Divergent syntheses of all 16 carbasugar stereoisomers via stereoconversion of carba-β-D-altropyranose derivatives

Tetrahedron:

Asymmetry

Tetrahedron: Asymmetry 16 (2005) 2729–2747

Divergent syntheses of all 16 carbasugar stereoisomers via

stereoconversion of carba-b-^D-altropyranose derivatives

Seok-Ho Yu and Sung-Kee Chung^*

Department of Chemistry, Division of Molecular and Life Sciences, Pohang University of Science and Technology,

Pohang 790-784, Republic of Korea

Received 9 June 2005; accepted 1 July 2005

Available online 16 August 2005

Abstract—We have developed practical synthetic routes to enantiopure D- and L-carba-b-altrose derivatives and all the possible ster-

eoisomers via their divergent stereoconversions. Carba-b-^D-altrose was prepared from 3-cyclohexene-1-carboxylic acid and con-

verted to carba-b-^D-mannose, carba-b-D-idose, and carba-b-D-talose derivatives via regio- and stereoselective oxidation/reduction

of 3-OH and/or 4-OH. The four carbasugar stereoisomers were then transformed to the remaining 12 carbasugar stereoisomers

and their 1,2-epoxides by regio- and stereoselective manipulation of hydroxyl groups in C1 and C2, which includes oxidation/reduc-

tion, Mitsunobuꢀs reaction, oleﬁnation/dihydroxylation, and epoxidation/ring-opening protocols.

1. Introduction

saccharide analogues as glycosidase inhibitors or glyco-

syltransferase inhibitors.^3a,c,d,4They also synthesized

some carbasugar analogues of glycosylceramide as

potential ceramide glycosyltransferase inhibitors.⁵Other

groups have also investigated carbasugar nucleotide

analogues as glycosyltransferase inhibitors.⁶

Recent glycobiology studies have revealed the versatile

and critical roles of cell-surface carbohydrates in the rec-

ognition processes of cells via carbohydrate–protein

interactions, which eventually result in cell adhesion, cell

growth, immune response, fertilization, viral infection,

inﬂammation, metastasis of cancer, etc.¹The major

issues in glycobiology now are the understanding at

the molecular level of the carbohydrate–protein inter-

actions in pathophysiologically important processes,

and how to eﬃciently develop molecular tools that can

regulate such carbohydrate–protein interactions, thus

leading to therapies. In this context, much of the

research has been focused on developing glycomimetic

molecules both as biochemical probes and potential

drug candidates.²These research eﬀorts require diverse

structures of carbohydrate mimetics, among which

non-hydrolyzable analogues³are thought to be highly

desirable because of their stability in vivo.

Application of carbasugars to diverse carbohydrate

mimetics is still limited because of the paucity of readily

available carbasugars as building block. To be widely

used as diverse carbohydrate mimetics, all required car-

basugars such as enantiopure stereoisomers of carbasu-

gars as glycosyl acceptor mimics and their 1,2-epoxide

derivatives as glycosyl donor mimics should be made

available by practical routes. In addition, the available

building blocks of 16(32) of possible stereoisomers and

8(16) of possible 1,2-epoxides should be appropriately

protected for further synthetic elaborations. Although

a variety of synthetic methods^3a–h,7have been developed

for carbasugars since the pioneering work by McCas-

land et al. in 1966,⁸there are no general and practical

synthetic routes deﬁned for ready access to the carba-

sugar building blocks.

Carbasugars are suitable building blocks for non-hydro-

lyzable carbohydrate mimetics due to their structural

resemblance to cyclic monosaccharides and inherent sta-

bility to glycosidases. Ogawa et al. have provided the

early leading role in this area and have synthesized a

number of carbasugars, including disaccharide and tri-

Recently, we have investigated practical synthetic routes

to all 16 enantiopure carbasugar analogues for a- and b-

aldohexopyranose stereoisomers and their 1,2-epoxide

derivatives. We imagined that systematic stereochemical

manipulation of one carbasugar to other stereoisomers

might be more practical in obtaining all the desired

*

Corresponding author. Tel.: +82 54 279 2103; fax: +82 54 279

3399; e-mail: skchung@postech.ac.kr

doi:10.1016/j.tetasy.2005.07.010

2730

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

OR₁

OR₂

R₆O

OR₁

OR₂

R₆O

R₄O

R₆'O

R₄'O

O

R₄O

+

O

R₆'O

R₄'O

OR₃

OR₃'

Glycosyl Donor Mimic

8 (16) stereoisomers

Glycosyl Acceptor Mimic

16 (32) stereoisomers

OH

OR₃'

oligosaccharide mimetics

C1 & C2 variation

5a

OR₁

OR₂

6

R₆O

R₄O

1

5

3

R₄O

OR₂

R₄O

OR₃

C3 & C4 variation

OR₃

1,2-olefin derivative

4 (8) stereoisomers

one stereoisomer

of carbasugar

C3 and C4 variants

4 (8) stereoisomers

Figure 1.

carbasugar stereoisomers rather than using multiple syn-

thetic routes for each stereoisomer. It was envisioned

that a series of operations involving (1) the synthesis

of a suitable carbasugar stereoisomer in enantiopure

form (both of ^D- and L-form), followed by (2) conver-

sion to its ꢁC3 and C4 stereo-variantsꢀ, and then (3)

conversion of the resulting four (eight) stereoisomers

to their 1,2-epoxides and 12 more stereoisomers might

provide practical synthetic routes to all stereoisomeric

carbasugar building blocks (Fig. 1). This stereoconver-

sion strategy may have some advantages. First, since

all stereoisomers can be obtained from one key interme-

diate, only one resolution on a practical scale is neces-

sary. Second, a limited set of orthogonal protecting

groups for various hydroxyl groups can be utilized in

a number of stereoselective manipulations throughout

the stereoconversion strategy.

sions to carba-b-mannopyranose, carba-b-idopyranose,

and carba-b-talopyranose derivatives as ꢁC3 and C4 ste-

reo-variantsꢀ.⁹We herein report the successful develop-

ment of C1 and/or C2 stereoconversion routes from the

four ꢁC3 and C4 stereo-variantsꢀ to the remaining 12

stereoisomers of all 16 carbasugars (^D-forms only) as

well as some of their 1,2-epoxide derivatives.

2. Results and discussion

General strategy. The ^D- and L- of carba-b-altropyr-

anose derivatives have been synthesized from commer-

cially available 3-cyclohexene-1-carboxylic acid via

sequential and stereoselective introductions of necessary

hydroxyl groups combined with an eﬃcient enzymatic

resolution. The C3 and C4 variants of carba-b-altropyr-

anose, that is, carba-b-mannopyranose, carba-b-idopyr-

anose, and, carba-b-talopyranose derivatives, have been

synthesized via procedures involving regioselective ben-

zoylation and stereoselective oxidation/reduction

(Fig. 2).⁹For the syntheses of the remaining 12 stereo-

isomers (^D-forms only) and their 1,2-epoxide deriva-

tives, we used suitable stereo-inversion methods for C1

and C2 of the four stereoisomers ^D-2a, D-3a, D-4a, and

The initial challenges in these conversion strategies

included the practical supply of a suitable enantiopure

stereoisomer and regio- and stereo-selective manipula-

tions of various hydroxyl groups of carbasugars. We

previously reported in a preliminary fashion a practical

synthesis of enantiopure ^D- and L- of carba-b-altropyra-

nose derivatives and their straightforward stereoconver-

O

OTBDPS

OH

OMOM

4

HO

+

2

3

1

OH

3-cyclohexene-

1-carboxylic acid

D-1

carba-β-D-altropyranose D-2a

C3 and/or C4

stereoinversion

OTBDPS

OMOM

OH

OTBDPS

OMOM

OTBDPS

BzO

OMOM

BzO

HO

OMOM

HO

OBz

carba-β-D-idopyranose D-4a carba-β-D-talopyranose D-5a

carba-β-D-mannopyranose D-3a

Figure 2.

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2731

carba-α-altrose

carba-β-allose

carba-α-allose

OTBDPS

OH

OTBDPS

carba-α-mannose

carba-β-glucose

carba-α-glucose

BnO

O

C1 and/or C2

OBn

BnO

epoxidation

stereo-inversion

carba-α-idose

carba-β-gulose

carba-α-gulose

carba-β-D-altrose D-2c

carba-β-D-mannose D-3d

carba-β-D-idose D-4d

carba-β-D-talose D-5d

OBn

α- and β-1,2-epoxides

carba-α-talose

carba-β-galactose

carba-α-galactose

C3 and C4 stereovariants

C1 and C2 variants

Figure 3.

D-5a depending on their stereochemistry at C3 and C4.

First, each 1,2-diol derivative of the ꢁC3 and C4 stereo-

variantsꢀ was prepared by protecting the C3 and C4

hydroxyl groups as benzyl ether and subsequently remov-

ing the MOM groups in ^D-2a, D-3a, D-4a, and D-5a.

of the b-1,2-epoxide derivatives were stereoselectively

synthesized via bromoacetoxy intermediates that were

easily derived from the 1,2-diol derivatives (Fig. 3).

2.1. Transformation of carba-b-^D-altropyranose to carba-

a-^D-altropyranose, carba-b-D-allopyranose, and carba-a-

D-allopyranose derivatives

These four cis-1,2-diols were subjected to either an oxi-

dation/reduction, a Mitsunobu reaction, oleﬁnation/

dihydroxylation, or epoxidation/ring-opening proce-

dures as deemed necessary. During the stereoconver-

sions of those four carbasugar stereoisomers, several

a- and b-1,2-epoxide derivatives were also synthesized

by the epoxidation of 1,2-oleﬁn derivatives, while some

Syntheses of carba-a-^D-altrose, carba-a-D-allose, and

carba-b-^D-allose derivatives were accomplished by

regioselective protection and oxidation/reduction of

1-OH and 2-OH of carba-b-^D-altrose derivatives

(Scheme 1). After protection of 3- and 4-OH of

OTBDPS

OR

OTBDPS

OBz

OTBDPS

OH

c

R'O

BnO

OR

BnO

+

OH

OBz

OR'

OBn

43 : 57

D-2a: R = MOM, R' = H

D-2b: R = MOM, R' = Bn

D-2c: R = H, R' = Bn

a

b

D-2d

D-2e

d

OTBDPS

O

OTBDPS

O

e

BnO

OBz

BnO

OBz

OH

OBn

D-7

D-6

D-8

carba-β-D-allose

D-7 : D-2d = ~ 85 : 15

D-7 : D-2d : D-6 = ~ 57 : 3 : 30

g

f

OTBDPS

OR'

BnO

d

BnO

f

OMOM

OH

O

OBn

BnO

OMOM

OBn OR

carba-α-D-allose

D-11

D-10

carba-α-D-altrose

D-9a: R = H, R' = Bz

h

i

D-9b: R = MOM, R' = Bz

D-9c: R = MOM, R' = H

(D-11 : D-9c > 99 : 1)

(D-9a : D-2e = 75 : 25)

˚

Scheme 1. Reagents and conditions: (a) NaH (4 equiv), BnBr (4 equiv), Bu₄NI (0.2 equiv), THF, rt, 90%; (b) TMSBr (10 equiv), molecular sieve 4 A,

CH₂Cl₂, ꢀ20 ꢁC, 64%; (c) (i) (EtO)₃CPh (2 equiv), TSA (0.1 equiv), CH₂Cl₂, rt, (ii) 80% aq AcOH, 95%; (d) PCC (3 equiv), molecular sieves 4 A,

CH₂Cl₂, rt, D-2d or reﬂux, D-2e; (e) BH₃ÆMe₂S (5 equiv), THF, 0 ꢁC; (f) NaBH₄(5.0 equiv), MeOH (50 equiv), CH₂Cl₂, 0 ꢁC; (g) PCC (3.0 equiv),

˚

molecular sieves 4 A, CH₂Cl₂, rt, 2 h; (h) MOMCl (10 equiv), (i-Pr)₂NEt (10 equiv), CH₂Cl₂, reﬂux, 15 h, 84%; (i) NaOMe (5 equiv), MeOH, rt, 14 h.

2732

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

H^-

O

TBDPSO

BnO

TBDPSO

BnO

OBz

OH

OBn

D-6

OBn

D-7

H^-

OTBDPS

TBDPSO

H

OBz

H

O

BnO

OH

OBz

H

OBz

BnO

OH

BnO

OBn

H

BnO

D-9a

D-8

δ 5.46, triplet, J = 3.1Hz

δ 5.53, triplet, J = 8.1Hz

in ¹H NMR (acetone-d₆)

in ¹H NMR (CDCl₃)

OTBDPS

TBDPSO

H^-

BnO

OMOM

OBn

OH

OBn

O

OMOM

in benzene-d₆

OBn

OH

D-11

D-10

Figure 4.

carba-b-D-altrose D-2a as benzyl ethers by treatment

with NaH, BnBr, and Bu₄NI,¹⁰subsequent deprotection

of the MOM groups with TMSBr¹¹gave carba-b-D-al-

trose 1,2-diol derivative ^D-2c. Treatment of this diol

D-2c with triethyl orthobenzoate and TSA, followed

by hydrolysis in 80% aq AcOH,¹²gave a mixture of

monobenzoates (^D-2d/D-2e = 43:57). Oxidation of D-2d

with PCC^3c,13gave the 2-keto derivative D-6, which

was reduced with NaBH₄to give a mixture of carba-b-

allose derivatives ^D-7 and D-2d (D-7/D-2d = ꢁ80:20).

As ^D-7 and D-2d were not easily separable, attempts

were made to enhance the selectivity for ^D-7 with other

reducing agents with no satisfactory results (^D-7/

D-2d ꢁ 85:15 by BH₃ÆMe₂S, THF, ꢁ75:25 by NaBH₄,

CeCl₃).^3dHowever, it was found that the oxidation rate

of 2-OH (axial) in ^D-2d was much faster than that of

2-OH (equatorial) in ^D-7.¹⁴Thus, a preferential oxida-

tion of ^D-2d in the mixture (D-7/D-2d = 85:15 by

BH₃ÆMe₂S) was carried out with PCC (3.0 equiv) for

2 h at rt, which resulted carba-b-^D-allose derivative

D-7 in good diastereomeric purity (D-7, 90% de, 60%)

and the 2-keto compound (^D-6, 30%).

to give equatorial alcohol as the major product (equato-

rial:axial = ca. 8:2–9:1) via axial attack of the hydride.¹⁶

This preference for equatorial alcohol can be enhanced

or diminished depending on the neighboring groups

present in the ketone. In many reported cases, the benz-

yloxy group seems to provide substantial steric hin-

drance to the axial approach of the hydride to the

carbonyl group, while the benzoate group does not.^9,17

In the reduction of D-6, the preference for equatorial

alcohol was expected to be increased by the 3-OBn

group, which might hinder the bottom side approach

of the hydride, while the observed ratio was 4:1 (^D-7/D-

2d). In the reduction of ^D-8, a similar preference for

equatorial alcohol was expected to give ^D-9a as the

major product (Fig. 4). However, the axial TBDPSOCH₂

group appeared to cause some steric hindrance to the

topside approach of the hydride, thus decreasing the

preference for ^D-9a to a degree. Interestingly, D-9a shows

two diﬀerent conformations depending on the solvents.

In the ¹H NMR of D-9a, while a small coupling constant

of H-2 peak (t, J = 3.1 Hz) supports a conventional chair

conformation in which the TBDPSOCH₂group has

equatorial orientation, the relatively large coupling con-

stant of H-2 peak (t, J = 8.1 Hz) in acetone-d₆suggests a

ﬂipped chair conformer as shown in Figure 4. In the

reduction of ^D-10, the preference for equatorial –OH is

completely negated by the serious neighboring group ef-

fects (1-OMOM, 3- and 4-OBn groups) to give ^D-11

exclusively. The coupling relationships in compounds

D-2–D-11 are summarized in Table 1.

Oxidation of ^D-2e with PCC gave 1-keto derivative D-8,

which upon reduction gave a mixture of carba-a-altrose

derivatives ^D-9a and D-2e (75:25 with NaBH₄, CH₂Cl₂/

MeOH, or BH₃ÆMe₂S in THF). Although the stereo-

selectivity in this reduction was not very high, the mix-

ture was readily separable to provide diastereomerically

pure carba-a-^D-altrose derivative D-9a (69%). Protection

of the 1-OH of ^D-9a as the MOM ether¹⁵and subse-

quent removal of the benzoyl group gave ^D-9c in good

yield. A similar oxidation (PCC)/reduction (NaBH₄)

protocol transformed the ^D-9c to a carba-a-D-allose

derivative ^D-11 with high stereoselectivity (D-11/D-

9c = >99:1).

2.2. Transformation of carba-b-^D-mannopyranose to

carba-a-^D-mannopyranose, carba-b-D-glucopyranose,

and carba-a-^D-glucopyranose derivatives

Adjusting the stereochemistry of C1 and/or C2 of the

carba-b-mannose derivative ^D-3a gave carba-b-glucose

D-12, carba-a-glucose D-14, and carba-a-mannose D-17

derivatives (Scheme 2). Due to the opposite stereochem-

NaBH₄reductions of cyclohexanone derivatives with

well-deﬁned chair conformations are generally known

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2733

Table 1.

Compd

Coupling constants (Hz)

J_H1–H2

J_H2–H3

J_H3–H4

J_H4–H5

J_H5–H5aa

J_H5–H5ab

J_H1–H5aa

J_H1–H5ab

D-2d^a

D-2e^a

D-6^a

3.6

Small

—

9.7

—

3.2

7.8

9.3

—

3.6

Small

—

Singlet

9.7

2.9

7.8

9.3

—

Small

nd

4.3

nd

4.1

nd

6.8

nd

5.8

6.0

4.7

12.2

12.0

12.9

nd

Small

13.5

nd

Small

10.4

4.3

nd

6.9

5.1

—

Small

8.5

12.5

12.1

4.7

12.2

12.0

13.0

11.3

—

2.9

4.6

nd

7.2

2.6

2.7

2.6

2.9

2.7

2.6

Small

2.2

10.4

10.7

9.8

3.3

9.9

4.9

2.6

Small

9.1

D-7^a

D-8^a

D-9a^a

D-9b^a

D-9c^b

D-10^a

D-11^b

Small

3.2

—: No vicinal proton pair exist.

Small: assumed from broad singlet.

nd: not determined.

^aIn CDCl₃.

^bIn C₆D₆.

OTBDPS

OMOM

OTBDPS

OH

OTBDPS

OH

d

c

R'O

RO

BnO

OMOM

OH

BzO

D-3a: R = H, R' = Bz

D-3b: R = R' = H

a

b

D-12

D-3d

D-3c: R = R' = Bn

carba-β-D-glucose

i

e

OTBDPS

BnO

OTBDPS

g or h

O

+

O

BnO

OBn

D-15

OBn

D-16

D-13

f

j

OTBDPS

OH

BnO

HO

OH

D-14

carba-α-D-glucose

D-17

carba-α-D-mannose

Scheme 2. Reagents and conditions: (a) NaOMe (0.1 equiv), MeOH, rt, 2 h, 92%; (b) NaH (4 equiv), BnBr (4 equiv), Bu₄NI (0.2 equiv), THF, rt,

˚

81%; (c) TMSBr (10 equiv), molecular sieves 4 A, CH₂Cl₂, ꢀ20 ꢁC, 78%; (d) PPh₃, DEAD, BzOH, toluene, reﬂux, 63%; (e) PPh₃, imidazole, I₂,

toluene, reﬂux, 90%; (f) OsO₄(cat.), NMO (2 equiv), acetone/water (8:1), rt, quantitative; (g) m-CPBA, D-15/D-16 = 1:4; (h) (i) NBS (or NIS),

dioxane/water (10:1), (ii) NaOMe/MeOH, ^D-15/D-16 = 1:4 (1:10 for NIS); (i) (i) (CH₃O)₃CCH₃(1.5 equiv), PPTS, CH₂Cl₂, (ii) AcBr (3.0 equiv),

Et₃N (0.1 equiv), CH₂Cl₂, (iii) NaOMe/MeOH, only D-15 was formed, 95%; (j) HClO₄(3% in water, 0.4 equiv), acetone, 0 ꢁC, 95%.

1

istry of C3 in D-3a compared to carba-b-altrose D-2a,

oxidation/reduction of 1- and/or 2-OH in carba-b-man-

nose derivatives was not expected as a suitable protocol

to produce the other stereoisomers. Thus, we used alter-

native strategies employing a Mitsunobu reaction, dide-

hydroxylation/dihydroxylation, and epoxidation/ring-

opening to obtain the desired stereoisomers. The 1,2-

diol ^D-3d was prepared by conventional protection and

deprotection of ^D-3a. Mitsunobu reaction¹⁸of D-3d with

PPh₃, DEAD, and BzOH gave carba-b-D-glucose deriv-

ative ^D-12 with inversion of only the axial –OH at C2.

The three proton peaks appear in the H NMR as trip-

lets at d = 3.69, 3.75, and 5.24 ppm each with J = 9.2,

9.3, and 9.3 Hz in acetone-d₆, indicating that H1, H2,

H3, and H4 have all axial orientations. Didehydroxyl-

ation of ^D-3d was successfully accomplished by a modi-

ﬁed ꢁSamuelssonꢀs procedureꢀ.¹⁹A preliminary reaction

of ^D-3d with PPh₃(4 equiv), imidazole (4 equiv), and

I₂(3.3 equiv) gave D-13 in a low yield together with

complex by-products. However, the use of a larger

excess amount of imidazole (PPh₃/imidazole/I₂=

4:8:3.3 equiv) was found to give the 1,2-oleﬁn derivative

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S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

δ 3.69 (J = 10.0, 9.0, 2.1 Hz)

TBDPSO

30%

Br^-

70 %

H

Br

LiBr, H⁺

Acetone

BnO

Br

+

OH

D-18

O

D-16

OH

D-19

7 : 3

Figure 5.

D-13 cleanly in a good yield. Subsequent dihydroxyl-

ation of ^D-13 with a catalytic amount of OsO₄and

The 1,2-diol derivative ^D-4d was prepared by protecting

the 3- and 4-OH groups as benzyl ether and removal of

the MOM groups in ^D-4a. Regioselective monobenzoyl-

ations of the 1,2-diol ^D-4d were carried out as follows.

Treatment of ^D-4d with triethyl orthobenzoate and

TSA, followed by hydrolysis in 80% aqueous AcOH,¹²

gave 2-O-benzoates D-4f as the major product (D-4e/D-

4f = 14:86, 85%). On the other hand, ^D-4d upon treat-

ment with BzCl, Et₃N, and Me₂SnCl₂²⁶gave 1-O-benzo-

ate (^D-4e) as the major product (D-4e/D-4f = 96:4, 98%).

Oxidation of 1-O-benzoate (^D-4e) with PCC gave 2-keto

compound ^D-20 in 97% yield. In the reduction of D-20,

compared to that of ^D-6, the preference for equatorial

alcohol was diminished presumably due to the axial 4-

OBn group, which hinders the topside approach of the

hydride. Treatment of ^D-20 with NaBH₄in CH₂Cl₂/

MeOH (20:1) gave a mixture of carba-b-^D-gulose D-21

and ^D-4e (D-21/D-4e = 43:57). Attempts to increase the

stereoselectivity by using diﬀerent reducing conditions

produced no improvement (^D-21/D-4e = ꢁ4:6 with

20

an excess NMO gave carba-a-^D-glucose derivative D-

14 as the sole product in quantitative yield. The coupling

constants of H1 (app q, J = 2.5 Hz) and H2 (dd, J = 9.2,

1

2.8 Hz) in the H NMR spectrum of D-14 are in good

agreement with its structure.

Several epoxidation conditions were examined on ^D-13

for its stereoselective conversion to the a- or b-1,2-epox-

ide derivatives. Treatment of ^D-13 with m-CPBA in

CH₂Cl₂gave a mixture of b-epoxide (D-15) and a-epox-

ide (^D-16) in a 1:4 ratio. Reaction of D-13 with NBS²¹

followed by treatment with NaOMe in MeOH resulted

in a similar ratio of the epoxides. Interestingly, the use

of NIS²²instead of NBS resulted in a mixture of D-15

and ^D-16 in the 1:10 ratio. The structure of D-16 was

conﬁrmed indirectly after its conversion to bromohyd-

rins (^D-18, D-19). Treatment of D-16 with LiBr and

AcOH²³gave a mixture of bromohydrins (D-18/D-

1

27

19 = 7:3). On the basis of H NMR analysis, the major

NaBH₄/CaCl₂or with BH₃ÆMe₂S). However, the car-

bromohydrin ^D-18 was found to have a structure shown

in Figure 5, thus conﬁrming the structure of ^D-16 as a-

epoxide. Apparently, the ring-opening reaction of the

a-epoxide ^D-16 did not follow the diaxial opening rule.

The reason for this observation is thought to be the

inﬂuence of the vicinal benzyloxy group at C3, which

may hinder the attack of the bromide anion at C2 site.

The speciﬁc synthesis of the b-epoxide ^D-15 was accom-

plished from 1,2-diol ^D-3d via the orthoacetate and

bromoacetoxy intermediates.²⁴Ring opening of the

ba-b-^D-gulose derivative D-21 could be separated as

pure diastereomer on silica gel. The recovered ^D-4e

could be recycled for the oxidation/reduction procedure

to provide more of ^D-21. The structure of carba-b-D-

gulose ^D-21 was conﬁrmed by analysis of coupling

constants of H1–H4, H5aa, and H5ab (J_H1–H2

=

9.7 Hz, J_H2–H3= J_H3–H4= 3.4 Hz, J_H1–H5aa= 5.0 Hz,

1

J

_H1–H5ab= 11.3 Hz) in the H NMR spectrum.

Preliminary experiments on the stereoinversion of car-

ba-b-idose ^D-4f to carba-a-idose by the oxidation/reduc-

tion protocol resulted in poor stereoselectivities

regardless of the conditions examined (carba-a-idose/

carba-b-idose = 1:2 by NaBH₄with or without CeCl₃

or CaCl₂, for example). Although the two epimers are

easily separable by column chromatography, the

observed selectivity was not satisfactory from a practical

viewpoint. Thus, we turned to the ring-opening reaction

of b-1,2-epoxide derivative ^D-22, which fortunately gave

carba-a-idose derivative ^D-23 with an excellent stereo-

selectivity. The b-1,2-epoxide ^D-22 was prepared from

1,2-diol derivative ^D-4d by sequential treatments²⁴with

(1) trimethyl orthoacetate, PPTS, (2) AcBr, Et₃N

(0.1 equiv), in CH₂Cl₂, and (3) NaOMe in MeOH.

Ring-opening reaction of b-1,2-epoxide ^D-22 with allyl

alcohol²⁸and TSA (0.26 equiv) gave carba-a-idose

derivative ^D-23 in 73% yield. In this ring-opening reac-

tion, the nucleophile attacked only C1 of the b-1,2-epox-

ide ^D-22 to give one stereoisomer (carba-a-idose). The

25

1,2-b-epoxide ^D-15 by treatment with aq HClO₄in

acetone gave carba-a-mannose derivative ^D-17 exclu-

sively, presumably due to the stereoselective diaxial

opening (The Furst–Plattenerꢀs rule). The conﬁgura-

¨

tions of D-17 are conﬁrmed by analysis of the

H1–H5 coupling constants (J_H1–H2= J_H2–H3= 2.8 Hz,

J_H3–H4= 8.8 Hz, J_H4–H5= 9.0 Hz) in the ¹H NMR

spectrum.

2.3. Transformation of carba-b-D-idopyranose to carba-a-

D-idopyranose, carba-b-D-gulopyranose, and carba-a-D-

gulopyranose derivatives

C1 and/or C2 stereoinversion of the carba-b-idose deriv-

ative ^D-4a gave carba-b-gulose D-21, carba-a-idose D-

23, and carba-a-gulose ^D-25 derivatives (Scheme 3).

Due to the variance of the C4 stereochemistry of car-

ba-b-idose ^D-4d from that of carba-b-altrose, the oxida-

tion/reduction protocol resulted in much decreased

selectivities in the inversion of C1 and C2 stereochemis-

try. However, carba-a-idose ^D-23 and carba-a-gulose D-

25 could be derived from 1,2-b-epoxide derivative ^D-22

with excellent stereoselectivities.

1

structure of carba-a-idose ^D-23 was conﬁrmed by H

NMR analysis (J_H1–H2= J_H2–H3= 8.7 Hz, J_H1–H5aa

=

11.2 Hz, J_H1–H5ab= 4.7 Hz) in acetone-d₆as an inverted

chair conformer in which C1–C4 substituents have all

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2735

OTBDPS

OMOM

OR

D-4a: R = H, R' = Bz

D-4b: R = R' = H

a

b

OMOM

D-4c: R = R' = Bn

OR'

c

OTBDPS

OR'

OBn

OTBDPS

OH

OBn

TBDPSO

BnO

h

d or e

O

OR

OH

OBn

D-4d

OBn

D-22

D-4e: R = Bz, R' = H

D-4f: R = H, R' = Bz

i

f

TBDPSO

BnO

TBDPSO

BnO

OTBDPS

O

OBn

f

OAllyl

OBz

OH

BnO

OBn

D-20

O

carba-α-D-idose

D-23

D-24

j

g

OTBDPS

OBn

OBz

OH

OBn

OBn OAllyl

carba-α-D-gulose

carba-β-D-gulose

D-21

D-25

Scheme 3. Reagents and conditions: (a) NaOMe (0.3 equiv), MeOH, rt, 5h, 94%; (b) NaH (6 equiv), BnBr (6 equiv), Bu₄NI (0.2 equiv), THF, rt,

˚

78%; (c) TMSBr (15 equiv), molecular sieves 4 A, CH₂Cl₂, ꢀ20 ꢁC, 69%; (d) Et₃N (2.0 equiv), Me₂SnCl₂(5.4 mol %), BzCl (1.2 equiv), 0 ꢁC, 98% (D-

4e/^D-4f = 94:6); (e) (i) (EtO)₃CPh (2 equiv), TSA (0.03 equiv), CH₂Cl₂, rt, (ii) 80% AcOH, 85% (D-4e/D-4f = 14:86); (f) PCC (3.0 equiv), molecular

˚

sieves 4 A, CH₂Cl₂, rt, 97% D-20, 99% D-24; (g) NaBH₄(5.0 equiv), MeOH (50 equiv), CH₂Cl₂, ꢀ20 ꢁC, 89% (D-21/D-4e = 43:57); (h) (i)

(CH₃O)₃CCH₃(1.5 equiv), PPTS (cat.), CH₂Cl₂, (ii) AcBr (3.0 equiv), Et₃N (0.1 equiv), CH₂Cl₂, (iii) NaOMe/MeOH, 95%; (i) TSA (0.26 equiv), allyl

alcohol, rt, 3.5 h, 73%; (j) L-Selectride^TM(5 equiv), THF, ꢀ20 ꢁC, 20 min, 73%.

equatorial orientations, while the C5-TBDPSOCH₂

group occupies the axial position. Oxidation of carba-

a-idose derivative ^D-23 with PCC gave the 2-keto deriv-

of the 1,2-a-epoxide derivative rather than Mitsunobu

reaction.

_TM29

ative ^D-24, which upon reduction with L-Selectride

The 1,2-diol derivative ^D-5d was prepared by the usual

protection and deprotection of ^D-5a. Stereoselective

preparation of the 1,2-b-epoxide derivative ^D-26 was car-

ried out from the 1,2-diol derivative ^D-5d by the same

procedure as used for the synthesis of other 1,2-b-epox-

ide derivatives, ^D-15 and D-22. Ring-opening reaction

of the 1,2-b-epoxide ^D-26 by treatment with allyl alcohol

and TSA (0.4 equiv) gave carba-a-^D-talose derivative D-

27a in 68% yield. In the ring opening, allyl alcohol again

attacked only the C1 position of the 1,2-b-epoxide to give

one stereoisomer, carba-a-^D-talose. Although there are

three axial substituents (C1, C2, and C4) in the cyclohex-

ane ring, the carba-a-^D-talose derivative D-27a was

found to have a conventional chair conformation as

shown in Scheme 4 on the basis of the ¹H NMR analysis

gave exclusively the desired carba-a-gulose derivative

D-25 (73%) without formation of D-23. The structure

of ^D-25 was again conﬁrmed by ¹H NMR analysis

(J_H1–H2= 3.4 Hz, J_H2–H3= 3.5 Hz, J_H3–H4= 3.7 Hz,

J

_H1–H5aa= 3.4 Hz, J_H1–H5ab= 3.4 Hz) in benzene-d₆

with the conformation as shown in Scheme 3.

2.4. Transformation of carba-b-^D-talopyranose to

carba-a-^D-talopyranose, carba-b-D-galactopyranose,

and carba-a-^D-galactopyranose derivatives

Regio- and stereoselective modiﬁcations of the C1 and/

or C2 stereochemistry in carba-b-^D-talose derivative D-5

gave carba-a-^D-talose D-27a, carba-a-D-galactose D-29,

and carba-b-^D-galactose D-31 derivatives (Scheme 4).

Due to the same stereochemistry at C3 of ^D-5d as that

of carba-b-mannose derivative ^D-3d, an analogous strat-

egy employing epoxidation/ring-opening and oleﬁn-

ation/dihydroxylation was successfully applied to the

carba-b-talose derivative. Inversion of the C2 stereo-

chemistry was carried out via a ring-opening reaction

in CDCl₃(J_H2–H3= 2.3 Hz, J_H3–H4= 2.3 Hz, J_H4–H5

=

small, J_H1–H5aa= 2.7 Hz, J_H1–H5ab= 2.3 Hz for D-27a).

An initial attempt to synthesize 1,2-oleﬁn derivative ^D-

28 by didehydroxylation of 1,2-diol derivative ^D-5d

was not successful, as the treatment of ^D-5d with

PPh₃, imidazole, and I₂resulted in a low yield (<30%)

2736

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

OTBDPS

OMOM

OTBDPS

OH

R'O

RO

BnO

d

c

O

OMOM

OH

BnO

D-5a: R = H, R' = Bz

D-5b: R = R' = H

OBn

D-26

a

b

D-5d

D-5c: R = R' = Bn

f

e

OTBDPS

OH

BnO

h

O

BnO

OBn

BnO

OBn

OAllyl

D-27a

carba-α-D-talose

D-28

D-30

g

i

OTBDPS

BnO

OTBDPS

OBn

OTBDPS

OAllyl

BnO

OH

+

BnO

OAllyl

OH

D-31

carba-β-D-galactose

HO

OH

D-29

7 : 3

D-27b

carba-α-D-talose

carba-α-D-galactose

Scheme 4. Reagents and conditions: (a) NaOMe (0.3 equiv), MeOH, rt, 4.5 h, 95%; (b) NaH (6 equiv), BnBr (6 equiv), Bu₄NI (0.2 equiv), THF, rt,

˚

94%; (c) TMSBr (20 equiv), molecular sieves 4 A, CH₂Cl₂, ꢀ20 ꢁC, 91%; (d) (i) (CH₃O)₃CCH₃(3.2 equiv), PPTS, CH₂Cl₂, (ii) AcBr (3.0 equiv), Et₃N

(0.1 equiv), CH₂Cl₂, (iii) NaOMe (3 equiv)/MeOH, 99%; (e) TSA (0.4 equiv), allyl alcohol, rt, 26 h, 68%; (f) (i) PPh₃(2 equiv), I₂(2 equiv), DMF, rt,

(ii) Zn powder (5 equiv), rt, 92%; (g) OsO₄(cat.), NMO (2 equiv), acetone/water (8:1), 6 h, rt, 91%; (h) m-CPBA, CH₂Cl₂, 22 h, rt, D-30/D-

26 = 54%:42%; (i) TSA (0.26 equiv), allyl alcohol, 40 ꢁC, 10 h, 53.8% D-31, 23% D-27b.

of D-28 with a number of by-products. Since the same

conditions for the didehydroxylation were successfully

applied to the carba-b-mannose derivative ^D-3d, the fail-

ure of the reaction with ^D-5d must be related to the

opposite stereochemistry at C4 in ^D-5d. The –OBn

group with axial orientation at C4 may sterically hinder

the formation of the phosphonium ion intermediate,

which is assumed to be involved in this reaction. Ther-

molysis of the 1,2-orthoformate derivative,³⁰prepared

from 1,2-diol ^D-5d, was tried in Ac₂O only to result in

decomposition of the starting material. However, it

was found that treatment of 1,2-b-epoxide ^D-26 with

PPh₃(2 equiv) and I₂(2 equiv) in DMF,³¹followed by

addition of Zn powder (5 equiv), gave the desired 1,2-

oleﬁn derivative, ^D-28, in 92% yield. Dihydroxylation

of the 1,2-oleﬁn derivative ^D-28 with a catalytic

amount of OsO₄and an excess of NMO (2 equiv) gave

a carba-a-galactose derivative ^D-29 as the sole product

in 91% yield. The structure and conformation of ^D-29

was conﬁrmed by ¹H NMR analysis as shown in Scheme

4 (J_H1–H2= 3.2 Hz, J_H2–H3= 9.7 Hz, J_H3–H4= 2.2 Hz,

J_H4–H5= 2.2 Hz, J_H1–H5aa= 3.0 Hz, J_H1–H5ab= 3.0 Hz).

by some other factors, such as hydrogen bonding or

hydrophobic interactions. Ring-opening reaction of the

1,2-a-epoxide ^D-30 was eﬀected with allyl alcohol and

TSA (0.26 equiv) at 40 ꢁC to aﬀord the remaining

stereoisomer, a carba-b-^D-galactose derivative D-31

together with a minor amount of a carba-a-^D-talose

derivative ^D-27b. The carba-b-galactose derivative D-31

was obtained by an apparent diequatorial ring-opening

process; a similar stereoselectivity was previously seen

in the ring-opening reaction of ^D-16 with LiBr and

AcOH. The structures and conformations of the car-

ba-b-^D-galactose D-31 derivatives were conﬁrmed as

shown in Scheme 4 by ¹H NMR analysis (J_H1–H2

9.4 Hz, J_H2–H3= 9.7 Hz, J_H3–H4= 2.1 Hz, J_H4–H5

2.1 Hz, J_H1–H5ab= 11.6 Hz).

=

In summary, we have successfully synthesized all 16 car-

basugar stereoisomers by the systematic manipulation of

the C1–C4 stereochemistry of one readily prepared ste-

reoisomer, that is, a carba-b-altrose derivative.

3. Conclusion

Epoxidation of ^D-28 with m-CPBA gave a mixture of

1,2-a-epoxide D-30 (54%) and 1,2-b-epoxide D-26

(42%). Compared to the epoxidation of ^D-13, treatment

of ^D-28 with m-CPBA was expected to give more a-

epoxide because the axial benzyloxy group at C4 might

provide additional steric hindrance to the topside

approach of peroxide. The observed stereoselectivity

suggests that the course of the epoxidation with m-

CPBA is inﬂuenced not only by steric hindrance but also

We have successfully developed divergent synthetic

routes to all possible carbahexopyranose stereoisomers

and their 1,2-epoxide derivatives by systematically

adjusting the hydroxyl stereochemistry of a carba-b-

altropyranose derivative, which is readily prepared as

both ^D- and L-form from commercially available 3-

cyclohexene-1-carboxylic acid. The carbasugar building

blocks that are made available by these synthetic routes

should ﬁnd use in the synthesis of various oligosaccha-

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2737

ride mimetics. In fact, we are currently carrying out the

combinatorial preparation of analogues of KRN7000,

an extremely exciting molecule displaying anticancer

and immunomodulatory activity, by attaching these

carbasugar residues to the readily available ceramide

library of sphingosine and phytosphingosine.³²Further-

more, it is now expected that the role of carbohydrates

in the life processes may be studied more eﬃciently with

the availability of these carbohydrate mimetics. Eventu-

ally, the ꢁglyco-mimeticsꢀ based on these synthetic car-

basugars are hoped to provide valuable therapeutic

tools for carbohydrate-related diseases, such as diabet-

ics, cancers, and viral diseases.

3.90 (dd, J = 10.6, 2.6 Hz, 1H, H-4), 3.96–4.1 (m, 4H,

H1, H2, H-3, H-6_b), 4.44–4.80 (m, 8H, 2 ·

–OCH₂Ph and 2 · –OCH₂OCH₃), 7.2–7.7 (m, 20H,

4Ph); ¹³C NMR (CDCl₃) d 20.1, 27.6, 29.02, 38.7,

56.0, 56.3, 65.0, 72.5, 73.8, 74.1, 76.4, 77.1, 77.2, 96.0,

98.2, 128.1, 128.3, 128.4, 128.5, 128.9, 129.0, 130.1,

130.2, 134.5, 134.7, 136.4, 136.5, 139.4; MS (FAB)

m/z 707 (M⁺+Na); HRMS (FAB) m/z calcd for

C₄₁H₅₂O₇SiNa 707.3380 found 707.3381 (M⁺+Na).

4.3. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-

5a-carba-b-^D-altropyranose, D-2c

To a solution of ^D-2b (304 mg, 0.443 mmol) and mole-

˚

cular sieves 4 A (400 mg, powder) in dry CH₂Cl₂

4. Experimental

(10 ml) at ꢀ20 ꢁC was added TMSBr (0.64 ml,

4.7 mmol). After stirring for 40 min at ꢀ20 ꢁC, the reac-

tion mixture was poured into satd aq NaHCO₃(30 ml).

After ﬁltering the resulting mixture on Celite, the ﬁltrate

was extractively worked up with EtOAc. The crude

product was chromatographed on silica gel to give

4.1. General procedure

All non-hydrolytic reactions were carried out in oven-

dried glassware under an inert atmosphere of dry argon

or nitrogen. All commercial chemicals were used as

obtained without further puriﬁcation, except for sol-

vents, which were puriﬁed and dried by standard meth-

ods prior to use. Melting points were determined on a

Thomas–Hoover apparatus and are uncorrected. Ana-

lytical TLC was performed on Merck 60 F254 silica

gel plates (0.25 mm thickness) and visualization done

with UV light, and/or by spraying a 5% solution of

phosphomolybdic acid followed by charring with a heat

gun. Column chromatography was performed on Merck

60 silica gel (70–230 mesh or 230–400 mesh). NMR spec-

tra were recorded on a Bruker AM 300 or DPX 300

spectrometer. Tetramethylsilane was used as the internal

standard for ¹H NMR. Low resolution mass spectra

were determined on a micromass PLATFORM II (EI,

FAB) and high resolution mass spectra (FAB) on a

JMS-700 at the Korea Basic Science Center, Daegu,

Korea. Optical rotations were measured with a JASCO

DIP-360 digital polarimeter. The standard extractive

work-up procedure consisted of pouring into a large

amount of water, extracting with organic solvent indi-

cated, washing the combined extracts successively with

water and brine, drying the extract on anhydrous

Na₂SO₄or MgSO₄, and evaporating the solvent.

compound ^D-2c (170 mg, 64%) as a colorless oil. D-2c:

15

½aꢂ_D¼ þ2.6 ðc 1.51; CHCl₃Þ; ¹H NMR (CDCl₃) d

1.08 (s, 9H, –C(CH₃)₃), 1.75–1.9 (m, 2H, H-5a_axand

H-5a_eq), 1.93 (d, J = 3.8 Hz, 1H, OH), 2.25 (m, 1H,

H-5), 2.32 (d, J = 1.8 Hz, 1H, –OH), 3.75 (dd,

J = 10.0, 4.8 Hz, 1H, H-6_a), 3.87 (dd, J = 10.0, 4.9 Hz,

1H, H-6_b), 3.93 (dd, J = 5.5, 2.6 Hz, 1H, H-3), 3.99

(dd, J = 8.6, 2.6 Hz, 1H, H4), 4.05–4.16 (m, 2H, H-1

and H-2), 4.47–4.7 (m, 4H, 2 · –OCH₂Ph), 7.2–7.7 (m,

20H, 4Ph); ¹³C NMR (CDCl₃) d 20.0, 27.7, 30.2, 38.9,

65.4, 69.1, 71.9, 72.5, 73.3, 76.4, 77.0, 128.1, 128.3,

128.9, 129.0, 130.2 (2s), 134.4 (2s), 136.3, 136.4, 139.3,

139.4; MS (FAB) m/z 597 (M⁺+1), 619 (M⁺+Na);

HRMS (FAB) m/z calcd for C₃₇H₄₄O₅SiNa 619.2856

found 619.2863 (M⁺+Na).

4.4. 1-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldi-

phenyl)silyl-5a-carba-b-^D-altropyranose, D-2d and 2-O-

benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-

5a-carba-b-^D-altropyranose, D-2e

To a solution of ^D-2c (100 mg, 0.167 mmol) in CH₂Cl₂

(2 ml) at rt were added (EtO)₃CPh (76 ll, 0.335 mmol)

and TSA (3.2 mg, 0.0167 mmol) in portions. After stir-

ring for 30 min, the reaction mixture was concentrated

by evaporation and the resulting residue treated with

80% aq AcOH (0.5 ml) and stirred for 10 min at rt. A

standard extractive work-up with EtOAc, followed by

chromatography on silica gel, gave compounds ^D-2d

4.2. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-1,2-

di-O-(methoxymethyl)-5a-carba-b-^D-altropyranose, D-2b

To a solution of ^D-2a (515 mg, 1.02 mmol) in dry THF

(20 ml) at 0 ꢁC was added NaH (267 mg, 55% in paraﬃn

liquid, 6.12 mmol). After stirring for 30 min at rt, BnBr

(0.727 ml, 6.12 mmol) and Bu₄NI (75.6 mg, 0.204 mmol)

were added. After stirring for 48 h at rt, the reaction

mixture was quenched with drops of satd aq NaHCO₃

and worked up by a standard extractive procedure with

EtOAc. A chromatography on silica gel gave compound

(46.5 mg, 39.6%) and ^D-2e (61.6 mg, 52.5%) as colorless

16

oils. ^D-2d: ½aꢂ_D¼ þ10.25 ðc 1.77; CHCl₃Þ; ¹H NMR

(CDCl₃) d 1.08 (s, 9H, –C(CH₃)₃), 1.97 (dt, J = 12.7,

4.3 Hz, 1H, H-5a_eq), 2.11 (app q, J = 12.2 Hz, 1H, H-

5a_ax), 2.35 (m, 1H, H-5), 3.75 (dd, J = 9.9, 3.6 Hz, 1H,

H-6_a), 3.94 (dd, J = 9.9, 4.4 Hz, 1H, H-6_b), 4.03–4.05

(m, 2H, H-1, H-3, H-4), 4.35 (t, J = 3.6 Hz, 1H, H-2),

4.46–4.75 (m, 4H, 2 · –OCH₂Ph), 5.49 (ddd, J = 10.6,

4.7, 3.0 Hz, 1H, H-1), 7.2–8.1 (m, 25H, 5Ph); ¹³C

NMR (CDCl₃) d 19.5, 26.7, 27.1, 38.0, 64.3, 69.8, 71.9,

72.7, 72.8, 75.5, 75.6, 127.6, 127.8, 127.9, 128.5, 128.6,

129.7, 129.8, 130.4, 133.3, 133.7, 135.8, 135.9, 138.5,

138.7, 165.8; MS (FAB) m/z 723 (M⁺+Na); MS

D-2b (633 mg, 90.2%) as

a colorless oil. D-2b:

25

½aꢂ_D¼ ꢀ18.1 ðc 1.76; CHCl₃Þ; ¹H NMR (CDCl₃) d

1.11 (s, 9H, –C(CH₃)₃), 1.88 (dt, J = 12.2, 4.0 Hz, 1H,

H-5a_eq), 2.03 (app q, J = 12.0 Hz, 1H, H-5a_ax), 2.20

(m, 1H, H-5), 3.37 (s, 3H, OCH₂OCH₃), 3.41 (s, 3H,

OCH₂OCH₃), 3.75 (dd, J = 9.7, 2.4 Hz, 1H, H-6_a),

2738

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

(FAB) m/z 597 (M⁺+1), 619 (M⁺+Na); HRMS (FAB)

4.26 (pseudo t, 1H, H-3), 4.5–5.1 (m, 4H, 2 ·

–OCH₂Ph), 5.31 (ddd, J = 11.3, 9.7, 5.1 Hz, 1H, H-1),

7.2–8.1 (m, 25H, 5Ph); ¹³C NMR (CDCl₃) d 20.0,

27.7, 30.2, 38.6, 64.2, 72.8, 74.4, 74.9, 75.3, 78.5, 79.8,

128.2, 128.3, 128.4, 129.0, 129.1, 130.3, 130.35, 130.41,

131.2, 133.6, 134.1, 134.2, 136.31, 136.36, 138.8, 139.3,

167.4 (PhC@O); MS (FAB) m/z 701 (M⁺+H), 723

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₄H₄₈O₆SiNa

723.3118 found 723.3112 (M⁺+Na).

m/z calcd for C₄₄H₄₈O₆SiNa 723.3118 found 723.3112

16

(M⁺+Na); D-2e: ½aꢂ_D¼ ꢀ17.8 ðc 1.80; CHCl₃Þ; ¹H

NMR (CDCl₃) d 1.12 (s, 9H, –C(CH₃)₃), 1.92 (m, 1H,

H-5a_eq), 2.14 (app q, J = 12.0 Hz, 1H, H-5a_ax), 2.25

(m, 1H, H-5), 3.67 (dd, J = 9.8, 1.6 Hz, 1H, H-6_a),

3.95 (dd, J = 10.4, 2.6 Hz, 1H, H-4), 4.06–4.11 (m, 2H,

H-3, H-6_b), 4.33 (m, 1H, H-1), 4.38–4.78 (m, 4H, 2 ·

–OCH₂Ph), 5.56 (app t, 1H, H-2), 7.12–8.1 (m, 25H,

5Ph); ¹³C NMR (CDCl₃) d 19.6, 27.1, 31.3, 37.6, 63.7,

67.3, 72.0, 73.2, 73.4, 74.1, 75.9, 127.6, 127.8, 127.9,

128.0, 128.4, 128.5, 128.7, 129.8, 129.9, 130.0, 133.4,

133.6, 135.8, 135.9, 138.3, 138.4, 167.2; MS (FAB)

m/z 723 (M⁺+Na); HRMS (FAB) m/z calcd for

C₄₄H₄₈O₆SiNa 723.3118 found 723.3112 (M⁺+Na).

4.7. (2S,3R,4R,5S)-2-Benzoyloxy-5-(tert-butyl-diphenyl-

silanyloxymethyl)-3,4-di-benzyloxy-cyclohexanone, ^D-8

To a stirred mixture of ^D-2e (40 mg, 57.1 lmol) and

˚

molecular sieves 4 A (powder, 40 mg) in CH₂Cl₂

(1.5 ml) at rt was added PCC (37 mg, 171.2 lmol). After

reﬂuxing for 4 h, the reaction mixture was ﬁltered

through a silica gel column and washed with EtOAc/n-

hexane (1:4). The ﬁltrate was concentrated to give ^D-8

4.5. (2R,4S,5R,6R)-2-Benzoyloxy-4-(tert-butyl-diphenyl-

silanyloxymethyl)-5,6-di-benzyloxy-cyclohexanone, ^D-6

To a stirred mixture of ^D-2d (30 mg, 42.8 lmol) and

molecular sieves 4 A (powder, 30 mg) in CH₂Cl₂(2 ml)

(37.4 mg, 53.5 lmol, 93.7%) as a colorless oil. ^D-8:

18

½aꢂ_D¼ ꢀ26.5 ðc 1.87; CHCl₃Þ; ¹H NMR (CDCl₃) d

˚

at rt was added PCC (27.6 mg, 0.128 mmol). After stir-

ring for 5 h, the reaction mixture was ﬁltered through a

silica gel column and washed with EtOAc/n-hexane

(1:4). The ﬁltrate was concentrated to give D-6

(29.8 mg, 42.6 lmol, 99.6%) as colorless oil. ^D-6:

1.04 (s, 9H, –C(CH₃)₃), 2.42 (app d, J = 14.7 Hz, 1H,

H-6_eq), 2.50 (m, 1H, H-5), 2.36 (dd, J = 14.5, 6.8 Hz,

1H, H-6_ax), 3.47 (dd, J = 10.7, 6.8 Hz, 1H, H-7_a), 3.61

(dd, J = 10.8, 4.1 Hz, 1H, H-7_b), 4.25 (pseudo t,

J = 3.3 Hz, 1H, H-4), 4.29 (dd, J = 9.8, 2.6 Hz, 1H, H-

3), 4.6–4.9 (m, 4H, 2 · –OCH₂Ph), 5.96 (d, J = 9.7 Hz,

1H, H-2), 7.2–8.2 (m, 25H, 5Ph); ¹³C NMR (CDCl₃) d

19.9, 27.6, 38.7, 40.4, 65.1, 73.4, 73.7, 76.6, 79.0, 79.3,

128.39, 128.44, 128.5, 129.0, 129.1, 130.5, 130.6, 130.7,

133.3, 133.5, 133.8, 136.3, 136.4, 138.7, 139.0, 166.2

(PhC@O), 202.3 (C-1); MS (FAB) m/z 699 (M⁺+H),

721 (M⁺+Na); HRMS (FAB) m/z calcd for C₄₄H₄₆O₆-

SiNa 721.2961 found 721.2960 (M⁺+Na).

20

1

½aꢂ_D¼ þ51.65 ðc 1.49; CHCl₃Þ; H NMR (CDCl₃)

d

1.09 (s, 9H, –C(CH₃)₃), 1.95 (app q, J = 12.9 Hz, 1H,

H-3_ax), 2.36 (ddd, J = 12.6, 6.9, 4.1 Hz, 1H, H-3_eq),

2.72 (m, 1H, H-4), 3.68 (dd, J = 10.7, 2.7 Hz, 1H, H-

5), 3.82 (dd, J = 10.0, 2.2 Hz, 1H, H-7_a), 4.06 (dd,

J = 10.0, 4.3 Hz, 1H, H-7_b), 4.30 (d, J = 2.6 Hz, 1H,

H-6), 4.33–4.92 (m, 4H, 2 · –OCH₂Ph), 6.04 (dd,

J = 13.0, 6.9 Hz, 1H, H-2), 7.2–8.2 (m, 25H, 5Ph); ¹³C

NMR (CDCl₃) d 20.0, 27.7, 30.8, 38.4, 63.8, 72.1, 72.6,

75.2, 79.8, 81.4, 128.3, 128.4, 128.8, 129.0, 129.1,

129.2, 129.5, 130.3, 130.4, 130.5, 130.6, 134.0, 136.3,

136.4, 137.5, 138.4, 166.3 (PhC@O), 204.8 (C-1); MS

(FAB) m/z 699 (M⁺+H), 721 (M⁺+Na); HRMS

(FAB) m/z calcd for C₄₄H₄₆O₆SiNa 721.2961 found

721.2967 (M⁺+Na).

4.8. 2-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldi-

phenyl)silyl-5a-carba-a-^D-altropyranose, D-9a

To a solution of ^D-8 (43 mg, 61.5 lmol) in CH₂Cl₂/

MeOH (20:1, 5 ml) at ꢀ10 ꢁC was added NaBH₄

(11.63 mg, 0.307 mmol) over 20 min. After stirring for

90 min at ꢀ10 ꢁC, the reaction mixture was treated with

AcOH (three drops) and stirred for an additional 1 h.

The reaction mixture was ﬁltered on a silica gel pad

and the ﬁltrate was concentrated to give a mixture

(^D-9a/D-2e = 3:1 by ¹H NMR analysis). This mix-

ture was chromatographed to give a mixture of ^D-9a

4.6. 1-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldi-

phenyl)silyl-5a-carba-b-^D-allopyranose, D-7

To a solution of ^D-6 (15 mg, 21.4 lmol) in THF (1.8 ml)

at 0 ꢁC, BH₃ÆMe₂S (107 lmol, 53.5 ll of 2 M solution in

THF) was added. After stirring for 1 h at rt, the reaction

mixture was quenched with a few drops of MeOH and

concentrated. The residue was ﬁltered on silica gel and

the ﬁltrate was concentrated to give a mixture of ^D-7

and ^D-2d (85:5). This mixture was treated with PCC

(13.8 mg, 3.0 equiv) in CH₂Cl₂(1.5 ml) for 2 h at rt

and the resulting mixture was ﬁltered on silica gel. The

ﬁltrate was concentrated and chromatographed to give

D-6 (4.5 mg, 30%) and a mixture of D-7/D-2d (95:5 by

(29.6 mg, 68.6%) and D-2e (8 mg, 18.5%). D-9a:

19

½aꢂ_D¼ ꢀ13.7 ðc 1.48; CHCl₃Þ; ¹H NMR (CDCl₃) d

1.14 (s, 9H, –C(CH₃)₃), 1.96 (d, J = 12.8 Hz, 1H, H-

5a_eq), 2.30 (td, J = 13.5, 2.9 Hz, 1H, H-5a_ax), 2.44 (m,

1H, H-5), 3.66 (dd, J = 9.9, 2.2 Hz, 1H, H-6_a), 3.76

(br d, J = 10.1 Hz, 1H, –OH), 4.0–4.1 (m, 2H, H-1,

and H-6_b), 4.13 (pseudo t, J = 2.9 Hz, 1H, H-3), 4.21

(dd, J = 9.9, 2.9 Hz, 1H, H-4), 4.4–4.85 (m, 4H, 2 ·

–OCH₂Ph), 5.54 (pseudo t, J = 3.2 Hz, 1H, H-2), 7.1–

8.2 (m, 25H, 5Ph); ¹³C NMR (CDCl₃) d 20.1, 27.7,

32.4, 35.1, 64.3, 69.2, 72.1, 72.6, 74.3, 76.3, 76.6, 128.3,

128.40, 128.43, 128.7, 128.8, 129.0, 129.18, 129.22,

130.3, 130.4, 134.0, 134.2, 136.3, 136.4, 138.1, 138.9,

165.8 (PhC@O); MS (FAB) m/z 701 (M⁺+H), 723

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₄H₄₈O₆SiNa

723.3118 found 723.3112 (M⁺+Na).

¹H NMR analysis, 9 mg, 60%) as colorless oils. D-7:

22

½aꢂ_D¼ ꢀ6.0 ðc 0.45; CHCl₃Þ; ¹H NMR (CDCl₃) d

1.10 (s, 9H, –C(CH₃)₃), 1.67 (app q, J = 12.5 Hz, 1H,

H-5a_ax), 2.09 (dt, J = 13.0, 4.6 Hz, 1H, H-5a_eq), 2.40

(m, 1H, H-5), 2.50 (br d, J = 10.1 Hz, 1H, –OH),

3.60–3.70 (m, 2H, H-2, H-6_a), 3.73 (dd, J = 9.8,

2.6 Hz, 1H, H-4), 4.02 (dd, J = 9.9, 4.0 Hz, 1H, H-6_b),

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2739

4.9. 2-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyl-

di-phenyl)silyl-1-O-methoxymethyl-5a-carba-a-

D-altropyranose, D-9b

n-hexane (1:2). The ﬁltrate was concentrated to give ^D-

20

10 (12.4 mg, 89.0%) as colorless oil. ^D-10: ½aꢂ_D

¼

þ3.0 ðc 0.62; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.03 (s,

9H, –C(CH₃)₃), 2.10 (app dd, J = 12.7, 6.8 Hz, 1H, H-

5_eq), 2.26 (dt, J = 12.3, 6.0 Hz, 1H, H-5_ax), 2.36 (m,

1H, H-4), 3.39 (s, 3H, –OCH₂OCH₃), 3.72 (app d,

J = 6.54 Hz, 2H, H-7_aand H-7_b), 4.25–4.37 (m, 3H,

H-2, H-3, and H-6), 4.4–4.9 (m, 6H, 2 · –OCH₂Ph and

–OCH₂OCH₃), 7.2–7.7 (m, 20H, 4Ph); ¹³C NMR

(CDCl₃) d 19.8, 27.5, 32.3, 40.1, 56.4, 65.5, 72.9, 73.4,

76.9, 81.6, 82.6, 96.4, 128.07, 128.13, 128.4, 128.6,

128.9, 129.1, 130.6, 133.5, 133.6, 136.20, 136.22, 138.6,

139.3, 204.7 (C-1); MS (FAB) m/z 661 (M⁺+Na);

HRMS (FAB) m/z calcd for C₃₉H₄₆O₆SiNa 661.2961

found 661.2965 (M⁺+Na).

To a solution of ^D-9a (25 mg, 35.8 lmol) in CH₂Cl₂

(3 ml) at 0 ꢁC were added (i-Pr)₂NEt (81 ll, 0.465 mmol)

and MOM–Cl (35.3 ll, 0.465 mmol), and the resulting

mixture was reﬂuxed for 15 h. After cooling to rt, the

reaction mixture was diluted with CH₂Cl₂and washed

with satd aq NaHCO₃, 1 M HCl, and satd aq NaHCO₃.

The organic layer was dried over MgSO₄, concentrated,

and chromatographed to give ^D-9b (22.4 mg, 30.1 lmol,

21

84.0%) as

a

colorless oil. D-9b: ½aꢂ_D¼ ꢀ2.8

ðc 1.12; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.10 (s, 9H,

–C(CH₃)₃), 1.90–2.15 (m, 2H, H-5a_eqand H-5a_ax),

2.38 (m, 1H, H-5), 3.25 (s, 3H, –OCH₂OCH₃), 3.62

(dd, J = 10.3, 6.6 Hz, 1H, H-6_a), 3.75–3.82 (m, 2H, H-

3, H-6_b), 3.94 (m, 1H, H-1), 4.06 (dd, J = 4.9, 2.7 Hz,

1H, H-4), 4.5–4.75 (m, 6H, 2 · –OCH₂Ph and

–OCH₂OCH₃), 5.73 (t, J = 7.8 Hz, 1H, H-2), 7.1–8.2

(m, 25H, 5Ph); ¹³C NMR (CDCl₃) d 19.9, 27.6, 29.3,

38.6, 56.0, 65.2, 72.6, 72.7, 74.8, 74.9, 75.9, 77.6, 96.2,

128.03, 128.06, 128.4, 128.5, 128.8, 128.9, 129.0, 130.4,

130.5, 131.2, 133.5, 133.98, 134.01, 136.3, 139.0, 139.5,

166.2 (PhC@O); MS (FAB) m/z 745 (M⁺+H), 767

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₆H₅₂O₇SiNa

767.3380 found 767.3380 (M⁺+Na).

4.12. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-1-O-

methoxymethyl-5a-carba-a-^D-allopyranose, D-11

To a solution of ^D-10 (10 mg, 15.6 lmol) in CH₂Cl₂/

MeOH (0.6 ml) at ꢀ10 ꢁC was added NaBH₄(3.0 mg,

78.3 mmol). After stirring for 30 min at ꢀ10 ꢁC, the

reaction mixture was treated with AcOH (two drops)

and stirred for an additional 1 h. The reaction mixture

was ﬁltered on silica gel pad and the ﬁltrate was concen-

trated to give a residue (^D-11/D-9c = >99:1 by ¹H NMR

analysis). This mixture was chromatographed to give ^D-

22

11 (10.0 mg, quantitative). D-11: ½aꢂ_D¼ þ16.7 (c

1

4.10. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-1-O-

methoxymethyl-5a-carba-a-^D-altropyranose, D-9c

0.50, CHCl₃); H NMR (C₆D₆with D₂O one drop) d

1.23 (s, 9H, –C(CH₃)₃), 1.57 (ddd, J = 14.2, 10.4,

3.2 Hz, 1H, H-5a_ax), 2.26 (dt, J = 14.3, 4.7 Hz, 1H, H-

5a_eq), 2.68 (m, 1H, H-5), 3.23 (s, 3H, OCH₂OCH₃),

3.47 (dd, J = 9.1, 2.2 Hz, 1H, H-4), 3.64 (br s, 1H,

H-2), 3.78 (m, 1H, H-1), 3.80 (dd, J = 9.7, 3.6 Hz,

1H, H-6_a), 3.98 (br s, 1H, H-3), 4.0 (dd, J = 9.8,

5.3 Hz, H-6_b), 4.36–4.93 (m, 6H, 2 · –OCH₂Ph and

–OCH₂OCH₃), 7.1–7.8 (m, 20H, 4Ph); ¹³C NMR

(CDCl₃) d 19.9, 27.6, 30.4, 37.4, 56.2, 64.9, 71.3, 73.2

(2s), 76.0, 77.9, 79.3, 96.7, 128.0, 128.1, 128.25, 128.28,

128.4, 128.9, 129.0, 130.38, 130.40, 134.1, 136.2, 136.3,

138.9, 139.6; MS (FAB) m/z 663 (M⁺+Na); HRMS

(FAB) m/z calcd for C₃₉H₄₈O₆SiNa 663.3118 found

663.3116 (M⁺+Na).

To a solution of ^D-9b (20 mg, 26.8 lmol) in MeOH

(2 ml) was added NaOMe (134 lmol, 30.7 ll of 25%

solution in MeOH). After stirring for 14 h at rt, the reac-

tion mixture was treated with AcOH (150 lmol, 8.75 ll)

and concentrated. The residue was dissolved in CH₂Cl₂,

ﬁltered on silica gel, and washed with EtOAc/n-hexane

(1:2). The ﬁltrate was concentrated to give ^D-9c

18

(16.1 mg, 93.6%) as a colorless oil. ^D-9c: ½aꢂ_D

¼

1

ꢀ8.6 ðc 0.80; CHCl₃Þ; H NMR (C₆D₆) d 1.22 (s, 9H,

–C(CH₃)₃), 1.99 (br dd, J = 12.5, 4.4 Hz, 1H, H-5a_eq),

2.25 (app td, J = 12.5, 5.8 Hz, 1H, H-5a_ax), 2.42 (m,

1H, H-5), 3.21 (s, 3H, OCH₂OCH₃), 3.24 (br s, 1H,

–OH), 3.58 (dd, J = 9.3, 2.6 Hz, 1H, H-3), 3.6–3.8 (m,

3H, H-1, H-6_a, and H-6_b), 4.04 (pseudo t, J = 2.6 Hz,

1H, H-4), 4.47 (t, J = 9.3 Hz, 1H, H-2), 4.6–4.8 (m,

6H, 2 · –OCH₂Ph and –OCH₂OCH₃), 6.9–7.9 (m,

20H, 4Ph); ¹³C NMR (CDCl₃) d 19.0, 27.6, 28.4, 30.4,

39.9, 56.1, 65.1, 72.6, 72.9, 74.4, 74.6, 79.0, 80.8, 97.3,

128.1, 128.28, 128.35, 128.4, 128.5, 128.9, 129.1, 130.5,

133.9, 134.0, 136.21, 136.24, 139.1, 139.6; MS (FAB)

m/z 663 (M⁺+Na); HRMS (FAB) m/z calcd for

C₃₉H₄₈O₆SiNa 663.3118 found 663.3118 (M⁺+Na).

4.13. 6-O-(tert-Butyldiphenyl)silyl-1,2-di-O-(methoxy-

methyl)-5a-carba-b-^D-mannopyranose, D-3b

To a solution of ^D-3a (912 mg, 1.45 mmol) in MeOH

(10 ml) was added NaOMe (145 lmol, 33 ll of 25%

solution in MeOH). After stirring for 2 h at rt, the reac-

tion mixture was treated with AcOH (one drop) and

concentrated. The residue was directly chromato-

graphed on silica gel to give ^D-3b (671 mg, 91.7%) as a

20

colorless oil. ^D-3b: ½aꢂ_D¼ ꢀ32.9 ðc 1.08; CHCl₃Þ; ¹H

4.11. (2R,3S,4S,6R)-2,3-Di-benzyloxy-4-(tert-butyl-

diphenyl-silanyloxymethyl)-6-methoxymethyloxy-

cyclohexanone, D-10

NMR (CDCl₃) d 1.05 (s, 9H, –C(CH₃)₃), 1.62–1.76 (m,

3H, H-5a_eq, H-5a_ax, H-5), 3.37–3.46 (2, 6H,

2 · OCH₂OCH₃), 3.67–3.83 (m, 5H), 4.03 (br s, 1H),

4.65–4.85 (m, 4H, 2 · –OCH₂OCH₃), 7.2–7.95 (m,

10H, 2Ph); ¹³C NMR (CDCl₃) d 19.9, 27.5, 28.3, 41.3,

56.2, 56.7, 66.7, 73.4, 75.2, 75.4, 82.1, 95.7, 99.2, 128.5,

130.5, 133.8, 133.9, 136.3; MS (FAB) m/z 527

(M⁺+Na); HRMS (FAB) m/z calcd for C₂₇H₄₀O₇SiNa

527.2441 found 527.2441 (M⁺+Na).

To a stirred mixture of ^D-9c (14 mg, 21.8 lmol) and

˚

molecular sieves 4 A (powder, 20 mg) in CH₂Cl₂

(1.5 ml) at rt was added PCC (14.1 mg, 65.5 lmol).

After reﬂuxing for 11 h, the reaction mixture was ﬁltered

through a silica gel column and washed with EtOAc/

2740

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

4.14. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-

1,2-di-O-(methoxymethyl)-5a-carba-b-^D-mannopyranose,

D-3c

chromatographed on silica gel column to give com-

pound ^D-12 (22 mg, 62.6%) as a colorless oil. D-12:

21

½aꢂ_D¼ þ47.9 ðc 0.76; CHCl₃Þ; ¹H NMR (acetone-d₆)

d 1.12 (s, 9H, –C(CH₃)₃), 1.78 (q, J = 11.5 Hz, 1H, H-

5a_ax), 1.85 (m, 1H, H-5), 2.20 (m, 1H, H-5a_eq), 3.69

(app t, J = 9.9 (9.2) Hz, 1H, H-4), 3.75 (app t, J = 9.3

(9.2) Hz, 1H, H-3), 3.85 (dd, J = 9.7, 2.0 Hz, 1H, H-

6_a), 3.9 (m, 1H, H-1), 3.97 (dd, J = 9.7, 4.6 Hz, 1H,

H-6_b), 4.45 (br d, J = 5.2 Hz, –OH), 4.57–4.92 (m, 4H,

2 · –OCH₂Ph), 5.25 (t, J = 9.3 Hz, 1H, H-2), 7.1–8.1

(m, 25H, 5Ph); ¹³C NMR (acetone-d₆) d 20.5, 28.0,

34.8, 42.3, 65.1, 71.3, 75.9, 76.5, 80.9, 82.1, 85.7, 128.7,

129.0, 129.1, 129.3, 129.5, 129.6, 129.8, 129.9, 131.0,

131.3, 132.5, 134.3, 134.8, 134.9, 137.0, 137.1, 140.1,

140.4, 167.0 (PhC@O); MS (FAB) m/z 723 (M⁺+Na);

HRMS (FAB) m/z calcd for C₄₄H₄₈O₆SiNa 723.3118

found 723.3115 (M⁺+Na).

To a solution of ^D-3b (620 mg, 1.23 mmol) in dry THF

(20 ml) at 0 ꢁC was added NaH (214 mg, 55% in paraﬃn

liquid, 4.90 mmol). After stirring for 30 min at rt, BnBr

(0.584 ml, 4.91 mmol) and Bu₄NI (91 mg, 0.246 mmol)

were added. After stirring for 36 h at rt, the reaction mix-

ture was quenched with drops of satd aq NaHCO₃and

extractively worked up with EtOAc. A chromato-

graphy on silica gel gave compound ^D-3c (688 mg, 81.4%)

20

as a colorless oil. ^D-3c: ½aꢂ_D¼ ꢀ4.5 ðc 1.16; CHCl₃Þ; d

1.11 (s, 9H, –C(CH₃)₃), 1.66 (m, 1H, H-5), 1.92 (dt, J =

12.5, 3.7 Hz, 1H, H-5a_eq), 1.95 (app q, J = 12.5 Hz,

1H, H-5a_ax), 3.44 and 3.47 (2s, 6H, 2 · –CH₂OCH₃),

3.46 (m, 1H, H-3), 3.64 (ddd, J = 12.2, 4.7, 2.3 Hz,

1H, H-1), 3.81 (dd, J = 9.7, 2.6 Hz, 1H, H-6_a), 3.87

(dd, J = 9.5, 4.0 Hz, 1H, H-6_b), 3.88 (app t,

J = 10.0 Hz, 1H, H-4), 4.16 (br s, 1H, H-2), 4.45–4.95

(m, 8H, 2 · –CH₂OCH₃and 2 · –OCH₂Ph), 7.1–7.7

(m, 20H, 4Ph); ¹³C NMR (CDCl₃) d 20.1, 27.6, 29.0,

42.0, 56.2 (2s), 64.6, 72.8, 73.9, 75.0, 76.0, 78.2, 84.6,

95.2, 97.7, 128.1, 128.3 (2s), 128.4, 128.5, 128.7, 129.0,

129.1, 130.3, 134.3, 134.4, 136.4 (2s), 139.2, 139.5; MS

(FAB) m/z 707 (M⁺+Na); HRMS (FAB) m/z calcd

for C₄₁H₅₂O₇SiNa 707.3380 found 707.3375 (M⁺+Na).

4.17. (1R,2R,3S)-1,2-Di-benzyloxy-3-(tert-butyl-di-

phenyl-silanyloxymethyl)-cyclohex-5-ene, ^D-13

To a reﬂuxing mixture of ^D-3d (60.0 mg, 100 lmol),

PPh₃(105 mg, 400 lmol), and imidazole (27.2 mg,

400 lmol) in toluene (5 ml) was added a solution of I₂

(resublimed, 83.8 mg, 330 lmol) in toluene (1 ml). After

25 min, additional imidazole (30 mg) in toluene (1 ml)

was added to the mixture. After reﬂuxing for 3 h, the

reaction mixture was cooled to rt, diluted with EtOAc

(50 ml), and washed with half-saturated aqueous

4.15. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-5a-

carba-b-^D-mannopyranose, D-3d

Na₂S₂O₃. An extractive work-up followed by

a

chromatography on silica gel gave compound ^D-13

21

To a solution of ^D-3c (830 mg, 1.21 mmol) and molecular

(51 mg, 90.4%) as

a

colorless oil. D-13: ½aꢂ_D¼

ꢀ32.5 ðc 1.00; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.11 (s,

9H, –C(CH₃)₃), 2.02 (m, 1H, H-3), 2.21 (dt, J = 18.0,

4.9 Hz, H-4a_eq), 2.40 (m, 1H, H-4a_ax), 3.77 (m, 2H, H-

2 and H-7_a), 3.98 (dd, J = 9.9, 5.0 Hz, 1H, H-7_b), 4.21

(m, 1H, H-3), 4.6–4.95 (m, 4H, 2 · –OCH₂Ph), 5.70

(br d, J = 10.1 Hz, 1H, H-6, oleﬁn), 5.81 (m, 1H, H-5,

oleﬁn), 7.1–7.7 (m, 20H, 4Ph); ¹³C NMR (CDCl₃) d

19.6, 27.2, 28.8, 41.5, 63.7, 71.9, 74.6, 79.5, 81.8, 126.3,

127.6, 127.77, 127.83, 127.9, 128.0, 128.1, 128.5, 128.6,

128.8, 129.8, 133.8, 133.9, 135.9, 136.0, 138.9, 139.1;

MS (FAB) m/z 585 (M⁺+Na); HRMS (FAB) m/z calcd

for C₃₇H₄₂O₃SiNa 585.2801 found 585.2808 (M⁺+Na).

˚

sieves 4 A (2 g, powder) in dry CH₂Cl₂(8.5 ml) at ꢀ20 ꢁC

was added TMSBr (2.0 ml, 14.7 mmol). After stirring for

4 h at ꢀ20 ꢁC, the reaction mixture was poured into satd

aq NaHCO₃. After ﬁltering the resulting mixture on Cel-

ite, the ﬁltrate was extractively worked up with EtOAc.

The crude product was chromatographed on silica gel

to give compound ^D-3d (567 mg, 78.4%) as a colorless

20

oil. D-3d: ½aꢂ_D¼ þ2.1 ðc 1.00; CHCl₃Þ; ¹H NMR

(CDCl₃, with D₂O one drop) d 1.05 (s, 9H, –C(CH₃)₃),

1.57 (m, 1H, H-5), 1.82 (dt, J = 12.2, 4.3 Hz, 1H, H-

5a_eq), 1.95 (app q, J = 12.3 Hz, 1H, H-5a_ax), 3.45 (dd,

J = 9.2, 2.8 Hz, 1H, H-3), 3.62 (ddd, J = 11.4, 4.7,

2.8 Hz, 1H, H-1), 3.70 (dd, J = 9.8, 2.5 Hz, 1H, H-6_a),

3.77 (app t, J = 9.5 Hz, 1H, H-4), 3.84 (dd, J = 9.8,

5.0 Hz, 1H, H-6_b), 4.16 (pseudo t, J = 2.8 Hz, 1H, H-

2), 4.4–4.9 (m, 4H, 2 · –OCH₂Ph), 7.0–7.7 (m, 20H,

4Ph); ¹³C NMR (CDCl₃) d 20.1, 27.7, 31.4, 41.5, 64.3,

70.5, 71.6, 73.1, 76.0, 77.8, 84.3, 128.2, 128.4 (2s),

128.7, 129.1, 129.3, 130.4, 134.2, 134.3, 136.4, 136.5,

138.7, 139.3; MS (FAB) m/z 597 (M⁺+1), 619

(M⁺+Na); HRMS (FAB) m/z calcd for C₃₇H₄₄O₅SiNa

619.2856 found 619.2850 (M⁺+Na).

4.18. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-5a-

carba-a-^D-glucopyranose, D-14

To a solution of ^D-13 (50 mg, 88.9 lmol) and 4-meth-

ylmorpholine-N-oxide (NMO) (20.9 mg, 0.178 mmol)

in acetone/water (4 ml, 8:1) at rt was added a catalytic

amount of OsO₄. After stirring for 5 h, Na₂SO₃

(112 mg) was added and the resulting mixture stirred

for an additional 30 min at rt. The reaction mixture

was diluted with EtOAc and washed with 1 M HCl

and satd aq NaHCO₃. The organic layers were dried

over MgSO₄, concentrated, and chromatographed on

4.16. 2-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldiphe-

nyl)silyl-5a-carba-b-^D-glucopyranose, D-12

silica gel column to give compound ^D-14 (53 mg,

21

To a solution of ^D-3d (30 mg, 50.26 lmol), PPh₃

(79.1 mg, 301 lmol), and BzOH (36.7 mg, 301 lmol) in

dry toluene (1 ml) at rt was added DEAD (52.4 mg,

301 lmol). After reﬂuxing overnight, the reaction

mixture was ﬁltered and the ﬁltrate concentrated and

quantitative) as

a

colorless oil. D-14: ½aꢂ_D¼

þ37.8 ðc 1.43; CHCl₃Þ; ¹H NMR (CDCl₃, with D₂O

one drop) d 1.07 (s, 9H, –C(CH₃)₃), 1.68 (td, J = 12.4,

2.15 Hz, 1H, H-5a_ax), 1.75 (dt, J = 14.4, 3.7 Hz, 1H,

H-5a_eq), 2.09 (m, 1H, H-5), 3.52 (dd, J = 9.2, 2.8 Hz,

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2741

H-2), 3.58 (t, J = 10.0 Hz, 1H, H-4), 3.62 (dd, J = 9.9,

2.1 Hz, 1H, H-6_a), 3.73 (t, J = 9.2 Hz, 1H, H-3), 4.02

(dd, J = 10.0, 3.6 Hz, 1H, H-6_b), 4.09 (pseudo q,

J = 2.5 Hz, 1H, H-1), 4.60–5.02 (m, 4H, 2 · –OCH₂Ph),

5.23 (t, J = 9.2 Hz, 1H, H-2), 7.1–7.63 (m, 20H, 4Ph);

¹³C NMR (CDCl₃) d 20.0, 27.7, 31.0, 36.6, 63.6, 69.0,

75.2, 75.5, 76.1, 81.6, 84.3, 128.3, 128.38, 128.42,

128.7, 129.1, 129.5, 130.4, 134.0, 134.2, 136.39, 136.44,

139.2, 139.3; MS (FAB) m/z 597 (M⁺+1), 619

(M⁺+Na); HRMS (FAB) m/z calcd for C₃₇H₄₄O₅SiNa

619.2856 found 619.2853 (M⁺+Na).

130.3, 134.1, 134.3, 136.4, 136.5, 139.2, 139.3; MS

(FAB) m/z 579 (M⁺+1), 601 (M⁺+Na); HRMS (FAB)

m/z calcd for C₃₇H₄₂O₄SiNa 601.2750 found 601.2748

21

(M⁺+Na); D-16: ½aꢂ_D¼ ꢀ26.0 ðc 0.64; CHCl₃Þ; ¹H

NMR (CDCl₃) d 1.09 (s, 9H, –C(CH₃)₃), 1.67 (m, 1H,

H-5), 2.15 (m, 2H, H-5a_axand H-5a_eq), 3.21 (t,

J = 3.7 Hz, 1H, H-2), 3.30 (m, 1H, H-2), 3.51 (dd,

J = 11.3, 8.1 Hz, 1H, H-4), 3.59 (dd, J = 9.9, 2.4 Hz,

1H, H-6_a), 3.81 (d, J = 8.0 Hz, 1H, H-4), 4.01 (dd,

J = 9.9, 4.1 Hz, 1H, H-6_b), 4.60–4.91 (m, 4H, 2 ·

–OCH₂Ph), 7.1–7.7 (m, 20H, 4Ph); ¹³C NMR (CDCl₃)

d 20.0, 27.7, 28.2, 35.4, 53.89, 53.91, 63.5, 73.4, 75.1,

79.8, 81.7, 128.0, 128.3, 128.6, 128.7, 128.9, 129.2,

130.3, 130.4, 134.0, 134.1, 136.3, 136.4, 138.5, 139.4;

MS (FAB) m/z 579 (M⁺+1), 601 (M⁺+Na); HRMS

(FAB) m/z calcd for C₃₇H₄₂O₄SiNa 601.2750 found

601.2752 (M⁺+Na).

4.19. 1,2-Anhydro-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-b-^D-mannopyranose, D-15 and

1,2-anhydro-3,4-di-O-benzyl-6-O-(tert-butyldi-

phenyl)silyl-5a-carba-a-^D-glucopyranose, D-16

Method A: To a solution of ^D-13 (50 mg, 88.9 lmol) in

CH₂Cl₂(2 ml) at 0 ꢁC was added m-CPBA (50–60%,

36.8 mg, 0.11 mmol). After stirring for 26 h at rt, the

reaction mixture was quenched with Na₂SO₃(22 mg)

and the resulting mixture stirred for 30 min. The reac-

tion mixture was extractively worked up with EtOAc

and chromatographed on silica gel to give ^D-15 (8 mg,

15.5%) and ^D-16 (33 mg, 64.2%); Method B: To a solu-

tion of ^D-13 (50 mg, 88.9 lmol) in dioxane/water (10:1,

1.5 ml) at rt were added NBS (or NIS) (0.178 mmol)

and one drop of 0.1 M HCl. After stirring overnight at

rt, the reaction mixture was diluted with EtOAc and

washed with 5% aq Na₂S₂O₃, and satd aq NaHCO₃.

The organic phase was dried (MgSO₄) and concentrated

to give the crude mixture of bromohydrins (or iodohyd-

rins). To this crude mixture in MeOH (3 ml) was added

NaOME (85 ll, 25% in MeOH). After stirring for 6 h at

rt the reaction mixture was extractively worked up with

EtOAc, and chromatographed on silica gel column to

give ^D-15 and D-16 (8 mg and 32 mg for NBS, 4 mg

and 40 mg for NIS); Method C: To a solution of ^D-3d

(62 mg, 103.9 lmol) in CH₂Cl₂(1 ml) at rt were added

(MeO)₃CCH₃(20 ll, 158 lmol) and a catalytic amount

of pyridinium p-toluenesulfonate (PPTS, ca. 0.01 equiv).

After stirring for 40 min at rt, the reaction mixture was

treated with one drop of Et₃N and concentrated and

dried in vacuo. To the residue dissolved in CH₂Cl₂

(1 ml) at 0 ꢁC were added one drop of Et₃N and AcBr

(29 mg, 2.35 equiv). After stirring for 4 h at rt, the reac-

tion mixture was extractively worked up with CH₂Cl₂to

give a crude mixture of bromo acetoxy compound. To

the crude mixture in MeOH (2 ml) at rt was added

NaOMe (70 ll, 25% in MeOH). After stirring for

30 min, the reaction mixture was extractively worked

up with EtOAc and chromatographed on silica gel to

4.20. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-5a-

carba-a-^D-mannopyranose, D-17

To a solution of ^D-15 (20 mg, 34.5 lmol) in acetone

(3 ml) at 0 ꢁC was added HClO₄(0.3 M, 53 ll,

15.9 lmol). After stirring for 8 h at 0 ꢁC, the reaction

mixture was quenched with Na₂SO₃(10 drops) and the

resulting mixture extractively worked up with EtOAc

and chromatographed on silica gel to give ^D-17

(19.5 mg, 94.6%) as

a

colorless oil. D-17:

21

1

½aꢂ_D¼ þ3.0 ðc 0.44; CHCl₃Þ; H NMR (acetone-d₆) d

1.07 (s, 9H, –C(CH₃)₃), 1.75 (m, 1H, H-5_eq), 2.0 (m,

2H, H-5a_axand H-5), 3.76 (dd, J = 9.8, 2.2 Hz, 1H, H-

6_a), 3.83 (dd, J = 8.8, 2.8 Hz, 1H, H-3), 3.90 (t,

J = 9.1 Hz, 1H, H-4), 3.96 (dd, J = 9.6, 4.7 Hz, 1H, H-

6_b), 4.0 (m, 1H, H-1), 4.16 (pseudo t, J = 2.8 Hz, 1H,

H-2), 4.52–4.93 (m, 4H, 2 · –OCH₂Ph), 7.1–7.7 (m,

20H, 4Ph); ¹³C NMR (CDCl₃) d 20.0, 27.7, 30.4, 39.8,

64.4, 69.4, 72.6, 73.4, 74.9, 77.2, 82.4, 128.2, 128.3,

128.38, 128.43, 128.6, 129.0, 129.2, 130.3, 134.3, 134.4,

136.36, 136.41, 138.8, 139.4; MS (FAB) m/z 597

(M⁺+1), 619 (M⁺+Na); HRMS (FAB) m/z calcd for

C₃₇H₄₄O₅SiNa 619.2856 found 619.2860 (M⁺+Na).

4.21. Bromohydrins ^D-18 and D-19 from D-16

To a solution of ^D-16 (10 mg, 17 lmol) in THF (0.5 ml)

at rt were added AcOH (30 mg, 0.5 mmol) and LiBr

(80 mg, 0.92 mmol). After stirring overnight, the reac-

tion mixture was extractively worked up with EtOAc

and chromatographed on silica gel to give ^D-18 (7 mg,

61.4%) and ^D-19 (3 mg, 26.3%). D-18: ¹H NMR (CDCl₃)

d 1.10 (s, 9H, –C(CH₃)₃), 1.65 (m, 1H, H-5), 2.0 (app. q,

J = 13.1 Hz, 1H, H-5a_ax), 2.28 (dt, J = 13.4, 4.0 Hz, 1H,

H-5_eq), 2.67 (d, J = 2.1 Hz, 1H, –OH), 3.40 (t,

J = 9.0 Hz, 1H, H-3), 3.59 (app t, J = 10.5 (9.3) Hz,

1H, H-4), 3.69 (app ddd, J = 10.0, 9.0, 2.1 Hz, 1H, H-

2), 3.71 (dd, J = 10.0, 2.4 Hz, 1H, H-6_a), 3.82–3.92 (m,

2H, H-1 and H-6_b), 4.53–4.90 (m, 4H, 2 · –OCH₂Ph),

7.0–7.65 (m, 20H, 4Ph); MS (FAB) m/z 659 (M⁺+1),

681 (M⁺+Na); HRMS (FAB) m/z calcd for

C₃₇H₄₃BrO₄SiNa 659.2192 found 659.2192 (M⁺+1). D-

give ^D-15 (51 mg, 84.7%) with the starting material D-

21

3d (6.2 mg, 10%). ^D-15: ½aꢂ_D¼ þ3.1 ðc 1.17; CHCl₃Þ;

¹H NMR (CDCl₃) d 1.10 (s, 9H, –C(CH₃)₃), 1.74 (m,

1H, H-5), 2.0–2.2 (m, 2H, H-5a_axand H-5a_eq), 3.31 (t,

J = 4.1 Hz, 1H, H-1), 3.35 (dd, J = 4.0, 1.7 Hz, 1H, H-

2), 3.67 (dd, J = 10.0, 2.8 Hz, 1H, H-6_a), 3.72 (dd,

J = 10.9, 8.2 Hz, 1H, H-4), 3.83 (dd, J = 10.3, 5.25 Hz,

1H, H-6_b), 3.85 (dd, J = 8.3, 1.7 Hz, 1H, H-3), 4.5–4.9

(m, 4H, 2 · –OCH₂Ph), 7.1–7.7 (m, 20H, 4Ph); ¹³C

NMR (CDCl₃) d 20.0, 27.4, 27.7, 30.4, 42.4, 54.2, 56.1,

63.9, 73.2, 75.8, 82.5, 128.1, 128.4, 128.6, 129.0, 129.1,

1

19: H NMR (CDCl₃) d 1.09 (s, 9H, –C(CH₃)₃), 1.72

(dt, J = 14.1, 4.8 Hz, 1H, H-5_eq), 2.14 (m, 1H, H-5),

2.40 (ddd, J = 13.8, 9.6, 3.0 Hz, 1H, H-5a_ax), 3.69 (dd,

2742

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

J = 10.0, 4.0 Hz, 1H, H-6_a), 3.8–4.0 (m, 3H, H-3, H-4,

and H-6_b), 4.18 (m, 1H, H-1), 4.39 (m, 1H, H-2),

4.5–4.82 (m, 4H, 2 · –OCH₂Ph), 7.1–7.7 (m, 20H,

4Ph); MS (FAB) m/z 659 (M⁺+1), 681 (M⁺+Na);

HRMS (FAB) m/z calcd for C₃₇H₄₃BrO₄SiNa

659.2192 found 659.2193 (M⁺+1).

ing mixture on Celite, the ﬁltrate was extractively

worked up with EtOAc and chromatographed on silica

gel to give compound ^D-4d (550 mg, 69%) as a colorless

21

oil. D-4d: ½aꢂ_D¼ þ7.2 ðc 1.08; CHCl₃Þ; ¹H NMR

(CDCl₃) d 1.11 (s, 9H, –C(CH₃)₃), 1.39 (app q, J =

12.4 Hz, 1H, H-5a_ax), 1.58 (dt, J = 12.7, 4.2 Hz, 1H,

H-5a_eq), 2.24 (m, 1H, H-5), 3.61 (dd, J = 9.8, 5.9 Hz,

1H, H-6_a), 3.77 (t, J = 9.6 Hz, 1H, H-6_b), 3.87 (ddd,

J = 11.4, 4.7, 3.2 Hz, 1H, H-1), 3.95 (t, J = 3.3 Hz,

1H, H-3 or H-4), 3.99 (br s, 1H, H-4 or H-3), 4.02 (br

s, 1H, H-2), 4.4–4.7 (m, 4H, 2 · –OCH₂Ph), 7.2–7.7

(m, 20H, 4Ph); ¹³C NMR (CDCl₃) d 20.0, 27.2, 27.6,

38.7, 64.7, 68.5, 72.5, 72.8, 74.4, 75.2, 76.2, 128.3,

128.4, 128.6, 128.8, 128.9, 129.2, 129.3, 130.4, 130.5,

134.1, 134.3, 136.26, 136.30, 137.9, 138.5; MS (FAB)

m/z 597 (M⁺+1), 619 (M⁺+Na); HRMS (FAB) m/z

calcd for C₃₇H₄₄O₅SiNa 619.2856 found 619.2861

(M⁺+Na).

4.22. 6-O-(tert-Butyldiphenyl)silyl-1,2-di-O-(methoxy-

methyl)-5a-carba-b-^D-idopyranose, D-4b

To a solution of ^D-4a (1.5 g, 2.46 mmol) in MeOH

(15 ml) was added NaOMe (0.739 mmol, 169 ll of 25%

solution in MeOH). After stirring for 5 h at rt, the reac-

tion mixture was treated with AcOH (44 mg) and con-

centrated. The residue was extractively worked up with

EtOAc and chromatographed on silica gel to give ^D-4b

21

(1.17 g, 94.1%) as

a

colorless oil. D-4b: ½aꢂ_D¼

ꢀ31.8 ðc 1.58; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.07 (s,

9H, –C(CH₃)₃), 1.64 (dt, J = 13.7, 4.4 Hz, 1H, H-5a_eq),

1.72 (m, 1H, H-5a_ax), 2.30 (m, 1H, H-5), 2.61 (br s,

1H, –OH), 3.30 and 3.44 (2s, 6H, 2 · –OCH₂OCH₃),

3.65 (dd, J = 10.0, 6.2 Hz, 1H, H-6a), 3.67 (m, 1H),

3.80 (m, 2H), 3.99 (dt, J = 8.2, 3.5 Hz, 1H), 4.04–4.15

(m, 2H), 4.6–4.8 (m, 4H, 2 · –OCH₂OCH₃), 7.3-7.7

(m, 10H, 2Ph); ¹³C NMR (CDCl₃) d 19.9, 26.2, 27.5,

39.6, 56.1, 56.6, 61.1, 66.0, 71.6, 73.2, 73.8, 79.4, 96.0,

97.6, 128.4, 130.4, 134.1, 134.2, 136.3; MS (FAB) m/z

527 (M⁺+Na); HRMS (FAB) m/z calcd for C₂₇H₄₀O₇-

SiNa 527.2441 found 527.2445 (M⁺+Na).

4.25. 1-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldi-

phenyl)silyl-5a-carba-b-^D-idopyranose, D-4e and 2-O-

benzoyl-3,4-di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-

5a-carba-b-^D-idopyranose, D-4f

Method A: To a solution of ^D-4d (80 mg, 0.134 mmol) in

dry THF (2 ml) at rt were added sequentially Et₃N

(37.4 ll, 0.268 mmol) and Me₂SnCl₂(1.5 mg, 7.0 lmol,

5.4 mol %). To the resulting mixture at 0 ꢁC was added

dropwise BzCl (18.7 ll, 0.161 mmol) in THF (0.1 ml).

After stirring for 6 h at rt, the reaction mixture was

quenched with H₂O (three drops), extractively worked

up with EtOAc, and chromatographed on silca gel to

give ^D-4e (89.6 mg, 0.128 mmol, 91.9%) and D-4f

(5.9 mg, 0.008 mmol, 6.0%) as an oil; Method B: To a

solution of ^D-4d (100 mg, 0.167 mmol) in CH₂Cl₂

(2 ml) were added (EtO)₃CPh (76 ll, 0.335 mmol) and

TSA (ca. 1 mg, 5.0 lmol) at rt. After stirring for

30 min, the reaction mixture was concentrated by evap-

oration and the resulting residue was treated with 80%

aq AcOH (1 ml) and stirred for 10 min at rt. The result-

ing mixture was extractively worked up with EtOAc,

and chromatographed on silica gel column to give com-

pounds ^D-4e (14.6 mg, 12.3%) and D-4f (86.6 lg, 73.1%)

4.23. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-1,2-

di-O-(methoxymethyl)-5a-carba-b-^D-idopyranose, D-4c

To a solution of ^D-4b (1.00 g, 1.981 mmol) in dry THF

(35 ml) at 0 ꢁC was added NaH (518 mg, 55% in paraﬃn

liquid, 11.9 mmol). After stirring for 30 min at rt, BnBr

(1.41 ml, 11.9 mmol) and Bu₄NI (146 mg, 0.396 mmol)

were added. After stirring for 24 h at rt, the reaction

mixture was quenched with drops of satd aq NaHCO₃

and worked up by a standard extractive procedure.

The crude product was chromatographed on silica gel

to give compound ^D-4c (1.06 g, 78%) as a colorless oil.

21

1

D-4c: ½aꢂ_D¼ ꢀ7.1 ðc 1.78; CHCl₃Þ; H NMR (CDCl₃)

d 1.10 (s, 9H, –C(CH₃)₃), 1.46 (pseudo d, J = 13.0 Hz,

1H, H-5a_eq), 2.1 (m, 1H, H-5a_ax), 2.28 (m, 1H, H-5),

3.37 and 3.41 (2s, 6H, 2 · –OCH₂OCH₃), 3.74 (pseudo

t, J = 3.9 Hz, 1H), 3.80–3.93 (m, 4H), 4.02 (m, 1H),

4.39–4.81 (m, 8H, 2 · –OCH₂Ph, 2 · –OCH₂OCH₃),

7.2–7.71 (m, 20H, 4Ph); ¹³C NMR (CDCl₃) d 19.7,

24.5, 27.3, 39.4, 55.8, 55.9, 64.1, 72.4, 73.6 (2s), 76.2,

76.8, 95.0, 97.1, 127.8, 128.0, 128.16, 128.20, 128.6,

128.8, 130.0, 134.2, 134.3, 136.0, 138.8, 139.1; MS

(FAB) m/z 707 (M⁺+Na); HRMS (FAB) m/z calcd

for C₄₁H₅₂O₇SiNa 707.3380 found 707.3376 (M⁺+Na).

21

1

as colorless oils. ^D-4e: ½aꢂ_D¼ þ0.3 ðc 1.25; CHCl₃Þ; H

NMR (CDCl₃with D₂O one drop) d 1.08 (s, 9H,

–C(CH₃)₃), 1.64 (dt, J = 12.7, 4.0 Hz, 1H, H-5a_eq),

1.78 (app q, J = 12.4 Hz, 1H, H-5a_ax), 2.40 (m, 1H, H-

5), 3.61 (dd, J = 9.8, 5.9 Hz, 1H, H-6_a), 3.80 (t,

J = 9.7 Hz, 1H, H-6_b), 3.96 (t, J = 3.4 Hz, 1H, H-3 or

H-4), 4.06 (br s, 1H, H-4 or H-3), 4.26 (br s, 1H, H-2),

4.4–4.7 (m, 4H, 2 · –OCH₂Ph), 5.32 (ddd, J = 11.8,

4.7, 3.2 Hz, 1H, H-1), 7.2–8.1 (m, 25H, 5Ph); ¹³C

NMR (CDCl₃) d 20.0, 23.2, 27.6, 38.9, 64.5, 70.6, 72.7,

72.9, 74.4, 75.2, 76.4, 128.5, 128.6, 128.8, 128.9, 129.0,

129.2, 129.3, 130.4, 130.5, 131.2, 133.5, 134.0, 134.3,

136.3, 137.8, 138.5, 166.8 (PhC@O); MS (FAB) m/z

701 (M⁺+1), 723 (M⁺+Na); HRMS (FAB) m/z calcd

for C₄₄H₄₈O₆SiNa 723.3118 found 723.3112 (M⁺+Na);

4.24. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-5a-

carba-b-^D-idopyranose, D-4d

21

1

To a solution of ^D-4c (915 mg, 1.34 mmol) and molecu-

D-4f: ½aꢂ_D¼ ꢀ24.8 ðc 0.89; CHCl₃Þ; H NMR (CDCl₃

with D₂O one drop) d 1.11 (s, 9H, –C(CH₃)₃), 1.67

(dt, J = 12.5, 4.0 Hz, 1H, H-5a_eq), 1.88 (app q,

J = 11.8 Hz, 1H, H-5a_ax), 2.30 (m, 1H, H-5), 3.75 (dd,

J = 9.4, 6.1 Hz, 1H, H-6_a), 3.88 (br s, 1H, H-3 or H-

˚

lar sieves 4 A (2 g, powder) in dry CH₂Cl₂(9 ml) at

ꢀ20 ꢁC was added TMSBr (2.69 ml, 20.0 mmol). After

stirring for 2 h at ꢀ20 ꢁC, the reaction mixture was

poured into satd aq NaHCO₃. After ﬁltering the result-

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2743

4), 3.91 (t, J = 9.6 Hz, 1H, H-6_b), 4.15 (t, J = 3.7 Hz, H-

4 or H-3), 4.19 (m, 1H, H-1), 4.3–4.8 (m, 4H, 2 ·

–OCH₂Ph), 5.43 (pseudo t, J = 3.3 Hz, 1H, H-2), 7.2–

8.0 (m, 25H, 5Ph); ¹³C NMR (CDCl₃) d 20.0, 27.6,

28.4, 39.5, 64.9, 68.4, 73.2, 73.7, 73.9, 75.0, 75.9, 128.1,

128.4, 128.5, 128.8, 129.0, 129.2, 130.3, 130.6, 130.7,

133.7, 134.2, 136.3, 136.4, 138.6, 138.9, 167.3

(PhC@O); MS (FAB) m/z 701 (M⁺+1), 723 (M⁺+Na);

HRMS (FAB) m/z calcd for C₄₄H₄₈O₆SiNa 723.3118

found 723.3120 (M⁺+Na).

130.5, 131.1, 133.6, 134.1, 134.3, 136.2, 138.5, 139.0,

167.5 (PhC@O); MS (FAB) m/z 701 (M⁺+1), 723

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₄H₄₈O₆SiNa

723.3118 found 723.3120 (M⁺+Na).

4.28. 1,2-Anhydro-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-b-^D-idopyranose, D-22

To a solution of ^D-4d (153 mg, 0.260 mmol) in CH₂Cl₂

(3 ml) at rt were added (MeO)₃CCH₃(51 ll, 0.40 mmol)

and a catalytic amount of PPTS (ca. 0.01 equiv). After

stirring for 40 min at rt, the reaction mixture was treated

with one drop of Et₃N and concentrated and dried in

vacuo. To the residue dissolved in CH₂Cl₂(3 ml) at

0 ꢁC were added two drops of Et₃N and AcBr

(77.1 mg, 0.627 mmol). After stirring for 4 h at rt, the

reaction mixture was poured into satd aq NaHCO₃

and extractively worked up with CH₂Cl₂to give a crude

mixture of bromo acetoxy compounds. To the crude

mixture in MeOH (5 ml) at rt was added NaOMe

(178 ll, 25% in MeOH). After stirring for 30 min, the

reaction mixture was extractively worked up with

EtOAc and chromatographed on silica gel to give ^D-22

4.26. (2R,4S,5S,6R)-2-Benzoyloxy-4-(tert-butyl-diphen-

yl-silanyloxymethyl)-5,6-di-benzyloxy-cyclohexanone,

D-20

To a stirred mixture of ^D-4e (63 mg, 89.9 lmol) and

˚

molecular sieves 4 A (powder, 100 mg) in CH₂Cl₂

(4 ml) at rt was added PCC (58.1 mg, 0.27 mmol). After

stirring for 7 h, the reaction mixture was ﬁltered through

a silica gel column and washed with EtOAc/n-hexane

(1:4). The ﬁltrate was concentrated to give ^D-20

(61.2 mg, 87.6 lmol, 97.4%) as a colorless oil. ^D-20:

21

½aꢂ_D¼ ꢀ24.7 ðc 1.025; CHCl₃Þ; ¹H NMR (CDCl₃) d

1.06 (s, 9H, –C(CH₃)₃), 2.00 (app q, J = 12.5 Hz, 1H,

H-3_ax), 2.13 (m, 1H, H-3_eq), 2.77 (m, 1H, H-4), 3.62

(dd, J = 9.7, 6.5 Hz, 1H, H-7_a), 3.77 (t, J = 9.6 Hz,

1H, H-7_b), 4.08 (d, J = 3.7 Hz, 1H, H-6), 4.18 (br s,

1H, H-5), 4.38–4.83 (m, 4H, 2 · –OCH₂Ph), 5.93 (dd,

J = 12.5, 6.8 Hz, 1H, H-2), 7.2–8.1 (m, 25H, 5Ph); ¹³C

NMR (CDCl₃) d 19.8, 27.4, 30.2, 38.5, 64.0, 72.7, 73.0,

74.3, 78.8, 81.3, 128.3, 128.66, 128.74, 128.85, 128.89,

129.1, 130.1, 130.2, 130.3, 130.4, 133.7, 133.9, 134.0,

136.08, 136.12, 137.4, 138.2, 166.2 (PhC@O), 204.7 (C-

1); MS (FAB) m/z 699 (M⁺+H), 721 (M⁺+Na); HRMS

(FAB) m/z calcd for C₄₄H₄₆O₆SiNa 721.2961 found

721.2969 (M⁺+Na).

(106.2 mg, 70.7%) with the starting material ^D-4d

21

(38.4 mg, 24.8%). ^D-22: ½aꢂ_D¼ þ30.3 ðc 0.94; CHCl₃Þ;

¹H NMR (CDCl₃) d 1.09 (s, 9H, –C(CH₃)₃), 1.84

(ddd, J = 18.2, 9.0, 4.2 Hz, 1H, H-5a_ax), 2.17 (m, 2H,

H-5 and H-5a_eq), 3.17 (d, J = 3.6 Hz, 1H, H-2), 3.25

(t, J = 3.7 Hz, 1H, H-1), 3.65–3.83 (m, 4H, H-3, H-4,

H-6_a, H-6_b), 4.49–4.65 (m, 4H, 2 · –OCH₂Ph), 7.27–

7.7 (m, 20H, 5Ph); ¹³C NMR (CDCl₃) d 19.8, 23.2,

27.5, 36.2, 52.6, 53.9, 64.1, 72.4, 73.4, 74.2, 76.9, 128.1,

128.2, 128.4, 128.8, 129.0, 130.1, 134.3, 134.5, 136.10,

136.14, 138.5, 139.1; MS (FAB) m/z 579 (M⁺+1), 601

(M⁺+Na); HRMS (FAB) m/z calcd for C₃₇H₄₂O₄SiNa

601.2750 found 601.2745 (M⁺+Na).

4.27. 1-O-Benzoyl-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-b-^D-gulopyranose, D-21

4.29. 1-O-Allyl-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-a-^D-idopyranose, D-23

To a solution of ^D-20 (41 mg, 58.7 lmol) in CH₂Cl₂/

MeOH (4.8 ml) and at ꢀ20 ꢁC was added NaBH₄

(7.0 mg, 0.185 mmol). After stirring for 30 min at

ꢀ20 ꢁC, the reaction mixture was treated with AcOH

(three drops) and stirred for an additional 10 min. The

reaction mixture was ﬁltered on silica gel pad and the ﬁl-

trate was concentrated to give a mixture of (^D-21/D-

4e ꢁ 43:57). This mixture was chromatographed to give

D-21 (R_f= 0.60 in TLC with EtOAc/n-hexane = 1:7,

To a solution of ^D-22 (26.8 mg, 46.3 lmol) in allyl alco-

hol (1.5 ml) at rt was added TSA (2.3 mg, 0.26 equiv).

After stirring for 3.5 h at rt, Et₃N (two drops) was added

and the resulting mixture concentrated by co-evapora-

tion with EtOAc (5 ml · 3). The residue was chromato-

graphed on silica gel column to give ^D-23 (21.6 mg,

20

1

73.2%). ^D-23: ½aꢂ_D¼ þ19.3 ðc 1.05; CHCl₃Þ; H NMR

(acetone-d₆) d 1.09 (s, 9H, –C(CH₃)₃), 1.40 (ddd,

J = 13.4, 11.2, 4.8 Hz, 1H, H-5a_ax), 2.40 (dt, J = 13.4,

4.4 Hz, 1H, H-5a_eq), 2.5 (m, 1H, H-5), 3.52 (td, J =

8.7, 3.7 Hz, 1H, H-2), 3.68–3.71 (m, 2H, H-3, H-4),

3.75 (ddd, J = 11.2, 8.7, 4.7 Hz, 1H, H-1), 3.90 (m,

2H, H-6_aand H-6_b), 4.09 (d, J = 3.6 Hz, 1H, –OH),

4.18–4.21 (m, 2H, –OCH₂CH@CH₂), 4.55 (s, 2H,

–OCH₂Ph), 4.81 (s, 2H, –OCH₂Ph), 5.10 (pseudo dd,

J = 10.5, 1.7 Hz, 1H, –OCH₂CH@CH_aH_b), 5.31 (ddd,

J = 17.2, 3.5, 1.7 Hz, 1H, –OCH₂CH@CH_aH_b), 5.97

(m, 1H, –OCH₂CH@CH₂), 7.1–7.72 (m, 20H, 4Ph);

¹³C NMR (CDCl₃) d 19.7, 27.5, 27.7, 37.4, 62.6, 71.3,

72.7, 75.3, 76.7, 77.0, 81.3, 81.8, 117.5, 128.1, 128.3,

128.4, 128.86, 128.93, 130.2, 130.3, 133.8, 134.0, 135.8,

15.6 mg, 37.9%) and ^D-4e (R_f= 0.72 in TLC with

20

EtOAc/n-hexane = 1:7, 21.1 mg, 51.4%). ^D-21: ½aꢂ_D

¼

ꢀ42.7 ðc 0.97; CHCl₃Þ; ¹H NMR (CDCl₃with D₂O

one drop) d 1.08 (s, 9H, –C(CH₃)₃), 1.56 (app q,

J = 12.4 Hz, 1H, H-5a_ax), 1.76 (dt, J = 12.2, 4.1 Hz,

1H, H-5a_eq), 2.35 (m, 1H, H-5), 3.60 (dd, J = 9.8,

5.7 Hz, 1H, H-6_a), 3.79 (t, J = 9.7 Hz, 1H, H-6_b), 3.98

(t, J = 3.5 Hz, 1H, H-3), 4.03 (dd, J = 9.7, 3.4 Hz, 1H,

H-2), 4.12 (br s, 1H, H-4), 4.5–4.7 (m, 4H, 2 ·

–OCH₂Ph), 5.27 (ddd, J = 11.3, 9.8, 5.0 Hz, 1H, H-1),

7.2–8.1 (m, 25H, 5Ph); ¹³C NMR (CDCl₃) d 20.0,

27.6, 38.3, 64.3, 72.5, 73.80, 73.82, 74.4, 74.8, 78.9,

128.4, 128.5, 128.66, 128.74, 129.0, 129.1, 129.3, 130.4,

2744

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

136.2, 138.7, 139.4; MS (FAB) m/z 637 (M⁺+1), 659

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₀H₄₈O₅SiNa

659.3169 found 659.3165 (M⁺+Na).

4.32. 6-O-(tert-Butyldiphenyl)silyl-1,2-di-O-(methoxy-

methyl)-5a-carba-b-^D-talopyranose, D-5b

To a solution of ^D-5a (1.5 g, 2.46 mmol) in MeOH

(15 ml) was added NaOMe (0.739 mmol, 169 ll of 25%

solution in MeOH). After stirring for 4.5 h at rt, the

reaction mixture was treated with AcOH (44 mg) and

concentrated. The residue was extractively worked up

with EtOAc and chromatographed on silica gel to

4.30. (2R,3S,4S,6R)-6-Allyloxy-4-(tert-butyl-diphenyl-

silanyloxymethyl)-2,3-di-benzyloxy-cyclohexanone, ^D-24

To a stirred mixture of ^D-23 (18 mg, 28.3 lmol) and

˚

give ^D-5b (1.18 g, 94.8%) as a colorless oil. D-5b:

molecular sieves 4 A (powder, 30 mg) in CH₂Cl₂(1 ml)

18

½aꢂ_D¼ ꢀ26.1 ðc 1.0; CHCl₃Þ; ¹H NMR (acetone-d₆

at rt was added PCC (18.3 mg, 84.8 lmol). After stirring

for 3.5 h, the reaction mixture was ﬁltered through a sil-

ica gel column and washed with EtOAc/n-hexane (1:3).

with one drop of D₂O) d 1.04 (s, 9H, –C(CH₃)₃), 1.58

(app q, J = 12.5 Hz, 1H, H-5a_ax), 1.68 (dt, J = 12.4,

4.3 Hz, 1H, H-5a_eq), 1.80 (m, 1H, H-5), 3.33 and 3.41

(2s, 6H, 2 · –OCH₂OCH₃), 3.56 (m, 1H, H-3), 3.63

(dd, J = 9.5, 6.4 Hz, 1H, H-6_a), 3.8 (ddd, J = 11.6, 4.8,

2.5 Hz, 1H, H-1), 3.90 (dd, J = 9.5, 8.0 Hz, 1H, H-6_b),

3.98 (br s, 1H, H-4), 4.19 (br s, 1H, H-2), 4.60–4.85

(m, 4H, 2 · –OCH₂OCH₃), 7.4–7.8 (m, 10H, 2Ph); ¹³C

NMR (CDCl₃) d 19.9, 23.8, 27.5, 41.5, 56.2, 57.0, 65.0,

70.9, 71.5, 75.3, 82.1, 95.4, 99.1, 128.4, 130.3, 134.3,

134.5, 136.26, 136.32; MS (FAB) m/z 505 (M⁺+1), 527

(M⁺+Na); HRMS (FAB) m/z calcd for C₂₇H₄₀O₇SiNa

527.2441 found 527.2441 (M⁺+Na).

The ﬁltrate was concentrated to give ^D-24 (17.9 mg,

21

28.2 lmol, 99.8%) as a colorless oil. ^D-24: ½aꢂ_D

¼

þ12.8 ðc 0.9; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.03 (s,

9H, –C(CH₃)₃), 1.68 (ddd, J = 13.2, 11.7, 5.0 Hz, H-

5_ax), 2.44 (m, 2H, H-5_eqand H-4), 3.82 (dd, J = 9.1,

5.6 Hz, 1H, H-3), 3.87 (dd, J = 10.4, 3.7 Hz, 1H, H-

7_a), 3.99 (pseudo dd, J = 12.8, 6.0 Hz, 1H, –OCH_aH_b-

CH@CH₂), 4.11 (dd, J = 10.1, 5.7 Hz, 1H, H-7_b), 4.28

(dd, J = 12.8, 5.3 Hz, 1H, –OCH_aH_bCH@CH₂), 4.51

(dd, J = 12.4, 6.9 Hz, 1H, H-6), 4.53–4.91 (m, 5H, H-2

and 2 · –OCH₂Ph), 5.20 (pseudo dd, J = 10.3, 1.2 Hz,

1H, –OCH₂CH@CH_aH_b), 5.30 (pseudo dd, J = 17.2,

1.5 Hz, 1H, –OCH₂CH@CH_aH_b), 5.97 (1H, –OCH₂-

CH@CH₂), 7.1–7.72 (m, 20H, 4Ph); ¹³C NMR (CDCl₃)

d 19.8, 27.6, 32.0, 37.9, 63.8, 71.9, 73.9, 74.1, 79.2, 82.5,

85.4, 118.2, 128.27, 128.34, 128.47, 128.51, 129.01,

129.03, 130.5, 130.6, 133.5, 133.7, 135.2, 136.3, 136.4,

138.7, 139.0, 206.2 (C-1); MS (FAB) m/z, 657

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₀H₄₆O₅SiNa

657.3012 found 657.3021 (M⁺+Na).

4.33. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-1,2-

di-O-(methoxymethyl)-5a-carba-b-^D-talopyranose, D-5c

To a solution of ^D-5b (1.00 g, 1.981 mmol) in dry THF

(35 ml) at 0 ꢁC was added NaH (518 mg, 55% in paraﬃn

liquid, 11.9 mmol). After stirring for 30 min at rt, BnBr

(1.41 ml, 11.9 mmol) and Bu₄NI (146 mg, 0.396 mmol)

were added. After stirring for 3 days at rt, the reac-

tion mixture was quenched with drops of satd aq NaH-

CO₃, extractively worked up with EtOAc, and

4.31. 1-O-Allyl-3,4-di-O-benzyl-6-O-(tert-butyldiphen-

yl)silyl-5a-carba-a-^D-gulopyranose, D-25

chromatographed on silica gel to give compound ^D-5c

20

(1.28 g, 94.3%) as

a

colorless oil. D-5c: ½aꢂ_D¼

ꢀ2.6 ðc 1.21; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.04 (s,

9H, –C(CH₃)₃), 1.46 (md, J = 11.7 Hz, 1H, H-5a_eq),

1.60 (m, 1H, H-5), 1.86 (app q, J = 12.1 Hz, 1H, H-

5a_ax), 3.26 (s, 1H, H-3), 3.37 and 3.39 (2s, 6H, 2 ·

–OCH₂OCH₃), 3.55 (m, 2H, H-1, H-6_a), 3.78 (t,

J = 8.4 Hz, 1H, H-6_b), 4.10 (s, 1H, H-2), 4.37 (s, 1H,

H-4), 4.5–5.1 (m, 8H, 2 · –OCH₂Ph, 2 · –OCH₂OCH₃),

7.2–7.62 (m, 20H, 4Ph); ¹³C NMR (CDCl₃) d 19.8, 25.0,

27.4, 41.4, 56.0, 65.1, 71.4, 73.6, 74.3, 74.6, 75.3, 81.8,

94.8, 97.6, 127.4, 127.7, 128.1, 128.17, 128.21, 128.5,

128.9, 130.1, 130.2, 134.23, 134.29, 136.1, 139.0, 140.5;

MS (FAB) m/z 707 (M⁺+Na); HRMS (FAB) m/z

calcd for C₄₁H₅₂O₇SiNa 707.3380 found 707.3383

(M⁺+Na).

To a solution of ^D-24 (14.4 mg, 22.7 lmol) in THF

(1.5 ml) at ꢀ20 ꢁC was added L-Selectride^TM(113 ll,

1 M solution in THF). After stirring for 20 min, the

reaction mixture was quenched by several drops of satd

aq NaHCO₃, and was extractively worked up with

EtOAc, and puriﬁed by silica gel column chromato-

19

graphy to give ^D-25 (10.6 mg, 73.4%). D-25: ½aꢂ_D

¼

þ17.2 ðc 0.53; CHCl₃Þ; ¹H NMR (C₆D₆with D₂O

drop) d 1.26 (s, 9H, –C(CH₃)₃), 1.64 (br t, J = 12.5

(10.8) Hz, 1H, H-5a_ax), 1.78 (br d, J = 13.7 Hz, 1H, H-

5a_eq), 2.66 (m, 1H, H-5), 3.72 (pseudo q, J = 3.4 Hz,

1H, H-1), 3.81 (dd, J = 9.8, 6.7 Hz, 1H, H-6_a), 3.84

(dd, J = 9.8, 5.3 Hz, 1H, H-6_b), 3.9–4.03 (m, 3H, H4,

OCH₂CH@CH₂), 4.11 (t, J = 3.5 Hz, 1H, H-2), 4.15

(t, J = 3.7 Hz, 1H, H-3), 4.38–4.70 (m, 4H, 2 ·

–OCH₂Ph), 5.12 (pseudo dd, J = 10.4, 1.5 Hz, 1H,

–OCH₂CH@CH_aH_b), 5.37 (pseudo dd, J = 17.2,

1.7 Hz, 1H, –OCH₂CH@CH_aH_b), 5.92 (m, 1H, –OCH₂-

CH@CH₂), 7.1–7.9 (m, 20H, 4Ph); ¹³C NMR (CDCl₃) d

19.9, 25.8, 27.6, 34.9, 64.3, 69.3, 71.1, 73.3, 73.7, 76.2,

76.6, 78.2, 117.2, 128.18, 128.24, 128.28, 128.35, 128.4,

128.97, 129.01, 130.3, 134.2, 134.4, 136.0, 136.28,

136.3, 139.3, 139.4; MS (FAB) m/z 637 (M⁺+1), 659

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₀H₄₈O₅SiNa

659.3169 found 659.3169 (M⁺+Na).

4.34. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-5a-

carba-b-^D-talopyranose, D-5d

To a solution of ^D-5c (900 mg, 1.31 mmol) and molecu-

˚

lar sieves 4 A (2 g, powder) in dry CH₂Cl₂(10 ml) at

ꢀ20 ꢁC was added TMSBr (3.46 ml, 26.2 mmol). After

stirring for 3 h at ꢀ20 ꢁC, the reaction mixture was

poured into satd aq NaHCO₃. After ﬁltering the result-

ing mixture on Celite, the ﬁltrate was extractively

worked up with EtOAc and chromatographed on silica

gel to give compound ^D-5d (490 mg, 63%) as a colorless

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

2745

18

oil. D-5d: ½aꢂ_D¼ ꢀ1.2 ðc 1.0; CHCl₃Þ; ¹H NMR

1H, H-3), 3.72–3.79 (m, 2H, H-1 and H-6_b), 3.89–4.04

(m, 2H, –OCH₂CH@CH₂), 4.19 (br s, 1H, H-2), 4.33

(br s, 1H, H-4), 4.56–5.07 (m, 4H, 2 · –OCH₂Ph), 5.17

(dq, J = 10.3, 1.5 Hz, 1H, –OCH₂CH@CH_aH_b), 5.31

(ddd, J = 17.2, 3.1, 1.6 Hz, 1H, –OCH₂CH@CH_aH_b),

5.87 (m, 1H, –OCH₂CH@CH₂), 7.3–7.68 (m, 20H,

4Ph); ¹³C NMR (CDCl₃) d 19.6, 22.0, 27.2, 38.2, 64.4,

70.35, 70.44, 70.6, 75.8, 76.5, 78.0, 78.4, 116.9, 127.9,

127.98, 128.03, 128.2, 128.68, 128.74, 130.00, 130.03,

133.9, 135.4, 135.9, 138.7, 139.4; MS (FAB) m/z 637

(M⁺+1), 659 (M⁺+Na); HRMS (FAB) m/z calcd for

C₄₀H₄₈O₅SiNa 659.3169 found 659.3173 (M⁺+Na).

(CDCl₃, with D₂O one drop) d 1.05 (s, 9H, –C(CH₃)₃),

1.36 (app q, J = 12.0 Hz, 1H, H-5a_ax), 1.49 (dt,

J = 12.7, 4.3 Hz, 1H, H-5a_eq), 1.58 (m, 1H, H-5), 3.29

(t, J = 2.6 Hz, 1H, H-3), 3.40 (m , 1H, H-1), 3.55 (dd,

J = 9.9, 5.5 Hz, H, H-6_a), 3.70 (t, J = 9.7 Hz, 1H, H-

6_b), 4.18 (s, 1H, H-2), 4.23 (s, 1H, H-4), 4.52–5.03 (m,

4H, 2 · –OCH₂Ph), 7.2–7.63 (m, 20H, 4Ph); ¹³C NMR

(CDCl₃) d 19.8, 27.1, 27.5, 40.4, 64.4, 70.6 (2s), 72.5,

76.3, 78.2, 128.2, 128.31, 128.34, 128.4, 128.5, 129.0,

129.1, 130.31, 130.34, 133.9, 136.06, 136.08, 138.2,

138.5; MS (FAB) m/z 597 (M⁺+1), 619 (M⁺+Na);

HRMS (FAB) m/z calcd for C₃₇H₄₄O₅SiNa 619.2856

found 619.2854 (M⁺+Na).

4.37. (1R,2S,3S)-1,2-Di-benzyloxy-3-(tert-butyl-

diphenyl-silanyloxymethyl)-cyclohex-5-ene, ^D-28

4.35. 1,2-Anhydro-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-b-^D-talopyranose, D-26

To a mixture of ^D-26 (92.0 mg, 0.159 mmol) and PPh₃

(83.4 mg, 0.318 mmol) in DMF (1 ml) was added I₂

(resublimed, 80.7 mg, 0.318 mmol). After 25 min, Zn

dust (52 mg, 0.795 mmol) was added to the mixture.

After stirring for 1 h, the reaction mixture was

directly loaded on a silica gel column and eluted with

To a solution of ^D-5d (201.7 mg, 0.338 mmol) in CH₂Cl₂

(4 ml) at rt were added (MeO)₃CCH₃(140 ll,

1.09 mmol) and a catalytic amount of PPTS (ca.

0.01 equiv). After stirring for 2 h at rt, the reaction mix-

ture was treated with two drops of Et₃N, concentrated,

and dried in vacuo. To the residue dissolved in CH₂Cl₂

(4 ml) at 0 ꢁC were added three drops of Et₃N and AcBr

(103 mg, 0.838 mmol). After stirring for 3 h at rt, the

reaction mixture was extractively worked up with

CH₂Cl₂to give a crude mixture of the bromo acetoxy

compounds. To the crude mixture in MeOH (4 ml)

was added NaOMe (230 ll, 25% in MeOH) at rt. After

stirring for 50 min, the reaction mixture was extractively

worked up with EtOAc and chromatographed on silica

EtOAc/n-hexane (1:20) to give compound D-28

20

(82.3 mg, 92.0%) as a colorless oil. ^D-28: ½aꢂ_D

¼

ꢀ27.4 ðc 1.07; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.07 (s,

9H, –C(CH₃)₃), 1.96 (m, 3H, H-3, H-4a_ax, H-4a_eq),

3.58 (pseudo dd, J = 10.1, 5.3 Hz, 1H, H-7_a), 3.76 (dd,

J = 10.1, 7.3 Hz, 1H, H-7_b), 4.11 (br s, 1H, H-2), 4.22

(m, 1H, H-1), 4.61–5.01 (m, 4H, 2 · –OCH₂Ph), 5.72

(pseudo d, J = 10.2 Hz, 1H, H-6, oleﬁn), 5.79 (m, 1H,

H-5, oleﬁn), 7.27–7.66 (m, 20H, 4Ph); ¹³C NMR

(CDCl₃) d 20.0, 25.6, 27.6, 41.1, 65.2, 71.5, 74.2, 74.7,

78.2, 126.9, 127.8, 128.07, 128.13, 128.2, 128.3, 128.8,

129.0, 129.1, 130.3, 134.48, 134.53, 136.2, 139.6, 140.3;

MS (FAB) m/z 563 (M⁺+1), 585 (M⁺+Na); HRMS

(FAB) m/z calcd for C₃₇H₄₂O₃SiNa 585.2801 found

585.2802 (M⁺+Na).

gel to give ^D-26 (178.62 mg, 91.3%) with the starting

20

material D-5d (16.3 mg, 8.1%). D-26: ½aꢂ_D

¼

ꢀ11.5 ðc 1.0; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.06 (s,

9H, –C(CH₃)₃), 1.6–1.8 (m, 3H, H-5, H-5a_ax, H-5a_eq),

3.31 (br s, 2H, H-1, H-2), 3.52 (dd, J = 10.0, 6.5 Hz,

1H, H-6_a), 3.60 (dd, J = 10.0, 7.9 Hz, 1H, H-6_b), 3.77

(pseudo d, J = 2.7 Hz, 1H, H-3), 4.04 (br d,

J = 2.6 Hz, 1H, H-4), 4.56–4.97 (m, 4H, 2 · –OCH₂Ph),

7.27–7.62 (m, 20H, 5Ph); ¹³C NMR (CDCl₃) d 19.9,

23.1, 27.6, 41.6, 53.0, 53.2, 65.1, 71.5, 74.6, 75.1, 77.8,

127.8, 128.3, 128.4, 128.8, 129.1, 130.4, 134.3, 134.4,

136.2, 139.2, 140.1; MS (FAB) m/z 579 (M⁺+1), 601

(M⁺+Na); HRMS (FAB) m/z calcd for C₃₇H₄₂O₄SiNa

601.2750 found 601.2747 (M⁺+Na).

4.38. 3,4-Di-O-benzyl-6-O-(tert-butyldiphenyl)silyl-5a-

carba-a-^D-galactopyranose, D-29

To a solution of ^D-28 (20.4 mg, 36.3 lmol) and 4-meth-

ylmorpholine-N-oxide (NMO) (8.5 mg, 72.6 lmol) in

acetone/water (2 ml, 8:1) at rt was added a catalytic

amount of OsO₄. After stirring for 6 h, Na₂SO₃

(112 mg) was added and the resulting mixture was

further stirred for 30 min at rt. The reaction

mixture was extractively worked up with EtOAc and

4.36. 1-O-Allyl-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-a-D-talopyranose, D-27a

chromatographed on silica gel to give compound ^D-29

18

(19.8 mg, 91.4%) as a colorless oil. ^D-29: ½aꢂ_D

¼

þ46.9 ðc 1.0; CHCl₃Þ; ¹H NMR (CDCl₃) d 1.09 (s,

9H, –C(CH₃)₃), 1.55 (m, 2H, H-5a_ax, H-5a_eq), 2.23 (m,

1H, H-5), 2.59 (br s, 2H, 2 · –OH), 3.55 (dd, J = 9.7,

5.5 Hz, 1H, H-6_a), 3.71 (dd, J = 9.7, 2.2 Hz, 1H, H-3),

3.74 (dd, J = 9.7 Hz, 1H, H-6_b), 4.07 (dd, J = 9.7,

3.2 Hz, 1H, H-2), 4.13 (pseudo q, J = 3.0 Hz, 1H, H-

1), 4.38 (pseudo t, J = 2.2 Hz, 1H, H-4), 4.57–4.99 (m,

4H, 2 · –OCH₂Ph), 7.2–7.7 (m, 20H, 4Ph); ¹³C NMR

(CDCl₃) d 19.6, 27.3, 27.7, 38.1, 64.4, 68.7, 71.5, 72.2,

73.8, 74.6, 81.8, 127.59, 127.64, 128.0, 128.1, 128.2,

128.4, 128.5, 129.0, 129.96, 130.02, 134.0, 135.9, 138.4,

139.6; MS (FAB) m/z 596 (M⁺+1), 619 (M⁺+Na);

To a solution of ^D-26 (21.5 mg, 37.1 lmol) in allyl alco-

hol (1.5 ml) at rt was added TSA (2.9 mg, 0.4 equiv) in

portions. After stirring for 26 h at rt, Et₃N (two drops)

was added and the resulting mixture concentrated by

co-evaporation with EtOAc (15 ml). The residue was ﬁl-

tered on a silica gel pad and the ﬁltrate concentrated and

chromatographed on silica gel column to give ^D-27a

21

(16.0 mg, 67.6%). ^D-27a: ½aꢂ_D¼ þ3.2 ðc 0.80; CHCl₃Þ;

¹H NMR (CDCl₃) d 1.09 (s, 9H, –C(CH₃)₃), 1.45 (dt,

J = 13.9, 2.7 Hz, 1H, H-5a_eq), 1.64 (td, J = 13.7,

2.3 Hz, 1H, H-5a_ax), 2.09 (m, 1H, H-5), 3.55 (dd,

J = 9.8, 5.8 Hz, 1H, H-6_a) 3.70 (pseudo t, J = 2.3 Hz,

2746

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 16 (2005) 2729–2747

HRMS (FAB) m/z calcd for C₃₇H₄₄O₅SiNa 619.2856

(m, 6H, H-1, H-3, H-6_a, H-6_b, –OCH₂CH@CH₂),

4.33–4.71 (m, 4H, 2 · –OCH₂Ph), 5.18 (pseudo dq,

J = 10.3, 1.3 Hz, 1H, –OCH₂CH@CH_aH_b), 5.26 (pseu-

do dq, J = 17.2, 1.5 Hz, –OCH₂CH@CH_aH_b), 5.90 (m,

1H, –OCH₂CH@CH₂), 7.2–7.7 (m, 20H, 4Ph); ¹³C

NMR (CDCl₃) d 20.0, 27.7, 29.9, 40.5, 62.7, 66.6, 71.0,

71.4, 74.5, 76.2, 80.0, 83.7, 117.9, 127.9, 128.1, 128.2,

128.3, 128.4, 128.8, 129.0, 130.1, 135.0, 135.3, 136.27,

136.34, 139.2, 139.5; MS (FAB) m/z 637 (M⁺+1), 659

(M⁺+Na); HRMS (FAB) m/z calcd for C₄₀H₄₈O₅SiNa

659.3169 found 659.3170 (M⁺+Na).

found 619.2852 (M⁺+Na).

4.39. 1,2-Anhydro-3,4-di-O-benzyl-6-O-(tert-butyl-

diphenyl)silyl-5a-carba-a-^D-galactopyranose, D-30

To a solution of ^D-28 (50 mg, 88.8 lmol) in CH₂Cl₂

(2 ml) at 0 ꢁC was added m-CPBA (50–60%, 39.9 mg,

0.116 mmol). After stirring for 22 h at rt, the reaction

mixture was quenched with aq Na₂SO₃(22 mg) and

the resulting mixture stirred for 30 min. The reaction

mixture was extractively worked up with EtOAc and

chromatographed on silica gel to give ^D-30 (27.9 mg,

Acknowledgments

54.2%) and ^D-26 (21.5 mg, 41.8%) as colorless oils. D-

20

30: ½aꢂ_D¼ ꢀ16.4 ðc 1.03; CHCl₃Þ; ¹H NMR (CDCl₃)

This work was supported by POSTECH/BSRI Research

Fund (2004) and KISTEP/Glycobiology research pro-

gram (2004-02087).

d 1.07 (s, 9H, –C(CH₃)₃), 1.59–1.9 (m, 3H, H-5, H-

5a_ax, H-5a_eq), 3.31 (dd, J = 3.7, 1.4 Hz, 1H, H-1 or H-

2), 3.34 (br d, J = 3.6 Hz, 1H, H-2 or H-1), 3.51 (dd,

J = 9.5, 5.2 Hz, 1H, H-6_a), 3.60 (d, J = 3.1 Hz, 1H, H-

3), 3.68 (t, J = 9.5 Hz, 1H, H-6_b), 4.08 (br s, 1H, H-4),

4.54–5.06 (m, 4H, 2 · –OCH₂Ph), 7.27–7.65 (m, 20H,

4Ph); ¹³C NMR (CDCl₃) d 19.6, 23.0, 27.2, 36.0, 54.0,

54.4, 64.6, 71.8, 73.3, 75.0, 78.7, 127.6, 127.7, 127.8,

128.0, 128.5, 128.8, 129.98, 130.01, 133.9, 135.9, 138.6,

139.8; MS (FAB) m/z 579 (M⁺+1), 601 (M⁺+Na);

HRMS (FAB) m/z calcd for C₃₇H₄₂O₄SiNa 601.2750

found 601.2751 (M⁺+Na).

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Article Doi

Divergent syntheses of all 16 carbasugar stereoisomers via stereoconversion of carba-β-D-altropyranose derivatives

DOI: 10.1016/j.tetasy.2005.07.010

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Full text of DOI:10.1016/j.tetasy.2005.07.010

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