, 300 MHz) d 5.84

(d, J_1,2¼3.6 Hz, 1H, H-1), 4.68 (d, 1H, H-2), 4.29 (m, 1H,

H-5), 4.10 (dd, J_5,6a¼6.2 Hz, J_6a,6b¼8.9 Hz, 1H, H-6a), 3.92

(dd, J_5,6b¼4.4 Hz, 1H, H-6b), 3.59 (d, J_4,5¼8.9 Hz, 1H,

H-4), 2.02 (s, 2H, NH₂), 1.49 (s, 3H, CH₃), 1.38 (s, 3H,

CH₃), 1.29 (s, 6H, 2£CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

118.6 (CN), 113.7 [OC(CH₃)₂], 110.1 [OC(CH₃)₂], 103.9

(C-1), 83.3 (C-2), 81.6 (C-4), 75.0 (C-5), 67.6 (C-6), 62.7

(C-3), 27.1, 26.8, 26.7, 25.2 (4£CH₃); MS (ES): 285.08

[Mþ1]^þ. Anal. Calcd for C₁₃H₂₀N₂0₅(284.31 g/mol): C,

54.92; H, 7.09; N, 9.85. Found: C, 54.58; H, 6.87; N, 9.43.

[MþNa]^þ, 899.2 [2MþNa]^þ. Anal. Calcd for C₂₀H₂₆N₂O₇S

(438.50 g/mol): C, 55.78; H, 5.98; N, 6.39; S, 7.31. Found:

C, 55.98; H, 5.71; N, 6.24; S, 7.12.

4.8.24. 3-Amino-3-C-cyano-3-deoxy-1,2:5,6-di-O-iso-

propylidene-3-N-methyl-3-N-methanesulfonyl-a-^D-allo-

furanose (3Bc). Following the general method (B), a

solution of 3Ba (0.52 g, 1.43 mmol) in acetone (20 mL) was

reacted with K₂CO₃(0.29 g, 2.14 mmol) and CH₃I

(0.18 mL, 2.86 mmol). The reaction mixture was reﬂuxed

for 45 min to yield, after ﬂash chromatography (EtOAc),

compound 3Bc (0.51 g, 95%) as a colourless solid: mp 127–

129 8C; [a]²_D³þ73 (c 0.26, CHCl₃); IR (ATR) n 2992, 2937,

1381, 1350, 1260, 1211, 1157, 1028 cm²^{1 1}H NMR

;

(CDCl₃, 300 MHz) d 5.88 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.15

(d, 1H, H-2), 4.48 (m, 1H, H-5), 4.40 (d, J_4,5¼7.6 Hz, 1H,

H-4), 4.27 (dd, J_6a,6b¼8.9 Hz, J_5,6b¼6.4 Hz, 1H, H-6b),

4.04 (dd, J_5,6a¼6.0 Hz, 1H, H-6a), 3.17 (s, 3H, NCH₃), 3.10

(s, 3H, SO₂CH₃), 1.58 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 1.39

(s, 3H, CH₃), 1.37 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz)

d 115.4 (CN), 113.5, 110.4 [2£OC(CH₃)₂], 103.1 (C-1),

84.9 (C-2), 78.7 (C-4), 74.2 (C-5), 67.8 (C-6), 66.8 (C-3),

40.3 (SO₂CH₃), 35.1 (NCH₃), 26.3 (2£CH₃), 26.0 (CH₃),

24.7 (CH₃); MS (APCIþ) m/z 377.27 [Mþ1]^þ, 399.25

[MþNa]^þ, 415.17 [MþK]^þ, 775.29 [2MþNa]^þ. Anal.

Calcd for C₁₅H₂₄N₂0₇S (376.13 g/mol): C, 47.86; H, 6.43;

N, 7.44; S, 8.52. Found: C, 47.58; H, 6.34; N, 7.40; S, 8.55.

4.8.22. 3-Amino-3-C-cyano-3-deoxy-1,2:5,6-di-O-isopro-

pylidene-3-N-methanesulfonyl-a-^D-allofuranose (3Ba).

Following the general method (A), 2B (2 g, 7.1 mmol),

DMAP (430 mg, 3.52 mmol), CH₃SO₂Cl (1.63 mL,

21.1 mmol) in pyridine (17.7 mL) for 2 h gave, after ﬂash

chromatography (EtOAc/petroleum ether, 25:75), com-

pound 3Ba (2.03 g, 80%) as a colourless solid: mp 128–

131 8C; [a]²_D⁰þ13 (c 1.04, CH₂Cl₂); IR (ATR) n 1331,

1210, 1149, 1079, 1038 cm²¹; ¹H NMR (CDCl₃, 300 MHz)

d 5.90 (d, J_1,2¼3.6 Hz, 1H, H-1), 5.50 (s, 1H, NH), 5.15 (d,

1H, H-2), 4.37 (ddd, J_5,4¼9.1 Hz, J_5,6b¼6.2 Hz,

J_5,6a¼4.3 Hz, 1H, H-5), 4.15 (d, J_6a,6b¼9.1 Hz, 1H, H-6b),

3.96 (d, 1H, H-6a), 3.76 (dd, 1H, H-4), 3.14 (s, 3H,

CH₃SO₂), 1.52 (s, 3H, CH₃), 1.43 (s, 6H, 2£CH₃), 1.39 (s,

3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 116.1 (CN), 114.2

[OC(CH₃)₂], 110.8 [OC(CH₃)₂], 104.6 (C-1), 82.4 (C-2),

79.8 (C-4), 74.4 (C-5), 67.5 (C-6), 63.2 (C-3), 43.1

(SO₂CH₃), 26.5 (3£CH₃), 24.6 (CH₃); MS (APCIþ) m/z

385.20 [MþNa]^þ, 401.18 [MþK]^þ. Anal. Calcd for

C₁₄H₂₂N₂0₇S (362.11 g/mol): C, 46.40; H, 6.12; N, 7.73.

Found: C, 46.25; H, 5.95; N, 7.61.

4.8.25. 3-Amino-3-N-benzyl-3-C-cyano-3-deoxy-1,2:5,6-

di-O-isopropylidene-3-N-methanesulfonyl-a-^D-allofura-

nose (3Bd). Following the general method (B), a solution of

3Ba (1.5 g, 4.14 mmol) in acetone (50 mL) was treated with

K₂CO₃(0.86 g, 6.20 mmol) and BnBr (1.0 mL, 8.3 mmol).

The reaction was reﬂuxed for 19 h to yield, after ﬂash

chromatography (EtOAc), compound 3Bd (1.47 g, 78%) as

a colourless solid: mp 130–131 8C; [a]³_D¹þ55 (c 0.52,

CHCl₃); IR (ATR) n 1649, 1337, 1205, 1151, 1030, 819,

1

697 cm²¹; H NMR (CDCl₃, 300 MHz) d 7.54–7.32 (m,

5H, C₆H₅), 5.82 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.17 (d, 1H,

H-2), 4.84 (d, J_A,B¼15.8 Hz, 1H, H-A, NCH₂C₆H₅), 4.72

(d, 1H, H-B, NCH₂C₆H₅), 4.60 (d, J_4,5¼7.4 Hz, 1H, H-4),

4.51 (ddd, 1H, H-5), 4.27 (dd, J_5,6a¼6.3 Hz, J_6a,6b¼8.8 Hz,

1H, H-6a), 4.00 (dd, J_5,6b¼6.7 Hz, 1H, H-6b), 2.92 (s, 3H,

SO₂CH₃), 1.42 (s, 3H, CH₃), 1.40 (s, 3H, CH₃), 1.36 (s, 3H,

CH₃), 1.32 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

136.6–128.4 (C₆H₅), 116.3 (CN), 113.9 [OC(CH₃)₂], 110.9

[OC(CH₃)₂], 103.1 (C-1), 85.4 (C-2), 79.3 (C-4), 75.0 (C-5),

69.6 (C-6), 68.4 (C-3), 52.2 (NCH₂C₆H₅), 42.3 (SO₂CH₃),

26.8 (CH₃), 26.5 (CH₃), 26.3 (CH₃), 25.5 (CH₃); MS

(APCIþ) m/z 475.34 [MþNa]^þ, 491.26 [MþK]^þ, 927.36

[2MþNa]^þ. Anal. Calcd for C₂₁H₂₈N₂0₇S (452.16 g/mol):

C, 55.74; H, 6.24; N, 6.19; S, 7.09. Found: C, 55.99; H, 6.50;

N, 6.11; S, 7.04.

4.8.23. 3-Amino-3-C-cyano-3-deoxy-1,2;5.6-di-O-isopro-

pylidene-3-N-phenylmethanesulfonyl-a-D-ribofuranose

(3Bb). Following the general method (A), 2B (0.137 g,

0.14 mmol), DMAP (0.03 g, 0.24 mmol), C₆H₅CH₂SO₂Cl

(0.28 g, 1.45 mmol) in dry pyridine (10 mL) for 30 h gave,

after ﬂash chromatography (EtOAc/petroleum ether, 8:2)

compound 3Bb (0.127 g, 60%) as a colourless solid: mp

138–139 8C; [a]²_D⁵216 (c 0.35, CHCl₃); IR (KBr) n 3330,

2923, 2853, 1457, 1376, 1338, 1213, 1164, 1082, 1044,

1

836 cm²¹; H NMR (CDCl₃, 200 MHz) d 7.52–7.36 (m,

5H, CH₂SO₂C₆H₅), 5.98 (d, J_1,2¼3.5 Hz, 1H, H-1), 5.31 (d,

1H, H-2), 5.29 (br s, 1H, NH), 4.58 (d, J_A,B¼13.7 Hz, 1H,

H-A, SO₂CH₂C₆H₅), 4.44 (d, 1H, H-B, SO₂CH₂C₆H₅), 4.41

(ddd, J_4,5¼9.34 Hz, J_5,6a¼6.22 Hz, J_5,6b¼3.66 Hz, 1H,

H-5), 4.17 (dd, J_5,6a¼6.22 Hz, J_6a,6b¼9.34 Hz, 1H, H-6a),

4.05 (dd, J_5,6b¼3.66 Hz, 1H, H-6b), 3.87 (dd, J_4,5¼9.34 Hz,

1H, H-4), 1.69 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 1,28 (s, 3H,

CH₃), 1.07 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 50 MHz) d

131.0–128.8 (SO₂CH₂C₆H₅), 116.4 (CN), 114.5

[OC(CH₃)₂], 110.9 [OC(CH₃)₂], 104.6 (C-1), 82.8 (C-2),

79.6 (C-4), 74.5 (C-5), 67.4 (C-6), 63.4 (C-3), 60.1

(SO₂CH₂C₆H₅), 26.7, 26.6, 26.4, 24.6, (4£CH₃); MS

(APCIþ) m/z 439.1 [Mþ1]^þ, 456.1 [MþNH₄]^þ, 461.1

4.8.26. 3-N-Allyl-3-amino-3-C-cyano-3-deoxy-1,2:5,6-di-

O-isopropylidene-3-N-methanesulfonyl-a-^D-allo-

furanose (3Be). Following the general method (B), a

solution of 3Ba (1.5 g, 4.14 mmol) in acetone (30 mL) was

treated with K₂CO₃(0.86 g, 6.20 mmol) and AllBr

(0.72 mL, 8.28 mmol). The reaction was reﬂuxed for 24 h

to yield, after ﬂash chromatography (EtOAc), compound

3Be (0.79 g, 47%) as a colourless solid: mp 107–108 8C;

[a]³_D⁰þ63 (c 0.54, CHCl₃); IR (ATR) n 2992, 2362, 1381,

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4721

1337, 1155, 1033, 961, 860, 824 cm²¹; H NMR (CDCl₃,

300 MHz) d 5.98 (m, 1H, NCH₂CHvCH₂), 5.81 (d,

J_1,2¼3.8 Hz, 1H, H-1), 5.19 (m, 2H, NCH₂CHvCH₂),

5.09 (d, 1H, H-2), 4.50 (d, J_4,5¼7.4 Hz, 1H, H-4), 4.42 (m,

1H, H-5), 4.33 (dd, J_A,B¼8.1 Hz, J_B,b¼17.1 Hz, 1H, H-B,

NCH₂CHvCH₂), 4.22 (dd, J_5,6a¼6.3 Hz, J_6a,6b¼8.9 Hz,

1H, H-6a), 4.07 (m, 1H, H-A, NCH₂CHvCH₂), 3.96 (dd,

J_5,6b¼6.5 Hz, 1H, H-6b), 3.08 (s, 3H, SO₂CH₃), 1.54 (s, 3H,

CH₃), 1.43 (s, 3H, CH₃), 1.37 (s, 3H, CH₃), 1.32 (s, 3H,

CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 136.3 (NCH₂-

CHvCH₂), 118.2 (NCH₂CHvCH₂), 116.0 (CN), 113.9

[OC(CH₃)₂], 110.9 [OC(CH₃)₂], 103.3 (C-1), 84.8 (C-2),

78.8 (C-4), 74.9 (C-5), 68.7 (C-6), 68.3 (C-3), 50.8

(NCH₂CHvCH₂), 41.8 (SO₂CH₃), 26.8 (CH₃), 26.6

(CH₃), 26.5 (CH₃), 25.4 (CH₃); MS (APCIþ) m/z 425.5

[MþNa]^þ, 441.5 [MþK]^þ. Anal. Calcd for C₁₇H₂₆N₂0₇S

(402.15 g/mol): C, 50.73; H, 6.51; N, 6.96; S, 7.97. Found:

C, 50.54; H, 6.29; N, 6.76; S, 7.96.

J_5,6b¼6.3 Hz, 1H, H-6b), 1.54 (s, 3H, CH₃), 1.54 (s, 3H,

CH₃), 1.24 (s, 3H, CH₃), 0.90 (s, 3H, CH₃); ¹³C NMR

(CDCl₃, 75 MHz) d 137.3–128.3 (12 C, 2£C₆H₅), 116.3

(CN), 113.9 [OC(CH₃)₂], 111.0 [OC(CH₃)₂], 103.1 (C-1),

85.5 (C-2), 78.9 (C-4), 75.2 (C-5), 69.7 (C-3), 68.6 (C-6),

60.4 (SO₂CH₂CH₃), 53.1 (NCH₂C₆H₅), 26.7 (2£CH₃), 25.8

(CH₃), 25.6 (CH₃); MS (APCIþ) m/z 551.31 [MþNa]^þ,

567.30 [MþK]^þ. Anal. Calcd for C₂₇H₃₂N₂0₇S

(528.19 g/mol): C, 61.35; H, 6.10; N, 5.30; S, 6.07.

Found: C, 61.24; H, 6.30; N, 5.28; S, 5.95. 4Be: mp 105–

107 8C; [a]³_D²þ39 (c 0.51, CHCl₃); IR (ATR) n 3364, 2975,

1

1654, 1372, 1215, 1148, 1073, 1022, 877, 731 cm²¹; H

NMR (CDCl₃, 300 MHz) d 7.61–7.25 (m, 10H, 2£C₆H₅),

5.82 (d, J_1,2¼3.9 Hz, 1H, H-1), 4.75 (d, 1H, H-2), 4.72 (d,

J_A,B¼14.0 Hz, 1H, H-A, NCH₂C₆H₅), 4.61 (d, 1H, H-B,

NCH₂C₆H₅), 4.53 (d, J_4,5¼6.0 Hz, 1H, H-4), 4.36 (s, 2H,

NH₂), 4.19 (m, 1H, H-5), 3.97 (dd, J_5,6a¼6.1 Hz,

J_6a,6b¼8.3 Hz, 1H, H-6a), 3.90 (dd, J_5,6b¼7.3 Hz, 1H,

H-6b), 1.59 (s, 3H, CH₃), 1.43 (s, 3H, CH₃), 1.36 (s, 6H,

2£CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 145.2 (C-4⁰),

137.2–126.9 (12 C, 2£C₆H₅), 113.5 [OC(CH₃)₂], 110.0

[OC(CH₃)₂], 107.5 (C-5⁰), 103.9 (C-1), 84.9 (C-2), 77.1

(C-4), 73.0 (C-5), 71.2 (C-3), 67.1 (C-6), 47.9 (NCH₂C₆H₅),

26.7 (CH₃), 26.6 (CH₃), 26.3 (CH₃), 25.7 (CH₃); MS

(APCIþ) m/z 529.41 [Mþ1]^þ, 551.38 [MþNa]^þ, 567.36

[MþK]^þ, 1079.49 [MþK]^þ. Anal. Calcd for C₂₇H₃₂N₂0₇S

(528.19 g/mol): C, 61.35; H, 6.10; N, 5.30; S, 6.07. Found:

C, 61.30; H, 6.27; N, 5.42; S, 6.29.

4.8.27. 3-Amino-3-C-cyano-3-deoxy-1,2;5,6-di-O-iso-

propylidene-3-N-methyl-3-N-phenylmethanesulfonyl-a-

D-ribofuranose (3Bf). Following the general method (B),

3Bb (74 mg, 0.17 mmol), K₂CO₃(30 mg, 0.25 mmol), CH₃I

(0.02 ml, 0.34 mmol) in acetone (3 mL) for 4 h gave,

after ﬂash chromatography (EtOAc/petroleum ether,

9:1), product (3Bf) (73 mg, 95%) as a colourless solid:

mp 37–39 8C; [a]²_D⁵þ101 (c 0.37, CHCl₃); IR (KBr) n

3435, 2989, 1456, 1378, 1352, 1215, 1153, 1032 cm²¹; ¹H

NMR (CDCl₃, 200 MHz) d 7.53–7.34 (m, 5H, SO₂CH₂C₆-

H₅), 5.87 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.22 (d, 1H, H-2),

4.58–4.27 (m, 5H, H-5, SO₂CH₂C₆H_5,H-6b, H-4), 4.03

(dd, J_5,6a¼6.2 Hz, J_6a,6b¼9.0 Hz, 1H, H-6a), 2.77 (s, 3H,

NCH₃), 1.55 (s, 3H, CH₃), 1.51 (s, 3H, CH₃), 1.45 (s,

3H, CH₃),1.37 (s, 3H, CH₃) ¹³C NMR (CDCl₃, 50 MHz)

4.8.29. 1,2:5,6-Di-O-isopropylidene-a-^D-erythro-pento-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰-N-methyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Bd). Follow-

ing the general method (C), 3Bb (0.50 g, 1.14 mmol),

K₂CO₃(0.23 g, 1.71 mmol) and CH₃I (0.14 mL,

2.28 mmol) in acetone (20 mL) for 48 h gave after ﬂash

chromatography (EtOAc/petroleum ether, 3:7), unreacted

3Bb (43 mg, 8%), (EtOAc/petroleum ether, 7:3), 4Bd

(400 mg, 77%) as a colourless solid. 4Bd: mp 210–

211 8C; [a]²_D⁵þ38 (c 0.33, CHCl₃); IR (KBr) n 3480,

2930, 1647, 1264, 1147, 1069 cm²^{1 1}H NMR (CDCl₃,

;

200 MHz) d 7.61–7.40 (m, 5H, C₆H₅), 5.88 (d, J_1,2¼3.9 Hz,

1H, H-1), 4.79 (d, 1H, H-2), 4.52 (d, J_4,5a¼6.4 Hz, 1H, H-4),

4.35 (br s, 2H, NH₂), 4.25 (m, 1H, H-5), 4.11 (dd,

J_5,6a¼6.2 Hz, J_6a,6b¼8.2 Hz, 1H, H-6a), 3.98 (dd,

J_5,6b¼6.9 Hz, 1H, H-6b), 3.09 (s, 3H, NCH₃), 1.67 (s, 3H,

CH₃), 1.44 (s, 3H, CH₃),1.38 (s, 3H, CH₃), 1.36 (s, 3H,

CH₃); ¹³C NMR (CDCl₃, 50 MHz) d 144.9 (C-4⁰), 129.6–

127.0 (C₆H₅), 126.6 (C-5⁰), 113.5 [OC(CH₃)₂], 110.1

[OC(CH₃)₂], 103.5 (C-1), 85.3 (C-2), 75.5 (C-4), 72.9

(C-5), 70.1 (C-3), 67.0 (C-6), 27.7 (NCH₃), 26.3 (2£CH₃),

26.0, 25.4 (2£CH₃); MS (APCIþ) m/z 453 [Mþ1]^þ, 927

[2MþNa]^þ. Anal. Calcd. for C₂₁H₂₈N₂O₇S (452.52 g/mol):

C, 55.74; H, 6.24; N, 6.19; S, 7.08. Found: C, 55.57; H, 5.98;

N, 5.99; S, 6.82.

d

131.4–128.3 (6 C, SO₂CH₂C₆H₅), 115.6 (CN),

113.5 [OC(CH₃)₂], 110.6 [OC(CH₃)₂], 103.0 (C-1),

85.7 (C-2), 78.6 (C-4), 74.3 (C-5), 68.2 (C-6), 67.3

(C-3), 60.3 (SO₂CH₂C₆H₅), 36.9 (NCH₃), 26.3, 26.2,

26.1, 25.2 (4£CH₃); MS (APCIþ) m/z 453 [Mþ1]^þ,

470 [MþNH₄]^þ, 475 [MþNa]^þ, 927 [2MþNa]^þ.

Anal. Calcd. for C₂₁H₂₈N₂O₇S (452.52 g/mol): C, 55.74;

H, 6.24; N, 6.19; S, 7.08. Found: C, 56.00; H, 6.09; N, 5.94;

S, 6.91.

4.8.28. 3-Amino-3-N-benzyl-3-C-cyano-3-deoxy-1,2:5,6-

di-O-isopropylidene-3-N-phenylmethanesulfonyl a-^D-

allofuranose (3Bg). Following the general method (B),

3Bb (900 mg, 2.05 mmol), K₂CO₃(0.42 g, 3.07 mmol),

BnBr (0.49 mL, 4.10 mmol) in acetone (40 mL) for 4 h gave

successively, after ﬂash chromatography (EtOAc/petroleum

ether, 2:8), compound (3Bg) (172 mg, 16%) as a colourless

solid, unreacted 3Bb (386 mg, 43%), and with (EtOAc/

petroleum ether, 7:3)₀, 1,2:5,6-di-O-isopropylidene-a-^D-

ribofuranose-3-spiro-3 -(4⁰-amino-2⁰-N-benzyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Be) (78 mg,

7%) as a colorless solid. 3Bg: mp 115–117 8C; [a]³_D⁰þ82

(c 0.49, CHCl₃); IR (ATR) n 1447, 1348, 1200, 1145, 1033,

4.8.30. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰-N-benzyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Be). Follow-

ing the general method (C), 3Ab (0.5 g, 1.14 mmol), K₂CO₃

(0.23 g, 1.71 mmol) and BnBr (0.27 mL, 2.28 mmol) in

acetone (20 mL) for 28 h gave, after ﬂash chromatography

(EtOAc/petroleum ether, 7:3), compound 4Be (374 mg,

62%).

866, 698 cm²¹; H NMR (CDCl₃, 300 MHz) d 7.38 (m,

1

10H, 2£C₆H₅), 5.78 (d, J_1,2¼3.7 Hz, 1H, H-1), 5.15 (d, 1H,

H-2), 4.57 (m, 4H, H-4, H-5, NCH₂C₆H₅, SO₂CH₂C₆H₅),

4.43 (d, J_A,B¼13.7 Hz, 1H, H-B, SO₂CH₂C₆H₅), 4.32 (dd,

J_5,6a¼5.7 Hz, J_6a,6b¼8.5 Hz, 1H, H-6a), 4.23 (d,

J_A,B¼16.4 Hz, 1H, H-B, NCH₂C₆H₅), 4.00 (dd,

4722

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4.8.31. 1,2:5,6-Di-O-isopropylidene-a-D-erythro-pento-

furanose-3-spiro-3⁰-(2⁰-N-allyl-4⁰-amino-5⁰-phenyl-5⁰H-

2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Bf). Following

the general method (C), 3Bb (400 mg, 0.91 mmol),

K₂CO₃(0.19 g, 1.36 mmol) and AllBr (0.15 mL,

1.82 mmol) in acetone (20 mL) for 17 h gave after ﬂash

chromatography (EtOAc/petroleum ether, 6:4) compound

4Bf (213 mg, 49%) as a colourless oil: [a]³_D²þ56 (c 0.52,

CHCl₃); IR (ATR) n 3463, 3342, 2986, 1655, 1375, 1266,

1212, 1155, 1069, 873 cm²¹. ¹H NMR (CDCl₃, 300 MHz) d

7.42 (m, 5H, C₆H₅), 6.16 (m, 1H, NCH₂CHvCH₂), 5.84 (d,

[a]³_D²þ43 (c 0.51, CHCl₃); IR (ATR) n 2981, 2356, 1649,

1370, 1255, 1211, 1130, 1071, 871 cm²¹; ¹H NMR (CDCl₃,

300 MHz) d 7.59–7.30 (m, 5H, NCH₂C₆H₅), 5.80 (d,

J_1,2¼3.8 Hz, 1H, H-1), 5.46 (s, 1H, H-5⁰), 4.70 (s, 1H, H-2),

4.59 (m, 3H, NH₂, H-A, NCH₂C₆H₅), 4.52 (d, J_A,B

¼

14.1 Hz, 1H, H-B, NCH₂C₆H₅), 4.41 (d, J_4,5¼6.5 Hz, 1H,

H-4), 4.14 (m, 1H, H-5), 4.05 (dd, J_5,6a¼6.3 Hz,

J_6a,6b¼8.3 Hz, 1H, H-6a), 3.95 (dd, J_5,6b¼6.5 Hz, 1H,

H-6b), 1.56 (s, 3H, CH₃), 1.49 (s, 3H, CH₃), 1.37 (s, 6H,

2£CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 151.8 (C-4⁰),

137.4–127.9 (6 C, NCH₂C₆H₅), 113.5 [OC(CH₃)₂], 110.0

[OC(CH₃)₂], 103.7 (C-1), 94.2 (C-5⁰), 84.8 (C-2), 77.1

(C-4), 72.8 (C-3, C-5), 67.2 (C-6), 47.9 (NCH₂C₆H₅), 26.7

(CH₃), 26.5 (CH₃), 26.4 (CH₃), 25.6 (CH₃); MS (APCIþ)

m/z 453.57 [Mþ1]^þ, 475.34 [MþNa]^þ, 491.26 [MþK]^þ,

927.36 [2MþNa]^þ. Anal. Calcd for C₂₁H₂₈N₂0₇S

(452.16 g/mol): C, 55.74; H, 6.24; N, 6.19; S, 7.09.

Found: C, 56.02; H, 6.30; N, 6.44; S, 7.25.

J_1,2¼3.9 Hz, 1H, H-1), 5.30 (dd, J_A,B¼1.0 Hz, J_A,b

¼

17.0 Hz, 1H, NCH₂CH¼CH₂), 5.14 (dd, J_B,b¼10.1 Hz,

1H, NCH₂CH¼CH₂), 4.68 (d, 1H, H-2), 4.46 (s, 2H, NH₂),

4.44 (d, J_4,5¼6.3 Hz, 1H, H-4), 4.20 (m, 1H, H-5), 4.11 (m,

2H, NCH₂CH¼CH₂), 4.03 (dd, J_5,6a¼6.1 Hz, J_6a,6b

¼

8.3 Hz, 1H, H-6a), 3.92 (dd, J_5,6b¼7.1 Hz, 1H, H-6b),

1.62 (s, 3H, CH₃), 1.42 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.32

(s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 145.2 (C-4⁰),

135.3 (NCH₂CH¼CH₂), 129.8–126.9 (6 C, C₆H₅), 118.2

(NCH₂CHvCH₂), 113.6 [OC(CH₃)₂], 110.1 [OC(CH₃)₂],

107.8 (C-5⁰), 103.9 (C-1), 84.8 (C-2), 76.5 (C-4), 73.0 (C-5),

70.8 (C-3), 67.2 (C-6), 46.4 (NCH₂CHvCH₂), 26.6 (CH₃),

26.5 (CH₃), 26.3 (CH₃), 25.6 (CH₃); MS (APCIþ) m/z 501.5

[MþNa]^þ, 517.5 [MþK]^þ, 979.6 [2MþNa]^þ. Anal. Calcd

for C₂₃H₃₀N₂0₇S (478.18 g/mol): C, 57.72; H, 6.32; N, 5.85;

S, 6.70. Found: C, 57.77; H, 6.53; N, 5.67; S, 6.61.

4.8.34. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(2⁰-N-allyl-4⁰-amino-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (4Bc). Following the

general method (D), Cs₂CO₃(216 mg, 0.66 mmol) was

added to a solution of 3Be (267 mg, 0.66 mmol) in CH₃CN

(10 mL). The reaction mixture was reﬂuxed for 6 h then

evaporated to dryness. The residue was puriﬁed by ﬂash

chromatography (EtOAc/petroleum ether, 8:2) to give 4Bc

(177 mg, 66%) as a colourless solid: mp 205–207 8C; [a]_D³²

þ40 (c 0.50, CHCl₃); IR (ATR) n 3430, 3337, 2981, 1636,

1375, 1249, 1211, 1073, 1031, 873 cm²¹; ¹H NMR (CDCl₃,

300 MHz) d 6.10 (m, 1H, NCH₂CHvCH₂), 5.81 (d,

J_1,2¼3.9 Hz, 1H, H-1), 5.60 (s, 1H, H-5⁰), 5.28 (dd,

J¼17.2 Hz, 1H, NCH₂CHvCH₂), 5.14 (dd, J¼10.1 Hz,

1H, NCH₂CHvCH₂), 4.87 (d, 2H, NH₂), 4.63 (d, 1H, H-2),

4.31 (d, J_4,5¼6.7 Hz, 1H, H-4), 4.04 (m, 5H, H-5, H-6,

NCH₂CHvCH₂), 1.58 (s, 3H, CH₃), 1.42 (s, 3H, CH₃), 1.34

(s, 3H, CH₃), 1.31 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz)

d 151.9 (C-4⁰), 135.2 (NCH₂CHvCH₂), 118.2 (NCH₂-

CHvCH₂), 113.6 [OC(CH₃)₂], 110.3 [OC(CH₃)₂], 103.7

(C-1), 94.3 (C-5⁰), 84.7 (C-2), 76.5 (C-4), 72.8 (C-5), 72.3

(C-3), 67.3 (C-6), 46.3 (NCH₂CHvCH₂), 26.7 (CH₃), 26.4

(CH₃), 26.3 (CH₃), 25.5 (CH₃); MS (APCIþ) m/z 425.2

[MþNa]^þ, 441.2 [MþK]^þ, 827.3 [2MþNa]^þ. Anal. Calcd

for C₁₇H₂₆N₂0₇S (402.15 g/mol): C, 50.73; H, 6.51; N, 6.96;

S, 7.97. Found: C, 50.61; H, 6.37; N, 6.84; S, 7.66.

4.8.32. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰-N-methyl-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (4Ba). Following the

general method (D), Cs₂CO₃(0.21 g, 0.66 mmol) was

added to a solution of 3Bc (0.25 g, 0.66 mmol) in CH₃CN

(4 mL). The reaction mixture was reﬂuxed for 30 min then

evaporated to dryness. The residue was puriﬁed by ﬂash

chromatography (EtOAc/petroleum ether, 7:3) to give 4Ba

(0.10 g, 40%) as a colourless solid: mp 238–240 8C; [a]_D²⁶

þ45 (c 0.18, CHCl₃); IR (ATR) n 3414, 3332, 2981, 1650,

1370, 1260, 1213, 1071 cm²¹; ¹H NMR (CDCl₃, 300 MHz)

d 5.82 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.64 (s, 1H, H-5⁰), 4.69 (s,

1H, NH₂), 4.68 (d, 1H, H-2), 4.38 (d, J_4,5¼6.9 Hz, 1H, H-4),

4.19 (q, J_5,6a¼J_5,6b¼6.4 Hz, 1H, H-5), 4.11 (dd, J_6b,6a

¼

8.3 Hz, 1H, H-6b), 3.98 (dd, 1H, H-6a), 2.99 (s, 3H, NCH₃),

1.63 (s, 3H, CH₃), 1.43 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.34

(s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 151.4 (C-

4⁰), 113.4, 110.1 [2£OC(CH₃)₂], 103.2 (C-1), 94.4 (C-5⁰),

85.1 (C-2), 75.4 (C-5), 72.6 (C-4), 71.4 (C-3), 67.0 (C-

6), 27.1 (NCH₃), 26.2 (CH₃), 26.1 (CH₃), 25.9 (CH₃),

25.1 (CH₃); MS (APCIþ) m/z 377.34 [Mþ1]^þ, 399.12

[MþNa]^þ, 415.24 [MþK]^þ, 775.29 [2MþNa]^þ. Anal.

Calcd for C₁₅H₂₄N₂0₇S (376.13 g/mol): C, 47.86; H,

6.43; N, 7.44; S, 8.52. Found: C, 47.64; H, 6.18; N, 7.45;

S, 8.37.

4.8.35. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰-N-methyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Bd). Follow-

ing the general method (D), Cs₂CO₃(40 mg, 0.12 mmol)

was added to a solution of 3Bf (46 mg, 0.10 mmol) in

CH₃CN (4 mL). The reaction mixture was reﬂuxed for 2 h

then evaporated to dryness. The residue was puriﬁed by

ﬂash chromatography (EtOAc/petroleum ether, 4:6) to give

4Bd (44 mg, 96%).

4.8.33. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰-N-benzyl-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (4Bb). Following the

general method (D), Cs₂CO₃(0.27 g, 0.83 mmol) was

added to a solution of 3Bd (378 mg, 0.83 mmol) in

CH₃CN (5 mL). The reaction mixture was reﬂuxed for 1 h

then evaporated to dryness. The residue was puriﬁed by

ﬂash chromatography (EtOAc/petroleum ether, 9:1) to give

4Bb (364 mg, 96%) as a colourless solid: mp 88–90 8C;

4.8.36. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰-N-benzyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (4Be). Follow-

ing the general method (D), Cs₂CO₃(50 mg, 0.15 mmol)

was added to a solution of 3Bg (82 mg, 0.15 mmol) in

CH₃CN (5 mL). The reaction mixture was reﬂuxed for 1 h

then evaporated to dryness. The residue was puriﬁed by

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4723

0

ﬂash chromatography (EtOAc/petroleum ether, 5:5) to give

4Be (65 mg, 79%).

3.99 (dd, 1H, H-5b), 3.58 (d, J_{5 a,5 b}¼13.2 Hz, 1H, H-5⁰b),

3.36 (d, 1H, H-5⁰a), 3.01 (s, 3H, NCH₃), 2.14 (s, 2H, NH₂),

1.60 (s, 3H, CH₃), 1.36 (s, 3H, CH₃); ¹³C NMR (CDCl₃,

75 MHz) d 113.0 [OC(CH₃)₂], 106.4 (C-1), 95.5 (C-4⁰), 82.4

(C-2), 79.7 (C-4), 79.4 (C-3), 70.3 (C-5), 57.1 (C-5⁰), 28.3

(NCH₃), 27.1 (CH₃), 26.4 (CH₃); MS (APCIþ) m/z 329.2

[MþNa]^þ. Anal. Calcd for C₁₁H₁₈N₂0₆S (306.09 g/mol): C,

43.13; H, 5.92; N, 9.14; S, 10.47. Found: C, 43.35; H, 5.73;

N, 9.07; S, 10.66.

4.8.37. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-5⁰H-2⁰,3⁰-dihydroiso-

thiazole-1⁰,1⁰-dioxide) (4Bg). Following the general

method (E), n-BuLi (1.1 mL, 1.65 mmol, 1.6 M in hexane)

was added to a solution of 3Ba (200 mg, 0.55 mmol) in THF

(5 mL). The reaction mixture was stirred for 5 min at

210 8C. The crude was ﬂash chromatographed with EtOAc

to give 4Bg (120 mg, 60%) as a colourless solid: mp 230–

233 8C; [a]²_D⁵þ12 (c 0.48, CH₂Cl₂); IR (ATR) n 1650,

4.8.40. (1S,3R,7R,8R,12S,14R)-12-Amino-9-N-benzyl-5-

dimethyl-10-thia-10,10-dioxide-9-aza-2,4,6,13-tetra-

oxatetracyclo[6.6.0.0^3,7.0^8,12]tetradecane (5Ab). Follow-

ing the general method (F), acetic acid (16 mL) and water

(4 mL) were added to the compound 4Ab (255 mg,

0.41 mmol). After 1 h and ﬂash chromatography (EtOAc/

petroleum ether, 7:3) compound 5Ab (91 mg, 58%) was

isolated as a colourless solid: mp 92–94 8C; [a]²_D⁵þ22 (c

0.9, CHCl₃); IR (KBr) n 3486, 2928, 1629, 1496, 1457,

1370, 1266, 1219, 1118, 1068, 1029 cm²^{1 1}H NMR

;

(CDCl₃, 300 MHz) d 5.86 (d, J_1,2¼3.6 Hz, 1H, H-1), 5.54

(s, 1H, NH), 5.05 (s, 1H, SO₂CH), 4.75 (s, 2H, NH₂), 4.60

(d, 1H, H-2), 4.32 (ddt, J_5,6b¼J_5,6a¼5.7 Hz, J_4,5¼7.1 Hz,

1H, H-5), 4.03 (m, 3H, H-4, H-6a, H-6b), 1.55 (s, 3H, CH₃),

1.41 (s, 3H, CH₃), 1.33 (s, 3H, CH₃), 1.30 (s, 3H, CH₃); ¹³

C

NMR (CDCl₃, 75 MHz) d 153.0 (C-4⁰), 113.7 [OC(CH₃)₂],

110.3 [OC(CH₃)₂], 103.7 (C-1), 95.4 (C-5⁰), 82.9 (C-2), 78.4

(C-4), 73.1 (C-5), 70.4 (C-3), 66.8 (C-6), 26.5 (CH₃), 26.3

(2£CH₃), 25.2 (CH₃); MS (APCIþ) m/z 385.20 [MþNa]^þ.

Anal. Calcd for C₁₄H₂₂N₂0₇S (362.11 g/mol): C, 46.40; H,

6.12; N, 7.73; S, 8.85. Found: C, 46.35; H, 5.98; N, 7.64; S,

8.58.

1384, 1295, 1211, 1154, 1072, 1021 cm²^{1 1}H NMR

;

(CDCl₃, 200 MHz) d 7.31–7.25 (m, 5H, C₆H₅), 5.65 (d,

J_1,2¼3.8 Hz, 1H, H-1), 4.99 (d, 1H, H-2), 4.78 (s, 2H,

NCH₂C₆H₅), 4.37 (d, J_4,5b¼3.5 Hz, 1H, H-4), 3.71 (d,

0

J_5a,5b¼10.0 Hz, 1H, H-5a), 3.61 (d, J_{5 a,5 b}¼13.0 Hz, 1H,

H-5⁰a), 3.29 (dd, 1H, H-5b), 3.27 (d, 1H, H-5⁰b), 2.00 (br s,

2H, NH₂), 1.61 (s, 3H, CH₃), 1.30 (s, 3H, CH₃); ¹³C NMR

4.8.38. 1,2:5,6-Di-O-isopropylidene-a-^D-ribo-hexo-

furanose-3-spiro-3⁰-(4⁰-amino-5⁰-phenyl-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (4Bh). Following the

general method (E), n-BuLi (1.37 mL, 3.42 mmol, 2.5 M

in hexane) was added to a solution of 3Bb (500 mg,

1.14 mmol) in THF (10 mL). The reaction mixture was

stirred for 20 min at 210 8C. The crude was ﬂash

chromatographed (EtOAc/petroleum ether, 8:2) to give

4Bh (404 mg, 80%) as a colourless solid: mp 95–97 8C;

[a]²_D⁹þ46 (c 0.54, CHCl₃); IR (ATR) n 2986, 1644, 1375,

(CDCl₃, 50 MHz)

d

137.6–128.0 (C₆H₅), 112.6

[OC(CH₃)₂], 106.1 (C-1), 95.6 (C-4⁰), 81.6 (C-2), 80.3

(C-4), 78.5 (C-3), 70.0 (C-5), 58.5 (C-5⁰), 44.8

(NCH₂C₆H₅), 26.9 (CH₃), 25.9 (CH₃); MS (APCIþ) m/z

383 [Mþ1]^þ, 405 [MþNa]^þ, 765 [2Mþ1]^þ, 787

[2MþNa]^þ. Anal. Calcd for C₁₇H₂₂N₂0₆S (382.46 g/mol):

C, 53.39; H, 5.80; N, 7.33; S, 8.38. Found: C, 53.12; H, 5.97;

N, 7.12; S, 8.42.

4.8.41. (1S,3R,7R,8R,12S,14R)-12-Amino-5-dimethyl-10-

thia-10,10-dioxide-9-aza-2,4,6,13-tetraoxatetracyclo-

[6.6.0.0^3,7.0^8,12]tetradecane (5Ac). Following the general

method (F), acetic acid (18 mL) and water (12 mL) were

added to the compound 4Ag (1.08 g, 2.02 mmol). After 1 h

30 min and ﬂash chromatography (EtOAc) compound 5Ac

(343 mg, 57%) was isolated as a colourless oil: [a]²_D⁹þ42 (c

0.69, CHCl₃); IR (ATR) n 2987, 1647, 1378, 1314, 1217,

1

1205, 1145, 1058, 866, 745, 696 cm²¹; H NMR (acetone

d₆, 300 MHz) d 7.56–7.39 (m, 5H, C₆H₅), 6.18 (d,

J_1,2¼3.8 Hz, 1H, H-1), 4.79 (d, 1H, H-2), 4.50 (m, 1H,

H-5), 4.30 (d, J_4,5¼4.6 Hz, 1H, H-4), 4.08 (m, 2H, H-6),

1.58 (s, 3H, CH₃), 1.43 (s, 3H, CH₃), 1.38 (s, 3H, CH₃), 1.30

(s, 3H, CH₃); ¹³C NMR (acetone d₆, 75 MHz) d 147.1

(C-4⁰), 129.4–127.7 (6 C, C₆H₅), 113.3 [OC(CH₃)₂], 109.2

[OC(CH₃)₂], 106.7 (C-5⁰), 104.6 (C-1), 83.0 (C-2), 80.0

(C-4), 73.5 (C-5), 68.8 (C-3), 65.8 (C-6), 26.2 (2£CH₃),

26.0 (CH₃), 25.4 (CH₃); MS (APCIþ) m/z 439.40 [Mþ1]^þ,

461.37 [MþNa]^þ, 477.36 [MþK]^þ, 899.42 [2MþNa]^þ,

916.45 [2MþK]^þ. Anal. Calcd for C₂₀H₂₆N₂0₇S

(438.15 g/mol): C, 54.78; H, 5.98; N, 6.39; S, 7.31.

Found: C, 54.61; H, 5.71; N, 6.53; S, 7.46.

1164, 1010, 912, 876, 732 cm²¹

;

¹H NMR (CDCl₃,

300 MHz) d 5.85 (d, J_1,2¼3.9 Hz, 1H, H-1), 5.67 (s, 1H,

NH), 4.90 (d, 1H, H-2), 4.45 (d, J_4,5b¼2.9 Hz, 1H, H-4),

4.13 (d, J_5a,5b¼10.7 Hz, 1H, H-5a), 4.05 (dd, 1H, H-5b),

3.60 (d, J_{5 a,5 b}¼13.3 Hz, 1H, H-5⁰a), 3.38 (d, J_{5 a,NH}¼1.6

Hz, 1H, H-5⁰b), 2.25 (s, 2H, NH₂), 1.54 (s, 3H, CH₃), 1.37

(s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 113.2

[OC(CH₃)₂], 106.4 (C-1), 96.7 (C-4⁰), 84.1 (C-4), 79.9

(C-2), 77.6 (C-3), 69.6 (C-5), 58.9 (C-5⁰), 27.3 (CH₃), 27.0

(CH₃); MS (APCIþ) m/z 314.99 [MþNa]^þ. Anal. Calcd for

C₁₀H₁₆N₂0₆S (292.07 g/mol): C, 41.09; H, 5.52; N, 9.58; S,

10.97. Found: C, 41.35; H, 5.58; N, 9.64; S, 10.88.

0

4.8.39. (1S,3R,7R,8R,12S,14R)-12-Amino-5-dimethyl-9-

N-methyl-10-thia-10,10-dioxide-9-aza-2,4,6,13-tetra-

oxatetracyclo[6.6.0.0^3,7.0^8,12]tetradecane (5Aa). Follow-

ing the general method (F), acetic acid (12 mL) and water

(3 mL) were added to the compound 4Aa (157 mg,

0.28 mmol). After 1 h 10 min and ﬂash chromatography

(EtOAc/petroleum ether, 7:3) compound 5Aa (31 mg, 35%)

was isolated as a colourless solid: mp 139–141 8C; [a]_D²⁵

þ117 (c 0.59, CHCl₃); IR (ATR) n 3364, 2915, 1370, 1293,

1235, 1121, 1060 cm²¹; ¹H NMR (CDCl₃, 300 MHz) d 5.77

(d, J_1,2¼3.8 Hz, 1H, H-1), 4.97 (d, 1H, H-2), 4.80 (d,

J_4,5¼3.1 Hz, 1H, H-4), 4.18 (dd, J_5a,5b¼10.7 Hz, 1H, H-5a),

4.8.42. 1,2-O-Isopropylidene-a-^D-erythro-pento-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰N-methyl-5⁰-phenyl-

5⁰H-2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (6Aa). Follow-

ing the general method (F), acetic acid (8 mL) and water

(2 mL) were added to the compound 4Ad (374 mg,

0.60 mmol). After 2 h 30 min and ﬂash chromatography

(EtOAc) compound 6Aa (199 mg, 87%) was isolated as a

4724

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

colourless oil: [a]²_D⁹þ42 (c 0.34, DMSO); IR (ATR) n 1633,

1249, 1205, 1140, 1063, 1025, 877 cm²¹; ¹H NMR (DMSO

d₆, 300 MHz) d 7.40 (m, 5H, C₆H₅), 6.15 (d, J_1,2¼3.9 Hz,

1H, H-1), 5.79 (s, 2H, NH₂), 5.03 (s, 1H, OH), 4.69 (d, 1H,

H-2), 4.48 (dd, J_4,5a¼1.9 Hz, J_4,5b¼7.7 Hz, 1H, H-4) 3.53

(m, 2H, H-5), 2.88 (s, 3H, NCH₃), 1.58 (s, 3H, CH₃), 1.31 (s,

3H, CH₃); ¹³C NMR (DMSO d₆, 75 MHz) d 147.5 (C-4⁰),

129.8-128.3 (6 C, C₆H₅), 112.8 [OC(CH₃)₂], 104.3 (C-1),

102.6 (C-5⁰), 84.7 (C-2), 77.7 (C-4), 69.7 (C-3), 59.7 (C-5),

27.9 (NCH₃), 26.7 (2£CH₃); MS (APCIþ) m/z 405.0

[MþNa]^þ, 421.05 [MþK]^þ, 787.09 [2MþNa]^þ. Anal.

Calcd for C₁₇H₂₂N₂0₆S (382.12 g/mol): C, 53.39; H, 5.80;

N, 7.33; S, 8.38. Found: C, 53.35; H, 5.98; N, 7.52; S, 8.65.

compound 4Ba (1.27 g, 3.37 mmol). After 2 h 15 min and

ﬂash chromatography (EtOAc/petroleum ether, 9:1) com-

pound 5Ba (1.03 g, 90%) was isolated as a colourless solid:

mp 180–182 8C; [a]³_D⁰þ88 (c 0.25, MeOH); IR (ATR) n

1370, 1282, 1260, 1112, 1014, 866 cm²¹; ¹H NMR (DMSO

d₆, 300 MHz) d 5.84 (d, J_1,2¼3.6 Hz, 1H, H-1), 4.83 (t,

J_OH,6¼5.9 Hz, 1H, OH), 4.78 (d, 1H, H-2), 4.71 (s, 1H,

0

H-4), 4.08 (t, J_5,6¼6.6 Hz, 1H, H-5), 3.57 (d, J_{5 a,5 b}¼13.8

Hz, 1H, H-5⁰a), 3.46 (d, 1H, H-5⁰b), 3.31 (m, 2H, H-6), 2.83

(s, 3H, NCH₃), 1.50 (s, 3H, CH₃), 1.27 (s, 3H, CH₃); ¹³C

NMR (DMSO d₆, 75 MHz) d 112.5 [OC(CH₃)₂], 106.7

(C-1), 96.4 (C-4⁰), 84.2 (C-5), 82.4 (C-2), 81.1 (C-4), 79.9

(C-3), 61.7 (C-6), 57.4 (C-5⁰), 27.9 (NCH₃), 27.5 (CH₃),

27.1 (CH₃); MS (APCIþ) m/z 358.99 [MþNa]^þ. Anal.

Calcd for C₁₂H₂₀N₂0₇S (336.10 g/mol): C, 42.85; H, 5.99;

N, 8.33; S, 9.53. Found: C, 42.71; H, 5.84; N, 8.64; S, 9.61.

4.8.43. 1,2-O-Isopropylidene-a-^D-erythro-pento-

furanose-3-spiro-3⁰-(4⁰-amino-2⁰N-benzyl-5⁰-phenyl-5⁰H-

2⁰,3⁰-dihydroisothiazole-1⁰,1⁰-dioxide) (6Ab). Following

the general method (F), acetic acid (12 mL) and water

(3 mL) were added to the compound 4Ae (185 mg,

0.40 mmol). After 1 h 30 min and ﬂash chromatography

(EtOAc) compound 6Ab (63 mg, 72%) was isolated as a

colourless solid: mp 108–110 8C; [a]³_D⁰þ54 (c 0.57,

DMSO); IR (ATR) n 1649, 1452, 1375, 1271, 1151, 1068,

1025, 871, 751, 685 cm²¹; ¹H NMR (MeOH d₆, 300 MHz)

d 7.45 (m, 10H, 2£C₆H₅), 6.05 (d, J_1,2¼3.9 Hz, 1H, H-1),

4.86 (m, 5H, H-2, NH₂, OH, H-A NCH₂C₆H₅), 4.69 (d,

J_A,B¼14.8 Hz, 1H, H-B NCH₂C₆H₅), 4.57 (dd,

J_4,5a¼2.9 Hz, J_4,5b¼7.3 Hz, 1H, H-4), 3.76 (m, 2H, H-5),

1.60 (s, 3H, CH₃), 1.40 (s, 3H, CH₃); ¹³C NMR (MeOH d₄,

75 MHz) d 147.5 (C-4⁰), 137.6–127.2 (12 C, 2£C₆H₅),

113.4 [OC(CH₃)₂], 104.4 (2 C, C-1, C-5⁰), 84.9 (C-2), 78.0

(C-4), 70.4 (C-3), 59.6 (C-5), 46.1 (NCH₂C₆H₅), 25.5

(CH₃), 25.2 (CH₃); MS (APCIþ) m/z 481.10 [MþNa]^þ,

497.08 [MþK]^þ, 939.13 [2MþNa]^þ. Anal. Calcd for

C₂₃H₂₆N₂0₆S (458.15 g/mol): C, 60.25; H, 5.72; N, 6.11;

S, 6.99. Found: C, 60.37; H, 5.62; N, 6.04; S, 6.72.

4.8.46. (1S,3R,7R,8R,12S,14R)-12-Amino-9-N-benzyl-14-

hydroxymethylene-5-dimethyl-10-thia-10,10-dioxide-9-

aza-2,4,6,13-tetraoxatetracyclo[6.6.0.0^3,7.0^8,12]tetra-

decane (5Bb). Following the general method (F), acetic

acid (30 mL) and water (20 mL) were added to the

compound 4Bb (2.35 g, 5.2 mmol). After 4 h 30 min and

ﬂash chromatography (EtOAc/petroleum ether, 6.5:3.5)

compound 5Bb (1.17 g, 54%) was isolated as a colourless

solid: mp 127–129 8C; [a]³_D¹þ31 (c 0.33, MeOH); IR

(ATR) n 1375, 1293, 1123, 1058, 1016, 860 cm²¹; ¹H NMR

(DMSO d₆, 300 MHz) d 7.41–7.30 (m, 5H, C₆H₅), 5.89 (d,

J_1,2¼3.5 Hz, 1H, H-1), 4.87 (d, 1H, H-2), 4.71 (t,

J_OH,6¼5.9 Hz, 1H, OH), 4.61 (d, J_A,B¼13.6 Hz, 2H,

NCH₂C₆H₅), 4.53 (s, 1H, H-4), 4.00 (m, 1H, H-5), 3.61

(d, J_{5 a,5 b}¼13.7 Hz, 1H, H-5⁰a), 3.48 (d, 1H, H-5⁰b), 3.16

(m, 1H, H-6a), 3.00 (m, 1H, H-6b), 1.53 (s, 3H, CH₃), 1.31

(s, 3H, CH₃); ¹³C NMR (DMSO d₆, 75 MHz) d 138.2–

128.2 (6C, C₆H₅), 112.8 [OC(CH₃)₂], 107.2 (C-1), 95.9

(C-4⁰), 85.0 (C-5), 82.9 (C-4), 82.5 (C-2), 80.5 (C-3), 61.7

(C-6), 58.2 (C-5⁰), 46.4 (NCH₂C₆H₅), 27.8 (CH₃), 27.2

(CH₃); MS (APCIþ) m/z 413.16 [Mþ1]^þ, 435.16

[MþNa]^þ, 451.12 [MþK]^þ. Anal. Calcd for C₁₈H₂₄N₂0₇S

(412.13 g/mol): C, 52.42; H, 5.86; N, 6.79; S, 7.77. Found:

C, 52.35; H, 5.73; N, 6.69; S, 7.49.

0

4.8.44. 1,2-O-Isopropylidene-a-^D-erythro-pento-

furanose-3-spiro-3⁰-(4⁰-amino-5⁰-phenyl-5⁰H-2⁰,3⁰-

dihydroisothiazole-1⁰,1⁰-dioxide) (6Ac). Following the

general method (F), acetic acid (8 mL) and water (2 mL)

were added to the compound 4Ah (290 mg, 0.47 mmol).

After 50 min and ﬂash chromatography (EtOAc/petroleum

ether, 7:3) compound 6Ac (130 mg, 74%) was isolated as a

colourless oil: [a]²_D⁸þ24 (c 0.37, DMSO); IR (ATR) n 1644,

4.8.47. (1S,3R,7R,8R,12S,14R)-12-Amino-14-hydroxy-

methylene-5-dimethyl-10-thia-10,10-dioxide-9-aza-

2,4,6,13-tetraoxatetracyclo[6.6.0.0^3,7.0^8,12]tetradecane

(5Bc). Following the general method (F), acetic acid

(18 mL) and water (12 mL) were added to the compound

4Bg (776 mg, 2.14 mmol). After 2 h 30 min and ﬂash

chromatography (EtOAc/petroleum ether, 8:2) compound

5Bc (495 mg, 71%) was isolated as a colourless solid: mp

198–200 8C; [a]³_D⁰þ94 (c 0.20, MeOH); IR (ATR) n 3403,

3364, 2921, 2844, 2356, 1375, 1299, 1167, 1079, 1014,

1

1271, 1101, 1063, 1025, 893, 866, 762 cm²¹; H NMR

(DMSO d₆, 300 MHz) d 7.43 (m, 5H, C₆H₅), 6.14 (d,

J_1,2¼4.0 Hz, 1H, H-1), 5.72 (s, 2H, NH₂), 4.98 (s, 1H, OH),

4.55 (d, 1H, H-2), 4.11 (dd, J_4,5a¼1.5 Hz, J_4,5b¼8.2 Hz, 1H,

H-4), 3.69 (m, 1H, H-5a), 3.58 (m, 1H, H-5b), 1.44 (s, 3H,

CH₃), 1.31 (s, 3H, CH₃); ¹³C NMR (DMSO d₆, 75 MHz) d

147.4 (C-4⁰), 129.7–128.3 (C₆H₅), 112.7 [OC(CH₃)₂], 104.6

(C-1), 104.2 (C-5⁰), 82.6 (C-2), 82.1 (C-4), 68.7 (C-3), 59.4

(C-5), 27.2 (CH₃), 27.0 (CH₃); MS (APCIþ) m/z 390.96

[MþNa]^þ, 759.09 [2MþNa]^þ. Anal. Calcd for

C₁₆H₂₀N₂0₆S (368.10 g/mol): C, 52.16; H, 5.47; N, 7.60;

S, 8.70. Found: C, 52.35; H, 5.78; N, 7.64; S, 8.58.

844 cm²^{1 1}H NMR (DMSO d₆, 300 MHz) d 5.88 (d,

;

J_1,2¼3.7 Hz, 1H, H-1), 4.99 (t, J_OH,6¼5.3 Hz, 1H, OH), 4.66

(d, 1H, H-2), 4.31 (s, 1H, H-4), 4.07 (t, J_5,6¼6.3 Hz, 1H,

H-5), 3.49 (m, 3H, H-6, H-5⁰a), 3.36 (d, J_{5 a,5 b}¼14.0 Hz,

1H, H-5⁰b), 1.46 (s, 3H, CH₃), 1.29 (s, 3H, CH₃); ¹³C NMR

(DMSO d₆, 75 MHz) d 112.3 [OC(CH₃)₂], 107.0 (C-1), 98.5

(C-4⁰), 85.3 (C-₀4), 83.9 (C-5), 80.2 (C-2), 78.3 (C-3), 61.9

(C-6), 60.3 (C-5 ), 27.8 (CH₃), 27.5 (CH₃); MS (APCIþ) m/z

345.0 [MþNa]^þ, 361.0 [MþK]^þ, 667.0 [2MþNa]^þ. Anal.

Calcd for C₁₁H₁₈N₂0₇S (322.08 g/mol): C, 40.99; H, 5.63; N,

8.69; S, 9.95. Found: C, 40.76; H, 5.83; N, 8.51; S, 9.72.

0

4.8.45. (1S,3R,7R,8R,12S,14R)-12-Amino-14-hydroxy-

methylene-5-dimethyl-9-N-methyl-10-thia 10,10-di-

oxide-9-aza-2,4,6,13-tetraoxatetracyclo[6.6.0.0^3,7.0^8,12]-

tetradecane (5Ba). Following the general method (F),

acetic acid (24 mL) and water (16 mL) were added to the

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4725

4.9. X-ray crystal analysis structure of 5Bc

7.59–7.37 (m, 10H, 2£C₆H₅), 5.82 (d, J_1,2¼3.8 Hz, 1H,

H-1), 4.83 (d, J_A,B¼14.4 Hz, 1H, H-A, NCH₂C₆H₅), 4.78

(d, 1H, H-2), 4.56 (d, 1H, H-B, NCH₂C₆H₅), 4.51 (s, 2H,

NH₂), 4.44 (d, J_4,5¼8.9 Hz, 1H, H-4), 3.83 (m, 2H, H-5,

H-6a), 3.65 (dd, J_5,6b¼6.7 Hz, J_6a,6b¼11.6 Hz, 1H, H-6b),

1.57 (s, 3H, CH₃), 1.34 (s, 3H, CH₃); ¹³C NMR (CDCl₃,

75 MHz) d 146.1 (C-4⁰), 136.9–126.3 (12 C, 2£C₆H₅),

113.7 [OC(CH₃)₂], 107.2 (C-5⁰), 103.6 (C-1), 84.7 (C-2),

76.3 (C-4), 71.6 (C-3), 69.8 (C-5), 64.7 (C-6), 48.0

(NCH₂C₆H₅), 26.4 (2£CH₃); MS (APCIþ) m/z 489.2

[Mþ1]^þ, 511.1 [MþNa]^þ, 527.1 [MþK]^þ. Anal. Calcd

for C₂₄H₂₈N₂0₇S (488.16 g/mol): C, 59.00; H, 5.78; N, 5.73;

S, 6.56. Found: C, 59.27; H, 5.81; N, 5.84; S, 6.79.

Crystal data: C₁₁H₁₈N₂O₇S, molecular mass¼322.33,

˚

3

orthorhombic, P2₁2₁2₁, a¼7.0092(6) A, b¼10.7175(8) A,

3

˚

18.772(2) A, V¼1410.1(2) A , Z¼4, D_c¼1.518 mg/m ,

F(000)¼680, m¼0.266 mm²¹. Data collection: SMART

CCD-BRUKER diffractometer, with graphite-mono-

˚

chromated Mo Ka radiation (l¼0.71073 A) operating at

50 kV and 20 mA. The intensity data were collected over an

hemisphere of the reciprocal space by combination of three

exposure sets. Each exposure of 30 s covered 0.3 in v.

Reﬂection range for the data collection were

2.178,u,28.728. The ﬁrst 50 frames were recollected at

the end of the data collection to monitor crystal decay. A

total of 8803 reﬂections were measured and 3319 were

considered observed [I.2((I) criterium].

4.9.3. 1,2-O-Isopropylidene-a-^D-ribo-hexofuranose-3-

spiro-3⁰-(4⁰-amino-5⁰-phenyl-5⁰H-2⁰,3⁰-dihydroiso-

thiazole-1⁰,1⁰-dioxide) (6Bc). Following the general

method (F), acetic acid (18 mL) and water (12 mL) were

added to the compound 4Bh (279 mg, 0.63 mmol). After 5 h

20 min, the solvent was eliminated under vacuum. The

residue was triturated with a solution of EtOAc–petroleum

ether to give after ﬁltration 6Bc (53.5 mg, 21%) as a

colourless solid: mp 104–106 8C; [a]³_D⁴þ4 (c 0.06, MeOH);

Structure solution and reﬁnement: the structure was solved

by direct methods. The reﬁnement was done by full matrix

least-squares procedures on F²(SHELXTL version 5.1).¹⁰

The non-hydrogen atoms were reﬁned anisotropically. The

hydrogen atoms were located from Fourier difference and

the coordinates was reﬁned except those involved in methyl

group that reﬁned as riding on the carbon bonded atom.

Final R(Rw) value was 3.71 (8.74). Further crystallographic

details for the structure reported in this paper may be

obtained from the Cambridge Crystallographic Data Center,

on quoting the depository number CCDC- 223921.

1

IR (ATR) n 1644, 1249, 1151, 1101, 1036, 860 cm²¹; H

NMR (MeOH d₄, 300 MHz) d 7.57–7.43 (m, 5H, C₆H₅),

6.03 (d, J_1,2¼3.8 Hz, 1H, H-1), 4.71 (s, 1H, H-2), 4.18 (d,

J_4,5¼8.2 Hz, 1H, H-4), 4.04 (m, 1H, H-5), 3.77 (dd,

J_5,6a¼2.9 Hz, J_6a,6b¼11.7 Hz, 1H, H-6a) 3.65 (dd,

J_5,6b¼5.7 Hz, 1H, H-6b), 1.61 (s, 3H, CH₃), 1.40 (s, 3H,

CH₃); ¹³C NMR (MeOH d₄, 75 MHz) d 149.0 (C-4⁰),

132.0–127.5 (6C, C₆H₅), 113.4 [OC(CH₃)₂], 105.7 (C-5⁰),

104.3 (C-1), 83.7 (C-2), 78.1 (C-4), 70.7 (C-5), 69.6 (C-3),

63.9 (C-6), 25.6 (CH₃); MS (APCIþ) m/z 421.05 [MþNa]^þ.

Anal. Calcd for C₁₇H₂₂N₂0₇S (398.11 g/mol): C, 51.25; H,

5.57; N, 7.03; S, 8.05. Found: C, 51.35; H, 5.60; N, 7.34; S,

8.23.

4.9.1. 1,2-O-Isopropylidene-a-^D-ribo-hexofuranose-3-

spiro-3⁰-(4⁰-amino-2⁰N-methy-5⁰-phenyl-5⁰H-2⁰,3⁰-di-

hydroisothiazole-1⁰,1⁰-dioxide) (6Ba). Following the

general method (F), acetic acid (6 mL) and water (4 mL)

were added to the compound 4Bd (301 mg, 0.66 mmol).

After 2 h 15 min, the solvent was eliminated under vacuum.

The residue was triturated with a solution of EtOAc–

petroleum ether to give after ﬁltration 6Ba (265 mg, 100%)

as a colourless solid: mp 115–116 8C; [a]²_D⁸þ54 (c 0.19,

CHCl₃); IR (ATR) n 3419, 2986, 2915, 1645, 1252, 1139,

1047, 1017, 876, 701 cm²¹; ¹H NMR (DMSO d₆, 300 MHz)

d 7.47–7.35 (m, 5H, C₆H₅), 6.02 (d, J_1,2¼3.9 Hz, 1H, H-1),

5.72 (s, 2H, NH₂), 4.67 (d, 1H, H-2), 4.41 (d, J_4,5¼7.3 Hz,

1H, H-4), 3.74 (m, 1H, H-5), 3.56 (m, 1H, H-6a) 3.42 (m,

1H, H-6b), 2.90 (s, 3H, NCH₃), 1.55 (s, 3H, CH₃), 1.30 (s,

3H, CH₃); ¹³C NMR (DMSO d₆, 75 MHz) d 148.2 (C-4⁰),

129.7–128.5 (6 C, C₆H₅), 112.8 [OC(CH₃)₂], 103.4 (2 C,

C-1, C-5⁰), 85.9 (C-2), 75.4 (C-4), 70.7 (C-3), 70.4 (C-5),

64.1 (C-6), 28.2 (NCH₃), 26.8 (CH₃), 26.7 (CH₃); MS

(APCIþ) m/z 413.1 [Mþ1]^þ, 435.1 [MþNa]^þ, 847.1

[2MþNa]^þ. Anal. Calcd for C₁₈H₂₄N₂0₇S (412.13 g/mol):

C, 52.42; H, 5.86; N, 6.79; S, 7.77. Found: C, 52.57; H, 5.62;

N, 6.81; S, 7.58.

4.9.4. Acetylation of compound 5Aa. Following the

general method (G), pyridine (1 mL) and Ac₂O (0.5 mL)

were added to compound 5Aa (53 mg, 0.17 mmol). The

reaction mixture is stirred at room temperature for 7 days.

The solvent was removed under vacuo with toluene and the

residue was ﬂash chromatographed (MeOH/CH₂Cl₂, 1:99)

to give successively 7a (19 mg, 31%) and 8a (7 mg, 12%) as

white solids. 7a: mp 103–104 8C; [a]²_D⁰þ58 (c 0.10,

acetone); IR (ATR) n 3344, 2360, 2338, 1675, 1514, 1296,

1

1056 cm²¹; H NMR (CDCl₃, 300 MHz) d 5.83 (s, 1H,

NHCOCH₃), 5.70 (d, J_1,2¼3.7 Hz, 1H, H-1), 5.05 (d, 1H,

H-2), 5.00 (d, J_{5 a,5 b}¼13.6 Hz, 1H, H-5⁰a), 4.87 (d,

J_4,5b¼2.8 Hz, 1H, H-4), 4.30 (d, J_5a,5b¼10.6 Hz, 1H,

H-5a), 4.20 (dd, 1H, H-5b), 3.40 (d, 1H, H-5⁰b), 3.00 (s,

3H, NCH₃), 2.10 (s, 3H, COCH₃), 1.60 (s, 3H, CH₃), 1.35 (s,

3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d 170.2 (CO), 113.5

[OC(CH₃)₂], 105.8 (C-1), 95.0 (C-4⁰), 82.7 (C-3), 81.8

(C-2), 79.0 (C-3), 72.8 (C-5), 50.7 (C-5⁰), 27.8 (NCH₃), 27.2

(CH₃), 26.5 (CH₃); MS (APCIþ) m/z 371.3 [MþNa]^þ,

387.2 [MþK]^þ. Anal. Calcd for C₁₃H₂₀N₂0₇S

(348.10 g/mol): C, 44.82; H, 5.79; N, 8.04; S, 9.20.

Found: C, 44.75; H, 5.73; N, 8.05; S, 9.37. 8a: mp 219–

220 8C; [a]²_D⁰þ12 (c 0.05, acetone); IR (ATR) n 2359,

2336, 1737, 1644, 1240, 1128, 1059, 1017 cm²¹; ¹H NMR

(CDCl₃, 300 MHz) d 5.88 (d, J_1,2¼3.9 Hz, 1H, H-1), 5.62

(s, 1H, H-5⁰), 4.72 (d, 1H, H-2), 4.69 (dd, J_4,5a¼4.2 Hz,

0

4.9.2. 1,2-O-Isopropylidene-a-^D-ribo-hexofuranose-3-

spiro-3⁰-(4⁰-amino-2⁰N-benzyl-5⁰-phenyl-5⁰H-2⁰,3⁰-di-

hydroisothiazole-1⁰,1⁰-dioxide) (6Bb). Following the

general method (F), acetic acid (6 mL) and water (4 mL)

were added to the compound 4Be (220 mg, 0.41 mmol).

After 1 h 10 min and ﬂash chromatography (EtOAc/

petroleum ether, 5:5) compound 6Bb (131 mg, 64%) was

isolated as a colourless solid: mp 91–92 8C; [a]²_D⁸20.38 (c

0.08, CHCl₃); IR (ATR) n 2356, 1737, 1644, 1370, 1216,

1145, 1058, 1014, 866 cm²¹; ¹H NMR (CDCl₃, 300 MHz) d

4726

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

J_4,5b¼7.4 Hz, 1H, H-4), 4.63 (s, 2H, NH₂), 4.26 (m, 2H,

H-5), 3.02 (s, 3H, NCH₃), 2.12 (s, 3H, OCOCH₃), 1.66 (s,

3H, CH₃), 1.37 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

171.0 (CO), 151.1 (C-4⁰), 114.0 [OC(CH₃)₂], 104.1 (C-1),

95.0 (C-5⁰), 84.7 (C-2), 73.3 (C-4), 71.1 (C-3), 61.7 (C-5),

27.3 (NCH₃), 26.5 (CH₃), 26.3 (CH₃), 21.1 (OCOCH₃); MS

(APCIþ) m/z 371.3 [MþNa]^þ, 387.2 [MþK]^þ, 719.3

[2MþNa]^þ, 735.2 [2MþK]^þ. Anal. Calcd for

C₁₃H₂₀N₂0₇S (348.10 g/mol): C, 44.82; H, 5.79; N, 8.04;

S, 9.20. Found: C, 44.68; H, 5.84; N, 8.18; S, 9.34.

H-6a), 4.03 (dd, J_5,6b¼5.7 Hz, J_6a,6b¼11.6 Hz, 1H, H-6b),

0 0 0 0

3.67 (d, J_{5 a,5 b}¼13.3 Hz, 1H, H-5⁰a), 3.34 (d, J_{5 a,5 b}¼13.3

Hz, 1H, H-5⁰b), 3.06 (s, 3H, N–CH₃), 2.20 (br s, 2H, NH₂),

2.12 (s, 3H, CH₃CO), 1.62 (s, 3H, CH₃), 1.37 (s, 3H, CH₃);

¹³C NMR (CDCl₃, 50 MHz) d 1₀70.6 (CO), 112.6

[OC(CH₃)₂O], 106.4 (C-1), 95.9 (C-4 ), 81.4 (C-2), 80.9

(C-4), 80.6 (C-5), 79.1 (C-3), 62.8 (C-6), 57.2 (C-5⁰), 27.8

(NCH₃), 26⁰6, 25.9 [OC(CH₃)₂O], 20.8 (CH₃CO); MS

(APCIþ) m/z 379.2 [Mþ1]^þ, 401.2 [MþNa]^þ, 757.2

[2Mþ1]^þ, 779.3 [2MþNa]^þ. Anal. Calcd for

C₁₄H₂₂N₂O₈S (378.40 g/mol): C, 44.44; H, 5.86; N, 7.40;

S, 8.47. Found: C, 44.74; H, 5.64; N, 7.31; S, 8.59.

Following the general method (G), pyridine (1 mL) and

Ac₂O (1 mL) were added to compound 5Ba (30 mg,

0.079 mmol). The reaction mixture was stirred at rt for

15 h. The solvent was removed under vacuo with toluene

and the residue was ﬂash chromatographed (hexane/AcOEt,

1:1) to give 10 (20 mg, 60%) and unreacted 5Ba (10 mg,

33%). 10: mp 59–61 8C; [a]²_D⁵þ83 (c0.27, CHCl₃);

IR(KBr) n 3435, 2963, 1744, 1685, 1519, 1376, 1311,

4.9.5. Acetylation of compound 5Ab. Following the

general method (G), pyridine (2 mL) and Ac₂O (1 mL)

were added to compound 5Ab (89 mg, 0.23 mmol). The

reaction mixture is stirred at room temperature for 16 h.

The solvent was removed under vacuo with toluene and the

residue was ﬂash chromatographed (MeOH/CH₂Cl₂, 1:99)

to give successively 7b (44 mg, 44%) and 8b (12 mg, 12%)

as white solids. 7b: mp 205–206 8C; [a]²_D⁰þ9 (c 0.20,

acetone); IR (ATR) n 3245, 2356, 2339, 1651, 1531, 1314,

1155, 1070, 1016, 837 cm²¹; ¹H NMR (CDCl₃, 300 MHz) d

7.43–7.28 (m, 5H, C₆H₅), 5.90 (s, 1H, NHCOCH₃), 5.70 (d,

J_1,2¼3.7 Hz, 1H, H-1), 5.18 (d, 1H, H-2), 4.87 (m, 3H,

H-5⁰a, NCH₂C₆H₅), 4.53 (d, J_4,5b¼3.5 Hz, 1H, H-4), 4.00

(d, J_5a,5b¼10.6 Hz, 1H, H-5a), 3.72 (dd, 1H, H-5b), 3.93 (d,

1262, 1157, 1098. 1024, 802 cm²¹

;

¹H NMR (CDCl₃,

200 MHz) d 6.03 (br s, 1H, NH), 5.73 (d, J_1,2¼3.9 Hz, 1H,

H-1), 5.10 (d, J_1,2¼3.9 Hz, 1H, H-2), 4.76 (d, J_5a,5b

¼

14.1 Hz, 1H, H-5⁰a), 4.74 (s, 1H, H-4), 4.54 (t, J_5,6a¼6.1 Hz,

1H, H-5), 4.25 (dd, J_5,6a¼6.3 Hz, J_6a,6b¼11.9 Hz, 1H,

H-6a), 4.09 (dd, J_5,6b¼5.6 Hz, J_6a,6b¼11.9 Hz, 1H, H-6b),

3.57 (d, J_5a,5b¼14.1 Hz, 1H, H-5⁰b), 3.04 (s, 3H, NCH₃),

2.10 (s, 3H, CH₃CO), 2.05 (s, 3H, CH₃CO), 1.59 (s, 3H,

CH₃), 1.33 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 50 MHz) d

170.8 (CO), 170.5 (CO), 113.3 [OC(CH₃)₂O], 106.2 (C-1),

95.1 (C-4⁰), 83.3 (C-5), 82.5 (C-3), 80.8 (C-2), 80.7 (C-4),

62.7 (C-6), 51.9 (C-5⁰), 27.9 (NCH₃), 27.0, 26.3

[OC(CH₃)₂O], 24.5 (CH₃CON), 21.0 (CH₃COO); MS

(APCIþ) m/z 421.3 [Mþ1]^þ, 443.2 [MþNa]^þ, 863.3

[2Mþ1]^þ. Anal. Calcd for C₁₆H₂₄N₂O₉S (420.44 g/mol):

C, 45.71; H, 5.75; N, 6.66; S, 7.63. Found: C, 45.66; H, 5.69;

N, 6.51; S, 7.96. Following the general method (G), 5Ba

(48 mg, 0.14 mmol) was treated with pyridine (1 mL) and

Ac₂O (1 mL), at rt for 3 days, gave, after ﬂash chromato-

graphy (hexane: AcOEt, 1:1), compounds 10 (41 mg, 70%)

and 11 (9 mg, 14%, 86% pure). 11: amorphous; IR (KBr) n

3449, 2990, 1752, 1637, 1498, 1377, 1249, 1216, 1114,

J_{5 a,5 b}¼13.7 Hz, 1H, H-5⁰b), 2.05 (s, 3H, NCOCH₃), 1.68 (s,

3H, CH₃), 1.36 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz) d

170.4 (CO), 137.8–128.4 (C₆H₅), 113.5 [OC(CH₃)₂], 106.1

(C-1), 95.0 (C-4⁰), 82.3 (C-4), 81.0 (C-2), 80.3 (C-4), 72.7

(C-5), 52.7 (C-5⁰), 45.4 (OCH₂C₆H₅), 27.4 (CH₃), 26.4

(CH₃), 24.7 (NCOCH₃); MS (APCIþ) m/z 447.3 [MþNa]^þ,

463.3 [MþK]^þ, 871.3 [2MþNa]^þ. Anal. Calcd for

C₁₉H₂₄N₂0₇S (424.13 g/mol): C, 53.76; H, 5.70; N, 6.60;

S, 7.55. Found: C, 53.75; H, 5.62; N, 6.73; S, 7.88. 8b: mp

90–91 8C; [a]²_D⁰þ17 (c 0.10, acetone); IR (ATR) n 2354,

0

1

2336, 1741, 1648, 1230, 1128, 1017, 873 cm²¹; H NMR

(CDCl₃, 300 MHz) d 7.54–7.31 (m, 5H, C₆H₅), 5.87 (d,

J_1,2¼3.8 Hz, 1H, H-1), 5.61 (s, 1H, H-5⁰), 4.82 (d, 1H, H-2),

4.79 (m, 2H, NCH₂C₆H₅), 4.72 (s, 2H, NH₂), 4.43 (dd,

J_4,5a¼8.0 Hz, J_4,5b¼2.3 Hz, 1H, H-4), 4.05 (dd,

J_5a,5b¼12.4 Hz, 1H, H-5a), 3.94 (dd, 1H, H-5b), 1.96 (s,

3H, OCOCH₃), 1.71 (s, 3H, CH₃), 1.34 (s, 3H, CH₃); ¹³C

NMR (CDCl₃, 75 MHz) d 170.8 (CO), 151.3 (C-4⁰), 137.5–

128.1 (C₆H₅), 114.2 [OC(CH₃)₂], 104.2 (C-1), 94.5 (C-5⁰),

84.7 (C-4), 74.7 (C-4), 71.3 (C-3), 61.9 (C-5), 45.0

(NCH₂C₆H₅), 26.8 (CH₃), 26.2 (CH₃), 21.0 (OCOCH₃);

MS (APCIþ) m/z 447.3 [MþNa]^þ, 463.3 [MþK]^þ, 871.3

[2MþNa]^þ. Anal. Calcd for C₁₉H₂₄N₂0₇S (424.13 g/mol):

C, 53.76; H, 5.70; N, 6.60; S, 7.55. Found: C, 53.66; H, 5.81;

N, 6.64; S, 7.84.

1

1054 cm²¹; H NMR (CDCl₃, 200 MHz) d 7.65 (br s, 1H,

NH), 7.39 (s, 1H, H-5⁰), 5.85 (d, J_1,2¼3.9 Hz, 1H, H-1), 5.22

(m, J_5,6a¼2.4 Hz, J_5,6b¼5.8 Hz 1H, H-5), 4.67 (d,

J_1,2¼3.8 Hz, 1H, H-2), 4.61 (d, J¼10.1 Hz 1H, H-4), 4.55

(dd, J_5,6a¼2.4 Hz, J_6a,6b¼12.2 Hz, 1H, H-6a), 4.09 (dd,

J_5,6b¼5.8 Hz, J_6a,6b¼12.2 Hz, 1H, H-6b), 3.04 (s, 3H,

NCH₃), 2.21 (s, 3H, CH₃CO), 2.09 (s, 3H, CH₃CO), 2.07

(s, 3H, CH₃CO), 1.65 (s, 3H, CH₃), 1.35 (s, 3H, CH₃); ¹³C

NMR (CDCl₃, 50 MHz) d 170.6 (CO), 169.6 (CO), 168.3

(CO), 140.1 (C-4⁰), 114.1 [OC(CH₃)₂O], 108.5 (C-5⁰), 102.8

(C-1), 85.0 (C-2), 77.4 (C-3), 71.3 (C-4), 67.6 (C-5), 63.6

(C-6), 26.8 (NCH₃), 26⁰0, 25.9 [OC(CH₃)₂O], 24.7

(CH₃CO), 20.7 (CH₃CO), 20.6 (CH₃CO); MS (APCIþ)

m/z 463.3 [Mþ1]^þ, 480.3 [MþNH₄]^þ, 485.3 [MþNa]^þ,

947.3 [2MþNa]^þ.

4.9.6. Acetylation of compound 5Ba. Following the

general method (G), pyridine (1 mL) and Ac₂O (1 mL)

were added to compound 5Ba (50 mg, 0.15 mmol). The

reaction mixture was stirred at rt for 4 h. The solvent was

removed under vacuo with toluene and the residue was ﬂash

chromatographed (hexane/AcOEt, 1:1) to give 9 (47 mg,

84%) as a colorless solid and 10 (1 mg, 1%). 9: mp 211–

213 8C; [a]²_D⁵þ107 (c 0.90, CHCl₃); IR. (KBr) n 3448,

4.9.7. Acetylation of compound 6Ba. Following the

general method (G), pyridine (2 mL) and Ac₂O (1 mL)

were added to the compound 6Ba (75 mg, 0.18 mmol).

After 12 h and ﬂash chromatography (EtOAc/petroleum

ether, 5:5) product 12a (75 mg, 84%) was isolated as a

1

3362, 2987, 2939, 1738, 1633, 1294, 1249,1022 cm²¹; H

NMR (CDCl₃, 200 MHz) d 5.84 (d, J_1,2¼3.9 Hz, 1H, H-1),

5.00 (d, J_1,2¼3.9 Hz, 1H, H-2), 4.72 (s, 1H, H-4), 4.42 (t,

J¼5.8 Hz), 4.22 (dd, J_5,6a¼5.8 Hz, J_6a,6b¼11.6 Hz, 1H,

A. N. Van Nhien et al. / Tetrahedron 60 (2004) 4709–4727

4727

colorless solid: mp 126–127 8C; [a]²_D⁰þ54 (c 0.25, CHCl₃);

IR (ATR) n 3356, 2356, 2327, 1733, 1648, 1379, 1256,

1213, 1133, 1058, 1034 cm²¹; ¹H NMR (CDCl₃, 300 MHz)

d 7.41 (m, 5H, C₆H₅), 5.86 (d, J_1,2¼3.8 Hz, 1H, H-1), 5.86

(ddd, J_4,5¼10.0 Hz, J_5,6a¼2.4 Hz, J_5,6b¼5.9 Hz, 1H, H-5),

4.77 (d, 1H, H-2), 4.65 (d, 1H, H-4), 4.55 (dd,

J_6a,6b¼12.1 Hz, 1H, H-6a), 4.46 (s, 2H, NH₂), 4.11 (dd,

1H, H-6b), 3.09 (s, 3H, NCH₃), 2.12 (s, 3H, OCOCH₃), 2.07

UNED) for support and fruitful collaboration. CT thanks

`

the Ministere Franc¸ais de la Recherche (France) for a

fellowship. DP thanks the Conseil Regional de Picardie and

´

`

the Ministere Franc¸ais de la Recherche for ﬁnancial support

and to G. Mackenzie for helpful discussions, and careful

revising the manuscript. J.M.C. thanks the CSIC for

continuous support and inspiration; without its help some

parts of this work would have been impossible. The authors

thank the referees for their critical and useful comments.

(s, 3H, OCOCH₃), 1.65 (s, 3H, CH₃), 1.36 (s, 3H, CH₃); ¹³

C

NMR (CDCl₃, 75 MHz) d 171.0, 170.5 (2£CO), 144.7

(C-4⁰), 129.9–126.4 (6C, C₆H₅), 113.9 [OC(CH₃)₂], 108.2

(C-5⁰), 103.5 (C-1), 85.9 (C-4), 71.7 (C-2), 70.5 (C-3), 68.2

(C-5), 64.2 (C-6), 27.8 (NCH₃), 26.7 (CH₃), 26.4 (CH₃),

21.5 (OCOCH₃), 21.1 (OCOCH₃); MS (APCIþ) m/z 519.1

[MþNa]^þ, 534.9 [MþK]^þ. Anal. Calcd for C₂₂H₂₈N₂0₉S

(496.15 g/mol): C, 53.22; H, 5.68; N, 5.64; S, 6.46. Found:

C, 53.30; H, 5.47; N, 5.42; S, 6.29.

References and notes

1. Cram, D. J. Fundamentals of carbanion chemistry; Academic:

New York, 1965; p 48.

´

2. (a) Solladie, G.; Carren˜o, M. C. Optically active b-keto

sulfoxides and analogues in asymmetric synthesis in organo-

sulfur chemistry. In Synthetic aspects; Page, P., Ed.;

´

Academic: London, 1995; p 1. (b) Solladie, G. Synthesis

4.9.8. Acetylation of compound 6Bb. Following the

general method (G), pyridine (1 mL) and Ac₂O (0.5 mL)

were added to the compound 6bB (50 mg, 0.10 mmol).

After 12 h and ﬂash chromatography (EtOAc/petroleum

ether, 4.5:5.5) product 12b (55 mg, 95%) was isolated as a

colorless solid: mp 94–95 8C; [a]²_D⁰þ78 (c 0.25, CHCl₃);

IR (ATR) n 2355, 2331, 1743, 1659, 1494, 1372, 1240,

1216, 1155, 1056, 1023 cm²¹; ¹H NMR (CDCl₃, 300 MHz)

d 7.64–7.38 (m, 10H, 2£C₆H₅), 5.88 (d, J_1,2¼3.8 Hz, 1H,

H-1), 5.39 (ddd, J_4,5¼9.9 Hz, J_5,6a¼2.3 Hz, J_5,6b¼5.8 Hz,

1H, H-5), 4.85 (d, 1H, H-2), 4.75 (d, J_A,B¼14.2 Hz, 1H,

H-A NCH₂C₆H₅), 4.69 (d, H-4), 4.59 (d, 1H, H-B

NCH₂C₆H₅), 4.54 (dd, J_6a,6b¼12.1 Hz, 1H, H-6a), 4.41 (s,

2H, NH₂), 4.05 (dd, 1H, H-6b), 2.22 (s, 3H, OCOCH₃), 2.08

1981, 185. (c) Posner, G. In The chemistry of sulfones and

sulfoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.;

Wiley: New York, 1988; p 823. (d) Simpkins, N. S. Sulfones in

organic synthesis; Pergamon: New York, 1993. (e) Boche, G.

Angew. Chem. Int. Ed. Engl. 1989, 28, 277. (f) Oae, S. Y.;

Uchida, Y. The chemistry of sulphones and sulphoxides; Patai,

S., Rappoport, Z., Stirling, C. J. M., Eds.; Wiley: New York,

1988; 12, p 583, Chapter 12. (g) King, J. In The chemistry of

sulfonic acids, esters and their derivatives; Patai, S.,

Rappoport, Z., Eds.; Wiley: New York, 1991; p 249, Chapter 6.

3. For a review, see: Postel, D.; Nguyen Van Nhien, A.; Marco,

J. L. Eur. J. Org. Chem. 2003, 3713.

(s, 3H, OCOCH₃),1.60 (s, 3H, CH₃), 1.39 (s, 3H, CH₃); ¹³

C

4. (a) Marco, J. L.; Ingate, S. Tetrahedron Lett. 1997, 38, 4835.

(b) Ingate, S.; Marco, J. L.; Witvrouw, M.; Pannecouque, C.;

De Clercq, E. Tetrahedron 1997, 53, 17795. (c) Marco, J. L.;

NMR (CDCl₃, 75 MHz) d 171.0–170.6 (2£CO), 144.3

(C-4⁰), 136.7–126.3 (12C, 2£C₆H₅), 113.8 [OC(CH₃)₂],

108.5 (C-5⁰),103.5 (C-1), 85.6 (C-2), 73.1 (C-4), 71.3 (C-3),

68.4 (C-5), 64.2 (C-6), 48.2 (NCH₂C₆H₅), 26.6 (CH₃), 26.4

(CH₃), 21.8 (OCOCH₃), 21.1 (OCOCH₃); MS (APCIþ) m/z

595.1 [MþNa],^þ611.1 [MþK].^þAnal. Calcd. for

C₂₈H₃₂N₂O₉S (572.18 g/mol): C, 58.73; H, 5.63; N, 4.89;

S, 5.60. Found: C, 58.57; H, 5.72; N, 4.74; S, 6.82.

´

Ingate, S.; Chinchon, P. M. Tetrahedron 1999, 55, 7625.

(d) Marco, J. L.; Ingate, S.; Manzano, P. Tetrahedron Lett.

1998, 39, 4123. Corrigendum: Tetrahedron Lett. 1999, 40,

´

3075. (e) Marco, J. L.; Ingate, S.; Jaime, C.; Bea, I.

Tetrahedron 2000, 56, 2523.

5. Postel, D.; Nguyen Van Nhien, A.; Pillon, M.; Villa, P.;

Ronco, G. Tetrahedron Lett. 2000, 41, 6403.

6. Postel, D.; Nguyen Van Nhien, A.; Villa, P.; Ronco, G.

Tetrahedron Lett. 2001, 42, 593.

7. Sowa, W.; Can, J. Chem. 1968, 46, 1586.

Acknowledgements

L.D. thanks the MECD (Spain) for a fellowship, and the

8. Mazur, A.; Tropp, E.; Engel, R. Tetrahedron 1984, 40, 3949.

´

CAM (Spain) for ﬁnancial support (Grupo Estrategico).

J.M.C. thanks to Prof. Paloma Ballesteros (Dpto. de

´ ´ ´

Quımica Organica y Biologıa, Facultad de Ciencias,

` `

9. Poszavacz, L.; Simig, G. J. Org. Chem. 1997, 62, 7021.

10. SHEXTL. Version 5.10, Bruker Analytical X-Ray Systems.

1997.

Article Doi

Synthesis and transformations of [1,2-O-isopropylidene-α-D-erythro (and α-D-ribo)furanose]-3-spiro-3′-(4′-amino-5′H- 2′,3′-dihydroisothiazole-1′,1′-dioxide) derivatives

DOI: 10.1016/j.tet.2004.03.063

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